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CURRENT THERAPY IN PAIN ISBN: 978-1-4160-4836-7
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Knowledge and best practice in this field are constantly changing. As new research and experience broaden
our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate.
Readers are advised to check the most current information provided (i) on procedures featured or (ii) by
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method and duration of administration, and contraindications. It is the responsibility of the practitioner,
relying on his or her own experience and knowledge of the patient, to make diagnoses, to determine dosages
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The Publisher
Library of Congress Cataloging-in-Publication Data
Current therapy in pain / [edited by] Howard S. Smith. – 1st ed.

p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4160-4836-7
1. Pain–Treatment. I. Smith, Howard S., 1956-
[DNLM: 1. Pain–therapy. WL 704 C9758 2009]
RB127.C92 2009
616’.0472–dc22 2008008166
Executive Publisher: Natasha Andjelkovic

Editorial Assistant: Isabel Trudeau
Design Direction: Steven Stave
Printed in United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1
I would like to dedicate this book to the memory of my mother, Arlene; to my wife Joan, and our children, Alyssa,
Joshua, Benjamin, and Eric; and to my father Nathan, and stepmother Priscilla.
Contributors
Salahadin Abdi, MD, PhD Joseph F. Audette, MA, MD Rafael Benoliel, BDS, LDS, RCS (Eng)
Professor and Chief, University of Miami Assistant Professor, Department of Professor and Chairman, Department of
Pain Center, Department of Physical Medicine and Rehabilitation, Oral Medicine, Faculty of Dental
Anesthesiology, Perioperative Medicine Harvard Medical School, Boston, Medicine, Hadassah Hebrew University,
and Pain Management, University of Massachusetts Jerusalem, Israel
Miami Miller School of Medicine, Miami, COMPLEMENTARYAND ALTERNATIVE OROFACIAL PAIN
Florida MEDICINE FOR NONCANCER PAIN
PAINFUL DIABETIC PERIPHERAL Karen Bjoro, PhD(c), RN
NEUROPATHY; PAIN IN CHILDREN; Mark L. Baccei, PhD Doctoral Student, The University of Iowa,
BOTULINUM TOXINS FORTHE TREATMENT Research Assistant Professor, Department Iowa City, Iowa; Nurse Researcher,
OF PAIN; EPIDURAL STEROID INJECTIONS; of Anesthesiology, University of Cincinnati Department of Orthopedics, Neurology
RADIOFREQUENCY TREATMENT; College of Medicine, Cincinnati, Ohio and Neurosurgery, Ulleval University
CRYOANALGESIA FOR CHRONIC PAIN PATHOPHYSIOLOGY OF PAIN Hospital, Oslo, Norway
ASSESSMENT OF PAIN IN THE NONVERBAL
Janet Abrahm, MD Misha-Miroslav Backonja, MD AND/OR COGNITIVELY IMPAIRED
Associate Professor of Medicine, Harvard Professor, Department of Neurology, OLDER ADULT
Medical School; Director, Pain and Anesthesiology and Rehabilitation
Palliative Care Program, Dana-Farber Medicine, University of Wisconsin School Didier Bouhassira, MD
Cancer Institute and Brigham and of Medicine and Public Health; Professor, Université de Versailles Saint Quentin,
Women’s Hospital, and Division Chief, University of Wisconsin Hospital and Versailles; Research Director, INSERM (U
Palliative Care, Dana-Farber Cancer Clinics, Madison, Wisconsin 792), Centre d’Evaluation et de Traitement
Institute, Boston, Massachusetts NEUROPATHIC PAIN-DEFINITION, de la Douleur, Hôpital Ambroise Paré,
PAIN IN THE PALLIATIVE CARE POPULATION IDENTIFICATION, AND IMPLICATIONS Boulogne, France
FOR RESEARCH ANDTHERAPY BRAIN IMAGING IN PAINFUL STATES:
Sanjeev Agarwal, MD EXPERIMENTAL AND CLINICAL PAIN
Assistant Professor, and Director, Zahid H. Bajwa, MD
Interventional Physiatry, SUNY Downstate Assistant Professor of Anesthesia and Daniel Brookoff, MD, PhD
Medical Center, Brooklyn, New York Neurology, Harvard Medical School; Director, Center for Medical Pain
STEROIDS; SYMPATHETIC BLOCKADE Director, Education and Clinical Pain Management, Presbyterian/St. Luke’s
Research, Beth Israel Deaconess Medical Medical Center, Denver, Colorado
Phillip J. Albrecht, PhD Center, Boston, Massachusetts GENITOURINARY PAIN SYNDROMES:
Assistant Professor, Center for HEADACHES OTHERTHAN MIGRAINE; INTERSTITIAL CYSTITIS, CHRONIC
Neuropharmacology and Neuroscience, TRIGEMINAL NEURALGIA PROSTATITIS, PELVIC FLOOR DYSFUNCTION,
Albany Medical College; Integrated Tissue AND RELATED DISORDERS; SICKLE
Dynamics, LLC, Albany New York Jeffrey R. Basford, MD, PhD CELL ANEMIA
COMPLEX REGIONAL PAIN SYNDROME Professor of Physical Medicine and
PATHOPHYSIOLOGY Rehabilitation, Department of Physical Patricia Bruckenthal, PhD, RN, ANP-C
Medicine and Rehabilitation, Mayo Clinic, Clinical Associate Professor, Stony Brook
Catalina Apostol, MD Rochester, Minnesota University School of Nursing; Nurse
Resident in Pain/Anesthesiology, TRANSCUTANEOUS ELECTRICAL NERVE Practitioner, Pain and Headache
Department of Anesthesiology, University STIMULATION Treatment Center, Department of
of Miami, Miami, Florida Neurology, North Shore/Long Island
BOTULINUM TOXINS FORTHE TREATMENT Allison Baum, DPT Jewish Health System, Manhasset, New
OF PAIN Spinal Cord Injury Peer Mentor York
Coordinator, St. Charles Hospital and ASSESSMENT OF PAIN IN OLDER ADULTS
Charles E. Argoff, MD Rehabilitation Center, Port Jefferson,
Professor of Neurology, Albany Medical New York Sean Burgest, MD
College; Director, Comprehensive Pain PHYSICAL MEDICINE APPROACHES Medical Director, The Burgest Clinic,
Program, Albany Medical Center, Albany, TO PAIN MANAGEMENT Austin, Texas
New York FAILED BACK SURGERY SYNDROME
NEUROPATHIC PAIN-DEFINITION, Joseph M. Bellapianta, MD, MS
IDENTIFICATION, AND IMPLICATIONS Department of Orthopaedic Surgery,
FOR RESEARCH ANDTHERAPY; Albany Medical Center, Albany, New York
ANTIDEPRESSANTS; BOTULINUM HAND PAIN; FOOT PAIN
TOXINS FORTHE TREATMENT OF PAIN
vii
viii CONTRIBUTORS
Allen L. Carl, MD Daniel Clayton, MD, PhD Andrew Dubin, MD, MS

Professor of Orthopaedic Surgery and Resident, Division of Neurosurgery, Duke Associate Professor of Physical Medicine
Pediatrics, Albany Medical College, Albany, University Medical Center, Durham, North and Rehabilitation, Albany Medical
New York Carolina College; Attending Physician, Albany
BACK PAIN NEUROSURGICALTREATMENT OF PAIN Medical Center Hospital; Medical Director,
Capital Region Spine, Albany, New York
Juan Cata, MD Steven P. Cohen, MD POST AMPUTATION PAIN DISORDERS;
Resident, Institute of Anesthesiology, Associate Professor, Department of POSTSTROKE PAIN
Critical Care, and Comprehensive Anesthesiology, and Director of Medical
Pain Management, Cleveland Clinic, Education, Johns Hopkins University Demetri Economedes, DO
Cleveland, Ohio School of Medicine, Baltimore, Maryland; Department of Orthopaedic Surgery,
INTERPLEURAL ANALGESIA Director of Pain Research and Colonel, Albany Medical Center, Albany, New York
United States Army, Walter Reed Army HAND PAIN
Brian D. Cauley, MD, MPH Medical Center, Washington, DC
Resident, Department of Anesthesiology SPINAL ANALGESIA Eli Eliav, DMD, PhD
and Critical Care, Massachusetts Professor and Director, Division of
General Hospital, Harvard Medical School, Alane B. Costanzo, MD Orofacial Pain, and Susan and Robert
Boston, Massachusetts Anesthesiology Resident, University of Carmel Endowed Chair in Algesiology,
POSTHERPETIC NEURALGIA Miami Miller School of Medicine, Jackson University of Medicine and Dentistry of
Memorial Hospital, Miami, Florida New Jersey-New Jersey Dental School,
Lucy Chen, MD EPIDURAL STEROID INJECTIONS Newark, New Jersey
Instructor, Harvard Medical School; OROFACIAL PAIN
Attending Physician, Massachusetts Sukdeb Datta, MD, DABIPP, FIPP
General Hospital, Boston, Massachusetts Associate Professor, and Program Director, Jennifer A. Elliott, MD
OPIOIDTOLERANCE, DEPENDENCE, Vanderbilt University Pain Medicine Assistant Professor, Department of
AND HYPERALGESIA Fellowship, Vanderbilt University Medical Anesthesiology, University of Missouri-
Center; Director, Vanderbilt University Kansas City School of Medicine; Staff Pain
Jianguo Cheng, MD, PhD Interventional Pain Center, Nashville, Physician, Saint Luke’s Hospital, Kansas
Staff, Department of Pain Management, Tennessee City, Missouri
Institute of Anesthesiology, Critical Care, EPIDURAL ADHESIOLYSIS PATIENT-CONTROLLED ANALGESIA;
and Comprehensive Pain Management, 2-AGONISTS
Cleveland Clinic, Cleveland, Ohio Emily A. Davis, MSN, ACNP
INTERPLEURAL ANALGESIA Division of Neurosurgery, Duke University Nasr Enany, MD
Medical Center, Durham, North Carolina Assistant Professor and Attending
Pradeep Chopra, MD, MHCM SPINAL CORD STIMULATION FORTHE Anesthesiologist, University of Cincinnati,
Assistant Professor (Clinical), Brown TREATMENT OF CHRONIC INTRACTABLE Cincinnati, Ohio
Medical School, Providence, Rhode Island; PAIN; NEUROSURGICALTREATMENT OF PAIN SYMPATHETIC BLOCKADE
Assistant Professor (Adjunct), Boston
University Medical Center, Boston, Timothy R. Deer, MD Jonathan Epstein, MD, MA
Massachusetts President and Chief Executive Officer, Fellow, Obstetric Anesthesia, Mount Sinai
THORACIC PAIN The Center for Pain Relief; Clinical Medical Center, New York, New York
Professor, West Virginia University, TRAMADOL
Paul J. Christo, MD, MBA Charleston, West Virginia
Assistant Professor, Johns Hopkins EPIDEMIOLOGY OF COMPLICATIONS IN Ike Eriator, MD, MPH
University School of Medicine; Director, INTERVENTIONAL PAIN MANAGEMENT Associate Professor, University of
Multidisciplinary Pain Fellowship, and Mississippi School of Medicine; Chief,
Director, Pain Treatment Center, Martin L. DeRuyter, MD Pain Management Services, University of
The Johns Hopkins Hospital, Associate Professor of Anesthesiology and Mississippi Medical Center, Jackson,
Baltimore, Maryland Staff Anesthesiologist, University of Kansas Mississippi
PELVIC PAIN; POSTHERPETIC NEURALGIA; Medical Center, University of Kansas CANCER PAIN MANAGEMENT
COMPLEX REGIONAL PAIN SYNDROME: School of Medicine, Kansas City, Kansas
TREATMENTAPPROACHES PERIOPERATIVE EPIDURAL ANALGESIA; David Euler, LicAc
CONTINUOUS PERIPHERAL NERVE Co-Director, Continuing Medical
Daniel Ciampi de Andrade, MD CATHETERTECHNIQUES Education Course, Harvard Medical
Université de Versailles Saint Quentin, School, Boston, Massachusetts
Versailles; Clinical Fellow, INSERM (U Anthony Dragovich, MD COMPLEMENTARYAND ALTERNATIVE
792), Centre d’Evaluation et de Traitement Director, Pain Management Center, MEDICINE FOR NONCANCER PAIN
de la Douleur, Hôpital Ambroise Paré, Womack Army Medical Center, Fort
Boulogne, France Bragg, North Carolina; Assistant Professor, Vania E. Fernandez, MD
BRAIN IMAGING IN PAINFUL STATES: Department of Anesthesiology, Uniformed Assistant Professor of Anesthesiology,
EXPERIMENTAL AND CLINICAL PAIN Services University of the Health Sciences, University of Miami School of Medicine;
Bethesda, Maryland Pain Management Fellow, Department of
Eli Cianciolo, MD SPINAL ANALGESIA Anesthesiology, Perioperative Medicine
Clinical Instructor and Pain Medicine and Pain Management, Jackson Memorial
Fellow, Harvard Medical School, and Hospital, Miami, Florida
Massachusetts General Hospital, Boston, PAINFUL DIABETIC PERIPHERAL
Massachusetts NEUROPATHY
NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS AND CYCLOOXYGENASE-2
INHIBITORS
CONTRIBUTORS ix
Richard Field, MD Greg Hobelmann, MD Clete A. Kushida, MD, PhD, RPSGT

Pain Fellow, Massachusetts General Postdoctoral Fellow, Division of Pain Director, Stanford University Center for
Hospital, and Harvard Medical School, Medicine, Department of Anesthesiology Human Sleep Research; Associate
Boston, Massachusetts and Critical Care Medicine, Johns Hopkins Professor, Stanford University Medical
RADIOFREQUENCY TREATMENT University School of Medicine, Baltimore; Center, Stanford University Center of
Pain Medicine Specialists, P.A., Towson, Excellence for Sleep Disorders, Stanford,
Nanna Brix Finnerup, MD Maryland California
Associate Research Professor, Aarhus PELVIC PAIN PAIN AND SLEEP
University, Aarhus, Denmark
SPINAL CORD INJURY Steven H. Horowitz, MD Elizabeth Demers Lavelle, MD
Clinical Professor of Neurology, University Assistant Professor, SUNY Upstate Medical
Colleen M. Fitzgerald, MD of Vermont College of Medicine, University, Syracuse, New York
Assistant Professor, Feinberg School of Burlington, Vermont; Assistant in HAND PAIN; BACK PAIN; HIP PAIN; KNEE
Medicine, Northwestern University; Neurology, Massachusetts General PAIN; FOOT PAIN; RHEUMATOID ARTHRITIS;
Medical Director, Women’s Health Hospital, Boston, Massachusetts MYOFASCIALTRIGGER POINTS; INTRA-
Rehabilitation, Rehabilitation Institute of NEUROPATHIC PAIN: IS THE EMPEROR ARTICULAR INJECTIONS
Chicago, Chicago, Illinois WEARING CLOTHES?
FEMALE PERINEAL/PELVIC PAIN:THE Lori A. Lavelle, DO
REHABILITATION APPROACH Christina K. Hynes, MD Staff Physician, Altoona Arthritis and
Clinical Instructor, Feinberg School of Osteoporosis Center, Duncansville,
Marc D. Fuchs, MD Medicine, Northwestern University; Pennsylvania
Associative Clinical Professor, Department Attending Physician, Rehabilitation RHEUMATOID ARTHRITIS; INTRA-ARTICULAR
of Orthopaedic Surgery, Albany Medical Institute of Chicago, Chicago, Illinois INJECTIONS
College, Albany, New York FEMALE PERINEAL/PELVIC PAIN:THE
HIP PAIN REHABILITATION APPROACH William F. Lavelle, MD
Assistant Professor, Department of
Aimee Furdyna, BS Kenneth C. Jackson, II, PharmD Orthopaedic Surgery, SUNY Upstate
Department of Orthopaedic Surgery, Associate Professor, Pacific University Medical University, Syracuse, New York
Albany Medical Center, Albany, New York School of Pharmacy; Associate Editor, HAND PAIN; BACK PAIN; HIP PAIN; KNEE
BACK PAIN Journal of Pain and Palliative Care PAIN; FOOT PAIN; RHEUMATOID ARTHRITIS;
Christine Gallati, BS Pharmacotherapy, Hillsboro, Oregon MYOFASCIALTRIGGER POINTS; INTRA-
Research Assistant, Pharmaceutical OPIOID PHARMACOTHERAPY ARTICULAR INJECTIONS
Research Institute at Albany College of ChaunceyT. Jones, MD Andrew Linn, MD
Pharamacy, Albany, New York Resident, Department of Anesthesiology Clinical Fellow in Anesthesia, Harvard
PAIN AND SLEEP and Critical Care Medicine, Johns Hopkins Medical School, and Beth Israel Deaconess
Padma Gulur, MD University School of Medicine, Baltimore, Medical Center, Boston, Massachusetts
Pain Specialist, Center for Pain Medicine, Maryland TRIGEMINAL NEURALGIA
Massachusetts General Hospital; Instructor COMPLEX REGIONAL PAIN SYNDROME:
TREATMENTAPPROACHES Dave Loomba, MD
in Anesthesia, Harvard Medical School, Assistant Professor, University of
Boston, Massachusetts Douglas Keene, MD California, Davis, Sacramento;
PAIN IN CHILDREN Director of Pain Management, Department Anesthesiologist, Enloe Medical Center,
Payam Hadian, BA of Anesthesia, Milton Hospital, Milton, Chico, California
College of Arts and Sciences, Massachusetts; Co-founder, Boston SACROILIAC JOINT PAIN
University of Rochester, Rochester, PainCare, Waltham, Massachusetts
RADIOFREQUENCY TREATMENT Karan Madan, MBBS, MPH
New York Instructor in Anaesthesia, Harvard Medical
DIAGNOSIS ANDTREATMENT OF Kenneth L. Kirsh, PhD School; Staff, Pain Management Center,
FACET-MEDIATED CHRONIC Assistant Professor, Pharmacy Practice and Department of Anesthesia, Perioperative
LOW BACK PAIN Science, University of Kentucky; Attending and Pain Medicine, Brigham and Women’s
R. Norman Harden, MD Clinical Psychologist, The Pain Treatment Hospital, Boston, Massachusetts
Director, Center for Pain Studies, and Center of the Bluegrass, Lexington, PAIN AND PAIN MANAGEMENT RELATEDTO
Addison Chair, Rehabilitation Institute of Kentucky HIV INFECTION
Chicago; Associate Professor, Feinberg POTENTIAL DOCUMENTATION TOOLS FOR
OPIOIDTHERAPY; PAIN IN THE SUBSTANCE Gagan Mahajan, MD
School of Medicine, Northwestern Associate Professor, and Director,
University, Chicago, Illinois ABUSE POPULATION
Fellowship in Pain Medicine, University of
INTERDISCIPLINARY MANAGEMENT FOR Jan Kraemer, MD California, Davis, Sacramento, California
COMPLEX REGIONAL PAIN SYNDROME Clinical Fellow, Harvard Medical School, SACROILIAC JOINT PAIN
Keela Herr, PhD, RN, FAAN, AGSF Boston, Massachusetts
HEADACHES OTHERTHAN MIGRAINE Jianren Mao, MD, PhD
Professor and Chair, Adult and Associate Professor, Harvard Medical
Gerontology, The University of Iowa Michael A. Krieves, BS School; Attending Physician, Massachusetts
College of Nursing, Iowa City, Iowa Department of Orthopaedic Surgery, General Hospital, Boston, Massachusetts
ASSESSMENT OF PAIN IN THE NONVERBAL Albany Medical Center, Albany, New York OPIOIDTOLERANCE, DEPENDENCE, AND
AND/OR COGNITIVELY IMPAIRED OLDER HIP PAIN; KNEE PAIN HYPERALGESIA
ADULT
x CONTRIBUTORS
John D. Markman, MD Mila Mogilevsky, DO, PT Ike Onyedika, BS

Director, Neuromedicine Pain Resident Physician, Rehabilitation Institute Department of Orthopaedic Surgery,
Management Center and Translational of Chicago, Department of Physical Albany Medical Center, Albany, New York
Pain Research, Department of Medicine and Rehabilitation, Northwestern HAND PAIN
Neurosurgery, University of Rochester University, Chicago, Illinois
School of Medicine and Dentistry, PHYSICAL MEDICINE APPROACHES TO PAIN Susan Elizabeth Opper, MD
Rochester, New York MANAGEMENT Assistant Professor of Medicine, University
LUMBAR SPINAL STENOSIS: CURRENT of Missouri-Kansas City School of
THERAPYAND FUTURE DIRECTIONS; Xavier Moisset, MD Medicine; Director, Pain Management
DIAGNOSIS ANDTREATMENT OF FACET- Université de Versailles Saint Quentin, Services, Saint Luke’s Hospital, Kansas
MEDIATED CHRONIC LOW BACK PAIN Versailles; Clinical Fellow, INSERM City, Missouri
(U 792), Centre d’Evaluation et de NECK PAIN
Eric M. May, MD Traitement de la Douleur, Hôpital
Assistant Professor of Anesthesiology, Ambroise Paré, Boulogne, France Richard K.Osenbach, MD
University of Missouri-Kansas City; Staff BRAIN IMAGING IN PAINFUL STATES: Director, Neurosurgical Services, Cape Fear
Anesthesiologist, Saint Luke’s Hospital, EXPERIMENTAL AND CLINICAL PAIN Valley Medical Center, Fayetteville,
Kansas City, Missouri North Carolina
CONTINUOUS PERIPHERAL NERVE Muhammad A. Munir, MD SPINAL CORD STIMULATION FORTHE
CATHETERTECHNIQUES Chairman, Southwest Ohio Pain Institute, TREATMENT OF CHRONIC INTRACTABLE
West Chester, Ohio PAIN; NEUROSURGICALTREATMENT OF PAIN
Gary McCleane, MD, FFARCSI STEROIDS; NONSTEROIDAL
Consultant in Pain Management, Rampark ANTI-INFLAMMATORY DRUGS AND Joshua Pal, MD
Pain Centre, Lurgan, Northern Ireland, CYCLOOXYGENASE-2 INHIBITORS; Clinical Fellow, Harvard Medical School,
United Kingdom SYMPATHETIC BLOCKADE Boston, Massachusetts
PAIN IN THE ELDERLY; OPIOIDS ISSUES; HEADACHES OTHERTHAN MIGRAINE
ANTIEPILEPTIC DRUGS; LOCAL Beth B. Murinson, MS, MD, PhD
Assistant Professor of Neurology, Johns Marco Pappagallo, MD
ANESTHETICS; MUSCLE RELAXANTS; Professor, Department of Anesthesiology,
TOPICAL ANALGESIC AGENTS Hopkins University School of Medicine;
Active Staff, Johns Hopkins Medical Mount Sinai School of Medicine; Director,
James McLean, MDy Institutions, The Johns Hopkins Hospital, Pain Medicine Research and Development,
Pain Fellow, Rehabilitation Institute Baltimore, Maryland Mount Sinai Medical Center, New York,
of Chicago; Department of A MECHANISM-BASED APPROACH TO PAIN New York
Physical Medicine and Rehabilitation, PHARMACOTHERAPY:TARGETING PAIN NEUROPATHIC PAIN-DEFINITION,
Feinberg School of Medicine, MODALITIES FOR OPTIMALTREATMENT IDENTIFICATION, AND IMPLICATIONS FOR
Northwestern University, Chicago, EFFICACY RESEARCH ANDTHERAPY;TRAMADOL
Illinois Amar Parikh
PHYSICAL MEDICINE APPROACHES TO PAIN Lida Nabati, MD
Instructor of Medicine, Harvard Medical Research Assistant, Albany Medical
MANAGEMENT College, Albany, New York
School; Attending Physician, Division of
Sangeeta R. Mehendale, MD, PhD Palliative Care, Dana-Farber Cancer POST AMPUTATION PAIN DISORDERS
Research Associate, Department of Institute, Boston, Massachusetts Winston C.V. Parris, MD, FACPM
Anesthesia and Critical Care, Pritzker PAIN IN THE PALLIATIVE CARE POPULATION Professor of Anesthesiology, and Director,
School of Medicine, University of Chicago, Pain Programs, Duke University Medical
Chicago, Illinois Srdjan S. Nedeljkovic¤, MD
Fellowship Director, Pain Medicine Center; Division Chief, Duke Pain and
GASTROINTESTINAL DYSFUNCTION Palliative Care Center, Duke University
WITH OPIOID USE Program, and Staff, Pain Management
Center, Department of Anesthesia, Hospital, Durham, North Carolina
Harold Merskey, DM, FRCPC, Perioperative and Pain Medicine, Brigham CANCER PAIN MANAGEMENT
FRCPsych and Women’s Hospital; Assistant Professor Steven D. Passik, PhD
Professor Emeritus of Psychiatry, of Anaesthesia, Harvard Medical School, Associate Professor of Psychiatry, Weill
University of Western Ontario, London, Boston, Massachusetts College of Medicine, Cornell University
Ontario, Canada PAIN AND PAIN MANAGEMENT RELATEDTO Medical Center; Associate Attending
THE TAXONOMY OF PAIN HIV INFECTION Psychologist, Memorial Sloan Kettering
Tobias Moeller-Bertram, MD Lisa J. Norelli, MD, MPH, MRCPsych Cancer Center, New York, New York
Assistant Clinical Professor, Assistant Professor of Psychiatry, Albany PAIN IN THE SUBSTANCE ABUSE
Department of Anesthesiology, Medical College; Director of Psychiatry, POPULATION
University of California, San Diego, Capital District Psychiatric Center, Albany, Gira Patel, LicAc
La Jolla, California New York Clinical Associate, Osher Integrative Care
BOTULINUM TOXINS FORTHE TREATMENT HYPNOTIC ANALGESIA Center, Harvard Medical School Osher
OF PAIN Institute; Division for Research and
Akiko Okifuji, PhD
Professor of Anesthesiology, and Attending Education in Complementary and
Psychologist, Pain Management Center, Integrative Medical Therapies, Arnold Pain
University of Utah, Salt Lake City, Utah Clinic, Beth Israel Deaconess Hospital,
PSYCHOLOGICAL ASPECTS OF PAIN Boston, Massachusetts
COMPLEMENTARYAND ALTERNATIVE
MEDICINE FOR NONCANCER PAIN
y
Deceased
CONTRIBUTORS xi
Eric M. Pearlman, MD, PhD Scott S. Reuben, MD ThomasT. Simopoulos, MD

Director, Pediatric Education, and Professor of Anesthesiology and Pain Instructor in Anaesthesia, Harvard Medical
Assistant Professor of Pediatrics, Medicine, Tufts University School of School; Director of Interventional Pain
Mercer University School of Medicine; Medicine, Boston; Director, Acute Pain Management, Beth Israel Deaconess
Savannah Neurology, P.C., Savannah, Service, Baystate Medical Center, Medical Center, Boston, Massachusetts
Georgia Springfield, Massachusetts FAILED BACK SURGERY SYNDROME
MIGRAINE HEADACHES PERIOPERATIVE USE OF COX-2 AGENTS
Jeremy C. Sinkin, BA
Richard A. Pertes, DDS Frank L. Rice, PhD Department of Neurosurgery, University of
Clinical Professor, Division of Orofacial Professor, Center for Neuropharmacology Rochester School of Medicine and
Pain, University of Medicine and Dentistry and Neuroscience, Albany Medical College; Dentistry, Rochester, New York
of New Jersey-New Jersey Dental School, Integrated Tissue Dynamics, LLC, Albany, LUMBAR SPINAL STENOSIS: CURRENT
Newark, New Jersey New York THERAPYAND FUTURE DIRECTIONS
OROFACIAL PAIN COMPLEX REGIONAL PAIN SYNDROME
PATHOPHYSIOLOGY David J. Skinner, MD
Annie Philip, MD Assistant Professor, Departments of
Assistant Professor, Department of Melissa A. Rockford, MD Anesthesiology and Pain Management,
Anesthesiology, University of Rochester Assistant Professor of Anesthesiology, Mount Sinai School of Medicine; Assistant
School of Medicine and Dentistry, University of Kansas Medical Center, Professor, Mount Sinai Medical Center,
Rochester, New York University of Kansas School of Medicine, New York, New York
DIAGNOSIS ANDTREATMENT OF Kansas City, Kansas TRAMADOL
FACET-MEDIATED CHRONIC LOW PERIOPERATIVE EPIDURAL ANALGESIA
BACK PAIN Michelle Skinner, MS
Carl Rosati, MD Graduate Student, Department of
Mark Anthony Quintero, MD Associate Professor of Surgery, Albany Psychology, University of Utah, Salt Lake
Pain Management Fellow, Department of Medical College; Trauma Director, Albany City, Utah
Anesthesiology, Perioperative Medicine Medical Center, Albany, New York PSYCHOLOGICAL ASPECTS OF PAIN
and Pain Management, University of ABDOMINAL PAIN
Miami Miller School of Medicine, Jackson Howard S. Smith, MD, FACP, FACNP
Memorial Hospital, Miami, Florida Mike A. Royal, MD, JD, MBA Associate Professor of Anesthesiology,
CRYOANALGESIA FOR CHRONIC PAIN Vice President, Clinical Development - Internal Medicine, Physical Medicine and
Analgesics, Cadence Pharmaceuticals, Inc., Rehabilitation, Albany Medical College,
Lynn Rader, MD San Diego, California Academic Director of Pain Management,
Clinical Instructor, Feinberg School of ACETAMINOPHEN Department of Anesthesiology, Albany
Medicine, Northwestern University; Medical Center, Assistant Director of
Attending Physician, Rehabilitation Christine N. Sang, MD, MPH Clinical Research at The Pharmaceutical
Institute of Chicago, Chicago, Illinois Director, Translational Pain Research, Research Institute, Albany College of
PHYSICAL MEDICINE APPROACHES TO PAIN Brigham and Women’s Hospital, Harvard Pharmacy, Albany, New York
MANAGEMENT Medical School, Boston, Massachusetts NEUROPATHIC PAINçDEFINITION,
GLUTAMATE RECEPTOR ANTAGONISTS IDENTIFICATION, AND IMPLICATIONS FOR
Lakshmi Raghavan, PhD RESEARCH ANDTHERAPY; POTENTIAL
Associate Director, Research and Nalini Sehgal, MD, FABPMR
Associate Professor, Department of DOCUMENTATION TOOLS FOR OPIOID
Development, Vyteris Corporation, Inc. THERAPY; POST AMPUTATION PAIN
Fair Lawn, New Jersey Orthopedics and Rehabilitation, University
of Wisconsin School of Medicine and DISORDERS; COMPLEX REGIONAL PAIN
PAIN IN CHILDREN SYNDROME PATHOPHYSIOLOGY; PAIN AND
Public Health; Medical Director,
Rakesh Ramakrishnan, BS Interventional Pain Program, and Pain SLEEP; OPIOIDS ISSUES; ACETAMINOPHEN;
Department of Orthopaedic Surgery, Fellowship Program Director, University of ANTIDEPRESSANTS; GLUTAMATE RECEPTOR
Albany Medical Center, Albany, New York Wisconsin Hospital and Clinics, Madison, ANTAGONISTS; BOTULINUM TOXINS FOR
HIP PAIN; KNEE PAIN Wisconsin THE TREATMENT OF PAIN; CRYOANALGESIA
CRYOANALGESIA FOR CHRONIC PAIN FOR CHRONIC PAIN
Alan M. Rapoport, MD
Clinical Professor of Neurology, David Ashutosh Sharma, PhD Paul E. Spurgas, MD
Geffen School of Medicine at UCLA, Los Chief Strategic Officer, Vyteris, Inc., Fair Associate Professor of Neurosurgery,
Angeles, California; Founder and Director Lawn, New Jersey Division of Neurosurgery, Albany Medical
Emeritus, The New England Center for PAIN IN CHILDREN Center, Albany, New York; Temple
Headache, P.C., Stamford, Connecticut University, Philadelphia, Pennsylvania
MIGRAINE HEADACHES Lee S. Simon, MD VERTEBROPLASTYAND KYPHOPLASTY
Associate Clinical Professor of Medicine,
Rahul Rastogi, MD Harvard Medical School, Beth Israel Steven C. Stain, MD
Assistant Professor, Washington University Deaconess Medical Center, Boston, Neil Lempert Professor, and Chair,
in St. Louis; Assistant Professor and Massachusetts Department of Surgery, Albany Medical
Attending Anesthesiologist, Barnes-Jewish OSTEOARTHRITIS: ETIOLOGY, PATHOGENESIS, College; Chief of Surgery, Albany Medical
Hospital, St. Louis, Missouri ANDTREATMENT Center Hospital, Albany, New York
SYMPATHETIC BLOCKADE ABDOMINAL PAIN
xii CONTRIBUTORS
Steven Stanos, DO Chris Warfield, BA James P.Wymer, MD, PhD

Assistant Professor, Feinberg School of Research Assistant, Arnold Pain Assistant Professor of Neurology, Albany
Medicine, Northwestern University; Management Center, Beth Israel Deaconess Medical College; Upstate Clinical Research,
Medical Director, Rehabilitation Institute Medical Center, Boston, Massachusetts Albany, New York
of Chicago, Chicago, Illinois COGNITIVE THERAPY FOR CHRONIC PAIN GLUTAMATE RECEPTOR ANTAGONISTS
PHYSICAL MEDICINE APPROACHES TO PAIN
MANAGEMENT Ajay D.Wasan, MD, MSc Chun-SuYuan, MD, PhD
Assistant Professor, Harvard Medical Cyrus Tang Professor, Department of
Roland Staud, MD School; Departments of Anesthesiology Anesthesia and Critical Care, Pritzker
Professor of Medicine, University of and Psychiatry, Brigham and Women’s School of Medicine, University of Chicago,
Florida, Gainesville, Florida Hospital, Boston, Massachusetts Chicago, Illinois
FIBROMYALGIA SYNDROME ANTIDEPRESSANTS GASTROINTESTINAL DYSFUNCTION WITH
OPIOID USE
Richard L.Uhl, MD Lynn R.Webster, MD, FACPM, FASAM
Professor of Surgery, Albany Medical Medical Director, Lifetree Clinical Jun-Ming Zhang, MD, MSc
College, Albany; Adjunct Professor of Research and Pain Clinic, Salt Lake City, Associate Professor and Director of
Biomedical Engineering, Rensselaer Utah Research, Department of Anesthesiology,
Polytechnic Institute, Troy; Chief, PAIN AND SLEEP University of Cincinnati College of
Orthopaedic Surgery, Albany Medical Medicine, Cincinnati, Ohio
Center Hospital, Albany, New York Richard Whipple, MD PATHOPHYSIOLOGY OF PAIN; STEROIDS;
SHOULDER PAIN; ELBOW PAIN Assistant Clinical Professor, Department of NONSTEROIDAL ANTI-INFLAMMATORY
Orthopaedic Surgery, Albany Medical DRUGS AND CYCLOOXYGENASE-2
Mark Wallace, MD College, Albany, New York INHIBITORS
Professor of Clinical Anesthesiology, and HAND PAIN
Program Director, Center for Pain YiLi Zhou, MD, PhD
Medicine, Department of Anesthesiology, Joshua Wootton, MDiv, PhD Courtesy Clinical Assistant Professor,
University of California, San Diego, La Assistant Professor, Department of University of Florida; Medical Director,
Jolla, California Anaesthesia, Harvard Medical School; Comprehensive Pain Management of
BOTULINUM TOXINS FORTHE TREATMENT Director of Pain Psychology, Arnold Pain North Florida, Gainesville, Florida
OF PAIN Management Center, Beth Israel Deaconess DIAGNOSIS AND MINIMALLY INVASIVE
Medical Center, Boston, Massachusetts TREATMENT OF LUMBAR DISCOGENIC PAIN
Deirdre M.Walsh, DPhil, BPhysio COGNITIVE THERAPY FOR CHRONIC PAIN
Professor of Rehabilitation Research,
Health and Rehabilitation Sciences
Research Institute, University of Ulster,
Newtownabbey, County Antrim, Northern
Ireland, United Kingdom
TRANSCUTANEOUS ELECTRICAL NERVE
STIMULATION
Preface
The International Association for the Study of Pain (IASP) has complaints in some patients may need therapies targeting periph-
defined pain as ‘‘an unpleasant sensory and emotional experience eral, spinal, as well as supraspinal mechanisms in efforts to fully
associated with actual or potential tissue damage, or defined in address their issues.
terms of such damage’’. Donald Price in his 1999 book Despite an explosion of basic science pain research, the transla-
Psychological Mechanisms of Pain and Analgesia by IASP Press pro- tion of these advances into tangible and clinically useful diagnostic
posed an alternative definition, arguing that the IASP definition and therapeutic measures to identify and ameliorate various human
does not emphasize the experiential nature of pain. He holds that painful conditions has lagged. Unfortunately, despite valiant efforts,
pain is a ‘somatic perception containing (1) a bodily sensation with too many people continue to exist with horrific pain and suffering,
qualities like those reported during tissue-damaging stimulation, some who have been helped a little, and some who have not been
(2) an experienced threat associated with this sensation, (3) a feeling helped at all. The field of Pain Medicine is still relatively in its
of unpleasantness or other negative emotion based on this experi- infancy, but continues to gradually mature. Thus, it was heartening
enced threat’. to learn that as we approach the tail end of the ‘‘decade of pain’’;
In 1931, the French medical missionary, Dr. Albert Schweitzer Elsevier is adding the book ‘‘Current Therapy in Pain’’ to its criti-
wrote ‘‘Pain is a more terrible lord of mankind than even death cally acclaimed ‘‘Current Therapy’’ series. Perhaps one of the best
itself’’. These words emphasize the scope of total human suffering known books in this series is Conn’s Current Therapy, which was
due to pain which may dramatically affect a person’s life/quality of initially published in 1943 and has been revised yearly since. After
life. Pain remains among one of the most debilitating symptoms as 65 years, Current Therapy in Pain has surfaced in efforts to deliver
well as one of the most common symptoms which patients report. a source of current information on the field of pain medicine
Blair Smith and Nicole Torrance have addressed the which will be updated reasonably frequently. In keeping with
Epidemiology of Chronic Pain as a chapter in the book, the style of the series ‘‘Current Therapy in Pain’’ is clinically
Systematic Reviews in Pain Research: Methodology Refined edited oriented. However, in contrast to other Current Therapy texts,
by Henry J. McQuay, Eija Kalso, and R. Andrew Moore and pub- ‘‘Current Therapy in Pain’’ does not present all chapters without
lished by IASP Press in 2008. They write that it seems that up to half references. Although I initially set out with the intention to keep
of the adult population suffers from chronic pain as defined by the this format, which is seen in some chapters, it became apparent that
broad IASP definition and that 10-20% experience chronic pain it would be challenging to have all the chapters without references,
when measures of clinical significance are added to the definition. largely due to the immaturity and dynamic nature of the field of
They further state that the incidence of chronic pain (though diffi- pain medicine.
cult to estimate) may be between 5% and 10% per year and is The text is organized to initially present background informa-
associated with poor health-related quality of life in all studies tion on pain —taxonomy, pathophysiology and assessment.
that measured this variable. Various treatment strategies for acute pain are then presented.
Numerous potential therapeutic targets exist which may modulate The next sections deal with a number of conditions/syndromes/
nociceptive processing including: ion channels, TRP channels, ASIC issues which are painful or may interface with pain. Section IV is
channels, stretch-activated channels, signaling molecules/casades devoted to Pain in Special Populations. Finally, Sections VII
(pERK, p38MAPK protein kinases), neurotrophins (BDNF, GDNF, through XIII deal with treatment approaches to pain (pharmaco-
NGF) inflammatory mediators, cytokines, adhesion molecules, logic, behavioral medicine, physical medicine and rehabilitation,
immune cells/glia, neurotransmitters (SP, NK1, CCK), adrenergic neuromodulation, complementary and alternative medicine, neuro-
receptors, purinergic receptors, toll-like receptors, and glutamate surgical, and interventional). The text, although not comprehensive
receptors. Furthermore, it is not uncommon that opposing anti- of all pain-relieving strategies, is felt to present a reasonable repre-
inflammatory processes may exist for certain pro-inflammatory/ sentation of available therapeutic options which may help alleviate
pro-nociceptive processes (e.g., acetylation of MKP-1 promotes the pain. Furthermore, because of the dynamic nature of pain and the
interaction of MKP-1 with its substrate p38 MAPK, which results in attempt to present current information, it is not intended that all
dephosphorylation of p38 MAPK). However, some of these targets do treatment strategies presented in the text are ‘‘tried and true’’ thera-
not have clinically available agents to specifically enhance or inhibit pies which have stood the test of time, but only that they are or may
their function and even if these agents existed, clinicians would not be available options for certain circumstances, now or in the future.
know which agents to utilize for a specific individual patient’s pain It is hoped that the experts who contributed to this text have
complaints. presented information which may be helpful/educational to clini-
Furthermore, analgesics, modalities, neuromodulation, and cians and/or patients and that future editions continue to present
interventional techniques, etc. should not be used ‘‘in a vacuum’’, current and useful information related to the ever-changing field of
but rather optimally in conjunction with physical medicine, beha- pain medicine.
vioral medicine, and other techniques as part of an interdisciplinary HOWARD S. SMITH, MD
team approach. Additionally, it is conceivable that some pain
xiii
Acknowledgments
The editor would like to thank and acknowledge the enormous The editor would also like to acknowledge and thank Dr. Kevin
efforts of Pya Seidner who helped to bring this project to fruition. W. Roberts, Chairman of the Department of Anesthesiology for
The editor would like to acknowledge and thank the Albany Medical College, for his continued support throughout
Reflex Sympathetic Dystrophy Association (RSDA) for the use this project.
of Dr. R. Norman Harden’s chapter which was initially written
for RSDA.
xv
Foreword
I distinctly remember the moment, more than 25 years ago. It is avoidance of the subject when medical trainees ask me those diffi-
frozen in my memory as if it occurred yesterday. With eyes closed, cult questions about the most common problem experienced by
my senses recall the dim lighting, the squeaking of aged and rarely people seeking medical care: pain! But how can most clinicians—
waxed tongue-and-groove flooring underfoot, the musty smell of who have so many areas of medicine to keep up on—also keep up
weathered paper, dried binding glue and dust. This was the library on all the advances in pain assessment and management?
in the teaching hospital that served as my ‘‘home away from home’’ The answer lies between the covers of this well-written, compre-
as a neophyte physician. And that was where I went to seek help hensive yet pointedly practical text. In this new addition to the
when I began to steadily encounter patients with pain problems. highly valued ‘‘Current Therapy’’ series, Dr. Howard Smith has
And there were, it seemed, so many . . . yet, on whose behalf my assembled many of the leading authorities in this rapidly-evolving
attending physicians shrugged their collective shoulders and skill- field to do that all-important and selfless work: write a book that
fully redirected the stream of discussion to more discernible pathol- really can, and will, help to improve peoples’ lives. Would that I
ogy. There was no malice, just discomfort, and I discovered why. could have discovered such a gem when I went searching, way back
No one knew anything. The library shelves were devoid of journals in ‘‘the dark ages’’ of the late 20th century!
and texts on the subject. PERRY G. FINE, MD
Fast forward to 2008, and there is such an outpouring of pain- Professor of Anesthesiology
related literature, I have to purposefully block out my schedule Pain Research Center
every Friday afternoon to peruse what comes across my desk just University of Utah School of Medicine
to keep up before the week ends. Sure, I have learned that it’s okay Salt Lake City, Utah
to say ‘‘I don’t know’’, but there will be no shoulder-shrugging or
xvii
I
PAIN BACKGROUND
Chapter 1 These disputes form an interesting adjunct to classification and

may or may not be illuminating, but resolving them is not part of
THE TAXONOMY OF PAIN the primary function of a classificatory system. Classification is not
a means of reaching an absolute truth but rather a means of estab-
lishing ways to code data that can be shared and compared between
Harold Merskey different practitioners or investigators.
The main task of the classifier is simply to make sure that indi-
viduals can identify and locate types of objects or events. The clas-
sifier is not required to establish a true ‘‘meaning.’’1 Thus, if
physicians in different parts of the world wish to exchange infor-
mation about headache, it is not necessarily important to resolve,
first, whether Migraine should or should not include phonophobia
INTRODUCTION in its classification. Rather, it is important to identify headaches that
are unilateral or bilateral, and then whether photophobia, phono-
Taxonomy is the theory and practice of classification. For an ideal phobia, nausea, and vomiting occur together with varying durations
classification, each item to be considered should be independent of of the event. Thus, data can be collected for comparison between
all other items so that it stands in its own place in the classification. different groups with respect to the items used to identify particular
For example, if we wish to classify peoples’ names for a telephone events, and any consequences that we wish to suppose follow from
directory, each name must represent a separate and distinguishable them, such as loss of response to different treatments and so forth.
item. The classification must also be comprehensive (Box 11). If Of course, this does mean that one has to have some sort of idea
two or more people have names such as John A. Smith, then an about which criteria one wishes to put together in one classificatory
additional criterion must be used to distinguish each John A. Smith slot and which criteria go into another classificatory slot. We are not
and this can be done by adding a street address. If there are two really interested in comparing cases of headache with cases of
John A. Smiths, each with his own telephone number at exactly the elephantiasis. That separation is easily made. Separations between
same address—most likely father and son, or if there are three, types of headache become a topic for study within the framework of
grandfather, father, and son—they may use a numeric superscript an overall definition.
or a numeric postscript as John A. Smith1, John A. Smith2, John It is just as well that classification can be used in the way just
A. Smith.3 That provides a perfect classification useful for the pur- mentioned. Were that not the case, we would be left with irrecon-
pose for which it is intended and of little or no interest besides. cilable arguments and spend all our time trying to determine
Natural classifications such as animal, vegetable, or mineral are whether all physical illnesses were hereditary and secondary to psy-
more exciting and even sometimes intellectually beautiful, for chological status, or whether some physical illnesses certainly were
example, the periodic table in chemistry. Nearly always (apart per- due to environmental causes and others resulted from ill treatment
haps from some isotopes made by people) this meets the highest in childhood.
standards of classification also. Each element has a place of its own A workable system of classification needs to proceed on the basis of
into which it fits and no other element with which it can be con- information that is largely agreed and to define areas of disagreement
fused. Evolutionary classifications of flora and fauna similarly so that these can be further explored. This is a reasonable way to avoid
achieve great success, although disputes may arise in marginal controversy about medical diagnoses and to pursue knowledge.
cases (Box 12).
Medical classification lacks the rigor of either the telephone
directory or the periodic table. It is exceptionally untidy, but it is EXISTING MEDICAL CLASSIFICATIONS
taken to reflect in some way ‘‘the absolute truth’’ or at least the
wonderful truth, as known to the best practitioners. Accordingly, Existing medical classifications vary enormously but are all, or
physicians endeavor to create true descriptions of individual ‘‘true’’ nearly all, illogical. In the International Classification of Diseases
disorders, each helping to some extent to improve upon the worth and Related Health Problems, 10th edition (ICD-10),2 for example,
of the previous ones. Classification may then be bedeviled by an we find that conditions are classified by causal agent (e.g., infectious
argument about the criteria that apply to a particular diagnosis, for diseases or neoplasms); by systems of the body (e.g., gastrointestinal
example, what is Cervicogenic Headache? What is the difference or genitourinary); or by symptom pattern and type of psychiatric
after an injury between that and Migraine if Migraine occurs with illnesses (including affective psychosis, schizophrenic psychosis,
photophobia or phonophobia and nausea? Are there two or more organic psychoses, depressive and anxiety disorders, and personality
disorders, each with its essential characteristics? disorders) (Box 13).
1
2 Chapter 1 THE TAXONOMY OF PAIN
Box 11 IDEAL CLASSIFICATION Box 13 MEDICAL CLASSIFICATION

Comprehensive By Cause
Specific place for each item Bacteria
By Organ
Pneumonia
All of the psychiatric conditions just mentioned, except for By System
Personality Disorders, are segregated into a category known in the Pneumonia
American Psychiatric Association’s Diagnostic and Statistical Parkinson’s Disease
Manual of Mental Disorders in several editions (DSM-IV TR, at By Site
present3) as ‘‘Axis I Type Disorders,’’ and Personality Disorders Low back pain
are classified in an additional axis (Axis II). Patients may have
By Symptom
any number of disorders from Axis I (e.g., Major Depressive Headache
Disorder plus Post-Traumatic Stress Disorder), and another diag-
nosis as well on Axis II (e.g., 301.4 Obsessive Compulsive
Personality Disorder) (Box 14).
Medical diagnoses can also be classified by time of occurrence in five different Axes on which conditions might be classified includ-
relation to stages of life, for instance, congenital anomalies, condi- ing Axis I: Clinical Disorders; Axis II: Personality Disorders, Mental
tions originating in the perinatal period, or presenile and senile Retardation, or Specific Development Disorders; Axis III: General
disorders. At the lowest level of classification, that is, the simplest Medical Conditions; Axis IV: Psychosocial and Environmental
and least complex description of phenomena, conditions used to be Problems; and Axis V: Global Assessment of Functioning. This
classified simply as ‘‘Symptoms, Signs and Ill-Defined Conditions’’ system allows us to classify both symptom patterns and people,
and are now classified as Symptoms and Signs, which actually con- an interesting conclusion, although the classification of people is
stitute a group on their own in the ICD-10.2 Not only illness is notoriously unreliable whether by psychiatrists or by anyone else in
classified in medical lists. There was also a code in ICD-94: ICD650 the medical context.
for delivery in a completely normal case of pregnancy. The nearest To add to these hazards, we can also note that we may diagnose
to this now appears in ICD-10 as Single Spontaneous Delivery. psychiatric conditions from serology (e.g., genetics [e.g., Huntington’s
Within the major medical groups of ICD-9 and -10 and partic- chorea]), symptom pattern (e.g., schizophrenia, depression, bipolar
ularly the neurologic section, there are subdivisions by symptom illness), reported mechanism (e.g., tension headache), and even
pattern (e.g., epilepsy or migraine), by the presence of hereditary the presence or the absence of irrational behavior (e.g., psychosis
or degenerative disease (e.g., cerebral degenerations that may be vs. neurosis, although the latter term is not much used nowadays
manifest in childhood or adult life), and by symptom pattern and was dropped from DSM-III onward).
(e.g., Parkinson’s disease, chorea, and types of cellular change). One of the obvious responses in a situation in which classifica-
Accordingly, there are also diagnoses by location (e.g., spinocer- tion cannot be provided on a theoretical basis is to provide agreed
ebellar disease) and by infectious causes within the neurologic operational definitions. This brings us back to the starting point of
group (which is defined first by location, e.g., meningitis). this discussion at which it was pointed out that only two things
If we look at pain disorders, there are codes in the ICD-10 for really matter in a classification system, one is a distinction between
‘‘Migraine’’ (G43) and 9 subtypes, and separately for ‘‘Other A, B, and C and the other is that everything from A to Z will be
Headache Syndromes’’ (G44) with 10 subcategories. There are included that is part of the material to be classified.
codes for ‘‘Juvenile Ankylosing Spondylitis’’ (M081) and for Thus, it follows that even within medicine, the range of classi-
‘‘Ankylosing Spondylitis in adults’’ (M45), as for ‘‘Seropositive ficatory systems can be enormous. There are highly specialized and
Rheumatoid Arthritis’’ (M05) with 6 subordinate categories and valuable classifications that will code the varieties and degrees of a
for ‘‘Other Rheumatoid Arthritis’’ with 9 subordinate categories single diagnostic category such as stroke,6 and there are also classi-
(M06). Among Symptoms and Signs, we find ‘‘Headache’’ (R51). fications that cover not just the type of illness or condition exam-
In the Cardiologic section, R07 includes precordial pain in the ined but simply the reason for consultation. Thus, the ICCPC, the
anterior chest wall (NOS); this may be pain in the musculoskeletal International Classification of Conditions in Primary Care7 does
system or refer to a neuralgic type of pain and precordial pain, not classify diseases but rather the reason for contact between the
which may well not be cardiac. If we look at Endocrinology, we family practitioner and her or his patient. Such a classification will
may simply diagnose ‘‘Diabetes,’’ which was once one disorder include the reason for a patient being in the doctor’s office
but is now defined in terms of 5 subtypes on a biochemical and (e.g., advice on a symptom, review of treatment, completion of
therapeutic basis. Among Musculoskeletal conditions, we have a referral form, and completion of an insurance company form).
‘‘Fibromyalgia’’ defined by a distribution of pain and tender
points and not by what might be its supposed innermost essence,
and ‘‘Repetitive Strain Syndrome’’ is diagnosed, whether rightly
wrongly, on the basis of pain in parts that are overused. Box 14 AMERICAN PSYCHIATRIC ASSOCIATION
To resolve some of the problems of comparing these illnesses, DIAGNOSTIC AND STATISTICAL MANUAL OF
the American Psychiatric Association’s DSM-III5 provided at least MENTAL DISORDERS
Box 12 TYPES OF CLASSIFICATION

Natural
Mineral
Vegetable
Artificial From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Telephone directory 4th ed. (DSM-IV).Washington, DC: APA Press, 2000.
I PAIN BACKGROUND 3
All these items are classifiable and can be examined for whatever region of the body because this was the least controversial and
statistical purpose desired. The one thing classification does not do should be the first basis for classification.
is provide a statement of absolute truth about the ultimate meaning The next step was to look at whether systems, patterns of pain,
of all medical disorders—or even one. or etiology should come next. Etiology again lost out. The system
involved seemed to be the next obvious agreed basis for arranging
observations on pain. Not only was etiology displaced from the first
CLASSIFICATIONOF PAIN position and the second position, but there was also agreement that
it should be left to the end to work out what we could best do about
In 1983, citing others, it was said that, ‘‘There has long been a need it. Accordingly, the next part of the classification system focused
for classification in the field of pain.’’1 A classification of pain was upon the temporal characteristics of pain and the pattern of occur-
prepared originally for the International Association for the Study rence for which coding was provided. Everyone was comfortable
of Pain, and first published in 1986,8 with a second edition in 1994. after that in grading the pain according to its intensity, and so, the
The aim of the classification is described in the introduction to the first four Axes of a pain classification had emerged as regions,
1994 volume9 as being to classify the major causes of chronic pain systems, temporal characteristics, and intensity combined with
and to organize descriptions of the syndromes. It turned out slightly duration since onset. Finally, room was left for etiology, and that
differently. was classified as genetic or congenital: trauma; surgery; infective or
At first, it was not felt possible nor desirable to classify all painful parasitic; inflammatory but with no known infective agent and
conditions. A good classification of pain was principally required immune reactions; neoplasm; toxic; metabolic; degenerative; dys-
for practitioners who were specializing in the treatment of painful functional (including psychophysiologic); unknown or other; and
disorders and who needed to distinguish them from other disorders lastly, psychological origins. Each of these codings acquired a
and disabilities. Thus, it was inappropriate to include the pain of number from 0 to 9 (Box 15).
appendicitis or tonsillectomy in a classification of chronic pain, but As an example of how the coding system works, consider
it was desirable to have a systematic arrangement of conditions that common migraine. Migraine was coded 4 in the third Axis on the
commonly caused chronic pain. Any attempt to do otherwise basis the pattern of occurrence being one of recurring irregularly.
would, of course, have amounted to writing an extensive textbook A period is inserted for convenience of citing extra numbers. Axis IV
of medicine. The purpose of such a classification would be to pro- reflects the patient’s statement of intensity and time since the onset
vide a means of communication between specialists in the field of of pain, so that a mild pain present for 1 month or less was coded
pain, enable them to know that when one published a report on, for at.1, and a severe pain present for more than 6 months was coded
example, sprain injuries, the same disorders would be at least at.9. Because this criterion can vary from case to case within the
broadly similar to that which a different person would call by the same diagnostic category, the letter X was placed to reflect the fourth
same name, even internationally. A few types of acute pain were Axis and to signify that each case would have its features determined
admitted to the classification for comparative purposes and because on the occasion of coding and not arbitrarily beforehand.
they frequently gave rise to chronic pain (e.g., postherpetic neur- Code 7 concerning Migraine was a statement indicating modesty
algia). The Taxonomy of Chronic Pain, which was produced by the about knowledge of the exact origins of the condition. Thus, the
Task Force on Taxonomy of the International Association for the initially constructed code for Common Migraine ran 004.X7.
Study of Pain (IASP), known as the Sub-Committee, thus attempted However, Classical Migraine also satisfies these criteria, and there-
to cover the major causes of chronic pain and some illustrative fore, Classical Migraine was coded as 004.X7a and Common
examples of acute pain. Migraine was coded as 004.X7b.
That being easily decided, the most difficult problem was to A code of 0 is given for the head, face, and mouth; 0 for the nervous
determine the best approach to organizing pain syndromes. It is system, whether central, peripheral autonomi,c or special senses.
obviously theoretically possible to arrange pain syndromes by As indicated, the X code symbol was used to permit the clinician
region of the body or by organ system (e.g., cardiac pains, muscu- to determine the features of that particular case in accordance with
loskeletal pains, and pain due to neurologic illness, and so forth). whether the intensity was mild, medium, or severe, and the dura-
Alternatively, one might arrange pain syndromes by their purported tion was less than 1 month, between 1 month and 6 months, or
causes (e.g., postherpetic neuralgia, which it is immediately obvious more than 6 months. Thus, mild intensity of more than 6 months
also could come under the Neurologic rubric. was rated as 3, medium intensity of more than 6 months was rated
as 6, severe intensity equal to or more than 1 month but less than
6 months was rated at 8, and so on.
THE IASP CLASSIFICATION Lastly as indicated, codes were given for etiology. Despite using
five places organized at a default sequence of XXX.XX which in the
The Task Force on Taxonomy of the IASP decided, after some vig- case of common migraine, as just discussed, was shown as 004.X7b,
orous discussion, that it would be unwise to classify on the basis of a number of classifications could theoretically use these additional
etiology. Etiology is the topic that most concerns practitioners codes. In order to discriminate between conditions occupying the
because we think that it leads us to make the most useful diagnoses. same five Axis locations, additional letters were required, namely
Diagnosis is seen as the avenue to correct treatment. To give up the a, b, c, and d, so that Classical and Common Migraine were coded
idea that we can classify by etiology first means recognizing that the as 0004.X7a and 004.X7b, respectively.
empirical methods of medicine are not yet good enough to provide
etiologic classification, at least in the field of pain.
An attempt was made by a group at the National Institutes for
Dental Research in the late 1970s to classify orofacial pain by
etiology. The IASP subcommittee concluded that, although the clas-
Box 15 IASP CLASSIFICATION
sification was detailed and well worked out, there was insufficient I. Site
agreement on etiology to make that approach satisfactory for pain II. System
as a whole. An impressive classification had actually been developed III. Pattern of Pain
by the late Dr. John Bonica in his classic work, The Management of IV. Intensity and Duration of Pain
Pain.10 Bonica had started with regions of the body and turned to V. Etiology
diagnosis only after he had arranged the subject by region. The IASP, International Association for the Study of Pain.8
committee was unanimous that the best way to start was by
4 Chapter 2 PATHOPHYSIOLOGY OF PAIN
Rather, it is necessary to have a structured method of characterizing

Box 16 USES OF CLASSIFICATION SYSTEMS syndromes, whether or not this describes their supposed true essence
or is in accordance with particular claims about etiology or signifi-
Communication cance. Given the structured method, we can proceed to identify the
Uniform standards of diagnosis
subordinate phenomena that may lead to a more refined diagnosis.
Statistical Even when there is a refined diagnosis, it still may not be something
Service delivery that can be called an absolute truth but rather a step on the way to
Financial improved management, which is what clinical medicine is actually
Billing and planning about. Such a modest aim nevertheless does not inhibit clinical
description from proceeding to more fundamental analyses by inter-
ested scientists who may or may not be the clinicians.
This system of coding by special characteristics is intended to
allow comparisons between groups of cases. To the best of my
knowledge, it has not been used a lot in clinical practice or in REFERENCES
research investigations. However, a number of the diagnostic cate- 1. Merskey H. Development of a universal language of pain syndromes.
gories have been popular, clinicians frequently referring to the In Bonica JJ (ed): Advances in Pain Research and Therapy, Vol 5.
descriptions and characteristics provided for them. This particularly New York: Raven, 1983; pp 3752.
applies to fibromyalgia and complex regional pain syndrome, con- 2. World Health Organization. International Classification of Diseases and
ditions in which there was more doubt about the traditional appre- Related Health Problems, 10th rev. (ICD-10). Geneva: WHO, 1992.
ciation of the disorder. The section on Back Pain is also used by 3. American Psychiatric Association. Diagnostic and Statistical Manual of
some. As well, occasional rare syndromes that appeared in the clas- Mental Disorders, 4th ed. (DSM-IV). Washington, DC: APA Press, 2000.
4. World Health Organization: International Classification of Diseases
sification were conveniently identified through it by members of the and Related Health Problems, 9th rev. (ICD-9). Geneva: WHO, 1978.
IASP who were able to refer to relevant sections of the classification 5. American Psychiatric Association. Diagnostic and Statistical Manual of
in order to assist a diagnosis. This was noted, for example, with the Mental Disorders, 3rd ed. (DSM-III). Washington, DC: APA Press, 1980.
fairly rare syndrome of painful legs and moving toes, which some- 6. Capildeo R, Haberman S, Rose FC. New classification of stroke.
times also involves the arms and which is due to dorsal ganglion or Preliminary communication. Br Med J 1977;2:15781580.
spinal cord damage. This is a condition that was on occasion 7. Lamberts H, Wood M. International Classification of Primary Care.
previously treated as ‘‘hysteria.’’ Oxford: Oxford University Press, 1989. (Reprinted with corrections,
1989.)
8. Merskey H (ed): Classification of chronic pain: descriptions of
chronic pain syndromes and definitions of pain terms. Monograph
THE USES OF CLASSIFICATION for the Sub-Committee on Taxonomy, International Association for
the Study of Pain. Pain (suppl 3). Amsterdam: Elsevier Science, 1986.
The uses of classification are thus essentially pragmatic (Box 16). It 9. Merskey H, Bogduk N (eds): Classification of Chronic Pain:
is important to understand that issues as to what a ‘‘real illness’’ is or Descriptions of Chronic Pain Syndromes and Definitions of Pain
what constitutes ‘‘a genuine syndrome’’ are not easily solved and Terms, 2nd ed. Seattle: IASP Press, 1994.
should not get in the way of the diagnosis and treatment of patients. 10. Bonica JJ. The Management of Pain. Philadelphia: Lippincott, 1953.
Chapter 2 severe tissue damage, chronic and/or neuropathic pain is persistent

and maladaptive.
PATHOPHYSIOLOGY OF PAIN
Jun-Ming Zhang and Mark L. Baccei CLASSIFICATIONOF PAIN
Pain involves sensory, emotional, and cognitive components.
Although it may be classified in many ways, pain can often be
categorized as nociceptive, neuropathic, mixed, or idiopathic pain.
Nociceptive Pain
Pain is termed nociceptive when the clinical evaluation suggests
INTRODUCTION that it is sustained primarily by the nociceptive system.
Nociceptive pain is pain that is proportionate to the degree of
Pain is defined as ‘‘an unpleasant sensory and emotional experi- actual tissue damage. A more severe injury results in a pain that
ence associated with actual or potential tissue damage, or is perceived to be greater than that caused by a less severe injury.
described in terms of such damage.’’ Under normal physiologic Such pain serves a protective function. Sensing a noxious stimulus,
conditions, pain is elicited by the activation of specific nociceptors a person behaves in certain ways to reduce the injury and promote
(nociceptive pain). However, it may also result from a lesion or healing (e.g., pulling his or her finger away from a hot object).
dysfunction of peripheral afferent fibers or the central nervous This ‘‘good’’ pain serves a positive function. Examples of nocicep-
system (CNS) itself (neuropathic pain). Although acute tive pain include acute burns, bone fracture, and other somatic
nociceptive pain serves as a warning signal regarding possible and visceral pains.
Rather, it is necessary to have a structured method of characterizing

Box 16 USES OF CLASSIFICATION SYSTEMS syndromes, whether or not this describes their supposed true essence
or is in accordance with particular claims about etiology or signifi-
Communication cance. Given the structured method, we can proceed to identify the
Uniform standards of diagnosis
subordinate phenomena that may lead to a more refined diagnosis.
Statistical Even when there is a refined diagnosis, it still may not be something
Service delivery that can be called an absolute truth but rather a step on the way to
Financial improved management, which is what clinical medicine is actually
Billing and planning about. Such a modest aim nevertheless does not inhibit clinical
description from proceeding to more fundamental analyses by inter-
ested scientists who may or may not be the clinicians.
This system of coding by special characteristics is intended to
allow comparisons between groups of cases. To the best of my
knowledge, it has not been used a lot in clinical practice or in REFERENCES
research investigations. However, a number of the diagnostic cate- 1. Merskey H. Development of a universal language of pain syndromes.
gories have been popular, clinicians frequently referring to the In Bonica JJ (ed): Advances in Pain Research and Therapy, Vol 5.
descriptions and characteristics provided for them. This particularly New York: Raven, 1983; pp 3752.
applies to fibromyalgia and complex regional pain syndrome, con- 2. World Health Organization. International Classification of Diseases and
ditions in which there was more doubt about the traditional appre- Related Health Problems, 10th rev. (ICD-10). Geneva: WHO, 1992.
ciation of the disorder. The section on Back Pain is also used by 3. American Psychiatric Association. Diagnostic and Statistical Manual of
some. As well, occasional rare syndromes that appeared in the clas- Mental Disorders, 4th ed. (DSM-IV). Washington, DC: APA Press, 2000.
4. World Health Organization: International Classification of Diseases
sification were conveniently identified through it by members of the and Related Health Problems, 9th rev. (ICD-9). Geneva: WHO, 1978.
IASP who were able to refer to relevant sections of the classification 5. American Psychiatric Association. Diagnostic and Statistical Manual of
in order to assist a diagnosis. This was noted, for example, with the Mental Disorders, 3rd ed. (DSM-III). Washington, DC: APA Press, 1980.
fairly rare syndrome of painful legs and moving toes, which some- 6. Capildeo R, Haberman S, Rose FC. New classification of stroke.
times also involves the arms and which is due to dorsal ganglion or Preliminary communication. Br Med J 1977;2:15781580.
spinal cord damage. This is a condition that was on occasion 7. Lamberts H, Wood M. International Classification of Primary Care.
previously treated as ‘‘hysteria.’’ Oxford: Oxford University Press, 1989. (Reprinted with corrections,
1989.)
8. Merskey H (ed): Classification of chronic pain: descriptions of
chronic pain syndromes and definitions of pain terms. Monograph
THE USES OF CLASSIFICATION for the Sub-Committee on Taxonomy, International Association for
the Study of Pain. Pain (suppl 3). Amsterdam: Elsevier Science, 1986.
The uses of classification are thus essentially pragmatic (Box 16). It 9. Merskey H, Bogduk N (eds): Classification of Chronic Pain:
is important to understand that issues as to what a ‘‘real illness’’ is or Descriptions of Chronic Pain Syndromes and Definitions of Pain
what constitutes ‘‘a genuine syndrome’’ are not easily solved and Terms, 2nd ed. Seattle: IASP Press, 1994.
should not get in the way of the diagnosis and treatment of patients. 10. Bonica JJ. The Management of Pain. Philadelphia: Lippincott, 1953.
Chapter 2 severe tissue damage, chronic and/or neuropathic pain is persistent

and maladaptive.
PATHOPHYSIOLOGY OF PAIN
Jun-Ming Zhang and Mark L. Baccei CLASSIFICATIONOF PAIN
Pain involves sensory, emotional, and cognitive components.
Although it may be classified in many ways, pain can often be
categorized as nociceptive, neuropathic, mixed, or idiopathic pain.
Nociceptive Pain
Pain is termed nociceptive when the clinical evaluation suggests
INTRODUCTION that it is sustained primarily by the nociceptive system.
Nociceptive pain is pain that is proportionate to the degree of
Pain is defined as ‘‘an unpleasant sensory and emotional experi- actual tissue damage. A more severe injury results in a pain that
ence associated with actual or potential tissue damage, or is perceived to be greater than that caused by a less severe injury.
described in terms of such damage.’’ Under normal physiologic Such pain serves a protective function. Sensing a noxious stimulus,
conditions, pain is elicited by the activation of specific nociceptors a person behaves in certain ways to reduce the injury and promote
(nociceptive pain). However, it may also result from a lesion or healing (e.g., pulling his or her finger away from a hot object).
dysfunction of peripheral afferent fibers or the central nervous This ‘‘good’’ pain serves a positive function. Examples of nocicep-
system (CNS) itself (neuropathic pain). Although acute tive pain include acute burns, bone fracture, and other somatic
nociceptive pain serves as a warning signal regarding possible and visceral pains.
I PAIN BACKGROUND 5
Table 21. Comparison of ‘‘Good’’ Pain and ‘‘Bad’’ liver) sensory stimuli by opening ion channels in their membrane.
Pain This results in a depolarization of the sensory neuron, which can
trigger the generation of an action potential that propagates to the
Nociceptive Pain Neuropathic Pain dorsal horn of the spinal cord. It is now clear that the size of the
sensory neuron can provide significant clues as to its function.
Warns of acute or Pain caused by nerve injury Large-diameter DRG neurons possess large myelinated axons with
potential damage Spontaneous, evoked activity rapid conduction velocities in the Ab range (>30 m/sec) and gen-
Protective function Develops in days or months erally transmit information about innocuous mechanosensation
Can be differentiated Associated with inflammation, (e.g., touch, vibration). Noxious stimulation is transmitted via
from touch neuropathy small-diameter DRG neurons that give rise to either thin myelinat-
Transient Associated with peripheral and ed Ad fibers (which conduct impulses at 230 m/sec) or small
Well localized central sensitization unmyelinated C-fibers (with conduction velocities of < 2 m/sec).
C- and Pain outlasts duration of the The signals carried by all three types of sensory afferents are
integrated by the synaptic network within the spinal dorsal horn,
Ad-fibermediated stimulus
which consists of both local circuit interneurons and second-order
Increased activity, Pain sensed in noninjured areas projection neurons that transmit impulses from the spinal cord to
wide dynamic range Elicited by Ab (?) as well as C and higher brain areas (including the thalamus) predominantly via the
neurons Ad fibers spinothalamic tract (STT). The output of these STT neurons
Opioid sensitive Opioid insensitive depends on the net balance between inhibitory and facilitatory
mechanisms within the dorsal horn. For example, repetitive stimu-
Neuropathic Pain lation of tactile Ab mechanoreceptive inputs can activate spinal
interneurons and inhibit the response of STT neurons by decreasing
Unlike nociceptive pain, neuropathic pain occurs through periph- the amount of glutamate released from the presynaptic terminals of
eral nervous system (PNS) changes, such as neuroma formation, nociceptive C-fibers in the dorsal horn. This is believed to underlie
generation of ectopic discharge from the injured axons or the the effectiveness of both transcutaneous electrical nerve stimulation
somata of the dorsal root ganglion (DRG) neurons, or through (TENS) and dorsal column stimulation as clinically therapeutic
CNS changes that can lead to enhanced excitability of central interventions for patients with pain. In contrast, responses of STT
pain networks (termed central sensitization) in patients with a pro- neurons to nociceptive stimuli can be facilitated if they have been
longed exposure to noxious stimuli or nerve injury. It is dispropor- subjected to long-term excessive input from C-fiber nociceptive
tionate to the degree of tissue damage and can also persist in the neurons (sensitization), which can be caused by chronic inflamma-
absence of continued noxious stimulation (i.e., the pathophysiolo- tion or other chronic noxious stimulation of C-fibers. The excit-
gic changes become independent of the inciting event). Thus, neu- ability of STT neurons is also modulated by descending projections
ropathic pain serves no protective function and provides no benefit to the spinal cord from higher areas of the CNS (such as the rostral
to the overall health of the person. The underlying causes of neu- medulla), which can cause both facilitation and inhibition under
ropathic pain are discussed in a later section (Table 21). different conditions.
The activation of third-order neurons in the thalamus by STT
inputs allows the transmission of the noxious information to the
Mixed Pain cerebral cortex, where the perception of pain is generated. Evidence
exists that numerous supraspinal control areas—including the retic-
In a given patient, components of continued nociceptive pain may ular formation, midbrain, thalamus, hypothalamus, the limbic
coexist with a component of neuropathic pain. Patients with per- system of the amygdala and the cingulate cortex, basal ganglia,
sistent back and leg pain after lumbar spine surgery (failed low back and cerebral cortex—modulate the sensation of pain (Table 22).
surgery syndrome) represent a common example. Some patients
with complex regional pain syndrome (CRPS; reflex sympathetic
dystrophy or causalgia) may develop painful complications that PERIPHERAL AND CENTRAL
are nociceptive (e.g., joint ankylosis, myofascial pain) and that MECHANISMS OF PATHOLOGIC PAIN
coexist with the underlying neuropathic pain.
Pathologic pain occurs when prolonged nociception continues to
drive pain that outlasts its physiologic usefulness (as a signal to
Idiopathic Pain avoid harm and promote healing) and when pain-processing
mechanisms themselves function abnormally. The latter occurs in
Idiopathic pain may be defined as pain that persists without any neuropathic pain syndromes, such as postherpetic neuralgia and
identifiable organic lesions or that is disproportionate to the degree central pain due to stroke (Table 23). The mechanisms underlying
of tissue damage. neuropathic pain involve both peripheral and central components.
Although a comprehensive summary of the changes that occur in
the nervous system after peripheral nerve injury is outside the scope
PERIPHERAL AND CENTRAL of the present chapter, we highlight some key mechanisms later.
MECHANISMS OF NOCICEPTIVE PAIN
Understanding the pathophysiology of abnormal or nonphysiologic Peripheral Mechanisms
pain requires basic knowledge of the pathways mediating the
perception of somatosensory stimuli under normal conditions. Altered Expression of Ion Channels in Axotomized
The first step in this process involves the transduction of the sensory Sensory Neurons
stimulus (which can be mechanical, thermal, or chemical) into an
electrical potential by first-order afferent neurons in the DRG Spontaneous activity originating from the somata is rarely observed
located external to the spinal cord. These neurons express special- in DRG cells with normal, uninjured axons.1 However, this is a
ized receptors at their distal ends that respond to specific types of common phenomenon after the peripheral axons are injured and
external (e.g., the skin) or internal (e.g., visceral organs such as the reflects underlying alterations in the complement of voltage-gated
Table 22. Spinocerebral Ascending Pathways
Spinothalamic pathway Crosses the midline and ascends on the opposite side of the spinal cord to the ventral posterolateral nucleus
of the thalamus. This nucleus is subdivided for specific areas of the body, and each area projects to its own
section of the primary sensory cortex—a thin band of cortex in the parietal lobe just posterior to the
central sulcus. This discriminative pathway transmits to consciousness precise information about the
location of pain.
Spinoreticular pathway Ascends on both sides of the spinal cord to the intralaminar nuclei of both the right and the left thalamus.
From there, the next neuron in the chain takes the information to many areas of the brain—e.g., the
anterior part of the cingulate gyrus (emotion), the amygdala (memory and emotion), and the
hypothalamus (emotion and the vascular response to emotion).
Dorsal column pathway Transmits visceral nociception (as well as somatic touch and position sense) to the thalamus.
Spinomesencephalic Travels with the spinotectal tract to the periaqueductal gray matter and superior colliculus of the midbrain. This
tract may be the same as, or related to, the pathway traveling to the parabrachial nucleus in the brainstem—which in
turn projects to the amygdala, hypothalamus, and other limbic system structures in the forebrain.
Spinohypothalamic A recently described route; does not synapse in the reticular formation. It carries information of emotional
pathway significance from the skin, lips, sex organs, gastrointestinal tract, intracranial blood vessels, tongue, and
cornea directly to the hypothalamus.
ion channels expressed by DRG neurons.2-10 There is now compel- are involved in controlling the release of neurotransmitters
ling evidence that the expression of sodium channel subtypes from the terminals of sensory, central, and sympathetic neurons
(e.g., Nav1.3, Nav1.7, Nav1.8, and Nav1.9) is dramatically altered in the spinal cord, these alterations have significant implications
by nerve injury and may account for the increased excitability of for nociceptive processing under pathologic conditions. In fact,
neuropathic DRG neurons in models of chronic pain.11-13 The accu- the ability of anticonvulsants (carbemazepine and gabapentin) to
mulation of Nav1.3 channels in the injured DRG somata and neu- reduce mechanical allodynia (both in the clinic and in experi-
roma may play a significant role in the development and mental models of neuropathic pain) may involve, among other
maintenance of ectopic discharges. Meanwhile, the loss of sodium mechanisms, an interaction with Ca2+ channels localized on the
currents mediated by the Nav1.8, and Nav1.9 subtypes in injured injured DRG neurons.
DRG neurons leads to a hyperpolarization of the resting membrane
potential. Paradoxically, this may contribute to the enhanced excit-
Sympathetic Excitation of Injured Sensory Neurons
ability of these neurons by relieving the steady-state inactivation of
other Na+ channel subtypes (such as Nav1.3), thus increasing the size CRPS II (causalgia) is a classic example of sympathetically main-
of overall Na+ influx and the likelihood of action potential discharge. tained pain (SMP) associated with PNS injury. It is characterized by
A reduction in the density of potassium channels (or an alter- a distal burning sensation that is exacerbated by cold and gentle
ation in their functional properties) after axotomy may also mechanical stimulation.14 Clinically, SMP appears to be a signifi-
increase the excitability of sensory neurons. Indeed, it has been cant component of various painful conditions such as CRPS, phan-
shown that K+ conductance is decreased significantly in nerve- tom pain, neuralgias, and herpes zoster. Clinical observations and
injured DRG cells. This is also supported by observations that mex- animal studies have shown that coupling of the activated
iletine, which can lead to an attenuation of neuropathic pain, also sympathetic nervous system and the sensitized sensory nervous
facilitates K+ currents in DRG neurons. system is important for development of SMP. Under normal phys-
Previous work has also demonstrated that peripheral nerve injury iologic conditions, the afferent sensory nervous system and the
causes alterations in the expression of voltage-sensitive Ca2+ channels efferent sympathetic nervous system are anatomically separated
in DRG neurons. Because these channels (particularly N-type) and functionally independent of each other. There is evidence, how-
ever, that an abnormally enhanced communication between these
Table 23. Clinical Causes of Neuropathic Pain two systems may occur under pathologic conditions. For example,
sympathetic stimulation may excite sensory neurons in animals
with inflamed peripheral tissue or after peripheral nerve injury.
Nerve injury Nerve compression (entrapment Chemical or surgical sympathectomy may relieve allodynia and
neuropathies, tumors) hyperalgesia and improve chronic pain behavior. These observa-
Nerve crush, stretching, incomplete tions suggest that increased activity of the sympathetic nervous
transection (trauma) system may be involved in the sensitization of sensory neurons
Neuropathy (diabetes, irradiation, toward the development of neuropathic pain.
ischemia, toxic) Sympathetic-sensory coupling may occur either centrally or
Neuroma (amputation, nerve peripherally. The DRG has been identified as an important site
for peripheral sympathetic-sensory coupling. Within the normal
transection)
DRG, sympathetic axons are only found accompanying blood
Dorsal root Compression (disk, tumor, scar vessels. After peripheral nerve injury, sympathetic efferent fibers
ganglion tissue) extensively sprout into both DRG and spinal nerves. Sprouting
Root avulsion fibers sometime form distinctive basket-like webs (sympathetic
Inflammation (postherpetic baskets) or rings wrapping around medium and large DRG neu-
neuralgia) rons.15 Although it is currently unclear what triggers the sprouting
Spinal cord, brainstem, Spinal cord, brainstem, thalamus, of sympathetic nerve fibers in the ganglia, recent studies16 suggest
thalamus, cortex cortex that sympathetic sprouting is associated with the inflammatory
responses within the axotomized DRG and may be mediated by
Infarction, tumors, trauma
abnormal spontaneous activity of the DRG neurons.
I PAIN BACKGROUND 7
should be noted that other types of receptors (e.g., metabotropic

Inflammatory Cytokines and Chemokines
glutamate receptors, TrkB receptors) are also capable of inducing
Proinflammatory cytokines such as tumor necrosis factor-a synaptic plasticity in the dorsal horn.
(TNF-a), interleukin (IL)-1 and IL-6, and chemokines (e.g., mono-
cyte chemoattractant protein-1 [MCP-1]) may be produced in and
Loss of Central Inhibition
by peripheral nerve tissue during physiologic and pathologic pro-
cesses by resident and recruited macrophages, mast cells, endotheli- Much attention has been given to the possibility that the hyperexcit-
al cells, Schwann cells, and neurons. After PNS injury, macrophages ability of spinal neurons after nerve injury reflects a loss of synaptic
and Schwann cells that gather around the nerve injury site secrete inhibition in the dorsal horn. This has emerged from previous
cytokines and specific growth factors required for nerve regenera- experiments showing that the blockade of spinal g-aminobutyric
tion. The cytokines may be synthesized in the DRG or may be acidAreceptor (GABAAR) and glycine receptor (GlyR) (the two
transported in a retrograde fashion from the periphery, via axonal major inhibitory neurotransmitter receptors in the spinal cord)
or nonaxonal mechanisms, to the DRG and dorsal horn of the mimics the signs of central sensitization. More recent studies have
spinal cord, where they can have profound effects on neuronal shown that such a reduction in inhibitory strength can indeed occur
activity and pain sensitivity. in the dorsal horn through a variety of mechanisms.
For example, peripheral nerve injury induces a marked reduction
in the amplitude of GABAAR-mediated synaptic currents in super-
Spinal Mechanisms: Central Sensitization ficial dorsal horn neurons and a corresponding increase in the
fraction of cells that receive no GABAergic input at all. This is accom-
After peripheral nerve injury, strong activation of nociceptive affer- panied by a reduction in the expression of the GAD65 enzyme, which
ents, particularly C-fiber nociceptors, may lead to sensitization of is largely responsible for the synthesis of GABA in the dorsal horn.
dorsal horn neurons (i.e., ‘‘central sensitization’’).17 This can result These changes are believed to result from the selective death of
in the following alterations in the physiologic properties of dorsal GABAergic interneurons in the region after nerve damage, but the
horn neurons: (1) increased size of the receptive field (i.e., the area of mechanisms underlying this cell death are not yet clear.
the body that, when stimulated, evokes action potential firing in The inhibition of neuronal excitability that normally results from
the cell); (2) lower thresholds; neurons begin to fire in response to the activation of GABAAR and GlyR reflects the influx of Cl across
low-threshold afferent inputs that were previously too weak to evoke the cell membrane. The magnitude (and direction) of this flow
action potential discharge; (3) increased magnitude of action poten- depends on the relative concentration of Cl inside versus outside
tial discharge in response to nociceptive inputs; and (4) increased the neuron. Recent work has shown that sciatic nerve injury leads to a
spontaneous impulse activity. These alterations are believed to sig- decrease in the expression of the Cl transporter KCC2 (which serves
nificantly contribute to the hyperalgesia, allodynia, and spontaneous to pump Cl out of the cell) in dorsal horn neurons and a subsequent
pain that result from peripheral nerve injury. As a result, the mechan- build-up in the concentration of intracellular Cl, thereby reducing
isms underlying central sensitization have been intensely studied, the electrochemical force normally driving the Cl ions into the cell.
and the most relevant findings are briefly summarized later. Thus, after nerve injury, less Cl enters the cell through an open
GABAAR (or GlyR), which translates into weaker synaptic inhibition.
Long-term Potentiation of Nociceptive Inputs in Under normal conditions, the production of pain from the acti-
vation of nociceptors with mechanical stimuli is inhibited in the
the Dorsal Horn
spinal dorsal horn by the concurrent activation of Ab mechanore-
The repetitive activation of high-threshold C-fibers (as might occur ceptive afferents. This occurs in large part through the activation of
at the time of a peripheral nerve injury) can result in a prolonged inhibitory spinal interneurons by Ab sensory fibers. However, given
increase in the strength of their synaptic connections with dorsal the previously discussed reductions in the efficacy of GABAergic and
horn neurons. The result is that a given impulse traveling along the glycinergic transmission, this mechanism will be much less effective
nociceptive fiber can produce a greater depolarization of the after peripheral nerve injury, allowing for greater firing in the STT
second-order neurons in the spinal cord. This may reflect the inser- output cells in the spinal cord. This likely contributes to the allody-
tion of additional glutamate receptors at the postsynaptic site or by nia/hyperalgesia in patients with peripheral nerve damage.
altering the function of receptors that already exist at the synapse.
Importantly, in lamina I of the dorsal horn, this potentiation of Spinal Glial Activation
synaptic efficacy occurs selectively on spinal projection neurons
(i.e., the output cells of the dorsal horn). Thus, strong activation There is now significant evidence showing that glial activation in the
of nociceptive sensory afferents can lead to a greater synaptic drive spinal cord appears to be important for both the initiation and the
onto spinal projection neurons and a subsequent facilitation of pain maintenance of pathologic pain. Astrocytes and microglia are acti-
transmission from the spinal cord to the brain. vated by neuronal signals including substance P, glutamate, and
Additional work has demonstrated that the activation of the fractalkine. Fractalkine is a chemotactic cytokine (chemokine)
N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is that is constitutively expressed in the nervous system where it is
necessary to induce long-term potentiation (LTP) at nociceptive tethered to the extracellular membrane surface of primary afferent
synapses in the superficial dorsal horn. Within lamina I of the neurons in an inactive form via a mucin stalk. After nerve insult, the
spinal cord, the activation of the substance P receptor (NK1) is mucin stalk breaks, releasing fractalkine in an active state, which is
also required. Both of these receptors likely contribute to LTP by then free to bind to the CX3C receptor-1 (CX3CR-1) on glia,
elevating the levels of intracellular calcium in the dorsal horn resulting in glial activation. Activation of glia by these substances
neuron and thus activating downstream signaling cascades invol- leads to the release of mediators that then may act on other glia and
ving protein kinases. Animal studies have confirmed that both spinal neurons. These include proinflammatory cytokines (IL-1b),
NMDA and NK1 receptors are involved in the induction and main- TNF-a, IL-6, adenosine triphosphate (ATP), nitric oxide, and exci-
tenance of the central sensitization produced by high-threshold tatory amino acids released from microglia and astrocytes. These
nociceptive afferent inputs at the behavioral level. Because central cytokines have been shown to be critical mediators of allodynia.
sensitization is likely to contribute to the postinjury pain hypersen- Evidence also points to a role for spinal microglia in the weak-
sitivity states in humans,18 these data have a bearing on the poten- ening of GABAergic inhibition that is observed after nerve
tial importance of NMDA and NK1 antagonists for preemptive injury. Activation of microglia with ATP results in the release
analgesia and the treatment of established pain states. However, it of brain-derived neurotrophic factor (BDNF) from these cells.
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CONCLUSION
Understanding the pathophysiology of pain requires knowledge of SUGGESTED READINGS
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4. Burchiel KJ. Spontaneous impulse generation in normal and Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain.
denervated dorsal root ganglia: sensitivity to alpha-adrenergic Science 2000;288:17651769.
stimulation and hypoxia. Exp Neurol 1984;85:257272. Zhang J-M, Li H, Munir MA. Decreasing sprouting of noradrenergic
5. DeSantis M, Duckworth JW. Properties of primary afferent neurons sympathetic fibers in pathologic sensory ganglia: new mechanism and
from muscle which are spontaneously active after a lesion of their approach for treating neuropathic pain using local anesthetics. Pain
peripheral processes. Exp Neurol 1982;75:261264. 2004;109:143149.
II
ASSESSMENT OF PAIN AND
ITS TREATMENT
Chapter 3 discovered therein have clinical relevance (with exceptions).57

Such mechanisms include spontaneous and ectopic afferent
NEUROPATHIC PAIN: IS THE discharges, alterations in ion channel expression, peripheral collat-
eral sprouting of afferent neurons, sprouting of sympathetic
neurons into dorsal root ganglia, nociceptor sensitization, recruit-
EMPEROR WEARING CLOTHES? ment of silent nociceptors, dorsal horn deafferentation, central
sensitization with changes in receptive field properties, decreased
Steven H. Horowitz descending inhibition, and cerebral cortical reorganization, among
others.1,510
The disorders associated with neuropathic pain include poly-
neuropathies such as those secondary to diabetes mellitus, alcohol-
ism, and amyloidosis; idiopathic small fiber neuropathy; hereditary
neuropathies; mononeuropathies, or neuronopathies such as tri-
geminal, glossopharyngeal, and postherpetic neuralgias; entrapment
INTRODUCTION neuropathies; and traumatic nerve injuries producing complex
regional pain syndrome (CRPS) type II. CRPS type I is also con-
Current concepts of acute and chronic pain disorders distinguish sidered a neuropathic pain disorder, although evidence for nerve
‘‘nociceptive,’’ ‘‘inflammatory,’’ ‘‘functional,’’ and ‘‘neuropathic’’ damage and/or dysfunction is more controversial. Neuropathic pain
pains.1 Nociceptive pain is the most common pain experienced can occur in central nervous system conditions, especially spinal
when pain receptors (nociceptors) are activated, as in tissue injury. cord injury, multiple sclerosis, and cerebrovascular lesions involving
Inflammatory pain also involves nociceptor activation as a conse- the brainstem and thalamus.
quence of inflammation. Transduction, conduction, and transmis- In reality, the diagnosis of neuropathic pain is often problematic.
sion of nociceptor activity to conscious awareness involves Clinically, a distinction between nociceptive, inflammatory, and
peripheral and central nervous system pain pathways that, when neuropathic pains is not precise, and conditions such as diabetes
intact, function in a protective and adaptive manner.1 Damage to, mellitus, cancer, and neurologic diseases with dystonia or spasticity
or dysfunction of, these pain (somatosensory) pathways, peripherally can produce mixed pain pictures suggestive of multiple pathophy-
or centrally, can result in a different, less frequent, but nevertheless siologic mechanisms.8 As with other pains, the perception of
important pain picture—that of neuropathic pain. Neuropathic pain neuropathic pain is purely subjective, not easily described nor
confers no functional benefit and may be considered a ‘‘maladaptive’’ directly measured. Also, pain pathway responses to damage are
response of the nervous system to the primary pathology.1 not static, but dynamic; signs and symptoms change with pathway
After earlier periods of debate and uncertainty, the International activation and responsiveness and with chronicity. Further, the
Association for the Study of Pain (IASP), in 1986 and then in 1994, multiplicity of disorders that have neuropathic pain as a component
sought to codify the concept of neuropathic pain as ‘‘pain initiated of their clinical presentations makes a single underlying pain mech-
or caused by a primary lesion or dysfunction of the nervous anism unlikely. More than one type of pain, and therefore, very
system.’’2 Spirited attacks arose thereafter and have continued likely more than one mechanism, may occur in a single patient,
unabated, mostly over the terms ‘‘lesion’’ and ‘‘dysfunction.’’ The and the same symptoms can be caused by disparate mechan-
definition has been considered narrow if the pain relates to a lesion isms.810 For these and other reasons, including the failure of etiol-
and broad if it relates to dysfunction.3 Either way, it presupposes a ogy-based or anatomy-based classifications to be therapeutically
demonstrable abnormality exclusive to the nervous system; not the helpful, a mechanistic approach to neuropathic pain management
result of ongoing tissue injury elsewhere.4 It is the word ‘‘demon- is currently advocated.1 Ideally, specific mechanisms or combina-
strable’’ that is operative in this chapter. tions of mechanisms would relate to specific signs and symptoms
The definition also presupposes underlying pathophysiologic (specific somatosensory phenotypes) and, ultimately, specific thera-
mechanisms affecting somatosensory components that are respon- pies.11 Unfortunately, no objective methods of diagnosing underly-
sible for this special type of pain and are common to multiple ing pain mechanisms exist at present.12 Should such methods be
nervous system disorders. It further assumes, given the limitations developed, diseases-based symptom palliation strategies can be sup-
of human experimentation, that animal models are reasonable plemented with ‘‘targeted’’ mechanism-specific pharmacologic
correlates of the human pain condition and pain mechanisms management.13
9
10 Chapter 3 NEUROPATHIC PAIN: IS THE EMPEROR WEARING CLOTHES?
PATIENT HISTORYAND SYMPTOMS nerve injury, especially of sweating, skin temperature, and skin
color, in conjunction with the aforementioned pain, fulfill the
Despite these complexities, there are several features to the clinical diagnostic criteria of CRPS (discussed below). With chronicity,
presentation of neuropathic pain that support its diagnosis and trophic changes of the skin and nails may develop, as well as
should be sought during history taking. In the case of mononeuro- motor signs such as weakness, tremor, and dystonia. Nerve per-
pathies secondary to trauma, the severity of the pain often exceeds cussion at points of compression, entrapment, or irritation can
the severity of the inciting injury and the pain extends past the elicit pins-and-needles or ‘‘electrical’’ sensations (Tinel’s sign) in
healing period. CRPS can follow minor skin or joint trauma, the territory of the nerve percussed.
bone fractures, or injections. The pain is stimulus-independent In small fiber neuropathies, deficits occur in thermal and pain
and described as ‘‘burning,’’ ‘‘lancinating,’’ ‘‘electric shocklike,’’ perceptions and sometimes touch, whereas large fiber functions
‘‘jabbing,’’ and/or ‘‘cramping’’; it is often accompanied by pins- (e.g., muscle strength, reflexes, and perception of vibratory and
and-needles sensations and sometimes by intractable itching proprioceptive stimuli) are normal. In combined large and small-
(positive symptoms). These symptoms do not adhere to specific fiber polyneuropathies, all these functions are compromised.
peripheral nerve distributions and often begin and remain most Symmetrical distal autonomic dysfunction is often present but
pronounced distally. The pain may be worse at night when activity rarely severe.
ceases and/or during cold, damp weather, and it is exacerbated by In patients with significant neuropathic pain, clinical neurologic
movement of the affected limb. Multiple types of pain (constant deficits are demonstrable in many conditions, but not in others,
pain with paroxysms and stimulus-evoked pains) can be experi- for example, trigeminal and glossopharyngeal neuralgias and,
enced simultaneously. It is useful to separate stimulus-independent more than occasionally, postherpetic neuralgia. Patients with
and stimulus-evoked pains to differentiate ongoing from provoked small fiber mono- or polyneuropathies, despite describing typical
activities.6,9 Spread of symptoms outside the initial site of injury is neuropathic pain symptoms, may have normal examinations. There
common; in the case of unilateral pain, there may be spread to is the temptation to attribute their pain complaints to functional
homologous sites in the opposite limb (mirror pain). Positive and or psychogenic causes; however, at least from a logical perspective,
negative (numbness, loss of sensation) symptoms can occur con- that cannot always be the case, and if they are known to have a
currently, sometimes accompanied by autonomic symptoms. particular disease such as diabetes or suffered an injury in which
Spontaneous pain, often without complaints of sensory loss, is a nerve damage is likely, pain may be their only manifestation of
feature of the cranial mononeuralgias—trigeminal, glossopharyn- neural dysfunction. In such situations and in cases in which further
geal, and postherpetic. Of course, location, intensity, and duration diagnostic information would be helpful, ancillary testing can
of pain are extremely important. be employed.
In generalized polyneuropathies, rapid progression solely affect-
ing sensory fibers is more likely to be painful, especially if inflam-
mation and ischemia are prominent, as in the vasculitidies.8 In ANCILLARY TESTS
painful polyneuropathies, for example, idiopathic small fiber neu-
ropathy and diabetic polyneuropathy with predominant small fiber Any consideration of the utility of ancillary tests to support the
(Ad- and C-fibers) damage, the burning, lancinating, jabbing pains diagnosis of specific neuropathic pain mechanisms must take into
with pins-and-needles sensations are nerve-lengthdependent and account several factors:
bilaterally symmetrical, beginning distally in the feet. Over time,
1. Currently, available tests only evaluate nervous system structures
symptoms ascend more proximally in the lower extremities and
and functions presumed germane to pain perception and trans-
may eventually affect the hands. This centripetal progression also
mission; from their results, the presence, extent, and mechan-
occurs in intercostal nerve distributions, beginning anteriorly over
isms of neuropathic pain are, at best, inferred. This situation is
the midline of the torso with later symmetrical lateral extension to
similar to testing for diabetes mellitus using peripheral nerve,
the flanks. In patients with painful polyneuropathies, Otto and cow-
ophthalmologic, and renal studies without the availability of
orkers14 found that 88% complained of deep aching pain, 86% of
plasma glucose levels.
paresthesias, 69% pain on pressure (as when walking), and 59% of
2. There is a spectrum of clinical and pathophysiologic manifesta-
paroxysmal pain. Autonomic complaints, for example, abnormal
tions of neural injury within each disorder, and chronic pain
sweating, impotence, orthostatic hypotension, and gastrointestinal
exists in only a small percentage of affected patients. For exam-
and bladder symptoms, are frequent.
ple, neuropathic pain develops in approximately 16% of patients
with diabetes mellitus and a third of patients with diabetic neu-
ropathy15; Postherpetic neuralgia, defined as chronic pain pres-
CLINICAL EXAMINATION ent 4 or more months after resolution of the acute herpes zoster
(shingles) rash, occurs in 13% to 20% of shingles patients16; and
Among the more common and important clinical signs in neu-
after direct nerve injury during phlebotomy, persistent pain is
ropathic pain disorders are positive sensations—stimulus-evoked
rare, perhaps present after 1:1,500,000 procedures.17
hypersensitivities such as allodynia to innocuous stimuli
3. The presence of pain is presumed to reflect damage to the
(e.g., light touch and cold) and hyperalgesia to noxious stimuli
small myelinated (Ad-) and unmyelinated (C-) nociceptive
(e.g., pinprick). They occur focally in mononeuropathies and
fibers within peripheral nerves.8 Because these fiber types also
distally and symmetrically in polyneuropathies. Various forms
mediate certain clinical functions that are measurable (e.g., per-
of hyperalgesia include touch-evoked (or static) mechanical
ception of noxious and temperature stimuli and autonomic
hyperalgesia to gentle pressure, pinprick hyperalgesia, blunt-
activity), many tests have focused on demonstrating defects in
pressure hyperalgesia, and punctate hyperalgesia that increases
these modalities to verify Ad- or C-fiber damage and invoke a
with repetitive stimulation (windup-like pain).8,9 Paradoxically,
basis for the pain.
these hypersensitivities can occur in areas in which the patient
also complains of and demonstrates loss of sensation. Persistence
of stimulus-evoked pain after stimulus withdrawal (aftersensa-
tion) can occur in the same anatomic distributions. As with Clinical Neurophysiology
symptoms, spread of allodynia and hyperalgesia outside the orig-
inal site of injury is common and may extend to homologous Neurophysiologic testing, principally nerve conduction studies and
sites in the opposite limb. Focal autonomic abnormalities after electromyography (EMG), are frequently employed in suspected
II ASSESSMENT OF PAIN AND ITS TREAT MENT 11
disorders of the peripheral nervous system. The usual techniques, to light touch) in one, and hyperactive deafferentation of spinal
with surface electrodes for nerve stimulation and evoked potential cord neurons (thermal and mechanical hypoesthesia without hyper-
recording, measure activity of the largest and fastest conducting algesia or allodynia) in the other.11
sensory and motor myelinated nerve fibers (Aab-). The most The shortcomings of QST are: (1) It has never been used to
significant measured parameters are maximum nerve conduction differentiate between neuropathic and nonneuropathic pains, and
velocity (NCV), for the segment of nerve between the stimulating QST abnormalities occur in nonneuropathic pain conditions.3 (2)
and the recording electrodes, and amplitude and configuration of Abnormal findings are not specific for peripheral nerve dysfunction;
the resulting signals—the compound motor action potential central nervous system disorders will also affect sensory thresholds.
(CMAP) evoked from motor fibers and the sensory nerve action (3) Most significant, QST is a subjective psychophysical test entirely
potential (SNAP) evoked from sensory fibers. For central nervous dependent upon patient motivation, alertness, and concentration.
system or proximal peripheral nerve disorders, somatosensory and Patients can willingly perform poorly, and even when not doing so,
magnetic evoked potential studies can be helpful. EMG is the there are large intra- and interindividual variations.
needle examination of muscles and evaluates muscle and motor
nerve fiber activities.
Unfortunately, Ad- and C-fiber activities cannot be tested with Autonomic FunctionTesting
these techniques. Slowing in maximum NCVs and/or loss of CMAP
or SNAP amplitudes occur as a consequence of large fiber dysfunc- The evaluation of autonomic functions in patients with suspected
tion. Abnormal EMG features such as acute and chronic denerva- neuropathic pain can be clinically useful because of anatomic simi-
tion indicate involvement of large motor nerve fibers from the larities between pain and autonomic fibers outside the central
anterior horn cell distally. If present in a patient with neuropathic nervous system and because disorders associated with neuropathic
pain, these abnormalities can corroborate the clinical impression of pain frequently have signs and symptoms of autonomic dysfunction
peripheral nerve damage either individually or in general as in a (e.g., dry eyes or mouth, skin temperature and color changes, sweat-
polyneuropathy (e.g., diabetic or alcoholic neuropathy). However, ing abnormalities, orthostatic hypotension, heart rate responses to
painful polyneuropathies or focal nerve lesions with exclusive or deep breathing, edema). The majority of autonomic tests study
predominant small fiber involvement can have normal NCVs and skin temperature and sudomotor, baroreceptor, vasomotor, and
EMG. Nerve conduction studies may be of value in the serial inves- cardiovagal functions; they have been extensively reviewed.20,21 A
tigation of patients who present with painful small fiber neuropa- semiquantitative composite autonomic symptoms score (CASS),
thies, because there is indirect electrodiagnostic evidence of composed of the results of sudomotor, cardiovagal, and adrenergic
progression to large fiber involvement 5 to 10 years after the testing, has been devised.22 Pupillary, gastrointestinal, and sexual
onset of pain. However, some patients had preserved large fiber function tests are occasionally helpful.
functions over a 10-year period.18 The value of autonomic testing in a generalized neuropathic
pain disorder, small fiber neuropathy with burning feet, has been
demonstrated in several studies of patients with normal or only
Quantitative SensoryTesting mildly abnormal electrophysiologic (NCVs/EMG) findings.23,24
Autonomic abnormalities were seen in greater than 90% of patients,
Quantitative sensory testing (QST), used with increasing frequency the most useful tests being the quantitative sudomotor axon reflex
especially in clinical therapeutic trials, measures sensory thresholds test (QSART), thermoregulatory sweat test, heart rate responses to
for pain, touch, vibration, and hot and cold temperature sensations. deep breathing, Valsalva ratio, and surface skin temperature.23,24
Commercially available devices range from hand-held tools to However, in a recent study of patients with diabetic polyneuropa-
sophisticated computerized equipment with complicated testing thy, discordance was noted between efferent C-fiber responses in
algorithms, standardization of stimulation and recording proce- sudomotor tests (QSART and sweat imprint) and primary afferent
dures, and comparisons with age- and gender-matched control (nociceptor) C-fiber axon-reflex flare responses. These findings
values. With this technology, specific fiber functions can be indicate that these two C-fiber subclasses can be differentially
assessed: Ad-fibers with cold, cold-pain, and mechanical pain detec- damaged or may have different patterns of regeneration and rein-
tion thresholds; C-fibers with heat and heat-pain detection thresh- nervation.25 Abnormal autonomic functions can also occur in pain-
olds; and large fiber (Aab-) functions with vibration detection less peripheral neuropathies.
thresholds and mechanical detection thresholds to von Frey The relationship between autonomic dysfunction and pain is
hairs.11,19 Elevated sensory thresholds correlate with sensory loss; more complicated in CRPS in which focal sudomotor and vasomo-
lowered thresholds occur in allodynia and hyperalgesia.19 Certain tor abnormalities occurring at some point in time are essential for
QST findings may relate to specific pathophysiologic mechanisms the diagnosis,2, pp 3943 and sympathetic blockade has been a main-
associated with neuropathic pain: heat hyperalgesia to peripheral stay of diagnosis and therapy for decades. As would be expected,
sensitization and static mechanical hyperalgesia or dynamic the vast majority of CRPS patients have autonomic abnormalities,
mechanical allodynia to central sensitization.11 In generalized particularly involving sweating and skin temperature.26 However,
polyneuropathies, when all quantitative sensory thresholds are ele- there are patients with identical focal pain, but no clinical evidence
vated, it is inferred that all fiber types are affected, whereas if a of autonomic dysfunction. These patients do not meet the current
dissociation exists wherein vibration thresholds are normal but definition of CRPS and their condition has been termed ‘‘post-
the other thresholds are elevated, a small fiber neuropathy is sus- traumatic neuralgia.’’27 Their autonomic functions have not been
pected. In asymptomatic patients, abnormal QST thresholds suggest well studied.
subclinical nerve damage.
The quantitation of an individual patient’s sensory perceptions,
when compared with normative values, gives a clearer distinction Skin Biopsy
between normal and abnormal responses and allows for analyses
across patient and disease groups and for baseline standards in Since the mid 1990s, the histologic analysis of unmyelinated
longitudinal studies. Further, certain patterns of QST data may cutaneous axons has grown in importance in the diagnosis of
have pathophysiologic significance. In two patients with posther- peripheral nerve disorders, both generalized and focal, including
petic neuralgia and similar levels of chronic pain, the QST results those associated with neuropathic pain. When a skin punch
suggested peripheral and central sensitization (heat hyperalgesia, biopsy is exposed to certain antibodies—most frequently, protein
mechanical hyperalgesia to pinprick and blunt stimuli, allodynia gene product (PGP) 9.5—epidermal fibers are labeled and can be
12 Chapter 3 NEUROPATHIC PAIN: IS THE EMPEROR WEARING CLOTHES?
visualized at light-microscopic magnifications.28,29 Intraepidermal 3. In a study of IENF density in diabetic patients with and without
nerve fiber (IENF) density and morphology (e.g., tortuosity, com- bilateral symmetrical chronic neuropathic foot pain, ‘‘small fiber
plex ramifications, clustering, and axon swellings) can be quanti- dropout does not always parallel large fiber function and in fact
fied28,29 and compared with control values.30 A reduced IENF differs between people with or without pain depending upon the
density is seen in idiopathic small fiber neuropathies,31 diabetic degree of sensory loss . . .. In individuals with little objective sign
neuropathy, and impaired glucose tolerance neuropathy,32 each of of neuropathy, abnormalities of small nerve fibers are more likely
which is associated with neuropathic pain. In one study, skin biopsy to play a central role in the genesis of pain. In those with severe
findings were found to be a more sensitive measure than QSART or objective signs of neuropathy, a role of small fiber dysfunction in
QST in diagnosing neuropathy in patients with burning feet and causing pain is still possible but less certain, as there is a great
normal NCVs.33 Conversely, disorders with severe loss of pain deal of overlap in IENF [density] in those with or without
sensation such as congenital insensitivity to pain with anhidrosis pain.’’40 The authors conclude that IENF loss ‘‘cannot explain
(hereditary sensory and autonomic neuropathy IV [HSAN IV]) and pain in all cases, suggesting that different mechanisms underpin
familial dysautonomia with sensory loss (Riley-Day syndrome the genesis of pain at various stages of neuropathy.’’40
[HSAN III]) also have severe loss of intraepidermal fibers, as does 4. These same authors also report in diabetic patients that whereas
a predominantly large fiber neuropathy, Friedreich’s ataxia, in QST is useful in detecting the presence of neuropathy, and those
which pain is unusual.28,29 Thus, the loss of IENFs is not specific with neuropathic pain had greater sensory loss than those with-
for the presence of neuropathic pain. out pain, the abnormalities detected by QST do not predict the
A recent study suggests that the presence of large axonal swel- presence of pain in diabetic neuropathy. They specifically state
lings (>5 times the nerve fiber diameter) on an initial skin biopsy that whereas the cold detection threshold is a sensitive indicator
may predict progression of small fiber neuropathies, because this of neuropathy, it is not a sensitive indicator for the presence of
finding was associated with decreases in IENF densities on subse- pain, and heat perception was even less so.41
quent biopsies. Also, those patients with these large axon swellings
were more likely to present with paresthesias (tingling or pins and Along with the disparity in C-fiber subtype involvement in
needles) than with burning or ‘‘lightning’’ pains.34 diabetic small fiber neuropathy,25 these results indicate that the
Additional tests of potential diagnostic value in patients with specificity of ancillary testing and our attempts to target mechan-
neuropathic pain, particularly in focal pain syndromes such as ism-specific therapies in neuropathic pain are inadequate at present
CRPS, are bone scintigraphy, bone densitometry, and nerve or and reinforce the aforementioned caveats about inferential conclu-
sympathetic ganglion blockade. Serum immunoelectrophoresis sions from indirect data. The diagnosis of neuropathic pain
can be helpful in painful polyneuropathies associated with mono- mechanisms is in its nascent stages and ancillary testing remains
clonal gammopathies and acquired amyloid polyneuropathy. ‘‘subordinate,’’ ‘‘subsidiary,’’ ‘‘auxiliary’’ (as defined in Webster’s
Specific serum antibody tests are valuable in painful neuropathies Third New International Dictionary) to history and clinical
associated with neoplasia, celiac disease, and human immunodefi- examination.
ciency virus.35 Cruccu and associates3 also noted that nociceptive Because of these difficulties and the lack of a diagnostic ‘‘gold
reflex testing, laser-evoked potentials, and functional neuroimaging standard,’’4244 there has been renewed interest in patient symptoms
may be helpful in assessing function in nociceptive pathways but and signs with the intent of establishing clinical parameters indicative
are not widely used at this time. The latter two technologies may of neuropathic pain. Several questionnaires and scales have been
have great value in the future. developed,4,12,4248 each using descriptors of the types discussed in
the ‘‘History’’ section, earlier, and based on several premises:
1. Determination of which chronic pain patients have neuropathic
DISCUSSION pain is predicated upon observer interpretation of evidence of
nervous system injury, for example, ‘‘The clinical diagnosis was
Determining the causes of neuropathic pain is more than an epis-
classified by the . . . clinician as nociceptive or neuropathic pain
temologic exercise. At its essence, it is a quest to identify mechan-
based on clinical features, known pathology and radiological or
isms of dysfunction through which treatment strategies can be
electrophysiological evidence’’12; ‘‘suspicion of neuropathic pain
created to reduce, ameliorate, or eliminate symptomatology. To
(by the referring physician)’’43; ‘‘pain . . . which could be clearly
date, predictors of which patients will develop neuropathic pain
attributed to a peripheral or central nervous system injury . . .
or who will respond to specific therapies are lacking, and present
based on medical history, physical examination and electromyo-
therapies have been developed mainly through trial and error.36
graphy, laboratory tests and/or imaging when indicated.’’46,47
Our current inability to make therapeutically meaningful decisions
2. There is a relationship between nervous system damage or dys-
based on ancillary test data and defined mechanisms is illustrated by
function and a special (neuropathic) pain with unique features.
the following:
In these conditions, the clinical features are not attributable to
1. In assessing the response of patients with painful distal sensory other etiologies.
neuropathies to the 5% lidocaine patch, no relationship could be 3. The questionnaires and scales have the potential to isolate certain
established between treatment response and distal leg skin symptoms and signs, which when present indicate that the pain
biopsy, QST, or sensory nerve conduction study results.36 is neuropathic. In their absence, the pain is nonneuropathic in
From a mechanistic perspective, the hypothesis that the lidocaine origin. One immediate concern with this approach is the poten-
patch would be most effective in patients with relatively intact tial for circular reasoning—the criteria for classifying patients
epidermal innervation, whose neuropathic pain is presumed due into neuropathic or nonneuropathic pain groups include some
to ‘‘irritable nociceptors,’’ and least effective in patients with few of the outcome variables,43 thereby making the results self-ful-
surviving epidermal nociceptors, presumably with ‘‘deafferen- filling and logically inconsistent.
tation pain,’’ was unproved.36 The results obviously vary from study to study, but one clear
2. In Fabry’s disease, in which small fibers are exclusively affected,37 finding is that no single or group of pain descriptors was dispositive
enzyme replacement therapy failed to influence IENF density, for neuropathic pain. At its best, in the Bennett and colleagues’
had mixed effects on cold and warm QST thresholds, and had studies,12,44,48 this approach attained 75% to 82% success in correctly
beneficial effects on sudomotor findings.38,39 This occurred in classifying pain type (sensitivity and specificity), with other studies
the presence of clinical improvement as manifested in modest reporting less than 73% accuracy.42,43,4547 Even in the best-
reductions in pain scores and in pain interference in daily life.39 results studies,12,44,48 individual descriptors thought specific for
neuropathic pain (e.g., hot-burning, stabbing-shooting sensations) 5. Horowitz SH. Venipuncture-induced neuropathic pain: the clinical
occurred in only 60% to 85% of definite neuropathic pain patients, syndrome, with comparison to experimental nerve injury models.
and some of these same descriptors were seen in up to one third Pain 2001;94;225229.
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2003;97:785790.
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7. Klein T, Magerl W, Rolke R, Treede R-D. Human surrogate models
‘‘the overall picture is that there are surprisingly few clusters of neuropathic pain. Pain 2005;115:227233.
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11. Rolke R, Baron R, Maier C, et al. Quantitative sensory testing in the
any existing tool that relies on assessment of clinical features.’’44 German Research Network on Neuropathic Pain (DFNS):
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and his colleagues48 hypothesized (and provided data in support) 12. Bennett M. The LANSS Pain Scale: the Leeds assessment of
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15. Daousi C, MacFarlane IA, Woodward A, et al. Chronic painful
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position to extrapolate and make a safe bridging between clinical 23. Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in
phenomenology and pathophysiological mechanisms in animals. painful neuropathy. Neurology 2001;56:861868.
Therefore, a detailed mechanism-based classification is currently 24. Low VA, Sandroni P, Fealey RD, Low PA. Detection of small-fiber
not feasible.’’ I agree. We have moved from the point at which neuropathy by sudomotor testing. Muscle Nerve 2006;34:5761.
we separated neuropathic pain from other types of pain by recog- 25. Berghoff M, Kilo S, Hilz MJ, Freeman R. Differential impairment of
nizing similarities in the pain of patients with varied neurologic the sudomotor and nociceptor axon-reflex in diabetic peripheral
conditions, to realizing that neuropathic pain is, itself, highly het- neuropathy. Muscle Nerve 2006;33:494499.
erogeneous46,47 and multifactorial. Now, it may be beneficial to 26. Chelimsky TC, Low PA, Naessens JM, et al. Value of autonomic testing
in reflex sympathetic dystrophy. Mayo Clin Proc 1995;70:10291040.
abandon the concept of neuropathic pain as a single entity. The 27. Wasner G, Schattschneider J, Binder A, Baron R. Complex regional
situation resembles that of Hans Christian Andersen’s metaphorical pain syndrome—diagnostic, mechanisms, CNS involvement and
child who, when watching the emperor’s processional, revealed therapy. Spinal Cord 2003;41:6175.
what all could see but none would admit. 28. Kennedy WR. Opportunities afforded by the study of unmyelinated
nerves in skin and other organs. Muscle Nerve 2004;29:756767.
29. Kennedy WR, Wendelschafer-Crabb G, Polydefkis M, McArthur JC.
REFERENCES Pathology and quantitation of cutaneous innervation. In Dyck PJ,
Thomas PK (eds): Peripheral Neuropathy, 4th ed. Philadelphia:
1. Woolf CJ. Pain: moving from symptom control toward mechanism- Elsevier Saunders, 2005; pp 869895.
specific pharmacologic management. Ann Intern Med 2004;140:441451. 30. Umapathi T, Tan WL, Tan NCK, Chan YH. Determinants of
2. Merskey H, Bogduk N. Classification of chronic pain: descriptions of epidermal nerve fiber density in normal individuals. Muscle Nerve
chronic pain syndromes and definitions of pain terms. In Merskey H, 2006;33:742746.
Bogduk N (eds): Task Force on Taxonomy of the International 31. Holland NR, Stocks A, Hauer P, et al. Intraepidermal nerve fiber
Association for the Study of Pain. Seattle: IASP Press, 1994. density in patients with painful sensory neuropathy. Neurology
3. Cruccu G, Anand P, Attal N, et al. EFNS guidelines on neuropathic 1997;48:708711.
pain assessment. Eur J Neurol 2004;11:153162. 32. Polydefkis M, Griffin JW, McArthur J. New insights into diabetic
4. Galer BS, Jensen MP. Development and preliminary validation of a polyneuropathy. JAMA 2003;290:13711376.
pain measure specific to neuropathic pain: The Neuropathic Pain Scale. 33. Periquet MI, Novak V, Callino MP, et al. Painful sensory neuropathy:
Neurology 1997;48:332338. prospective evaluation using skin biopsy. Neurology 1999;53:16411647.
14 Chapter 4 ASSESSMENT OF PAIN IN OLDER ADULTS
34. Gibbons CH, Griffin JW, Polydefkis M, et al. The utility of skin 42. Krause SJ, Backonja M-M. Development of a neuropathic pain
biopsy for prediction of suspected small fiber neuropathy. Neurology questionnaire. Clin J Pain 2003;19:306314.
2006;66:256258. 43. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs
35. Mendell JR, Sahenk Z. Painful sensory neuropathy. N Engl J Med in patients with suspected neuropathic pain. Pain 2004;110:461469.
2003;348:12431255. 44. Bennett MI, Smith BH, Torrance N, Potter J. The S-LANSS score for
36. Herrmann DN, Pannoni V, Barbano RL, et al. Skin biopsy and identifying pain of predominantly neuropathic origin: validation for
quantitative sensory testing do not predict response to lidocaine patch use in clinical and postal research. J Pain 2005;6:149158.
in painful neuropathies. Muscle Nerve 2006;33:4248. 45. Backonja M-M, Krause SJ. Neuropathic pain questionnaire—short
37. Scott LJC, Griffin JW, Luciano C, et al. Quantitative analysis of form. Clin J Pain 2003;19:315316.
epidermal innervation in Fabry disease. Neurology 1999;52:12491254. 46. Bouhassira D, Attal N, Fermanian J, et al. Development and
38. Schiffmann R, Hauer P, Freeman B, et al. Enzyme replacement validation of the Neuropathic Pain Symptom Inventory. Pain
therapy and intraepidermal innervation density in Fabry disease. 2004;108:248257.
Muscle Nerve 2006;34:5356. 47. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain
39. Schiffmann R, Floeter MK, Dambrosia JM, et al. Enzyme replacement syndromes associated with nervous or somatic lesions and
therapy improves peripheral nerve and sweat function in Fabry development of a new neuropathic pain diagnostic questionnaire
disease. Muscle Nerve 2003;28:703710. (DN4). Pain 2005;114:2936.
40. Sorensen L, Molyneaux L, Yue DK. The relationship among pain, 48. Bennett MI, Smith BH, Torrance N, Lee AJ. Can pain be more or less
sensory loss, and small nerve fibers in diabetes. Diabetes Care neuropathic? Comparison of symptom assessment tools with ratings
2006;29:883887. of certainty by clinicians. Pain 2006;122:289294.
41. Sorensen L, Molyneaux L, Yue DK. The level of small nerve fiber 49. Attal N, Bouhassira D. Can pain be more or less neuropathic? Pain
dysfunction does not predict pain in diabetic neuropathy; a study 2004;110:510511.
using quantitative sensory testing. Clin J Pain 2006;22:261265.
Chapter 4 the older adults reside in a nursing home, 45% to 80%1,2 or are
community dwelling. The range reported for community-dwelling
ASSESSMENT OF PAIN IN elders is 25% to 50%.3,4 Pain continues to be an under-assessed and
under-treated condition in this population.5,6
OLDER ADULTS Lack of familiarity of common age-related changes and common
painful conditions among the elderly may contribute to the under-
recognition of the problem. Many times, diagnostic imaging studies
Patricia Bruckenthal
are poorly correlated with the clinical expressions of pain. This
may lead to confusion on the part of the examining clinician and
the potential for undervaluing the self-report of the patient and
poor treatment planning. A list of pain syndromes common in
older adults is presented in Box 41.
INTRODUCTION Musculoskeletal pain is one of the most common types of
pain experienced by community-dwelling older adults.79 The
Older adults often have multiple comorbidities that affect the pain underlying disorders responsible for chronic low back pain
presentation. Whereas the goals of a clinical assessment for pain in (CLBP) are varied and require specific physical examination
the older adult may be similar to those established for younger techniques. For example, of 111 older adults with CLBP, 84%
patients, certain characteristics of aging make this assessment reported sacroiliac joint pain, 19% reported pain consistent
more challenging for clinicians. These characteristics include reluc- with fibromyalgia, 96% myofacial pain, and 48% hip pain.10
tance of older individuals to report pain, the assumption that pain Rheumatic diseases, characterized by inflammation, degeneration,
is a normal part of aging, sensory and cognitive impairments, and or metabolic disorders, are the most common diseases reported
fear of the consequences of acknowledging pain, such as expensive by older adults residing in long-term care (LTC) facilities.11
testing or hospitalization. The pain experience can influence mood, Specific examination techniques for musculoskeletal disorders
physical functioning, and social interactions and indicates that pain are discussed later.
assessment in older adults is multidimensional and often a multi- Functional, cognitive, emotional, and societal consequences
disciplinary responsibility. have been associated with unrelieved pain in older adults.
The purpose of this chapter is to provide the clinician with the Decreased activity due to pain can lead to myofacial decondition-
foundation to perform a successful pain assessment for older adults ing and gait disturbances, which in turn, can result in injuries from
who are able to communicate by self-report. This will provide a falls. Appetite impairment has been reported in community-
comprehensive base on which to build a relevant plan of care. Pain dwelling adults with pain intensity scores higher than in those
assessment for those with cognitive impairment is the focus of without appetite impairment.12 Pain in the elderly has been asso-
Section II, Chapter 5, Assessment of Pain in the Nonverbal and/ ciated with increased sleep disturbances.13 These consequences can
or Cognitively Impaired Older Adult. lead to less than optimal participation in rehabilitation efforts
and decreased quality of life in general. Increased costs due to
health care utilization have also been implicated as a result of
PREVALENCE OF PAIN INOLDER unrelieved pain in the elderly.14 Consideration of the unique char-
ADULTS acteristics included in the history and physical assessment for pain
in older adults will assist clinicians in the development and imple-
Prevalence statistics for persistent pain in older adults range from mentation of an individualized treatment plan that will optimize
25% to 80%. Pain prevalence reports vary depending on whether successful outcomes.
34. Gibbons CH, Griffin JW, Polydefkis M, et al. The utility of skin 42. Krause SJ, Backonja M-M. Development of a neuropathic pain
biopsy for prediction of suspected small fiber neuropathy. Neurology questionnaire. Clin J Pain 2003;19:306314.
2006;66:256258. 43. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs
35. Mendell JR, Sahenk Z. Painful sensory neuropathy. N Engl J Med in patients with suspected neuropathic pain. Pain 2004;110:461469.
2003;348:12431255. 44. Bennett MI, Smith BH, Torrance N, Potter J. The S-LANSS score for
36. Herrmann DN, Pannoni V, Barbano RL, et al. Skin biopsy and identifying pain of predominantly neuropathic origin: validation for
quantitative sensory testing do not predict response to lidocaine patch use in clinical and postal research. J Pain 2005;6:149158.
in painful neuropathies. Muscle Nerve 2006;33:4248. 45. Backonja M-M, Krause SJ. Neuropathic pain questionnaire—short
37. Scott LJC, Griffin JW, Luciano C, et al. Quantitative analysis of form. Clin J Pain 2003;19:315316.
epidermal innervation in Fabry disease. Neurology 1999;52:12491254. 46. Bouhassira D, Attal N, Fermanian J, et al. Development and
38. Schiffmann R, Hauer P, Freeman B, et al. Enzyme replacement validation of the Neuropathic Pain Symptom Inventory. Pain
therapy and intraepidermal innervation density in Fabry disease. 2004;108:248257.
Muscle Nerve 2006;34:5356. 47. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain
39. Schiffmann R, Floeter MK, Dambrosia JM, et al. Enzyme replacement syndromes associated with nervous or somatic lesions and
therapy improves peripheral nerve and sweat function in Fabry development of a new neuropathic pain diagnostic questionnaire
disease. Muscle Nerve 2003;28:703710. (DN4). Pain 2005;114:2936.
40. Sorensen L, Molyneaux L, Yue DK. The relationship among pain, 48. Bennett MI, Smith BH, Torrance N, Lee AJ. Can pain be more or less
sensory loss, and small nerve fibers in diabetes. Diabetes Care neuropathic? Comparison of symptom assessment tools with ratings
2006;29:883887. of certainty by clinicians. Pain 2006;122:289294.
41. Sorensen L, Molyneaux L, Yue DK. The level of small nerve fiber 49. Attal N, Bouhassira D. Can pain be more or less neuropathic? Pain
dysfunction does not predict pain in diabetic neuropathy; a study 2004;110:510511.
using quantitative sensory testing. Clin J Pain 2006;22:261265.
Chapter 4 the older adults reside in a nursing home, 45% to 80%1,2 or are
community dwelling. The range reported for community-dwelling
ASSESSMENT OF PAIN IN elders is 25% to 50%.3,4 Pain continues to be an under-assessed and
under-treated condition in this population.5,6
OLDER ADULTS Lack of familiarity of common age-related changes and common
painful conditions among the elderly may contribute to the under-
recognition of the problem. Many times, diagnostic imaging studies
Patricia Bruckenthal
are poorly correlated with the clinical expressions of pain. This
may lead to confusion on the part of the examining clinician and
the potential for undervaluing the self-report of the patient and
poor treatment planning. A list of pain syndromes common in
older adults is presented in Box 41.
INTRODUCTION Musculoskeletal pain is one of the most common types of
pain experienced by community-dwelling older adults.79 The
Older adults often have multiple comorbidities that affect the pain underlying disorders responsible for chronic low back pain
presentation. Whereas the goals of a clinical assessment for pain in (CLBP) are varied and require specific physical examination
the older adult may be similar to those established for younger techniques. For example, of 111 older adults with CLBP, 84%
patients, certain characteristics of aging make this assessment reported sacroiliac joint pain, 19% reported pain consistent
more challenging for clinicians. These characteristics include reluc- with fibromyalgia, 96% myofacial pain, and 48% hip pain.10
tance of older individuals to report pain, the assumption that pain Rheumatic diseases, characterized by inflammation, degeneration,
is a normal part of aging, sensory and cognitive impairments, and or metabolic disorders, are the most common diseases reported
fear of the consequences of acknowledging pain, such as expensive by older adults residing in long-term care (LTC) facilities.11
testing or hospitalization. The pain experience can influence mood, Specific examination techniques for musculoskeletal disorders
physical functioning, and social interactions and indicates that pain are discussed later.
assessment in older adults is multidimensional and often a multi- Functional, cognitive, emotional, and societal consequences
disciplinary responsibility. have been associated with unrelieved pain in older adults.
The purpose of this chapter is to provide the clinician with the Decreased activity due to pain can lead to myofacial decondition-
foundation to perform a successful pain assessment for older adults ing and gait disturbances, which in turn, can result in injuries from
who are able to communicate by self-report. This will provide a falls. Appetite impairment has been reported in community-
comprehensive base on which to build a relevant plan of care. Pain dwelling adults with pain intensity scores higher than in those
assessment for those with cognitive impairment is the focus of without appetite impairment.12 Pain in the elderly has been asso-
Section II, Chapter 5, Assessment of Pain in the Nonverbal and/ ciated with increased sleep disturbances.13 These consequences can
or Cognitively Impaired Older Adult. lead to less than optimal participation in rehabilitation efforts
and decreased quality of life in general. Increased costs due to
health care utilization have also been implicated as a result of
PREVALENCE OF PAIN INOLDER unrelieved pain in the elderly.14 Consideration of the unique char-
ADULTS acteristics included in the history and physical assessment for pain
in older adults will assist clinicians in the development and imple-
Prevalence statistics for persistent pain in older adults range from mentation of an individualized treatment plan that will optimize
25% to 80%. Pain prevalence reports vary depending on whether successful outcomes.
Box 41 CURRENT PAIN SYNDROMES IN OLDER ADULTS Present Pain Complaint
Assessment of the pain characteristics includes a detailed descrip-
Musculoskeletal Conditions tion of the onset, duration, frequency, intensity, location, and
Osteoarthritis
Degenerative disk disease contributing factors. For a variety of reasons, older adults may
Osteoporosis and fractures not be forthcoming regarding reports of pain. They also may use
Gout descriptions other than pain to describe what they are experiencing.
It is common for older adults to use terms such as ‘‘aching,’’
Neuropathic Conditions
Diabetic neuropathy
‘‘soreness,’’ ‘‘hurting,’’ ‘‘discomfort,’’20,21 or other descriptors.
Postherpetic neuralgia The onset and timing are important considerations. Wheras
Trigeminal neuralgia degenerative musculoskeletal disorders generally have an insidious
Central poststroke pain onset, a change in character from a less severe to a more intense pain
Radicular pain secondary to degenerative disease of the spine may indicate a progression of disease or a new-onset fracture. Pain
Rheumatologic Conditions that is more intense in the morning is a feature of cancerous bone
Rheumatoid arthritis pain. Tools to evaluate pain intensity specific to the geriatric popu-
Polymyalgia rheumatica lation have been identified and are outlined later. Older persons are
Fibromyalgia able to utilize a body pain map or diagram to indicate the location(s)
of their pain.22,23 Sometimes, the pain, although not present during
Adapted from HadjistavropoulosT, Herr K, Turk DC, et al. An interdisciplinary expert consensus
statement on assessment of pain in older persons. Clin J Pain 2007;23(1 suppl):S1S43; and rest, will manifest itself during activities and, therefore, this too
Hanks-Bell, et al, 2004. should be explored with the patient. A useful structured interview
technique that will elicit information on the present pain complaint
for older adults who can communicate is suggested in Box 42.
Associated symptoms, such as paresthesias, may indicate radicular
involvement of an extremity in pain. Fever or weight loss may her-
ald more ominous diagnoses including infection or malignancy.
ELEMENTS OF A COMPREHENSIVE
ASSESSMENT
Past Medical History
A comprehensive, multidimensional pain assessment in older
adults will ultimately lead to a more successful individualized This review should include a history of past medical, surgical, and
plan of care. Regardless of whether the pain is acute, postoperative, psychiatric conditions, as well as accidents/injuries. Dates of onset,
or chronic, the goal of the assessment is to identify the cause of current and past treatments, and treating practitioners should be
pain, conduct a thorough history of comorbid medical and obtained. Eliciting this information is important for several reasons.
psychosocial conditions, and perform an appropriate physical The existence of certain comorbid conditions will affect treatment
examination and diagnostic work-up. Often, a multidisciplinary decisions for pain. For example, nonsteroidal anti-inflammatory
approach may be needed, and after the initial assessment, the agents may be of limited use in those with a history of heart disease
clinician may determine that referral to an appropriate specialist or hypertension. Patients with liver disease will need to use aceta-
is necessary for specialized services or skilled procedures. For minophen cautiously. Preexisting renal disease will affect the use of
example, a mental health professional may be able to optimize a medications as well. Identification and documentation of preexist-
plan to treat depression or a substance abuse disorder or a physical ing conditions will facilitate treatment planning.
therapist may be consulted for evaluation of a conditioning
program. A review of existing medical records is also beneficial
to the assessment process.
Box 42 ASSESSMENT OF BRIEF PAIN IMPACT FOR VERBAL
PATIENTS
History of the Pain Complaint 1. How strong is your pain (right now, worst/average over past week)?
2. How many days over the past week have you been unable to do what
Several elements are recognized as essential for a comprehensive you would like to do because of your pain?
assessment of pain at any age. One such schema recommended 3. Over the past week, how often has pain interfered with your ability
for guiding a comprehensive pain assessment in older adults is to take care of yourself, for example with bathing, eating, dressing,
outlined in detail in the Initiative on Methods, Measurement, and and going to the toilet?
Pain Assessment in Clinical Trials (IMMPACT) project.1518 4. Over the past week, how often has pain interfered with your ability
Included in this review are necessary elements such as nuances to take care of your home-related chores such as going grocery
specific to older adults to assist the clinician in the assessment shopping, preparing meals, paying bills, and driving?
process. Techniques for assessing these age-specific elements are 5. How often do you participate in pleasurable activities such as hob-
bies, socializing with friends, and travel? Over the past week, how
described later. often has pain interfered with these activities?
Self-report of pain is still considered the most reliable source 6. How often do you do some sort of exercise? Over the past week,
for the cognitively intact and communicative older adult’s pain how often has pain interfered with your ability to exercise?
complaint.19 Sensory deficits in vision, hearing, and cognition are 7. Does pain interfere with your ability to think clearly?
common in this population and need to be identified prior 8. Does pain interfere with your appetite? Have you lost weight?
to beginning the interview. These may affect the patient’s ability 9. Does pain interfere with your sleep? How often over the past week?
to complete the assessment process, and adjustments to accom- 10. Has pain interfered with your energy, mood, personality, or relation-
modate for deficits need to be considered. This may become ship with other people?
especially relevant when selecting appropriate pain assessment 11. Over the past week, how often have you taken pain medications?
12. How would you rate your health at the present time?
instruments. It also may be beneficial to query other family
members or caregivers for additional perspectives on medical Reprinted with permission from Weiner D, Herr K. Comprehensive interdisciplinary assessment
and treatment planning: an integrative overview. In Weiner D, Herr K, Rudy T (eds): Persistent
history, predominant mood and affect, and physical and social Pain in Older Adults: An Interdisciplinary Guide forTreatment.NewYork: Springer, 2002; pp1857.
functioning.
Knowledge of the pattern of certain preexisting conditions can Depressive disorders are prevalent in people with chronic
also help with anticipatory planning. Sensory distal polyneuropathy pain.13,2931 Patients who are depressed may exhibit decreased
is the most common neurologic presentation in patients with dia- energy and engagement in treatment modalities or avoidance of
betes mellitus. Although most polyneuropathies are painless, 7.5% pleasant diversional activities. The Geriatric Depression Scale
of patients report unpleasant sensations of pain.24 Clinicians should (GDS)32 is one instrument that can be used to determine whether
be alert to evolving sensory complaints in diabetic patients, espe- further evaluation for depression is indicated. This instrument is of
cially those with poor glycemic control. Musculoskeletal disorders particular benefit in residential care elders, whereas the Center for
that have changed in presentation may signal progression of disease Epidemiological Studies Depression Scale (CESD)33,34 is more
and may require more intense investigation. Finally, results of any suited for community-dwelling elders.35
previous laboratory and diagnostic tests should be reviewed not Anxiety has also been closely associated with pain36,37 and often
only to guide future treatment decisions but also to avoid unnec- coexists with depression in this population. Anxiety may play a
essary repeat testing. part in fear-related behavior that might inhibit participation in
physical rehabilitation efforts. It may be useful for the clinician
under these circumstances to evaluate this disorder in more
Medication History detail. The Beck Anxiety Inventory38 is a brief screening tool that
has been used in the elderly for evaluating anxiety symptoms.
A careful medication history must be inclusive of all current and A distinction can be made between a situational anxiety response
past medications, dosages, side effects, and response. This consists and the more enduring personality anxiety trait, and these can be
of prescribed, over-the-counter, and herbal supplements. Alcohol evaluated using the State-Trait Anxiety Inventory.39 While eliciting
use should be specific to frequency and amount. Tobacco products trait versus state anxiety traits, it may be noted that in pain patients,
and illicit drug use are important elements of inquiry as well. It is the relationship between transient and enduring emotional
important to obtain the name and phone number of the current responses to pain and outcomes to treatment intervention need
pharmacy(ies) used. to be further explored. Emotional responses of depression and anxi-
ety, however, do have an impact on the overall pain experience and
are essential to the overall assessment.
Functional Assessment Assessment of the social support network and economic sta-
tus for older people in pain is important on several levels.
Essential elements of a functional assessment are broad and include Involvement with family and friends can provide pleasurable
cognitive, physical, and psychosocial dimensions. Data from these experiences and diversion away from a constant focus on pain.
aspects of the assessment establish a baseline to enable the clinician Supportive social contacts can provide transportation to clinic
to determine specific goals, the extent to which the patient can and treatment appointments. Osteoarthritis patients who partici-
participate, and response to the treatment plan. pated in spouse-assisted pain-coping skills training had a greater
Cognition is grossly assessed during the process of the health inter- reduction on pain and disability outcomes that those who partici-
view. Some areas of cognitive decline, such as fluid reasoning, proc- pated in conventional nonspousal participant training.40 In addi-
essing speed, and short-term memory, are part of the normal aging tion to the availability of social support, the type of relationship
process.25,26 Factors other than dementia that should be considered should be assessed. Negative social reinforcement may present in
as causative in cognitive decline include poor nutritional status, med- the form of overly solicitous family members who encourage
ication effect, depression, living environment,25 and pain.27 The sedentary behavior. Other negative effects are likely if long-term
Mini-Mental State Examination (MMSE)28 can be used to assess caregivers become resentful of their support role. Finally, economic
cognition, but it may not be able to pick up subtle changes. A more resources have a great impact on access to potential treatment
complete discussion on pain assessment in the cognitively impaired options and must be identified.
adult is addressed in detail in Section II, Chapter 5, Assessment of
Pain in the Nonverbal and/or Cognitively Impaired Older Adult.
Physical function incorporates the assessment of mobility, activ- Beliefs and Attitudes about Pain
ities of daily living (ADLs), sleep pattern, and appetite. The clinician
should ascertain the current level of physical activity and mobility The context in which older adults perceive pain is relevant to the
the patient is capable of. This includes an assessment of the level overall assessment. Pain can signify loss of independence or debil-
at which basic ADLs are being performed. It is helpful to identify itating illness or be regarded as a general consequence of the aging
activities previously preformed that the pain prohibits the patient process and therefore be underreported. Better treatment satisfac-
from doing currently. Ask if the patient engages in a regular exercise tion and outcomes are reported when there is greater agreement
program. These assessment parameters should establish the baseline between patient beliefs about the nature and treatment of pain and
of current physical function. the treatment received.41
Questions regarding sleep patterns are asked to evaluate whether Multiple constructs associated with beliefs and attitudes about
restorative sleep is being attained. Poor sleep may be the result of the pain have been studied and have an impact on the total pain expe-
aging process, depression, or pain. Identifying the cause will assist in rience and outcomes. Many of these are interrelated, such as coping,
developing an appropriate intervention for improving sleep. self-efficacy, catastrophizing, and pain-related fears. Coping and
Appetite suppression has been associated with a higher pain intensity self-efficacy are discussed later.
level in community-dwelling adults.12 Poor nutrition can contribute Two simplistic models of coping have been described as active
to fatigue and diminished function and well-being. By reviewing all versus passive4244 and adaptive versus maladaptive coping.45,46
the pertinent aspects of function, the clinician and patient can begin Patients use a variety of coping skills for managing pain. For
to establish realistic treatment goals in this domain. example, task persistence, activity pacing, and use of coping self-
statements were coping strategies most frequently used by a group
of predominantly female older adults living in retirement facil-
Psychosocial Assessment
ities.47 Prayer is often utilized by older adult women as a coping
Mood, social support systems, recreational involvement, and finan- mechanism for pain.48 Identifying coping skills among the elderly
cial resources are important to the psychosocial assessment. These is important so that the clinician can encourage the use of pre-
factors all influence the pain experience and how the patient in pain viously successful skills or modify treatment interventions to incor-
functions in these domains as well as responds to various treatments. porate teaching effective coping skills. Patients with passive or
maladaptive coping styles would likely benefit from psychological of motion of the cervical spine, lumbar spine, and hip, the quality,
interventions49 that would focus on more effective ways of coping. quantity, and elicitation of pain should be noted.
Self-efficacy refers to the belief that one can control or manage Specific examination maneuvers can offer clues to the etiology
certain outcomes of one’s life.50,51 Beliefs about the degree of con- of the pain complaint. Straight leg raising, Lasègue’s sign, is indic-
trol and self-efficacy in being able to manage pain have been well ative of nerve root compression. Crossed straight leg raising,
studied52,53 and are related to types of coping strategies used to exacerbation of leg pain when the contralateral leg is raised, may
manage pain.54 Participation in cognitive-behavioral pain-coping suggest lumbar disk herniation. Fabere maneuvers (Patrick’s test)
skills interventions can increase self-efficacy beliefs and have been include flexion, extension, abduction, and external rotation of the
shown to decrease pain intensity, disability, and depression.40,5557 hip. Pain during these movements is suggestive of degenerative joint
Patients who are identified as having poor beliefs regarding their disease of the hip, but it may also occur with sacroiliac pathology.
ability to manage pain may benefit from coping skills training Pain radiating down the arm produced by lateral tilt or rotation of
aimed at increasing self-efficacy. Examples of instruments that mea- the head (Spurling’s sign) in patients complaining of neck pain may
sure one’s perceived ability to manage pain are listed in Table 41. indicate cervical nerve root compression. Lhermitte’s sign is an
electric shocklike sensation in the torso or extremities associated
with cervical flexion and may be suggestive of a cervical cord
Pain Assessment Measurement Instruments lesion.62
An abundance of reliable and valid instruments are available to

Mobility/Balance
assist in the assessment of pain. The choice of which to use will
depend on factors including purpose of the tool, clinical setting, and Pain is a contributing factor of mobility impairment and falls in the
time constraints. Some instruments measure a single pain construct elderly and warrants an assessment of gait and balance. Gait changes
whereas others are multidimensional. Clinicians are encouraged to associated with aging include decreased step length, walking speed,
find instruments that are useful to their clinical needs and encom- ankle range of motion, and the ability to push-off with the toes. The
pass the broad pain assessment domains covered in this chapter. ability to rise unassisted from a seated position to standing, timed
Table 41 represents a sample of pain assessment instruments and averaged for 5 repetitions,63 and the timed ‘‘up and go’’ test64
that were extrapolated from reviews by Hadjistavropoulos and are simple, quick measures of basic functional mobility.
coworkers,18 Gibson and Weiner,58 and Herr and Garand.59 Many
of these are self-assessment/self-report instruments and can be
Neurologic
administered prior to the history and examination portion of the
pain assessment and reviewed by the clinician with the patient. When conducting a focused neurologic examination, strength, sen-
The choice of tools can be overwhelming. As a pragmatic yet com- sation, and deep tendon reflexes are assessed. In general, a sensory
prehensive approach, Hadjistavropoulos and coworkers18 recom- dermatomal level usually correlates with the anatomic level of the
mended the administration of the Brief Pain Inventory (BPI)60 lesion. Hyperalgesia, hyperpathia, and hypoesthesia can be tested by
and the Short-Form McGill Pain Questionnaire (SF-MPQ)61 as pinprick. Allodynia is tested using a cotton swab or paintbrush.
suitable for most cognitively intact older adults. These cover the Hyporeflexia may indicate nerve root compression whereas hyper-
multidimensional nature of the pain assessment and can be com- reflexia may be indicative of myelopathy from spinal cord compres-
pleted in approximately 10 minutes. Instruments that measure pain sion. Decreased vibratory sensation and hyporeflexia are signs
in cognitively impaired elders are covered in Section II, Chapter 5, consistent with peripheral neuropathy.
Assessment of Pain in the Nonverbal and/or Cognitively Impaired The physical assessment is important to help confirm etiology
Older Adult. and identify level of impairment, to determine level of function, and
to elicit emergent conditions in the older population. Ongoing
physical assessment continues to be imperative in order to evaluate
Physical Assessment the effectiveness of treatment, exacerbation of identified conditions,
or the emergence of new problems that need attention. Therefore, a
General follow-up physical examination guided by the medical history
should take place at each subsequent visit.
The focus of the physical assessment will vary depending on whether
the pain complaint is acute or chronic. In general, inflammation,
traumatic injury, and cancer-related conditions are associated with
acute pain, whereas neurologic and musculoskeletal etiologies cause ASSESSMENT CONSIDERATIONS FOR
more chronic pain conditions. This section focuses on the latter SPECIFIC PAINFUL CONDITIONS
assessment and suggestions for the former are included in the dis-
cussion of assessment of specific painful conditions. All patients Trigeminal Neuralgia
should have a brief examination of general health status, including
vision and hearing, cardiovascular, respiratory, and gastrointestinal Trigeminal neuralgia is characterized by severe, unilateral facial pain
systems, prior to the more focused examination. described as lancinating, electric shocklike jolts in one or more
When the painful region is examined, inspection is focused on distributions of the trigeminal nerve. The maxillary and mandibular
signs of inflammation, trophic changes, joint deformity, and vascu- divisions are most commonly affected. The causes vary by age. In
lar signs such as paleness, cyanosis, or mottled appearance. the elderly, compression of the trigeminal root by an artery or vein
or both is the cause about 80% of the time. Intracranial tumors and
demyelinating disease have also been implicated. The characteristic
Musculoskeletal Examination
jabs of pain last from 2 to 120 seconds and are often precipitated by
Assessment of the musculoskeletal system focuses on inspection of activities such as brushing, chewing, or talking. The paroxysms of
any joint deformities and disuse signs such as asymmetry of mus- pain are separated by pain-free intervals. Because there are no
cular bulk and tone. Note any spinal deformity including kyphosis, cranial nerve deficits, the diagnosis of tumor may be delayed.
lordosis, or scoliosis. Palpation includes the spinous processes and Careful clinical evaluation and magnetic resonance imaging
paraspinal muscles, sacroiliac joint, piriformis, or the fibromyalgia (MRI) are recommended for all patients presenting with trigeminal
tender points for more generalized pain complaints. During range neuralgia.65
Table 4^1. Selected Instruments for Pain Assessment in Older Adults
18
Chapter 4 ASSESSMENT OF PAIN IN OLDER ADULTS
Psychometrics Established
Domain Instrument Instrument Characteristics by Setting Comments
Pain intensity Numerical rating scale Available in a variety of scale ranges including Acute care Preferred by many older adults
(NRS) 05, 010, 020, and 0100. Subacute care Verbal version may be difficult for elders with
Pain clinic cognitive impairment
Long-term care (LTC) Vertical orientation of scale easier to use for elders
Assisted living
Community dwelling
Verbal descriptor scale Available in a variety of scale types including Acute care Most preferred by older adults
(VDS) 5-Point Verbal Rating Scale Subacute care Requires abstract thought
Pain Thermometer77 Pain clinic Thermometer adaptation may assist with tool
Present Pain Inventory (PPI)78 LTC understanding80
Graphic Rating Scale79 Assisted living
Community dwelling
Pictorial Pain Scales Facial pain scales tested in older adults: Acute care Preferred by many older adults
Faces Pain Scale (FPS)81 Subacute care Validated in white, African American, and Spanish
Wong-Baker FACES Scale82 Pain clinic Does not require language
LTC Requires abstract thinking
Assisted living
Community dwelling
Multidimensional Short-Form McGill 15 Pain quality words rated on a Likert scale, Community dwelling Measures sensory and affective dimensions
pain assessment Pain Questionnaire plus a visual analog scale (VAS) of pain Pain clinic Not recommended for illiterate or cognitively
(SF-MPQ)61 intensity, plus a PPI Acute care impaired
Brief Pain Inventory 11-Item instrument that gathers information Multiple settings including Measures intensity and pain interference
(BPI)60 on pain severity and level of pain interference cancer, chronic pain Does not measure quality or affective dimensions
on seven key aspects of function conditions, postoperative of pain
pain, and older adults Available in over 30 languages
Pain Disability Index Seven items using 11-point scale to measure Community dwelling Measures pain-related disability
(PDI)83 perceived pain interference with the Chronic pain Short and easy to use
performance of seven areas of daily function Needs further study for utility in outcomes measures
Geriatric Pain Measure 24-item questionnaire measuring five clusters Ambulatory geriatric clinic Measures intensity, interference, disengagement,
(GPM)84 of components: Pain Intensity, Disengagement, and pain with activity
Pain with Ambulation, Pain with Strenuous Limited evaluation data
Activities, and Pain with Other Activities
Multidimensional Pain 61 Items, made up of 13 subscales across three Multiple settings Measures pain intensity, interference, significant
Inventory (MPI)85 sections Pain clinic other support, general activity
Cross-culturally validated
Identifies adaptation styles and response to treatment
Lengthy to complete, approximately 20 min
Limited psychometric study in the elderly
Functional Pain Scale 05 Scored tool that combines pain severity and Community dwelling Measures intensity and function
(FPS)86 function and rates ability to tolerate activity Limited by indicators that measure interference based
on ability to watch TV, read, and use a telephone
Functional status Functional Status Index Two self-administered subscales: pain and Acute care Measures basic activities of daily living (ADLs) and
(FSI)87 difficulty; difficulty subscale focuses attention on Primary care instrumental ADLs
task performance rather than amount of pain Takes approximately 8 min to administer
experienced while performing the task
Physical Activity Scale88 Measures levels of physical activity in past week in Community dwelling Measures basic, instrumental, and advanced ADLs
areas of leisure, occupation, and household 8 min to complete
activities
Site-specific Oswestry Disability 10 Items measuring level of pain and interference Primary care Evaluates low back pain
disability Scale89 with physical activities, sleep, self-care, sex life, Measures basic, instrumental, and advanced ADL’s
social life, and travel 5 min to complete
Rowland Morris 24-Item instrument derived from the Sickness Includes, but not specific to, Evaluates low back pain
Disability Index77 Impact Profile in which the phrase ‘‘because of older adults Measures basic and instrumental ADLs
my back’’ was added to each statement, making it 5 min to complete
disease specific
Western Ontario And 24-Item instrument assesses pain, disability, and Includes, but not specific to, Evaluates hip and knee pain
McMaster Universities joint stiffness older adults 8 min to complete
Osteoarthritis Index
(WOMAC)90
Neck Pain and Disability 20-Item instrument designed to measure intensity Includes, but not specific to, Evaluates neck pain
Index91 of pain and interference with vocational, older adults 5 min to complete
recreational, social, and self-care activities as well
as emotions
Cognitive Cognitive Errors 48 Vignettes assessing four depression-related Adults with rheumatoid
processes; pain Questionnaire92 cognitive disorders: catastrophizing, arthritis, including, but not
specific overgeneralization, personalization, and selective specific to, older adults
abstraction; half of the vignettes use chronic pain
as the stimulus for the situation
II ASSESSMENT OF PAIN AND ITS TREAT MENT

Inventory of Negative 21 5-Point items made up of three subscales: Includes, but not specific to,
Thoughts in Response negative self-statements, negative social older adults
to Pain93 cognitions, and self-blame
Pain Attitudes 27 Items load on four factors representing stoicism Community dwelling Age-related increase in degree of reticence to pain,
Questionnaire94 (superiority, reticence) and cautiousness (self- self-doubt, and reluctance to label a sensation as
doubt, reluctance) painful was found
Pain Catastrophizing 13 Items made up of three subscales describing Not known
Scale95 catastrophizing thinking: helplessness,
rumination, and magnification
Arthritis Helplessness 5 Items tapping perceived (un)controllability of Includes, but not specific to, Helplessness correlated with greater age, lesser
Index96 arthritis symptoms older adults education, lower self-esteem, lower internal health
locus of control, higher anxiety and depression,
and impairment in performing ADLs
Arthritis Self-efficacy 20 Items measuring self-efficacy in three domains: Primary care Health outcomes and self-efficacy scores improved
Scale97 pain, function, and other symptoms Community dwelling when patients participated in the Arthritis Self-
Management Course
Affective Pain Anxiety Symptoms Multidisciplinary pain clinic
processes Scale98
19
Continued
Table 4^1. Selected Instruments for Pain Assessment in Older Adultsçcont’d
20
Chapter 4 ASSESSMENT OF PAIN IN OLDER ADULTS
Psychometrics Established
Domain Instrument Instrument Characteristics by Setting Comments
62 Items made up of four subscales: fear of pain, Includes, but not specific to, May be useful in the continued study of fear of
cognitive anxiety, somatic anxiety, escape and older adults pain and its contribution to the development and
avoidance maintenance of pain behaviors
Beck Anxiety Inventory38 21 Items answered on a 4-point scale
Tampa Scale of 17 Items addressing fears about pain Not known For older chronic pain patients, a stronger
Kinesiophobia99 and re(injury) mediating role for pain-related fear was
supported100
Items may represent catastrophic thinking rather
than fear of movement101
Survey of Activities and 11 Items, subscales include activity, restriction, fear May be able to differentiate fear of falling that
Fear of Falling in the of falling, and activity level leads to activity restriction from fear of falling that
Elderly102 accompanies activity
Geriatric Depression 30 Yes/no items; omits somatic and other Community dwelling Short form available
Scale (GDS)32 depressive symptoms possibly confounded LTC facility Performed better than the CESD in residential
with aging settings for elders
Center for 20 4-Point items Community dwelling Performed better than the GDS in community
Epidemiological Studies LTC facility dwelling elders
Depression Scale
(CESD)33
Coping skills Coping Strategies 42 Items assess seven strategies (making coping Widely used in older adults, especially those with
Questionnaire103 self-statements, ignoring pain sensations, osteoarthritis
reinterpreting pain sensations, praying/hoping,
catastrophizing, diverting attention, and
increasing activities), but various factor structures
have emerged
Chronic Pain Coping 65 Items assess behavioral coping strategies in 11 Short form available
Inventory104 domains Has been used, but not validated in older adults
Vanderbilt Pain Separate active (11 items) and passive (7 items)
Management subscales
Inventory42
Coping with Chronic 54 Items made up of six subscales: cognitive Includes, but not specific Not pain specific
Illness105,106 restructuring, emotional expression, wish- to, older adults
fulfilling fantasy, self-blame, information seeking,
and threat minimizing
Ways of Coping Scale 66 Items made up of numerous subscales and two Not pain specific
(Revised)107 higher-order factors: problem-focused and
emotion-focused coping. Revised
Adapted from Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary expert consensus statement on assessment of pain in older persons. Clin J Pain 2007;23(1
suppl):S1S43; Gibson SJ, Weiner DK. Pain in Older Persons. Seattle: IASP Press, 2005; and Herr KA, Garand L. Assessment and measurement of pain in older adults. Clin
Geriatr Med 2001;17:457478, vi.
Postherpetic Neuralgia initiated. Ongoing monitoring of the pain intensity, duration, and
effects of treatment should take place every 2 to 4 hours initially.
Postherpetic neuralgia (PHN) is a frequent complication after an Once every 8 hours is appropriate once the pain is well controlled.69
outbreak of herpes zoster in the elderly. Sensory findings include Older adults may use terms other than pain, so questions that relate
allodynia or hyperalgesia in the associated dermatomal region, the to discomfort and hurting may need to be asked.20 The patient
thoracic being more common than the facial. Patients with allodyn- should be observed during an activity such as ambulation, transfers,
ia complain of the wind or a piece of clothing causing pain. or repositioning, because behavior and pain levels may not be equal
Hyperalgesic patients describe provocation of pain by a relatively during different activities.20
mild stimulus, such as bumping up against a piece of furniture. Autonomic responses such as increased heart rate and blood
Tingling, severe itching, burning, or steady throbbing pain have pressure and altered respiratory rate are generally associated with
also been described. Pain associated with PHN can interfere with acute pain. The clinician should be cautioned that the absence of
ADLs and quality of life, and therefore, identification and interven- these signs does not indicate that pain is not present.70 In fact, no
tion are crucial.65 statistically significant differences were seen between self-reported
pain scores and heart rate, blood pressure, or respiratory rate in
adult patients presenting to an emergency department for a variety
Poststroke Pain of acute painful conditions.71 Clinicians should not rely on vital
signs as the sole indicator for the presence or degree of acute
Poststroke pain, an underrecognized consequence after stroke, pain. Patient self-report of pain remains the ‘‘gold standard.’’
occurs in 33% to 40% of patients who have had a stroke. The pain
may present as shoulder pain in the paretic limb or present as central
poststroke pain (CPSP). CPSP is characterized as pain that is severe LTC Facility
and persistent with accompanying sensory abnormalities.66,67
Pain assessment in nursing homes continues to be a challenge.
Common themes regarding pain assessment in LTC facilities per-
Metastatic Bone Pain sist. Two studies illustrate the significance of this problem.
Clark and colleagues72 conducted a qualitative study using focus
Bone pain that is worse at night, when lying down, or not associated groups in 12 nursing homes in Colorado. They identified that
with acute injury should raise suspicion of metastatic disease. Also, within nursing homes (1) there is an uncertainty in pain assess-
pains that gradually but rapidly increase in intensity or with weight ment, (2) that relationship-centered cues to residents’ pain are a
bearing or activity are suspicious. Frequent sites of metastatic pain solution to limitations of formal assessment, (3) cues to pain are
include the hip, vertebrae, femur, ribs, and skull. Examination behavioral changes and observable physical changes, and (4) specific
includes palpation of the affected site. residents’ characteristics, such as attitudes or being perceived as
‘‘difficult,’’ made pain assessment more challenging. These findings
have implications for practice. Education of staff regarding the
Temporal Arteritis complex nature of chronic pain and its psychosocial domains
may help clarify the ambiguity expressed regarding assessment.
Greater than 95% of the cases of temporal arteritis occur in patients Acknowledging the importance of family members’ and certified
over 50 years old. Presentation includes complaints of new-onset nursing assistants’ reports of behavioral and physical changes is
headache, malaise, scalp tenderness, and jaw claudication. Physical essential to the process. The use of pain assessment tools appropri-
examination reveals an indurated temporal artery that is tender ate for difficult patients or patients with communication impair-
with a diminished or absent pulse. Because irreversible blindness ment is helpful. It has been reported that the availability of various
is a consequence if untreated, timely assessment and treatment are assessment tools to suit patient preferences will increase the
essential.68 Generally, patients are started on glucocorticoids while frequency of diagnosing pain in nursing home residents.73
awaiting temporal artery biopsy. Similarly, Kaasalainen and coworkers74 found that pain assess-
ment was problematic in nursing homes and that appropriate pain
assessment strategies were closely linked to effective pain manage-
SETTING OF THE PAIN ASSESSMENT ment. Common themes emerged of negative myths about pain and
aging, inadequacy of current tools used in practice, and the inability
Much of the current literature on pain assessment and information to discriminate between pain and problems such as dementia and
provided in this chapter seem most suited for elders with chronic delirium. This lack of confidence in assessment was reflected in the
rather than acute pain. Psychosocial factors are more closely asso- ways that pain was treated.
ciated with chronic pain states and have been studied more inten- These findings suggest that engaging in a process committed to
sely. The nature of the pain being evaluated and the setting of the pain assessment at all levels in the LTC facility will have positive
evaluation will dictate which assessment techniques are warranted. implications for management of pain in this setting. Two useful
Whereas scales that measure pain intensity can be administered resources to facilitate implementing an institutional plan are
rapidly and are suitable for any setting, others require more time described in the American Geriatric Society Panel on Persistent
and are more likely to be helpful in the primary care office/clinic or Pain in Older Adults19 and the American Medical Directors
LTC facility. Some distinctions regarding the setting and type of Association Chronic Pain Management in the Long Term Care
pain are provided later. Setting guidelines.75 These evidence-based interdisciplinary guide-
lines form a basis for a comprehensive pain management program
that includes recognition, assessment, treatment, and monitoring
Acute Pain recommendations.
Older adults who present with acute pain require a rapid assessment
including a self-report of pain intensity and other descriptors of the CONCLUSION
present pain complaint. Past pain history and medication history
are also essential. Completion of a more comprehensive assessment An accurate assessment of pain provides the foundation for a suc-
can be delayed until the etiology and treatment of the pain has been cessful treatment plan in the older adult. This assessment is often
complex and multidimensional and varies depending on the prac- 16. Turk DC, Dworkin RH, Allen RR, et al. Core outcome domains for
tice setting in which the patient is encountered. Self-report remains chronic pain clinical trials: IMMPACT recommendations. Pain
the most reliable measure of the painful complaint. Self-report 2003;106:337345.
should be supplemented with existing medical records, information 17. Turk DC, Dworkin RH, Burke LB, et al. Developing patient-reported
outcome measures for pain clinical trials: IMMPACT
from family members and caregivers when possible, and the utili-
recommendations. Pain 2006;125:208215.
zation of additional instruments available to measures pain-related 18. Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary
constructs. expert consensus statement on assessment of pain in older persons.
The sheer range and choice of pain-related measurement instru- Clin J Pain 2007;23(1 suppl):S1S43.
ments can be daunting for the clinician. In many cases, particularly 19. AGS Panel on Persistent Pain in Older Persons. The management of
when evaluating an older adult with a chronic pain complaint, the persistent pain in older persons. American Geriatrics Society. J Am
process can be time consuming. Many assessment instruments can Geriatr Soc 2002;50:S205S224.
be given to the patient prior to the evaluation process and reviewed 20. Feldt KS, Ryden MB, Miles S. Treatment of pain in cognitively
with the patient during the examination. One suggestion toward a impaired compared with cognitively intact older patients with hip-
rational approach to assessment is described earlier and includes fracture. J Am Geriatr Soc 1998;46:10791085.
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1987;30:191197. McMaster Universities Osteoarthritis Index (WOMAC): a review of
62. Deen G. Back and neck pain. In Sirven J, Malamut B (eds): Clinical its utility and measurement properties. Arthritis Rheum
Neurology of the Older Adult, Philadelphia: Lippincott Williams & 2001;45:453461.
Wilkins, 2002; pp 191199. 91. Wheeler AH, Goolkasian P, Baird AC, Darden BV 2nd. Development
63. Tinetti ME. Performance-oriented assessment of mobility problems in of the Neck Pain and Disability Scale. Item analysis, face, and
elderly patients. J Am Geriatr Soc 1986;34:119126. criterion-related validity. Spine 1999;24:12901294.
64. Podsiadlo D, Richardson S. The timed "Up & Go": a test of basic 92. Lefebvre M. Cognitive distortion and cognitive errors in depressed
functional mobility for frail elderly persons. J Am Geriatr Soc psychiatric and low back pain patients. J Consult Clin Psychol
1991;39:142148. 1981;49:517525.
65. Dodick D, Capobianco D. Headaches. In Sirven J, Malamut B (eds): 93. Gil K, Williams D, Keefe F, Beckham J. The relationship of
Clinical Neurology of the Older Adult. Philadelphia: Lippincott negative thoughts to pain and psychological distress. Behav Ther
Williams & Wilkins, 2002; pp 176190. 1990;21:349-362.
66. Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. Incidence 94. Yong HH, Gibson SJ, Horne DJ, Helme RD. Development of a pain
of central post-stroke pain. Pain 1995;61:187193. attitudes questionnaire to assess stoicism and cautiousness for
67. Benrud-Larson LM, Wegener ST. Chronic pain in neurorehabilitation possible age differences. J Gerontol B Psychol Sci Soc Sci
populations: prevalence, severity and impact. Neurorehabilitation 2001;56:P279P284.
2000;14:127137. 95. Sullivan M, Bishop S, Pivik J. The Pain Catastrophizing Scale:
68. Spiera R, Spiera H. Inflammatory disease in older adults. Cranial development and validation. Psychol Assess 1995;7:524532.
arteritis. Geriatrics 2004;59:2529; quiz 30. 96. Nicassio PM, Wallston KA, Callahan LF, et al. The measurement of
69. Ardery G, Herr KA, Titler MG, et al. Assessing and managing acute helplessness in rheumatoid arthritis. The development of the arthritis
pain in older adults: a research base to guide practice. Medsurg Nurs helplessness index. J Rheumatol 1985;12:462467.
2003;12:718; quiz 19. 97. Lorig K, Chastain RL, Ung E, et al. Development and evaluation of a
70. Pasaro C, Reed B, McCaffery M. Pain in the Elderly, 2nd ed. scale to measure perceived self-efficacy in people with arthritis.
St. Louis: Mosby, 1999. Arthritis Rheum 1989;32:3744.
24 Chapter 5 ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT
98. McCracken LM, Zayfert C, Gross RT. The Pain Anxiety Symptoms 103. Rosenstiel AK, Keefe FJ. The use of coping strategies in chronic low
Scale: development and validation of a scale to measure fear of pain. back pain patients: relationship to patient characteristics and current
Pain 1992;50:6773. adjustment. Pain 1983;17:3344.
99. Kori S, Miller R, Todd D. Kinesiophobia: a new view of chronic 104. Jensen MP, Turner JA, Romano JM, Strom SE. The Chronic Pain
pain behavior. Pain Manage 1990;3:3543. Coping Inventory: development and preliminary validation. Pain
100. Cook AJ, Brawer PA, Vowles KE. The fear-avoidance model of 1995;60:203216.
chronic pain: validation and age analysis using structural equation 105. Felton BJ, Revenson TA. Coping with chronic illness: a study of
modeling. Pain 2006;121:195206. illness controllability and the influence of coping strategies on
101. Burwinkle T, Robinson JP, Turk DC. Fear of movement: factor psychological adjustment. J Consult Clin Psychol 1984;52:343353.
structure of the Tampa scale of kinesiophobia in patients with 106. Felton BJ, Revenson TA, Hinrichsen GA. Stress and coping in the
fibromyalgia syndrome. J Pain 2005;6:384391. explanation of psychological adjustment among chronically ill adults.
102. Lachman ME, Howland J, Tennstedt S, et al. Fear of falling Soc Sci Med 1984;18:889898.
and activity restriction: the survey of activities and fear of falling 107. Folkman S, Lazarus RS. If it changes it must be a process: study of
in the elderly (SAFE). J Gerontol B Psychol Sci Soc Sci emotion and coping during three stages of a college examination.
1998;53:4350. J Pers Soc Psychol 1985;48:150170.
Chapter 5 an episode of critical illness who are unable to communicate

owing to an unconscious state or the presence of an endotracheal
ASSESSMENT OF PAIN IN THE tube. General principles of pain assessment and specific recommen-
dations for pain assessment of nonverbal older adults are discussed.
NONVERBAL AND/OR Finally, a selection of behavioral pain assessment tools for use with
these nonverbal older adults is critiqued.
COGNITIVELY IMPAIRED OLDER
CHALLENGE OF DEMENTIA FOR PAIN
ADULT ASSESSMENT
Karen Bjoro and Keela Herr Dementia is one of the most frequent causes of cognitive impair-
ment in older adults, with a forecast worldwide increase in inci-
dence from 25 million in 2000 to 114 million by 2050.4 Dementia
involves the development of multiple cognitive deficits manifested
by impaired memory and involving cognitive disturbances and the
loss of language, the ability to recognize or identify objects, and
executive function.5 As dementia progresses to advanced stages,
INTRODUCTION individuals become increasingly dependent in all activities of daily
living, often requiring skilled nursing care.
Pain is a highly subjective and personal experience. Self-report is The burden of dementia in the older adult population is com-
widely accepted as the most reliable source of information on an pounded by a considerable pain burden.6 In institutionalized older
individual’s pain experience and is considered to be the ‘‘gold stan- adults with dementia, pain or potentially painful conditions are
dard’’ in most populations.1,2 Yet, older adults with severe cognitive common, with prevalence estimates ranging between 49% and
impairment or who are unconscious and/or intubated during an 83%.7,8 One large-scale nursing home study documented that half
episode of severe critical illness are unable to communicate their of the residents reported having pain in the past week and a fourth
pain experience. The inability to use verbal language represents a experienced pain daily.9 Moreover, a similar prevalence of pain was
major barrier to pain assessment and treatment. For these indivi- documented in subgroups of cognitively intact and impaired
duals, alternative approaches to pain assessment, involving obser- residents. The most common pain-associated conditions in the
vation of pain behaviors and proxy pain reports, are necessary. cognitively impaired residents were arthritis, previous hip fracture,
The ability to use language is a comprehensive and complex osteoporosis, pressure ulcers, depression, and a history of a recent
behavior acquired in early childhood. The primary faculties of lan- fall, unsteady gait, and verbally abusive behavior.9
guage include speaking, signing, and language comprehension, The severity of cognitive impairment and the progression of
whereas reading and writing are secondary abilities.3 With language language deficit vary by type and stage of disease, environmental
impairment (e.g., aphasia, dysphasia), the ability to communicate factors, and individual characteristics. In Alzheimer’s disease (AD),
orally, through signs, or in writing or the ability to understand which accounts for over half of dementia cases, memory deficit is
such communications may be severely compromised. Language the presenting symptom, with language impairments developing
impairment (e.g., aphasia, dysphasia) is associated with many med- gradually over the course of the illness.10 Typically, AD patients
ical illnesses and clinical states (Box 51). The loss of ability to com- are fluent until the middle to late stages of the disease, whereas
municate is a core feature of many types of cognitive impairment global language disturbance and mutism are generally present in
(e.g., dementia, delirium) and occurs frequently with severe critical the end stage of AD. With vascular dementia, the second most
illness as well as at the end of life, with the naturally occurring dete- prevalent type, the trajectory of language impairment resembles
rioration in cognition resulting from ensuing death and/or sedation. that observed in AD.11 By comparison, individuals with frontotem-
The purpose of this chapter is to review the current basis for poral dementia (behavioral type) and primary progressive aphasia
pain assessment in three nonverbal populations: those with show earlier onset of language impairment and more rapid
advanced dementia, those with delirium, and those experiencing decline.10 The subtype of dementia also appears to affect pain
98. McCracken LM, Zayfert C, Gross RT. The Pain Anxiety Symptoms 103. Rosenstiel AK, Keefe FJ. The use of coping strategies in chronic low
Scale: development and validation of a scale to measure fear of pain. back pain patients: relationship to patient characteristics and current
Pain 1992;50:6773. adjustment. Pain 1983;17:3344.
99. Kori S, Miller R, Todd D. Kinesiophobia: a new view of chronic 104. Jensen MP, Turner JA, Romano JM, Strom SE. The Chronic Pain
pain behavior. Pain Manage 1990;3:3543. Coping Inventory: development and preliminary validation. Pain
100. Cook AJ, Brawer PA, Vowles KE. The fear-avoidance model of 1995;60:203216.
chronic pain: validation and age analysis using structural equation 105. Felton BJ, Revenson TA. Coping with chronic illness: a study of
modeling. Pain 2006;121:195206. illness controllability and the influence of coping strategies on
101. Burwinkle T, Robinson JP, Turk DC. Fear of movement: factor psychological adjustment. J Consult Clin Psychol 1984;52:343353.
structure of the Tampa scale of kinesiophobia in patients with 106. Felton BJ, Revenson TA, Hinrichsen GA. Stress and coping in the
fibromyalgia syndrome. J Pain 2005;6:384391. explanation of psychological adjustment among chronically ill adults.
102. Lachman ME, Howland J, Tennstedt S, et al. Fear of falling Soc Sci Med 1984;18:889898.
and activity restriction: the survey of activities and fear of falling 107. Folkman S, Lazarus RS. If it changes it must be a process: study of
in the elderly (SAFE). J Gerontol B Psychol Sci Soc Sci emotion and coping during three stages of a college examination.
1998;53:4350. J Pers Soc Psychol 1985;48:150170.
Chapter 5 an episode of critical illness who are unable to communicate

owing to an unconscious state or the presence of an endotracheal
ASSESSMENT OF PAIN IN THE tube. General principles of pain assessment and specific recommen-
dations for pain assessment of nonverbal older adults are discussed.
NONVERBAL AND/OR Finally, a selection of behavioral pain assessment tools for use with
these nonverbal older adults is critiqued.
COGNITIVELY IMPAIRED OLDER
CHALLENGE OF DEMENTIA FOR PAIN
ADULT ASSESSMENT
Karen Bjoro and Keela Herr Dementia is one of the most frequent causes of cognitive impair-
ment in older adults, with a forecast worldwide increase in inci-
dence from 25 million in 2000 to 114 million by 2050.4 Dementia
involves the development of multiple cognitive deficits manifested
by impaired memory and involving cognitive disturbances and the
loss of language, the ability to recognize or identify objects, and
executive function.5 As dementia progresses to advanced stages,
INTRODUCTION individuals become increasingly dependent in all activities of daily
living, often requiring skilled nursing care.
Pain is a highly subjective and personal experience. Self-report is The burden of dementia in the older adult population is com-
widely accepted as the most reliable source of information on an pounded by a considerable pain burden.6 In institutionalized older
individual’s pain experience and is considered to be the ‘‘gold stan- adults with dementia, pain or potentially painful conditions are
dard’’ in most populations.1,2 Yet, older adults with severe cognitive common, with prevalence estimates ranging between 49% and
impairment or who are unconscious and/or intubated during an 83%.7,8 One large-scale nursing home study documented that half
episode of severe critical illness are unable to communicate their of the residents reported having pain in the past week and a fourth
pain experience. The inability to use verbal language represents a experienced pain daily.9 Moreover, a similar prevalence of pain was
major barrier to pain assessment and treatment. For these indivi- documented in subgroups of cognitively intact and impaired
duals, alternative approaches to pain assessment, involving obser- residents. The most common pain-associated conditions in the
vation of pain behaviors and proxy pain reports, are necessary. cognitively impaired residents were arthritis, previous hip fracture,
The ability to use language is a comprehensive and complex osteoporosis, pressure ulcers, depression, and a history of a recent
behavior acquired in early childhood. The primary faculties of lan- fall, unsteady gait, and verbally abusive behavior.9
guage include speaking, signing, and language comprehension, The severity of cognitive impairment and the progression of
whereas reading and writing are secondary abilities.3 With language language deficit vary by type and stage of disease, environmental
impairment (e.g., aphasia, dysphasia), the ability to communicate factors, and individual characteristics. In Alzheimer’s disease (AD),
orally, through signs, or in writing or the ability to understand which accounts for over half of dementia cases, memory deficit is
such communications may be severely compromised. Language the presenting symptom, with language impairments developing
impairment (e.g., aphasia, dysphasia) is associated with many med- gradually over the course of the illness.10 Typically, AD patients
ical illnesses and clinical states (Box 51). The loss of ability to com- are fluent until the middle to late stages of the disease, whereas
municate is a core feature of many types of cognitive impairment global language disturbance and mutism are generally present in
(e.g., dementia, delirium) and occurs frequently with severe critical the end stage of AD. With vascular dementia, the second most
illness as well as at the end of life, with the naturally occurring dete- prevalent type, the trajectory of language impairment resembles
rioration in cognition resulting from ensuing death and/or sedation. that observed in AD.11 By comparison, individuals with frontotem-
The purpose of this chapter is to review the current basis for poral dementia (behavioral type) and primary progressive aphasia
pain assessment in three nonverbal populations: those with show earlier onset of language impairment and more rapid
advanced dementia, those with delirium, and those experiencing decline.10 The subtype of dementia also appears to affect pain
in older cancer patients,26 and approximately 22% in nursing home

Box 5^1 CLINICAL STATES IN OLDER ADULTS ASSOCIATED residents.27
WITH INABILITY TO COMMUNICATE VERBALLY Delirium is characterized by recent onset of fluctuating aware-
ness and an inability to focus attention, a change in cognition
Dementias (e.g., memory deficit, disorientation) or perceptual disturbance,
Delirium and the presence of an underlying organic illness.5 There are
Cerebrovascular accident three clinical subtypes of delirium: hyperactive, hypoactive, and
State of unconsciousness/advanced life support/intubation
Severe depression mixed.28 Language disturbance in delirium is characteristically
Psychosis manifested by an impaired ability to articulate, name objects,
Mental disability write, or even speak. Speech may be rambling and irrelevant
Coma, persistent vegetative state or pressured and incoherent, with unpredictable shifting from sub-
Encephalopathy ject to subject.5 Thus, although older adults with delirium may be
Terminal illness able to speak, the content may be incomprehensible.
Although the pathophysiology of delirium remains unclear,
there is general agreement that delirium etiology is multifactori-
response. In frontotemporal dementia, a decrease in affective pain al.29,30 Inouye and Charpentier29 proposed that delirium may
response has been documented that could be explained by atrophy develop in a vulnerable individual owing to the interaction of pre-
of the prefrontal cortex. In contrast, with vascular dementia, an disposing and precipitating risk factors. Predisposing factors
increase in affective response is reported that may be related to (e.g., high age, dementia, multiple chronic diseases) increase the
white matter lesions and deafferentiation in these patients.12 vulnerability of an individual to noxious factors that interact with
Neuropathologic processes in dementia seriously affect the ability the underlying predisposing factors to precipitate the onset of
of those with advanced stages of disease to communicate pain. delirium. Whereas many potential precipitating factors have been
However, only a few studies have investigated the relationship identified (e.g., dehydration, electrolyte disturbance, polypharmacy,
between dementia and the neuropathology of pain, and these are lim- infection, hypoxia), delirium onset has also been linked to anteced-
ited to experimental pain studies in individuals with AD. Whereas ent pain in hip fracture patients,31 medical patients,32 and older
sensory discriminatory aspects of pain are processed in the lateral adults undergoing elective surgery.33,34 However, many of the
pain system (e.g., lateral thalamus), motivational affective aspects analgesics (e.g., meperidine31,35) and other adjuvant medications
are processed in the medial pain system (e.g., anterior cingulate used to treat pain (e.g., benzodiazepine35) can also trigger the
gyrus, hippocampus).13,14 Noxious stimuli transmitted via the onset of delirium. The relationship between pain, pain treatment,
lateral pain system are interpreted in the somatosensory cortex, and delirium is complex and unclear.
involving areas of the brain that are relatively unaffected by AD Pain assessment in older adults with delirium is extremely chal-
neuropathology. This explains the finding that sensory aspects of lenging. No diagnostic tests exist to determine the presence of either
pain remain intact in individuals with AD. Nevertheless, the lateral pain or delirium. Identification of pain in nonverbal older adults and
pain system does show some functional decline, as evidenced by an of delirium both rely on observation of behavioral presentation.
elevated pain threshold and reports of less intense pain in those with Moreover, there is considerable overlap between delirium behaviors
AD. By contrast, the medial pain system is severely affected by and nonverbal pain behaviors. Liptzin and Levkoff36 used behavioral
pathologic processes in AD.12,15 The affective pain response (e.g., items on the Delirium Symptom Interview37 to observe hypoactive
pain tolerance) was significantly increased in individuals with AD and hyperactive behaviors of patients with delirium (Table 51).
compared with those without dementia.12 Thus, empirical studies Interestingly, many behavioral symptoms of delirium also occur on
indicate that older adults with dementia are not less sensitive to pain a comprehensive list of nonverbal pain behaviors (Table 52)
but they may fail to interpret sensations as painful. (e.g., wandering, verbally abusive behavior, resistiveness to care).
Despite these findings, evidence suggests that older adults with Few studies have investigated pain assessment in older adults
advanced dementia underreport pain compared with those who are with ongoing delirium. One study showed that physicians and
cognitively intact. Research studies have documented a decrease in nurses were likely to misinterpret agitation as an expression of
the number of pain complaints with increasing severity of cognitive pain in patients with agitated delirium in whom the pain was
impairment in older adults with dementia.16,17 Inability to commu- well controlled before and after the delirium episode.38 Further, it
nicate is a major barrier to adequate pain assessment and treatment is unclear whether available behavioral pain tools may assist in pain
in older adults with advanced dementia. Cognitively impaired older detection in older adults during episodes of delirium. Only one pain
adults hospitalized with a hip fracture received significantly less assessment tool has been developed for use with this particular
opioid analgesia than those with less or no impairment.18,19 In patient population; however, initial testing of the tool was con-
the nursing home setting, pain is documented less frequently in ducted in cognitively intact older adults undergoing orthopedic
residents unable to communicate their pain, even though they surgery and not in those with cognitive impairments.39
have a similar number of painful diagnoses.9,20,21 Moreover, less Thus, the relationships between pain and delirium are complex
analgesia is prescribed and administered for cognitively impaired and unclear. Although improved pain treatment may reduce the
nursing home residents, even when the impaired residents have occurrence of delirium in older adults, there is a gap in the litera-
numbers of painful diagnoses similar to those in cognitively intact ture regarding assessment of pain in patients with delirium. It may
residents.22,23 Thus, the inability to communicate in older adults not be possible to identify pain definitively by behavioral presenta-
with dementia is a major barrier to both assessment and treatment. tion in patients with delirium and may require alternative
Language impairment is also common in delirium. approaches to pain assessment, such as analgesic trial, addressed
in later sections of this chapter.
CHALLENGE OF DELIRIUM FOR PAIN

ASSESSMENT CHALLENGE OF SEVERE CRITICAL
ILLNESS FOR PAIN ASSESSMENT
Delirium is a form of transient cognitive impairment often accom-
panied by loss of the ability to communicate effectively. The inci- Older adults have an increased prevalence of comorbid illness and
dence of delirium in older adults ranges from 16% to 62% with trauma and account for more than 60% of all ICU days.40 During
hip fracture,24 62% in the intensive care unit (ICU),25 25% to 45% episodes of severe critical illness, older people may lose the ability to
Table 5^1. Delirium Subtype and Associated Table 5^2. Common Pain Behaviors in Cognitively
Potential Behavioral Symptoms Impaired Older Persons
Delirium Subtype Behavioral Symptoms Behavior Examples

Hyperactive Hypervigilance Facial expressions Slight frown, sad, frightened face
Restlessness Grimacing, wrinkled forehead, closed
Fast or loud speech or tightened eyes
Irritability Any distorted expression
Combativeness Rapid blinking
Impatience Verbalizations, Sighing, moaning, groaning
Swearing vocalizations Grunting, chanting, calling out
Singing Noisy breathing
Laughing Asking for help
Uncooperative Verbal abusiveness
Euphoric Body movements Rigid, tense body posture; guarding
Anger Fidgeting
Wandering Increased pacing, rocking
Easy startling Restricted movement
Fast motor responses Gait or mobility changes
Distractability Changes in Aggressive, combative, resists care
Tangentiality interpersonal Decreased social interactions
Nightmares interactions Socially inappropriate, disruptive
Persistent thoughts Withdrawn
Hypoactive Unawareness Changes in Refusing food, appetite change
Decreased alertness activity patterns Increase in rest periods
Sparse or slow speech or routines Sleep, rest pattern changes
Lethargic Sudden cessation of common routines
Slowed movements Increased wandering
Staring Mental status Crying or tears
Apathy changes Increased confusion
Based on Liptzin B, Levkoff SE. An empirical study of delirium Irritability or distress
subtypes. Br J Psychiatry 1992;161:843845. From American Geriatrics Society (AGS) Panel on Persistent Pain
speak owing to an unconscious state, the presence of an endotra- in Older Persons. The management of persistent pain in older
cheal tube, or fatigue. persons. J Am Geriatr Soc 2002;50:S211. Used with permission.
Many older adults die in the ICU.41 However, patients able to
report the ICU experience in retrospect indicated that endotracheal and treatment. The evidence indicates the urgent need to improve
intubation, mechanical ventilation, and the consequent inability to methods of detecting and managing pain in these vulnerable popu-
speak are extremely stressful events.4143 Pain and the inability to lations and is addressed in the following section.
speak were reported to be moderately to extremely bothersome.
Endotracheal suctioning is a particularly painful procedure, and
the stressful experience associated with the endotracheal tube was
strongly associated with the subjects’ experiencing spells of terror.42 APPROACHES TO PAIN ASSESSMENT IN
Sources of pain during episodes of critical illness include existing NONVERBALOLDER ADULTS
an medical condition, traumatic injuries, the surgical/medical pro-
cedure, invasive instrumentation, blood draws, and other routine Assessment of pain is a critical component of a comprehensive
care such as turning, positioning, drain and catheter removal, and approach to pain management in all populations. The purpose of
wound care.4446 Adult patients described the experience of pain in pain assessment is to detect the presence and source of pain,
critical illness as a constant baseline aching pain with intermittent identify any comorbidities requiring attention, determine the
procedure-related pain that is experienced as sharp, stinging, stab- effect of pain on function, and collect data on which to base indi-
bing, shooting, and awful pain.45 Although most studies have been vidual treatment plans.6 Achievement of these goals is challenging
conducted with younger patients, it should be assumed that nonin nonverbal older adults. Nevertheless, general principles can guide
verbal older adults also experience these sensations. approaches to pain identification, measurement, and continuous
Identification of pain in nonverbal older patients who are unable monitoring, as well as selection of specific pain assessment strategies
to communicate their pain and discomfort owing to critical illness in nonverbal older adults.
requires astute observational skill. Moreover, the complexity of The American Society for Pain Management Nursing (ASPMN)
detecting pain is confounded by the overhanging threat of delirium recently published recommendations for pain assessment in non-
that occurs in approximately 62% of older adults in the ICU.25 verbal individuals.47 This comprehensive, hierarchical strategy
includes five key principles to guide pain assessment in nonverbal
populations: (1) obtain a self-report if at all possible, (2) investigate
Summary for possible pathologies that could produce pain, (3) observe
for behaviors that may indicate pain, (4) solicit a surrogate report,
The inability of nonverbal populations to communicate pain and and (5) use analgesics to evaluate whether pain management causes
discomfort represents a major barrier to adequate pain assessment a reduction in the behavioral indicators believed to be related
Is pain behavior present

during movement?*
Yes No
Search for pathology and treat

Also try:
• Medication before provocative Is pain
movement behavior No
• Strategies to alter pain-inducing present that is not
movement associated with
• Reassurance for fear-related movement?**
behavior
Maintain vigilance: monitor symptoms and response to therapy.
Maintain vigilance: monitor symptoms and response to therapy.

Yes
No Do pain Yes Are basic

behaviors comfort needs
persist? being met?†
No Yes
Provide for Do pain No Figure 5^1. Pain assessment in elders

basic comfort behaviors with severe cognitive impairment. *For
needs persist?
example, grimacing, guarding,
Is there evidence combativeness, groaning with
of pathology (e.g., movement; resisting care; **for
fracture, infection, Yes example, agitation, fidgeting, sleep
constipation)? disturbance, diminished appetite,
irritability, reclusiveness, disruptive
behavior, rigidity, rapid blinking; {for
example, toileting, thirst, hunger, visual
or hearing impairment. (From Reuben
No Yes DB, Herr KA, Pacala JT, et al.Geriatrics At
Your Fingertips: 20072008 Edition. New
Empirical trial Treat cause of York:The American Geriatrics Society, 2007.
of analgesic the pathology Used with permission.)
to pain.47 These principles reflect a decision making process, illu- distracting conversation, the respondent is asked to recall the
strated in Figure 51, that may guide and support health care clin- number and the word. Patients receive one point each for being
icians and are discussed in greater depth in the following section. able to provide an initial number and word and one half point each
for recalling the number and the word. Only respondents who score
a three are identified as providing reliable pain reports.
Obtain a Self-report Strategies that increase the likelihood of obtaining a self-report
of pain from a cognitively impaired individual may include use of a
Attempts should be made to obtain a self-report of pain from all modified verbal rating scale with a limited number of descriptors,
patients. The ability of cognitively impaired patients to report their careful instruction on tool use and repetition, focus on the indivi-
pain consistently and accurately varies widely across levels of cog- dual’s current pain rather than past pain experience, and adaptation
nitive impairment.48 Research indicates that individuals with mild of tools to compensate for possible sensory impairments.48,52
and moderate dementia and even some with severe dementia are However, despite these efforts, many patients’ impairments will
able to self-report.7,4850 Even a limited yes/no response to a query be severe enough to require alternative approaches to assessment.
regarding pain presence is important information regarding the
patient’s own pain experience.
With increasing cognitive impairment, the ability to reliably use Search for Potential Causes of Pain
self-report instruments wanes. Although no clear method has been
identified to address reliability in using self-report instruments, Pathologic conditions should be considered as a potential cause of
Buffum and colleagues51 described a Pain Screening Tool, an pain and discomfort in the assessment process. History and general
approach developed for evaluating cognitive ability to reliably com- physical evaluation, examination of any painful regions, as well as
plete pain intensity scales. Patients are asked to provide a number consideration of any pain medication regimen provide essential
from 0 to 3 and a word to describe their pain. After 1 minute of information for clinical decisions. Musculoskeletal and neurologic
conditions are among the most common causes of pain in older of pain assessments. Important issues for consideration when using
adults and should be given priority in the clinical examination. behavioral observation to detect pain or when selecting a behavioral
Moreover, evaluation of the patient’s cognitive status is a crucial pain tool are summarized in Table 53. In the following section, we
element of geriatric focused-pain assessment because both acute provide recommendations that may maximize observational pain
and chronic pain can affect cognition. When pain-associated assessment approaches in nonverbal older adults.
pathologies are identified, the presence of pain may be assumed Behavioral indicators for pain assessment must be appropriate to
and appropriate pain intervention strategies should be implemen- the patient population, setting, and type of pain problems encoun-
ted. Pain should be treated preemptively prior to initiation of any tered. The shorter behavioral pain tools tend to be direct observa-
procedures known to cause pain.1,47 A change in behavior should tionfocused including specific behaviors that may be observed in a
initiate a search for any acute problems as a source of pain or direct encounter by trained observers (e.g., grimacing, guarding,
discomfort (e.g., pneumonia, urinary tract infection, a recent fall). restlessness, moaning, fighting the ventilator).54,55 The patient
Detailed guidelines with recommendations for assessment of pain may be observed for a specified period and activity for the presence
pathology in older adults are available.6 or absence, intensity, or frequency of pain behaviors.54,56 Shorter
behavioral tools require no previous history with the patient, an
advantage in the acute care setting. Longer pain scales are more
Observe for Behaviors that May Indicate Pain comprehensive including more subtle behavioral indicators in addi-
tion to those commonly observed. Items such as changes in activity
When older adults are unable to communicate the presence of pain patterns or routines, interpersonal interactions, or mental status
owing to cognitive impairments, unconsciousness, or severe critical require involvement of family and caregivers familiar with the
illness, reliance on external signs of pain, such as nonverbal beha- patient’s baseline or typical behaviors. Thus, longer tools may be
viors and physiologic changes, becomes a necessary approach to more appropriate in the long-term care (LTC) setting in which
pain detection. The American Geriatrics Society (AGS) Panel on patients may be observed over time while performing everyday
Persistent Pain in Older Persons2 compiled a comprehensive list activities.
of nonverbal behaviors observed in older adults with cognitive With chronic pain states, changes in physiologic indicators are
impairment with six categories of pain behavioral indicators: often not observed. In acute pain situations, physiologic and behav-
facial expressions, verbalizations/vocalizations, body movements, ioral indicators may increase temporarily, but these changes may be
changes in interpersonal interactions, changes in activity patterns attributed to underlying physiologic conditions and medications.
or routines, and mental status change (see Table 52). This frame- Thus, changes in vital signs are not reliable as single indicators of
work provides a valuable resource for evaluating the relevance and pain, but changes in physiologic indicators (e.g., blood pressure,
comprehensiveness of behaviors included on a particular behavioral pulse, oxygen saturation) should be considered a cue to begin fur-
pain tool for use with older adults.53 ther assessment for pain or other stressors. Moreover, an absence of
Observational approaches to pain assessment rely on interpre- increased vital signs does not indicate an absence of pain.57,58
tation of behaviors. The inherent subjectivity involved in observa- The conditions of behavioral observation are also important to
tional approaches represents challenges to the reliability and validity ensure reliability of assessments. Observation of behaviors should
Table 5^3. Key Issues in Behavioral Pain Assessment in Older Adults with Cognitive Impairment
Issue Key Considerations

Specific vs. subtle Specific behaviors are obvious and commonly observed in pain states (e.g. facial expressions, verbalizations/
behaviors vocalizations, body movements)2
Subtle behaviors reflect change from usual individual behavioral pattern and are less obvious pain indicators
(e.g., changes in interpersonal interactions, activity patterns or mental status)2
Subtle behaviors require interpretation and validation that pain is the etiology
Direct observation Specific, obvious indicators may be observed directly; no prior history with the patient is required
vs. surrogate Subtle behaviors of change from baseline require reassessment over time by individuals familiar with the patient
report Use of surrogate reporting requires caution due to evidence of disagreements between self-report of pain by
cognitively impaired individuals and proxy report8487
Pain presence vs. Patient self-report and proxy report of pain severity show increasing disagreement with increasing severity of
severity cognitive impairment50
Evidence documents surrogate/proxy ability to recognized pain presence but not intensity84
Professional caregivers tend to underestimate patient pain severity84,86,88
Family members tend to overestimate patient pain severity and level of discomfort89
A behavioral pain tool score is not the same as a pain intensity rating; pain behavior tool score and score on
pain intensity ratings should not be compared90
Sensitivity vs. A comprehensive indicator set including obvious and less obvious pain behaviors increases sensitivity of
specificity behavioral tools to detect pain when present91
A narrow indicator set with only obvious indicators increases specificity of behavioral tools to rule out pain
when pain is not present, but are less sensitive in detecting pain in those with less obvious pain
presentation91
Screening vs. Behavioral pain assessment may assist in screening for presence of pain, but does not provide diagnostic
diagnostic certainty regarding exact nature and cause of possible pain to guide treatment6466,68
certainty In situations in which uncertainty prevails, an empirical analgesic trial is warranted as a pain assessment
strategy1,6,47
occur during movement or activity that is likely to elicit a pain recognizing and validating pain in those presenting with atypical
response if pain is present. Studies have demonstrated that obser- pain behaviors.
vation of pain behaviors at rest is misleading and can result in false
judgments that pain is absent, leading to underdetection and under-
treatment.18,54,59,60 Moreover, serial observations should be per- Summary
formed under similar circumstances (e.g., time of day, activity
performed) to ensure comparability of behavioral pain assessments This section has outlined key components of a comprehensive
over time. approach to pain assessment in nonverbal older adults. A multi-
faceted approach is recommended that combines direct observation
of behaviors, family/caregiver input, and evaluation of response to
Solicit Support of Surrogate Reporters treatment. A standardized behavioral pain tool may be used as one
component of a comprehensive approach to pain assessment and is
In the absence of pain self-report, surrogate observation is an addressed in the following section.
important source of information. Family members or others who
know the patient well (e.g., spouse, child, caregiver) should be
encouraged to provide information regarding usual and past beha-
viors as well as to assist in the identification of subtle, less obvious BEHAVIORAL PAIN ASSESSMENT
changes in behavior that may indicate pain presence. In LTC, the TOOLS FORUSE WITHOLDER ADULTS
certified nursing assistant is a key health care provider who has been
shown to be effective in recognizing the presence of pain.61,62 In Since the late 1990s, a number of standardized tools for pain assess-
settings in which health care providers do not have a history with ment based on observation of behaviors have been developed for
the patient, family members are likely to be the caregivers with the use with nonverbal older adult populations. Several reviews of avail-
most familiarity with typical pain behaviors or changes in usual able tools53,6972 have indicated that, although there are tools with
activities that might suggest pain presence. A family member’s potential, currently no tool has sufficiently strong reliability and
report of their impression of a patient’s pain and response to an validity to support recommendation for broad adoption in clinical
intervention should be included as one component of pain assess- practice. Moreover, reviews have called for further tool testing in
ment that encompasses multiple sources of information. When larger samples and/or in diverse clinical settings. In an earlier com-
engaging multiple care providers and surrogates in pain screening prehensive review, Herr and associates53 critiqued 10 tools for use
procedures, training is important to safeguard the reliability of with nonverbal adults with advanced dementia based on published
behavioral observations. Moreover, when introducing new behav- reports of psychometric data. Since the publication of this review,
ioral tools to the clinical setting, interrater reliability between care- some tools have undergone further testing and development. In the
givers should be established initially as well as on a regular basis to following discussion, a selection of tools is presented with updated
calibrate observations, thus reducing subjectivity and the potential critiques. Further, we have included two recently developed tools
for bias associated with this method. for use with critically ill adult patients who are unconscious and/or
intubated that have not previously been critiqued for relevance,
reliability, and validity for use with this patient population. Table
Conduct an AnalgesicTrial 54 provides an overview of characteristics of the selected tools
with presentation of tool items and scoring range, reliability, valid-
If, after following the initial steps in this multifaceted approach to ity, and clinical utility.
pain assessment, behaviors persist that may indicate pain, an anal-
gesic trial is warranted. The underlying supposition is that any
reduction in behaviors after analgesic intervention is related to The Checklist of Nonverbal Pain Indicators18,54
improved pain control. Early unblinded trials provided preliminary
support for this approach.63 Buffum and coworkers64 did not dem- The Checklist of Nonverbal Pain Indicators (CNPI), developed to
onstrate significant changes in agitated behavior believed to be pain measure pain in cognitively impaired older adults, includes six
related in persons with advanced dementia; however, the acetamin- conceptually sound behavioral items commonly observed in direct
ophen dose was only 1500 mg/day. In a randomized, controlled trial observation situations. Initial tool testing supports the reliability
(RCT) evaluating low-dose opioids in persons with dementia, and validity of this tool for use in acute care, although internal
Manfredi and associates65 reported decreased agitation in the consistencies were low, suggesting a need for further testing. In a
over-85 age group and suggested that less response in the younger tool evaluation in Norwegian nursing homes, the test-retest and
old group could be related to low dosing of analgesic. In a recent interrater reliabilities reported were low to moderate when admi-
double-blind crossover RCT with patients with dementia receiving nistered by various categories of nursing personnel as an element of
3000 mg/day of acetaminophen, Chibnall and colleagues66 demon- daily care, and moreover, concurrent validity was supported.73 In
strated increased levels of social activity and interaction compared another recent study in LTC,91 sensitivity of the CNPI was moder-
with the times the patients were receiving placebo. An analgesic trial ate, while at the same time, nearly half the residents who reported
is an integrated component of the Serial Trial Intervention (STI), a having pain showed no pain behaviors on the CNPI, thus giving rise
clinical protocol developed by Kovach and colleagues,67 that uses a to concerns about the ability of the tool to detect pain in those
systematic method for assessing and treating potential pain-related unable to report. Because the CNPI lacks indicators of subtle
behaviors in patients with severe dementia. A recent RCT of the STI behaviors, the tool’s ability to detect pain in those with less
demonstrated significantly less discomfort and behavioral symp- obvious behavioral presentation is questioned. Thus, this tool
toms returning to baseline more frequently in the treatment may be more appropriate for use in acute care. However, additional
group and has been shown to be effective in increasing recognition testing in larger and more acute care samples is needed.
and treatment of pain in persons with dementia.68 Although an
analgesic trial is a promising approach, selecting and titrating
analgesics for this purpose have not been clearly explicated or The Doloplus 274
studied. The use of an analgesic trial as a means to evaluate pain
as the cause of potential pain-related behaviors requires further The Doloplus 2 is a French tool developed for multidimensional
investigation but is likely an important step in the process of assessment of pain in nonverbal older adults. Psychometric
Table 5^4. Characteristics of Selected Behavioral Pain Assessment Tools for Nonverbal Older Adults with Dementia or Severe Critical
Illness (Unconscious/Intubated)
Tool Name Items/Scoring Range Reliability Validity Feasibility/Utility Summary

Tools for Nonverbal Older Adults with Advanced Dementia
CNPI18,54,73,91 6 items, including Internal consistency: Moderate discriminant validity Language of original: CNPI includes only common
nonverbal vocalizations, 0.540.64 supported by higher scores on English obvious behaviors observed
facial grimacing or Interrater reliability: movement vs. at rest Translations: Norwegian by direct observation
wincing, bracing, k = 0.620.82 Convergent validity supported and Dutch Tool appears to lack ability to
rubbing, restlessness, 74%94% by moderate correlations with Easy to use detect pain in individuals with
vocal complaints. k = 0.450.69 VDS with movement, but Scoring instructions less common pain
Items scored present or Test-retest: only weak correlation at rest provided presentation (e.g., nursing
absent at rest and on 34%41% In LTC: Score interpretation home residents)
movement k = 0.230.66 Sensitivity: 55% unclear CNPI appears more appropriate
Total score range 012 Specificity: 85% Tested in acute care and for pain assessment in acute
Convergent validity supported long-term care care and procedural pain
by significant positive situations
relationship between self-
report of pain intensity and
CNPI score
Concurrent validity supported
by positive correlation with
nurse-rated VAS
Doloplus 249,7476 10 items; three Internal consistency: Convergent validity supported Language of original: Psychosocial subscale appears
dimensions of somatic Total scale: 0.82 by moderate positive French to need revision based on
(n = 5), psychomotor Subscales: correlations with self-report Translations: psychometric results
(n = 2), psychosocial Somatic: 0.630.7 of pain on VAS (r = 0.65) Dutch, Norwegian, Nurses report tool is difficult to
(n = 3) Psychomotor: 0.70.8 and on VAS, VRS, and FPS English score and interpret
Score range: 030 Psychosocial: 0.580.63 (r = 0.31 0.40). English translation English tool version needs
Reflects progression of Interrater reliability: Predictive validity supported issues are evident and testing in English-speaking
experienced pain, not Not established by significant prediction of English version is not population
current pain experience Test-retest: expert rated NRS-11 score; tested
Not established four items explained 62% of Estimated time to
the expert score; four items complete 5 minutes
explained 68% of the variance Tool manual is clear
of the expert-rated pain score Tool evaluation by nurses
Sensitivity: 71% shows the tool is
Specificity: 76% difficult to score and
Concurrent validity indicated interpret
by moderate correlations with
PACSLAC, PAINAD, a nurse-
rated VAS, and an expert-
rated VAS
PACSLAC75,77 60 items, four Internal consistency: Discriminant validity supported Language of original:
dimensions: Retrospective data: 0.85 by English
Facial expression Total tool: 0.620.84 Moderate ability to Translations: Tool most preferred by nurses
(n = 13) Subscales: 0.120.76 differentiate between pain, Dutch when compared with
Activity/body movements Interrater reliability: 0.92 calm, and distress events Appears easy to use; PAINAD and Doloplus 2
(n = 20) Test-retest: Good based on rater memory estimated time to Promising tool but item
Social/personality/mood intrarater Ability to differentiate levels complete 5 min reduction and subscale
(n = 12) reliabilities of pain: at rest, during Nurses report that some revisions needed
Physiologic/eating/ influenza vaccination, and items on the tool are
sleeping/vocal (n = 15) during mobilization/bathing redundant
Score range: 060 Congruent validity supported by
significant positive correlations
with PAINAD, self-report, and
proxy rating on VAS
PACSLAC-D-Revised92 24 items; three subscales: Internal consistency: Correlation with original Available in Dutch and Promising preliminary tool
facial and vocal Total tool: 0.820.86 PACSLAC suggests validity is English translation needs prospective testing in
expressions (n = 10) Subscales: 0.720.82 retained Clinical utility not yet independent sample
resistance/defense (n = 6) Interrater reliability: evaluated Testing in English-speaking
social-emotional aspects/ Not yet established population needed
mood (n = 8) Test-retest:
Score range: 024 Not yet evaluated
PAINAD75,7880,9396 5 items: breathing, Internal consistency: Discriminant validity supported Language of original: Actual interval time for test-
negative vocalizations, 0.500.67 by English retest not reported
facial expression, body 0.690.74 1. Moderate ability to Translations: Measurement of pain severity
language, consolability Interrater reliability: differentiate pleasant and Dutch, German, Italian via observation of behaviors
Score range: 010 r = 0.820.97 aversive activities Requires 5 minute not supported in the
0.750.81 2. Before and after pain observation period literature, although tool
Test-retest: medication Uncertainty about when appears to discriminate
r = 0.90 (P < .001) 3. Ability to differentiate levels to implement between levels of pain
Time interval: morning/ of pain: at rest, during consolability item Usefulness of breathing and

evening shift scores influenza vaccination, and Nurses evaluate tool as consolability items for pain
r = 0.88 (interval: 15 during mobilization/bathing too concise detection is questioned
days) Ability to detect change before Concerning validity. there was
r = 0.89 and after pain medication in no indication as to whether
treatment group vs. controls; raters were blind to the
moderate effect size intervention, and subjects
Convergent validity indicated were not randomly allocated
by positive correlations with to treatment or control group
DS-DAT, PACSLAC and
nurse-rated VAS
Scores on the DS-DAT
decreased following pain
intervention
Divergent validity indicated by
no correlation with MMSE
and GDS and Cornell
Depression Scale and AMT
score
31
Continued
32
Chapter 5 ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT
Table 5^4. Characteristics of Selected Behavioral Pain Assessment Tools for Nonverbal Older Adults with Dementia or Severe Critical
Illness (Unconscious/Intubated)çcont’d
Tool Name Items/Scoring Range Reliability Validity Feasibility/Utility Summary
Tools for Nonverbal Older Adults with Severe Critical Illness (unconscious/intubated)
BPS8183 Three behavioral items: Interrater reliability: Discriminant validity indicated Language of original: Psychometric evaluation largely
facial expression, 0.640.72 by significantly higher BPS French based on observations as unit
movements of upper Interrater reliability: scores during painful Translation: of analysis rather than
limbs, compliance with k = 0.74 (P < .01) procedure (repositioning) English patients
ventilation Good interrater reliability compared with rest periods Appears easy to use; Internal consistency is variable;
Scoring range: 312 (r2 = 0.910.89) and nonsignificant increase in requires 4 min, on interrater reliability varies
Percent agreement: average BPS during a less average, to complete widely across studies
36%91% painful procedure (eye care) Reported less difficulty Tool not evaluated in sample of
Test-retest: The higher the sedation/ agreeing on pain level older adults
Not established analgesia administered, the when pain level was
lower the BPS value as well as low, but greater when
BPS change assessing increased pain
Factor analysis supports content level
validity in adults Interpretation of tool
Support for tool ability to score unclear
detect change in clinical status
and detect painful procedures
is indicated by large effect size
for both subscale scores and
for total BPS scores
Despite significant increase in
physiologic variables (HR and
mean arterial BP) between rest
and painful procedure times,
correlations among BPS score
and HR/BP were not
significant.
Significant negative correlations
with Ramsay sedation scale;
the higher the sedation level,
the lower the BPS scores
CPOT55 4 items, including facial Internal consistency: Criterion validity with Language of original tool: Evidence of internal
expression, body Not established intubated/conscious patients French consistency is needed
movements, muscle Interrater reliability: indicated by significantly Requires 1-min Evaluation of French tool
tension, compliance to k = 0.520.88 higher CPOT scores for observation period conducted in French-speaking
ventilator if the patient Test-retest: patients reporting pain Interpretation of score population
is intubated or Not established presence compared with lack unclear Evaluation in English is needed
vocalization if of pain during positioning, at Tool evaluation in older adult
extubated rest, and recovery samples is warranted
Scoring range: 08 postprocedure Tool evaluation in larger
Moderate criterion validity in samples and with a variety of
extubated conscious patients conditions is needed
indicated by moderate
correlations between CPOT
scores and self-reported pain
intensity scores during
positioning, at rest and
recovery post-procedure
Moderate ability to discriminate
pain indicated by significantly
higher CPOT scores during
positioning than during rest
in three situations: (1)
intubated and unconscious,
(2) intubated and conscious,
and (3) extubated and
conscious
BP, blood pressure; BPS, Behavioral Pain Scale; CNPI, Checklist of Nonverbal Pain Indicators; CPOT, Critical Care Pain Observation Tool; FPS, Faces Pain Scale; GDS, Geriatric Depression Scale; HR,

heart rate; LTC, long-term care; MMSE, Mini-Mental State; NRS, numerical rating scale; PACSLAC, Pain Assessment Checklist for Seniors with Limited Ability to Communicate; PAINAD, Pain in
Advanced Dementia; VAS, visual analog scale; VDS, verbal descriptor scale.
33
evaluations are available based on French-, Dutch-, and Norwegian- the PAINAD as too concise, with too few pain cues included.75
speaking populations, but not on English-speaking ones. The In one study, raters did not use the breathing item in painful situa-
Doloplus 2 addresses many key indicators noted in the literature tions in over 80% of participants with pain.75 In another study,
and AGS Guidelines. Doloplus reflects the progression of experi- nurses expressed uncertainty regarding the consolability item.80
enced pain, not current pain experience; thus, intrarater and inter- Thus, the limited number of items restricts the ability of the
rater reliabilities of the tool represent a particular challenge PAINAD to detect pain in persons with dementia with more
and have not yet been adequately established. Although internal subtle behavioral presentation.
consistencies for the total scale and the psychomotor reactions
subscale were strong, reliabilities for somatic reactions and psycho-
social reactions subscales were low.75 Moreover, a Norwegian Behavioral Pain Scale81
study demonstrated that the four most informative tool items
explained 68% of the variance of the expert score, with the psycho- The Behavioral Pain Scale (BPS) is a French tool developed for crit-
social reactions subscale contributing little to the tool.76 Thus, ically ill, sedated adult patients undergoing mechanical ventilation.
despite evidence to support validity,49,75,76 there is indication of Initial reports of tool testing in trauma and postoperative ICUs in
need for a tool revision. Moreover, although clinicians report France81 and Morocco82 appear to provide initial support for relia-
the ctool manual is clear, in clinical testing, nurses reported that bility and validity; however, results are largely based on the total
the tool is difficult to score and interpret.75,76 number of observations rather than on individual patients. Initial
validation studies were conducted with younger adults; thus, testing
in older adult populations is needed. An English version of the BPS
was tested in Australia in unconscious medical and surgical ICU
The Pain Assessment Checklist for Seniors with patients, including some older patients (median age 64 yr, range
Severe Dementia77 1682).83 Reported reliabilities were variable, suggesting a need for
further testing under more tightly controlled conditions. Data were
The Pain Assessment Checklist for Seniors with Severe Dementia skewed toward the lower end of the BPS, which may indicate inac-
(PACSLAC), developed by a Canadian team, is a conceptually curate scaling of items. Patients were not assessed for delirium in
sound comprehensive checklist of pain behaviors that addresses any of these three BPS studies. Thus, further testing of the BPS is
all six pain behavioral categories included in the AGS Guidelines. needed to establish reliability and validity using patients as the unit of
In preliminary testing, the PACSLAC showed initial reliability and analysis, and moreover, testing in older adults is needed.
validity based on retrospective judgments. In recent prospective
testing of a Dutch version of the tool, interrater and intrarater
reliabilities were high.75 The tool includes 60 behavioral items; Critical Care Pain ObservationTool55
however, nearly half the items were not observed in over 90% of
the study subjects, suggesting a need for item reduction. Moreover, The Critical Care Pain Observation Tool (CPOT) is a French tool
although internal consistency for total tool score was good, results developed by a Canadian team for assessment of pain behaviors in
for subscale scores were poor to moderate, suggesting a need for critically ill patients unable to communicate verbally. The CPOT
tool revision. PACSLAC also showed good construct and congruent attempts to measure pain intensity via behavioral observation,
validity and was rated the most preferred behavioral pain tool which has not been substantiated in the literature. Initial tool test-
by Dutch nurses. Thus, the Dutch research team found the ing was conducted in cognitively intact adult surgical patients with
PACSLAC to be the most promising tool for further development.75 no delirium while unconscious, conscious, intubated, and after
extubation. Internal consistency was not reported, and interrater
reliability was only moderate; thus, further testing is necessary to
The Pain Assessment Checklist for Seniors with establish reliability. Initial tool validity was supported. Although
Severe DementiaçDutch-Revised75 this tool shows promise, tool testing in critically ill older adult
samples as well as testing in English-speaking populations are
The PACSLAC—Dutch-Revised (PACSLAC-D-Revised) is a 24- needed.
item preliminary tool with three subscales derived from the original
PACSLAC based on factor analysis. Internal consistencies of the
total tool and revised subscales are good. Moreover, the reduced Summary
version of the scale correlated highly with the original tool, suggest-
ing that validity is retained. However, further prospective, confir- This review demonstrates progress is being made in the develop-
matory testing in an independent sample is needed. ment and validation of behavioral pain tools for use with nonverbal
older adults. Yet, despite advances, no single pain behavioral
tool has been shown to be superior for use with older adults who
The Pain Assessment in Advanced Dementia are unable to communicate verbally owing to dementia or to
Scale78 unconscious state and/or intubation. Continued and concerted
effort is needed to develop and validate tools for nonverbal
The Pain Assessment in Advanced Dementia (PAINAD) scale was populations.
developed as a short, easy-to-use observation tool for behavioral
pain assessment in nonverbal older adults with advanced dementia.
Originally developed in English, the PAINAD has been translated CONCLUSION
and tested in Italian,79 Dutch,75 and German.80 Although inter-
rater75,7880 and test-retest75,79,80 reliabilities have been supported, Pain is an important health problem for nonverbal older adults
internal consistency is only moderate, with the breathing item scor- with dementia and delirium and during episodes of severe critical
ing persistently low.75 Evidence currently supports several types of illness requiring appropriate strategies for these vulnerable popula-
validity. However, despite mounting evidence of reliability and tions. A comprehensive approach to assessment is advocated,
validity, issues persist. The PAINAD attempts to measure severity including multiple sources of information to ensure a valid and
based on scoring of behaviors that has not been substantiated in the reliable basis on which to make treatment decisions. Behavioral
literature. Moreover, in clinical testing, nurses report experiencing observation and surrogate report are essential components of a
multifaceted approach to assessment that may include standardized 25. McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care
behavioral pain tools. Although some currently available tools for unit: occurrence and clinical course in older patients. J Am Geriatr
behavioral assessment in nonverbal older adults show promise, Soc 2003;51:591598.
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ity to warrant recommendation for broad adoption in clinical Meier DE (eds): Geriatric Palliative Care. New York: Oxford
University Press, 2003; pp 286303.
practice. 27. Culp KR, Wakefield B, Dyck MJ, et al. Bioelectrical impedance
analysis and other hydration parameters as risk factors for delirium in
rural nursing home residents. J Gerontol A Biol Sci Med Sci
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22. Horgas AL, Tsai P. Analgesic drug prescription and use in cognitively 49. Pautex S, Herrmann F, Le Lous P, et al. Feasibility and reliability of
impaired nursing home residents. Nurs Res 1998;47:235242. four pain self-assessment scales and correlation with an observational
23. Bernabei R, Gambassi G, Lapane K, et al. Management of pain in rating scale in hospitalized elderly demented patients. J Gerontol A
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51. Buffum MD, Miaskowski C, Sands L, Brod M. A pilot study of the 77. Fuchs-Lacelle S, Hadjistavropoulos T. Development and preliminary
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dementia. Geriatr Nurs 2001;22:8085. to Communicate (PACSLAC). Pain Manag Nurs 2004;5:3749.
52. Herr K, Garand L. Assessment and measurement of pain in older 78. Warden V, Hurley AC, Volicer L. Development and psychometric
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53. Herr K, Bjoro K, Decker S. Tools for assessment of pain in nonverbal scale. J Am Med Dir Assoc 2003;4:915.
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Symptom Manage 2006;31:170192. Pain Assessment in Advanced Dementia (PAINAD) scale. Arch
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Manage Nurs 2000;1:1321. 80. Schuler MS, Becker S, Kaspar R, et al. Psychometric properties of the
55. Gelinas C, Fillion L, Puntillo KA, et al. Validation of the Critical- German Pain Assessment in Advanced Dementia scale (PAINAD-G)
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2006;15:420427. 81. Payen JF, Bru O, Bosson JL, et al. Assessing pain in critically ill
56. Hurley AC, Volicer BJ, Hanrahan PA, et al. Assessment of discomfort sedated patients by using a behavioral pain scale. Crit Care Med
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57. Pasero C, McCaffery M. Pain in the critically ill. Am J Nurs 82. Aissaoui Y, Zeggwagh AA, Zekraoui A, et al. Validation of a
2002;102:5960. behavioral pain scale in critically ill, sedated, and mechanically
58. McCaffery M, Pasero C: Pain: Clinical Manual, 2nd ed. St. Louis: ventilated patients. Anesth Analg 2005;101:14701476.
Mosby, 1999. 83. Young J, Siffleet J, Nikoletti S, Shaw T. Use of a behavioural pain
59. Bell ML. Postoperative pain management for the cognitively impaired scale to assess pain in ventilated, unconscious and/or sedated patients.
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60. Hadjistavropoulos T, LaChapelle DL, MacLeod FK, et al. Measuring 84. Manfredi PL, Breuer B, Meier DE, Libow L. Pain assessment in
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61. Mentes JC, Teer J, Cadogan MP. The pain experience of cognitively 85. Cohen-Mansfield J, Creedon M. Nursing staff members’ perceptions
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62. Nygaard HA, Jarland M. Chronic pain in nursing home 86. Cohen-Mansfield J, Lipson S. Pain in cognitively impaired nursing
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Laegeforen 2005;125:13491351. Soc 2002;50:10391044.
63. Kovach CR, Weissman DE, Griffie J, et al. Assessment and treatment 87. Horgas AL, Dunn K. Pain in nursing home residents. Comparison of
of discomfort for people with late-stage dementia. J Pain Symptom residents’ self-report and nursing assistants’ perceptions.
Manage 1999;18:412419. incongruencies exist in resident and caregiver reports of pain;
64. Buffum MD, Sands L, Miaskowski C, et al. A clinical trial of the therefore, pain management education is needed to prevent suffering.
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65. Manfredi PL, Breuer B, Wallenstein S, et al. Opioid treatment for 2005;6:6875.
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2003;18:700705. impaired nursing home residents. J Pain Symptom Manage
66. Chibnall JT, Tait RC, Harman B, Luebbert RA. Effect of 2002;24:562571.
acetaminophen on behavior, well-being, and psychotropic medication 90. Pasero C, McCaffery M. No self-report means no pain-intensity
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J Am Geriatr Soc 2005;53:19211929. 91. Jones KR, Fink R, Hutt E, et al. Measuring pain intensity in nursing
67. Kovach CR, Noonan PE, Griffie J, et al. Use of the Assessment of home residents. J Pain Symptom Manage 2005;30:519527.
Discomfort in Dementia protocol. Appl Nurs Res 2001;14:193200. 92. Zwakhalen SMG, Hamers JPH, Berger MPF. Improving the clinical
68. Kovach CR, Noonan PE, Schlidt AM, et al. The Serial Trial usefulness of a behavioural pain scale for older people with dementia.
Intervention: an innovative approach to meeting needs of individuals J Adv Nurs 2007;58:493502.
with dementia. J Gerontol Nurs 2006;32:1825. 93. Lane P, Kuntupis M, MacDonald S, et al. A pain assessment tool for
69. Hadjistavropoulos T. Assessing pain in older persons with people with advanced Alzheimer’s and other progressive dementias.
severe limitations in ability to communicate. In Gibson SJ, Weiner Home Healthc Nurse 2003;21:3237.
DK (eds): Pain in Older Persons. Seattle: IASP Press, 2005; 94. Basler HD, Huger D, Kunz R, et al. Assessment of pain in advanced
pp 135-151. dementia. Construct validity of the German PAINAD. Schmerz
70. Stolee P, Hillier LM, Esbaugh J, et al. Instruments for the assessment 2006;20:519526.
of pain in older persons with cognitive impairment. J Am Geriatr Soc 95. Leong IY, Chong MS, Gibson SJ. The use of a self-reported pain
2005;53:319326. measure, a nurse-reported pain measure and the PAINAD in nursing
71. Zwakhalen SM, Hamers JP, Abu-Saad HH, Berger MP. Pain in elderly home residents with moderate and severe dementia: a validation
people with severe dementia: a systematic review of behavioural pain study. Age Ageing 2006;35:252256.
assessment tools. BMC Geriatr 2006;6:3. 96. Leong IY, Nuo TH. Prevalence of pain in nursing home residents
72. van Herk R, van Dijk M, Baar FP, et al. Observation scales for pain with different cognitive and communicative abilities. Clin J Pain
assessment in older adults with cognitive impairments or 2007;23:119127.
communication difficulties. Nurs Res 2007;56:3443.
73. Nygaard HA, Jarland M. The Checklist of Nonverbal Pain Indicators
(CNPI): testing of reliability and validity in Norwegian nursing
homes. Age Ageing 2006;35:7981. SUGGESTED READINGS
74. Lefebvre-Chapiro S, The Doloplus group. The Doloplus 2
scale—evaluating pain in the elderly. Eur J Palliat Care American Geriatric Society (AGS) Panel on Persistent Pain in Older
2001;8:191-194. Persons. The management of persistent pain in older persons. J Am
75. Zwakhalen SM, Hamers JP, Berger MP. The psychometric quality and Geriatr Soc 2002;50:S205S224.
clinical usefulness of three pain assessment tools for elderly people Closs SJ, Barr B, Briggs M, et al. A comparison of five pain assessment
with dementia. Pain 2006;126:210220. scales for nursing home residents with varying degrees of cognitive
76. Holen JC, Saltvedt I, Fayers PM, et al. The Norwegian Doloplus-2, impairment. J Pain Symptom Manage 2004;27:196205.
a tool for behavioural pain assessment: translation and pilot- Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary expert
validation in nursing home patients with cognitive impairment. consensus statement on assessment of pain in older persons. Clin J Pain
Palliat Med 2005;19:411417. 2007;23:S1S43.
Herr K, Bjoro K, Decker S. Tools for assessment of pain in nonverbal Proctor WR, Hirdes JP. Pain and cognitive status among nursing home
older adults with dementia: a state-of-the-science review. J Pain residents in Canada. Pain Res Manage 2001;6:119125.
Symptom Manage 2006;31:170192. Scherder E, Oosterman J, Swaab D, et al. Recent developments in pain in
Herr K, Coyne PJ, Key T, et al. Pain assessment in the nonverbal patient: dementia. BMJ 2005;330:461464.
position statement with clinical practice recommendations. Pain Zwakhalen SM, Hamers JP, Berger MP. The psychometric quality and
Manage Nurs 2006;7:4452. clinical usefulness of three pain assessment tools for elderly people with
McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care dementia. Pain 2006;126:210220.
unit: occurrence and clinical course in older patients. J Am Geriatr Soc
2003;51:591598.
Chapter 6 from the IASP definition and proposed that the definition for NP
be ‘‘pain initiated or caused by a primary lesion of the nervous
NEUROPATHIC system.’’ Conversely, Jensen and coworkers3 opined that going
back to a pure neuroanatomic description of NP overlooks the
plasticity of the nervous system and its continuous modulation,
PAIN—DEFINITION, which may change after activation or injury. In 2002, Merskey4
noted that without the word ‘‘dysfunction’’ in the definition of
IDENTIFICATION, AND NP, the entity of trigeminal neuralgia may require two subcate-
gories, one neuropathic with a definable lesion and one not. In
IMPLICATIONS FOR RESEARCH 2006, Gary Bennett suggested that given the present level of under-
standing, a clean separation between inflammatory pain and NP
may not be realistic in many patients, and a satisfying definition
AND THERAPY of NP may not be currently possible.
A clinically acceptable definition of NP is vitally important because
Howard S. Smith, Misha-Miroslav Backonja, effective treatment of NP remains a challenge and the number of
Marco Pappagallo and Charles E. Argoff patients with NP is significant and growing. A group consisting of
neurologists, neuroscientists, clinical neurophysiologists, and neuro-
surgeons established a task force in collaboration with the IASP
Special Interest Group on Neuropathic Pain (NeuPSIG) and put
forth a revised definition and grading system for NP.5
Treede and associates5 proposed that NP be redefined/reworded
as ‘‘pain arising as a direct consequence of a lesion or disease
INTRODUCTION affecting the somatosensory system.’’ Peripheral NP and
central NP are proposed to refer to lesions/disease of the periph-
Neuropathic pain (NP) presents a puzzle to patients and a challenge eral nervous system (PNS) and central nervous system (CNS),
to clinicians because it manifests simultaneously with seemingly respectively.5
contradictory positive (pain) and negative (lack of sensation) sen- The NP grading system is used to decide on the level of certainty
sory phenomena. The lack of a conceptual framework within which with which the presence or absence of NP can be determined in an
progress in the science of pain can translate into improvement in individual patient.5 The grading of certainty for the presence of NP
clinical care and vice versa presents additional difficulty when consists of
addressing NP.
Definite NP: all (14).
Derasari1 stated that the main impact of effective taxonomy is
Probable NP: 1 and 2, plus either 3 or 4.
the framework for the interpretation of the differences and simila-
Possible NP: 1 and 2, without confirmatory evidence from 3 or 4.
rities in living organisms in light of comparative genetics, biochem-
istry, physiology, embryology, behavior, and etiology. Commonly The levels ‘‘definite’’ and ‘‘probable’’ indicate that the presence
accepted terminology and classifications of pain have recently come of this condition has been established. The level ‘‘possible’’ indicates
under scrutiny as our understanding of central and peripheral that the presence of this condition has not yet been established,
pathophysiologic processes has continued to grow. One key exam- which should instigate additional investigations in this patient,
ple has been NP. Simple distinctions such as that of nociceptive either immediately or during follow-up. If a patient does not fulfill
pain versus NP are woefully inadequate. The term nociceptive pain the criteria for any of these three levels, it is considered unlikely that
refers to pain that is transmitted under laboratory conditions of this patient has NP.5
pain stimulation that do not truly exist in any clinical situation. The criteria to be evaluated for each patient are
More importantly, the lack of specificity of the term as proposed by
1. Pain with a distinct neuroanatomically plausible distribution.*
the International Association for the Study of Pain (IASP) is con-
2. A history suggestive of a relevant lesion or disease affecting the
tradictory to the preferred approach—the mechanism-based diag-
peripheral or central somatosensory system.{
nosis and treatment of all painful conditions.
NP remains a significant challenge to diagnose and treat effec-
tively. Perhaps, this is in part related to the difficulty in defining NP.
The IASP defined NP as ‘‘pain initiated or caused by a primary *A region corresponding to a peripheral innervation territory or to the topo-
lesion or dysfunction in the nervous system.’’ graphic representation of a body part in the CNS.
{
Controversy exists regarding the definition of NP and what it The suspected lesion or disease is reported to be associated with pain, including
entails. Max2 argued for removal of the words ‘‘or dysfunction’’ a temporal relationship typical for the condition.
Herr K, Bjoro K, Decker S. Tools for assessment of pain in nonverbal Proctor WR, Hirdes JP. Pain and cognitive status among nursing home
older adults with dementia: a state-of-the-science review. J Pain residents in Canada. Pain Res Manage 2001;6:119125.
Symptom Manage 2006;31:170192. Scherder E, Oosterman J, Swaab D, et al. Recent developments in pain in
Herr K, Coyne PJ, Key T, et al. Pain assessment in the nonverbal patient: dementia. BMJ 2005;330:461464.
position statement with clinical practice recommendations. Pain Zwakhalen SM, Hamers JP, Berger MP. The psychometric quality and
Manage Nurs 2006;7:4452. clinical usefulness of three pain assessment tools for elderly people with
McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care dementia. Pain 2006;126:210220.
unit: occurrence and clinical course in older patients. J Am Geriatr Soc
2003;51:591598.
Chapter 6 from the IASP definition and proposed that the definition for NP
be ‘‘pain initiated or caused by a primary lesion of the nervous
NEUROPATHIC system.’’ Conversely, Jensen and coworkers3 opined that going
back to a pure neuroanatomic description of NP overlooks the
plasticity of the nervous system and its continuous modulation,
PAIN—DEFINITION, which may change after activation or injury. In 2002, Merskey4
noted that without the word ‘‘dysfunction’’ in the definition of
IDENTIFICATION, AND NP, the entity of trigeminal neuralgia may require two subcate-
gories, one neuropathic with a definable lesion and one not. In
IMPLICATIONS FOR RESEARCH 2006, Gary Bennett suggested that given the present level of under-
standing, a clean separation between inflammatory pain and NP
may not be realistic in many patients, and a satisfying definition
AND THERAPY of NP may not be currently possible.
A clinically acceptable definition of NP is vitally important because
Howard S. Smith, Misha-Miroslav Backonja, effective treatment of NP remains a challenge and the number of
Marco Pappagallo and Charles E. Argoff patients with NP is significant and growing. A group consisting of
neurologists, neuroscientists, clinical neurophysiologists, and neuro-
surgeons established a task force in collaboration with the IASP
Special Interest Group on Neuropathic Pain (NeuPSIG) and put
forth a revised definition and grading system for NP.5
Treede and associates5 proposed that NP be redefined/reworded
as ‘‘pain arising as a direct consequence of a lesion or disease
INTRODUCTION affecting the somatosensory system.’’ Peripheral NP and
central NP are proposed to refer to lesions/disease of the periph-
Neuropathic pain (NP) presents a puzzle to patients and a challenge eral nervous system (PNS) and central nervous system (CNS),
to clinicians because it manifests simultaneously with seemingly respectively.5
contradictory positive (pain) and negative (lack of sensation) sen- The NP grading system is used to decide on the level of certainty
sory phenomena. The lack of a conceptual framework within which with which the presence or absence of NP can be determined in an
progress in the science of pain can translate into improvement in individual patient.5 The grading of certainty for the presence of NP
clinical care and vice versa presents additional difficulty when consists of
addressing NP.
Definite NP: all (14).
Derasari1 stated that the main impact of effective taxonomy is
Probable NP: 1 and 2, plus either 3 or 4.
the framework for the interpretation of the differences and simila-
Possible NP: 1 and 2, without confirmatory evidence from 3 or 4.
rities in living organisms in light of comparative genetics, biochem-
istry, physiology, embryology, behavior, and etiology. Commonly The levels ‘‘definite’’ and ‘‘probable’’ indicate that the presence
accepted terminology and classifications of pain have recently come of this condition has been established. The level ‘‘possible’’ indicates
under scrutiny as our understanding of central and peripheral that the presence of this condition has not yet been established,
pathophysiologic processes has continued to grow. One key exam- which should instigate additional investigations in this patient,
ple has been NP. Simple distinctions such as that of nociceptive either immediately or during follow-up. If a patient does not fulfill
pain versus NP are woefully inadequate. The term nociceptive pain the criteria for any of these three levels, it is considered unlikely that
refers to pain that is transmitted under laboratory conditions of this patient has NP.5
pain stimulation that do not truly exist in any clinical situation. The criteria to be evaluated for each patient are
More importantly, the lack of specificity of the term as proposed by
1. Pain with a distinct neuroanatomically plausible distribution.*
the International Association for the Study of Pain (IASP) is con-
2. A history suggestive of a relevant lesion or disease affecting the
tradictory to the preferred approach—the mechanism-based diag-
peripheral or central somatosensory system.{
nosis and treatment of all painful conditions.
NP remains a significant challenge to diagnose and treat effec-
tively. Perhaps, this is in part related to the difficulty in defining NP.
The IASP defined NP as ‘‘pain initiated or caused by a primary *A region corresponding to a peripheral innervation territory or to the topo-
lesion or dysfunction in the nervous system.’’ graphic representation of a body part in the CNS.
{
Controversy exists regarding the definition of NP and what it The suspected lesion or disease is reported to be associated with pain, including
entails. Max2 argued for removal of the words ‘‘or dysfunction’’ a temporal relationship typical for the condition.
38 Chapter 6 NEUROPATHIC PAIN ç DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH AND THER APY
Table 6^1. Comparison of Items within Five Neuropathic ScreeningTools*
LANSS{ DN4{ NPQ painDETECT ID Pain

Symptoms
Pricking, tingling, pins and needles
Electric shocks or shooting
Hot or burning
Numbness
Pain evoked by light touching
Painful cold or freezing pain
Pain evoked by mild pressure
Pain evoked by heat or cold
Pain evoked by changes in weather
Pain limited to joints{
Itching
Temporal patterns
Radiation of pain
Autonomic changes
Clinical Examination
Brush allodynia
Raised soft touch threshold
Raised pinprick threshold
DN4, Douleur Neuropathic 4 Questions; LANSS, Leeds Assessment of Neuropathic Symptoms and Signs; NPQ, Neuropathic Pain Questionnaire.
*Shaded areas highlight features shared by two or more tools.
{
Tools that involve clinical examination.
{
Used to identify nonneuropathic pain.
From Bennett MI, Attal N, Backonja MM, et al. Using screening tools to identify neuropathic pain. Pain 2007;127:199203.
3. Demonstration of the distinct neuroanatomically plausible dis- CURRENT SCREENING TOOLS FOR NP
tribution by at least one confirmatory test.{
4. Demonstration of the relevant lesion or disease by at least one Multiple measurement tools exist to assess the intensity of pain,
confirmatory test.§5 however. In 1997, Galer and Jensen6 published the NPS in efforts
to assess the intensity of, specifically, NP. The NPS is essentially a
Treede and associates5 pointed out that controversy over measurement tool of NP severity. The NPS was designed to assess
whether diseases such as complex regional pain syndrome I consti- distinct pain qualities associated with NP.6 In 2005, Jensen and
tute NP will not be resolved by their proposed definition. However, colleagues7 proposed that the NPS may have utility in assessing
it is conceivable that future tools/research may help sort this changes in pain qualities after analgesic treatments (e.g., lidocaine
out. This new definition and criteria will likely yield a lower sensi- 5% patch).
tivity but higher specificity than the IASP definition for the identi- NP presents some unique issues, and it may be difficult at
fication of NP. times to correctly recognize the neuropathic qualities of various
Although the precise incidence of NP in the general population painful complaints by patients. In 2007, Bennett and coworkers8
is unknown, it appears that NP exists in a significant portion of the reviewed five screening tools used to identify NP (with up to
population and, thus, presents a major clinical problem. Torrance 80% sensitivity and specificity) (Table 61). It can be appreciated
and colleagues mailed a questionnaire (which included the Self- that the first three items (‘‘pricking, tingling, pins and needles,’’
complete Leeds Assessment of Neuropathic Symptoms and Signs ‘‘electric shocks or shooting,’’ and ‘‘hot or burning’’) are present in
[S-LANSS] and the Neuropathic Pain Scale [NPS]; described later) all tools, with the next two items (‘‘numbness’’ and ‘‘pain evoked
to six family practices in three U.K. cities and found that chronic by light touching’’) present in 80% of the tools in Table 61.
pain with neuropathic features appears to be more common in the
general population than previously suggested.
Leeds Assessment of Neuropathic Symptoms and
Signs
In 2001, Bennett9 published the Leeds Assessment of Neuropathic
{
As part of the neurologic examination, these tests confirmed the presence of Symptoms and Signs (LANSS), which contains five symptom and
negative or positive neurologic signs concordant with the supplemented by lab- two clinical examination items and is easy to score within clinical
oratory and objective tests to uncover subclinical abnormalities. settings. In 2005, Bennett and associates10 validated a self-report
§
As part of the neurologic examination, these tests confirm the diagnosis of the tool, the S-LANSS. The original LANSS was developed in a
suspected lesion or disease. These confirmatory tests depend on which lesion or sample of 60 patients with chronic nociceptive pain or NP and
disease is causing NP.5 validated in a further sample of 40 patients. Sensitivity and
specificity in the latter group were 85% and 80%, respectively, A score of 1 is given to each positive item and a score of 0 is given to
compared with clinical diagnosis. each negative item. The total score is the sum of the 10 items. The
The LANSS has subsequently been tested and validated in sev- DN4 is easy to score, and a total score of 4 or more out of 10
eral settings. Although the LANSS was not designed as a measure- suggests NP. The DN4 showed 83% sensitivity and 90% specific-
ment tool, Khedr and colleagues11 showed sensitivity to treatment ity when compared with clinical diagnosis in the development
effects. study. The first 7 sensory descriptors (based solely on patient inter-
view) can be used as a self-report questionnaire with similar results
(Box 61). DN4 is complementary to the NPS or the Neuropathic
Douleur Neuropathique 4 Questions Pain Symptom Inventory (NPSI). In 2004, Bouhassira and associ-
ates13 published the NPSI for the evaluation of different symptoms
In 2005, Bouhassira and coworkers12 published a comparison of and dimensions of NP. The final version of the NPSI includes
pain syndromes associated with nervous or somatic lesions utilizing 10 descriptors (plus 2 temporal items) that allow discrimination
a new NP diagnostic questionnaire. The French Neuropathic and quantification of five distinct clinically relevant dimensions
Pain Group developed a clinician-administered questionnaire of NP syndromes. It has been suggested that NPSI is particularly
called DN4, which stands for ‘‘douleur neuropathique 4 questions’’ suitable to assess treatment outcome.
(i.e., ‘‘neuropathic pain four questions,’’ in French). The DN4
was validated in 160 patients with either NP or nociceptive pain.
The most common etiologies of NP (n = 89) were traumatic nerve Neuropathic Pain Questionnaire
injury, postherpetic neuralgia (PHN), and poststroke pain.
Nonneurologic conditions included osteoarthritis, inflammatory In 2003, Krause and Backonja14 published the Neuropathic Pain
arthropathies, and mechanical low back pain. It consists of Questionnaire (NPQ), which consists of 12 items, including
7 items related to symptoms and 3 related to clinical examination. 10 related to sensations or sensory responses and 2 related to
affect. It was developed in 382 patients with a broad range of
chronic pain diagnoses. The discriminant function was initially
calculated on a random sample of 75% of the patients and then
cross-validated in the remaining 25%. The NPQ demonstrated
Box 6^1 COMPARISON OF PAIN SYNDROMES ASSOCIATED 66% sensitivity and 74% specificity compared with clinical diag-
nosis in the validation sample. Backonja and Krause15 also pub-
WITH NERVOUS OR SOMATIC LESIONS AND
lished a short form of the NPQ, which maintained similar
DEVELOPMENT OF A NEW NEUROPATHIC PAIN discriminative properties with only 3 items: (1) positive sensory
DIAGNOSTICS QUESTIONNAIRE (DN4) phenomena (‘‘increased pain due to touch’’); (2) negative sen-
sory phenomena (‘‘numbness’’); and (3) phenomena suggestive
Please complete this questionnaire by ticking one answer for each of paresthesia and dysesthesia (‘‘tingling’’).
item in the 4 questions below:
INTERVIEW OF THE PATIENT

painDETECT
Question 1: Does the pain have one or more of the following
characteristics? In 2005, Freynhagen and colleagues16 published the screening tool
referred to as painDETECT, which was developed and validated in
yes no German. painDETECT incorporated an easy-to-use, patient-based
1 - Burning (self-report) questionnaire with nine items that do not require a
2 - Painful cold clinical examination. There are seven weighted sensory descriptor
3 - Electric shocks items (‘‘never’’ to ‘‘very strongly’’) and two items relating to the
spatial (‘‘radiating’’) and temporal characteristics of the individual
Question 2: Is the pain associated with one or more of the following
pain pattern. The painDETECT questionnaire (PD-Q) was devel-
symptoms in the same area?
oped in cooperation with the German Research Network on
yes no Neuropathic Pain; validated in a prospective, multicenter study of
4 - Tingling 392 patients with either NP (n = 167) or nociceptive pain (n = 225);
5 - Pins and needles and subsequently applied to a population of roughly 8000 patients
6 - Numbness with low back pain. The tool correctly classified 83% of patients
7 - Itching to their diagnostic group with a sensitivity of 85% and a specificity
of 80%. It is also available in English.
EXAMINATION OF THE PATIENT
Question 3: Is the pain located in an area where the physical

examination may reveal one or more of the following characteristics? ID Pain
yes no In 2006, Portenoy17 published the ID Pain, which consists of five
8 - Hypoesthesia to touch sensory descriptor items and one item relating to whether pain is
9 - Hypoesthesia to prick located in the joints (used to identify nociceptive pain). It also does
not require a clinical examination (Table 62). The tool was devel-
Question 4: In the painful area, can the pain be caused or oped in a multicenter study of 586 patients with chronic pain of
increased by: nociceptive, mixed, or neuropathic etiology and validated in a mul-
ticenter study of 308 patients with similar pain classifications. The
yes no
10-Brushing
tool was designed to screen for the likely presence of a neuropathic
component to the patient’s pain.
From Bouhassira D, Attal N, Alchaar H, et al.Comparison of pain syndromes associated with ner- In the validation study, 22% of the nociceptive group, 39% of
vous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire
(DN4). Pain 2005;114:2936. the mixed group, and 58% of the neuropathic group scored above 3
points, the recommended cut-off score.
Table 6^2. ID Pain Questionnaire Neuropathic pain

mechanisms
None Severe
OA
Phantom
pain (post
pain mechanisms
PHN trauma)
Inflammatory
CRPS
PDN
RA CIDP
Severe
From Portenoy R. Development and testing of a neuropathic
pain screening questionnaire: ID Pain. Curr Med Res Opin Figure 6^1. Spectrum of pathophysiologic mechanisms, neuropathic
2006;22:15551565. and inflammatory, and their influence on common painful disorders.
CIDP, chronic inflammatory diabetic polyneuropathy; CRPS, complex
CATEGORIZING NP regional pain syndrome; OA, osteoarthritis; PDN, painful diabetic
neuropathy; PHN, postherpetic neuralgia; RA, rheumatoid arthritis.
Traditionally, neurologic research and practice have followed a dis-
tinction between the PNS and the CNS, and in many regards, this
division has served the field of neurology very well—for example, more of a ‘‘mixed picture’’ and the specific type of insults appears to
clearly distinct clinical courses have been mapped for demyelinating be somewhat dose-dependent. The systematically obtained clinical
disorders of the PNS (e.g., inflammatory demyelinating polyradicu- and experimental data would then determine whether a particular
loneuropathy) and of the CNS (e.g., demyelinating disorder of mul- pain disorder is neuropathic or whether it presents a transitional
tiple sclerosis), although both can be progressive and, as part of form (i.e., at the overlapping borders of NP and other pain pro-
presentation, have chronic pain. Conversely, pain does not neces- cesses) (Fig. 61).
sarily respect that distinction between the PNS and the CNS because Conventional older classifications have divided persistent pain
any time a painful event occurs, the whole system is activated, from into two mutually exclusive categories: nociceptive and neuropath-
nociception, to modulation, to perception—leading to a reaction to ic. Clinicians later realized that in practice, pain complaints were
pain. Petersen and coworkers18 shed light on the fact that NP, even not strictly black and white, and they considered a categorization of
though it may appear ‘‘centralized,’’ may still exhibit ongoing persistent pain as (1) neuropathic, (2) nonneuropathic (e.g., noci-
nociceptive input from the periphery. A further conceptual chal- ceptive), or (3) nonneuropathic with neuropathic features/qualities/
lenge for NP is that, although the clinical course and expression of characteristics or a neuropathic component. This third category
the disorder are under the influence of the underlying disease pro- refers to a single pain complaint that contains a mix of nonneuro-
cess (e.g., painful diabetic peripheral neuropathy vs. spinal cord pathic pain with a neuropathic component.
injury), most of its phenomenologic manifestations including ongo- Rasmussen and associates20 examined whether symptoms and
ing pain, pain paroxysms, and various types of hyperalgesia are signs cluster in patients with increasing evidence of NP. They
frequently similar, regardless of whether injury occurs to the PNS used three categories of NP (‘‘definite,’’ ‘‘possible,’’ and ‘‘unlikely’’)
or the CNS. The nature and the extent of the nervous system injury based on detailed sensory examination and found a considerable
and the natural course of repair that follows with involvement of overlap of symptoms and signs between the categories, using the
inflammatory processes all add to the complexity and dynamic Short-form McGill Pain Questionnaire (SF-MPQ).21
nature of NP in each particular case. Distinguishing NP from nonneuropathic pain in a specific patient’s
NP has its own signature characteristics. There are books complaint is an interesting challenge because in many patients there
(Pappagallo M [ed]. The Neurological Basis of Pain. New York: is a likely mix. A single pain complaint from a patient may represent
McGraw-Hill, 2005), journals (The Journal of Neuropathic Pain a fusion or mesh of NP and inflammatory pain. Attempts to ‘‘tease
and Symptom Palliation), and groups (the NeuPSIG of the IASP) out’’ ‘‘how much’’ (if any) of the pain complaint is neuropathic in
largely devoted specifically to NP. Modern neuroimaging methods nature may potentially be worthwhile because it may affect medical
(position-emission tomography [PET] and functional magnetic res- decision making regarding the planning of treatment strategies.
onance imaging [fMRI]) have overall indicated that acute physio- Backonja and Stacey22 evaluated NP relative to overall pain
logic pain and NP have distinct, although overlapping, brain rating. Intensity of symptoms as rated by NPQ and NPS items
activation patterns but that there is no unique ‘‘neuropathic pain varied widely, with the least intense being ‘‘itch and cold sensation’’
matrix’’ or ‘‘allodynia network.’’19 on NPS and ‘‘heat and emotional upset’’ on NPQ. The most intense
The distinction between inflammatory pain and NP in many ratings were ‘‘unpleasant and sharp’’ on NPS and ‘‘distressing and
regards is arbitrary, but on a practical level, the distinction may stabbing’’ on NPQ (Fig. 62).
have direct implications for the diagnostic steps and therapeutic Smith and colleagues23 sent the S-LANSS questionnaire to 6000
planning in addition to the natural course of the disease for each adults from general practices in the United Kingdom, along with
type of pain. Insult or irritation of nerves may promote inflamma- chronic pain identification and severity questions, the Brief Pain
tion and inflammation may affect neural function. In fact, even in Inventory (BPI), the NPS, and the SF-MPQ general health
the basic sciences, various animal models may not be ‘‘black and questionnaires.
white.’’ Although the air pouch model appears to be largely inflam- The chronic Pain of Predominantly Neuropathic Origin
matory and the chronic constriction injury model appears largely (POPNO) group reported higher pain severity and had significantly
neuropathic, injection of formalin into the rodent hind paw poorer scores for all interference items of the BPI than those with
(traditionally considered an inflammatory model) may actually be chronic pain (non-POPNO).23 Mean scores from the NPS were also
INTENSITY OF SYMPTOMS AS RATED ON NPQ issue of Pain. Weingarten and coworkers27 mailed a short question-
95% Bonferroni CI for the Mean naire that included questions on pain and, specifically, the S-LANSS
to nearly 6000 community adults and received over 3500 replies.10
10
A subsample of these respondents were invited for clinical assess-
8 ment, and finally, a comparison was made between clinical assess-
ment and responses to S-LANSS after a gap of 3 to 12 months.26
Intensity rating
6
Weingarten and coworkers27 asked subjects only for ‘‘any pain in
the last 3 months as opposed to pain lasting for more than
3 months.’’26 The prevalence of NP derived from the survey of
4
Weingarten and coworkers27 (8.8%) is very close to that reported
by Torrance and associates.24
2
Patient’s symptoms remain the cornerstone of pain assess-
0 ment; however, patients’ complaints should not be the sole deter-
minant in categorizing NP. NP needs to be carefully assessed
g
s
l
ng
by trained pain specialists, starting with a complete and thorough

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d
t
na
ea
es
in
lin
in
ol
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io
ot
H
bn
ng
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history and physical examination. This would include assessing
ab
r
ot
o
Bu
tre
Ti
Sh
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St
is
mechanical and thermal hyperalgesia/allodynia as well as a

N
detailed, more traditional neurologic examination. The combina-

INTENSITY OF SYMPTOMS AS RATED ON NPQ tion of history, physical examination, and ancillary confirmatory
95% CI for the Mean testing, although providing enough information to categorize NP
based on the criteria of Treede and associates,5 is not sufficient
10 to precisely dissect all patient’s pain complaints into neuropathic,
nonneuropathic, or mixed. Ideally, a valid specific tool for the
8 examination of patients with chronic pain will be developed that
Intensity rating
will allow the examiner at the conclusion to be able to accurately

6 predict whether or not NP is present. Or perhaps testing may be
developed that could be used in conjunction with data from the
4 history and physical examinations to aid in the identification of
an NP component.
2 Furthermore, when appropriate, this information may be sup-
plemented with various laboratory testing, imaging, electrodiagnos-
0 tic testing, quantitative sensory testing (QST), as well as specific
testing of the skin such as provocative or challenge testing, assessing
t
d
p
ve
ce
p
l
ot
hy
an
ul
ol
ee
ar
whether various agents (e.g., capsaicin) exacerbate, alleviate, or do

D
iti
Itc
rfa
C
as
Sh
D
ns
Su
PS
le
not affect preexisting spontaneous pain, and analysis of skin punch

Se
np
N
biopsies. In addition, the future information from PET imaging or

Figure 6^2. Intensity of neuropathic pain symptoms as rates on the fMRI may be useful to supplement these data.
Neuropathic Pain Questionnaire (NPQ) and the Neuropathic Pain Over the last 2 decades, QST has been developed to complement
Scale (NPS). (Reproduced from Backonja MM, Stacey B. Neuropathic traditional neurologic bedside examination in the analysis of soma-
pain symptoms relative to overall pain rating.J Pain 2004;5:491497.). tosensory aberrations.28 This approach, derived from experimental
psychophysics, consists of measuring the responses (i.e., nonpainful
significantly higher for the chronic POPNO group reporting the sensations and pain) evoked by mechanical and thermal stimuli, the
worst health.23 After adjusting for pain severity, age, and sex, the intensity of which is controlled by automated devices.29
chronic POPNO group was still found to have poorer scores than QST is based on precise definition of the stimulus properties
the non-POPNO group in all domains of the SF-MPQ and all (modality, intensity, spatial, and temporal characteristics), analysis
interference items in the BPI, indicating poorer health and greater of the quality of evoked sensation, and quantification of its inten-
disability.23 This study supports the importance of identifying NP sity.29 In addition to the evaluation of sensory thresholds (i.e., the
in the community and the need for multidimensional management detection threshold for innocuous stimuli and pain threshold), QST
strategies that address all aspects of health.23 includes the assessment of sensations evoked by suprathreshold
Postal surveys were carried out in large community samples stimuli.3032 The German Research Network on Neuropathic Pain
from the United Kingdom23,24 and France25 in attempts to gain (DFNS) developed a comprehensive QST protocol consisting of
information regarding the epidemiology of NP in the general 7 tests measuring 13 parameters and defined a set of normative
population. Although different NP questionnaires were used data for thermal and mechanical detection and pain thresholds
(i.e., S-LANSS in the United Kingdom and DN4 in France), similar for the hand, foot, and face in healthy volunteers.33
estimates of the prevalence of chronic pain with neuropathic char- The expected role of QST in the definition of a mechanisms-
acteristics were reported in the general population, around 7% to based approach to NP has not yet been met. QST has helped to
8%.26 Interestingly, these population-based studies showed that the determine selective roles for different peripheral fibers or ascending
subset of respondents with NP features had several associated clin- pathways in specific conditions.3436 However, there are probably
ical characteristics that differed from other respondents with no simple relationships between the pattern of sensory deficits
chronic pain, even after controlling for pain severity. These char- and NP symptoms37; and the ultimate aim of marrying clinical
acteristics include significantly worse quality of life, greater inter- symptoms and signs with pain pathophysiology still has to be
ference from pain, and pain of longer duration.26 accomplished.29
One limitation inherent to this approach is the lack of direct Max38 stated that small academic clinical trials so far have failed
information regarding the etiology of pain. In other words, how to identify obvious differences in the response to various drugs of
sure can we be that a positive responder to a postal screening tool different pain symptoms in the same condition. In contrast, there
would be diagnosed with NP if seen by a pain specialist in a clinic? are clear differences in the analgesic responses of patient groups
Weingarten and coworkers27 addressed this very question and distinguished on the basis of etiology or tissue origin of pain, factors
reported on a community validation study of the S-LANSS in an that tend to be associated with groups of mechanisms.38
An emphasis has been on supplementing a disease-based treat- between anxiety and pain in humans. The influence of pain on
ment approach with one based on symptoms (used as an indicator) psychiatric comorbidities and vice versa are extremely complex
and their underlying putative mechanisms.39 This approach accounts and far from clear. The availability of many specific assessment
for the observation that patients with one disease entity (e.g., diabetic tools for human as well as bench research provides ample oppor-
neuropathy) may have vastly different symptoms arising from tunities to study those relationships.
different mechanisms and that patients with different diseases may Backonja and Argoff42 proposed a framework to assist in
have similar symptoms arising from the same mechanism.40 obtaining a complete clinical picture about each individual patient.
Treatment of NP should be supplemented by the signs and The suggested multidimensional assessment approach (Table 63)
symptoms manifested by the patient as well as by any pertinent provides the means of assessing critical dimensions of chronic pain
ancillary data including history and physical examination informa- specifically and, on the basis of that assessment, rank-ordering
tion challenge testing, imaging electrodiagnostic studies, QST, and components that contribute to the patient’s presentation at any
skin biopsies. By specifically targeting the mechanisms underlying given time.42 It provides for the complexity as well as the dynamic
these symptoms, an improved therapeutic response may be rea- nature of pain. Certainly, use of validated pain-intensity rating
lized.41 The clinician may need to explore ‘‘rational polypharma- scales are still considered the ‘‘gold standards’’ for pain-intensity
cotherapy’’ on a case-by-case basis when a single agent is ineffective assessment, but use of a more comprehensive approach may
in relieving a patient’s reported symptoms.41 provide insight into how any particular component of pain,
including multiple components of NP, behave in time and respond
to treatments.
CLINICAL IMPLICATIONS
The challenge for NP diagnosis and assessment is the complexity MDPA
not only of the primary manifestation of symptoms but also the
many other manifestations of NP as a disease that crosses more than I. Medical etiology related to pain (e.g., diabetes) and medical
one domain. For this complexity to be captured and communi- comorbidities that could influence manifestation of pain symp-
cated, a model of Multidimensional Pain Assessment (MDPA) has toms (e.g., hypothyroidism).
been proposed by Backonja and Argoff.42 II. Pain mechanisms, such as neuropathic, inflammatory,
The clinical implications of NP and challenges for the diag- myofascial.
nosis and assessment originate from the fact that the inciting III. Psychiatric comorbidity (e.g., depression, anxiety), patients’
illness or injury may have many consequences in addition to coping skills, and tendency to catastrophize.
pain. As discussed previously, each illness, be it PHN or diabetes IV. Impact of pain on ability to function (with loss of function
mellitus, has a specific clinical course and associated comorbid- comes the disabilities) and quality of life.
ities. Those comorbidities may be medical, such as hypertension
and hypothyroidism, or psychiatric, such as depression and anx- The most significant implication of applying this approach is the
iety. Medical and psychiatric comorbidities may or may not ability to comprehensively assess pain and to prioritize necessary
further affect NP. Even though many comorbidities do not steps of treatment. Assessment should be made for each dimension
have direct effects on the clinical manifestations of NP, some and each dimension should be rated as ‘‘none,’’ ‘‘mild,’’ ‘‘mod-
comorbidities may indirectly affect it (e.g., as hypothyroidism, erate,’’ or ‘‘severe’’ to allow ranking. The severity of items for
which if untreated, can contribute to worsening of neuropathy each particular dimension would determine the order of further
and consequently pain). diagnostic investigations and treatment steps. Clinical experience
Psychiatric comorbidities and pain, in general, may pose an even points to the fact that most, if not all, patients with chronic painful
bigger challenge. In this regard, NP is perhaps most complicated disorders have diagnoses on each of these dimensions. It is tempting
because of its severity, chronicity, and lack of response to traditional to concentrate on one component with which the clinician is most
treatments. Ploghaus and coworkers,43 through advances in neuroi- comfortable and to ignore others or to see all of the components as
maging, elegantly demonstrated a neural basis for the relationship separate and isolated entities. However, it is crucial to remember
that these components interact constantly and have to be consid-
ered together.
Table 6^3. The Multiple Dimensions of Neuropathic SAFE (measuring social functioning, analgesia or pain relief,
Pain physical functioning, and emotional functioning) is another
multidimensional tool (not specific to NP) that can be used to
assess various domains of functioning in patients with persistent
Severity Rating (None,
pain.44 Similarly, other investigators have addressed the need for a
Specific Mild, Moderate, Severe)
multidimensional assessment of persistent pain not only at baseline
Dimension Parameters or (04)
but also during follow-up in efforts to interpret treatment outcomes.
I Medical Specific etiology A consensus meeting of the Initiative on Methods,
etiology and medical Measurement, and Pain Assessment in Clinical Trials
comorbidities (IMMPACT) provided recommendations for interpreting clinical
II Pain Neuropathic, importance of treatment outcomes in clinical trials of the efficacy
mechanisms inflammatory, and effectiveness of chronic pain treatments.
myofascial, A group of 40 participants from universities, governmental
agencies, a patient self-help organization, and the pharmaceutical
incidence, other
industry considered methodologic issues and research results rele-
III Psychiatric Psychiatric vant to determining the clinical importance of changes in the spe-
comorbidity comorbidities cific outcome measures recommended assessing four core chronic
and coping skills pain outcome domains: (1) Pain intensity, assessed by a 0 to 10
IV Function, QOL Disabilities, numerical rating scale; (2) physical functioning, assessed by the
impaired QOL Multidimensional Pain Inventory and BPI interference scales; (3)
emotional functioning, assessed by the Beck Depression Inventory
QOL, quality of life. and Profile of Mood States; and (4) participant ratings of overall
Table 6^4. Provisional Clinical Trial Outcome Measures
Outcome Domain and Measure Type of Improvement* Method{ Change

1. Pain intensity
010 Numerical rating scale Minimally important Anchor 10%20% decrease
Moderately important Anchor 30% decrease
Substantial Anchor 50% decrease
2. Physical functioning
Multidimensional Pain Inventory Clinically important Distribution 0.6-point decrease
Interference Scale46 Minimally important Distribution 1-point decrease
Brief Pain Inventory
Interference Scale47
3. Emotional functioning
Beck Depression Inventory48, 49 Clinically important Distribution 5-point decrease
Profile of Mood States50 Clinically important Distribution 1015-point decrease
Total Mood Disturbance51 Clinically important Distribution 212-point change{
Specific subscales51
4. Global rating of improvement
Patient Global Impression of Minimally important Anchor Minimally improved
Change52 Moderately important Anchor Much improved
Substantial Anchor Very much improved
*Because few studies have examined the importance of worsening on these measures, benchmarks are only provided for improvement in scores.
{
Specific method used in determining benchmark provided in final column; distribution-based methods were based on use of 0.5 standard deviation or
1.0 standard error of the mean or both.
{
The magnitude of a clinically important change depends on the specific subscale, as does the direction of change that reflects an improvement.
Reproduced with modification from Dworkin RH, Oconnor AB, Backonja M, et al. Pharamacologic management of neuropathic pain:
evidence-based recommendations. Pain 2007;132:237251.
improvement, assessed by the Patient Global Impression of Change the approach to NP is included in order to illustrate current con-
scale (all four domains being assessed by two or more different ventional strategies (Box 62).
methods)45 (Table 64). However, even adhering to these strategies, existing pharmaco-
Finally, although this chapter does not address treatment logic treatments for NP are limited, with no more than 40% to 60%
strategies, a stepwise pharmacologic management algorithm in of patients obtaining partial relief of their pain.45
Box 6^2 STEPWISE PHARMACOLOGIC MANAGEMENT OF NEUROPATHIC PAIN

Step 1
Assess pain and establish the diagnosis of NP53,54; if uncertain about the diagnosis, refer to a pain specialist or neurologist.
Establish and treat the cause of NP; if uncertain about availability of treatments addressing NP etiology, refer to appropriate specialist.
Identify relevant comorbidities (e.g., cardiac, renal, or hepatic disease, depression, gait instability) that might be relieved or exacerbated by NP treatment or
that might require dosage adjustment or additional monitoring of therapy.
Explain the diagnosis and treatment plan to the patient and establish realistic expectations.
Step 2
Initiate therapy of the disease causing NP, if applicable.
Initiate symptom treatment with one or more of the following:
A second aryamineTCA (nortriptyline, desipramine) or an SSNRI (duloxetine, venlafaxine).
A calcium channel a2d ligand, either gabapentin or pregabalin.
For patients with localized peripheral NP: topical lidocaine used alone or in combination with one of the other first-line therapies.
For patients with acute NP, neuropathic cancer pain, or episodic exacerbations of severe pain, and when prompt pain relief during titration of a first-line
medication to an efficacious dosage is required, opioid analgesics or tramadol may be used alone or in combination with one of the first-line therapies.
Evaluate patient for nonpharmacologic treatments, and initiate if appropriate.
Step 3
Reassess pain and health-related quality of life frequently.
If substantial pain relief (e.g., average pain reduced to 3/10) and tolerable side effects, continue treatment.
If partial pain relief (e.g., average pain remains 4/10) after an adequate trial, add one of the other first-line medications.
If no or inadequate pain relief (e.g., <30% reduction) at target dosage after an adequate trial, switch to an alternative first-line medication.
Step 4
If trials of first-line medications alone and in combination fail, consider second- and third-line medications or referral to a pain specialist or multidisciplinary
pain center.
NP, neuropathic pain; SSNRI, selective serotonin and norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.
Reproduced from Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007;132:237251.
Thus, many patients may periodically suffer in silence, adjust and peripheral neuropathic pain. J Neurol Neurosurg Psychiatry
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to alternative pain-relieving efforts. Closs and associates55 inter- 12. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes
viewed patients with persistent pain in attempts to learn about associated with nervous or somatic lesions and development of a new
neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114:2936.
how individual sufferers manage the effects of NP. The most
13. Bouhassira D, Attal N, Fermanian J, et al. Development and validation
common management strategy was the use of conventional medica- of the Neuropathic Pain Symptom Inventory. Pain 2004;108:248257.
tions, often associated with poor effectiveness and unpleasant side 14. Krause SJ, Backonja MM. Development of a neuropathic pain
effects. Complementary and alternative medicine strategies were questionnaire. Clin J Pain 2003;19:306314.
often sought but were largely associated with suboptimal results. 15. Backonja MM, Krause SJ. Neuropathic pain questionnaire—short
Many patients found resting or retreating helpful.55 Patients exhib- form. Clin J Pain 2003;19:315316.
ited a repeating cycle of attempt followed by new attempts. Some 16. Freynhagen R, Baron, Gockel U, Tölle TR. painDIRECT: a new
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gical, social, emotional, and practical support to allow them to do patients with back pain. Curr Med Res Opin 2006;22:19111920.
this successfully.55 17. Portenoy R. Development and testing of a neuropathic pain screening
questionnaire: ID Pain. Curr Med Res Opin 2006;22:15551565.
Currently, optimal therapeutic approaches to NP involve inter-
18. Petersen KL, Rice FL, Suess F, et al. Relief of post-herpetic neuralgia
disciplinary treatment teams working closely together with the by surgical removal of painful skin. Pain 2002;98:119126.
appropriate use of behavioral medicine, physical medicine, inter- 19. Moisset X, Bouhassira D. Brain imaging of neuropathic pain.
ventional, and neuromodulation techniques in conjunction with Neuroimage 2007;37(suppl 1):S80S88.
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22. Backonja MM, Stacey B. Neuropathic pain symptoms relative to
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management of neuropathic pain: evidence-based recommendations. Government Printing Office1976.
Pain 2007;132:237251. 53. Cruccu G, Anand P, Attal N, et al. EFNS guidelines on neuropathic
46. Kerns RD, Turk DC, Rudy TE. The West HavenYale pain assessment. Eur J Neurol 2004;11:153162.
Multidimensional Pain Inventory (WHYMPI). Pain 1985;23:345356. 54. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in
47. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain neuropathic pain: diagnosis, mechanisms, and treatment
Inventory. Ann Acad Med 1994;23:129138. recommendations. Arch Neurol 2003;60:15241534.
48. Beck AT, Ward CH, Mendelsohn M, et al. An inventory for 55. Closs SJ, Staples V, Reid I, et al. Managing the symptoms of
measuring depression. Arch Gen Psychiatry 1961;4:561571. neuropathic pain: an exploration of patients’ experiences. J Pain
49. Beck AT, Steer RA. Beck Depression Inventory. San Antonio, TX: Symptom Manage 2007;34:422433.
Psychological Corporation, 1993.
Chapter 7 incorporated into a chosen probe molecule. The choice of the probe
molecule depends on the physiologic aspect studied (e.g., glucose,
BRAIN IMAGING IN PAINFUL water, neurotransmitter receptor agonist). The combination of
this molecule with isotopes to form a complex (H215O, 18F-deox-
STATES: EXPERIMENTAL AND yglucose) should not change the physiologic characteristics of
the molecule. As the complex is carried by the blood stream and
arrives at its functional target, the isotope continuously emits posi-
CLINICAL PAIN trons (positively charged electrons). These positrons eventually col-
lide with electrons within the body. Such collisions release two
Daniel Ciampi de Andrade, Xavier Moisset and photons, moving in opposite directions. These emitted photons
Didier Bouhassira are detected by a technique called coincidence detection, in which
two scintillation detectors 1808 apart are stimulated simultaneously.
This makes it possible to localize and to quantify the probe mole-
cule within a selected brain region and is the basis of dynamic
detection and three-dimensional localization in PET studies.
INTRODUCTION However, the scanner detects the site of the collision, which is
not identical to the site at which the positron left the isotope.
Brain functional imaging has opened up new possibilities for inves- Positrons may travel some millimeters within the body before col-
tigating the brain structures involved in pain perception in humans, liding with an electron, rendering the spatial resolution of PET
providing the fields of neurology and neuroscience with fruitful scans low (4 mm).1
15
insights into the physiology and pathophysiology of this process. O is a commonly used isotope in studies of pain. It is com-
We review here studies investigating changes in brain activity bined into natural molecules, such as water, to form H215O. It is
associated with experimental and clinical pain by hemodynamic used to detect changes in regional cerebral blood flow (rCBF) as an
imaging methods: positron-emission tomography (PET) and func- indicator of neuronal activity.2,3 The results, expressed as the area
tional magnetic resonance imaging (fMRI). Studies using modern ‘‘activated,’’ correspond to the net change in blood flow in this
electrophysiologic methods (e.g., electroencephalography, record- specific brain region. For the calculation of this net change, it is
ings of evoked potentials, magnetoencephalography) are not necessary to compare the pattern of activation found in the condi-
included here, although these methods also involve brain imaging. tion studied with a second set of scans in ‘‘control’’ conditions
Studies relating to chronic pain conditions of uncertain origin, such (e.g., provoked pain vs. rest).
as fibromyalgia, irritable bowel syndrome, and burning mouth syn- One of the drawbacks of this technique is its poor time resolu-
drome, are also not included. tion, because long scan periods, of up to 60 seconds, are required.
All the hemodynamic changes occurring during the acquisition
period are, therefore, pooled together in the final image.
Furthermore, only a limited number of scans can be taken, owing
PRINCIPLES OF HEMODYNAMIC to the use of radioactive molecules, and it may be necessary to study
IMAGING the various conditions of interest in different sessions.1
One of the advantages of PET is that it can be used to assess
PET physiologic processes, such as mapping of neurotransmitter systems
and drug uptake in vivo, depending on the probe molecule chosen.
PET is a nuclear medicine technique for the three-dimensional Studies with [18F] fluorodopa and opioid receptor ligands have
detection of an emitting isotope in a certain region of the body. made a major contribution to studies in the field of pain and
Emitting isotopes are produced in a cyclotron and are chemically neurology.
41. Smith HS, Sang CN. The evolving nature of neuropathic pain: 50. McNair DM, Lorr M, Droppleman LF. Profile of Mood States
individualizing treatment. Eur J Pain 2002;6:1318. (POMS) Manual, San Diego, CA: Educational and Industrial Testing
42. Backonja MM, Argoff CE. Neuropathic pain: definition and implications for Service, 1992.
research and therapy. J Neuropathic Pain Symptom Palliat 2005;1:1117. 51. Haythornthwaite JA, Edwards RR. Profile of Mood States (POMS)
43. Ploghaus A, Narain C, Beckmann CF, et al. Exacerbation of pain by Presented at the fourth meeting of the Initiative on Methods,
anxiety is associated with activity in a hippocampal network. Jf Measurement, and Pain Assessment in Clinical Trials (IMMPACT-
Neurosci 2001;21:98969903. IV); June. Available at www.immpact.org/immpact4/
44. Smith HS, Audette JF, Witkower A. Playing it "SAFE". J Cancer Pain Haythornthwaite.pdf (2004) (accessed June 1, 2007).
Symptom Palliat 2005;1:310. 52. Guy W: ECDEU Assessment Manual for Psychopharmacology
45. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic (DHEW Publication No. ADM 76-338), Washington, DC: U.S.
management of neuropathic pain: evidence-based recommendations. Government Printing Office1976.
Pain 2007;132:237251. 53. Cruccu G, Anand P, Attal N, et al. EFNS guidelines on neuropathic
46. Kerns RD, Turk DC, Rudy TE. The West HavenYale pain assessment. Eur J Neurol 2004;11:153162.
Multidimensional Pain Inventory (WHYMPI). Pain 1985;23:345356. 54. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in
47. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain neuropathic pain: diagnosis, mechanisms, and treatment
Inventory. Ann Acad Med 1994;23:129138. recommendations. Arch Neurol 2003;60:15241534.
48. Beck AT, Ward CH, Mendelsohn M, et al. An inventory for 55. Closs SJ, Staples V, Reid I, et al. Managing the symptoms of
measuring depression. Arch Gen Psychiatry 1961;4:561571. neuropathic pain: an exploration of patients’ experiences. J Pain
49. Beck AT, Steer RA. Beck Depression Inventory. San Antonio, TX: Symptom Manage 2007;34:422433.
Psychological Corporation, 1993.
Chapter 7 incorporated into a chosen probe molecule. The choice of the probe
molecule depends on the physiologic aspect studied (e.g., glucose,
BRAIN IMAGING IN PAINFUL water, neurotransmitter receptor agonist). The combination of
this molecule with isotopes to form a complex (H215O, 18F-deox-
STATES: EXPERIMENTAL AND yglucose) should not change the physiologic characteristics of
the molecule. As the complex is carried by the blood stream and
arrives at its functional target, the isotope continuously emits posi-
CLINICAL PAIN trons (positively charged electrons). These positrons eventually col-
lide with electrons within the body. Such collisions release two
Daniel Ciampi de Andrade, Xavier Moisset and photons, moving in opposite directions. These emitted photons
Didier Bouhassira are detected by a technique called coincidence detection, in which
two scintillation detectors 1808 apart are stimulated simultaneously.
This makes it possible to localize and to quantify the probe mole-
cule within a selected brain region and is the basis of dynamic
detection and three-dimensional localization in PET studies.
INTRODUCTION However, the scanner detects the site of the collision, which is
not identical to the site at which the positron left the isotope.
Brain functional imaging has opened up new possibilities for inves- Positrons may travel some millimeters within the body before col-
tigating the brain structures involved in pain perception in humans, liding with an electron, rendering the spatial resolution of PET
providing the fields of neurology and neuroscience with fruitful scans low (4 mm).1
15
insights into the physiology and pathophysiology of this process. O is a commonly used isotope in studies of pain. It is com-
We review here studies investigating changes in brain activity bined into natural molecules, such as water, to form H215O. It is
associated with experimental and clinical pain by hemodynamic used to detect changes in regional cerebral blood flow (rCBF) as an
imaging methods: positron-emission tomography (PET) and func- indicator of neuronal activity.2,3 The results, expressed as the area
tional magnetic resonance imaging (fMRI). Studies using modern ‘‘activated,’’ correspond to the net change in blood flow in this
electrophysiologic methods (e.g., electroencephalography, record- specific brain region. For the calculation of this net change, it is
ings of evoked potentials, magnetoencephalography) are not necessary to compare the pattern of activation found in the condi-
included here, although these methods also involve brain imaging. tion studied with a second set of scans in ‘‘control’’ conditions
Studies relating to chronic pain conditions of uncertain origin, such (e.g., provoked pain vs. rest).
as fibromyalgia, irritable bowel syndrome, and burning mouth syn- One of the drawbacks of this technique is its poor time resolu-
drome, are also not included. tion, because long scan periods, of up to 60 seconds, are required.
All the hemodynamic changes occurring during the acquisition
period are, therefore, pooled together in the final image.
Furthermore, only a limited number of scans can be taken, owing
PRINCIPLES OF HEMODYNAMIC to the use of radioactive molecules, and it may be necessary to study
IMAGING the various conditions of interest in different sessions.1
One of the advantages of PET is that it can be used to assess
PET physiologic processes, such as mapping of neurotransmitter systems
and drug uptake in vivo, depending on the probe molecule chosen.
PET is a nuclear medicine technique for the three-dimensional Studies with [18F] fluorodopa and opioid receptor ligands have
detection of an emitting isotope in a certain region of the body. made a major contribution to studies in the field of pain and
Emitting isotopes are produced in a cyclotron and are chemically neurology.
46 Chapter 7 BR AIN IMAGING IN PAINFUL STATES: EXPERIMENTAL AND CLINICAL PAIN
fMRI BRAIN IMAGING IN EXPERIMENTAL

PAIN:THE PHYSIOLOGIC PAIN MATRIX
fMRI can be used to detect variations in regional tissue oxygenation
due to changes in oxygen uptake and blood supply to various areas Many studies on the use of fMRI and PET to investigate the brain
of the brain. Most fMRI studies are based on a technique in which correlates of experimental pain in normal subjects have been pub-
deoxygenated blood is used as a contrast agent: blood oxygenation lished. Many designs and experimental paradigms have been used,
leveldependent (BOLD) imaging. Individuals are usually scanned and certain findings have been reported consistently in all studies.
in the two sets of conditions to be compared. A voxel-by-voxel Activation in response to experimental painful stimuli has continu-
substraction of images from both sets of scans is then undertaken, ously been reported in a network of brain structures frequently
looking for areas in which rCBF significantly changes across con- referred to as the physiologic pain matrix. Six main areas are usually
ditions. Deoxyhemoglobin (DeoxyHb) molecules have four included in the pain matrix: the primary and secondary somatosen-
unpaired electrons with paramagnetic properties, modifying the sory cortices (S1 and S2), the insular cortex (IC), the anterior cin-
signal in T2-weighted images. A local increase in the ratio of oxy- gulate cortex (ACC), the thalamus (Th), and the prefrontal cortex
to deoxyhemoglobin results in regional enhancement of the (PFC)1,410 (Fig. 71).
T2-weighted signal, indicating a net increase in local blood flow. Pain perception is not identical to nociception. Nociception
This increase is generally linked to a primary increase in regional involves the physiologic activation of specialized receptors (noci-
metabolism, which may serve as a marker of tissue synaptic activity ceptors) by noxious stimuli (e.g., heat, cold, chemical damage,
and function. Neuronal function is thus indirectly inferred from intense pressure). Pain is a much broader subjective experience,
hemodynamic measures. with at least three main aspects or dimensions, and is not neces-
fMRI offers temporal resolution of 100 msec to 3 seconds, which sarily associated with nociceptor activation. The sensory-
shortens the period of painful stimulation during experimental discriminative dimension is related to the quality of the stimulus
studies, compared with PET studies. It has a spatial resolution of (e.g., burning, freezing, pressure), its intensity, location, and tem-
about 2 mm, allowing a finer anatomic localization of changes poral pattern. The emotional-affective dimension relates to the
in signal. Because no radioactivity is used, scans may be repeated unpleasantness of pain and its emotional impact, including auto-
an unlimited number of times in a given individual. The draw- nomic changes. The cognitive-motivational component is related to
backs of this technique include the presence of pulsation artifacts attention, memory, and behavioral aspects accompanying the expe-
and the need for strict timing of stimulus induction and image rience of pain. Consistent with this multidimensional concept of
acquisition.1 pain, it has been suggested that different structures from the phys-
fMRI usually gives more false-negative than false-positive iologic pain matrix are preferentially associated with specific pain
results. Because results depend on a complex statistical analysis of components. Hence, S1, S2, and IC (mostly its posterior portion)
two conditions, a lack of increase in signal does not necessarily are believed to be preferentially associated with the sensory-
mean that there was no activation in a given area. It simply discriminative component of pain. The anterior IC and ACC are
means that the increase in signal was not statistically superior to believed to be more specifically linked to the emotional-affective
the signal already present during the control condition. aspect of pain. These structures are also involved in empathy with
Hemodynamic studies based on both BOLD fMRI, and PET pain in others. ACC activation, which is frequently reported in pain
scans show changes in rCBF that are generally interpreted as studies, may actually be more closely correlated with pain intensity
linked to local metabolic changes. However, it remains unclear than with stimulus strength, highlighting the role of this structure
whether there is a similar relationship between hemodynamic and in pain evaluation. The PFC, a major integration center, is also
metabolic changes for chronic pain. Both techniques evaluate local frequently activated during experimental pain and is related to
metabolism indirectly, but it is not possible to differentiate excita- the cognitive-motivational aspect of pain.
tory from inhibitory activity. Thus, in a given experiment, a region The structures included in the physiologic pain matrix can be
of the brain may show an increase in rCBF, but it is not certain schematically organized into two distinct functional pathways:
whether this region is working to stimulate or to inhibit the struc- the medial and the lateral pain systems. In the lateral pain system,
tures connected to it. painful signals are conveyed through the spinothalamic tract
S 1***
SMA***
PPC*
DLPF***
AAC***
S 2***
Ins*** Amy2
OFC*** Th***
Cer*
Figure 7^1. The physiologic pain matrix.The main regions displaying an increase in regional cerebral blood flow (rCBF) or blood oxygenation
leveldependent (BOLD) responses are indicated. ACC, anterior cingulate cortex; Amy, amygdala; Cer, cerebellum; DLPF, dorsolateral prefrontal
cortex; Ins, insula; OFC, orbitofrontal cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; SMA, supplementary
motor cortex; Th, thalamus.The number of stars *, **, *** associated with each structure is a symbolic correlate of the number of studies
showing significant changes. (Adapted from references1, 49.)
NEUROPATHIC PAIN SYMPTOMS
Evoked pain
Spontaneous pain
Non nociceptive Nociceptive

stimuli stimuli
CONTINUOUS PAROXYSMAL ALLODYNIA HYPERALGESIA

Figure 7^2. Multiple symptoms in patients with
neuropathic pain.The patients may present various
combinations of spontaneous and evoked pain,
Mechanical and/or thermal depending on different mechanisms. Evoked pain
includes both allodynia and hyperalgesia induced by
various typesofmechanicalandthermalstimuli.
(AdaptedfromMoissetX,BouhassiraD.Brainimagingin
Dynamic Static Heat Cold neuropathicpain.Neuroimage2007;37(Suppl1):S8088.)
(STT) to the ventrolateral nuclei of the thalamus and then to S1, S2, allodynia) because this is the most frequently documented clinical
the parietal operculum, and IC. This lateral system seems to be pain type. These findings are compared with those obtained in
more specifically involved in the sensory-discriminative aspect of nociceptive pain and complex regional pain syndrome (CRPS) stu-
pain. In the medial pain system, pain signals are transmitted dies, although data are scarce for these types of pain.
through the STT to the medial thalamic and intralaminar nuclei, Neuropathic pain is defined as pain initiated or caused by a pri-
and then relayed to the ACC, IC, amygdala, hippocampus, mary lesion or dysfunction in the nervous system. It comprises
and hypothalamus. Within this system, information is also trans- an enormous group of heterogeneous conditions, which may be
mitted from the spinal cord to higher centers by other tracts. peripheral or central in origin. Its clinical diagnosis is based on
(e.g., the spinoreticular, spinomesencephalic, and spinohypothala- the presence of certain signs and symptoms, the topologic distribu-
mic tracts). Thus, the medial system seems to be more closely tion of which may depend on the site of neural damage. Commonly
related to the cognitive-motivational and emotional-affective found signs include the presence of evoked pain, such as allodynia
aspects of pain, including the autonomic and neuroendocrine and hyperalgesia (Fig. 72). Allodynia is pain elicited by a normally
responses associated with pain perception. nonpainful stimulus (e.g., stroking the skin with a cotton swab).
Brain regions not usually included in the physiologic pain Hyperalgesia corresponds to an increase in the level of pain caused
matrix have also been shown to be activated in several studies of by a suprathreshold stimulus (e.g., the subject rates his or her pain
experimental pain. These structures include the motor/premotor higher than would be expected for a given painful stimulation).
cortex, the supplementary motor area, the inferior/posterior pari- Evoked pain is usually associated with spontaneous pain, which
etal cortex, the basal ganglia, the cerebellum, and many brainstem may be continuous or paroxysmal, frequently described as
nuclei, particularly the periaqueductal gray matter. The activation ‘‘burning,’’ ‘‘freezing,’’ or ‘‘electric shocklike.’’1113
of these areas is often regarded as related to attentional processes The mechanisms of neuropathic pain are poorly understood.
and the preparation, selection, and inhibition of motor responses However, there is growing evidence that the different neuropathic
associated with the painful stimulus. However, many of these symptoms may involve different mechanisms, and consequently,
structures have extramotor functions. For example, the cerebellum they may respond differently to commonly used therapeutic mole-
receives information indirectly from different association cortices cules. This finding highlights the need to tailor individual treatment
via the pontine nuclei and passes information on to the motor and regimens to the symptoms of each patient.1417 Modern brain
premotor cortices. It is also involved in learning, being activated imaging has greatly contributed to our understanding of the par-
during verbal tasks and deactivated after practice. The ventral ticular mechanisms of the many different symptoms present in
striata (accumbens and olfactory tuberculus) have a role in the neuropathic pain.
limbic loop of the basal ganglia circuitry and are highly connected
to the insula, amygdala, and hippocampus. Further studies are
required to determine the specific role of the activation of these
areas in the presence of pain stimuli. Imaging Spontaneous Pain in Patients with
Neuropathic Pain
BRAIN IMAGING OF CLINICAL PAIN Spontaneous pain is a major complaint in patients with neuropathic
pain and is a major cause of disability. It may be continuous or
Hemodynamic brain imaging has been used far less frequently in paroxysmal in nature and is often described as ‘‘burning,’’
studies of clinical pain than in studies of experimental pain. This is ‘‘stabbing,’’ or ‘‘tingling.’’
probably due to the complexity and heterogeneity of clinical situa- Only a few studies and case reports have described changes in
tions. It is difficult, for example, to find sufficient numbers of brain activity during spontaneous neuropathic pain. In 1988,
homogeneous patients with the same disorder. Many clinical Laterre and coworkers18 used PET to evaluate changes in rCBF in
variables may bias the interpretation of imaging studies. These a patient with postischemic pain syndrome and continuous pain
variables include the duration and severity of the disease, the pres- (Fig. 73A). They described lower levels of glucose utilization in the
ence and type of treatment, and associated conditions that may contralateral thalamus. This finding has since been reproduced in
change brain activation (e.g., depression, anxiety). almost all studies of spontaneous neuropathic pain.1921 However,
This review is focused on the available information relating to the patients included in these studies were highly heterogeneous.
neuropathic pain and its associated phenomena (e.g., hyperalgesia, In some studies, it was not entirely clear whether the patients
DLPF***
AAC***
Ins*** S 2*** vStr*

Th***
S 1***
SMA***
PPC*
DLPF*** ?
? AAC***
S 2***
Ins***
OFC*** LN*
Th***
Cer*
B
Figure 7^3. A, Changes in brain activity associated with spontaneous neuropathic pain.The regions display increases or decreases in rCBF
or BOLD responses. B, Changes in brain activity associated with mechanical allodynia in patients with neuropathic pain.The regions displaying
an increase in activity are indicated in red. ACC, anterior cingulate cortex; Cer, cerebellum; DLPF, dorsolateral prefrontal cortex; Ins, insula;
LN, lentiform nucleus; OFC, orbitofrontal cortex; PPC, posterior parietal cortex; S1, primary somatosensory cortex; S2, secondary
somatosensory cortex; SMA, supplementary motor cortex; Th, thalamus; vStr, ventral striatum.The number of stars *, **, *** associated
with each structure is a symbolic correlate of the number of studies showing significant changes. (A, Adapted from references1820, 50; B,
adapted from references 2431.)
suffered true neuropathic pain.20 In others, the presence of contin- in control scans (during rest or stimulation of the homologous
uous, spontaneous pain during the scan was not fully assessed.18 nonpainful side). These studies have included only small numbers
However, despite these limitations, these data suggest that the lat- of patients with different etiologies of pain. Despite these limita-
eral pain system—particularly S1, S2, and the posterior insula, all of tions, a fairly consistent response pattern has been reported
which are major components of the pain matrix—may not play a for mechanical allodynia. The increase in signal in the main com-
major role in spontaneous neuropathic pain. The underactivation ponents of the lateral pain system (S1, S2, and lateral thalamus) was
of the contralateral thalamus has been reported, and this result present in most studies when compared with both nonpainful stim-
conflicts with data for microelectrode recordings from the thalamus ulation of the homologous contralateral side and rest con-
of patients with chronic pain undergoing stereotaxic surgery or ditions2430 (see Fig. 7-3B). In contrast, most studies have
from animal studies.22,23 Marked hyperactivity has been observed reported an absence of activation of the ACC and IC.25,29,31 These
in the thalamic neurons in both of these situations. It has been findings may be due to these regions playing no major role in
suggested that underactivation of the thalamus may result from mechanical allodynia. However, this apparent lack of activation
deafferentation due to chronic neuropathic lesions, but this of the ACC and IC may also have been due to most patients pre-
cannot account for the surprising increase in thalamic signal after senting continuous pain in resting conditions. Thus, these struc-
analgesic procedures, such as cordotomy.18 A dissociation of blood tures were probably already activated during the ‘‘painful rest’’
flow and metabolism has also been suggested, together with the condition and were not further activated during allodynic stimula-
existence of a possible compensatory mechanism preventing exces- tion. Another region consistently activated in these studies is
sive nociceptive inputs from reaching higher centers. All these pos- the PFC. Hemodynamic changes in the various parts of the PFC
sibilities require further assessment in studies including larger (orbitofrontal, medial, and dorsolateral) have been reported in
numbers of patients. almost all studies of mechanical allodynia. A recent meta-analysis
showed PFC to be the brain region most frequently activated
in studies of chronic pain.4 This structure may be involved not
only in the cognitive-evaluative aspect of pain but also in pain
Imaging Evoked Pain in Patients with modulation, through its connection with the diencephalon and
Neuropathic Pain brainstem, as highlighted by the role of this structure in the
placebo effect.32
Most studies have focused on dynamic mechanical allodynia Similar results have been reported in studies based on an exper-
(i.e., pain evoked by a light tactile stimulus, such as a brush imental model of mechanical allodynia induced by intradermal or
stroke). Few studies have analyzed cold allodynia. Brain activation topical applications of capsaicin in normal individuals.3336 In par-
during the painful stimulus is often compared with the pattern seen ticular, despite the obvious differences between clinical and
experimental allodynia, these studies also reported preferential acti- allow for faster motor responses to diverge from painful stimuli.
vation of different sectors of the various regions of the PFC. The more anterior ACC, which is closer to heteromodal association
Thus, mechanical allodynia does not seem to involve the whole cortices, would be involved in the cognitive evaluation of a painful
physiologic pain matrix but, rather, a preferential activation of the stimulus. However, it remains unclear whether this relationship
sensory-discriminative lateral pain system and the PFC. The sharp between the different ACC regions and their respective functions
contrast between this pattern of activation and that associated with is also present in other chronic pain syndromes.
spontaneous pain is consistent with the involvement of different CRPS I is associated with dynamic changes in brain activity, as
mechanisms in specific components of neuropathic pain suggested by a study comparing the brain activity evoked by heat
syndromes. stimuli before and after a sympathetic block (SB).40 In the subgroup
Very few studies have assessed the changes in brain activity of patients who responded to the SB, it was found that an over-
associated with cold allodynia.2729 The only direct comparison of activation of PFC and ACC and an underactivation of the contra-
brain activation associated with cold and dynamic allodynia in a lateral thalamus were all reversed after successful pain control by the
small group of patients with syringomyelia suggested that these two procedure.
subtypes of allodynia induced distinct changes in brain activity.29 Cortical reorganization, which is characterized by a reduction in
However, further studies with a larger number of patients are the BOLD signal in S1 and S2 during nonpainful tactile stimulation
required to determine whether this difference reflects true differ- of the affected limb, has also been reported in CRPS I patients. The
ences in the mechanisms of these two types of allodynia. pain relief associated with behavioral therapy over 1 to 6 months
was correlated with the restoration of tactile discrimination task
scores and an increase in S1/S2 signals contralateral to the affected
IMAGING OF THE CRPS limb.41
CRPS I (formerly known as sympathetic reflex dystrophy) is char-

acterized by disproportionate pain (both spontaneous and evoked)
associated with local autonomic and trophic disturbances occurring IMAGING NOCICEPTIVE/
after minor trauma in the absence of a detectable nerve lesion. The INFLAMMATORY PAIN
pathophysiology of this syndrome is unclear. CRPS I and neuro-
pathic pain display similarities in clinical presentation, resulting in Very few imaging studies have been carried out on patients with
suggestions that they may involve common mechanisms. Studies chronic nociceptive pain. Most of these studies did not assess clin-
assessing mechanical allodynia (both dynamic and static) in CRPS ical pain directly. Instead, they investigated responses to experimen-
I patients have generally compared the pattern of brain activation tal pain (painful heat or pressure) in patients with chronic
on the painful side with that on the homologous contralateral nociceptive pain (Fig. 7-4).
(nonpainful) side. They have reported activation of the lateral In a study in patients with rheumatoid arthritis (RA), a classic
(S1, S2) and medial (insula, ACC, PFC) pain systems.3739 The model of chronic nociceptive pain, painful heat stimuli induced a
presence of ACC activation reported in most studies contrasts decrease in rCBF in the PFC and ACC. Effective coping strategies in
with the findings obtained for mechanical allodynia associated these patients have been proposed to explain these surprising obser-
with well-defined neuropathic pain. This highlights the difficulty vations.42,43 However, conflicting results were reported in a more
involved in identifying the role in pain perception of a complex recent study from the same group44 assessing the patterns of brain
structure, such as the ACC, which may be more active in pain activation in RA patients at rest, during acute spontaneous arthritis-
anticipation and evaluation than in pain perception itself. There related pain, and experimental heat pain. In this study, the authors
is also a growing body of data to suggest that the different regions reported a stronger signal in structures from the medial pain system
of the ACC have different functions in the integration of (ACC, amygdala, and orbitofrontal cortex [OFC]) for arthritic pain
homeostatic information provided by the limbic cortex and the than for evoked pain. The unpleasantness of pain was also closely
cognitive-evaluative processes taking place in the PFC. Also, the correlated with the activation of these structures, but no major
more posterior part of the ACC has been shown to be positively hypoactivation was described. These apparently conflicting results
related to the intensity of the induced allodynic pain in CRPS may be accounted for by the small number of patients (six) eval-
I patients.37 This region is closer to the motor cortex and would uated in the first study.43
S 1***
DLPF***
AAC***
S 2*** LN*
Ins*** Th*
OFC***
Cer*
Figure 7^4. Changes in brain activity associated with experimentally evoked pain in low back pain (LBP) and rheumatoid arthritis
patients.The regions displaying an increase in rCBF or BOLD responses are indicated. ACC, anterior cingulate cortex; Cer, cerebellum; DLPF,
dorsolateral prefrontal cortex; Ins, insula; LN, lentiform nucleus; OFC, orbitofrontal cortex; S1, primary somatosensory cortex; S2, secondary
somatosensory cortex; Th, thalamus.The number of stars *, **, *** associated with each structure is a symbolic correlate of the number of
studies showing significant changes. (Adapted from references 44, 4649.)
Low back pain (LBP) is a highly prevalent condition and is the 6. Treede RD, Kenshalo DR, Gracely RH, Jones AK. The cortical
second most frequent symptom-related reason for which patients representation of pain. Pain 1999;79:105111.
consult a physician.45 It is frequently classified as a type of nocicep- 7. Casey KL. Forebrain mechanisms of nociception and pain: analysis
tive pain, although its mechanisms are probably complex and through imaging. Proc Natl Acad Sci U S A 1999;96:76687674.
8. Peyron R, Garcia-Larrea L, Gregoire MC, et al. Haemodynamic brain
remain poorly understood. It may be idiopathic or secondary to
responses to acute pain in humans: sensory and attentional networks.
various conditions (e.g., fractures, inflammatory diseases, surgery). Brain 1999;122:17651780.
An elegant study showed a differential pattern of activation 9. Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain
during two different components of spontaneous pain in LBP responses to pain. A review and meta-analysis. Neurophysiol Clin
patients: ‘‘increasing’’ and ‘‘high constant" pain.46 During an increase 2000;30:263288.
in spontaneous pain, an increase in the signal from the IC, S1, S2, 10. Tracey I. Nociceptive processing in the human brain. Curr Opin
mid-ACC, and cerebellum was detected. Changes in IC activity Neurobiol 2005;15:478487.
were found to be positively correlated with the increase in spontane- 11. Bouhassira D, Attal N, Fermanian J, et al. Development and
ous pain. In contrast, when pain remained at high constant levels, validation of the neuropathic pain symptom inventory. Pain
the activity of the medial PFC (including the rostral ACC) increased; 2004;108:248257.
12. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain
this increase being directly correlated with pain intensity. Interes- syndromes associated with nervous or somatic lesions and
tingly, these authors also described a decrease in cortical density in development of a new neuropathic pain diagnostic questionnaire
the same area of the dorsolateral PFC (DLPF) in LBP patients.47 (DN4). Pain 2005;114:2936.
In LBP patients, the application of a painful heat stimulus to the 13. Bennett MI, Attal N, Backonja MM, et al. Using screening tools to
lower back induced a significantly stronger bilateral signal in the IC, identify neuropathic pain. Pain 2007;127:199203.
S2, and ACC and a significantly stronger signal in the right DLPF 14. Attal N, Gaude V, Brasseur L, et al. Intravenous lidocaine in central
than that observed in normal controls. pain. A double-blind placebo-controlled psycho-physical study.
Other studies have evaluated brain processing in LBP patients Neurology 2000;544:564574.
15. Attal N, Rouaud J, Brasseur L, et al. Systemic lidocaine in pain due to
during experimental pain distant from the lower back region.
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Derbyshire and colleagues48 compared responses to painful heat 2004;62:218225.
stimulation of the hand in LBP patients. Activation, mostly 16. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms,
observed in the cerebellum, midbrain, thalamus, lentiform nucleus, mechanisms, and management. Lancet 1999;353:19581964.
PFC, midcingulate cortex, and IC, was similar in patients and con- 17. Baron R. Mechanisms of disease: neuropathic pain—a clinical
trols. In another study, painful pressure stimuli applied to the perspective. Nat Clin Pract Neurol 2006;2:95106.
thumb induced similar patterns of brain activation in patients 18. Laterre EC, De Volder AG, et al. Brain glucose metabolism in
with LBP (or fibromyalgia) and controls, but the intensity of the thalamic syndrome. J Neurol Neurosurg Psychiatry 1988;51:427428.
signals was greater in patients.49 19. Di Piero V, Jones AK, Iannotti F, et al. Chronic pain: a PET study of
These studies in patients with RA and LBP tend to confirm that the central effects of percutaneous high cervical cordotomy. Pain
1991;46:912.
the changes in brain activity associated with clinical nociceptive 20. Iadarola MJ, Max MB, Berman KF, et al. Unilateral decrease in
pain are different, at least quantitatively, from those induced by thalamic activity observed with positron emission tomography in
experimental pain. In particular, chronic clinical nociceptive/ patients with chronic neuropathic pain. Pain 1995;63:5564.
inflammatory pain seems to be more specifically associated with 21. Hsieh JC, Belfrage M, Stone-Elander S, et al. Central representation of
changes in the medial pain system. chronic ongoing neuropathic pain studied by positron emission
tomography. Pain 1995;63:225236.
22. Mao J, Mayer D, Price DD. Patterns of increased brain activity
indicative of pain in a rat model of peripheral mononeuropathy.
CONCLUSIONS J Neurosci 1993;13:26892702.
23. Hua SE, Garonzik IM, Lee JI, Lenz FA. Microelectrode studies of
Modern functional imaging of the brain has helped to improve our normal organization and plasticity of human somatosensory thalamus.
understanding of the mechanisms of normal physiologic pain and, J Clin Neurophysiol 2000;17:559574.
to a much lesser extent, of some specific clinical pain states. The 24. Cesaro P, Mann MW, Moretti JL, et al. Central pain and thalamic
available data tend to indicate that pathologic pain does not corre- hyperactivity: a single photon emission computerized tomographic
spond simply to the abnormal activation of a single "pain matrix," study. Pain 1991;47:329336.
but rather that different types of pain (e.g., neuropathic, nocicep- 25. Petrovic P, Ingvar M, Stone-Elander S, et al. A PET activation study
tive) and probably different pain symptoms (spontaneous continu- of dynamic mechanical allodynia in patients with mononeuropathy.
ous pain, allodynia) involve different brain mechanisms. These Pain 1999;83:459470.
findings highlight the need for a more rational and pathophysiolo- 26. Schweinhardt P, Glynn C, Brooks J, et al. An fMRI study of cerebral
processing of brush-evoked allodynia in neuropathic pain patients.
gic classification of pain syndromes. Future studies should also help Neuroimage 2006;32:256265.
to define the place of functional neuroimaging in mechanism-based 27. Peyron R, Garcia-Larrea L, Gregoire MC, et al. Allodynia after
approaches to chronic pain. lateral-medullary (Wallenberg) infarct. A PET study. Brain
1998;121:345356.
28. Peyron R, Schneider F, Faillenot I, et al. An fMRI study of cortical
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2. Friston KJ, Frith CD, Lidall PF, Frackowiak RS. Comparing functional syringomyelia. Brain 2006;129:963976.
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Metab 1991;11:690699. responses in CNS circuits to mechanical (brush) and thermal (cold
3. Friston KJ, Frith CD, Lidall PF, Frackowiak RS. Plastic transformation and heat) stimuli. J Neurosci 2006;18:1064610657.
of PET images. J Comput Assist Tomogr 1991;15:634639. 31. Witting N, Kupers RC, Svensson P, Jensen TS. A PET activation
4. Moisset X, Bouhassira D. Brain imaging in neuropathic pain. study of brush-evoked allodynia in patients with nerve injury pain.
Neuroimage 2007;37(suppl 1):S8088. Pain 2006;120:145154.
5. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain 32. Wager TD, Rilling JK, Smith EE, et al. Placebo-induced changes in
mechanisms of pain perception and regulation in health and disease. FMRI in the anticipation and experience of pain. Science
Eur J Pain 2005;9:463484. 2004;303:11621167.
33. Iadarola MJ, Berman KF, Zeffiro TA, et al. Neural activation during 42. Jones KP, Derbyshire SWG. Reduced cortical responses to noxious
acute capsaicin-evoked pain and allodynia assessed with PET. Brain heat in patients with rheumatoid arthritis. Ann Rheum Dis
1998;121:931947. 1997;56:601607.
34. Baron R, Baron Y, Disbrow E, Roberts TP. Brain processing of 43. Jones KP, Derbyshire SWG. Cerebral mechanisms operating in the
capsaicin-induced secondary hyperalgesia: a functional MRI study. presence and absence of inflammatory pain. Ann Rheum Dis
Neurology 1999;53:548557. 1996;55:411420.
35. Lorenz J, Cross D, Minoshima S, et al. A unique representation of 44. Kulkarni B, Bentley DE, Elliot R, et al. Arthritic pain is processed in
heat allodynia in the human brain. Neuron 2002;35:383393. brain areas concerned with emotions and fear. Arthritis Rheum
36. Lorenz J, Minoshima S, Casey KL. Keeping pain out of mind: the role 2007;56:13451354.
of the dorsolateral prefrontal cortex in pain modulation. Brain 45. Deyo RA, Weinstein JN. Low back pain. N Engl J Med
2003;126:10791091. 2001;344:363-370.
37. Maihofner C, Forster C, Birklein F, et al. Brain processing during 46. Baliki MN, Chialvo DR, Geha PY, et al. Chronic pain and the
mechanical hyperalgesia in complex regional pain syndrome: a emotional brain: specific brain activity associated with spontaneous
functional MRI study. Pain 2006;114:93103. fluctuations of intensity of chronic back pain. J Neurosci
38. Maihofner C, Handwerker HO, Birklein F. Functional imaging of 2006;26:1216512173.
allodynia in complex regional pain syndrome. Neurology 47. Apkarian AV, Sosa Y, Sonty S, et al. Chronic back pain is associated
2006;66:711717. with decreased prefrontal and thalamic gray matter density.
39. Pleger B, Ragert P, Schwenkreis P, et al. Patterns of cortical reorganization J Neurosci 2004;17:1041010415.
parallel impaired tactile discrimination and pain intensity in complex 48. Derbyshire SWG, Jones AKP, Creed F, et al. Cerebral responses to
regional pain syndrome. Neuroimage 2006;32:503510. noxious thermal stimulation in chronic low back pain patients and
40. Apkarian V, Thomas PS, Krauss BR, Szeverenyi NM. Prefrontal normal controls. Neuroimage 2002;16:158168.
cortical hyperactivity in patients with sympathetically mediated 49. Giesecke T, Gracely RH, Grant MAB, et al. Evidence of augmented
chronic pain. Neurosci Lett 2001;5:193197. central pain processing in idiopathic chronic low back pain. Arthritis
41. Pleger B, Tegenthoff M, Ragert P, et al. Sensorimotor returning in Rheum 2004;50:613623.
complex regional pain syndrome parallels pain reduction. Ann Neurol
2005;57:425429.
Chapter 8 There is a burgeoning interest in the development of tools that

POTENTIAL DOCUMENTATION can be useful for screening patients up front to determine the
relative risk for patients having problems with prescription drug
abuse or misuse (Box 82). To date, a number of tools have
TOOLS FOR OPIOID THERAPY arisen, including the Screening Tool for Addiction Risk (STAR),
Drug Abuse Screening Test (DAST), Screener and Opioid
Howard S. Smith and Kenneth L. Kirsh Assessment for Patients with Pain (SOAPP), and the Opioid Risk
Tool (ORT). The choice in tools for a more thorough ongoing
assessment, however, has been somewhat more limited up until
now and is the focus of the discussion.
Oversight by regulatory agencies, state medical boards, and
various peer-review groups includes examination of appropriate
medical care as well as proper documentation. As the old axiom
INTRODUCTION states, ‘‘if it isn’t written, it didn’t happen.’’ In cases of OT for
chronic pain, issues beyond typical office visit charting may deserve
The field of pain management is still relatively young compared with attention and documentation. Although there are no explicit
other medical specialties, but it has experienced a tremendous period requirements for what and how to document issues related to
of growth since the late 1980s. Realization has grown that chronic OT, it is belived by some that the use of specific tools and instru-
pain affects the lives of millions of people and that this issue must be ments in the chart on some or all visits may boost adherence to
addressed. Indeed, we see that issues with pain are the number-one documentation expectations as well as the consistency of such doc-
reason that patients go to see their physicians. However, this umentation. Assessment tools may also be helpful in the analysis of
increased recognition of the problem has been somewhat tempered persistent pain.
by the souring of the regulatory climate and the growth of prescrip-
tion drug abuse. Because of this, there has been a trend for clinicians
to shy away from using high opioid doses or even utilizing this AREAS OF INTEREST FOR
modality at all in the treatment of chronic pain (Box 81). DOCUMENTATION
Despite these fears and concerns, the use of long-term opioid
therapy (OT) to treat chronic nonmalignant pain is growing, based It is important to consider four main domains in assessing pain
in part on evidence from clinical trials and a growing consensus outcomes and to better protect your practice for those patients you
among pain specialists. The appropriate use of these drugs requires maintain on an opioid regimen: (1) pain relief, (2) functional out-
skills in opioid prescribing, knowledge of addiction medicine comes, (3) side effects, and (4) drug-related behaviors. These
principles, and a commitment to perform and document a domains have been labeled the ‘‘Four A’s’’ (Analgesia, Activities
comprehensive assessment repeatedly over time. Inadequate assess- of daily living, Adverse effects, and Aberrant drug-related beha-
ment can lead to undertreatment, compromise the effectiveness of viors) for teaching purposes. There are, of course, many different
therapy when implemented, and prevent an appropriate response ways to think about these domains, and multiple attempts to cap-
when problematic drug-related behaviors occur. ture them are discussed later.
33. Iadarola MJ, Berman KF, Zeffiro TA, et al. Neural activation during 42. Jones KP, Derbyshire SWG. Reduced cortical responses to noxious
acute capsaicin-evoked pain and allodynia assessed with PET. Brain heat in patients with rheumatoid arthritis. Ann Rheum Dis
1998;121:931947. 1997;56:601607.
34. Baron R, Baron Y, Disbrow E, Roberts TP. Brain processing of 43. Jones KP, Derbyshire SWG. Cerebral mechanisms operating in the
capsaicin-induced secondary hyperalgesia: a functional MRI study. presence and absence of inflammatory pain. Ann Rheum Dis
Neurology 1999;53:548557. 1996;55:411420.
35. Lorenz J, Cross D, Minoshima S, et al. A unique representation of 44. Kulkarni B, Bentley DE, Elliot R, et al. Arthritic pain is processed in
heat allodynia in the human brain. Neuron 2002;35:383393. brain areas concerned with emotions and fear. Arthritis Rheum
36. Lorenz J, Minoshima S, Casey KL. Keeping pain out of mind: the role 2007;56:13451354.
of the dorsolateral prefrontal cortex in pain modulation. Brain 45. Deyo RA, Weinstein JN. Low back pain. N Engl J Med
2003;126:10791091. 2001;344:363-370.
37. Maihofner C, Forster C, Birklein F, et al. Brain processing during 46. Baliki MN, Chialvo DR, Geha PY, et al. Chronic pain and the
mechanical hyperalgesia in complex regional pain syndrome: a emotional brain: specific brain activity associated with spontaneous
functional MRI study. Pain 2006;114:93103. fluctuations of intensity of chronic back pain. J Neurosci
38. Maihofner C, Handwerker HO, Birklein F. Functional imaging of 2006;26:1216512173.
allodynia in complex regional pain syndrome. Neurology 47. Apkarian AV, Sosa Y, Sonty S, et al. Chronic back pain is associated
2006;66:711717. with decreased prefrontal and thalamic gray matter density.
39. Pleger B, Ragert P, Schwenkreis P, et al. Patterns of cortical reorganization J Neurosci 2004;17:1041010415.
parallel impaired tactile discrimination and pain intensity in complex 48. Derbyshire SWG, Jones AKP, Creed F, et al. Cerebral responses to
regional pain syndrome. Neuroimage 2006;32:503510. noxious thermal stimulation in chronic low back pain patients and
40. Apkarian V, Thomas PS, Krauss BR, Szeverenyi NM. Prefrontal normal controls. Neuroimage 2002;16:158168.
cortical hyperactivity in patients with sympathetically mediated 49. Giesecke T, Gracely RH, Grant MAB, et al. Evidence of augmented
chronic pain. Neurosci Lett 2001;5:193197. central pain processing in idiopathic chronic low back pain. Arthritis
41. Pleger B, Tegenthoff M, Ragert P, et al. Sensorimotor returning in Rheum 2004;50:613623.
complex regional pain syndrome parallels pain reduction. Ann Neurol
2005;57:425429.
Chapter 8 There is a burgeoning interest in the development of tools that

POTENTIAL DOCUMENTATION can be useful for screening patients up front to determine the
relative risk for patients having problems with prescription drug
abuse or misuse (Box 82). To date, a number of tools have
TOOLS FOR OPIOID THERAPY arisen, including the Screening Tool for Addiction Risk (STAR),
Drug Abuse Screening Test (DAST), Screener and Opioid
Howard S. Smith and Kenneth L. Kirsh Assessment for Patients with Pain (SOAPP), and the Opioid Risk
Tool (ORT). The choice in tools for a more thorough ongoing
assessment, however, has been somewhat more limited up until
now and is the focus of the discussion.
Oversight by regulatory agencies, state medical boards, and
various peer-review groups includes examination of appropriate
medical care as well as proper documentation. As the old axiom
INTRODUCTION states, ‘‘if it isn’t written, it didn’t happen.’’ In cases of OT for
chronic pain, issues beyond typical office visit charting may deserve
The field of pain management is still relatively young compared with attention and documentation. Although there are no explicit
other medical specialties, but it has experienced a tremendous period requirements for what and how to document issues related to
of growth since the late 1980s. Realization has grown that chronic OT, it is belived by some that the use of specific tools and instru-
pain affects the lives of millions of people and that this issue must be ments in the chart on some or all visits may boost adherence to
addressed. Indeed, we see that issues with pain are the number-one documentation expectations as well as the consistency of such doc-
reason that patients go to see their physicians. However, this umentation. Assessment tools may also be helpful in the analysis of
increased recognition of the problem has been somewhat tempered persistent pain.
by the souring of the regulatory climate and the growth of prescrip-
tion drug abuse. Because of this, there has been a trend for clinicians
to shy away from using high opioid doses or even utilizing this AREAS OF INTEREST FOR
modality at all in the treatment of chronic pain (Box 81). DOCUMENTATION
Despite these fears and concerns, the use of long-term opioid
therapy (OT) to treat chronic nonmalignant pain is growing, based It is important to consider four main domains in assessing pain
in part on evidence from clinical trials and a growing consensus outcomes and to better protect your practice for those patients you
among pain specialists. The appropriate use of these drugs requires maintain on an opioid regimen: (1) pain relief, (2) functional out-
skills in opioid prescribing, knowledge of addiction medicine comes, (3) side effects, and (4) drug-related behaviors. These
principles, and a commitment to perform and document a domains have been labeled the ‘‘Four A’s’’ (Analgesia, Activities
comprehensive assessment repeatedly over time. Inadequate assess- of daily living, Adverse effects, and Aberrant drug-related beha-
ment can lead to undertreatment, compromise the effectiveness of viors) for teaching purposes. There are, of course, many different
therapy when implemented, and prevent an appropriate response ways to think about these domains, and multiple attempts to cap-
when problematic drug-related behaviors occur. ture them are discussed later.
52 Chapter 8 POTENTIAL DOCUMENTATION TOOLS FOR OPIOID THER APY
ASSESSING OPIOID THERAPYADVERSE

Box 8^1 CURRENT DIAGNOSIS
EFFECTS
Problems with prescription drug abuse and diversion have created a Documentation of adverse effects in a majority of charts from many
heightened level of tension and fear over the use of opioids in pain
management. pain clinics tends to be addressed in the chart by a brief note of the
It is essential that pain clinicians provide a rationale for engaging in this presence or absence of one or more adverse effects (e.g., nausea,
modality of treatment and provide ample documentation in this constipation, itching) recorded by busy clinicians. Similar to the
regard. goal of the PADT, having a standardized form that is used at
Assessment and documentation are cornerstones for both protecting every visit and filled out by the patients before being seen by
your practice and obtaining optimal patient outcomes while on opioid health care providers may provide certain advantages.
therapy. Patients with persistent pain on oral OT have asked to ‘‘come
off’’ the opioids because of adverse effects, even if they perceived
that opioids were providing reasonable analgesic effects. The dis-
tress that may be caused by opioid adverse effects may also be seen
in acute postoperative pain patients, who may occasionally ask to
stop their opioids (despite the perception that these are effective
THE PAIN ASSESSMENTAND analgesics) because of the significant distress and suffering that they
DOCUMENTATION TOOL believe they are experiencing from an opioid adverse effect.
Therefore, it appears crucial to assess opioid adverse effects.
The Pain Assessment and Documentation Tool (PADT) is a simple Ideally, this should be done in a manner that allows the clinician
charting device, based upon the Four A’s, that is designed to focus to follow trends as well as to compare the patient’s perceived inten-
on key outcomes and provide a consistent way to document prog- sity of the adverse effects versus the intensity of pain and/or other
ress in pain management therapy over time. Twenty-seven clini- symptoms or adverse effects.
cians completed the preliminary version of the PADT for 388 The Numerical Opioid Side Effect (NOSE) assessment tool
opioid-treated patients. The result of this work is a brief, two- (Appendix 81) is a self-administered survey that can be completed
sided chart note that can be readily included in the patient’s medical by the patient in minutes and entered into an electronic database or
record. It was designed to be intuitive, pragmatic, and adaptable to inserted into a hard-copy chart on each patient visit. The NOSE
clinical situations. In the field trial, it took clinicians between 10 and assessment tool is easy to administer and to interpret and may
20 minutes to complete the tool. The revised PADT is substantially provide clinicians with important clinical information that could
shorter and should require a few minutes to complete. By addres- potentially affect various therapeutic decisions. Although most clin-
sing the need for documentation, the PADT can assist clinicians in icians probably routinely assess adverse effects of treatments, it is
meeting their obligations for ongoing assessment and documenta- sometimes difficult to find legible, clear, and concise documenta-
tion. Although the PADT is not intended to replace a progress note, tion of such information in outpatient records. Furthermore, the
it is well suited to complement existing documentation with a documentation that does exist may not always attempt to
focused evaluation of outcomes that are clinically relevant and ‘‘quantify’’ the intensity of treatment-related adverse effects or
address the need for evidence of appropriate monitoring. lend itself to looking at trends (see Appendix 81).
The decision to assess the four domains subsumed under the
shorthand designation the ‘‘Four A’s’’ was based on clinical experi-
ence, the positive comments received by the investigators during ASSESSING OT EFFICACY
educational programs on opioid pharmacotherapy for nonmalig-
nant pain, and an evolving national movement that recognizes The Initiative on Methods, Measurements, and Pain Assessment in
the need to approach OT with a ‘‘balanced’’ response. This response Clinical Trials (IMMPACT) recommended that six core outcome
recognizes both the legitimate need to provide optimal therapy to domains—(1) pain, (2) physical functions, (3) emotion, (4) partic-
appropriate patients and the need to acknowledge the potential for ipant rating of improvement and satisfaction with treatment, (5)
abuse, diversion, and addiction. The value of assessing pain relief, symptoms and adverse events, and (6) participant disposition—-
side effects, and aspects of functioning has been emphasized should be considered when designing chronic pain clinical trials.
repeatedly in the literature. Documentation of drug-related beha- The authors believe that the use of a unidimensional tool such as
viors is a relatively new concept being explored for the first time in the numeric rating scale-11 (NRS-11) provides a suboptimal assess-
the PADT. ment of chronic pain as well as OT efficacy. Clinicians should
attempt to assess multiple domains (preferably with multidimen-
sional tools) in efforts to achieve a global picture of the patient’s
baseline status as well as the patient’s response to OT in various
domains.
It has been proposed that the use of a collection of various tools
may provide adjunct information and help clinicians to create a more
Box 8^2 CURRENT THERAPY complete picture regarding longitudinal trends of overall progress/
functioning for their patients with chronic pain on OT. Assessing
Several potential tools and documentation strategies are available
individual outcomes during outpatient multidisciplinary chronic
that will aid clinicians in providing evidence for the continuation of
this type of treatment for their patients. pain treatment is often an extremely challenging task. Many tools
The Pain Assessment and Documentation Tool (PADT) is a global and instruments are currently available, but the Treatment
charting tool that captures domains of analgesia, activities of daily Outcomes in Pain Survey tool (TOPS) has been specifically designed
living, adverse side effects, and potentially aberrant drug-taking to assess and follow outcomes in the chronic pain population and has
behaviors. been described as an augmented SF-36. The Medical Outcomes
The Numerical Opioid Side Effect (NOSE) assessment tool is a specific Study (MOS) Short Form 36-item questionnaire (SF-36) compares
instrument designed for the quantification of adverse effects. the health status of large populations without a preponderance of
TheTranslational Analgesia Scale (TAS) is a patient-generated tool that one single medical condition. The SF-36 assesses eight domains,
attempts to quantify the degree of ‘‘translational analgesia’’ or
improvements in various domains over time as a result of treatment.
but it has not been found to be especially useful for following
the changes in function and pain in chronic pain populations.
The eight domains of the SF-36 are bodily pain (BP), general better after tapering off opioids. Furthermore, more evidence
health (GH), mental health (MH), physical functioning (PF), role regarding the hyperalgesic actions of opioids in certain circum-
emotional (RE), social functioning (SF), role physical (RP), and stances is mounting.
vitality (VT). The TOPS scale initially had nine domains, but The periodic assessment of the patient with chronic pain should
one (satisfaction with outcomes) was modified in subsequent ver- be performed in multiple domains (e.g., social, analgesia, functional,
sions. The nine domains of TOPS are Pain Symptom, Family/Social emotional). The authors believe to be suboptimal the relatively
Disability, Functional Limitations, Total Pain Experience, Objective common practice of evaluating patients with chronic pain by obtain-
Work Disability, Life Control, Solicitous Responses, Passive ing a NRS-11 pain score at each assessment and basing opioid anal-
Coping, and Satisfaction with Outcomes. This enhanced SF- gesic treatment solely on this score. Although tools exist that assess
36 (TOPS scale) was constructed by obtaining patient data multiple domains used in research, there is no simple, convenient,
from the SF-36 with 12 additional role functioning questions. and universally acceptable instrument that is utilized in busy clinical
These additional questions were taken in part from the 61-item pain practices.
Multidimensional Pain Inventory (MPI) and the 10-item To address this issue, a recent tool has been developed. The
Oswestry Disability Questionnaire, with four additional pain- SAFE Score is a multidomain assessment tool that may have poten-
related questions similar to those found in the MOS pain-related tial utility for rapid dynamic assessment in the busy clinic setting.
questions, the Brief Pain Inventory, and a six-item coping scale The SAFE Score is a clinician-generated tool and may be best uti-
from the MOS. lized in conjunction with the Translational Analgesic Score (TAS; a
The questions adapted from the Oswestry Disability patient-generated tool) as an adjunct. These are discussed, in turn,
Questionnaire (designed for back pain patients) include questions in the following sections.
that relate to impairment (pain), physical functioning (how long
the patient can sit and/or stand), and disability (ability to travel or
have sexual relations). The patient-generated index is an instrument The TAS
that attempts to individualize a patient’s perception of their quality
of life. The TAS is a patient-generated tool that attempts to quantify the
Although the TOPS instrument is an extremely useful tool, it is degree of ‘‘translational analgesia’’ (Appendix 82). It is simple,
time-consuming, is based entirely on the patient’s subjective rapid, user-friendly, and suitable for use in busy pain clinics. The
responses, and requires that the clinician has access, whether by a patient can be handed the TAS sheet with questions to fill out at
special computer program or by sending forms away, for scoring. As each visit while in the waiting room and the responses are averaged
a result, it may not be an ideal instrument to use in every pain clinic for an overall score, which is recorded in the chart. The authors
and may not provide the clinician with an immediate answer of encourage clinicians to have all patients write down specific exam-
how the patient is doing relative to previous visits (although it may ples of things that they can do now or do frequently that they could
have that potential with adequate time, scanning equipment, and not do or did rarely when their pain was less controlled.
computer software). Alternatively, the patient’s responses can be entered into a compu-
terized record (with graphs of trends) if the pain clinic’s medical
records are electronic.
TRANSLATIONAL ANALGESIA In the sample provided, the patient answered all 10 questions
with responses; hence, the average is the sum of all responses (26)
A concept that may possess potential utility for clinicians is transla- divided by 10. Therefore, the TAS is 2.6. A patient who at each visit
tional analgesia. Translational analgesia refers to improvements in consistently has a TAS of 10.0 clearly represents a therapeutic suc-
physical, social, or emotional function that are realized by the cess on her or his current treatment. Conversely, a patient who at
patient as a result of improved analgesia, or essentially, what did each visit consistently has a TAS of 0.0 would represent a subopti-
the pain relief experienced by the patient ‘‘translate’’ into in terms mal therapeutic result (by TAS criteria). Clinicians are encouraged
of perceived improved quality of life. In most cases, a sustained and to document at least one or two specific examples of translational
significant improvement in pain perception that is deemed worth- analgesia (e.g., perhaps various activities the patient can now per-
while to the patient should ‘‘translate’’ into improvement in quality form as a result of pain relief or can now perform frequently as a
of life or improved social, emotional, or physical function. result of pain relief that the patient could not do or do only infre-
Improvements in social, emotional, or physical domains are often quently pretherapy) on the bottom or reverse side of the TAS sheet.
spontaneously reported by patients but, in most cases, should be Treatment decisions regarding escalation or tapering of opioids,
able to be ascertained or elicited via ‘‘focused’’ interview techniques changing agents, adding agents, obtaining consultations, instituting
with the patient, significant others, and family, ‘‘focused’’ physical physical medicine or behavioral medicine techniques remain the
examination, or a combination of any of these. Improvements may medical judgment of practitioners and should be based on a careful
be subtle and could include a range of daily function activities or reevaluation of the patient and not on a number.
other signs (e.g., going out more with friends, doing laundry, show- The concept of translational analgesia is not meant to imply that
ing improved mood/relations with family members). It is important opioids should be tapered, weaned, and/or discontinued. If a
to note that this issue is certainly not exclusive to OT and is believed patient has a very low TAS that and essentially unchanged over
to apply to other treatments. time (especially in conjunction with a SAFE score in the ‘‘red
The authors do not deem it inappropriate or inhumane to taper zone’’), then this should prompt the clinician to reevaluate the
relatively ‘‘high-dose’’ OT in a patient with chronic pain who notes patient and consider a change in therapy. This could mean pursuing
that her or his NRS-11 pain score has dropped from 9/10 to 8/10 various therapeutic options including perhaps increasing the dose
after escalating to more than 1 g of long-acting morphine prepara- of opioids. However, if a patient has a high TAS and a SAFE score in
tion per day, but in whom the patient as well as the patient’s family the green zone, the patient should probably continue OT.
or significant other cannot describe (and the clinician cannot elicit)
any significant ‘‘translational analgesia.’’ A patient with chronic
pain who demonstrates a failure to ‘‘get off the couch,’’ despite THE SAFE SCORE
equivocal or minimally improved analgesia, should not be consid-
ered as a therapeutic success. But should this viewpoint be seen as Another tool advocated to help with this purpose is SAFE Score.
cruel or as a punishment for these patients? Rome and colleagues Although it has not yet been rigorously validated, it is simple and
demonstrated that at least a subpopulation of patients seems to do practical and may possess clinical utility. It is a score generated by
the health care provider that is meant to reflect a multidimensional Table 8^2. Tracking a Change in Status Using the
assessment of outcome to OT. It is not meant to replace more SAFE ScoringTool
elaborate patient-based assessment tools but could possibly serve
as an adjunct and possibly in the future shed some light on the Example C Example D
difference between patients’ perceptions of how they are doing on
OT versus the physician-based view of outcome. Social 5 Social 3
At each visit, the clinician rates the patient’s functioning and Analgesia 3 Analgesia 4
pain relief in four domains. The domains assessed include social Function 5 Function 3
functioning (S), analgesia or pain relief (A), physical functioning Emotional 5 Emotional 3
(F), and emotional functioning (E). The ratings in each of the four
Red Zone SAFE score 18 Green Zone SAFE score 13
domains are combined to yield a SAFE score, which can range from
4 to 20.
The SAFE Tool is both practical in its ease and clinically useful
(Appendix 83). The goals of the SAFE Tool are multifold.
Specifically, they include the need to demonstrate that the clinician Table 82 illustrates how the SAFE tool can be used to track
has routinely evaluated the efficacy of the treatment from multiple changes in the status of the same patient on two consecutive visits.
perspectives; to guide the clinician toward a broader view of treat- In the change in scores from example C to example D, although
ment options beyond adjusting the medication regimen; and to analgesia deteriorates from fair to borderline, significant improve-
document the clinician’s rationale for continuation, modification, ment is shown in the other domains. The clinician may feel this is
or cessation of OT. satisfactory for this particular patient and continue with the current
medication regimen. Once again, too narrow a focus on analgesic
response may lead to unnecessary dose escalation. This case also
Interpretation of Scores illustrates the situation in which even though the total score at visit
D is greater than 12 and would be a yellow zone, it is assigned as a
Scores can be broken down into three distinct categories. First, the green zone because there was a decrease of more than 2 in the total
green zone represents a SAFE score of 4 to 12 and/or a decrease of score. Alternately, the clinician may determine that a borderline
2 points in the total score from baseline. With a score in the green analgesic response is not optimal. The choices for intervention
zone, the patient is considered to be doing well and the plan would may include rotating to another opioid agent, increasing the current
be to continue with the current medication regimen or consider opioid dose, adding adjuvant medications, referring for nonphar-
reducing the total dose of the opioids. Second, the yellow zone macologic treatment, or discontinuing high-dose opioids.
represents a SAFE score of 13 to 16 and/or a rating of 5 in any Table 83 again illustrates a single patient on two consecutive
category and/or an increase of 2 or more from baseline in the visits. Here, analgesia has remained good over time, but there has
total score. With a score in the yellow zone, the patient should been a negative impact on the domains of function and emotion.
be monitored closely and reassessed frequently. Finally, the red Pain specialists who are focused on the pain scores of such a patient
zone represents a SAFE score of 17 or higher. With a score in may be comfortable with continuing the established treatment plan.
the red zone, a change in the treatment would be warranted However, using SAFE, an expanded view of the patient’s overall
(Tables 81 to 83). status will alert the clinician to monitor the patient’s physical and
Once the color determination is made, a decision can be made emotional functioning in future visits. If the ratings in the psycho-
regarding treatment options. Treatment options depend on the pat- logical and physical domains persist, the clinician may recommend
tern of scores. If attempts are made to address problems in specific that the patient pursue psychosocial treatment or physical rehabil-
domains and the patient is still not showing an improvement in the itation in addition to maintaining the medication regimen.
SAFE score, the patient may not be an appropriate candidate for
long-term OT.
Table 81 illustrates green zone cases. Example A shows good CONCLUSION
analgesic response to opioids, with a fair response in the other
domains. No change in treatment would be necessary unless adverse Assessment and documentation are cornerstones for both protect-
reactions to the medications require an adjustment or discontinua- ing your practice and obtaining optimal patient outcomes while on
tion. Example B illustrates borderline analgesic response, but good opioid therapy. A growing number of assessment tools exist for
social and emotional responses and a fair physical functioning clinicians to guide the evaluation of a group of important outcomes
response. Some pain specialists may determine that the medication during OT and provide a simple means of documenting patient
regimen should be optimized. For others, this pattern of ratings care. They all have the capability to prove helpful in clinical man-
may reflect a reasonable improvement in quality of life for the agement and offer mechanisms for documenting the types of prac-
patient. Therefore, continuing the present medication regimen tice standards that those in the regulatory and law enforcement
would be a reasonable option. communities seek to ensure.
Table 8^1. Green Zone Cases Using the SAFE Table 8^3. Tracking a Specific Domain Change in
ScoringTool Status Using the SAFE ScoringTool
Example A Example B Example E Example F

Social 3 Social 2 Social 3 Social 3
Analgesia 2 Analgesia 4 Analgesia 2 Analgesia 2
Function 3 Function 3 Function 3 Function 4
Emotional 3 Emotional 1 Emotional 3 Emotional 4
Green Zone SAFE score 11 Green Zone SAFE score 10 Green Zone SAFE score 11 Yellow Zone SAFE score 13
SUGGESTED READINGS Passik SD, Kirsh KL, Whitcomb LA, et al. A new tool to assess and
document pain outcomes in chronic pain patients receiving opioid
Berry PH, Dahl JL. The new JCAHO pain standards: implications for pain therapy. Clin Ther 2004;26:552561.
management nurses. Pain Manage Nurs 2000;1:312. Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review of
Cicero TJ, Inciardi JA, Munoz A. Trends in abuse of Oxycontin and other critical issues. J Pain Symptom Manage 1996;11:203217.
opioid analgesics in the United States: 20022004. J Pain 2005;6:662672. Rome JD, Townsend CO, Bruce BK, et al. Chronic noncancer pain
Collett BJ. Opioid tolerance: the clinical perspective. Br J Anaesth
rehabilitation with opioid withdrawal: comparison of treatment
1998;81:5868.
outcomes based on opioid use status at admission. Mayo Clin Proc
Friedman R, Li V, Mehrotra D. Treating pain patients at risk: evaluation 2004;79:759768.
of a screening tool in opioid-treated pain patients with and without Smith HS (ed). Opioid Therapy in the 21st Century. New York, Oxford:
addiction. Pain Med 2003;4:182185. Oxford University Press; 2008.
Katz N. The impact of pain management on quality of life. J Pain
Smith HS, Audette J, Witkower A. Playing it ‘‘SAFE.’’. J Cancer Pain
Symptom Manage 2002;24(suppl 1):S38S47.
Symptom Palliation 2005;1:310.
Lipman AG. Does the DEA truly seek balance in pain medicine?. J Pain
Smith HS, Passik S (eds). Pain and Chemical Dependency. New York,
Palliat Care Pharmacother 2005;19:79.
Oxford: Oxford University Press; 2008.
McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated
pharmacotherapeutic opportunities to enhance compliance, quality of
patients: preliminary validation of the Opioid Risk Tool. Pain Med
life, and analgesia. Am J Ther 2001;8:181186. 2005;6:432442.
Passik SD, Kirsh KL. Fear and loathing in the pain clinic. Pain Med
2006;7:363364.
Appendix 81
NUMERICAL OPIOID SIDE EFFECT
(NOSE) ASSESSMENT TOOL
Not Present As Bad As You Can Imagine
0 1 2 3 4 5 6 7 8 9 10
1. Nausea, vomiting,
and/or lack of appetite
2. Fatigue, sleepiness,
trouble concentrating,
hallucinations, and/or
drowsiness/somnolence
3. Constipation
4. Itching
5. Decreased sexual
desire/function and/or
diminished libido
6. Dry mouth
7. Abdominal pain or
discomfort/cramping
or bloating
8. Sweating
9. Headache and/or
dizziness
10. Urinary retention
Appendix 82 any improvements in your socializing, recreational activities,

physical functioning, concentration, mood, interpersonal rela-
TRANSLATIONAL ANALGESIC SCORE tionships, activities of daily living, and/or overall quality of life?
For each of the following questions—respond by comparing your 0 1 2 3 4 5 6 7 8 9 10

current state over the past month to your baseline status before you
started your current treatment regimen by circling a number from 0
to 10, with 0 being no improvement and 10 being maximal
improvements: —Please write below—specific examples of things you can do now
or currently do frequently that you could not do or did only rarely
1. Over the past month, my pain treatment has improved my abil-
when your pain was not controlled as well as it is now.
ity to do usual daily activities—including household work, work,
TAS = _______________
school, and/or social activities.
The TAS is expressed as a number between 0 to 10 with a decimal
0 1 2 3 4 5 6 7 8 9 10 being the average of the responses to the 10 questions (or fewer—if
the patient is paraplegic, then she or he would not answer the ques-
2. Over the past month, my pain treatment has improved my abil- tions regarding going up stairs, etc.).
ity to concentrate on work or daily activities.
As an example, a patient’s response to the TAS tool is shown
0 1 2 3 4 5 6 7 8 9 10 below:
3. Over the past month, my pain treatment has improved the ity to do usual daily activities— including household work,
degree to which I feel too tired to do work (feeling that I work, school, and/or social activities.
could not get going and everything I did was an effort) or too
tired to perform daily activities and/or socialize because of my
pain. 0 1 2 3 4 5 6 7 8 9 10
0 1 2 3 4 5 6 7 8 9 10 2. Over the past month, my pain treatment has improved my abil-

ity to concentrate on work or daily activities.
4. Over the past month, my pain treatment has improved the
degree to which I feel distress, restless, agitated, or could go 0 1 2 3 4 5 6 7 8 9 10
and lie down and/or be alone because of my pain.
0 1 2 3 4 5 6 7 8 9 10 degree to which I feel too tired to do work (feeling that I
could not get going and everything I did was an effort) or too
5. Over the past month, my pain treatment has improved my mood tired to perform daily activities, and/or socialize because of my
or feelings of being: depressed, frustrated, anxious, irritable, pain.
tense, hopeless, annoyed, or just plain fed up because of my pain.
0 1 2 3 4 5 6 7 8 9 10
0 1 2 3 4 5 6 7 8 9 10
6. Over the past month, my pain treatment has improved my abil- 4. Over the past month, my pain treatment has improved the
ity to sleep. degree to which I feel distress, restless, agitated, or could go
and lie down and/or be alone because of my pain.
0 1 2 3 4 5 6 7 8 9 10
0 1 2 3 4 5 6 7 8 9 10
ity to walk, sit, and/or stand for long periods.
5. Over the past month, my pain treatment has improved my mood
0 1 2 3 4 5 6 7 8 9 10 or feelings of being: depressed, frustrated, anxious, irritable,
tense, hopeless, annoyed, or just plain fed up because of my pain.
ity to go up stairs and/or move or lift objects. 0 1 2 3 4 5 6 7 8 9 10

ity to sleep.
extent to which my pain interferes with optimal interpersonal 0 1 2 3 4 6 7 8 9 10
5
relationships and/or intimacy.

ity to walk, sit, and/or stand for long periods.
10. Over the past month, to what degree have you, your significant 0 1 3 4 5 6 7 8 9 10
other, your family, your coworkers, and/or your friends noticed 2
8. Over the past month, my pain treatment has improved my abil- 10. Over the past month, to what degree have you, your significant
ity to go up stairs, and/or move or lift objects. other, your family, your coworkers, and/or your friends noticed
any improvements in your socializing, recreational activities,
0 1 2 3 4 5 6 7 8 9 10 physical functioning, concentration, mood, interpersonal rela-
tionships, activities of daily living, and/or overall quality of life?
extent to which my pain interferes with optimal interpersonal 0 1 2 3 4 5 6 7 8 9 10
relationships and/or intimacy.
0 1 2 3 4 5 6 7 8 9 10 TAS = 2.6
Appendix 83
Sample SAFE Form
Rating Criterion
Social 1 2 3 4 5
Marital, family, supportive conflictual
friends, leisure, harmonious discord
recreational socializing isolated
engaged bored
Analgesia 1 2 3 4 5
Intensity, comfortable intolerable
frequency, effective ineffective
duration controlled uncontrolled
Function 1 2 3 4 5
Work, ADLs, independent dependent
home management, active unmotivated
school, training, productive passive
physical activity energetic deconditioned
Emotional 1 2 3 4 5
Cognitive, stress, clear confused
attitude, mood, relaxed tense
behavior, optimistic pessimistic
neurovegetative signs upbeat depressed
composed distressed
Total Score
The patient’s status in each of the four domains is rated as follows:

1 = Excellent
2 = Good
3 = Fair
4 = Borderline
5 = Poor
ADLs, activities of daily living.
III
ACUTE PAIN
Chapter 9
PATHOPHYSIOLOGYOF ACUTE PAIN
PERIOPERATIVE USE Peripheral sensitization, a reduction in the threshold of nociceptor
afferent peripheral terminals, is a result of inflammation
OF COX-2 AGENTS at the site of surgical trauma.9 Central sensitization, an
activity-dependent increase in the excitability of spinal neurons,
Scott S. Reuben is a result of persistent exposure to nociceptive afferent input
from the peripheral neurons.10 Taken together, these two pro-
cesses contribute to the postoperative hypersensitivity state
(‘‘spinal windup’’) that is responsible for a decrease in the pain
threshold, both at the site of injury (primary hyperalgesia) and
in the surrounding uninjured tissue (secondary hyperalgesia)11
(Fig. 9–1).
INTRODUCTION As a result of this peripheral sensitization, low-intensity stimuli
that would normally not cause a painful response prior to sensiti-
The primary goal of postoperative pain relief is to provide zation now become perceived as pain, an effect termed allodynia
subjective comfort, inhibit trauma-induced afferent pain trans- (Fig. 9–2).
mission, and blunt the autonomic and somatic reflex responses The proinflammatory cytokine interleukin-1b (IL-1b) is up-
to pain. By accomplishing this, we should enhance restoration of regulated at the site of inflammation and plays a major role in
function by allowing the patient to breath, cough, and ambulate inducing cyclooxygenase-2 (COX-2) in local inflammatory
more easily. Subsequently, these effects should improve overall cells by activating the transcription factor nuclear factor kB
postoperative outcome. Despite our increased knowledge of (NF-kB).12 IL-1b is also responsible for the induction of COX-
the pathophysiology and pharmacology of nociception since the 2 in the central nervous system (CNS) in response to peripheral
late 1990s, acute postoperative pain still remains a major prob- inflammation. Interestingly, it is not the consequence either of
lem.1 Patients continue to report that their primary concern neural activity arising from the sensory fibers innervating
before surgery is the severity of postoperative pain.1,2 This is the inflamed tissue or of systemic IL-lb in the plasma. Instead,
justified, because one survey revealed that 31% of patients peripheral inflammation produces some other signal molecule
suffered from severe or extreme pain and another 47% from that enters the circulation, crosses the blood-brain barrier, and
moderate pain.1 acts to elevate IL-lb, leading to COX-2 expression in neuronal
Unrelieved postoperative pain may not only result in suffering and nonneuronal cells throughout the CNS.13–15 Thus, there
and discomfort but also lead to multiple physiologic and psycho- appear to be two forms of input from peripheral inflamed
logical consequences, which can contribute to adverse periop- tissue to the CNS. The first is mediated by electrical activity in
erative outcomes.3 This can potentially contribute to a higher sensitized nerve fibers innervating the inflamed area, which sig-
incidence of myocardial ischemia, impaired wound healing,4,5 nals the location of the inflamed tissue as well as the onset,
and delayed gastrointestinal motility, resulting in prolonged duration, and nature of any stimuli applied to this tissue.16
postoperative ileus.6 Further, unrelieved acute pain leads to This input is sensitive to peripherally acting COX-2 inhibitors
poor respiratory effort and splinting that can result in atelectasis, and to neural blockade with local anesthetics, as with epidural
hypercarbia, and hypoxemia, contributing to a higher incidence or spinal anesthesia.17 The second is a humoral signal originating
of postoperative pneumonia.3 In addition, acute pain causes from the inflamed tissue, which acts to produce a widespread
psychological distress and anxiety, leading to sleeplessness and induction of COX-2 in the CNS. This input is not affected by
helplessness, impairing postoperative rehabilitation, and poten- regional anesthesia13,14 and will be blocked only by centrally
tially causing long-term psychological consequences.7 Finally, it acting COX-2 inhibitors.14,17,18 One implication of this is that
has been recognized that unrelieved acute pain may contribute patients who receive neuraxial anesthesia for surgery might also
to a higher incidence of chronic postsurgical pain.8 Therefore, need a centrally acting COX-2 inhibitor to optimally reduce post-
strategies aimed at reducing acute pain may not only provide operative pain and the postoperative stress response.14,17,18
subjective comfort for our patients but also result in im- Therefore, the permeability of the blood-brain barrier to cur-
proved postoperative outcomes and a reduction in health care rently used nonsteroidal anti-inflammatory drugs (NSAIDs) and
expenditures. COX-2 inhibitors becomes important.19
59
60 Chapter 9 PERIOPER ATIVE USE OF COX-2 AGENTS
Central
sensitization
CNS
Spinal
wind-up
Inflammatory
mediators
Spinal cord Hydrogen ions, histamines, purines,

leukotrienes, norepinephrine,
potassium ions, cytokines,
Primary nerve growth factor, BK, PGs, 5-HT,
hyperalgesia neuropeptides
Surgical
trauma
Secondary
hyperalgesia
Peripheral
sensitization
Figure 9^1. Surgical trauma leads to the release of inflammatory mediators at the site of injury, resulting in a reduction in the pain threshold
at the site of injury (primary hyperalgesia) and in the surrounding uninjured tissue (secondary hyperalgesia). Peripheral sensitization results from
a reduction in the threshold of nociceptor afferent terminals secondary to surgical trauma.Central sensitization is an activity-dependent increase
in the excitability of spinal neurons (spinal wind-up) as a result of persistent exposure to afferent input from peripheral neurons. BK, bradykinin;
CNS, central nervous system; 5-HT, serotonin; PGs, prostaglandins.
MULTIMODAL ANALGESIA
In July 2000, the Joint Commission for Accreditation of Health
Care Organizations (JCAHO) introduced a new standard for pain
Sensitized management, declaring pain level to be the ‘‘fifth vital sign.’’20
pain response
The Commission concluded that acute and chronic pain were
10 major causes of patient dissatisfaction in our health care
system, leading to slower recovery times, creating a burden for
8 patients and their families, and increasing the costs to the health
Pain intensity
Normal care system.20 However, the increased efforts aimed at reducing

pain patients’ postoperative pain scores may have further increased the
6 Injury response risk of adverse effects when health care providers attempted to
achieve sufficient analgesia by opioids alone.21–23
4 The concept of multimodal analgesia was introduced in the
late 1990s as a technique to improve analgesia and reduce the
incidence of opioid-related adverse events.24 The rationale for
2 this strategy is the achievement of sufficient analgesia through
the additive or synergistic effects between different analgesics.
0 This allows for a reduction in the doses of these drugs and,
Stimulus intensity
thus, a lower incidence of adverse effects. Currently, the
ALLODYNIA American Society of Anesthesiologists Task Force on Acute
Figure 9^2. Nociceptive afferent input from trauma can sensitize Pain Management25 and the Agency for Health Care Policy and
the nervous system to subsequent stimuli.The normal pain Research26 advocate the use of NSAIDs in a multimodal analge-
response as a function of stimulus intensity is depicted by the curve sic approach for the management of acute pain. The practice
on the right. After trauma, the pain response curve is shifted to guidelines for acute pain management in the perioperative
the left. As a result, noxious stimuli become more painful setting specifically state ‘‘unless contraindicated, all patients
(hyperalgesia), and nonpainful stimuli (shaded region) now become should receive around-the-clock regimen of NSAIDs, coxibs, or
painful (allodynia). acetaminophen.’’25
III ACUTE PAIN 61
COX INHIBITION AND POSTOPERATIVE postoperative pain after dental, orthopedic, thoracic, abdominal,
PAIN MANAGEMENT and gynecologic surgeries.31,35 Although all NSAIDs inhibit the
COX enzyme, differences in their pharmacodynamic and pharma-
Currently, the administration of NSAIDs is one of the most com- cokinetic properties may make some NSAIDs more suitable as post-
mon nonopioid analgesic techniques utilized for the management of operative analgesics. Unfortunately, with the exception of dental
postoperative pain.27 NSAIDs are useful as the sole analgesic after surgery, there are very few studies comparing the analgesic efficacies
minor surgical procedures.28 Because of their ceiling effect for of NSAIDs for postoperative pain. The Oxford League Table of
analgesia,29 NSAIDs alone provide insufficient analgesia after analgesics36 may be used to indirectly compare the efficacy of
major surgery, but they demonstrate a significant opioid-sparing these NSAIDs against each other. This Table is based on using
effect.30 The use of NSAIDs has become increasingly popular because comparisons of different analgesics with placebo in similar clinical
of the concern over opioid-related side effects, such as nausea, vomit- circumstances, with similar patients included, similar pain measure-
ing, sedation, pruritus, ileus, and urinary retention. Advantages of ment, and similar outcome measures, and deriving the number-
utilizing NSAIDs as part of the perioperative ‘‘analgesic cocktail’’ needed-to-treat (NNT) (Table 9–2). The efficacy of analgesics is
include lack of sedation and respiratory depression, a low abuse commonly expressed as NNT, which represents the number of
potential, and no interference with bowel or bladder function.31
In addition, unlike opioids (which are effective for reducing sponta-
neous pain at rest), NSAIDs demonstrate comparable efficacy for
Table 9^2. Oxford LeagueTable of Analgesics
pain both at rest and with movement,32 the latter of which may be in Acute Pain
more important for causing postoperative physiologic impairment.33
For these reasons, it is recommended that unless contraindicated, Patients in At Least
nonselective NSAIDs should be considered the drugs of choice Comparison 50% Pain
for the management of mild to moderate postoperative pain.26 Analgesic (N) Relief (%) NNT CI
Nonselective NSAIDs encompass a chemically diverse group of Valdecoxib 40 mg 473 73 1.6 1.4–1.8
compounds including salicylates, proprionic acids, pyrazoles, acetic Ibuprofen 800 mg 76 100 1.6 1.3–2.2
acids, oxicams, fenamates, and naphthyl-alkanones34 (Table 9–1).
These NSAIDs have been reported efficacious in the management of Ketorolac 20 mg 69 57 1.8 1.4–2.5
Ketorolac 60 mg 116 56 1.8 1.5–2.3
(IM)
Table 9^1. Nonsteroidal Anti-inflammatory Drugs Rofecoxib 50 mg 1900 63 1.9 1.8–2.1
Diclofenac 100 mg 411 67 1.9 1.6–2.2
Generic Drug Name Trade Name Piroxicam 40 mg 30 80 1.9 1.2–4.3
p-Aminophenol Derivatives Lumiracoxib 400 252 56 2.1 1.7–2.5
Acetaminophen Tylenol mg
Salicylates Parecoxib 40 mg 349 63 2.2 1.8–2.6
(IV)
Aspirin
Diflunisal Dolobid Diclofenac 50 mg 738 63 2.3 2.0–2.7
Choline magnesium trisalicylate Trisalicylate, Trilisate Naproxen 440 mg 257 50 2.3 2.0–2.9
Salsalate Mono-Gesic Aspirin 1200 mg 279 61 2.4 1.9–3.2
Proprionic Acids Ketorolac 10 mg 790 50 2.6 2.3–3.1
Ibuprofen Motrin, Advil, Nuprin Piroxicam 20 mg 280 63 2.7 2.1–3.8
Fenoprofen Nalfon Diclofenac 25 mg 204 54 2.8 2.1–4.3
Naproxen Naprosyn, Anaprox, Meperidine 100 mg 364 54 2.9 2.3–3.9
Alleve (IM)
Ketoprofen Orudis Morphine 10 mg 946 50 2.9 2.6–3.6
Flurbiprofen Ansaid (IM)
Pyrazoles Parecoxib 20 mg 346 50 3.0 2.8–3.7
Phenylbutazone Butazolidin (IV)
Acetic Acids Naproxen 220/250 183 58 3.1 2.2–5.2
Indomethacin Indocin mg
Tolmetin Tolectin Ketorolac 30 mg 359 53 3.4 2.5–4.9
Sulindac Clinoril (IM)
Diclofenac Voltaren, Cataflam Acetaminophen 2759 46 3.8 3.4–4.4
Etodolac Lodine 1000 mg
Ketorolac Toradol Aspirin 1000 mg 716 46 4.0 3.2–5.4
Oxicams Aspirin 600/650 mg 5061 38 4.4 4.0–4.9
Piroxicam Feldene Celecoxib 200 mg 418 34 4.5 3.3–7.2
Meloxicam Mobic Codeine 60 mg 1305 15 16.7 11.0–48.0
Fenamates Placebo >10,000 18 N/A N/A
Meclofenamic acid Meclomen
Mefenamic Ponstel CI, confidence interval; IM, intramuscular; IV, intravenous; N/A, not
Naphthyl-alkanone applicable; NNT, number needed to treat.
*The medical coverage of mass-participation events presents a unique,
Nabumetone Relafen
exciting, and challenging opportunity to literally bring medical.
patients who need to receive the active drug for one patient to utilized as an analgesic for decades in Europe, propacetamol
achieve at least 50% relief of pain compared with placebo over has not yet received approval by the U.S. Food and Drug
a 4- to 6-hour treatment period.37 For example, an NNT of Administration (FDA).
2 means that for every two patients who receive the drug, one
patient will get at least 50% relief because of the treatment
(the other patient may or may not obtain relief, but it does not Aspirin
reach the 50% level). The NNT is useful for comparison of relative
efficacy of analgesics because these NNT comparisons are treat- Aspirin has been known to be an effective analgesic for many years
ment-specific and are compared with placebo. NSAIDs do extre- and is commonly used in the treatment of both acute and chronic
mely well in the single-dose postoperative comparison, with NNT pain conditions. Aspirin has an elimination half-life that increases
values ranging between 1.6 and 3.4.36 For example, the NNT is 1.6 from 2.5 hours at low doses to 19 hours at high doses.53 It is well
for ibuprofen 800 mg, 1.9 for diclofenac 100 mg, 2.3 for naproxen absorbed in the stomach and small intestine, with peak blood level
440 mg, 2.6 for ketorolac 10 mg, 2.7 for piroxicam 20 mg, and 3.4 achieved 1 hour after an oral dose. There is then rapid conversion of
for intramuscular ketorolac 30 mg.36 At these doses, the majority of aspirin to salicylates from a high first-pass effect, which occurs in
NSAIDs are more effective than single doses of either intramuscular the wall of the small intestine and the liver. The metabolic pathways
morphine 10 mg or meperidine 100 mg, which have an NNT of 2.9. follow first-order and zero-order kinetics.53 A quantitative system-
However, these opioids are more effective than both acetaminophen atic review of 72 randomized single-dose trials with 3253 patients
1000 mg and aspirin 1000 mg, which have an NNT of 3.8 and 4.0, given aspirin revealed a significant analgesic effect versus that of
respectively.36,38 placebo.38 Aspirin demonstrated a clear dose-response for pain
relief, even though these were single-dose studies. Significant benefit
of aspirin over placebo was shown for aspirin 600/650 mg, 1000 mg,
Acetaminophen and 1200 mg, with NNT for at least 50% pain relief of 4.4, 4.0, and
2.4, respectively.38 No apparent ceiling effect for analgesia was
Acetaminophen has demonstrated analgesic efficacy for acute post- observed in this dose range. A comparison of the analgesic efficacy
operative pain in a variety of analgesic models.39 A meta-analysis of of aspirin with acetaminophen has revealed that these two drugs
47 randomized, double-blind, placebo-controlled clinical trials result in similar postoperative pain relief.38 These results are similar
enrolling 4186 patients concluded that acetaminophen is an effec- to those of a previous study demonstrating that aspirin and aceta-
tive analgesic for acute postoperative pain and gives rise to few minophen are equianalgesic and, milligram per milligram, equipo-
adverse effects.39 Another meta-analysis of randomized, controlled tent in a variety of pain models.54 Although it possesses similar
trials of acetaminophen for postoperative pain revealed that it in- analgesic efficacy to that of acetaminophen, the use of aspirin as a
duced a morphine-sparing effect of 20% (9 mg) over the first postoperative analgesic has been limited by its greater side effect
24 hours postoperatively (95% confidence interval [CI] –15 to –3 profile. Unlike acetaminophen, the administration of aspirin causes
mg).40 A recent qualitative review of acetaminophen, NSAIDs, and a significant inhibitory effect on platelet function,55 resulting in
their combination concluded that acetaminophen may provide greater perioperative blood loss.56 Aspirin, which irreversibly acet-
analgesic efficacy similar to that of other NSAIDs after major ortho- ylates the COX enzyme, causes inhibition of platelet aggregation for
pedic surgery.40 It was concluded that acetaminophen may be the lifespan of the platelet, which is 10 to 14 days.55 In contrast,
a viable alternative to NSAIDs in high-risk patients because of the nonselective NSAIDs reversibly inhibit the COX enzyme, causing a
lower incidence of adverse effects.41 Further, it may be appropriate transient reduction in the formation of thromboxane A2 (TXA2)
to administer acetaminophen with an NSAID because these two and inhibition of platelet activation, which resolves after most of the
analgesics may confer an additive or synergistic effect.42 drug is eliminated.55 In addition, even single doses of aspirin were
Acetaminophen may be administered via either oral, rectal, or intra- associated with significantly more drowsiness and gastric irritation
venous routes for the management of postoperative pain. Oral than placebo, with numbers-needed-to-harm of 28 and 38, respec-
doses of 650 mg have been shown to be more effective than doses tively.38 For these reasons, the widespread use of aspirin as a post-
of 300 mg; but little additional benefit is seen at doses above 1000 operative analgesic has been curtailed.
mg, indicating a possible ceiling effect.43 The bioavailability of rectal
acetaminophen is more variable, approximately 80% of that of
tablets and, the rate of absorption is slower, with maximum Ketorolac
plasma concentration achieved about 2 to 3 hours after adminis-
tration.44 Doses of 40 to 60 mg/kg of rectal acetaminophen have Ketorolac is currently the only parenteral NSAID for clinical anal-
been shown to have opioid-sparing effect in various postoperative gesic use in the United States. Ketorolac is almost entirely bound
pain models.45 Propacetamol is a prodrug of acetaminophen that to plasma proteins (>99%), which results in a small apparent
can be administered parenterally. The drug is completely hydro- volume of distribution with extensive metabolism by conjugation
lyzed within 6 minutes of administration, and 1 g of propacetamol and excreted via the kidney.57 The analgesic effect occurs within
yields 0.5 g of acetaminophen.46 Under these conditions, the phar- 30 minutes, with maximum effect between 1 and 2 hours and dura-
macokinetic profile is analogous to that observed after the oral tion of 4 to 6 hours.57 Ketorolac demonstrates analgesia well beyond
administration of acetaminophen 0.5 g, except for a significantly its anti-inflammatory properties, which are between those of indo-
higher maximal plasma concentration as a result of the complete methacin and naproxen; but ketorolac can provide analgesia
bioavailability of the injectable formulation.46 Similar to oral acet- 50 times that of naproxen.57 Ketorolac has antipyretic effects
aminophen, intravenous propacetamol demonstrates a ceiling effect 20 times that of aspirin and, thus, can mask a febrile response
for postoperative pain.47 The maximum effective intravenous dose when administered during the postoperative period. Premarketing
of paracetamol is 5 mg/kg, resulting in a serum concentration of clinical studies have demonstrated efficacy of ketorolac 30 to 90 mg
14 mg/ml, which is a lower dose than previously suggested.47 After comparable with those of morphine 6 to 12 mg, meperidine 50 to
the intravenous injection of propacetamol, acetaminophen easily 100 mg, and propacetamol 2 g for the treatment of moderate post-
crosses the blood-brain barrier, ensuring a central analgesic operative pain.58 However, some studies have revealed that ketor-
effect.46 Injectable propacetamol has been shown to reduce opioid olac is ineffective as the sole postoperative analgesic in the
consumption by about 35% to 45% in postoperative orthopedic management of moderate to severe postoperative pain.59,60
pain studies48–51 and has demonstrated analgesic efficacy similar Similar to other NSAIDs, ketorolac demonstrates an analgesic
to that of ketorolac after gynecologic surgery.52 Although widely ceiling effect.29 Therefore, its efficacy as an analgesic monotherapy
III ACUTE PAIN 63
is usually insufficient for moderately severe to severe pain after The coxibs pose a real and attractive alternative to traditional
major surgery. However, ketorolac can be utilized as an opioid- NSAIDs in cases in which bleeding is a concern, including total
sparing technique in the multimodal management of postoperative joint arthroplasty and tonsillectomy. Prior to the introduction of
pain. Depending upon the type of surgery, ketorolac demonstrated coxibs, many patients undergoing elective total joint arthroplasty
an opioid-sparing effect of a mean of 36%.58 Despite this reduction were instructed to discontinue their use of NSAIDs 7 to 10 days
in opioid use, the administration of ketorolac was not associated prior to surgery.104 Continuing conventional NSAIDs before total
with a concomitant reduction in opioid side effects (e.g., nausea, joint arthroplasty has been associated with a twofold increase in the
vomiting, pruritus, urinary retention).58 incidence of perioperative bleeding, resulting in higher transfusion
Oral ketorolac was approved for use in the United States requirements.90 The use of NSAIDs has been associated with other
approximately 3 years after the parenteral form and has an postoperative complications, including wound hematoma, upper
efficacy similar to that of naproxen and ibuprofen.61 The recom- gastrointestinal tract bleeding, and hypotension.89 The likelihood
mended maximum total daily dose of oral ketorolac is 40 mg, of developing these complications was found to be 5.8 times greater
and it is indicated only as a continuation of the parenteral ther- for patients using NSAIDs 24 hours before surgery than for those
apy.62 The combined duration of use is not to exceed 5 days without such usage.89 We have observed that discontinuing NSAIDs
because of the increased risk of serious adverse events.62 before total joint arthroplasty results in an arthritic flare, not only in
The appropriate analgesic dose of parenteral ketorolac is contro- the operative joint but also in other arthritic joints, leading to
versial. Since ketorolac has been marketed, there have been increased preoperative pain.104 Increased pain before total joint ar-
reports of death owing to gastrointestinal and operative site throplasty is the leading cause for increased postoperative pain,
bleeding.63 In the first 3 years after ketorolac was approved in prolonged hospital admission, and impaired rehabilitation.105 The
the United States (in 1990), 97 fatalities were reported.64 As administration of perioperative coxibs for total joint arthroplasty
a consequence, the drug’s license was suspended in Germany has demonstrated a reduction in perioperative pain and improve-
and France.65 In a response to these adverse events, the drug’s ment in outcomes without an added risk of increased perioperative
manufacturer recommended reducing the dose of ketorolac from bleeding.104,106
150 to 120 mg per day.62 The European Committee for The use of traditional NSAIDs for tonsillectomy is also associ-
Proprietary Medicinal Products recommended a further maximal ated with an increased risk for perioperative bleeding and reopera-
daily dose reduction to 60 mg for the elderly and 90 mg for the tion for bleeding.101 A meta-analysis of randomized, controlled
nonelderly.66 Currently, there is consensus that the maximum trials involving the effects of NSAIDs on bleeding after tonsillec-
daily dose should be as low as 30 to 40 mg.29,67 Further, ketor- tomy concluded that ‘‘the use of NSAID therapy after tonsillectomy
olac is contraindicated as a preemptive analgesic before any should be abandoned both at the hospital and at home.’’101
major surgery and is contraindicated intraoperatively when he- However, these authors did not account for the use of coxibs in
mostasis is critical because of the increased risk of bleeding.62 their meta-analysis. A subsequent study evaluated the safety and
efficacy of administering rofecoxib 1 mg/kg prior to pediatric ton-
sillectomy.107 This study revealed a significant reduction in postop-
COX-2^Specific Inhibitors (Coxibs) erative pain, opioid use, and the incidence of postoperative nausea
and vomiting without an increase in intraoperative surgical bleed-
Celecoxib was the first COX-2–specific inhibitor (coxib) approved ing or in the likelihood of reoperation for bleeding. These data
by the FDA in December 1998, followed by rofecoxib in May 1999, support previous findings that coxibs do not increase perioperative
and then valdecoxib in November 2001.68 Parecoxib (an injectable blood loss68–75 and that these NSAIDs may prove useful for the
prodrug of valdecoxib), etoricoxib, and lumiracoxib have not management of post-tonsillectomy pain.
received FDA approval but are available in several countries outside In an attempt to determine whether an individual COX-2–selec-
the United States. Numerous review articles have documented the tive inhibitor possesses greater analgesic efficacy for acute postop-
efficacy of coxibs for the management of postoperative pain after erative pain, several meta-analyses have been performed108–111 in
dental, orthopedic, thoracic, gynecologic, and otolaryngologic sur- which the NNT for one patient to achieve 50% pain relief was
geries.69–75 A systematic review of COX-2 inhibitors compared with calculated. In these studies, the NNTs for the COX-2 inhibitors
traditional NSAIDs concluded that these two classes of NSAIDs valdecoxib 40 mg, rofecoxib 50 mg, and parecoxib 40 mg were
provided similar efficacy for the management of postoperative 1.6, 1.9, and 2.2, respectively. These values are similar to those
pain.74 reported for the traditional NSAIDs.36 The only COX-2 inhibitor
Although nonspecific NSAIDs are considered to play an to perform less well than the other coxibs or most traditional
integral role in the management of postoperative pain,25,26 their NSAIDs was celecoxib 200 mg with an NNT of 4.5.110 However,
routine use has been limited in the perioperative setting because subsequent to this meta-analysis, celecoxib received approval by the
of concerns of platelet dysfunction, renal toxicity, and gastroin- FDA for the management of acute pain. The celecoxib dose for
testinal toxicity.28 Although short-term use of NSAIDs for the acute pain is 400 mg followed by a 200-mg dose within the first
management of acute pain does not seem to impair renal func- 24 hours then 200 mg twice daily on subsequent days.112 Because
tion,76 there are numerous reports of NSAID-induced renal fail- celecoxib is currently the only selective COX-2 inhibitor available in
ure when these drugs are utilized for the perioperative the United States, future randomized, controlled clinical trials uti-
management of pain.77–82 Similarly, there have been numerous lizing these recommended doses are necessary to determine the
reports of gastrointestinal ulceration or bleeding associated with analgesic efficacy of this NSAID for acute pain postoperative
brief exposure to NSAIDs for the perioperative management management.
of pain.83–87 Finally, the use of traditional NSAIDs may result
in an increased incidence of perioperative blood loss and blood
Celecoxib
transfusion requirements, resulting in increased morbidity and
mortality after a variety of surgical procedures.99–101 Because Celecoxib has approval for the relief of pain from osteoarthritis,
these major side effects are related to the inhibition of the rheumatoid arthritis, acute pain, and dysmenorrhea and to reduce
COX-1 enzyme, the perioperative use of coxibs appears to be the number of adenomatous colorectal polyps in familial adenom-
a safer alternative to traditional NSAIDs for the perioperative atous polyposis.112 The concomitant administration of celecoxib
management of pain.74,102 The specificity of COX-2–selective with aluminum- or magnesium-containing antacids results in a
inhibitors accounts for their safer gastrointestinal profile103 and reduction of plasma levels of this NSAID. Peak plasma levels
lack of antiplatelet activity55,68 relative to nonspecific NSAIDs. occur 3 hours after oral administration, and the drug crosses into
the central spinal fluid.19 Celecoxib is 97% protein bound, with an the site of the inflammatory process, with the potential for a more
apparent volume of distribution of 400 L, suggesting extensive dis- effective reduction of inflammation. Further, there is a potential for
tribution into tissues.112 It is metabolized via cytochrome P-450 fewer side effects because lower doses of the drug may be used,
2C9 and eliminated predominantly by the liver. It is not indicated resulting in lower plasma concentrations of the NSAID.121 It has
for pediatric use and is a category C drug for pregnancy. Celecoxib been demonstrated that even without a reduction in dose, the top-
can increase plasma lithium levels, and the concomitant adminis- ical administration of NSAIDs results in much lower plasma con-
tration of diflucan can increase plasma levels of celecoxib. centrations of the drug compared with the same dose of NSAID
The drug has a half-life of about 11 hours.112 Adverse events administered orally.122,123 For these reasons, the topical administra-
noted in the various clinical trials include headache, edema, dys- tion of NSAIDs demonstrates a lower incidence of adverse events,
pepsia, diarrhea, nausea, and sinusitis. It is contraindicated in including gastrointestinal toxicity, compared with the oral route.124
patients who have a sulfonamide allergy or a known hypersensitivity A quantitative systematic review of topical NSAIDs for acute pain
to aspirin or other NSAIDs. Celecoxib has been shown to have confirmed the benefit of this route of administration.125 After a
no effect on platelet function measured by serum thromboxane review of the literature, it was concluded that both the topical
production and ex vivo platelet aggregation.113 In fact, celecoxib and the oral routes provided comparable analgesic efficacy for
in doses of 1200 mg/day administered for 10 consecutive days acute pain. Further, the topical route was associated with a low
in healthy adults demonstrated no effect on platelet aggregation incidence of systemic adverse events that were no different from
or bleeding time.113 those of placebo.125 Similarly, the local infiltration of NSAIDs into
Previous studies have shown analgesic efficacy with the periop- the surgical site should provide for effective analgesia with minimal
erative administration of celecoxib 200 mg for dental, orthopedic, side effects. NSAIDs have been administered intra-articularly for
and otolaryngologic surgeries.110,114–117 However, these clinical knee surgery, as components of intravenous regional anesthesia
investigations may have underestimated the analgesic efficacy of (IVRA) for hand surgery, and by wound infiltration for inguinal
celecoxib because they did not utilize the appropriate dose for post- herniorrhaphy, mastectomy, tonsillectomy, and hand surgery.126
surgical pain. The need for an initial loading dose of celecoxib is A meta-analysis of local infiltration of NSAIDs revealed that there
related to its large volume of distribution (400 L). In a dose-ranging was good evidence for a clinically relevant peripheral analgesic
study after otolaryngologic surgery,118 celecoxib 400 mg was more action of intra-articular NSAIDs whereas the results of IVRA and
effective than 200 mg in reducing severe postoperative pain and the wound infiltration with NSAIDs in postoperative pain were incon-
need for rescue analgesic medication in the postoperative period. clusive.126 Unfortunately, the incidence of systemic side effects was
However, even this study was flawed because these investigators not evaluated in any of these clinical studies.
failed to administer a subsequent dose of celecoxib 200 mg within In addition to targeting peripheral prostaglandin synthesis with
the first 24 hours postoperatively. The first clinical investigation to the use of local NSAID administration, alternative formulations
document the analgesic efficacy of celecoxib administered for post- of ketorolac have been developed as a means of blocking the up-
operative pain management according to the current acute pain regulation of COX-2 in the CNS after surgical trauma. Because
guidelines demonstrated a 31% reduction in 24-hour morphine ketorolac is unable to cross the blood-brain barrier effectively,127
use and a significant decrease in pain scores.119 This represents studies are under way to determine the efficacy of this drug when
a significant improvement in analgesic efficacy compared with a pre- administered via the intranasal route.128 Intranasal drug delivery is
vious study in which only a 9% reduction in morphine use was one of the focused delivery options for brain targeting because the
reported with the administration of a single 200-mg dose of cele- brain and nose compartments are connected to each other via the
coxib prior to the same surgical model.114 In addition to lower olfactory route and via the peripheral circulation.129 The adminis-
morphine use, celecoxib administration resulted in significantly tration of an intranasal formulation of ketorolac provides for rapid
lower pain scores at all postoperative time intervals except at uptake, with significant levels of the drug measured in the cerebro-
12 and 24 hours postsurgery, which coincides with the time spinal fluid.128 Further, minimal gastrointestinal side effects have
at which this drug needs to be redosed. been reported with this route of administration.128 Another method
of targeting central prostaglandin synthesis is to administer NSAIDs
via the intrathecal route. Unfortunately, the current formulation of
ROUTE OF ADMINISTRATIONOF ketorolac contains alcohol (10% wt/vol),62 which is neurotoxic,
NSAIDS thus precluding its use as an intrathecal analgesic. However, inves-
tigators have developed a preservative-free formulation of ketorolac,
It is common belief that parenteral NSAIDs are more efficacious in which has been safely administered to humans via the intrathecal
the management of acute pain than orally administered NSAIDs. route.130 These data support further investigation of this NSAID
Many physicians continue to administer NSAIDs via the parenteral when administered neuraxially for the management of acute
route even though patients are tolerating oral intake after surgery. postoperative pain.
Reasons for choosing the parenteral route are pharmacokinetic
based, that is, the rate of drug absorption may affect the efficacy
and onset of analgesia. However, one meta-analysis comparing TIMING OF ADMINISTRATIONOF
NSAIDs administered by different routes for the management of NSAIDS (PREEMPTIVE ANALGESIA)
acute and chronic pain failed to detect any difference in analgesic
efficacy.120 The intramuscular and rectal routes were associated with Preemptive analgesia as a concept began over 90 years ago, when
more local adverse effects, and the intravenous route resulted in Crile131 proposed that blocking noxious signals prior to a surgical
a greater risk of postoperative bleeding.120 The risk of gastrointes- incision may lead to some degree of CNS protection against postop-
tinal toxicity was similar with the administration of NSAIDs by erative pain, though at that time, the mechanism remained unclear. It
either the parenteral or the oral route. The authors concluded is now recognized that nociceptor function is dynamic and may be
that there is a strong argument to administer NSAIDs via the oral altered after tissue injury, leading to the amplification and prolon-
rather than the parenteral route for the management of postoper- gation of postoperative pain.132 As evidence continues to accumulate
ative pain as soon as patients are tolerating oral intake.120 concerning the role of neuroplasticity after surgery, many researchers
In an attempt to provide a peripheral analgesic effect, some have focused on methods by which to not simply treat the symptoms
investigators have utilized NSAIDs administered via either topical as they occur but also to prevent central sensitization from occurring
application or local wound infiltration for the management of acute through the utilization of preemptive analgesic techniques.11
pain. These routes provide for high concentrations of these agents at Currently, preemptive analgesia is taken to mean that a preoperative
III ACUTE PAIN 65
dose of analgesic is more effective than the same dose of the same EFFECTOF PERIOPERATIVE NSAID
drug given postoperatively.133 The evidence in support of preemptive ADMINISTRATIONON POSTOPERATIVE
analgesia has been equivocal, with one systematic review of the lit- OUTCOMES
erature demonstrating no beneficial effect134 whereas a more recent
review135 demonstrated an overall benefit of this concept. Although NSAIDs have been shown to reduce postoperative anal-
The preemptive analgesic effect of NSAIDs has been previously gesic requirements by 30% to 50% in most of the clinical trials,
studied after a wide variety of surgical procedures demonstrating concern still exists regarding the real clinical benefit of NSAIDs to
equivocal results.11,134–136 Unfortunately, many methodological reduce opioid-related adverse effects, thereby hastening recovery
problems have been encountered in these studies.137 Reuben and and reducing morbidity.3,21 Recently, several meta-analyses40,145,146
coworkers138 were the first investigators to examine the analgesic and systematic reviews75,147,148 have assessed the effects of NSAIDs
effects of administering the same dose of NSAID either before or on opioid-related side effects. The first meta-analysis, which
after arthroscopic knee surgery. The results of this study demon- included seven randomized, controlled trials (491 subjects), exam-
strated that preoperative NSAID administration produced a signif- ined the effect of acetaminophen on morphine-related adverse
icantly longer duration of postoperative analgesia, less 24-hour events.40 The studies compared the addition of acetaminophen
opioid use, and lower incidental pain scores compared with admin- versus placebo to standard patient-controlled analgesia (PCA) mor-
istering the same drug in the postoperative period. A review of 18 phine for pain control after major surgery. Although the use of
randomized, single- or double-blinded studies that used an NSAID acetaminophen decreased morphine use by 20% over the first
as the target intervention revealed that only 6 studies (33%) demon- 24 hours, there was no reduction in the risk of any opioid-related
strated a preemptive analgesic effect.136 Furthermore, the beneficial side effects. Although the effect of acetaminophen on postoperative
effects of preemptive NSAIDs observed in most studies were min- pain was not quantitatively analyzed as a single-pooled estimate, the
imal. The review by Moniche and associates134 included 20 clinical authors noted that only two of the six studies found that the use of
trials comparing preincisional with postincisional NSAIDs using a acetaminophen improved pain scores compared with those of
parallel or crossover design. The authors concluded that some placebo.
aspects of postoperative pain were improved by preemptive treat- The second meta-analysis, which included 22 randomized,
ment in 4 of the 20 trials. Overall, the data demonstrated preemp- controlled trials (2307 subjects), examined the effect of NSAIDs
tive NSAIDs to be of no analgesic benefit when compared with on morphine-related adverse events.145 Clinical studies included
postincisional administration of these drugs. In contrast, Ong and the addition of an NSAID versus placebo to standard PCA mor-
colleagues135 reviewed data from 16 randomized, controlled trials phine for postoperative pain management after a variety of surgical
with preemptive NSAIDs, concluding that these drugs improved procedures. This study demonstrated that NSAIDs decreased the
analgesic consumption and time to first analgesic request but not relative risk (RR) versus placebo of postoperative nausea and vom-
postoperative pain scores. iting by 30% (RR = 0.70; 95% CI = 0.59–0.84) and of sedation by
The administration of coxibs seems to possess a more favorable 29% (RR = 0.71; 95% CI = 0.54–0.95). However, NSAIDs did not
pharmacokinetic profile than other NSAIDs when administered reduce the risk of developing pruritus, urinary retention, or respi-
orally during the preoperative period. Unlike conventional ratory depression. The effects on pain were not assessed.
NSAIDs, coxibs may be administered without food to the fasting Another meta-analysis examined whether multimodal analgesia
preoperative patient138 and do not inhibit platelet aggregation with acetaminophen, NSAIDs, or selective COX-2 inhibitors pro-
resulting in increased perioperative blood loss.75 Further, all vided benefit when added to PCA morphine.146 Included in this
coxibs have demonstrated the ability to block both peripheral and meta-analysis were 10 randomized, controlled trials that examined
central prostaglandin synthesis.19 A recent systematic review of pre- the addition of acetaminophen, 14 that examined the addition of
operative COX-2–selective NSAIDs demonstrated the safety and COX-2 inhibitors, and 33 that assessed the addition of an NSAID to
efficacy of this class of NSAIDs for the management of postopera- standard PCA morphine for pain control after surgery. The results
tive pain.75 Only three studies139–141 compared the preoperative suggested all of the analgesics provided an opioid-sparing effect
administration of coxibs with traditional NSAIDs. Heigi and cow- (15%–55%); however, this decrease in opioid use did not consis-
orkers139 compared rofecoxib 50 mg with diclofenac 50 mg just tently result in a decrease in side effects. The use of NSAIDs was
before induction of anesthesia in vaginal hysterectomy or breast associated with a significant decrease in the relative risks of post-
surgery. Rofecoxib resulted in less intraoperative blood loss, less operative nausea, vomiting, and sedation, similar to those observed
postoperative nausea and vomiting, less antiemetic use, and greater in another meta-analysis.145 However, the use of acetaminophen or
patient satisfaction. Celik and associates140 compared rofecoxib 50 COX-2 inhibitors did not significantly decrease the risk of opioid-
mg with naproxen 550 mg before abdominal hysterectomy and related adverse events compared with placebo. NSAIDs (multiple
reported no difference with regard to postoperative pain, analgesic dose and infusion only), but not acetaminophen or single-dose
use, or nausea and vomiting. Gopikrishna and Parmeswaran141 NSAIDs, were associated with a statistically significant decrease in
compared rofecoxib 50 mg and ibuprofen 600 mg before root pain scores. The analgesic efficacy of COX-2 inhibitors was not
canal surgery and reported lower pain scores with rofecoxib at assessed in this meta-analysis.
12 and 24 hours postsurgery. Finally, three systematic reviews were conducted of the analgesic
Although the concept of preemptive analgesia is controver- efficacy of a COX-2 inhibitor compared with placebo in addition to
sial,134,135 we need to move beyond the importance of reducing a standard opioid analgesic regimen for postoperative pain manage-
only the nociceptive afferent input brought about by the surgical ment.75,147,148 One systematic review examined the effect of pre-
incision. The term preventive analgesia142 was introduced to empha- operative COX-2 inhibitors on postoperative outcomes in
size the fact that central neuroplasticity is induced by pre-, intra-, 22 randomized trials with 2246 subjects.75 Compared with placebo,
and postoperative nociceptive inputs. Thus, the goal of preventive preoperative administration of a COX-2 inhibitor reduced postop-
analgesia is to reduce central sensitization that arises from noxious erative pain and opioid use in 15 of the 20 trials; however, no signif-
inputs occurring throughout the entire perioperative period and icant differences were observed between placebo and COX-2
not just from those occurring during the surgical incision. Thus, inhibitors in the overall RR or incidence of postoperative nausea
NSAIDs should be utilized throughout the entire perioperative and vomiting in 13 of 17 trials. A second systematic review examined
period until the surgical wound has healed. Effective preventive the effect of coxibs versus placebo in 19 randomized, controlled trials
analgesic techniques utilizing NSAIDs may be useful in reducing including 26 comparisons of four COX-2 inhibitors (rofecoxib, cel-
not only acute pain but also chronic postsurgical pain and ecoxib, parecoxib, and valdecoxib).147 Despite a significant opioid-
disability.143,144 sparing effect averaging about 35% with coxibs, opioid-related
adverse events were significantly reduced in only 4 of the 26 compar- basis postoperatively. All patients were subsequently enrolled in a
isons. Quantitative analysis of combined data revealed a reduced risk 6-month accelerated rehabilitation protocol. This study demon-
for only dizziness. A third systematic review was a meta-analysis of strated that patients who received preemptive multimodal analgesic
9 trials (1738 subjects) that examined patients’ global evaluation of techniques had a reduction in the incidence of pain, opioid use,
analgesia after intravenous parecoxib for postoperative pain.148 postoperative nausea and vomiting, recovery room length of stay,
Compared with placebo, subjects that received parecoxib, especially and unplanned admission to the hospital. In addition to an improve-
the 40-mg dose, had a significantly superior analgesic outcome (e.g., ment in short-term outcomes, patients receiving a preventive mul-
they more frequently rated their pain control as ‘‘good’’ or timodal analgesic technique had a reduction in long-term
‘‘excellent’’). However, parecoxib did not decrease the risk of complications at 1 year after surgery.143 Long-term complications
opioid-related adverse events compared with those of placebo. included a lower incidence of anterior knee pain (4% vs. 14%),
On the basis of this available evidence,40,75,145–148 it appears that lower number of patients requiring repeat arthroscopy for lysis of
the use of NSAIDs, acetaminophen, and COX-2 inhibitors results scar tissue (2% vs. 8%), and a lower incidence of complex regional
in an opioid-sparing effect after surgery. However, this decrease in pain syndrome (1% vs. 4%) in the preventive multimodal analgesic
opioid use does not consistently translate into a decrease in opioid- group compared with the standard analgesic group, respectively.
related adverse events. One criticism of these findings is that many NSAIDs may play a pivotal role in the prevention of chronic
of the studies relied exclusively on spontaneous reports of patients’ postsurgical pain syndromes. It has been hypothesized that because
adverse events, which may be less than rates obtained through direct COX-2 plays an integral role in the processes of peripheral and
assessment.149 The use of an opioid-related symptom distress scale central sensitization,13 it is possible that early and sustained treat-
is valuable for the evaluation of symptom frequency, severity, and ment with COX-2 inhibitors may thwart the progression of acute to
distress after surgery.150 Utilizing this scale for patients receiving chronic pain.153 One study revealed that the administration of cel-
COX-2 inhibitors after laparoscopic cholecystectomy,151 it became ecoxib both prior to surgical incision and continually for the first 5
evident that a linear relationship exists between opioid doses and postoperative days resulted in a significant reduction in both acute
clinically meaningful opioid-related adverse events.150 Analysis of postoperative pain and the incidence of chronic donor site pain
available data suggests that once a threshold morphine dose in after spinal fusion surgery. Patients receiving celecoxib had a 74%
24 hours is reached, every 3- to 4-mg increase of morphine require- lower risk for developing this chronic neuropathic pain syndrome.
ments will be associated with one more clinically meaningful There are several potential explanations for the observed lower inci-
opioid-related symptom. This linear correlation identifies for the dence of chronic donor site pain in patients receiving perioperative
first time a connection between opioid-sparing effects and reduc- celecoxib. It has been suggested that effective treatment of acute
tion of adverse effects. Further, many of the studies assessing pain, particularly when accompanied by a neuropathic element,
opioid-related adverse effects40,75,145–148 used methodology that prevents the development of chronic postsurgical pain syn-
does not accurately reflect conditions in actual clinical practice. dromes.154 This reduction in chronic pain may be attributed to a
NSAIDs are more likely to be used in multiple doses (which dem- preemptive or preventive analgesic effect in which a reduction in
onstrate superior analgesia vs. placebo)146 rather than single doses spinal cord neuroplasticity derives from prompt reduction in the
for the management of postoperative pain. In addition, a more perioperative noxious afferent input associated with surgery.155 It is
comprehensive multimodal approach (e.g., combinations of regio- also possible that a reduction in COX-2 expression in the CNS after
nal analgesic techniques, other adjuvant analgesics, and opioids) is surgical trauma may have contributed to a later reduction in
probably needed to demonstrate a reduction in opioid-related chronic pain. It has been demonstrated that allodynia and spinal
adverse events and improvement in functional outcomes. prostaglandins appear to be functionally linked in the early period
The beneficial effects of utilizing a multimodal analgesic after nerve injury.156–158 However, several weeks after injury, this
approach, including regional analgesia and sustained COX-2 prostaglandin-dependent allodynia recedes and leaves long-term,
inhibition, were demonstrated in a clinical investigation for patients prostaglandin-independent allodynia.159 Thus, spinal prostaglandin
undergoing major knee surgery.106 This randomized, placebo- synthesis may be important for the induction and initial expression
controlled, double-blind trial evaluated the effect of combined pre- but not for the maintenance of spinal cord hyperexcitability.156,158
operative and 13-day course of postoperative administration of Thus, although NSAIDs are ineffective in the treatment of neuro-
a COX-2 inhibitor on opioid consumption and outcomes after pathic pain, they may be effective as a treatment strategy for pre-
total knee arthroplasty. This study documented a reduction in epi- venting the pathogenesis of this chronic pain syndrome.
dural analgesic use, in-hospital opioid consumption, pain scores,
postoperative vomiting, sleep disturbance, and increased patient
satisfaction in patients administered COX-2 inhibitors compared
with the results with placebo. Finally, improved knee range of ADVERSE EFFECTS OF COX INHIBITION
motion was observed both at discharge and 1 month after surgery
in the group receiving perioperative COX-2 inhibition. Allergy and Hypersensitivity
The benefits of utilizing NSAIDs as a component of a preventive
multimodal analgesic technique have also been demonstrated for All NSAIDs, including acetylsalicylic acid, may induce two types of
patients undergoing anterior cruciate ligament (ACL) surgery.143,150 hypersensitivity reactions, both of which are related to the inhibi-
A retrospective study of 1200 patients undergoing ACL surgery tion of prostaglandin synthesis. These include (1) Samter’s triad
examined the efficacy of administering a preventive multimodal (asthma triad), in which some patients suffer from the triad of
analgesic technique (n=500) versus a standard postoperative pain intolerance to aspirin and aspirin-like chemicals, nasal polyposis,
protocol (n=700).143,152 Patients in the preemptive multimodal and bronchial asthma, and (2) the syndrome of urticaria and an-
group received acetaminophen 1000 mg every 6 hours and rofecoxib gioedema. Approximately 10% of patients with Samter’s triad will
50 mg daily starting 48 hours prior to surgery. In addition, 30 min- develop angioedema and uticaria when exposed to NSAIDs.
utes prior to surgery, a femoral nerve block and an intra-articular The exact mechanism responsible for Samter’s triad is unknown,
injection of bupivacaine/clonidine/morphine were performed. but it is widely believed the disorder is caused by an anomaly in the
Postoperative analgesia included acetaminophen, rofecoxib, con- arachidonic cascade, which causes undue production of leukotrienes.160
trolled-release oxycodone, and a cryotherapy cuff. In contrast, When prostaglandin production is blocked by NSAIDs like aspirin, the
patients in the standard postoperative analgesic group received cascade shunts entirely to leukotrienes, producing the allergy-like
no preemptive analgesics prior to surgery and were administered effects. Leukotriene antagonists and inhibitors such as montelukast
ibuprofen and acetaminophen with oxycodone on an as-needed sodium (Singulair, Merck & Co., Inc., West Point, PA) show great
III ACUTE PAIN 67
promise in treating patients with Samter’s triad.160 Because the intol- prostaglandin H2 (PGH2) in the platelets by the action of TXA2
erance reactions to aspirin and NSAIDs are caused by inhibition of the synthase, whereas PGI2 is converted from PGH2 in the vascular
COX-1 enzyme, COX-2–selective inhibitors should be a safer alterna- endothelium by the action of PGI2 synthase (Fig. 9–3).
tive in the management of pain for these patients. Several studies have Furthermore, activated platelets divert some of their endoperoxides
confirmed these findings, demonstrating that celecoxib may be admi- to vascular cells ("endoperoxide steal") to further provide substrate
nistered safely to patients with a history of uticaria/angioedema, for PGI2 formation. TXA2 functions as a platelet activator and
naso-ocular symptoms, bronchospasm, and/or anaphalactoid reaction vasoconstrictor, whereas PGI2 is a platelet inhibitor and vasodilator.
induced by aspirin and/or NSAIDs.161–163 Because platelets do not contain COX-2, all synthesis of TXA2 in
In addition to these hypersensitivity reactions, patients must be the platelet is mediated by COX-1. Therefore, therapeutic doses of
asked about possible allergic reactions to sulfonamides before highly selective COX-2 inhibitors may be advantageous in the
prescribing certain NSAIDs. The overall incidence of sulfonamide perioperative period because there is no increased bleeding from
hypersensitivity in the general population is low, at approximately platelet effects.
3%.164 All sulfonamides can be regarded as belonging to one of two
main biochemical categories: arylamines and nonarylamines.165 The
key to a sulfonamide allergy is believed to be related to the forma- Renal
tion of a hydroxylamine metabolite unique to the arylamine
structure. Celecoxib, parecoxib, and valdecoxib belong to the non- Both COX-1 and COX-2 are constitutively expressed in the human
arylamine group of medications and are contraindicated in patients kidney. The predominant effect of COX-2 (constitutively expressed
allergic to sulfonamides. in both the cortical thick limb of the loop of Henle and the med-
ullary interstitial cells) is in water and electrolyte homeostasis.179
COX-1 appears to influence renal hemodynamic regulation such
Gastrointestinal that inhibition of COX-1 has been shown to reduce glomerular
filtration rate.179 All NSAIDs including COX-2 inhibitors are asso-
The first evidence that aspirin could damage the stomach was ciated with transient sodium and water retention, hypertension, and
reported in 1938 based on gastroscopic observations.166 edema, all possible within the first few days of therapy. Most of
Subsequently, endoscopic studies have consistently demonstrated these events are of minor clinical significance and resolve within
that gastric or duodenal ulcers develop in 15% to 30% of patients 1 to 8 weeks after discontinuation of NSAID therapy.180 Risk factors
who regularly take nonselective NSAIDs.167 Some of the risk factors for NSAID-induced renal toxicity include chronic NSAID use, mul-
identified for the development of NSAID-induced ulcers include tiple NSAID use, dehydration, volume depletion, congestive heart
advanced age, history of ulcer, concomitant use of corticosteroids, failure, vascular disease, hyperreninemia, shock, sepsis, systemic
higher doses of NSAIDs (including the use of more than one lupus erythematosus, hepatic disease, sodium depletion, nephrotic
NSAID), concomitant administration of anticoagulation, serious syndrome, concomitant drug therapy (diuretics, angiotensin-
systemic disorder, cigarette smoking, consumption of alcohol, and converting enzyme [ACE] inhibitors, b-blockers, potassium
concomitant infection with Helicobacter pylori.168 The mechanisms supplements), and age 60 years or older.180 Although short-term
by which NSAIDs cause ulceration in the stomach are by their use of NSAIDs for the management of acute pain does not
topical irritant effect on the epithelium and their ability to suppress seem to impair renal function,76 it would be sensible to delay
prostaglandin synthesis.169 The ability of NSAIDs to cause gastric NSAID or coxib administration in the presence of compromised
damage correlates with the duration of use, dose, and the ability to renal function or perioperative dehydration, hypovolemia, and
inhibit COX-1 in the gastric mucosa.168,170 Three studies demon- hypotension.
strated that some NSAIDs are associated with higher gastrointesti-
nal risks than others.171–173 In general, ibuprofen and etodolac have
the lowest risk among nonselective NSAIDs; diclofenac and naprox- Bone Healing
en have intermediate risks; and piroxicam, idomethacin, and ketor-
olac have the greatest risk for gastrointestinal complications. Another concern regarding the perioperative use of NSAIDs is
In contrast, the selective COX-2 inhibitors were found to have a the possible deleterious effect on osteogenesis and spinal
significantly lower risk of gastrointestinal toxicity when compared fusion.181–184 Prostaglandins have been known for many years
with traditional NSAIDs, with incidences similar to those of placebo.174 to have potent effects on bone metabolism, including both
Evidence from four large-scale randomized, controlled trials showed osteoblastic and osteoclastic activity, as well as being essential
that COX-2–selective inhibitors have reduced gastrointestinal toxicity in bone repair.185 The exact mechanism by which NSAIDs
compared with nonselective NSAIDs.175–178 The Vioxx Gastrointestinal impair spinal fusion has not yet been elucidated. It has been
Outcomes Research (VIGOR) trial,175 Celecoxib Long-term Arthritis hypothesized that the effect may be mediated by an inhibition
Study (CLASS),176 Therapeutic Arthritis Research and Gastrointestinal of the inflammatory process with concomitant reduction in blood
Event Trial (TARGET),177 and Successive Celecoxib Efficacy and flow in the early period of osteogenesis, decreased mesenchymal
Safety Studies (SUCCESS)178 provided evidence that COX-2 inhibitors cell proliferation, or inhibition of calcification of the bone
minimize the risk of gastrointestinal complications compared with matrix.181–183 Many investigators recommend that NSAIDs
those of traditional NSAIDs. should not be utilized in the multimodal management of acute
These findings174–178 combined with the possibility that even the pain for patients undergoing spinal fusion surgery.181–183
short-term perioperative use of NSAIDs has been associated with Although the data are conflicting, a large body of literature
gastrointestinal toxicity,83–87 suggest that coxibs may be safer alter- derived from laboratory animal studies suggests that COX-2
natives in the management of acute pain for those patients with a inhibitors either delay or inhibit bone healing.181–183 However,
past history of peptic ulcer disease or at greater risk for perforation. in these studies, NSAIDs were administered over several weeks
to months at doses greater than that approved for acute pain. It
has been suggested that the deleterious effects of COX-2 inhibi-
Hematologic tors on fracture healing may be reversible with short-term treat-
ment.186 Gerstenfeld and Einhorn187 concluded that
Platelet activity and hemostasis depend upon a constant balance ‘‘management of fracture-associated pain with inhibitors of
between the effects of prostaglandin I2 (PGI2) in the endothelium COX-2 should neither impair nor delay healing as long as the
and those of TXA2 in the platelets.55 TXA2 is converted from duration of treatment is consistent with current standards of
Membrane phospholipids
Phospholipase A2
Arachidonic acid
Cyclooxygenase
(constitutive COX-1)
_ (inducible COX-2)
NSAIDs
PGG2
Cyclooxygenase
(COX-1) or (COX-2)
PGI synthase TXA synthase

PGI2 PGH2 TXA2
(gastric mucosa, (platelets)

PGF synthase
platelets, PGD synthase
endothelium)
PGE isomerase
PGD2 PGF2-alpha
PGE2
(gastric mucosa,
kidney, peripheral nociceptor
spinal cord neurons)
Figure 9^3. The role of cyclooxygenase (COX) in prostaglandin (PG) synthesis. Prostaglandins (PGD2, PGE2, PGF2-a, and PGI2) and
thromboxanes (TXA2), which are mediators of inflammation and homeostasis, are products of a biochemical cascade by which membrane
phospholipids are converted to arachidonic acid, then to intermediate prostaglandins (PGG2 and PGH2) by COX, and to their final products by
a series of synthases. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce postoperative pain by suppressing COX-mediated production of
PGE2. (Adapted from Gilron I, Milne B, Hong M.Cyclooxygenase-2 inhibitors in postoperative pain management. Anesthesiology 2003;99:1198^1208; used
with permission from the American Society of Anesthesiologists, copyright 2003 by Lippincott Williams & Wilkins.)
care.’’ In addition, limiting the use of NSAIDs for short-term chronic postsurgical pain,8 that may be reduced with perioperative
use, physicians should prescribe the lowest effective dose for coxib administration.144
bone surgeries. In a retrospective study of 434 consecutive
patients undergoing elective decompressive posterior lumbar
laminectomy with instrumented spinal fusion by a single surgeon Cardiovascular
within an 8-year period, we revealed that the short-term periop-
erative administration of celecoxib, rofecoxib, or low-dose ketor- With a large surge in the clinical use of COX-2–selective inhibitors
olac (110 mg/day) had no significant deleterious effect on came a growing body of evidence that implicated their role (espe-
nonunion.188 In contrast, higher doses of ketorolac (120–240 cially that of rofecoxib—currently unavailable) in contributing to
mg/day), even when administered for less than 1 week, resulted an increased risk of serious cardiovascular thrombotic events, myo-
in a significant increase in the incidence of nonunion after spinal cardial infarction, and stroke (first receiving a great deal of atten-
fusion surgery. Further evidence for the safety of coxibs after tion with the VIGOR study).175 Although mechanisms of this risk
spinal fusion surgery was demonstrated in a recent prospective, remain uncertain, one theory holds that it relates to alteration of the
double-blind, randomized study in humans.119 This was the first PGI2 balance favoring TXA2 with subsequent promotion of platelet-
prospective study in humans that demonstrated that the periop- dependent thrombosis.
erative administration of celecoxib for 5 consecutive days after In the normal state, COX-1 is the major source of PGI2 in
spinal fusion surgery resulted in no increased incidence of non- endothelial cells; however, COX-2 plays a significantly greater role
union at 1 year follow-up compared with placebo. in generating PGI2. Therefore, COX-2 inhibition in atherosclerosis,
Because the short-term administration of NSAIDs appears to and thus PGI2 generation, may have important effects on the
have no deleterious effects on spinal fusion, it is possible that ‘‘antithrombotic balance.’’ Gislason and colleagues189 estimated
denying patients these medications may pose a greater risk than that in patients with a previous myocardial infarction, the excess
nonunion. We must be cognizant of the fact that unrelieved acute risk of mortality is roughly 6 deaths per 100 person-years of treat-
pain may be associated with significant morbidity, including ment with a COX-2 inhibitor compared with no NSAID treatment.
III ACUTE PAIN 69
The Multinational Etoricoxib and Diclofenac Arthritis Long- 19. Dembo G, Park SB, Kharasch ED. Central nervous system
term (MEDAL) Study Program (consisting of the Etoricoxib concentration of cyclooxygenase-2 inhibitors in humans.
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III ACUTE PAIN 73
Chapter 10 Some patients find the autonomy involved in self-directed analgesia

to be comforting, whereas others may prefer nurse-delivered anal-
PATIENT-CONTROLLED gesia and may find the idea of self-delivered analgesia to be anxiety
provoking. Fear of addiction or inadvertent overdosage may also
ANALGESIA cause underutilization of PCA by some individuals, which may
thereby result in inadequate analgesia.3
Traditional intermittent (as-needed) parenteral analgesia
Jennifer A. Elliott involves the administration of relatively large doses of opioid in
order to achieve sustained serum opioid levels above the minimum
effective analgesic concentration prior to the next dosing interval.
Unfortunately, this technique results in wide fluctuations in serum
opioid concentration. As a consequence of these wide swings in
serum opioid concentrations after intermittent parenteral adminis-
INTRODUCTION tration, patients may experience adverse effects of nausea or seda-
tion as opioid concentrations peak and inadequate analgesia as
Patient-controlled analgesia (PCA) has been in use for the manage- opioid concentrations drop off prior to the next dose. PCA allows
ment of pain since the early 1970s. This technique has historically for more frequent administration of smaller analgesic doses and,
been used in the provision of intravenous opioids for pain thereby, may reduce the degree of fluctuation in serum opioid
control. Since the late 1990s, a variety of new forms of PCA have concentrations and attendant undesired effects.4
been developed, including patient-controlled epidural analgesia Many studies have been performed to evaluate whether there
(PCEA), patient-controlled regional analgesia (PCRA), patient- are advantages to the use of PCA over those of conventional
controlled oral and intranasal analgesia, and patient-controlled intermittent intramuscular opioid administration for postopera-
transdermal fentanyl (currently in development). Just as options tive pain management.5–8 Several of these studies do not seem to
for patient-controlled delivery have expanded, monitoring capabil- indicate significant differences between these two modalities when
ities for the prevention of adverse events related to the use of these assessing opioid consumption, adverse effects, or length of post-
techniques have become more sophisticated. PCA is employed in operative hospitalization. However, the vast majority do demon-
the management of pain from a variety of conditions, including strate increased patient satisfaction with use of PCA. Some
surgical pain, cancer-associated pain, and pain related to disorders studies indicate that postoperative pulmonary complications
such as sickle cell anemia and pancreatitis. These techniques can be may be reduced when PCA is employed, and patient participa-
used in a wide array of patients, including those at extremes of age. tion in postoperative rehabilitation may be enhanced as well.9–11
It is important to recognize that whereas these techniques typically Some drawbacks to intramuscular analgesia that have been cited
allow for excellent pain control and patient satisfaction, they are not include unpredictable drug absorption and pain with administra-
without risk. Certain patient populations—such as those with tion that might result in decreased usage, especially among pedi-
obstructive sleep apnea, chronic obstructive pulmonary disease, atric patients. These factors may result in suboptimal
and renal dysfunction—may be more predisposed than others to postoperative analgesia.12
potential adverse events with the use of PCA. Likewise, these tech-
niques may not be appropriate for some individuals such as those
with significant cognitive dysfunction. When selecting a PCA tech- PCA DEVICES
nique, the practitioner must do so with an understanding of the
pharmacokinetics of the agent employed and of patient character- PCA devices consist of a pump connected to a timer. The medica-
istics that may increase the potential for adverse events. In addition, tion to be delivered is housed in a secure portion of the device
caregivers must be alert to potential technical and programming that is accessible with the use of a key or the entry of a numerical
errors that may occur and must appropriately monitor for evidence combination on a keypad. The medication is delivered to the
of adverse effects. PCA can be very satisfying for both patient and patient via tubing connected from the medication syringe or
provider if these principles are observed. cartridge to an intravenous (or other applicable) catheter. The
patient is able to use the device by activating a button connected
to the PCA pump by a cord. Safety features incorporated into PCA
PATIENT SELECTION AND POTENTIAL devices include alarms to alert to the presence of an empty syringe,
ADVANTAGES OF PCATHERAPY low battery, tubing occlusion, or air entrainment. The keypad used
by health care professionals to program the PCA device is locked
PCA can be a highly effective means of pain reduction. Successful during device use to prevent dose tampering by patients or visitors.
use of this modality depends upon proper education of both Reprogramming the device to reflect changes in the analgesic
prescriber and patient. Practitioners must appropriately select prescription typically requires use of a key or the keypad entry
dosing parameters, and patients must understand how to use the of a numerical combination.
device in order to achieve desired levels of analgesia. This mode of
analgesia has been used with success in a wide range of populations
including those at extremes of age.1,2 PCA SETUP
When PCA is considered for use in a patient, it must be ascer-
tained that the individual understands how to use the device and is When initiating PCA, the drug to be employed must be selected
physically capable of activating the demand button. Practitioners and several dosing parameters must be established.13 The
must also take into consideration some psychological factors that settings that must be chosen when starting PCA include a loading
may influence a patient’s satisfaction with this type of analgesia. dose, a demand dose, a lock-out interval, and a bolus dose
74 Chapter 10 PATIENT- CONTROLLED ANALGESIA
(an additional dose that can be delivered by nursing personnel device, as might occur with sleep. Effective bolus doses usually
if pain is uncontrolled). In addition, a continuous infusion and amount to two to three times the programmed demand dose.
1- or 4-hour maximum dose limit can be selected if desired. Bolus doses may be given as often as necessary. If frequent bolus
doses are needed, adjustment of the demand dose should be
considered.
Medications Used in PCA
Several opioids are currently available for use in PCA. The most Lock-out Interval
commonly employed agents include morphine, fentanyl, hydro-
morphone, and meperidine. Methadone, oxymorphone, and alfen- A lock-out interval is the period of time that the PCA device is
tanil have also been administered via PCA. Factors that may unable to deliver further demand doses after activation of the
influence the selection of opioid include patient disease states that demand button. This is usually set in a range of 5 to 10 minutes.
might influence drug metabolism or enhance the risk for opioid- Setting a lock-out interval allows the patient to appreciate the effects
related toxicity and any history of adverse effects from prior expo- of the delivered opioid dose prior to administration of another
sure to a particular opioid. In general, meperidine is not used by dose. The lock-out serves as an integral safety feature of PCA in
most pain management practitioners for PCA owing to potential that it prevents rapid stacking of doses on top of one another, as
adverse effects from one of its metabolites, normeperidine, with might otherwise occur if dosing was achieved every time a patient
repeated exposure to this drug. Normeperidine accumulation can attempted to activate the device. This significantly limits the poten-
result in neuroexictatory activity, including seizures. The risk of tial for inadvertent drug overdosage that could result from robust
such events occurring increases when meperidine is administered attempts to achieve rapid analgesia by repeatedly activating the
in large doses (>600 mg in 24 hr) and when it is repeatedly given demand button. When assessing the patient’s pattern of analgesic
over a period exceeding 24 hours. The risk of toxicity from this use, caregivers should observe the frequency of demands the patient
drug is most significant among patients with renal insufficiency, is attempting to obtain in addition to the actual opioid consump-
and therefore, use of meperidine in this patient population is not tion. This will typically appear as ‘‘demands’’ or ‘‘attempts’’ when
advised. reviewing the PCA device history feature. If the number of
‘‘demands’’ or ‘‘attempts’’ appears high compared with the actual
number of doses delivered, the patient may need to be reeducated
Loading Dose about how PCA works, with a reminder about the lock-out interval.
If both ‘‘demands’’ or ‘‘attempts’’ and actual number of opioid
A loading dose is typically administered at the time of initiation of doses administered appear frequent, the demand dose may need
PCA as a means of quickly achieving a serum opioid concentration to be increased to allow for enhanced analgesia.
that provides effective pain control. After administration of a load-
ing dose, patients can then self-administer additional opioid doses
via the demand mode to maintain satisfactory analgesia. A loading Continuous (Basal) Infusion
dose should generally be prescribed when patients are experiencing
significant pain upon starting PCA because use of the demand A continuous (basal) infusion can be added to PCA if desired. This
feature alone is unlikely to allow for timely establishment of suffi- will be delivered regardless of patient demands. Few studies indicate
cient analgesic serum opioid concentrations. a distinct advantage to the use of continuous infusions, although
Loading doses can be given before PCA is initiated as multiple some believe analgesia may be better maintained with the use of
small opioid doses, repeated at frequent intervals until adequate basal infusions, particularly when patients are not able to activate
analgesia is achieved (e.g., in the postanesthesia care unit the demand feature such as during periods of sleep. Total opioid
[PACU]). It is vitally important to understand that PCA should consumption may be increased in the presence of basal infusions.
be initiated only after the patient has achieved pain relief that is There is some concern that use of continuous infusions increases
‘‘in the ballpark of adequate analgesia.’’ the likelihood of PCA-related adverse events, with particular con-
cern for the possibility of respiratory depression. The primary indi-
cation for use of basal opioid infusions is as a substitution for
Demand Dose chronic baseline opioids when opioid-tolerant patients are unable
to continue their regular pain medications.
The demand dose is the dose of opioid delivered each time the
patient activates the PCA button, except during the established
lock-out interval. The size of the demand dose selected may be
influenced by factors such as age, weight (in pediatric patients), One- or 4 -Hour Maximum Dose
and any preexisting opioid tolerance. In general, elderly patients Limits can be placed on the total opioid delivered in a specified time
may respond well to lower demand doses, whereas chronic opioid interval. Most commonly, a 4-hour maximum dose is selected when
users will require higher demand doses than the average adult such restrictions in dosing are desired. Setting a dose limit may be
patient. Adjustment of the demand dose may be required if of particular importance when meperidine is employed in PCA.
evaluation of the patient’s utilization of the PCA reveals a high Owing to the potential for accumulation of normeperidine, as pre-
rate of demands. viously described, doses of meperidine should not exceed 600 mg in
24 hours. If dosing limits are not set, it might be fairly easy to
exceed such a total daily dose with the typical dosing parameters
Bolus Dose selected for this agent when initiating PCA. Setting a 1- or 4-hour
dosing limit may also provide some protection against overdosage
A bolus dose is an extra dose of medication that can be delivered by in the event of other programming errors. However, 1- or 4-hour
nursing personnel for inadequately controlled pain. A typical limits can also result in inadequate analgesia in patients requiring
scenario in which a bolus dose may need to be administered is large amounts of opioid because restrictive limits may cause them
movement-associated pain, such as when a patient participates to be ‘‘locked-out’’ from further doses for extended periods and can
in physical therapy. A bolus may also be necessary when a long cause such individuals to be dissatisfied with their analgesic
period has elapsed between demand activations of the PCA therapy (Table 10–1).
III ACUTE PAIN 75
Table 10^1. Current Therapy: Patient-Controlled If a patient’s level of consciousness declines while receiving PCA,
Analgesia Setup dose adjustment or termination of opioid administration may be
indicated. An emerging means of surveillance for evidence of devel-
Parameter Setting Range oping respiratory depression is the use of end-tidal carbon dioxide
(ETCO2) monitoring, which is discussed further later in this chapter.
Loading dose* Morphine 5–10 mg Other possible side effects of PCA that should be addressed if pres-
Meperidine 100–150 mg ent include nausea, pruritus, and constipation.
Fentanyl 50–100 mcg Certain patient populations deserve additional mention with
Hydromorphone 0.5–1.0 mg regards to monitoring for adverse effects when receiving PCA.
Demand dose* Morphine 1.0–1.5 mg Patients with various underlying organ dysfunctions may be
Meperidine 10–15 mg at higher risk of toxicity related to opioid administration. Any
Fentanyl 10–15 mcg patient with severe hepatic or renal disease may have decreased
capacity to metabolize or excrete opioids and may, therefore, be
Hydromorphone 0.1–0.2 mg
susceptible to opioid accumulation with attendant toxic effects.
Lock-out interval 5–10 min Pulmonary reserve may be compromised in patients with chronic
Bolus dose 2–3 times the selected demand dose obstructive pulmonary disease when using PCA, and patients with
Continuous dose This setting is not routinely used by obstructive sleep apnea may exhibit increased sensitivity to the
many pain practitioners, but if a sedative effects of opioids. In addition, significant hypotension
continuous infusion is desired, typical can increase sensitivity to opioid effects. This may relate to
initial doses are decreased cerebral perfusion, resulting in increased drug effects.
Decreased renal and hepatic blood flow under this circumstance
Morphine 1 mg/hr
may also contribute to prolongation of opioid effects.
Meperidine 10 mg/hr Hypotension related to hypovolemia may be exacerbated by
Fentanyl 10 mcg/hr opioid administration owing to vasodilatory effects of some opioids
Hydromorphone 0.1 mg/hr as well as diminished sympathetic nervous system outflow resulting
1- or 4-hr maximum Setting a 4-hour dosing limit is from relief of pain. Vigilance should be heightened for the occur-
dose limit optional with most agents, but a limit rence of adverse effects from opioid therapy in any of these patient
of 100 mg every 4 hr is advisable for populations (Box 10–1).
meperidine (total daily doses should
not exceed 600 mg)
POTENTIAL SOURCES OF
*These parameters reflect average ranges for opioid-naı̈ve patients. PCA-RELATED ADVERSE EVENTS
Opioid-tolerant patients may require larger doses, and frail or elderly
patients may require smaller doses. There are many potential causes of PCA-related adverse events.15,16
Undesired effects can occur from opioid use, particularly in patients
with comorbid conditions that have been described previously. Use of
concomitant sedatives with PCA can result in oversedation. In addi-
MONITORING OF THE PATIENT tion, human error and mechanical malfunctions of the PCA device
RECEIVING PCA can result in adverse events. Operator errors, such as improper device
setup and programming, and user-related errors, such as device tam-
As with any form of medical therapy, patients receiving PCA require pering or PCA by proxy, are potential human errors that can result in
appropriate monitoring to ensure efficacy of treatment and to adverse events. Mechanical failures related to defective medication
manage any possible adverse effects.14 Assessment of the patient’s syringes, electrical problems that cause inappropriate delivery of med-
pain should be made using such tools as verbal ratings, visual analog ication (either too much or too little), and failure of alarm systems
pain scales, or the FACES pain rating scale in the pediatric setting. In may also result in adverse PCA-related events.
conjunction with pain assessment, opioid consumption should be
quantified and the PCA device history should be reviewed to eval-
uate how effectively the patient is using it. If it is apparent that the Operator Errors
patient is frequently attempting to activate the demand button but
the actual number of opioid doses delivered is low, patient reedu- When setting up PCA, prescribing errors such as improper dose
cation on proper use of the device may be indicated. Conversely, selection and lock-out intervals may result in either inadequate
if the patient has been activating the device successfully and com- analgesia or opioid-related toxicity. Patients who are opioid tolerant
plains of inadequate pain control despite a high rate of opioid may experience poor analgesia if dosing parameters are restrictive,
delivery, adjustment of the demand dose may be appropriate. It is and the opioid-naı̈ve patient may become oversedated or nauseated
always advisable to assess patients for evidence of easily remediable with overzealous dosing. When the PCA device is programmed,
sources of pain, such as a distended bladder, when contemplating verification of the drug to be used, its concentration, and the
whether dose increases are necessary to enhance pain control. dosing parameters should be performed. These settings should be
Patients receiving PCA must be observed for evidence of adverse reconfirmed any time changes to the prescription are made, when
effects related to their pain treatment. Vital signs with attention to empty syringes are replaced, and when new personnel take over care
respiratory rate should be monitored regularly. Oxygen saturation of the patient such as at nursing shift change. Aside from program-
monitoring is often used in conjunction with PCA, although desat- ming errors, operator-related problems that may occur with PCA
uration is a late indicator of adverse respiratory effects from opioid include incorrect loading of the medication cartridge or syringe,
therapy. Perhaps most valuable as an early clinical indicator of failure to clamp or unclamp tubing, failure to turn the machine
opioid toxicity that could progress to respiratory depression is on after syringe change, and misplacement of the key to the PCA
diminished level of consciousness. For this reason, it is important device. Failure to plug the PCA machine into a power source
to assess patients for evidence of sedation while receiving PCA. can result in failure of the device once battery power is drained.
Sedation scales are used to indicate whether patients are awake, This may occur when the patient is transported to and from the
drowsy, sleeping but easily arousable, or difficult to arouse. hospital ward for procedures or physical therapy.
76 Chapter 10 PATIENT- CONTROLLED ANALGESIA
Box 10^1 CURRENT THERAPY: PATIENT MONITORING Box 10^2 CURRENT THERAPY: POTENTIAL SOURCES
DURING PCATHERAPY OF PCA-RELATED MISHAPS
Parameters that should be assessed regularly in patients receiving PCA: Operator Errors
Inappropriate patient selection
Vital Signs with Particular Attention to Respirations
Selection of inappropriate medication
(Breathing Rate/Depth)
Inappropriate prescribed dosing parameters
Normal respiratory rates are in the range of10 ^20 breaths per minute.
Insertion of wrong syringe into PCA device
Visual Analog,Verbal, or FACES Pain Scores PCA pump misprogramming
Typically, numerical pain scores are scaled 0 ^10 or 0 ^100. Higher scores Improper loading of syringe into PCA device
indicate increased severity of pain. Failure to clamp or unclamp PCA tubing
Failure to turn on PCA machine after syringe change
Sedation Scores
PCA key displacement
Sedation usually precedes onset of significant respiratory depression.
Inadequate training of staff regarding PCA and setup
Assessment of sedation usually involves documenting the patient’s level
Failure to respond to device or monitor alarms
of consciousness via a numerical rating system such as
1 = Wide awake Patient Errors
2 = Drowsy Failure to understand PCA therapy or use of device
3 = Sleeping but arousable Confusion between PCA button and nurse call button
4 = Difficult to arouse Physical inability to activate demand button
5 = Unable to arouse PCA by proxy
Intentional device tampering
Opioid Consumption
Evaluation of medication use by the patient helps to guide adjustments in Mechanical Problems
therapy. Assessment of opioid consumption allows for more accurate Electrical failure/battery failure
conversion between opioids and routes of administration. This is of Short circuiting of PCA device
particular importance in determining the needs of the opioid-tolerant Siphoning of medication
patient when switching to oral medication. Alarm malfunctions
Tubing defects/lack of antireflux valves
Oxygen Saturation
Accumulation of drug in tubing dead space
Monitoring of oxygen saturation is not mandatory but may be useful,
Hardware or software failure in PCA machine
particularly in individuals at risk of respiratory depression with opioid
therapy. Desaturation is a late indicator of respiratory depression, and
thus, oxygen saturation monitoring should not be the only means used
to assess for this adverse effect of opioid therapy.
in the tubing used to deliver the medication to the patient. Antireflux
End-tidal Carbon Dioxide valves are typically used in the tubing for PCA to prevent medication
Adequacy of ventilation can be assessed through use of end-tidal carbon
backflow that could cause large amounts of medication to be bolused
dioxide monitoring. This allows for earlier detection of respiratory
depression related to opioid therapy. This type of monitoring may not
to a patient if the tubing becomes obstructed and the obstruction is
yet be widely available in most institutions. suddenly relieved (Box 10–2).18,19
Side Effects
Common side effects of opioid therapy include nausea, sedation, pruri-
tus, and constipation. Monitoring for these and any other adverse effects NEW OPTIONS FOR PCA
of therapy should be included in patient assessments. Treatment for any
untoward effects should be provided as indicated. PCA has traditionally been delivered via the intravenous route.
PCEA and PCRA are other means of PCA that have more recently
been developed. In addition, patient-controlled oral, intranasal, and
subcutaneous analgesia have been studied with evidence of effec-
Patient Errors tiveness. Currently in development is a transdermal fentanyl ionto-
phoretic delivery system that will serve as an additional option for
User related problems may occur with PCA. Some patients may not noninvasive on-demand analgesia.
understand use of the PCA device or may confuse the demand button
for the nurse call button. Patients with arthritic conditions may find it
difficult to activate the demand button. Sometimes, well-intentioned PCEA
friends and family members may deliver PCA by proxy. This can cause
opioid toxicity, especially if the proxy continues to activate the device PCEA has most extensively been studied and used in the obstetric
when the patient falls asleep or manifests sedation. There have also patient,20 likely because epidural analgesia is very commonly
been cases of intentional device tampering by patients. employed in this patient population. This form of analgesia has
also been used successfully in postoperative patients, including
those having undergone extensive abdominal or spinal surgery.
Mechanical Problems The potential benefits of this form of PCA over conventional intra-
venous administration include reduction in total opioid consump-
Device malfunction may be caused by electrical failure or short- tion with consequent decrease in associated adverse effects. In
circuiting. In the case of electrical failure, the patient may suffer uncon- addition, several studies suggest that use of PCEA compares favor-
trolled pain owing to interruption of drug delivery. Conversely, ably with use of continuous epidural analgesia, with reduction in
short-circuiting may cause delivery of medication in the absence total local anesthetic dosing and attendant motor block.
of device activation. This could result in clinical opioid overdosage
if the malfunction goes unrecognized. Siphoning of medication may
occur if a defective or cracked syringe is placed in the PCA device.17 This PCRA
may also occur with inappropriate syringe seating or if the syringe
is placed at a level significantly higher than the patient’s body. PCRA has been used for plexus analgesia as well as direct wound
Other mechanical problems may relate to alarm malfunctions or defects infiltration analgesia, as with arthroscopically guided subacromial
III ACUTE PAIN 77
catheter placement after decompressive shoulder surgery.21 PCRA maximum of 15 ml/hr based upon the frequency of demands within
has been used with success in several surgical patient populations, the preceding hour. It subsequently will decrease the rate in 5-ml
including pediatric patients. Patient satisfaction with this technique increments if no demands are made over an hour. A study using
appears to be high, and use of elastomeric infusion pumps to deliver this device in laboring women showed no significant increase in the
the desired local anesthetic allows for continuation of this technique total volume of analgesic mixture used with the adapted PCEA
even after patient discharge to home.22 When consideration is made device, but did show evidence of increased maternal satisfaction
to utilize PCRA at home, however, care must be taken to ensure with this mode of analgesia.31
proper instruction of the patient and caregivers, and a physician In addition to advances in the sophistication of PCA delivery
must remain readily available to address any potential problems devices, monitoring capabilities for patients using these devices
or complications that may arise. have also improved. One major enhancement in patient safety for
those using PCA is the availability of ETCO2 monitoring. ETCO2 is an
indicator of patient ventilatory status. Changes in ventilatory
Noninvasive Forms of PCA pattern typically occur long before declines in oxygen saturation,
which has long been the parameter used to monitor for evidence of
Several options for noninvasive delivery of PCA have been evaluated respiratory depression. One PCA system currently incorporates the
with evidence of efficacy. Oral PCA and patient-controlled intrana- ability to monitor both ventilation and oxygenation and thus allows
sal analgesia are examples of these options.23,24 Modification of for early detection of adverse respiratory effects of opioid therapy.
existing systems for intravenous PCA allow for delivery of medica- The system alerts when respiratory parameters are out of range and
tion by these alternate routes. When using these alternate delivery does not permit delivery of any additional opioid doses. This system
modalities, it must be taken into consideration that dose adjustment may be especially useful in at-risk patient populations such as those
is necessary because of differences in the bioavailability of opioids with sleep apnea and those who appear to have large opioid require-
when compared with intravenous administration. Once appropriate ments but manifest evidence of sedation even in the presence of
dose conversions are made, these delivery methods may provide ongoing requests for additional analgesia. Perhaps in the future,
analgesia comparable with that of intravenous PCA. These techni- computer-integrated systems will become available that combine
ques are particularly useful when intravenous access is unavailable. A the options for variable infusion based upon patient needs and
transdermal fentanyl PCA delivery system is currently undergoing the ability to monitor for evidence of adverse effects on respiratory
clinical trials and is anticipated to enter the U.S. market in the near function. This combination of features would appear to offer the
future.25–28 This device is programmed to deliver 40 mcg of fentanyl optimal balance between patient satisfaction and safety.
via iontophoresis (through a low-intensity electrical current) when
activated. The fentanyl dose is delivered over 10 minutes, and the
device cannot be activated more frequently than in 10-minute inter- CONCLUSION
vals. The device is operable for 24 hours after the initial activation
and can deliver a maximum of 80 doses. There is no basal fentanyl PCA has been an important option for pain management for several
delivery between device activations, making it purely an on-demand decades. Intravenous PCA is widely used for a variety of painful
system. Studies have shown use of the PCA fentanyl transdermal conditions and has been especially useful in the management of
system to provide analgesia equivalent to that of intravenous acute postoperative pain. Newer PCA techniques such as PCEA,
PCA in postoperative patients. This appears to offer a promising PCRA, and noninvasive forms of PCA have further expanded the
alternative to conventional PCA because it eliminates the need for options available for the treatment of pain. PCA should be under-
intravenous access to deliver the analgesic and it does not require as taken with knowledge of the pharmacokinetic properties of the
much nursing time to implement and maintain. drugs employed and an awareness of patient factors that may
increase the potential for adverse events with PCA. Practitioners
and patients must be properly educated on use of PCA, and patients
SMART INFUSION AND MONITORING must be properly selected for this treatment modality. Advances in
SYSTEMS FOR PCA PCA technology such as variable-rate infusions that are calculated
based upon patient needs for analgesia and improved patient mon-
Some of the most recent advancements in PCA therapy involve the itoring will further enhance use of these techniques in the future.
development of smart systems capable of adapting therapy based
upon patient needs and computer-integrated systems that monitor
patient ventilation and oxygenation and can terminate infusion of REFERENCES
opioids when respiratory parameters fall outside prescribed
ranges.29 A PCA device with a computer-integrated handset has 1. McDonald AJ, Cooper MG. Patient-controlled analgesia: an
been developed that allows patients to select a pain intensity appropriate method of pain control in children. Paediatr Drugs
2001;3:(4)273–284.
rating on a scale of 1 to 10 prior to delivering an opioid bolus.
2. Lavand’Homme P, De Kock M. Practical guidelines on the
This device uses an algorithmic approach that calculates a bolus postoperative use of patient-controlled analgesia in the elderly. Drugs
dose based upon pain intensity ratings and adjusts a basal infusion & Aging 1998;13:(1)9–16.
based upon demand frequency. If the patient stops making 3. Kluger MT, Owen H. Patients’ expectations of patient-controlled
demands, the infusion is decreased and then discontinued if no analgesia. Anaesthesia 1990;45:1072–1074.
further demands are made within a specified time interval. One 4. Grass JA. Patient-controlled analgesia. Anesth Analg 2005;101:S44–S61.
study performed using this adapted PCA device showed that 5. Lindley C. Overview of current development in patient-controlled
although opioid consumption was higher when using the adapted analgesia. Support Care Cancer 1994;2:319–326.
PCA compared with conventional PCA, opioid-associated adverse 6. Jackson D. A study of pain management: patient controlled analgesia
effects were not increased, and patient bolus requests declined as the versus intramuscular analgesia. J Intravenous Nurs 1989;12(1):42–51.
7. Knudsen WP, Boettcher R, Vollmer WM, Griggs DK. A comparison
machine varied its infusion rate based upon the patient usage pat- of patient-controlled and intramuscular morphine in patients after
terns.30 Similarly, a computer-integrated PCEA device that initiates abdominal surgery. Hosp Pharm 1993;28(2):117–118, 120–122, 126, 138.
a basal infusion of a local anesthetic/opioid mixture has been 8. Boldt J, Thaler E, Lehmann A, et al: Pain management in cardiac
described. With this device, when a patient demands a PCEA surgery patients: comparison between standard therapy and patient-
bolus, the device initiates a basal infusion at 5 ml/hr of the analgesic controlled analgesia regimen. J Cardiothoraci Vascular Anesth
mixture. The basal infusion is increased in 5-ml increments to a 1998;12(6):654–658.
78 Chapter 11 PERIOPER ATIVE EPIDUR AL ANALGESIA
9. Lehmann KA. Recent development in patient-controlled analgesia. 22. Rawal N, Allvin R, Axellson K, Hallen J, Erkback G, Ohlsson T,
J Pain Symptom Manage 2005;29:(5S)S72–S89. Amilon A. Patient-Controlled Regional Analgesia (PCRA) at Home.
10. Walder B, Schafer M, Henzi I, Tramer MR. Efficacy and Safety of Anesthesiology 2002;96:(6)1290–1296.
Patient-Controlled Opioids Analgesia for Acute Postperative Pain. 23. Striebel HW, Roemer M, Kopf A, Schwagmeier R. Patient-controlled
Acta Anaesthesiol Scand 2001;45:795–804. oral analgesia with morphine. Can J Anaesth 1996;43(7):749–753.
11. Gust R, Pecher S, Gust A, et al. Effect of patient-controlled analgesia 24. Toussaint S, Maidl J, Schwagmeier R, Striebel HW. Patient-controlled
on pulmonary complications after coronary artery bypass grafting. intranasal analgesia: effective alternative to intravenous PCA for
Crit Care Med 1999;27(10):2218–2223. postoperative pain relief. Can J Anesth 2000;47(4):299–302.
12. Thomas VJ. Rose FD. Patient-controlled analgesia: a new method for 25. Viscusi ER, Reynolds L, Chung F, Atkinson LE, Khanna S. Patient-
old. J Adv Nurs 1993;18:1719–1726. Controlled Transdermal Fentanyl Hydrochloride vs Intravenous
13. Campbell L, Plummer J. Guidelines for the implementation of Morphine Pump for Postoperative pain. JAMA
patient-controlled analgesia. Dis Manage Health Outcomes 2004;291(11):1333–1341.
1998;4(1):27–39. 26. Chelly JE, Grass J, Houseman TW, Minkowitz H, Pue A. The Safety
14. Kluger MT, Owen H. Patient-controlled analgesia: can it be made and Efficacy of a Fentanyl Patient-Controlled Transdermal System for
safer? Anaesth Intensive Care 1991;19(3):412–420. Acute Postoperative Analgesia: A Multicenter, Placebo-Controlled
15. Cohen MR, Smetzer J. Patient-Controlled Analgesia Safety Trial. Anesth Analg 2004;98:427–433.
Issues. Journal of Pain & Palliative Care Pharmacotherapy 27. Koo PJS. Postoperative pain management with a patient-controlled
2005;19(1):45–50. transdermal delivery system for fentanyl. Am J Health Syst Pharm
16. Graves DA, Foster TS, Batenhorst RL, et al. Patient-controlled 2005;62:1171–1176.
analgesia. Ann Intern Med 1983;99:360–366. 28. Sinatra R. The fentanyl HCl patient-controlled transdermal system
17. Thomas DW, Owen H. Patient-Controlled Analgesia—The Need for (PCTS): an alternative to intravenous patient-controlled analgesia
Caution. Anaesth 1988;43:770–772. in the postoperative setting. Clin Pharmacokinet 2005;
18. Doyle DJ. Proposed Texonomy for Infusion Pump and Safety Hazards 44(suppl 1):1–6.
(Abstract). Anesth Analg 2006;102:9. 29. Maddox RR, Williams CK, Oglesby H, et al. Clinical experience with
19. Smythe M. Patient–Controlled Analgesia: A Review. Pharmacotherapy patient-controlled analgesia using continuous respiratory monitoring
1992;12:(2)132–143. and a smart infusion system. Am J Health Syst Pharm 2006;
20. Halpern SH, Muir H, Breen TW, Campbell DC, Barrett J, Liston R, 63:157-164.
Blanchard JW. A Multicenter Randomized Controlled Trial 30. Rudolph H, Cade JF, Morley PT, et al. Smart technology improves
Comparing Patient-Controlled Epidural with Intravenous Analgesia patient-controlled analgesia: a preliminary report. Anesth Analg
for Pain Relief in Labor. Anesth Analg 2004;99:1532–1538. 1999;89:1226–1232.
21. Axelsson K, Nordenson U, Johanzon E, et al. Patient-controlled 31. Lim Y, Sia AT, Ocampo CE. Comparison of computer integrated
regional analgesia (PCRA) with ropivacaine after patient controlled epidural analgesia vs. conventional patient
arthroscopic subacromial decompression. Acta Anaesthesiol Scand controlled epidural analgesia for pain relief in labour. Anaesthesia
2003;47:993–1000. 2006;61:339–344.
Chapter 11 adjuvants and modalities of administration have been introduced.2

The focus of this chapter is to review the favorable data supporting
PERIOPERATIVE EPIDURAL the application of epidural analgesia for specific surgeries, recom-
mend dosing schemes, present a troubleshooting algorithm for
ANALGESIA inadequate analgesia, discuss recent novel approaches, and com-
ment on adverse side effects and the American Society of Regional
Melissa A. Rockford and Martin L. DeRuyter Anesthesia (ASRA) guidelines for management of epidurals in the
setting of perioperative anticoagulation.
ANATOMY
Epidural analgesia is produced by placing specific medications
INTRODUCTION within the spinal epidural space. This space extends from the
foramen magnum to the sacral hiatus. Lumbar, thoracic, and
The first description of epidural analgesia dates back to Leonard J. caudal levels are the most common sites used for postoperative
Corning, a neurologist, who in 1885 inadvertently injected cocaine analgesia. The epidural space is bounded anteriorly by the posterior
into the epidural space of a patient. By 1900, epidural analgesia was longitudinal ligaments; posteriorly by the ligamentum flavum and
being used to treat the pain of childbirth, and in 1931, a continuous vertebral laminae; and laterally by the vertebral pedicles and inter-
technique was described. Considered the father of modern epidural vertebral foramina, through which the nerve roots exit the epidural
anesthesia, A. M. Dogliotti, a 1930’s Italian surgeon, was the first to space. The epidural space contains spinal nerve roots, fat, areolar
describe the ‘‘loss of resistance’’ technique. Phillip Bromage pub- tissue, lymph tissue, and blood vessels including a rich venous
lished the first textbook on epidural anesthesia in 1978. Bromage plexus. Spread of analgesia occurs in a segmental fashion both
introduced the administration of epidural morphine for postoper- cephalad and caudad from the site of injection. Thus, the extent
ative analgesia in 1980. The introduction of epidural patient- of spread is most affected by site of injection. Other factors that may
controlled analgesia with morphine followed in 1988.1 Administra- affect spread include patient age and volume of drug. Patient height,
tion of medications into the epidural space for postoperative anal- weight, position, parturience, degree of atherosclerosis, speed of
gesia is a common practice today. Opioids and local anesthetics as injection, and direction of the needle bevel do not seem to affect
single agents or in combination are widely prescribed, and new spread of epidural analgesia to a clinically significant extent.
9. Lehmann KA. Recent development in patient-controlled analgesia. 22. Rawal N, Allvin R, Axellson K, Hallen J, Erkback G, Ohlsson T,
J Pain Symptom Manage 2005;29:(5S)S72–S89. Amilon A. Patient-Controlled Regional Analgesia (PCRA) at Home.
10. Walder B, Schafer M, Henzi I, Tramer MR. Efficacy and Safety of Anesthesiology 2002;96:(6)1290–1296.
Patient-Controlled Opioids Analgesia for Acute Postperative Pain. 23. Striebel HW, Roemer M, Kopf A, Schwagmeier R. Patient-controlled
Acta Anaesthesiol Scand 2001;45:795–804. oral analgesia with morphine. Can J Anaesth 1996;43(7):749–753.
11. Gust R, Pecher S, Gust A, et al. Effect of patient-controlled analgesia 24. Toussaint S, Maidl J, Schwagmeier R, Striebel HW. Patient-controlled
on pulmonary complications after coronary artery bypass grafting. intranasal analgesia: effective alternative to intravenous PCA for
Crit Care Med 1999;27(10):2218–2223. postoperative pain relief. Can J Anesth 2000;47(4):299–302.
12. Thomas VJ. Rose FD. Patient-controlled analgesia: a new method for 25. Viscusi ER, Reynolds L, Chung F, Atkinson LE, Khanna S. Patient-
old. J Adv Nurs 1993;18:1719–1726. Controlled Transdermal Fentanyl Hydrochloride vs Intravenous
13. Campbell L, Plummer J. Guidelines for the implementation of Morphine Pump for Postoperative pain. JAMA
patient-controlled analgesia. Dis Manage Health Outcomes 2004;291(11):1333–1341.
1998;4(1):27–39. 26. Chelly JE, Grass J, Houseman TW, Minkowitz H, Pue A. The Safety
14. Kluger MT, Owen H. Patient-controlled analgesia: can it be made and Efficacy of a Fentanyl Patient-Controlled Transdermal System for
safer? Anaesth Intensive Care 1991;19(3):412–420. Acute Postoperative Analgesia: A Multicenter, Placebo-Controlled
15. Cohen MR, Smetzer J. Patient-Controlled Analgesia Safety Trial. Anesth Analg 2004;98:427–433.
Issues. Journal of Pain & Palliative Care Pharmacotherapy 27. Koo PJS. Postoperative pain management with a patient-controlled
2005;19(1):45–50. transdermal delivery system for fentanyl. Am J Health Syst Pharm
16. Graves DA, Foster TS, Batenhorst RL, et al. Patient-controlled 2005;62:1171–1176.
analgesia. Ann Intern Med 1983;99:360–366. 28. Sinatra R. The fentanyl HCl patient-controlled transdermal system
17. Thomas DW, Owen H. Patient-Controlled Analgesia—The Need for (PCTS): an alternative to intravenous patient-controlled analgesia
Caution. Anaesth 1988;43:770–772. in the postoperative setting. Clin Pharmacokinet 2005;
18. Doyle DJ. Proposed Texonomy for Infusion Pump and Safety Hazards 44(suppl 1):1–6.
(Abstract). Anesth Analg 2006;102:9. 29. Maddox RR, Williams CK, Oglesby H, et al. Clinical experience with
19. Smythe M. Patient–Controlled Analgesia: A Review. Pharmacotherapy patient-controlled analgesia using continuous respiratory monitoring
1992;12:(2)132–143. and a smart infusion system. Am J Health Syst Pharm 2006;
20. Halpern SH, Muir H, Breen TW, Campbell DC, Barrett J, Liston R, 63:157-164.
Blanchard JW. A Multicenter Randomized Controlled Trial 30. Rudolph H, Cade JF, Morley PT, et al. Smart technology improves
Comparing Patient-Controlled Epidural with Intravenous Analgesia patient-controlled analgesia: a preliminary report. Anesth Analg
for Pain Relief in Labor. Anesth Analg 2004;99:1532–1538. 1999;89:1226–1232.
21. Axelsson K, Nordenson U, Johanzon E, et al. Patient-controlled 31. Lim Y, Sia AT, Ocampo CE. Comparison of computer integrated
regional analgesia (PCRA) with ropivacaine after patient controlled epidural analgesia vs. conventional patient
arthroscopic subacromial decompression. Acta Anaesthesiol Scand controlled epidural analgesia for pain relief in labour. Anaesthesia
2003;47:993–1000. 2006;61:339–344.
Chapter 11 adjuvants and modalities of administration have been introduced.2

The focus of this chapter is to review the favorable data supporting
PERIOPERATIVE EPIDURAL the application of epidural analgesia for specific surgeries, recom-
mend dosing schemes, present a troubleshooting algorithm for
ANALGESIA inadequate analgesia, discuss recent novel approaches, and com-
ment on adverse side effects and the American Society of Regional
Melissa A. Rockford and Martin L. DeRuyter Anesthesia (ASRA) guidelines for management of epidurals in the
setting of perioperative anticoagulation.
ANATOMY
Epidural analgesia is produced by placing specific medications
INTRODUCTION within the spinal epidural space. This space extends from the
foramen magnum to the sacral hiatus. Lumbar, thoracic, and
The first description of epidural analgesia dates back to Leonard J. caudal levels are the most common sites used for postoperative
Corning, a neurologist, who in 1885 inadvertently injected cocaine analgesia. The epidural space is bounded anteriorly by the posterior
into the epidural space of a patient. By 1900, epidural analgesia was longitudinal ligaments; posteriorly by the ligamentum flavum and
being used to treat the pain of childbirth, and in 1931, a continuous vertebral laminae; and laterally by the vertebral pedicles and inter-
technique was described. Considered the father of modern epidural vertebral foramina, through which the nerve roots exit the epidural
anesthesia, A. M. Dogliotti, a 1930’s Italian surgeon, was the first to space. The epidural space contains spinal nerve roots, fat, areolar
describe the ‘‘loss of resistance’’ technique. Phillip Bromage pub- tissue, lymph tissue, and blood vessels including a rich venous
lished the first textbook on epidural anesthesia in 1978. Bromage plexus. Spread of analgesia occurs in a segmental fashion both
introduced the administration of epidural morphine for postoper- cephalad and caudad from the site of injection. Thus, the extent
ative analgesia in 1980. The introduction of epidural patient- of spread is most affected by site of injection. Other factors that may
controlled analgesia with morphine followed in 1988.1 Administra- affect spread include patient age and volume of drug. Patient height,
tion of medications into the epidural space for postoperative anal- weight, position, parturience, degree of atherosclerosis, speed of
gesia is a common practice today. Opioids and local anesthetics as injection, and direction of the needle bevel do not seem to affect
single agents or in combination are widely prescribed, and new spread of epidural analgesia to a clinically significant extent.
III ACUTE PAIN 79
OPIOIDS Table 11^1. Characteristics of Epidural Administered

Opioids
Opioids act primarily at two sites, spinal and supraspinal.3 Three
major subtypes of opioid receptors, m, d, and k, have been Onset Peak Duration
described. The most profound analgesic effects of opioids are Agent (min) (min) (hr)
mediated by m-receptors widely distributed in both the brain
(supraspinal) and the spinal cord (spinal). The d- and k-receptors Morphine 20 30–60 12–24
also contribute to analgesia at the spinal level. Parenterally admi- Fentanyl 4–10 20 1–5
nistered opioids primarily work at supraspinal sites, whereas Hydromorphone 15 20 8–12
opioids administered intrathecally directly communicate with the
spinal cord at presynaptic and postsynaptic receptors in the sub-
stantia gelatinosa of the dorsal horn. The analgesic effect of epidu- therefore, delayed respiratory depression may occur 6 to 12 hours
rally administered opioids is primarily achieved via spinal receptor after dosing. Lipophilic agents such as fentanyl and sufentanil have
activation. The onset of epidural analgesia is typically slower than shorter durations of analgesia, and intermittent bolusing for
intrathecally administered drugs because the drug must first cross ‘‘spinal’’ analgesia would require more frequent administration.
the dura before reaching the opioid receptors on the spinal cord. Clinically, these agents are better suited for continuous epidural
Epidural opioids also activate supraspinal opioid receptors either infusions. Hydromorphone has a lipid solubility between those
by vascular uptake of lipophilic agents such as fentanyl or by of morphine and fentanyl and can be administered either inter-
eventual cerebrospinal fluid (CSF) rostral migration of hydrophilic mittently or via continuous infusion. When compared with mor-
agents such as morphine. phine, hydromorphone has less associated pruritus and nausea.
Compared with intrathecal administration, the epidural admin- Tables 11–1 and 11–2 provide commonly administered epidural
istration of opioids has fewer side effects and fewer tendencies opioids, their characteristics, and dosing suggestions.
for respiratory depression. A significant determinant of a drug’s
pharmacokinetics is its tendency to be hydrophilic or lipophilic.
Consider and compare morphine (hydrophilic) and fentanyl LOCAL ANESTHETICS
(lipophilic). Epidural administration of morphine results in
a rapid rise in plasma concentration, similar to intravenous (IV) Postoperative epidural analgesia provided by local anesthetics pro-
dosing. Clinically, the analgesia associated with intravenously admi- duces a dermatomal distribution of paresthesia and analgesia. After
nistered morphine may be brief, whereas epidural administration administration of local anesthetic into the epidural space, the drug
provides extended analgesia. Implied is that only a small fraction of diffuses into the CSF at the region of the dural cuff. Locally, spinal
the drug is necessary to provide spinal-mediated analgesia, which nerve roots, dorsal root ganglia, and ‘‘rootlets’’ are blocked, as well as
occurs as the residual morphine fraction diffuses across the dura. In spinal nerves in the paravertebral space (which may account for a
comparison, fentanyl’s lipophilic properties likely account for early multiple-level block). Although numerous local anesthetics are appli-
serum levels of the opioid after epidural administration that are cable in producing epidural anesthesia, in considering postoperative
significantly lower when compared with concurrent IV administra- epidural analgesia, the longer-acting amides, bupivacaine and ropiva-
tion. Administration of lipophilic agents into the epidural space caine, are most commonly used. Box 11–1 provides dosing regimens
results in local uptake by epidural fat and other lipophilic tissues, for continuous catheters specific for surgical site, catheter insertion
limiting a rapid rise of serum levels. After 24 hours of continuous site, and type of medication (opioid, local anesthetic, or both).
infusion, serum levels of IV and epidural drug approach equality as
lipid deposits are saturated and drug is eluted into the circulatory
system. Ginosar and coworkers hypothesized a differential site of ADMINISTRATION
action (spinal versus supraspinal) of fentanyl based on the method
of epidural administration (i.e., bolus vs. continuous infusion).4 Continuous infusions have been the primary approach to postop-
They demonstrated that continuous infusion resulted in nonseg- erative epidural analgesia. Advancement in infusion pumps has
mental analgesia (suggesting opioid binding in the brain), whereas allowed for patient-controlled epidural analgesia (PCEA), employ-
bolus administration resulted in segmental analgesia (suggesting ing the same benefits found with IV opioid patient-controlled anal-
opioid binding at the spinal cord). gesia (IV PCA). Continuous infusions, although the mainstay, are
Although recognizing differences in spinal versus supraspinal not without management issues. Namely, failure rates for thoracic
sites of action, selection of a lipophilic versus hydrophilic drug and lumbar epidurals are reportedly as high as 32% and 27%,
may likely depend on the clinical setting in which a provider prac- respectively.5 Catheter malfunction and displacement, nursing
tices. If continuous infusion is not available (e.g., lack of nursing care, and attention to the infusion pump all demand utilization
supervision, lack of mechanical infusion pumps), administration of of limited resources. The recent introduction of liposomal mor-
morphine may be preferred. Morphine as a hydrophilic agent phine administered by single injection has been shown to provide
remains in the CSF to a greater extent and has considerable significant prolonged analgesia and avoids these concerns, but it is
analgesic duration. It is also associated with rostral spread, and not to be used without caution.
Table 11^2. PCEA: Suggested Dosing
Concentration PCEA Bolus 4 -hr Bolus

Agent (mcg/ml) Loading Dose Infusion Dose (mcg) Lock-out (min) Dose Limit
Morphine*{ 50–100 1–6 mg 0.1–1.0 mg/hr 50–200 30–45 4–6
Fentanyl 5–10 50–100 mcg 50–100 mcg/hr 15–20 10 10
Hydromorphone 10 0.4–1.0 mg 30–120 mcg/hr 20–40 15 10
*Onset of epidural morphine slow, therefore PCEA not advised.
{
Loading dose sensitive to age of patient.
PCEA, patient-controlled epidural analgesia.
pruritus. A recent review of analgesia for thoracic surgery found

Box 11^1 SUGGESTED DOSING REGIMENS FOR that epidural analgesia had significant benefits over parenteral and
CONTINUOUS EPIDURAL ANALGESIA IV PCA opioids.9,10 Median sternotomy associated with cardiac
surgery is significantly painful. Wound injection of local anesthetic
Thoracic,Upper Abdominal Analgesia may provide some benefit, but administration of epidural analgesia
Thoracic Catheter is associated with a lower autonomic stress response, significant
Fentanyl 5^10 mcg/ml, 30 ^70 mcg/hr analgesia, and lower IV opioid requirements.11 Segmental epidural
Hydromorphone 10 mcg/ml, 30 ^50 mcg/hr analgesia after breast surgery provides significant patient satisfac-
Morphine sulfate 50 ^100 mcg/ml,100 ^500 mcg/hr tion. In a prospective, randomized trial comparing epidural anal-
gesia versus IV PCA, the group that received epidural analgesia
Bupivacaine 0.1%, 3^ 8 ml/hr demonstrated improved pain control after breast reconstruction
Ropivacaine 0.2%, 3^ 8 ml/hr
with immediate transverse rectus abdominis musculocutaneous
Lumbar Catheter* flap reconstruction and a shortened hospitalization.12
Fentanyl 5^10 mcg/ml, 50 ^100 mcg/hr
Hydromorphone 10 mcg/ml, 40 ^ 80 mcg/hr
Morphine sulfate 100 mcg/ml, 400 ^ 800 mcg/hr
ABDOMINAL SURGERY
Lower Abdominal, Pelvic,Urologic, Lower Extremity Analgesia
Pain associated with laparotomy can be severe, and treatment with
Lumbar Catheter
Fentanyl 5^10 mcg/ml, 50 ^100 mcg/hr IV opioids is associated with undesirable side effects and perhaps
Hydromorphone 10 mcg/ml, 30 ^ 80 mcg/hr inadequate analgesia. A 2006 Cochrane meta-analysis, representing
Morphine sulfate 100 mcg/ml, 400 ^ 800 mcg/hr 1224 patients undergoing abdominal aortic surgery, reviewed the
efficacy of epidural analgesia versus systemic opioids.13 The authors
Bupivacaine 0.1%, 5^10 ml/hr concluded a favorable indication for epidural analgesia. They found
Ropivacaine 0.2%, 5^10 ml/hr better pain relief (particularly with movement) up to 3 days post-
*
No local anesthetic recommended. operatively, a reduction in number of days requiring postoperative
ventilation, and fewer cardiac, gastric, and renal complications.
LOWER ABDOMINAL/PELVIC/
EFFICACY UROLOGIC SURGERY
Epidural analgesia has earned a place among mechanisms of post- The severity and acute duration of pain after certain types of abdom-
operative pain control.6 Block and associates—in a meta-analysis inal, pelvic, and urologic surgery such as radical retropubic prostatec-
of 100 controlled trials with numerous surgeries (representing thor- tomy (RRP) make epidural analgesia an ideal form of pain control.14
acic, abdominal, pelvic, and lower extremities) comparing IV PCA Gottschalk and coworkers performed a randomized, double-blind
opioids, parenteral opioids, and epidural opioids (with or without clinical trial of 100 patients undergoing RRP and found that preemp-
local anesthetics)—demonstrated that epidurals provided better tive epidural analgesia significantly decreased postoperative pain both
postoperative analgesia.7 Epidurals were also associated with lower during hospitalization and after hospital discharge.15 In a recent study
than expected complications such as nausea, vomiting, and pruri- of 60 patients, Niiyama and associates demonstrated improved anal-
tus. Furthermore, patients receiving a combination of epidural local gesia in patients undergoing lower abdominal surgery when 0.2%
anesthetic and opioid as opposed to opioid alone exhibited greater ropivacaine was added to epidural morphine.16
improvements in analgesia.
The following sections review specific procedures and discuss data
supportive for epidural analgesia. Table 11–3 provides recommended LOWER EXTREMITY SURGERY
sites for catheter placement based on surgical procedure.
Postoperative epidural analgesia either combined with a general
anesthetic or as an extension of an intraoperative anesthetic has
THORACIC SURGERY been employed extensively in patients undergoing lower extremity
surgery, either vascular or orthopedic procedures.17,18 Early reports
Thoracotomies, median sternotomy incisions, and breast surgery demonstrated suitable analgesia, lower incidences of reoperation,
are commonly associated with significant postoperative pain. less blood loss, and lower incidence of deep vein thrombosis
Benzon and colleagues, in a prospective, randomized, double- (DVT).19 In a recent review of postoperative analgesia for patients
blind trial comparing thoracic epidural infusion of fentanyl to IV after total hip arthroplasty, Fischer and Simanski recommended the
PCA morphine, found that patients in the epidural group reported use of epidural analgesia but also cautioned about an added degree
lower pain scores, less pain associated with coughing, and less seda- of postoperative monitoring.20
tion.8 Both groups shared a similar incidence of postoperative
nausea and vomiting, whereas the epidural group reported more
TROUBLESHOOTING
Table 11^3. Recommended Sites for Catheter
Placement Common problems with epidural catheters include inadequate
analgesia, disconnected catheters, and motor block. Testing the
level of sensory block can be performed using temperature
Surgical Site Catheter Site
(cold/ice) or sensation (dull/sharp). Figure 11–1 provides a sug-
Thoracic T4–T8 gested algorithm for patients with complaint of inadequate analge-
Upper abdomen T6–T10 sia. If the provider suspects that the epidural catheter is not
Lower abdomen/pelvis T10–L3 functioning properly, catheter replacement should be considered.
Upon inspection, the provider should remove the catheter if it has
Lower extremity T12–L4
been disconnected and contaminated. If a catheter is disconnected
III ACUTE PAIN 81
INADEQUATE
ANALGESIA
Catheter
Check site
dislodged
Remove
Remove Catheter Dressing + CSF
Aspirate catheter*
catheter* disconnect and catheter
catheter
intact + Heme
Contaminated Able to Negative Withdraw

reconnect in aspirate 1–2 cm and
sterile fashion aspirate
Bolus dose Remove

Remove Negative + Heme
No block 6–10 mL catheter*
catheter* aspiration
1–2% lidocaine
Unilateral
block
Adequate
block
Withdraw 1–2 cm,

aspirate catheter
Consider Increase
adjuvant infusion rate
by 2 mL/hr
Negative Positive
aspirate aspirate
Bolus dose Remove

6–10 mL catheter*
1–2% lidocaine
No block
Remove
catheter*
*Consider replacing
Figure 11^1. Troubleshooting epidural infusions.
and the fluid within the catheter has not been displaced, it is possible the need for continuous infusion. The extended duration of activity
to reconnect the catheter using sterile technique. A bolus may be results from ‘‘time-released’’ elution of the drug from liposomal
necessary after periods of disconnect. Patients who complain of an aggregates of various sizes. DepoDur is intended for lumbar epidu-
excessive motor block should be evaluated for possible subarachnoid ral administration only. It should not be mixed with any other
catheter placement or supratherapeutic dosing of the epidural cath- agents, nor is injection of other agents into the epidural space
eter. Once a subarachnoid block is excluded, the epidural infusion recommended within 48 hours of DepoDur administration.21,22
can be decreased to balance the desired level of analgesia with the Clinical trials after hip surgery, major surgery of the lower
acceptable degree of motor block. abdomen, and elective cesarean section have shown improved anal-
gesia up to 48 hours after surgery. Side effects are similar to those of
opioids administered through an epidural catheter or intravenously.
Forty-eight hours of cardiopulmonary monitoring with concern for
RECENT NOVEL APPROACHES respiratory depression in the first 24 hours is recommended after
drug administration. Clinical trials found that the incidence of
DepoDur adverse respiratory event is dose related. Respiratory depression
requiring an intervention was found to occur within 16 to 24
Extended-release epidural morphine, DepoDur (Endo Pharmaceu- hours of administration. The recommended lumbar epidural dose
ticals, Inc, Chadds Ford, PA), is a relatively new formulation of is 10 to 15 mg (Table 11–4). A 20-mg dose can be considered in
morphine sulfate intended to provide extended pain relief without appropriate patients.
Table 11^4. Recommended Dosing for Depodur were presented regarding aseptic technique in the placement of
blocks and the management of catheters in suspicious clinical situa-
Type of Surgery Dose tions. These recommendations include thorough handwashing
before performing procedures, removal of all jewelry, use of sterile
Lower abdominal surgery 10–15 mg (1.0–1.5 ml) surgical gloves, routine use of masks, and use of alcohol-based
Elective cesarean section 10 mg (1 ml) chlorhexidine solution as the antiseptic solution.30
Pelvic surgery 10–15 mg (1.0–1.5 ml)
Lower extremity surgery 15 mg (1.5 ml)
ANTICOAGULATION AND EPIDURAL
ANALGESIA
Clonidine Fortunately, the risk of spinal hematoma after epidural analgesia is
low. However, the increasing use and variety of anticoagulants
Clonidine is an a2-agonist. When administered by the epidural in the perioperative setting demand an understanding and appre-
route, it prevents transmission of pain signals at presynaptic and ciation of the risk versus benefit of neuraxial analgesia in antic-
postjunctional receptors in the spinal cord. Clinical studies have oagulated patients. In 2002, ASRA held its Second Consensus
demonstrated sole analgesic properties as well as the ability to Conference on Neuraxial Anesthesia and Anticoagulation.31 This
prolong both the sensory and the motor components of a local anes- is the most recent peer-reviewed consensus identifying agents of
thetic epidural block.23 Side effects of clonidine are similar concern and formalizing a practice guideline. Table 11–7 sum-
when administered by epidural and IV routes. These include hypo- marizes ASRA’s recommendations.
tension, decreased heart rate, dizziness, anxiety, sedation, nausea, dry
mouth, confusion, and rebound hypertension. The dose for epidural
clonidine ranges from 6 to 40 mcg/hr as a continuous infusion with Warfarin
loading doses ranging from 4 to 8 mcg/kg. A study comparing IV to
PCEA clonidine as a single analgesic agent describes a PCEA bolus For patients on chronic oral anticoagulation (warfarin), the antico-
dose of 30 mcg every 15 minutes.24 Gradually decreasing the dose agulant therapy must be stopped (ideally 4–5 days before the
of epidural clonidine 2 to 4 days before discontinuing therapy is planned procedure) and the prothrombin time/International
recommended to prevent rebound hypertension. Normalized Ratio (PT/INR) measured before initiation of neuraxial
block. ‘‘Caution’’ needs to be taken when performing neuraxial
techniques in patients recently discontinued from chronic warfarin
ADVERSE EVENTS AND SIDE EFFECTS therapy. Practitioners do not have a unified recommendation for
the optimal INR before placing a central neuraxial needle, but
It is difficult to isolate the risks and incidence of severe complica- ideally close to normal should be safe.
tions associated with epidural therapy for postoperative analgesia For patients receiving both low-dose warfarin (<5 mg) and
because they are often discussed as secondary outcomes in small continuous epidural analgesia, it is advised to monitor PT/INR
trials. Common side effects of epidural analgesia are primarily a on a daily basis. Before removal of the catheter, a PT/INR should
result of the specific medication administered. Table 11–5 lists be checked if warfarin has been administered for more than 36
some of these commonly cited side effects. A large multicentered hours postoperatively. It is allowable to remove catheters when
French study, prospectively solicited from nearly 500 anesthesiolo- the INR is less than 1.5. The warfarin dose should be withheld or
gists, reported adverse events associated with regional anesthesia.25 reduced for patients with epidurals in place and an INR greater than
Included in its findings are incidences of complications associated 3.0. It is also advised to monitor routine neurologic testing of sen-
with epidural anesthesia and analgesia for obstetric and nonobste- sory and motor function during epidural analgesia infusion.
tric patients (Table 11–6). Overall, the incidence of serious compli- The concurrent use of medications affecting other components of
cations such as epidural abscess or hematoma is quite low.26,27 In a clotting mechanisms (aspirin, other nonsteroidal anti-inflammatory
1-year national survey performed by Wang and colleagues, the esti- drugs [NSAIDs], ticlopidine, clopidogrel, unfractionated heparin,
mated incidence of epidural abscess after epidural analgesia was and low-molecular-weight heparin [LMWH]) may increase the
reported to be 1 in 1930.28 However, a similar review of approxi- risk of bleeding complications without influencing the PT/INR.
mately 50,000 epidural anesthetics did not reveal a single report of
an epidural or intrathecal infection. Other reviews found the fre-
quency of bacterial infection after neuraxial block to be as low as 1.1 Subcutaneous Heparin
per 100,000.29 ASRA held a recent consensus conference on infec-
tious complications associated with regional anesthesia. Upon Patients receiving subcutaneous heparin thromboprophylaxis do
review of the literature and expert opinion, recommendations not seem to be at increased risk for epidural analgesia. The practi-
tioner must weigh the benefits of an epidural for postoperative
analgesia, and if favorable, the consensus supports that action.
Table 11^5. Common Side Effects of Epidural In cases requiring intraoperative heparin anticoagulation (e.g., hep-
Analgesia arin bolus before placement of aortic cross-clamp), a delay of
at least 1 hour after epidural placement is recommended.
Opioids Local Anesthetics
Nausea and vomiting Hypotension
Urinary retention Motor block LMWH
Pruritus Systemic toxicity LMWH presents a distinct problem. There is not an accepted lab-
Respiratory depression oratory test to determine the extent of a patient’s anticoagulation
Dysphoria while receiving LMWH. Monitoring of the anti-Xa level is not
Sedation recommended because the anti-Xa level is not predictive of the
risk of bleeding. For patients who receive perioperative LMWH,
Gastrointestinal dysfunction
the practitioner needs to coordinate and communicate with the
III ACUTE PAIN 83
Table 11^6. Complications Related To Epidural Anesthesia and Analgesia
Cauda Central
Cardiac Respiratory Peripheral Equina Neurologic
N Arrest Failure Seizures Neuropathy Syndrome Event Meningitis Death
Epidural 5561 0 0 1 0 0 0 1 0
(nonobstetric) (0.0–0.5) (0.0–0.5) (1.8) (0.0–0.5) (0.0–0.5) (0.0–0.5) (1.8) (0.0–0.5)
(0.0–0.9) (0.0–9.0)
Epidural 29732 0 3 2 0 0 0 0 0
(obstetric) (0.0–1.0) (1.0) (0.7) (0.0–1.0) (0.0–1.0) (0.0–1.0) (0.0–1.0) (0.0–1.0)
(0.0–2.7) (0.0–2.4)
Values expressed as N (N/10,000), (95% confidence interval [CI]).
Adapted from Auroy U, Benhamou D, Bargues L, et al. Major complications of regional anesthesia in France. Anesthesiology
2002;97:1274–1280.
surgical service to optimize the time interval between neuraxial Other Agents
needle placement and administration of LMWH. Antiplatelet or
oral anticoagulant medications administered in combination with Fondaparinux and other factor Xa inhibitors are potent agents and
LMWH may increase the risk of spinal hematoma, and it is best to efficacious in DVT prophylaxis. Currently, there are little clinical
avoid combination therapy at this time. Education of the entire data regarding risk of hematoma and neuraxial analgesia. Thus, it
patient care team is necessary to avoid such drug combinations. is recommended to avoid placement of central neuraxial needles
An alert mechanism via pharmacy or nursing must be in place and indwelling catheters in patients receiving these medications.
to inform the anesthesia provider when patients are receiving Antiplatelet agents, such as the thienopyridine derivatives ticlo-
anticoagulation. On the day of surgery, traumatic needle or catheter pidine and clopidogrel, should be discontinued 14 and 7 days,
placement may signify an increased risk of spinal hematoma respectively, before initiation of epidural analgesia. Glycoprotein
but does not necessitate postponement of surgery. However, IIb/IIIa inhibitors are contraindicated within 4 weeks of surgery.
initiation of LMWH therapy should be delayed for 24 hours Epidural analgesia is contraindicated in patients receiving fibrinolyt-
postoperatively. ic and thrombolytic therapy. Not enough information is available
Patients on preoperative LMWH should be assumed to have altered on thrombin inhibitors such as desirudin, lepirudin, and argatroban
coagulation status. Placement should occur at least 10 to 12 hours after to make a proper risk assessment, and it is best to avoid neuraxi-
the last prophylactic LMWH dose and 24 hours after the last therapeu- al analgesia in patients receiving these medications. NSAIDs,
tic dose. Neuraxial techniques should be avoided in patients who cyclooxygenase-2 inhibitors, and herbal drugs used alone do not
received LMWH 2 hours preoperatively (peak anticoagulant activity). seem to increase risk of hematoma associated with epidural analgesia.
Postoperative LMWH is a particular concern for practitioners
administering continuous epidural analgesia. A twice-daily dosing
regimen is associated with increased risk of bleeding. Therefore, in- CONCLUSIONS
dwelling catheters should be removed before initiating this LMWH
thromboprophylaxis dosing regimen. Single daily dosing allows for Epidural analgesia is a well-established modality for providing post-
safe maintenance of epidural catheters. Catheters should be removed operative pain relief. Data from individual trials, meta-analysis,
a minimum of 10 to 12 hours after the last dose of LMWH. expert opinion, and personal application generally support
Subsequent LMWH dosing should be delayed a minimum of improved outcomes by numerous measures. Not all studies show
2 hours after catheter removal. a clearly demonstrable benefit. This chapter provides supportive
Table 11^7. ASRA Guidelines for Regional Anesthesia in the Anticoagulated Patient
From American Society of Regional Anesthesia and Pain Medicine. Consensus Statements, Second Consensus Conference on Neuraxial
Anesthesia and Anticoagulation. http://www.asra.com/consensus-statements/2.html (accessed 1/21/2007).
84 Chapter 12 CONTINUOUS PERIPHER AL NERVE CATHETER TECHNIQUES
data for specific procedures and suggestions for a dosing scheme, 16. Niiyama Y, Kawamata T, Shimizu H, et al. The addition of epidural
highlights side effects, and reinforces the concerns of perioperative morphine to ropivacaine improves epidural analgesia after lower
anticoagulation for thromboprophlaxis in patients with indwelling abdominal surgery. Can J Anesth 2005;52:181–185.
central neuraxial catheters. 17. Guay J. The benefits of adding epidural analgesia to general
anesthesia: a meta-analysis. J Anesth 2006;20:335–340.
18. Christopherson R, Beattie C, Frank SM, et al. and the Perioperative
REFERENCES Ischemia Randomized Anesthesia Trial Study Group. Perioperative
morbidity in patients randomized to epidural or general anesthesia
1. Brill S, Gurman GM, Fisher A. A history of neuraxial administration for lower extremity vascular surgery. Anesthesiology 1993;79:422–434.
of local analgesics and opioids. Eur J Anaesthesiol 2003;20:682–689. 19. Buggy DJ, Smith G. Epidural anaesthesia and analgesia: better
2. Viscusi ER. Emerging techniques in the management of acute pain: outcome after major surgery? Growing evidence suggests so. BMJ
epidural analgesia. Anesth Analg 2005;101:S23–S29. 1999;319(7209):530–531.
3. Bernards CM. Understanding the physiology and pharmacology of 20. Fischer HBJ, Simanski CJP. A procedure-specific systematic review
epidural and intrathecal opioids. Best Pract Res Clin Anesthesiol and consensus recommendations for analgesia after total hip
2002;16(4):489–505. replacement. Anaesthesia 2005;60:1189–1202.
4. Ginosar Y, Riley ET, Angst MS. The site of action of epidural fentanyl 21. Gambling D, Hughes T, Martin G, et al. A comparison of Depodur,
in humans: the difference between infusion and bolus administration. a novel, single-dose extended-release epidural morphine, with
Anesth Analg 2003;97:1428–1438. standard epidural morphine for pain relief after lower abdominal
5. Ready LB. Acute pain: lessons learned from 25,000 patients. Reg surgery. Anesth Analg 2005;100:1065–1074.
Anesth Pain Med 1999;24:499–505. 22. Viscusi ER, Martin G, Hartrick CT, et al. and the EREM Study
6. Moraca R, Sheldon D, Thirlby R. The role of epidural anesthesia and Group. Forty-eight hours of postoperative pain relief after total hip
analgesia in surgical practice. Ann Surg 2003;238:663–673. arthroplasty with a novel, extended-release epidural morphine
7. Block BM, Liu SS, Rowlingson AJ, et al. Efficacy of postoperative formulation. Anesthesiology 2005;102:1014–1022.
epidural analgesia: a meta-analysis. JAMA 2003;290:2455–2463. 23. Förster JG, Rosenberg PH. Small dose of clonidine mixed with low-
8. Benzon HT, Wong HY, Belavic AM Jr, et al. A randomized dose ropivacaine and fentanyl for epidural analgesia after total knee
double-blinded comparison of epidural fentanyl infusion versus arthroplasty. Br J Anaesth 2004;93:670–677.
patient-controlled analgesia with morphine for postthoracotomy pain. 24. Bernard J-M, Kick O, Bonnet F. Comparison of intravenous and
Anesth Analg 1993;76(2):316–322. epidural clonidine for postoperative patient-controlled analgesia.
9. Wu CL, Cohen SR, Richman JV, et al. Efficacy of postoperative Anesth Analg 1995;81:706–712.
patient-controlled and continuous infusion epidural analgesia versus 25. Auroy U, Benhamou D, Bargues L, et al. Major complications of
intravenous patient-controlled analgesia with opioids. Anesthesiology regional anesthesia in France. Anesthesiology 2002;97:1274–1280.
2005;103:1079–1088. 26. Wedel DJ, Horlocker TT. Regional anesthesia in the febrile or infected
10. Gottschalk A, Cohen SP, Yang S, Ochroch A. Preventing and treating patient. Reg Anesth Pain Med 2006;31:324–333.
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11. Chaney MA. Intrathecal and epidural anesthesia and analgesia for hematoma, infection, and neurologic injury in obstetric patients with
cardiac surgery. Anesth Analg 2006;102:45–64. epidural analgesia/anesthesia. Anesthesiology 2006;105(2):394–399.
12. Correll DJ, Viscusi ER, Grunwald Z, Moore JH Jr. Epidural analgesia 28. Wang LP, Hauerberg J, Schmidt JF. Incidence of spinal epidural
compared with intravenous morphine patient-controlled analgesia: abscess after epidural analgesia: A national 1-year survey.
postoperative outcome measures after mastectomy with immediate Anesthesiology 1999;91:1928–1936.
TRAM flap breast reconstruction. Reg Anesth Pain Med 2001;26:444-449. 29. Aromaa U, Lahdensuu M, Cozanitis DA. Severe complications
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Chapter 12 infusions of local anesthetic via perineural catheters not only

capitalize on this technique but also extend the therapeutic
CONTINUOUS PERIPHERAL window for several days. Patients have better outcomes, require
less opioids, and can continue therapy at home in most situations.
In this chapter, we describe various upper and lower extremity
NERVE CATHETER TECHNIQUES blocks and the placement of catheters for continuous infusions.
Eric M. May and Martin L. DeRuyter

TECHNIQUE AND NEEDLE TYPE
Whereas, historically, various approaches have been described for
performing single-injection nerve blocks, when considering a cath-
eter placement, we believe that the most reliable technique
INTRODUCTION incorporates localization of the nerve via a nerve stimulator and
advancement of the catheter through the needle. Various products
Regional analgesia has been shown to be an effective therapy for exist; we are comfortable with the practicality, ease of use, and
postoperative analgesia in numerous clinical scenarios. Continuous success rate that obtained using the Contiplex Touhy Continuous
data for specific procedures and suggestions for a dosing scheme, 16. Niiyama Y, Kawamata T, Shimizu H, et al. The addition of epidural
highlights side effects, and reinforces the concerns of perioperative morphine to ropivacaine improves epidural analgesia after lower
anticoagulation for thromboprophlaxis in patients with indwelling abdominal surgery. Can J Anesth 2005;52:181–185.
central neuraxial catheters. 17. Guay J. The benefits of adding epidural analgesia to general
anesthesia: a meta-analysis. J Anesth 2006;20:335–340.
18. Christopherson R, Beattie C, Frank SM, et al. and the Perioperative
REFERENCES Ischemia Randomized Anesthesia Trial Study Group. Perioperative
morbidity in patients randomized to epidural or general anesthesia
1. Brill S, Gurman GM, Fisher A. A history of neuraxial administration for lower extremity vascular surgery. Anesthesiology 1993;79:422–434.
of local analgesics and opioids. Eur J Anaesthesiol 2003;20:682–689. 19. Buggy DJ, Smith G. Epidural anaesthesia and analgesia: better
2. Viscusi ER. Emerging techniques in the management of acute pain: outcome after major surgery? Growing evidence suggests so. BMJ
epidural analgesia. Anesth Analg 2005;101:S23–S29. 1999;319(7209):530–531.
3. Bernards CM. Understanding the physiology and pharmacology of 20. Fischer HBJ, Simanski CJP. A procedure-specific systematic review
epidural and intrathecal opioids. Best Pract Res Clin Anesthesiol and consensus recommendations for analgesia after total hip
2002;16(4):489–505. replacement. Anaesthesia 2005;60:1189–1202.
4. Ginosar Y, Riley ET, Angst MS. The site of action of epidural fentanyl 21. Gambling D, Hughes T, Martin G, et al. A comparison of Depodur,
in humans: the difference between infusion and bolus administration. a novel, single-dose extended-release epidural morphine, with
Anesth Analg 2003;97:1428–1438. standard epidural morphine for pain relief after lower abdominal
5. Ready LB. Acute pain: lessons learned from 25,000 patients. Reg surgery. Anesth Analg 2005;100:1065–1074.
Anesth Pain Med 1999;24:499–505. 22. Viscusi ER, Martin G, Hartrick CT, et al. and the EREM Study
6. Moraca R, Sheldon D, Thirlby R. The role of epidural anesthesia and Group. Forty-eight hours of postoperative pain relief after total hip
analgesia in surgical practice. Ann Surg 2003;238:663–673. arthroplasty with a novel, extended-release epidural morphine
7. Block BM, Liu SS, Rowlingson AJ, et al. Efficacy of postoperative formulation. Anesthesiology 2005;102:1014–1022.
epidural analgesia: a meta-analysis. JAMA 2003;290:2455–2463. 23. Förster JG, Rosenberg PH. Small dose of clonidine mixed with low-
8. Benzon HT, Wong HY, Belavic AM Jr, et al. A randomized dose ropivacaine and fentanyl for epidural analgesia after total knee
double-blinded comparison of epidural fentanyl infusion versus arthroplasty. Br J Anaesth 2004;93:670–677.
patient-controlled analgesia with morphine for postthoracotomy pain. 24. Bernard J-M, Kick O, Bonnet F. Comparison of intravenous and
Anesth Analg 1993;76(2):316–322. epidural clonidine for postoperative patient-controlled analgesia.
9. Wu CL, Cohen SR, Richman JV, et al. Efficacy of postoperative Anesth Analg 1995;81:706–712.
patient-controlled and continuous infusion epidural analgesia versus 25. Auroy U, Benhamou D, Bargues L, et al. Major complications of
intravenous patient-controlled analgesia with opioids. Anesthesiology regional anesthesia in France. Anesthesiology 2002;97:1274–1280.
2005;103:1079–1088. 26. Wedel DJ, Horlocker TT. Regional anesthesia in the febrile or infected
10. Gottschalk A, Cohen SP, Yang S, Ochroch A. Preventing and treating patient. Reg Anesth Pain Med 2006;31:324–333.
pain after thoracic surgery. Anesthesiology 2006;104:594–600. 27. Ruppen W, Derry S, McQuay H, et al. Incidence of epidural
11. Chaney MA. Intrathecal and epidural anesthesia and analgesia for hematoma, infection, and neurologic injury in obstetric patients with
cardiac surgery. Anesth Analg 2006;102:45–64. epidural analgesia/anesthesia. Anesthesiology 2006;105(2):394–399.
12. Correll DJ, Viscusi ER, Grunwald Z, Moore JH Jr. Epidural analgesia 28. Wang LP, Hauerberg J, Schmidt JF. Incidence of spinal epidural
compared with intravenous morphine patient-controlled analgesia: abscess after epidural analgesia: A national 1-year survey.
postoperative outcome measures after mastectomy with immediate Anesthesiology 1999;91:1928–1936.
TRAM flap breast reconstruction. Reg Anesth Pain Med 2001;26:444-449. 29. Aromaa U, Lahdensuu M, Cozanitis DA. Severe complications
13. Nishimori M, Ballangyne JC, Low JH. Epidural pain relief versus associated with epidural and spinal anaesthesias in Finland
systemic opioid-based pain relief for abdominal aortic surgery. 1987–1993. Acta Anaesthesiol Scand 1997;41:445–452.
Cochrane Database Syst Rev 2006;19:3CD005059. 30. Hebl JR. The importance and implications of aseptic techniques
14. Gupta A, Fant F, Axelsson K, et al. Postoperative analgesia after during regional anesthesia. Reg Anesth Pain Med 2006;31:311–323.
radical retropubic prostatectomy. Anesthesiology 2006;105:784–793. 31. Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the
15. Gottschalk A, Smith DS, Jobes DR, et al. Preemptive epidural anticoagulated patient: defining the risks (the second ASRA
analgesia and recovery from radical prostatectomy. JAMA Consensus Conference on Neuraxial Anesthesia and Anticoagulation).
Chapter 12 infusions of local anesthetic via perineural catheters not only

capitalize on this technique but also extend the therapeutic
CONTINUOUS PERIPHERAL window for several days. Patients have better outcomes, require
less opioids, and can continue therapy at home in most situations.
In this chapter, we describe various upper and lower extremity
NERVE CATHETER TECHNIQUES blocks and the placement of catheters for continuous infusions.
Eric M. May and Martin L. DeRuyter

TECHNIQUE AND NEEDLE TYPE
Whereas, historically, various approaches have been described for
performing single-injection nerve blocks, when considering a cath-
eter placement, we believe that the most reliable technique
INTRODUCTION incorporates localization of the nerve via a nerve stimulator and
advancement of the catheter through the needle. Various products
Regional analgesia has been shown to be an effective therapy for exist; we are comfortable with the practicality, ease of use, and
postoperative analgesia in numerous clinical scenarios. Continuous success rate that obtained using the Contiplex Touhy Continuous
III ACUTE PAIN 85
Nerve Block catheter products (B. Braun, Bethlehem, PA). Certain

nerve blocks are amenable to the use of ultrasound guidance to help
ensure proper needle tip location; however, this is not discussed.
STANDARD PREPARATION
After consent is obtained, patients are monitored, provided supple-
mental oxygen, and lightly sedated for the block procedure. Sedation
generally is achieved with midazolam 1 to 2 mg and fentanyl 50 to 100
mcg. The blocks are administered in a well-lighted area, and the
techniques are accomplished in a sterile fashion with the area
draped. Local anesthetic at the skin site is achieved with subdermal
1% lidocaine. A small skin nick can be used to facilitate needle inser-
tion. The stimulating needle is advanced, attempting to elicit the
desired motor response. Once achieved, the milliamperage from the
nerve stimulator is reduced to maintain a motor response at 0.5 mA.
Following a negative aspiration, the local anesthetic is delivered in
5-ml sequential aliquots with intermittent aspiration, thus establishing
an initial ‘‘block.’’ The agents commonly used are ropivacaine (0.5%)
or bupivacaine (0.5%). The 20-gauge catheter is inserted and
advanced 5 to 7 cm beyond the needle tip. The catheter is then
secured, bandaged, and labeled. We follow the American Society of
Regional Anesthesia and Pain Medicine (ASRA) consensus recom-
mendations for catheter placement and removal in patients taking
anticoagulant medications. These can be found with other ASRA
Consensus Statements at http://www.asra.com/consensus-statements.
POSTOPERATIVE CONTINUOUS
INFUSION SETUPS AND ALGORITHM
Continuous analgesia is obtained by a continuous infusion of local
anesthetic in addition to a multimodal analgesic regimen. The
desired effect is achieved by administering a long-acting local anes-
thetic such as ropivacaine (0.2%), bupivacaine (0.1%), or levobu-
pivacaine (0.1%). Compared with bupivacaine, ropivacaine has
been shown to produce less motor block, which may be a desirable
feature in ambulatory patients.
Generally, upper extremity infusions may start at 5 to 8 ml/hr
and lower extremity infusions at 8 to 10 ml/hr. A patient-controlled
analgesia (PCA) supplemental function of 4 ml every 30 minutes is
included in the continuous infusion therapy, along with opioid
supplementation if needed. Figure 12^1. Postoperative analgesia algorithm in patients with
A multimodal approach to postoperative analgesia emphasizes the peripheral perineural continuous infusion. IR, immediate release;
role of continuous peripheral nerve blocks with local anesthetic IV PCA, intravenous patient-controlled opioid analgesia; PCA,
infusions. The protocol we follow is outlined in Figure 12–1. This patient-controlled supplemental analgesia; SR, sustained release; VAS,
consists of acetaminophen and a daily oral nonsteroidal anti-inflam- visual analog score. (Copyright Eric L. May and Martin DeRuyter.)
matory drug such as the cyclooxygenase-2 (COX-2) inhibitor Celebrex.
Further pain-control modalities include adjustment of local anesthetic
infusion rates, addition of both immediate-release and sustained-
Indications
release oral narcotics, and addition of an intravenous (IV) PCA.
Open shoulder surgery, rotator cuff repair, acromioplasty, shoulder
arthroplasty, and proximal upper limb surgery.1,2
UPPER EXTREMITY TECHNIQUES
Technique
Blockade of the upper extremity is achieved by blocking the brachial
plexus. Blocks can be performed at numerous locations along Landmarks and patient positioning for continuous interscalene bra-
the brachial plexus; some sites are more amenable than others to chial plexus block are the same as those of the single-shot technique
continuous catheter placement. In addition, each site possesses (discussed earlier). The anesthesiologist should stand at the head of
certain advantages, and disadvantages to continuous infusions, the patient, facing caudad. This positioning facilitates stabilization
which are described for each procedure. of the needle and advancement of the catheter in a caudal direction.
A 3- to 5-cm stimulating needle is inserted at a slightly caudad angle
Interscalene Approach and advanced until a brachial plexus twitch is elicited (Fig. 12–2).
After the needle is stabilized, 20 to 40 ml of local anesthetic is
Blocks delivered and the catheter is inserted.
The interscalene site is shallow and catheters not uncommonly
Brachial plexus (C5–T1). leak and may easily become dislodged. In effort to minimize
It also can provide sympathetic (and motor) block in patients suffering

with vascular insufficiency or sympathetically mediated pain.2
Technique
e
ag
rtil Landmarks are the same as for the single-shot technique (described
ca
oid earlier), including the medial clavicular head, coracoid process, and
Cric midpoint of the clavicle. The coracoid process can be located by
SC elevating and raising the arm while palpating just medial to the
M
anterior shoulder. Two common approaches have been described
IS gr that facilitate catheter placement: the classic approach described by
oove
Raj and the vertical coracoid approach described by Wilson.
For the Raj approach, the patient lies supine with her or his head
slightly turned away from the side of the procedure. The anesthe-
siologist can stand either at the head on the side of the block or
on the opposite side of the block. Correct positioning by the anes-
thesiologist and convenient placement of equipment make catheter
advancement proceed smoothly. The operative limb is abducted to
908 at the shoulder and flexed at the elbow. The axillary pulse is
Figure 12^2. Interscalene block. (Copyright Eric L. May and identified. If this is not possible, the arm can remain neutral at
Martin DeRuyter.) the shoulder; in which case, the groove between the deltoid and
the pectoralis muscle is used as a landmark.
The midpoint of a line connecting the medial clavicular head
this complication, some providers prefer to ‘‘tunnel’’ the catheter. and the coracoid process is identified. The axillary artery can be
Utilizing a 3.5-inch Touhy needle, the catheter can be tracked sub- marked on the skin. A 4-inch nerve-stimulator needle is inserted
dermally to a distant exit site. 2 to 3 cm caudal to the midclavicular point at a 458 angle to the
Postoperatively, a continuous infusion of local anesthetic is horizontal plane. The needle is advanced parallel to the medial
started in the recovery room and maintained on the hospital ward. clavicular head–coracoid process line toward the axillary artery
pulse. Stimulation of the brachial plexus occurs soon after the
pectoralis muscle twitches cease.5 Motor activity in the hand is
Evidence for Continuous Nerve Block
identified. After reducing the stimulation to less than 0.5 mA and
Prospective, randomized, controlled trials demonstrated that con- witnessing the fade of motor activity along with a negative aspira-
tinuous interscalene analgesia reduced opioid requirements when tion of blood, between 30 and 40 ml of local anesthetic is delivered
compared with placebo.1 For open shoulder surgery, prospective, and the catheter is inserted toward the apex of the axilla.
randomized, controlled trials showed that continuous interscalene For the coracoid approach, the patient’s arm may remain
analgesia reduced the requirement for postoperative opioids over adducted. The coracoid process is identified and marked. The sti-
that of IV PCA. Continuous analgesia also provided better patient mulating needle is inserted perpendicular to the floor at a point
satisfaction and reduced opioid-related side effects.1 A retrospec- 2 cm caudal and 2 cm medial from the coracoid process. The bevel
tive, case-controlled study demonstrated increased shoulder range is directed toward the apex of the axilla (Fig. 12–3). Again, the
of motion the day after total shoulder arthroplasty in patients with end-point is to achieve satisfactory motor response with a 4-inch
continuous interscalene nerve block when compared with patients nerve-stimulating needle. Once identified, and after reducing the
treated with IV opioids.3,4 stimulation to less than 0.5 mA and witnessing the fade of motor
activity along with a negative aspiration of blood, between 30 and
40 ml of local anesthetic is delivered.
Caveats
It should be noted that accepting activity of the musculocuta-
The interscalene block is unreliable in providing satisfactory neous nerve (i.e., biceps or brachialis twitch) may result in
anesthetic blockade to the inferior trunk of the brachial plexus.
As a result, analgesia of the ulnar nerve is unreliable. In practice,
a continuous catheter is not placed in this location for postoperative
analgesia associated with hand surgery.2,5 In addition, the initial
loading bolus will often produce phrenic nerve blockade (85%–
100%); therefore, proper patient selection must be considered.
Less frequent and less troublesome are the associated hoarseness
secondary to blockade of the recurrent laryngeal nerve and
Horner’s syndrome secondary to sympathetic blockade.1
Infraclavicular Block
Blocks
Brachial plexus (C5–T1). Coracoid Process
Indications
The infraclavicular approach to brachial plexus block easily
facilitates catheter placement for continuous postoperative analgesia Figure 12^3. Infraclavicular block. (Copyright Eric L. May and
after surgery involving the humerus, elbow, forearm, wrist, and hand. Martin DeRuyter.)
III ACUTE PAIN 87
unsatisfactory blocks. In a significant percentage of patients, the is to be blocked. It is important to firmly fix the axillary artery with
musculocutaneous nerve splits early from the brachial plexus, and the palpating hand to facilitate accurate location of the catheter
delivery of the local anesthetic at that site will fail to adequately during placement. A 2-inch nerve-stimulator needle is inserted at
block the plexus. This approach avoids phrenic nerve blockade; a 458 angle to the skin and directed proximally (Fig. 12–4).
thus, it can be used in patients with lung disease.2 The needle is carefully advanced toward the axillary artery pulse
until the required motor response is elicited at the wrist or fingers.
To achieve the highest level of success, a motor response should be
Evidence
elicited from the nerve most involved by the surgery. After reducing
A prospective, randomized, double-blinded, controlled trial showed the stimulation to less than 0.5 mA and witnessing the fade
that infraclavicular brachial plexus block decreased pain, opioid use, of motor activity along with a negative aspiration of blood, between
sleep disturbances, and opioid-related side effects after orthopedic 30 and 40 ml of local anesthetic is delivered. A catheter is advanced
procedures of the forearm and hand.4 toward the apex of the axilla.
A randomized, double-blinded, prospective study compared the Because the brachial plexus can be superficial at the level of the
following regimens for continuous catheters placed for orthopedic axilla, the catheter is sometimes tunneled for 2 to 3 cm using an
surgery at or distal to the elbow: basal rate versus basal with bolus 18-gauge angiocatheter. As with a single-shot axillary nerve block,
versus bolus only. Patients in the continuous infusion with patient- the musculocutaneous nerve may need to be blocked with 5 ml of
controlled bolus had a lower level of oral analgesic use, longer additional local anesthetic deposited in the coracobrachial muscle.2
duration of infusion (for the same volume of anesthetic), and
a higher satisfaction rating than those patients with a basal infusion
Evidence
alone. These patients also had more potent analgesia, less sleep
disturbance, and higher satisfaction than the bolus group.6 Case series show satisfactory analgesia after hand and forearm proce-
dures with continuous infusions but have not compared these with IV
PCA or other modalities. A study by Salonen and coworkers7 did not
Axillary Brachial Plexus Block show a statistical difference in analgesia or need for supplemental
analgesics between patients receiving ropivacaine or saline.1 More
Blocks clinical trials are needed to investigate the efficacy of this approach.
Brachial plexus (C5–T1).

LOWER EXTREMITY TECHNIQUES
Indications
The axillary brachial plexus block is the most commonly used Lumbar Plexus BlockçPsoas Approach
brachial plexus block for procedures on the forearm, wrist, and
hand, as well as for chronic pain syndromes and vascular diseases.2 Blocks
Lumbar plexus.
Technique
Indications
Landmarks in the axilla are the same as those for the single-shot
technique (discussed earlier) and include the axillary artery, the Continuous lumbar plexus blocks are indicated for postoperative
inferior border of the pectoralis muscle medially, and the long pain management in patients undergoing hip, femur, or knee pro-
head of the biceps muscle laterally. Median, ulnar, and radial cedures. These blocks can be combined with general anesthesia for
nerves are most compactly arranged at the proximal aspect of the surgery on the knee, thigh, or hip or combined with a sciatic block
axilla (lateral edge of the pectoralis minor) and diverge as they for most surgeries on the lower extremity.2,8 They are also an effec-
travel distally.1 The patient is positioned supine, with the arm to tive alternative to neuraxial techniques in patients in whom an
be blocked abducted at 908 and the forearm flexed on the arm at epidural or a spinal block is contraindicated or technically difficult.
908. The anesthesiologist is positioned on the side of the patient that
Technique
Blockade of the lumbar plexus has been described as an anterior
‘‘3-in-1’’ technique or a posterior psoas compartment technique.
Our preference is to use the posterior psoas compartment approach
because it has been shown to provide more reliable anesthesia of the
obturator and lateral femoral cutaneous nerves.9,10 Another benefit
ery of the posterior approach is that the catheter is located farther from
y art the surgical site.
il lar
Ax The patient is placed in the lateral decubitus position with the
side to be blocked up and the hips and knees slightly flexed.
Landmarks are the same as for the single-shot technique (discussed
earlier) and include the iliac crest, the spinous processes, and the
posterior superior iliac spine (PSIS). Slight variations in needle
positioning are described in the literature. Some sources advocate
needle insertion 4 or 5 cm lateral to the interspinous line at the level
of a line drawn at the posterior iliac crests.2,5 Winnie initially sug-
gested insertion at the intersection of a line parallel to the spine
passing through the PSIS and a line joining the iliac crests. Multiple
studies showed this point to be too lateral.11–15 As a result, Winnie
recommended a slightly medial direction to the needle after
Figure 12^4. Axillary block. (Copyright Eric L. Mayand Martin
insertion. Our preference is to use the insertion point based on
DeRuyter.)
effective alternative to general anesthesia and that it provided

analgesia, adequate muscle relaxation, and postoperative pain
control.8 Decreased operative blood loss was also noted.9
A prospective, randomized study compared postoperative anal-
gesia and recovery after total knee replacement with a continu-
ous lumbar plexus block via the psoas compartment with a
continuous femoral nerve block and with the combination of con-
tinuous femoral and sciatic nerve catheters. The psoas block
patients required less supplementary analgesia in the first 48
hours than did the femoral block patients. However, continuous
femoral/sciatic patients required the least supplemental analgesia.
Postoperative functional outcomes at 7 days and 9 to 12 months did
not differ among groups.15
A prospective, randomized trial comparing continuous psoas
compartment lumbar plexus block to IV PCA reported better
analgesia and higher patient satisfaction with a psoas compartment
block.1,16 Another prospective multicenter trial reported 94% of
patients with excellent postoperative analgesia without additional
systemic opioids.11
Figure 12^5. Lumbar plexus block, psoas landmarks. (Copyright
Eric L. May and Martin DeRuyter.) Caveats
Differences of opinion exist on the optimal nerve-stimulator
research by Capdevila and associates.10 This point is at the junction current used to elicit a motor response. One source advocates not
of the lateral one third and the medial two thirds of a line between going lower than 0.5 to 1.0 mA because the needle may be in the
the spinous process of L4 and a line parallel to the spinal column dural sleeve if a twitch is elicited below this level.5
passing through the PSIS. L4 is estimated to be 1 cm cephalad to the The distance from the transverse process to the lumbar plexus
upper edge of the iliac crests (Fig. 12–5). has been extensively studied. Capdevila and associates10 found this
A 4-inch nerve-stimulator needle is inserted perpendicular to the distance to be 18 mm regardless of patient gender or body mass
skin while the palpating hand anchors the skin and paraspinous index.11 At the L4 level, motor response is usually elicited at a depth
muscles (Fig. 12–6). The needle tip orientation should be cephalad.5 of 6 to 8 cm, but it can be found anywhere between 5 and 10 cm.5,11
We attempt to contact the transverse process of L4, pull back Some sources recommend not going beyond a depth of 9 to 10 cm
slightly, and advance caudad to the transverse process until a quad- without redirecting the needle.2,5
riceps femoris twitch is elicited, apparent as a cephalad movement The optimal depth of catheter insertion has also been debated. We
of the patella. After this motor response is observed, the current is advocate a distance of 5 to 7 cm.11 Some sources recommend only
lowered to stimulate at less than 0.5 mA.2 Following a negative 3 to 4 cm in order to minimize the risk of kinking or displacement,
aspiration of blood, 20 to 30 ml of local anesthetic is delivered. whereas others advocate up to 8 to 10 in order to prevent catheter
For surgical anesthesia, 30 ml is usually necessary for a dense displacement because the skin in this region is very mobile.2,5
blockade of the lumbar plexus.5 If the block is used in combination
with a sciatic block, the volume may be reduced to minimize the
risk of local anesthetic overdose. Femoral Block
Evidence Blocks
A retrospective case series showed that continuous lumbar plexus Lumbar plexus (L2–L4).
block with sciatic nerve block and perioperative sedation was an
Indications
Femoral nerve block produces anesthesia of the entire anterior thigh
and most of the femur and knee joint, as well as the skin on the
medial lower leg. It can be used for postoperative analgesia after
thigh and knee surgery or combined with sedation and a sciatic
nerve block for lower extremity surgery.
Techniques
The patient is positioned supine with the leg to be blocked in a neu-
tral position. The needle insertion site is 1 cm lateral to the femoral
artery in the inguinal crease. The palpating hand is used to stabilize
the skin prior to needle insertion. A 2-inch nerve-stimulator needle
is inserted and advanced at a 458 to 608 cephalad angle until a
patellar twitch is elicited.5 After reducing the stimulation to less
than 0.5 mA and witnessing the fade of motor activity along with
a negative aspiration of blood, 20 to 30 ml of local anesthetic is
delivered. A catheter is advanced in a cephalad direction.
The fascia iliaca approach is a modification of the femoral nerve
Figure 12^6. Lumbar plexus block, psoas insertion. (Copyright block that may provide similar analgesia with slightly lower risk
Eric L. May and Martin DeRuyter.) of venopuncture. A nerve stimulator is typically not required for
III ACUTE PAIN 89
GT
tery Insertion site

ral ar In
Femo gu
in PSIS
al
lig
am
en
t
SH
Figure 12^7. Femoral block. (Copyright Eric L. May and Martin Figure 12^8. Sciatic block landmarks. (Copyright Eric L. May and
DeRuyter.) Martin DeRuyter.)
this technique. The inguinal ligament is marked from the anterior and the entire leg below the knee with the exception of the skin of the
superior iliac spine to the pubic tubercle in the supine patient. The medial lower leg. It can be used in combination with a continuous
needle insertion is 1 cm caudad to the junction of the lateral one third lumbar plexus block for hip or femur surgery or combined with a
and the medial two thirds of this line. This site is approximately 2 to 3 femoral or lumbar plexus block for procedures on the thigh and knee.
cm lateral to the femoral artery (Fig. 12–7). The needle is advanced at a It can also be used for amputation of the lower leg.5
458 to 608 cephalad angle until two pops are felt through the fascia lata
and the fascia iliaca, respectively. The angle is decreased to 308 and 20
Technique
ml of local anesthetic is injected. The catheter is advanced 15 to 20 cm
cephalad past the needle tip.1 The patient is positioned in the lateral decubitus position with the side
to be blocked up and a slightly forward pelvic tilt. The knees are slightly
bent and the foot on the upper leg is positioned over the dependent leg
Evidence
so twitches can be easily observed.5 The anatomic landmarks are the
Prospective clinical trials have showed improved analgesia and knee greater trochanter and the PSIS. These structures are marked and a line
range of motion with decreased incidence of nausea/vomiting when is drawn between them and divided in half. A perpendicular line drawn
continuous femoral nerve block was compared with IV PCA.1,17,18 through the midpoint and extending inferiorly for roughly 4 to 5 cm
Analgesia and range of motion were comparable with those of an identifies the needle insertion point (Fig. 12–8).
epidural block. Earlier mobilization was also achieved by continuous It is important to infiltrate deeper tissues with local anesthetic to
nerve block patients who underwent total knee arthroplasty.18,19 make advancement of the large, blunt-tipped needle more tolerable.
A prospective, randomized trial showed that patients with con- As with all blocks, stabilization with the palpating hand is crucial
tinuous fascia iliaca blockade required less postoperative morphine for needle manipulation and catheter advancement. A 4-inch nerve-
and had improved range of motion than those receiving placebo.20 stimulator needle is inserted perpendicular to the skin (Fig. 12–9).
A prospective, nonrandomized trial involving patients with total The bevel of the stimulating needle should be directed distally,
hip replacement found that continuous femoral block provided toward the patient’s foot, to aid catheter insertion. Initially, twitches
analgesia comparable with those of IV PCA and epidural blockade.
Continuous nerve block was associated with a lower incidence
of nausea, vomiting, pruritus, and sedation than those of IV PCA
and a lower incidence of urinary retention and hypotension than
epidural blockade.21
Caveats
Insertion of the continuous catheter 3 to 4 cm may make it more likely
to produce lateral femoral cutaneous and obturator nerve blockade.2
Sciatic Nerve BlockçPosterior Approach (Labat)
Blocks
Sacral plexus, sciatic nerve (L4–S3).
Indications
Sciatic nerve blockade produces anesthesia of the skin of the posterior Figure 12^9. Sciatic block insertion. (Copyright Eric L. May and
thigh, hamstring, and biceps muscles, part of the hip and knee joint, Martin DeRuyter.)
of the gluteus muscle are observed. As the needle is advanced

deeper, stimulation of the sciatic nerve results in twitches of the
hamstrings or foot. After reducing the stimulation to less than
0.5 mA and witnessing the fade of motor activity along with a neg-
ative aspiration of blood, 20 to 30 ml of local anesthetic is injected
and the catheter is inserted.
Evidence Vas
tus
A prospective trial demonstrated effective postoperative analgesia late
rali
in patients undergoing surgical procedures on the lower leg.22 s
Bic
eps
A prospective, randomized study compared postoperative anal- fem
gesia and recovery after total knee replacement with a continuous ori
s
lumbar plexus block via psoas compartment with a continuous
femoral nerve block and with the combination of continuous fem-
oral and sciatic nerve catheters. Continuous femoral/sciatic patients
required the least supplemental analgesia.15
Caveats Figure 12^10. Popliteal block, lateral approach. (Copyright Eric

For patients who cannot tolerate positioning for a posterior sciatic L. May and Martin DeRuyter.)
nerve block, a high lateral approach can be used.2 With the patient
supine and the leg in a neutral position, the needle insertion site
is identified 3 cm caudal to the greater trochanter and 2 cm posterior A 4-inch nerve-stimulator needle is inserted with the tip
to the femur. This site should be between the greater trochanter and oriented cephalad in a horizontal plane, perpendicular to the long
the ischial tuberosity, which can be identified by palpating the infe- axis of the leg (Fig. 12–10). Once the femur is contacted, the needle
rior aspect of the buttocks. The hamstring muscles and the sacrotu- is withdrawn and redirected 308 posteriorly. The needle is again
berous ligaments attach to the ischial tuberosity; occasionally, the advanced while watching for dorsiflexion or plantarflexion of the
hamstring muscles make it challenging to easily palpate the ischial foot or toes. After reducing the stimulation to less than 0.5 mA and
tuberosity. A 4- or 6-inch nerve-stimulator needle is inserted per- witnessing the fade of motor activity along with a negative aspira-
pendicular to the skin with the distal tip oriented cephalad. The tion of blood, 30 to 40 ml of local anesthetic is injected and the
femur is contacted; the needle is withdrawn and redirected 208 pos- catheter is inserted.
teriorly. The needle is advanced until a motor response is seen in the If this block is used in combination with a femoral nerve block,
foot, usually at a depth of 8 to 12 cm. After reducing the stimulation the bolus volume may be reduced in consideration of possible local
to less than 0.5 mA and witnessing the fade of motor activity along anesthetic toxicity.
with a negative aspiration of blood, 20 to 30 ml of local anesthetic is
injected and the catheter is inserted.
Evidence
A prospective, nonrandomized study with a retrospective control
Popliteal Nerve BlockçLateral Approach group compared continuous popliteal nerve analgesia with IV
PCA.1,24 The study showed that continuous nerve block provided
Blocks superior analgesia, lower postoperative morphine consumption, less
frequent incidence of nausea/vomiting, less urinary retention, and
Tibial and peroneal nerves. less sedation.
Two prospective randomized, controlled trials compared con-
tinuous popliteal nerve blockade with local anesthetic versus
Indications
saline.25,26 Continuous nerve block patients had lower pain
Blockade of the branches of the sciatic nerve at the popliteal scores, lower opioid requirements and less opioid-related side
fossa provides anesthesia and analgesia for surgery on the calf, effects, shorter length of hospital stay, and better sleep with fewer
ankle, Achilles tendon, and foot. It also is effective for calf tour- awakenings during the first 48 hours.26
niquet pain. A saphenous nerve block may be combined with a
popliteal nerve block to provide complete anesthesia for the
lower leg.5
THORACIC TECHNIQUES
Technique
Paravertebral Nerve Block
The sciatic nerve usually divides into the tibial and common
peroneal nerves approximately 70 mm proximal to the popliteal Blocks
fossa crease.5 The benefit of the lateral approach is that the patient Specific thoracic or lumbar dermatomes.
can remain in the supine position, rather than having to be turned
prone to perform the block via the classic posterior approach.
Indications
The lateral approach also provides a more secure placement of
the catheter away from the mobile knee joint.1,23 The knee is slightly Thoracic paravertebral block provides selective unilateral anesthe-
flexed by placing a pillow under it. The groove between the vastus sia and analgesia for breast or other chest wall surgery.27 Lumbar
lateralis anteriorly and the lateral tendon of the biceps femoris paravertebral block provides anesthesia and analgesia for inguinal
posteriorly is palpated and marked. The needle insertion site lies herniorrhaphy or analgesia after hip surgery.5 Paravertebral block
in this groove 8 cm proximal to the popliteal fossa crease or 10 cm can be utilized in patients in whom neuraxial techniques may
proximal to the superior border of the patella.2,5 be contraindicated owing to coagulopathy or intolerance of the
III ACUTE PAIN 91
hypotension that may result from significant sympathetic bolus-only dosing by allowing the patient to manually release
blockade. a clamp on the catheter. The risk of this method is that if the patient
forgets to reclamp the tubing, the entire reservoir of local anesthetic
can be delivered in less than an hour.30
Technique
Spring-powered pumps initially provide a greater than expected
The patient is positioned in the sitting or lateral decubitus position, basal rate with steady decreases to a less than expected rate by
similar to that required for neuraxial anesthesia. Surface bony land- reservoir exhaustion. It is unknown whether variability in basal
marks used to identify the correct spinal level include the spinous rate has affected outcomes. A manually delivered bolus dose can
processes, iliac crest, and the inferior tip of the scapulae, which be set with a lock-out interval. Settings are preset by the manufac-
corresponds to T7. Needle insertion should be perpendicular turer. Both spring and elastomeric pumps can be refilled.30
to the skin at a point 2.5 cm lateral to the midline. The bevel of Electronic infusion pumps provide the most accurate and consis-
a 2-inch nerve block needle is directed medially as the fingers tent basal rates over the duration of the infusion. These pumps can be
of the palpating hand fix the skin to avoid horizontal skin move- programmed by the clinician or patient (if clinicians permit) and
ment.5 The transverse process of the vertebra should be contacted allow the patient to deliver PCA boluses electronically by pressing a
and the depth noted. The needle is then withdrawn and redirected button. Electronic pumps have alarms that can both notify the patient
108 inferiorly to walk off the caudal border of the transverse process. of a malfunction and sound a false alarm. Nonelectronic pumps
Advance the needle 1 cm deeper than the transverse process and cannot alarm. Published data on pump reliability are limited.30
inject 4 to 5 ml of local anesthetic after negative aspiration of blood.
A catheter is advanced 3 cm past the needle tip.
REFERENCES
Evidence
1. Liu S, Salinas F. Continuous plexus and peripheral nerve blocks for
A prospective, randomized study on patients having breast cancer postoperative analgesia. Anesth Analg 2003;96:263–672.
surgery compared paravertebral nerve blocks with general anesthe- 2. Chelly J, Casati A, Fanelli G. Continuous Peripheral Nerve Block
sia and found that nerve block patients had lower visual analog Techniques, An Illustrated Guide. London: Mosby, 2001; pp 3–84.
3. Ilfeld BM, Wright TW, Enneking FK, Morey TE. Joint range of
pain scores at rest and with activity, reduced opioid consumption,
motion after total shoulder arthroplasty with and without
and lower incidence of postoperative nausea and vomiting a continuous interscalene nerve block: a retrospective case-controlled
(PONV).28 Other studies also demonstrated the benefits of this study. Reg Anesth Pain Med 2005;30:429–433.
technique for postoperative analgesia.29 4. Ilfeld BM, Morey TE, Wright TW, et al. Continuous interscalene
brachial plexus block for postoperative pain control at home:
a randomized, double-blinded, placebo-controlled study. Anesth
Caveats Analg 2003;96:1089–1095.
The needle should not be angled medially at insertion because of 5. Hadzic A, Vloka J. New York School of Regional Anesthesia
the risk of intraforaminal needle passage and nerve or spinal cord Peripheral Nerve Blocks, Principles and Practice. New York,
McGraw-Hill, 2004; pp 79–315.
injury.5 The depth of the transverse processes varies with patient
6. Ilfeld BM, Morey TE, Enneking FK. Infraclavicular perineural local
body habitus and the level at which the block is performed. The anesthetic infusion: a comparison of three dosing regimens for
deepest levels are at the high thoracic (T1–2) and low lumbar levels postoperative analgesia. Anesthesiology 2004;100:395–402.
where contact occurs at a depth of 6 to 8 cm. The shallowest depth of 7. Salonen M, Haasio J, Bachman M, et al. Evaluation of efficacy and
contact occurs at 2 to 4 cm for the midthoracic levels (T5–10).5 plasma concentrations of ropivacaine in continuous axillary brachial
plexus block: high dose for surgical anesthesia and low dose for
postoperative analgesia. Reg Anesth Pain Med 2000;25:47–51.
8. Stevens RD, Van Gessel E, Flory N, et al. Lumbar plexus block
EQUIPMENT reduces pain and blood lLoss associated with total hip arthroplasty.
Anesthesiology 2000;93:115–121.
9. Seeberger MD, Urwyler A. Paravascular lumbar plexus block: block
Catheters extension after femoral nerve stimulation and injection of 20 vs. 40
ml mepivacaine 10 mg/ml. Acta Anaesthesiol Scand 1995;39:769–773.
Types of catheters for continuous peripheral nerve blockade include 10. Capdevila X, Macaire P, Dadure C, et al. Continuous psoas
20-gauge multiorifice epidural catheters, 20- or 21-gauge epidural compartment block for postoperative analgesia after total hip
catheters with wire stylet, and 21-gauge stimulating catheters.2 srthroplasty: new landmarks, technical guidelines, and clinical
Inaccurate catheter placement is not uncommon. Some clinicians evaluation. Anesth Analg 2002;94:1606–1613.
first insert the catheter and then administer a bolus of local 11. Birnbaum K, Prescher A, Hessler S, Heller KD. The sensory
anesthetic via the catheter in an effort to avoid this problem. innervation of the hip joint: an anatomical study. Surg Radiol Anat
1997;19:371–375.
The stimulating catheters deliver current to the distal tip to provide
12. Farny J, Drolet P, Girard M. Anatomy of the posterior approach to
feedback on the position of the tip relative to the nerve before local anes- the lumbar plexus block. Can J Anaesthesiol 1994;41:480–485.
thetic injection. Although some evidence suggests this may improve 13. Deitemann JL, Sick H, Wolfram-Gabel R, et al. Anatomy and
accuracy of catheter placement, no investigations have yet shown computed tomography of the normal lumbosacral plexus.
definite increased accuracy of catheter placement using stimulating Neuroradiology 1987;29:58–68.
catheters over that of nonstimulating catheters.30,31 14. Morin AM, Kratz CD, Eberhart LHJ, et al. Postoperative analgesia
and functional recovery after total-knee replacement: comparison
of a continuous posterior lumbar plexus (psoas compartment) block,
a continuous femoral nerve block, and the combination of a
Infusion Devices continuous femoral and sciatic nerve block. Reg Anesth Pain Med
2005;30:434–445.
Options for infusion devices for postoperative inpatient and out- 15. Buckenmaier CC, Xenos JS, Nilsen SM. Lumbar plexus block with
patient infusions include disposable elastomeric devices, spring- perineural catheter and sciatic nerve block for total hip arthroplasty.
powered pumps, and electronic infusion pumps. Elastomeric J Arthroplasty 2002;17:499–502.
devices provide a more rapid than expected basal rate initially, 16. Chudinov A, Berkenstadt H, Salai M, et al. Continuous psoas
return to their expected rate within 2 to 12 hours, and increase to compartment block for anesthesia and perioperative analgesia in
a higher rate before reservoir exhaustion. These devices can provide patients with hip fractures. Reg Anesth Pain Med 1999;24:563–568.
92 Chapter 13 INTERPLEUR AL ANALGESIA
17. Ganapathy S, Wasserman R, Watson JT, et al. Modified continuous 24. Singelyn F, Aye F, Gouverneur JM. Continuous popliteal sciatic block:
femoral three-in-one block for postoperative pain after total knee an original technique to provide postoperative analgesia after foot
arthroplasty. Anesth Analg 1999;89:1197–1202. surgery. Anesth Analg 1997;84:383–386.
18. Capdevila X, Barthelet Y, Biboulet P, et al. Effects of perioperative 25. White PF, Issioui T, Skrivanek GD, et al. The use of a continuous
analgesic technique on the surgical outcome and duration of popliteal sciatic nerve block after surgery involving the foot and ankle:
rehabilitation after major knee surgery. Anesthesiology 1999;91:8–15. does it improve the quality of recovery? Anesth Analg 2003;
19. Singelyn F, Deyaert M, Pendeville E, et al. Effects of intravenous 97:1303-1309.
patient-controlled analgesia with morphine, continuous epidural 26. Ilfeld BM, Morey TE, Wang RD, Enneking FK. Continuous popliteal
analgesia, and continuous three-in-one block on postoperative pain sciatic nerve block for postoperative pain control at home: a
and knee rehabilitation after unilateral total knee arthroplasty. randomized, double-blinded, placebo-controlled study. Anesthesiology
Anesth Analg 1998;87:88–92. 2002;97:959–965.
20. Chelly JE, Greger J, Gebhard R, et al. Continuous femoral nerve 27. Klein SM, Evans H, Nielsen KC, et al. Peripheral nerve block
blocks improve recovery and outcome of patients undergoing total techniques for ambulatory surgery. Anesth Analg 2005;101:1663–1676.
knee arthroplasty. J Arthroplasty 2001;16:436–445. 28. Naja MZ, Ziade MF, Lonnqvist PA. Nerve-stimulator guided
21. Singelyn F, Gouverneur JM. Postoperative analgesia after total hip paravertebral blockade vs. general anaesthesia for breast surgery:
arthroplasty: IV PCA with morphine, patient-controlled epidural a prospective randomized trial. Eur J Anaesthesiol 2003;20:897–903.
analgesia, or continuous ‘‘3-in-1’’ block—a prospective evaluation by 29. Greengrass R, O’Brien F, Lyerly K, et al. Paravertebral block for breast
our acute pain service in more than 1,300 patients. J Clin Anesthesiol cancer surgery. Can J Anaesth 1996;43:858–861.
1999;11:550–554. 30. Ilfeld BM, Enneking FK. Continuous peripheral nerve blocks at home:
22. Grant SA, Nielsen KC, Greengrass RA, et al. Continuous peripheral nerve a review. Anesth Analg 2005;100:1822–1833.
block for ambulatory surgery. Reg Anesth Pain Med 2001;26:209–214. 31. Salinas FV, Neal JM, Sueda LA, et al. Prospective comparison of
23. Hadzic A, Vloka JD. A comparison of the posterior versus lateral continuous femoral nerve block with nonstimulating catheter
approaches to the block of the sciatic nerve in the popliteal fossa. placement versus stimulating catheter-guided perineural placement in
Anesthesiology 1998;88:1480–1486. volunteers. Reg Anesth Pain Med 2004;29:212–220.
Chapter 13 Also, interpleural analgesia is equally, if not more, effective than

intercostal nerve block and cryoanalgesia.11,16
INTERPLEURAL ANALGESIA
Jianguo Cheng and Juan Cata ANATOMIC BASIS OF INTERPLEURAL
ANALGESIA
The intercostal space of the posterior chest wall has three layers:
the external intercostal muscle; the posterior intercostal membrane,
which is the aponeurosis of the internal intercostal muscle;
and the intercostalis intimus muscle, which is a continuation of
INTRODUCTION the transversus abdominis. The intercostal nerves lie in between
the posterior intercostal membrane and the intercostalis intimus.
Interpleural anesthesia provides analgesia over the chest wall and The posterior intercostal membrane forms a complete barrier
upper abdomen. It involves placement of a catheter into the tissue beneath the external intercostal muscle, whereas the intercostal inti-
plane within the chest wall such that a single injection or continuous mus is incomplete and allows fluid to pass freely into the subpleural
infusion of local anesthetics spreads to several intercostal and paraver- space.35
tebral nerves. The terms intrapleural and interpleural have been used Interpleural analgesia can thus be accomplished by placing
interchangeably, but the latter is preferred. It was first described in a catheter either deep into the internal intercostal muscle but super-
1986 by Reiestad and Stromskag1 and has been used for management ficial to the parietal pleura or between the parietal and the visceral
of acute pain associated with multiple rib fractures,2 upper abdomi- layers of the pleura. The local anesthetic can diffuse to adjacent
nal surgeries,3–8 mastectomy,9 thoracotomy,10–17 nephrostomy and intercostal nerves and paravertebral nerves in either case, but central
nephrolithotomy,18,19 extracorporeal shock wave lighotripsy,20 esopha- spreading of anesthetics to the epidural or subarachnoid space does
gectomy,21 thoracoscopic sympathectomy,22 chemical pleurodesis,23 not usually occur. The mechanism of action for interpleural
and acute herpes zoster.24,25 It has also been utilized in patients with analgesia is, therefore, dependent on diffusion of the local anesthetic
pain associated with many other conditions,26–33 such as malignancy, to the intercostal and paravertebral nerves. The number of inter-
chronic pancreatitis, nephrolithotomy, acute herpes zoster, postherpet- costal and paravertebral nerves affected depends on the location of
ic neuralgia, and complex regional pain syndrome of the upper the catheter, the volume injected, and effects of gravity.
extremities. Whereas this technique is mostly used in adults, it can be The intercostal nerves are branches of the anterior divisions of
performed safely in the pediatric population17,33,34 (Table 13–1). the thoracic spinal nerves and innervate the thoracic and abdominal
Although thoracic epidural anesthesia may provide equally walls. Each intercostal nerve runs in a groove in the inferior aspect
effective or superior analgesia over the chest wall and upper abdomen of the rib along with the intercostal artery and vein. The interpleural
compared with interpleural anesthesia, it cannot replace the use of space is located between the parietal and the visceral pleura, which
interpleural anesthesia2,11 in many circumstances. Epidural anesthe- are delicate serous membranes that cover the surface of the lungs
sia may be impossible in many cases owing to such factors as obesity, and the inner surface of the chest wall. The space is 10 to 20 microns
scoliosis, difficult positioning, and high risk of neuroaxial coagulop- in width and has a static volume of 0.1 to 0.2 ml/kg. The microvilli-
athy. Compared with intravenous infusion of opioids, interpleural covered mesothelial surface of the parietal pleura facilitates the
anesthesia can provide better pain control and fewer side effects.11 absorption of the local anesthetic and its diffusion to the subpleural
17. Ganapathy S, Wasserman R, Watson JT, et al. Modified continuous 24. Singelyn F, Aye F, Gouverneur JM. Continuous popliteal sciatic block:
femoral three-in-one block for postoperative pain after total knee an original technique to provide postoperative analgesia after foot
arthroplasty. Anesth Analg 1999;89:1197–1202. surgery. Anesth Analg 1997;84:383–386.
18. Capdevila X, Barthelet Y, Biboulet P, et al. Effects of perioperative 25. White PF, Issioui T, Skrivanek GD, et al. The use of a continuous
analgesic technique on the surgical outcome and duration of popliteal sciatic nerve block after surgery involving the foot and ankle:
rehabilitation after major knee surgery. Anesthesiology 1999;91:8–15. does it improve the quality of recovery? Anesth Analg 2003;
19. Singelyn F, Deyaert M, Pendeville E, et al. Effects of intravenous 97:1303-1309.
patient-controlled analgesia with morphine, continuous epidural 26. Ilfeld BM, Morey TE, Wang RD, Enneking FK. Continuous popliteal
analgesia, and continuous three-in-one block on postoperative pain sciatic nerve block for postoperative pain control at home: a
and knee rehabilitation after unilateral total knee arthroplasty. randomized, double-blinded, placebo-controlled study. Anesthesiology
Anesth Analg 1998;87:88–92. 2002;97:959–965.
20. Chelly JE, Greger J, Gebhard R, et al. Continuous femoral nerve 27. Klein SM, Evans H, Nielsen KC, et al. Peripheral nerve block
blocks improve recovery and outcome of patients undergoing total techniques for ambulatory surgery. Anesth Analg 2005;101:1663–1676.
knee arthroplasty. J Arthroplasty 2001;16:436–445. 28. Naja MZ, Ziade MF, Lonnqvist PA. Nerve-stimulator guided
21. Singelyn F, Gouverneur JM. Postoperative analgesia after total hip paravertebral blockade vs. general anaesthesia for breast surgery:
arthroplasty: IV PCA with morphine, patient-controlled epidural a prospective randomized trial. Eur J Anaesthesiol 2003;20:897–903.
analgesia, or continuous ‘‘3-in-1’’ block—a prospective evaluation by 29. Greengrass R, O’Brien F, Lyerly K, et al. Paravertebral block for breast
our acute pain service in more than 1,300 patients. J Clin Anesthesiol cancer surgery. Can J Anaesth 1996;43:858–861.
1999;11:550–554. 30. Ilfeld BM, Enneking FK. Continuous peripheral nerve blocks at home:
22. Grant SA, Nielsen KC, Greengrass RA, et al. Continuous peripheral nerve a review. Anesth Analg 2005;100:1822–1833.
block for ambulatory surgery. Reg Anesth Pain Med 2001;26:209–214. 31. Salinas FV, Neal JM, Sueda LA, et al. Prospective comparison of
23. Hadzic A, Vloka JD. A comparison of the posterior versus lateral continuous femoral nerve block with nonstimulating catheter
approaches to the block of the sciatic nerve in the popliteal fossa. placement versus stimulating catheter-guided perineural placement in
Anesthesiology 1998;88:1480–1486. volunteers. Reg Anesth Pain Med 2004;29:212–220.
Chapter 13 Also, interpleural analgesia is equally, if not more, effective than

intercostal nerve block and cryoanalgesia.11,16
INTERPLEURAL ANALGESIA
Jianguo Cheng and Juan Cata ANATOMIC BASIS OF INTERPLEURAL
ANALGESIA
The intercostal space of the posterior chest wall has three layers:
the external intercostal muscle; the posterior intercostal membrane,
which is the aponeurosis of the internal intercostal muscle;
and the intercostalis intimus muscle, which is a continuation of
INTRODUCTION the transversus abdominis. The intercostal nerves lie in between
the posterior intercostal membrane and the intercostalis intimus.
Interpleural anesthesia provides analgesia over the chest wall and The posterior intercostal membrane forms a complete barrier
upper abdomen. It involves placement of a catheter into the tissue beneath the external intercostal muscle, whereas the intercostal inti-
plane within the chest wall such that a single injection or continuous mus is incomplete and allows fluid to pass freely into the subpleural
infusion of local anesthetics spreads to several intercostal and paraver- space.35
tebral nerves. The terms intrapleural and interpleural have been used Interpleural analgesia can thus be accomplished by placing
interchangeably, but the latter is preferred. It was first described in a catheter either deep into the internal intercostal muscle but super-
1986 by Reiestad and Stromskag1 and has been used for management ficial to the parietal pleura or between the parietal and the visceral
of acute pain associated with multiple rib fractures,2 upper abdomi- layers of the pleura. The local anesthetic can diffuse to adjacent
nal surgeries,3–8 mastectomy,9 thoracotomy,10–17 nephrostomy and intercostal nerves and paravertebral nerves in either case, but central
nephrolithotomy,18,19 extracorporeal shock wave lighotripsy,20 esopha- spreading of anesthetics to the epidural or subarachnoid space does
gectomy,21 thoracoscopic sympathectomy,22 chemical pleurodesis,23 not usually occur. The mechanism of action for interpleural
and acute herpes zoster.24,25 It has also been utilized in patients with analgesia is, therefore, dependent on diffusion of the local anesthetic
pain associated with many other conditions,26–33 such as malignancy, to the intercostal and paravertebral nerves. The number of inter-
chronic pancreatitis, nephrolithotomy, acute herpes zoster, postherpet- costal and paravertebral nerves affected depends on the location of
ic neuralgia, and complex regional pain syndrome of the upper the catheter, the volume injected, and effects of gravity.
extremities. Whereas this technique is mostly used in adults, it can be The intercostal nerves are branches of the anterior divisions of
performed safely in the pediatric population17,33,34 (Table 13–1). the thoracic spinal nerves and innervate the thoracic and abdominal
Although thoracic epidural anesthesia may provide equally walls. Each intercostal nerve runs in a groove in the inferior aspect
effective or superior analgesia over the chest wall and upper abdomen of the rib along with the intercostal artery and vein. The interpleural
compared with interpleural anesthesia, it cannot replace the use of space is located between the parietal and the visceral pleura, which
interpleural anesthesia2,11 in many circumstances. Epidural anesthe- are delicate serous membranes that cover the surface of the lungs
sia may be impossible in many cases owing to such factors as obesity, and the inner surface of the chest wall. The space is 10 to 20 microns
scoliosis, difficult positioning, and high risk of neuroaxial coagulop- in width and has a static volume of 0.1 to 0.2 ml/kg. The microvilli-
athy. Compared with intravenous infusion of opioids, interpleural covered mesothelial surface of the parietal pleura facilitates the
anesthesia can provide better pain control and fewer side effects.11 absorption of the local anesthetic and its diffusion to the subpleural
III ACUTE PAIN 93
Table 13^1. Applications of Interpleural Anesthesia needle is withdrawn. For single injection, 20 to 25 ml of 0.25%
bupivacaine can achieve a mean duration of analgesia of 7 hours
Pain States Reference (range 2–18 hr).1,4 Plasma concentration of the local anesthetic
peaks at 15 to 20 minutes after injection. Adding epinephrine to
Acute Pain the solution slightly delays and reduces the peak plasma concentra-
Multiple rib fractures Luchette et al, 1994 tion. For continuous infusion, a rate of 0.125 ml/kg/hr is usually
Cholecystectomy Stromskag et al, 1988 employed. A subcutaneous tunneled interpleural catheter can be
Mastectomy Higgins et al, 2005 placed in patients when a long-term infusion of analgesic is desired.
Thoracotomy Inderbitzi et al, 1992
Thoracoscopic sympathectomy Assalia et al, 2003
Transhepatic biliary procedures Razzaq et al, 2000 AGENTS USED FOR INTERPLEURAL
Percutaneous nephrostomy Trivedi et al, 1990 ANESTHESIA
Nephrolithotomy Saied et al, 1991 Bupivacaine is the most commonly used agent, and lidocaine is an
Extracorporeal shock wave lithotripsy Reiestad et al, 1989 alternative. Single or repeated injections of 0.25% to 0.5% in volumes
Acute herpes zoster Thwaites et al, 1995 of 10 to 40 ml are usually performed. A single injection of 20 ml of
Chemical pleurodesis Sherman et al, 1988 0.5% of bupivacaine with 5 mcg/ml of epinephrine produces a cuta-
Chronic Pain neous sensory block that extends from dermatome T4 to T10 or even
a more extensive block from dermatome T1 to T12.37 The onset of
Hepatic metastatic disease Waldman et al, 1989 analgesia after a single injection of 20 ml of 0.5% bupivacaine with
Chronic pancreatitis Vercauteren et al, 1994 epinephrine (1:200,000) is within 1 to 3 minutes. Complete pain
Postherpetic neuralgia Dionne et al, 1992 relief is achieved within 30 minutes, and the mean duration of the
Sihota et al, 1988 analgesic block is 7 hours. Quicker onset of interpleural blockade
Complex regional pain syndrome Shantha, 1991 is achieved with more concentrated solutions of bupivacaine, more
Tumor invasion brachial plexus Dionne et al, 1992 alkaline pH, and a mixture of lidocaine and bupivacaine.38 Repeated
Upper limb ischaemia Perkins, 1991 intrapleural bupivacaine administration may be used without signs of
toxicity and accumulation. Continuous infusion of bupivacaine and
Pediatric Pain
lidocaine can be used up to 72 hours for postoperative pain. Lower
Thoracotomy Weston et al, 1995 concentrations from 0.125% to 0.375% of bupivacaine are adminis-
Insertion peritoneal dialysis catheter Swinhoe et al, 1994 tered and usually preceded by an initial bolus of 20 ml of 0.5%. There
is no clinical evidence of toxicity at a mean steady-state plasma con-
centration of 2 mg/L bupivacaine.
space. The pleura receive nerve innervation from the phrenic There is no consistent level of dermatomal analgesia when 2%
and sympathetic nerves. Interpleural administration of anesthetics lidocaine with 1:200,000 epinephrine is injected intrapleurally. After
may, therefore, affect neural conduction of both nerve types. a single injection of lidocaine, the systemic absorption is rapid and
is not affected by the coadministration of epinephrine. Lidocaine is
also found in cerebral spinal fluid, most likely secondary to diffu-
TECHNIQUES OF INTERPLEURAL sion from the blood stream. A continuous infusion of 2% lidocaine
ANESTHESIA with 1:200,000 epinephrine can also be used during the first 48 to 72
hours after thoracic or upper abdominal surgery even though the
An epidural catheter is commonly inserted through a Tuohy needle effect of epinephrine on local anesthetic absorption is not clear.
at a level between T6 and T8. The entry point is anywhere between The addition of opioids such as fentanyl 2 mcg/ml to local anes-
8 cm lateral to the posterior midline and the posterior axillary line. thetic solution for interpleural anesthesia improves pain control after
A lateral decubitus position is often taken with the affected side up. thoracotomy and decreases the consumption of intravenous narco-
The level of each rib is palpated and marked and the entry point tics. Also, the administration of opioids alone may be more effective
determined. In contrast to the entry point at the inferior border of than systemic opioids. However, intrapleural opioid analgesia is no
the rib for individual intercostal nerve block, the entry point for more effective than the analgesia provided by local anesthetics.
interpleural anesthesia can be at the superior border of the selected Interpleural opioids may act on opioid receptors in the peripheral
rib to avoid trauma to the intercostal nerve and blood vessels by the nerves. Clonidine, a a2-adrenergic receptor agonist, has also been
large Tuohy needle used for interpleural anesthesia. used interpleurally as an adjuvant analgesic to synergistically increase
The skin is prepared with aseptic technique, and a skin wheal the efficacy of interpleural anesthesia without complications.
is raised with local anesthetic through a 22- to 25-gauge needle. Interpleural injection of bupivacaine and lidocaine does not sig-
A Tuohy needle is then introduced perpendicularly with the bevel nificantly affect heart rate, blood pressure, and cardiac output.39
facing superficially. It is ‘‘walked off ’’ the superior edge of the rib However, the coadministration of 20 ml of 0.5% of bupivacaine
and advanced to a position either just past the posterior intercostal with 5 mcg/ml of epinephrine can increase the cardiac output by
membrane or between the parietal and the visceral pleural space. 15% within 15 to 20 minutes after the injection.37 Compared with
The first position is often signified by a ‘‘pop’’ when the needle epidural analgesia, interpleural block produces a lower incidence of
pierces through the posterior intercostal membrane, whereas the hypotension and tachycardia.2,40 Unilateral interpleural analgesia
pleural space can be identified with a loss of resistance technique improves the forced vital capacity (FVC) and forced expiratory
that is similar to that of epidural anesthesia.36 The pleural pressure volume in 1 second (FEV1) after cholecystectomy or pneumonecto-
remains negative throughout the respiratory cycle, whereas the my.5 This is not seen, however, in patients with chronic pain.
pressure in the intercostal space oscillates from negative to positive The presence of large amounts of intrapleural fluids such as
at the end of inspiration and expiration, respectively. Spontaneous blood or empyema may decrease the efficacy of the block. The
ventilation should be maintained during the procedure. Controlled interpleural anesthetic may be diluted or trapped in the presence
ventilation increases the risk of tension pneumothorax during of binding proteins in such fluids. A significant amount of the
positive-pressure ventilation. local anesthetic may be lost in the presence of multiple chest
Once the pleural space is found, an epidural catheter is advanced tubes. The use of two interpleural catheters (one superior
4 to 6 cm past the tip of the needle and fixed in position as the and one inferior) may help to improve analgesia in certain
5. Scott NB, Mogensen T, Bigler D, Kehlet H. Comparison of the effects

Box 13^1 COMPLICATIONS OF INTERPLEURAL ANESTHESIA of continuous intrapleural vs epidural administration of 0.5%
bupivacaine on pain, metabolic response and pulmonary function
Tension pneumothorax following cholecystectomy. Acta Anaesthesiol Scand 1989;33:535–539.
Hemothorax 6. Stromskag KE, Reiestad F, Holmqvist EL, Ogenstad S. Intrapleural
Chest wall hematoma administration of 0.25%, 0.375%, and 0.5% bupivacaine with
Intrabronchial injection epinephrine after cholecystectomy. Anesth Analg 1988;67:430–434.
Horner’s syndrome 7. Rademaker BM, Sih IL, Kalkman CJ, et al. Effects of interpleurally
Systemic toxicity (seizures) administered bupivacaine 0.5% on opioid analgesic requirements and
Catheter migration endocrine response during and after cholecystectomy: a randomized
Infections double-blind controlled study. Acta Anaesthesiol Scand 1991;
35:108-112.
8. Demian AD, Wahba AM, Atia EM, Hussein SH. Bilateral interpleural
circumstances. Interpleural anesthesia (in efforts to achieve signif- versus lumbar epidural bupivacaine-morphine analgesia for upper
icant sensory blockade) is not recommended for patients who abdominal surgery. Middle East J Anesthesiol 2003;17:347–358.
9. Higgins PC, Ravalia A. Interpleural anaesthesia for mastectomy.
undergo pneumonectomy because high plasma concentrations of Anaesthesia 2005;60:1150–1151.
local anesthetics may be expected in such patients. 10. Inderbitzi R, Flueckiger K, Ris HB. Pain relief and respiratory
mechanics during continuous intrapleural bupivacaine administration
after thoracotomy. Thorac Cardiovasc Surg 1992;40:87–89.
COMPLICATIONS 11. Bachmann-Mennenga B, Biscoping J, Kuhn DF, et al. Intercostal
nerve block, interpleural analgesia, thoracic epidural block or systemic
Patients need to be monitored closely for potential complications opioid application for pain relief after thoracotomy? Eur J
(Box 13–1). Pneumothorax is a significant risk of interpleural Cardiothorac Surg 1993;7:12–18.
12. D’Andrilli A, Ibrahim M, Ciccone AM, et al. Intrapleural intercostal
anesthesia if a chest tube is not already in place. Hemothorax
nerve block associated with mini-thoracotomy improves pain control
and chest wall hematoma can result from incidental damage after major lung resection. Eur J Cardiothorac Surg 2006;29:790–794.
to the intercostal vasculature. Intrabronchial injection has been 13. Detterbeck FC. Efficacy of methods of intercostal nerve blockade for
reported after interpleural blockade. Horner’s syndrome can pain relief after thoracotomy. Ann Thorac Surg 2005;80:1550–1559.
result from unilateral sympathetic blockage, particularly after injec- 14. Karakaya D, Baris S, Ozkan F, et al. Analgesic effects of interpleural
tion of a relatively large volume of local anesthetic. Systemic bupivacaine with fentanyl for post-thoracotomy pain. J Cardiothorac
absorption is significant with continuous infusion for more than Vasc Anesth 2004;18:461–465.
2 days. Fortunately, clinical reports of systemic toxicity, which may 15. Rosenberg PH, Scheinin BM, Lepantalo MJ, Lindfors O. Continuous
lead to seizures, are rare. Spread of local anesthetic to epidural space intrapleural infusion of bupivacaine for analgesia after thoracotomy.
is rare and usually insignificant. Catheter displacement can occur Anesthesiology 1987;67:811–813.
16. Shafei H, Chamberlain M, Natrajan KN, et al. Intrapleural
and may be prevented by the use of a suture to anchor the catheter bupivacaine for early post-thoracotomy analgesia—comparison with
to the chest wall. Infection is a risk when the catheter is indwelling. bupivacaine intercostal block and cryofreezing. Thorac Cardiovasc
Although this technique has been performed in patients with Surg 1990;38:38–41.
a large variety of pulmonary conditions, it is not recommended 17. McIlvaine WB, Knox RF, Fennessey PV, Goldstein M. Continuous
for those with pleural adhesions, empyema, large pulmonary infusion of bupivacaine via intrapleural catheter for analgesia after
bullae, or bronchopleural fistulas. thoracotomy in children. Anesthesiology 1988;69:261–264.
18. Trivedi NS, Robalino J, Shevde K. Interpleural block: a new technique
for regional anaesthesia during percutaneous nephrostomy and
nephrolithotomy. Can J Anaesth 1990;37:479–481.
CONCLUSION 19. Saied MM, Sonbul ZM, el-Kenawy M, Atallah MM. Spinal and
interpleural bupivacaine for percutaneous nephrolithotomy. Middle
In summary, interpleural analgesia provides excellent analgesia over East J Anesth 1991;11:259–264.
the chest wall and upper abdomen and is applicable to a large vari- 20. Reiestad F, McIlvaine WB. Interpleural anesthesia for extracorporeal
ety of acute and chronic pain conditions. It is relatively safe and shock wave lithotripsy. Anesth Analg 1989;69:551–552.
convenient to use in many cases when epidural anesthesia is not 21. Tartiere J, Samba D, Lefrancois C, et al. Intrapleural bupivacaine
feasible or appropriate. The anatomic feature of the posterior chest analgesia after thoraco-abdominal incision for esophagectomy.
wall allows interpleurally administered local anesthetics to reach Eur J Anaesthesiol 1991;8:145–149.
many levels of the intercostal and paravertebral nerves. Injection 22. Assalia A, Kopelman D, Markovits R, Hashmonai M. Intrapleural
or continuous infusion of a local anesthetic can be supplemented analgesia following thoracoscopic sympathectomy for palmar
hyperhidrosis: a prospective, randomized trial. Surg Endosc
with epinephrine, opioids, or clonidine. The use of interpleural anes- 2003;17:921–922.
thesia may also significantly improve respiratory function. It has 23. Sherman S, Ravikrishnan KP, Patel AS, Seidman JC. Optimum
minimal effects on hemodynamic stability and rarely leads to anesthesia with intrapleural lidocaine during chemical pleurodesis
systemic toxicity. Nevertheless, patients should be closely monitored with tetracycline. Chest 1988;93:533–536.
for potential complications such as pneumothorax. 24. Thwaites BK, Powell DR. Interpleural block for acute combined
cervical and thoracic herpes zoster. Reg Anesth 1995;20:255–256.
25. Reiestad F, Kvalheim L, McIlvaine WB. Pleural analgesia for the
REFERENCES treatment of acute severe thoracic herpes. Reg Anesth 1989;14:244–246.
26. Waldman SD, Allen ML, Cronen MC. Subcutaneous tunneled
1. Reiestad R, Stromskag KE. Intrapleural catheter in the management intrapleural catheters in the long-term relief of right upper
of postoperative pain. Reg Anesth 1986;11:89–91. quadrant pain of malignant origin. J Pain Symptom Manage
2. Luchette FA, Radafshar SM, Kaiser R, et al. Prospective evaluation of 1989;4:86–89.
epidural versus intrapleural catheters for analgesia in chest wall trauma. 27. Dionne C. Tumour invasion of the brachial plexus: management of
J Trauma 1994;36:865–869. pain with intrapleural analgesia. Can J Anaesth 1992;39:520–521.
3. Bruce DL, Gerken MV, Lyon GD. Postcholecystectomy pain relief by 28. Vercauteren MP, Coppejans H, Adriaensen HA. Pancreatitis pain
intrapleural bupivacaine in patients with cystic fibrosis. Anesth Analg treatment: an overview. Acta Anaesth Belg 1994;45:99–105.
1987;66:1187–1189. 29. Sihota MK, Holmblad BR. Horner’s syndrome after intrapleural
4. Lee TL, Boey WK, Tan WC. Analgesia and respiratory function following anesthesia with bupivacaine for post-herpetic neuralgia. Acta
intrapleural bupivacaine after cholecystectomy. J Anesth 1990;4:20–28. Anaesthesiol Scand 1988;32:593–594.
III ACUTE PAIN 95
30. Shantha TR. Causalgia induced by telephone-mediated lightning 36. Kawamata M, Omote K, Namiki A, Miyabe M. Measurement of
electrical injury and treated by interpleural block. Anesth Analg intercostal and pleural pressures by epidural catheter. Anaesthesia
1991;73:507–508. 1994;49:208–210.
31. Perkins G. Interpleural anaesthesia in the management of upper limb 37. Ahlburg P, Molgaard J, Rasmussen BS, Noreng MF. Intrapleural
ischaemia. A report of three cases. Anaesth Intensive Care administration of 0.5% plain bupivacaine compared to 0.5%
1991;19:575–578. epinephrine: A hemodynamic and ventilatory study. Reg Anesth
32. Swinhoe CF, Pereira NH. Intrapleural analgesia in a child with a 1991;16:257–261.
mediastinal tumour. Can J Anaesth 1994;41:427–430. 38. Turner D, Williams S, Heavner J. Pleural permeability to local
33. Giaufre E, Bruguerolle B, Rastello C, et al. New regimen for anesthetics - the influence of concentration, pH, and local anesthetic
interpleural block in children. Paediatr Anaesth 1995;5:125–128. combinations. Reg Anesth 1989;14:128–132.
34. Weston PJ, Bourchier D. The pharmacokinetics of bupivacaine 39. Raffin L, Fletcher D, Sperandio M, et al. Interpleural infusion of 2%
following interpleural nerve block in infants of very low birthweight. lidocaine with 1:200,000 epinephrine for postthoracotomy analgesia.
Paediatr Anaesth 1995;5:219–222. Anesth Analg 1994;79:328–334.
35. McKenzie AG, Mathe S. Interpleural local anaesthesia: 40. Ramajoli F, De Amici D. Is there a bilateral block of the thoracic
anatomical basis for mechanism of action. Br J Anaesth sympathetic chain after unilateral intrapleural analgesia? Anesth Analg
1996;76:297–299. 1998;87:360–367.
IV
CHRONIC PAIN:
CANCER PAIN
Chapter 14 management of pain is, therefore, central to the medical care that
should be provided to all cancer patients.
CANCER PAIN MANAGEMENT Sadly, a few oncologists in some well-known medical centers are
reluctant to refer cancer patients with severe pain to pain centers
or pain clinics, and occasionally, when they do, the disease has
Winston C.V. Parris and Ike Eriator progressed so far that only palliative measures or hospice interven-
tions are appropriate at that time. It is hoped that with more educa-
tion, professional dialogue, and collaborative interactions, previously
held biases, perceptions, or justifiable concerns may be addressed,
and all clinicians directly or indirectly associated with the manage-
ment of cancer pain may work together in a mature, scholarly, and
efficient manner to address the needs of the cancer pain patient.
INTRODUCTION An interdisciplinary approach involving pharmacologic treatment
options, interventional measures, physical medicine and rehabilita-
The American Cancer Society estimated that, globally, there will be tion approaches, as well as behavioral interventions will produce the
more than 12 million new cancer cases in 2007 and that about best outcomes. Other specialists including counselors, social work-
20,000 people will die from cancer every day. By 2050, there will ers, and chaplains need to be involved, as appropriate.
be 27 million new cases worldwide and 17.5 million deaths annu- One of the satisfying aspects of cancer pain management today is
ally.1 According to the National Cancer Institute Surveillance the fact that, globally, strategies are evolving that are attempting to
Epidemiology and End Result report, 1,437,180 people in the address the inadequacies of cancer pain treatment. Cancer is a
United States will be diagnosed with cancer in 2008, and 565,650 worldwide problem that appears to be underreported in countries
people will die from cancer.2 Cancer remains a major cause of death where wars, famine, high infant mortalities, malaria, human immu-
in the developed world and is rapidly achieving that status in the nodeficiency virus (HIV) and acquired immunodeficiency disease
developing world. About 1 in 10 persons dies from cancer in the rest (AIDS), malnutrition, and reduced life expectancy are high. Even in
of the world, and 1 in 4 patients die from cancer in the United these countries, cancer pain exists, but understandably, it is not a
States. Approximately 30% of patients with cancer have pain early health care priority. The World Health Organization (WHO), the
in the course of the disease, and about 75% to 90% of cancer Pan-American Health Organization (PAHO), and some agencies of
patients have pain by the time the disease has reached advanced the United Nations have attempted to address the major issues
stages.3 About 50% of all patients diagnosed with cancer will need relating to the undertreatment of cancer pain; these actions are
physician-prescribed analgesia.4 The pain associated with cancer producing some good results. A very simple but important result
may be localized, or as in the majority of cases, it occurs in multiple is the increased availability of morphine and related opioids and a
sites, or even worse, it may be disseminated. The more severe forms decrease in the bureaucracy associated with the importation of these
of cancer pain seem to occur in patients whose cancer is either drugs into a country. This action has made it possible to begin to
untreated or unresponsive to treatment. offer patients some modicum of relief from cancer pain.
Despite the increasing prevalence of cancer, improvements in Within the United States, many organizations have attempted to
the detection and treatment of most cancers have resulted in a address the undertreatment of cancer pain and have largely suc-
significant increase in survival rates.5 Estimates indicate that ceeded in making cancer pain treatment mandatory and not
about 10 million people are living with cancer at the present optional. These organizations include the American Pain Society,
time.6 Pain in cancer survivors is also becoming increasingly the American Academy of Pain Medicine, the International
significant. The prevalence of chronic pain in breast cancer survi- Association for the Study of Pain, the Ad Hoc Committee on
vors is estimated to be at least 50%. The incidence of pain after Cancer Pain of the American Society of Clinical Oncology, and
treatment for head and neck cancer may be as high as 50%, and others. Progress has been made, but much more needs to be
long-term disability in these patients has been correlated with high done. It is important to control cancer pain for many reasons,
pain scores.7 For many cancer survivors, pain is a pivotal symptom. including
It is a constant reminder of their history and the possibilities of the
future. Cancer pain negatively affects a patient’s physical activity, 1. It is the right, ethical, and humanitarian thing to do.
social interaction, will to live, and quality of life.810 The effective 2. Unrelieved cancer pain results in unnecessary suffering.
97
98 Chapter 14 CANCER PAIN MANAGEMENT
3. Continued pain results in decreased physical activity, anorexia, locations are also not uncommon). The common causes of cancer
and sleep deprivation, which collectively produce debilitation. pain include
4. Continued pain has psychological implications that may result in
1. Pain due to tumor, including progression, tumor invasion, and
hopelessness, despair, and loss of the will to live.
related pathology. Examples include the Pancoast syndrome,
5. Prolonged pain may cause cancer patients to eventually reject
bony metastasis, and cerebral metastasis. Tumors may invade
active oncologic treatment.
neural tissues and lead to various plexopathies. Tumors may
6. Chronic cancer pain diminishes participation in and enjoyment
also produce compression of structures (e.g., the intestine) or
of the activities of daily living.
structural erosions (e.g., of the skin). Whenever a cancer patient
7. Cancer pain promotes loss of control, diminishes autonomy, and
or survivor has a significant exacerbation of pain, the possibility
adversely affects quality of life.
of a recurrence must be considered.
8. Severe intractable cancer pain may produce depression and, in a
2. Pain due to diagnostic testing or treatment, including surgery,
few cases, promote suicide or consideration of suicide.
chemotherapy, or radiation therapy. Patients are known to be
afraid to complain of pain to their provider because of fear of the
tests that may be ordered. Bone marrow aspirations, spinal
puncture, and biopsies can be significant sources of pain.
IMPEDIMENTS TOADEQUATE Procedural pain is very common after surgery for tumor or
CONTROLOF CANCER PAIN tumor-related effects. Good acute pain control may reduce the
incidence of chronic pain in cancer survivors.11 Phantom pain,
There are several reasons for the untreatment of cancer pain, and
radiation-induced pain, and chemotherapy-induced polyneu-
some of these may be related to
ropathy are common after therapy. Thirty percent to 70% of
1. Health care providers. patients treated with chemotherapy will develop chemother-
2. Health care system. apy-induced peripheral neuropathy (CIPN).5 Osteonecrosis is a
3. Patients. well-known complication of steroid therapy. The weight-bearing
4. Patients’ families. joints are most commonly affected, and surgery is often required
5. A combination of some or all of these. to relieve pain and restore function. Osteonecrosis may also
follow the use of other chemotherapeutic agents and radiation.
Some of the common reasons for inadequate pain management
Late effects of radiation include neural damage and connective
from a health care provider’s perspective are
tissue fibrosis. Radiation-induced brachial plexopathy can follow
1. Deficient education and inadequate training and knowledge of treatment for breast cancer. Chronic pelvic pain may follow
pain medicine. prostate brachytherapy.12 About 20% of patients treated with
2. Misinformed concern about regulatory issues relating to con- brachytherapy complain of dysuria 1 year after therapy.
trolled substances. Radiation myelopathy may follow injury to the spinal cord
3. Inadequate or nonassessment of pain. from radiation. It may present with pain or dysesthesia at or
4. Unrealistic and overexaggerated fear of addiction. below the level of injury. Late postradiation chronic pain syn-
5. Confusion over the clinical implication of tolerance, depen- dromes have onset that is greatly delayed, often by several years,
dency, habituation, and tachyphylaxis. from the radiation.6
3. Pain due to associated infections or immune deficiency states.
The other major impediments to effective cancer pain manage-
The median age for diagnosis of cancer is about 67 years. Of all
ment arise from
cancers, 76.7% tend to occur in people who are 55 years of age or
1. Patients’ reluctance to report pain and their inhibition to take older.1 Immunomodulation due to the cancer or the therapy can
opioids or to be known to have taken opioids. increase the predisposition of this age group to painful condi-
2. Unduly restrictive laws governing the regulation of opioids and tions such as herpes zoster and postherpetic neuralgia.
related drugs. 4. Pain due to other cancer-associated symptoms such as general
3. Inappropriate reimbursement by Medicare, Medicaid, and other malaise, cachexia, nausea, constipation, weight loss, shortness of
third-party payors for services rendered for cancer pain breath, anxiety, and myofascial dystrophy. These symptoms can
management. aggravate the pain, and pain treatment may also exacerbate some
4. General underfunding, low prioritization, and underapprecia- of these symptoms. For instance, constipation and nausea may
tion of the benefits of cancer pain management. be increased by opioid therapy.
5. Pain due to preexisting or coexisting medical conditions unre-
Many of these problems may be solved with education; dissemi-
lated to the cancer (e.g., arthritis, low back pain, and migraines).
nation of relevant and current information; open, unbiased, colle-
Having cancer does not make any patient immune from such
gial interactions; and governmental goodwill and responsiveness.
coexisting or preexisting painful medical conditions.
Health care providers, especially physicians and nurses, have to
increase their knowledge base on the principles and fundamentals
of pain management in general and cancer pain management in
particular. A detailed understanding of the pharmacology of CANCER PAIN AND EARLY DETECTION
opioids, sedatives, analgesics, hypnotics, anticonvulsants, and
other drugs used in pain management is essential. Depending on Improved survival in cancer patients is mainly due to early detec-
individual specialty and on practice style, knowledge of the available tion and aggressive treatment. Widespread screening for breast,
basic and interventional pain procedures to control pain in cancer prostate, and colon carcinomas has improved early detection and
pain patients is useful not only to treat the patient but also to effective treatment. Effective early screening techniques are yet to be
implement appropriate referrals to credentialed pain clinicians. developed for some cancers including those of the lung, pancreas,
and ovaries, and these have poor long-term survival.5 In such
patients with cancer of the lung, pancreas or ovaries, pain is often
SOURCES OF CANCER PAIN the presenting symptom.
The kind of pain occurring in a particular patient depends on the
There may be many causes of cancer pain, and in some patients, cancer type and stage of disease. Patients with more advanced disease
there may be multiple causes (multiple types of pain and multiple tend to have more severe pain. Further, some cancers (e.g., pancreatic
IV CHRONIC PAIN: CANCER PAIN 99
and ovarian) tend to metastasize early and disseminate very rapidly, pain, the effects of the medication administered, and the need to
whereas others may progress more slowly. When pain occurs in add or adjust rescue medication.
patients with slow progressing cancers or in patients whose life Pain assessment should be ongoing and should be recorded after
expectancy is greater than 6 months, great opportunity exists for each therapy to assess therapeutic efficacy. It is interesting to
offering therapeutic strategies that may be effective in controlling note that the Joint Commission for Accreditation of Hospital
cancer-related pain. That is not to say that if life expectancy is short, Organization (JCAHO) has mandated that pain assessment is no
these patients are not treated. On the contrary, the impact of suc- longer optional but is mandatory. The Veterans Administration
cessful therapy is more dramatic (both to the patient and to the Hospital systems have added pain assessment as the ‘‘fifth vital
treating providers) because the relief provided to the suffering sign,’’ after pulse, respiration, blood pressure, and temperature.
patient is so important that it allows those patients and their loved In legal circles, it is reported that a few cases have been successfully
ones to meaningfully enjoy the last days and to prepare for the litigated against providers who did not assess cancer patients’
inevitable death and dying process in a dignified way. In these pain and did not treat the pain. These events may hopefully sensi-
patients, different approaches are warranted and available to effec- tize health care providers to the need to assess patients with pain
tively manage pain. The goal is to evaluate the disease and its pro- and to offer appropriate therapy or obtain help (e.g., referral/
gression, to assess pain, and to develop a therapeutic plan of pain consultation).
management applicable to and effective for the individual patient. In assessing the cancer patient, it is important to recognize that
Primary tumors can be treated by surgery or radiation, thus there are specific pain syndromes that may be associated with par-
decreasing associated pain. But metastasis to other organs, which ticular neoplasms. When these pain syndromes are recognized, effec-
facilitates tumor-induced pain, is the most difficult to treat. tive therapy may be offered early, and as a consequence, unnecessary
Metastasis to the bone is the most frequent cause of pain in pain and suffering may be prevented. Some of these syndromes may
cancer patients, usually due to direct tumor invasion13 or distant result from spinal cord compression, invasion of nerves and
metastasis. Bone pain is often the most common presenting symp- plexuses, metastatic involvement, and visceral spread. Brachial plex-
tom indicating spread beyond the primary site. Bony metastasis opathy may be secondary to a direct extension from a Pancoast
most often occurs from the breast, prostate, lungs, and ovaries. tumor or lymph node metastasis from breast cancer or a lymphoma.
Many patients experience pain even before the bony metastasis Lumbosacral plexopathy may be due to a direct extension from
becomes radiologically evident. The pain is often described as colorectal, prostate, or cervical cancer or to metastasis from a lym-
‘‘dull,’’ ‘‘constant,’’ and ‘‘gradually increasing in intensity.’’ phoma or breast cancer. Cervical plexopathy may be due to a local
extension of a head and neck cancer or lymph node metastasis.
Cranial nerve neuralgia may occur owing to cancers of the head
Pain Assessment and neck or leptomeningeal metastasis. Paraneoplastic peripheral
neuropathy may be due to small cell lung cancer. Central pain
Regular pain assessments and reassessment of cancer pain patients may be due to spinal cord compression or cerebral metastasis.
should be done and recorded. As with any clinical syndrome, assess- Radiation therapy may be accompanied by myelopathy, plexo-
ment and measurement are critical to document and quantify the pathy, or neuropathy, depending on the site. Surgery may be
condition. That measurement is used to assess the efficacy, or lack followed by phantom pain, post-thoracotomy pain, or postamputa-
thereof, of a particular therapy and also to gauge the progress of the tion pain. Several chemotherapeutic agents, including the vinca
disease. In pain syndromes, there are no generally accepted or alkaloids, taxanes, and platinium-based compounds, can induce
reproducible objective measures of pain. Nevertheless, many sub- pain and a sensory neuropathy referred to as chemotherapy-induced
jective instruments have some utility in assessing cancer pain peripheral neuropathy (CIPN). CIPN involving C- and Ad-sensory
patients. All these instruments have limitations that may be affected nerve fibers is often characterized by development of a tingling and
by patient bias, physician/nurse bias, patient literacy, patient level of burning pain in the extremities and increased sensitivity to cold.
awareness, and other factors, and the resultant assessment may be Corticosteroids may produce proximal myopathy and a burning
flawed. Pain is subjective. The psychosocial and existential compo- perineal sensation.
nents should be assessed. Otherwise, treatment failures may result Breakthrough pain (BTP) is any transient and clinically signifi-
despite the appropriateness of the chosen modalities to address the cant pain that rises over adequately controlled baseline pain.14 BTP
physical component. Diagnostic evaluations may be necessary, if is a serious clinical problem that affects about 50% to 90% of
not already done, to better understand the pathogenesis, extent, patients with cancer pain (usually roughly two thirds). It tends to
and spread of the neoplastic process. be associated with more severe pain, reduced responsiveness to
As part of the pain assessment, it is imperative to have a detailed opioid medication, and pain-related psychological distress and
history and physical examination with a diagnosis and plan of man- functional impairment.15 Most patients experience about three
agement that includes emphasis on objectives of therapy, life expec- BTP episodes a day. Most of the episodes last less than half an
tancy, and treatment options appropriate for the occasion. hour and can reach peak intensity within a few minutes. BTP
Assessment should include the severity, location, quality, timing, may be predictable or can occur without warning. End-of-dose
and modulating factors of the pain. failure BTP manifests as pain occurring at the end of the dosing
The commonly used intensity scale instruments include interval.
1. Numerical pain scale.
2. Visual analog scale (VAS).
3. Simple descriptive pain scale. ANATOMIC BASIS OF THERAPIES
4. Subjective Pain Intensity Rating (SPIR).
The cancer pain pathway may be viewed, for treatment purposes, in
These scales are helpful in monitoring the effectiveness of treat- terms of the processes of transduction, transmission, modulation,
ment. Many other instruments are used to assess pain in chronic and perception. Analgesic agents work at various levels of this path-
pain patients, but they may be unwieldy, inappropriate, or too way. Current approaches to cancer pain management may best be
cumbersome for the cancer pain patient. Our personal preference understood in terms of a mechanistic-based approach along this
is the SPIR, which simply asks the patient to rate his or her pain on pathway. For instance, painful visceral sensation from the abdomen
a scale of 0 to 10, with 0 being no pain and 10 equivalent to the and pelvis is transmitted along the sympathetic nervous system.
worst imaginable pain. A pain diary kept by the patient may provide These relay in paired paravertebral ganglia in the anterolateral
more detailed information relating to the effects of activities on the aspect of the vertebral column. These sympathetic chains lack
motor or somatosensory fibers. Many of the ganglia can be blocked guidelines,2123 with the goal of providing pain relief with minimal
with local anesthetics or neurolytic agents for pain relief without side effects. Although most cancer pain can be treated satisfactorily
significant motor effects. with the conventional three-step WHO ladder approach, about
Interventional therapies are geared toward interrupting or 10% to 20% of such patients will require invasive interventions,24
modulating the nociceptive pathways. Nerve blocks employ local anes- leading to the proposal for the fourth (interventional) step.25,26 The
thetics, steroids, clonidine or other adjuvants, and neurolytic agents guidelines published by the American Society of Anesthesiologists27
such as alcohol or phenol to interrupt the pain signals. Radiofrequency focused more on regional anesthetic techniques.
lesioning can produce a more controlled neurolytic lesioning. One of the simplest but most profound aspects of cancer pain
Intraspinal medication administration takes advantage of a management is the utilization of the three-step ladder recommen-
direct application of the active agent close to the site of activity dation. This is relatively inexpensive, may be utilized in rural or
to decrease the perception of pain while minimizing the side effects. urban areas, in the hospital or the home setting in all countries, and
Stimulation techniques (e.g., spinal cord stimulator) use controlled is effective in managing 75% to 80% of patients with cancer pain.28
electrical energy across tissue to modulate pain.
Step 1: Mild pain is treated with first-line analgesics and adjuvants.
Vertebroplasty helps to relieve the compression of the vertebral
These drugs include acetaminophen, NSAIDs (including COX-2
body, thus decreasing the irritation of the periosteum. Neurosur-
inhibitors), anticonvulsants, antidepressants, and antiarrhyth-
gical techniques such as dorsal rhizotomy, anterolateral cordotomy,
mic drugs.
and cingulotomy are geared toward direct lesioning of specific areas
Step 2: For moderate cancer pain or for when the drugs used in step
of the pain pathway.
1 are ineffective. This step uses weak opioids (now known as
Whereas interventional approaches are based on the knowledge
opioids for mild-moderate pain), which are used in addition to
and understanding of various pain pathways to provide therapy
step 1 agents. Drugs include tramadol, codeine, or hydrocodone,
by mediating at specific points or areas, specific pharma-
which may be added to the drugs in step 1.
cologic classes of agents modulate the biochemical processes
Step 3: Moderate to severe pain is treated with strong opioids,
involved. For instance, cancer cells have high levels of cyclooxygen-
which may be supplemented with agents from steps 1 and 2.
ase (COX) isoenzymes, leading to high levels of prostaglandin.
Morphine is the prototype of the strong opioids. Other strong
Prostaglandins are known to sensitize or directly excite nociceptors
opioids include hydromorphone, methadone, oxymorphone,
by directly binding to several prostanoid receptors expressed by
and fentanyl.
nociceptors. Chronic inhibition of COX-2 has also been associated
with reduced osteoclastic activity, bone resorption, and tumor Some essential principles are applicable when the WHO three-
burden. Thus, nonsteroidal anti-inflammatory drugs (NSAIDs) step ladder recommendation is applied. Therapy should be
can partially attenuate cancer pain, although they are not suitable
1. By the mouth.
for extended use because of their side effect profile.
2. By the clock.
The analgesic effects of opioids are the result of pre- and post-
3. By the ladder.
synaptic modulation. Opioid binding to the presynaptic terminals
4. Individualized.
leads to suppression of voltage-gated calcium channels and to inhi-
5. Monitored with regular pain assessment and reassessment.
bition of the release of substance P and calcitonin generelated
peptide.16 At the postsynaptic terminals, opioids cause inhibition Thus, these drugs should be administered orally whenever pos-
of adenylyl cyclase and activation of the inwardly rectifying potas- sible, and the administration should be on a fixed schedule, not on
sium currents, resulting in hyperpolarization of the neurons.17 The an as-needed basis, along the guidelines of the WHO three-step
exact mechanism of effectiveness of acupuncture is unclear, but ladder recommendation. The WHO three-step ladder has been
it may lead to the production of increased levels of endorphins. criticized for not giving a prominent place to agents for the man-
Acupuncture can be effective in relieving pain and chemotherapy- agement of treatment-related adverse effects such as constipation.
induced nausea. Also, a number of patients may need more specialized therapies
Clonidine is an a2-adrenergic receptor agonist that modulates such as patient-controlled analgesia (PCA) or interventional
pain primarily by binding to the a2A-receptor. On the presynaptic options such as nerve blocks or catheter placement for adequate
receptors, clonidine binding results in decreased release of the pain control. Furthermore, in some patients who present with
neurotransmitters of the primary afferent neurons involved in relay- severe pain, it may not be appropriate to follow the various steps
ing pain signals. Clonidine binding on the postsynaptic neurons of the ladder. More recent guidelines23 have, therefore, placed
also causes hyperpolarization by increasing potassium conductance emphasis on flexibility, the possibility of skipping steps, and the
through the Gi-coupled channels. Clonidine also activates spinal ability to select specific drugs for specific patients. Attention to
cholinergic neurons, potentiating their analgesic effects.18 titration, individualization of therapy, analgesic polypharmacy,
Ziconotide is a synthetic neuroactive peptide that works by and ongoing management of side effects will help to strike the
blocking the voltage-sensitive N-type calcium channel in the super- appropriate balance between analgesia and adverse effects. Some
ficial dorsal horn of the spinal cord. agent-specific information worth noting is discussed later.
Endothelin antagonists also hold promise for attenuating cancer Acetaminophen has minimal anti-inflammatory effects and may
pain. Endothelins (1, 2, and 3) are a family of vasoactive peptides inhibit COX-3 (which has uncertain significance). In addition, its
expressed at high levels by several types of tumors. Endothelins may lack of gastrointestinal irritation and platelet toxicity may be clin-
contribute to cancer pain by directly sensitizing or exciting the ically useful in selected patients. The maximum recommended dose
nociceptors.19 High plasma endothelin levels have been clinically is 4 g per day. Its lack of anti-inflammatory effects may make it less
correlated with pain severity in patients with prostate cancer.20 useful by itself for bone pain.
The selective COX-2 inhibitors cause less gastrointestinal irrita-
tion in comparison to the regular (traditional) NSAIDs. They are
also devoid of platelet toxicity. Adverse cardiovascular effects
PHARMACOLOGIC MANAGEMENT (thromboses) are important and should be taken into consider-
ation. COX-2selective inhibitors may be a first-line medication
WHOAnalgesic Ladder in medically frail or elderly patients at risk for significant gastroin-
testinal hemorrhage. Celecoxib may be given as 200 mg daily, with a
The mainstay of pain control in patients with cancer rests with oral maximum daily dose of 600 mg. Meloxicam belongs to the regular
medications, and this may be done by following established NSAIDs, but it is COX-2 preferential at lower doses.
Tramadol is a weak opioid receptor agonist that also inhibits of bone pain. OPG, also known as osteoclastogenesis inhibitory
reuptake of norepinephrine and serotonin. It can be useful in factor, is a cytokine and a member of the tumor necrosis factor
patients with neuropathic pain. There is an increased seizure risk, receptor superfamily. As secretory decoy receptors, these agents pre-
especially when coadministered with drugs that lower the seizure vent the activation and proliferation of osteoclasts, thus inhibiting
threshold. The maximum recommended daily dose is 400 mg tumor-induced bone destruction. Calcitonin can also be helpful in
(300 mg for patients >75 yr). Tramadol is also available in extend- refractory pain and neuropathic pain. Radiopharmaceuticals such as
ed-release form and in combination with acetaminophen. strontium-89 can be helpful for refractory bone pain, and when
Opioids have been available throughout recorded history and effective, the effect can last for months.
have been used to assuage pain and suffering.29 Morphine was iso-
lated from opium in the early part of the 19th century, and today,
it still remains the ‘‘gold standard’’ for managing severe pain. It is Routes of Administration
available in several formulations and can be administered through
several routes. In situations in which opioids may not be administered orally,
Meperidine is metabolized to normeperidine, which may accu- alternate routes of administration should be considered. Tthese
mulate and cause central nervous system excitation, especially in routes may be required in a substantial proportion of patients at
patients with renal insufficiency or on prolonged high doses. some point. These routes include
Meperidine should be considered a second-line opioid medication
1. Transdermal: Preferred alternative route. Drug depot accumu-
in patients with terminal cancer.
lates in the skin and is gradually released into the systemic
Methadone is an opioid with N-methyl-D-aspartate
circulation.33 The transdermal route is not suitable for titration
(NMDA)receptor blocking effects. As such, it can be very useful
purposes because of the slowness in onset and dissipation. The
in patients with a neuropathic component to their pain. However,
transdermal route is commercially available for fentanyl.
methadone has a long and variable half-life and can be difficult to
2. Rectal: Used as if the dose is equivalent to the oral route.
titrate, especially in the terminal stages of life when changes in
Available medications for the rectal route include morphine,
metabolic functions are common.
hydromorphone, and oxymorphone.
The common side effects of most opioids consist of
3. Nasal: Available for butorphanol. Not customarily used in
1. Constipation cancer pain management.
2. Nausea and vomiting. 4. Buccal: Available for multiple fentanyl preparations. Suitable
3. Early- and late-onset respiratory depression. for BTP.
4. Sedation. 5. Sublingual: Available for buprenorphine. The efficacy of sub-
5. Pruritus. lingual morphine is controversial. Sublingual ketamine in doses
6. Urinary retention. of 25 mg may be effective in the short term for patients with
7. Myoclonus. advanced cancer and BTP (mostly within 5 min) on intrathecal
8. Seizure. opioid therapy and not responding to intravenous opioids for
9. Hallucinations and confusion. BTP.34
10. Sleep disturbance. 6. Intravenous: Indicated if the patient has an indwelling catheter
11. Tolerance and physical dependence. or if other routes are poorly tolerated or unavailable. May be
used for PCA, boluses or continuous infusion.
These have been well described in the literature. Recently, more
7. Subcutaneous: May be used for PCA, boluses or continuous
attention has focused on opioid-induced hyperalgesia, sexual
infusion. May be used on an ambulatory basis.
dysfunction, and inappropriate antidiuretic hormone secretion.
8. Intramuscular (seldom used).
Ample research and clinical evidence support the applicability of
9. Epidural: Available for continuous infusion or boluses. Catheter
anticonvulsants in the management of neuropathic pain, especially
may be externalized or connected to a subcutaneous port.
in combination with opioids.30 Gabapentin is a derivative of
10. Intrathecal: Available for continuous infusion or boluses.
g-aminobutyric acid (GABA) but is an agonist at the a2d-subunit
11. Intraventricular: Owing to the abundance of opioid receptors, it
of the calcium channel. Pregabalin is similar to gabapentin but has
has been found that small doses of morphine in the intraven-
higher absorption and higher bioavailability and may have fewer
trical space can produce long-lasting analgesia. Catheter sys-
side effects. Its dosing regime is simpler than that of gabapentin.
tems implanted in selected patients can provide a useful
The tricyclic antidepressants have proven analgesic effects in
alternative.35
patients with neuropathic pain and can be particularly useful in
such patients who may also have depression or insomnia. Newer All these routes of administration may have their individual
antidepressants tend to have a better side effect profile but have not indications. The pharmacokinetic effects of each route should be
been as well studied as the tricyclic antidepressants for analgesia. known and understood to optimize efficacy and safety. The intra-
Corticosteroids reduce inflammation and pain. They are helpful muscular route is seldom recommended because it is painful and
in pain from infiltration of neural structures, bone pain, and pain in has an unreliable, unpredictable, and erratic uptake from the cre-
patients with advanced disease ated depot. Significant systemic or spinal concentration differences
Baclofen produces increases in the inhibitory action of GABA can occur, depending on the chosen route. For instance, 300 mg of
and is helpful in neuropathic pain. Octreotide relieves the pain of morphine by mouth is about equianalgesic to 100 mg parenterally,
bowel obstruction. Lidocaine, in the form of Lidoderm patches, can 10 mg by the epidural route, and 1 mg by the intrathecal route.
be very helpful with certain local pain when applied over intact skin. Because of the decrease in the dose, delivery by the intrathecal route
Other adjuvant analgesics target specific agents in the pathogen- is associated with a lower incidence of many side effects than that of
esis of pain. Osteoclasts play an essential role in cancer induced bone the oral or parenteral route. Evidence supports the superiority of
loss and contribute to the etiology of cancer pain. Bisphosphonates the intrathecal route over oral administration in patients in whom
are a class of antiresorptive compounds that induce osteoclast oral opioid administration is limited by side effects. In a multi-
apoptosis and can reduce pain in patients with skeletal metastasis.31 center, randomized trial with 200 cancer patients, the mean
Because of their high affinity for calcium ions, bisphosphonates VAS pain score in the intrathecal drug delivery (IDD) group fell
target the mineralized matrix of bone. Clinical studies show that by 52%, compared with 39% in the comprehensive medical man-
ibandronate can induce long-lasting relief of bone cancer pain.32 agement (CMM) group.36 Toxicity scores fell by 50% in the IDD
Osteoprotegerins (OPGs) also hold promise for future treatment group compared with 17% the CMM group. Fifty-four percent of
patients in the IDD group survived for 6 months versus 37% in the reflex muscle spasm may be secondary to the invasion of tissue by
CMM group. the spreading tumor, and local anesthetic nerve block may be help-
The disadvantages of the intrathecal route include cost, technical ful in such cases. Pain secondary to complex regional pain syn-
expertise required for placement and management, and the possi- dromes resulting from tumor encroachment on nerves may be
bility of infections. The intrathecal approach is discussed in more relieved significantly with a sympathetic nerve block. Catheters
detail later. can be placed in the brachial or lumbar plexus for continuous infu-
sion. The stellate ganglion, celiac, lumbar sympathetic, and hypo-
gastric plexuses may also be blocked to control visceral pain from
Interventional Pain Management specific body regions.
Interventional pain management procedures are most often used in

concert with other analgesic regimes. Such invasive or interven- Intraspinal Analgesia
tional procedures are used for managing cancer pain that is
poorly responsive to conventional pharmacotherapy or associated Intraspinal analgesia is achieved by delivering the medication close
with intolerable side effects. These interventions may be used at any to its site of action, thus allowing for a reduction in the total dose
time during the course of the disease. In fact, in some situations, the of the medication with the potential for decreased side effects.
use of such interventional options may be less troublesome to the In general, patients with a poor response to systemic opioids are
patient than the ongoing aggressive medication management. not likely to do well with intraspinal opioid administration. The
Such invasive procedures should be employed only after a thor- delivery of medications to the intraspinal space may be in the form
ough history and physical examination have been done. Preexisting of intrathecal (subarachnoid) or epidural administration. Although
neurologic lesions should be documented. Pathophysiologic distur- the dose of medications has to be individualized, in general, epidu-
bances that may impair the tolerance of such invasive procedures ral administration of morphine requires only 10% of the intrave-
should be addressed, if possible. Because many cancer pain patients nous dose to achieve the equivalent analgesic effect, and intrathecal
may be undergoing chemotherapy or radiation therapy at the same administration requires only about 1% of the intravenous dose.37
time, it is important to ensure that the patient is in an optimal The intrathecal route is believed to be best suited for pain in the
immunologic state and that the coagulation profile is normal. lower half of the body.
Coagulopathy, site infection, and sepsis are contraindications to The intraspinal route, in general, is used when the systemic
such invasive procedures. opioid dose is limited by concurrent side effects. In addition to
Interventional therapies should be used in the context of a mul- the decrease in dose inherent in the use of the intraspinal route,
tidisciplinary approach to care. After interventional procedures, the nonopioid analgesics including local anesthetics and clonidine can
onset of ‘‘profound’’ analgesia may lead to overnarcotization, and be coadministered as part of balanced analgesia. This may be par-
such patients need to be carefully monitored after the procedure. ticularly applicable in certain cases of neuropathic pain that may be
The profound analgesia may also prompt the discontinuation of relatively resistant to intraspinal opioid therapy alone. Neuropathic
opioids, leading to withdrawal symptoms if a gradual tapering is pain syndromes like radiation fibrosis, direct neural involvement by
not initiated. tumor, CIPNs, and postsurgical nerve injuries tend not to respond
The goal of such interventional therapy should further those of to opioids as well as nociceptive pain, irrespective of the route of
the patient, and the therapy should only follow a full discussion of delivery.
the risks and benefits. For instance, neurolytic blocks may result in Before proceeding to intraspinal analgesia, patients should have
permanent sensory/motor deficits. Informed consent is necessary. been tried on other more conservative options, with aggressive
management of side effects. Because many of the opioid side effects
are mediated through the central nervous system, intraspinal anal-
Nerve Blocks gesia does not uniformly decrease such effects and, therefore, is not
always superior to systemic medication delivery. A trial lasting a few
Nerve blocks in patients with cancer pain may be classified based on days is useful in deciding whether the goals of such implantation
the agents used (e.g., local anesthetic, steroids, alcohol, phenol), on can be met. A longer trial period helps to decrease the effect of
the location of the nerves intercepted (somatic or visceral), or a placebo. During this trial, the patient is monitored for analgesia,
combination of both. Nerve blocks involving the lesioning of toxicity, and side effects.
nerves to achieve prolonged pain relief are often referred to as Contraindications to the use of the intraspinal routes include
neurolytic. Such neurolytic blocks are usually preceded by a tempo- patient refusal and the presence of sepsis, coagulopathy, hypovole-
rary blockade, which enables the patient to experience the new or mia, local infection, or extensive obliteration of anatomic space by
different sensation for a brief period of time. tumor or surgery.37
Local anesthetic nerve blocks may be diagnostic, prognostic, or Currently, many medication delivery systems are available to the
therapeutic. Diagnostic local anesthetic nerve blocks can help in clinician. The selection of such a drug delivery system is influenced
determining the pathway or mechanism of pain. For instance, a by several factors including life expectancy, patient/caregiver’s abil-
cervicothoracic sympathetic block can be helpful in the diagnosis ity to care for the system, payor issues, and follow-up care plan. The
of thoracic visceral pain. Lumbar sympathetic block can aid in epidural route is suitable in patients with short life expectancy or
identifying a contribution of the sympathetic nervous system, for those who need frequent patient-controlled doses or large infusion
instance, in patients with phantom limb pain. volumes. In general, a life expectancy of 3 months or greater is
Prognostic local anesthetic nerve block can be performed as a considered the economic break-even point for the implanted
prelude to a neurolytic procedure. A negative local anesthetic block system to become more cost effective than an external system.
usually predicts failure of long-term pain relief. Such prognostic The epidural route is more suitable for patients who have a
blocks also enable the patient to experience the pain relief that history of significant opioid tolerance and may, therefore, need
may result from the block and the associated motor and sensory higher doses of coadministered local anesthetics and in those who
effects. Sometimes, the patient may prefer to keep her or his pain need focal analgesia.38 For instance, in patients with chest wall
rather experience the numbness associated with such a block. tumor, a thoracic epidural infusion can provide adequate analgesia.
Therapeutic local anesthetic blocks in cancer patients with pain Lumbar epidural infusion will be more appropriate for patients
may be useful in the treatment of myofascial pain, sympathetically with cancer pain related to the pelvis, perineum, genitalia, and
mediated pain, and crisis management of severe pain. For example, rectum.39
Intraspinal analgesia, whether delivered via the subarachnoid or on ziconotide, the most common being confusion, somnolence, and
the epidural route, may be as a continuous infusion or an intermit- urinary retention.45 Previously considered as a fourth-line treat-
tent bolus administration. Continuous infusion requires the use of ment, in the recent Polyanalgesic Consensus Conference on intra-
catheters and an infusion pump. This infusion pump may be exter- thecal therapy,42 ziconotide moved up to being a first-line therapy.
nal (usually for short duration) or implanted (usually for prolonged Ziconotide has a narrow therapeutic window and requires a slow
administration). Tunneling of the catheter can help to decrease the titration to avoid dose-limiting side effects. Patients with a preex-
incidence of infection and, therefore, enable the catheter to be used isting psychiatric disorder may be at an increased risk for treatment
for a slightly longer duration compared with that for a regular complications.46 The high cost is also a limiting factor in the use of
nontunneled externalized catheter. Prolonged epidural infusion ziconotide.42
can be associated with abscess, infection, catheter obstruction, Other intrathecal analgesic agents with limited data include
fibrosis, and loss of analgesia.40 The intrathecal route is more ketamine, neostigmine, midazolam, and NSAIDs. The addition of
appropriate for prolonged administration. ketamine to conventional intrathecal therapies may be helpful in
cancer patients with refractory pain, especially of the neuropathic
type. Using a double-blind, cross-over trial, Yang and colleagues47
Intrathecal Medications compared the combination of 1 mg of intrathecal ketamine with
intrathecal morphine alone in 20 patients with terminal cancer pain.
Morphine is approved by the U.S. Food and Drug Administration They noted significantly lower morphine requirements, less rescue
(FDA) for treating cancer pain via the intrathecal route. It is the medications, and improved pain scores in the group treated with
most frequently used drug alone and in combination with other ketamine over the 48-hour study period. However, ketamine
drugs.41 However, in the clinical setting, several other opioids administration in the intrathecal space over a long period of time
including hydromorphone, fentanyl, and sufentanil are also used. may be associated with significant neurotoxicity.48
Hydromorphone is also used by many physicians, but on fewer
patients than morphine. Our practice has been, in the absence of
morphine allergy, to start with morphine and switch to hydromor- Other Side Effects and Complications of
phone if there are significant morphine-related side effects. Some Intraspinal Analgesia
mild adverse reactions occur even with small doses of intrathecal
morphine, suggesting that some of the side effects are not dose- Delayed respiratory depression from a gradual cephalad spread of
dependent.42 Formation of intrathecal granuloma, though un- the opioids is a much-feared complication of intrathecal delivery.
common, is a serious complication that may result in decreased With morphine, this may occur about 12 to 18 hours after the
analgesia or serious neurological complications. Fentanyl is used injection. Delayed respiratory depression is less likely with lipophilic
much less frequently. The use of sufentanil is rare. opioids. Much less appreciated is a slowly increasing respiratory
There are wide variations in the concentration as well as daily depression, a potential side effect of intrathecal morphine admin-
dosages of morphine, hydromorphone, or fentanyl administered as istration.49 Clinical correlates of this difficult-to-recognize problem
a single agent. Many physicians adjust the dosage of the drugs by a include increasing fatigue, exercise dyspnea, step-by-step loss of
fixed percentage (usually 10%20%). The usual practice is five to pulmonary function, and increasing morphine dose without anal-
eight adjustments before switching to a different drug or drug com- gesic improvement.
bination.41 It appears that physicians tend to tolerate more dosage Opioid administration through the intrathecal route may also be
adjustment for morphine or hydromorphone than for fentanyl or associated with side effects such as constipation, nausea/vomiting,
sufentanil. urinary retention, sweating, and features of hypogonadism.
Morphine is also the most frequently used drug in the epidural Whereas many of these side effects may diminish with time, con-
space. Because of its low lipid solubility, it tends to be distributed to stipation and sweating tend to persist. Peripheral edema may be
the higher centers of the central nervous system. Its onset of action associated with intrathecal opioid administration. It is usually
is slow, and its effects are prolonged. The catheter position is not as drug- and dose-dependent. The mechanism of opioid-induced
important with morphine, owing to its cephalic spread. peripheral edema remains currently unclear. However, partial sym-
However, if lipophilic opioids like fentanyl or sufentanil and pathetic blockade may be contributory. Venous stasis before pump
local anesthetics will be used, it is advisable to place the catheter insertion may be contributory.50
tip as close as possible to the affected dermatome. Mixing local Hypogonadism may result from low levels of testosterone and
anesthetic with opioids appears to provide good intermediate- to estrogen due to hypothalamic-pituitary suppression. It is recom-
long-term outcomes.43 mended that hormonal levels be monitored and replacement ther-
Bupivacaine is the most commonly used local anesthetic in com- apy done if needed.
bination with morphine in the epidural space and the concentration
varies from 0.04% to 0.25%. van Dongen and coworkers,44 in a
double-blind, randomized trial, compared intrathecal morphine Neurolytic Blocks
alone with a combination of intrathecal morphine and bupivacaine
in 20 cancer patients and found a synergistic effect and less toler- Neurolytic blocks work by causing a destructive lesion of the nerves
ance to the opioid in the combination group. or ganglia and are used for long-term pain relief. They usually
Clonidine in a dose of 300 to 700 mcg per day can also be used follow a temporary (diagnostic) block. Neurolytic block may be
to supplement analgesia in combination with morphine.43 Side accomplished through cryotherapy, radiofrequency lesioning,
effects include possible bradycardia, hypotension, nausea, dry gamma knife, or chemical neurolysis. The choice is influenced by
mouth, and sedation. It is currently recommended as a second- the nature and location of the pathology. Alcohol (50%100%
line medication in combination with opioids for intrathecal man- concentration) and phenol (6%12% concentration) are the most
agement of pain.42 commonly used chemical neurolytic agents. They produce neuronal
Ziconotide is FDA approved for neuraxial use in the treatment destruction and can be used for peripheral nerve destruction and
of chronic pain. In a multicentered, randomized, controlled, ganglion and subarachnoid neurolysis. Neuronal regeneration is
double-blind cross-over study involving 111 patients with cancer possible after use of both agents, and thus, sensory functions may
or AIDS, the 68 patients in the intrathecal ziconotide group return after a period of time, which is usually shorter with phenol
obtained significantly greater pain relief than the controls (53% than with alcohol. But the neurolytic block can usually be repeated
vs. 17.5%). However, side effects were noted in 31% of the patients if this occurs. Phenol has local anesthetic properties, and its
injection is less painful than alcohol. Alcohol injection is usually and spread of agent. The hypogastric plexus is analogous to the
preceded by local anesthetic injection to ameliorate the pain of celiac plexus in the upper abdomen. Considering the location of
injection. Phenol is often used as a 6% solution in glycerin, yielding the plexus, hypotension, diarrhea, and injury to the aorta or spinal
a viscous solution that is hyperbaric to cerebrospinal fluid on injec- cord should be unlikely.
tion (but becomes isobaric after roughly 15 min), coagulates pro- Plancarte and colleagues54 studied 227 patients with gynecologic,
teins, and may deteriorate during storage after about a year. The colorectal, or genitourinary cancers who had poor analgesia or intol-
block produced by phenol tends to be less profound and of shorter erable side effects with opioid management and were candidates for
duration than that produced by alcohol. superior hypogastric block. Twenty-one percent of the patients had
no relief with diagnostic local anesthetic block and were excluded.
Seventy-nine percent had favorable response to the local anesthetic
Celiac Plexus Block
block, and with neurolytic block, they were able to reduce opioid
This is the most commonly performed neurolytic block. It is indi- usage. Of the 18 patients enrolled owing to excessive sedation with
cated for pain in the upper abdomen or back related to cancer of the opioid management, 16 showed improvement after the procedure.
pancreas, stomach, liver, or distal esophagus. Celiac plexus neuro- There was no placebo-controlled group in this study, and changes in
lytic block may be done using a percutaneous approach or via direct quality of life were not evaluated. However, no procedure-related
vision at surgery. The percutaneous approaches are done under the complications were detected.
guidance of fluoroscopy, computed tomography, ultrasound, or
magnetic resonance imaging for accurate needle placement. Local
Other Neurolytic Blocks
anesthesia is infiltrated in the skin and subcutaneous and deeper
tissue to decrease the pain associated with needle placement. Blockade of the cervical sympathetic chain affects visceral afferent
Intravenous sedation with a small amount of benzodiazepine sensations of the head, neck, and upper extremities. This is usually
(e.g., midazolam) or analgesia with a small amount of an opioid approached at the C6 transverse process as the stellate ganglion
such as fentanyl is usually sufficient to provide conditions suitable block. Some patients with cancer of the head and neck may benefit
for the procedure. The choice of an intravenous agent depends on from this block, especially if they have neuropathic pain. Neurolytic
the patient’s physiologic status and preference. block of the mandibular nerve may help with jaw pain.
Common complications of neurolytic celiac plexus blocks Neurolytic blockade of the lumbar sympathetic plexus can be
include transient postural hypotension and diarrhea. Although used to treat pain of urologic cancers and phantom pain, whereas
side effects and complications are rare, serious complications can the ganglion impar block can help cancer pain of the perineal area.
occur even with image-guided needle placement.51 Thoracic plexus block is more often used to treat phantom pain,
Celiac plexus block is safe and efficient in the control of cancer postmastectomy pain, and post-thoracotomy pain and less often for
pain in the appropriate patient. In a meta-analysis to review the direct cancer pain. Neurolytic block of the intercostal nerve can help
safety and efficacy of celiac plexus block, Eisenbach and associates52 with chest wall pain. Specific regional sympathetic blocks can help
were able to group together 989 appropriate patients. Good- with herpes zoster pain.
to-excellent results were reported in 89% in the first 2 weeks Subarachnoid or epidural injection of alcohol or phenol had
after the block and partial-to-complete pain relief persisted in been used for decades to treat unilateral segmental cancer pain,
90% of the patients who were alive after 3 months. but the popularity has decreased owing to problems with precise
Wong and coworkers53 carried out a double-blind, randomized, localization. Inadvertent spread could lead to motor blockade or
controlled trial to assess the effect of neurolytic celiac plexus compromise of bladder and bowel functions.55
block on pain relief, quality of life, and survival in 100 adult patients Gamma knife therapy is noninvasive and a suitable alternative to
with unresectable pancreatic cancer. The patients were followed for transnasal injection of alcohol for pituitary ablation in managing
at least 1 year or until their death. Patients in the block group intractable pain.56
received a typical alcohol neurolytic celiac plexus block, whereas
those in the control group received a sham injection consisting of
a local anesthetic administered into the skin and deeper tissues. Both Neuroaugmentation
groups were allowed unlimited opioid use, managed by physicians
who were blinded with regard to the procedural intervention. Pain Spinal cord stimulators may play a role in managing pain in cancer
intensity was comparable in both groups at baseline, and there was a patients or for coexisting benign conditions.55 Patients with painful
significant decrease in both groups after 1 week. The decrease in pain conditions like peripheral neuropathy, phantom limb pain, post-
intensity in the neurolytic block group was 53%, whereas that in the herpetic neuralgia, and complex regional pain syndrome may ben-
control group was only 27%. The pain intensity was lower in the efit from a spinal cord stimulator.
neurolytic block group in subsequent follow-up. However, opioid
consumption, incidence of opioid adverse effects, and quality of life
were not significantly lower in the neurolytic block group than in the Vertebroplasty
control. At 1 year, 16% of patients in the neurolytic block group
were alive, compared with only 6% in the control group, although Percutaneous vertebroplasty was initially developed to treat aggres-
this difference did not reach statistical significance. sive spinal hemangioma. Since then, the indications have expanded
to include other tumors of the spine and painful compression frac-
tures resulting from osteoporosis.57 In this technique, bone cement
Superior Hypogastric Plexus Block
(polymethylmethacrylate) is injected through a special needle into a
Afferent fibers innervating the pelvic viscera (including the distal collapsed bone under image guidance. It is very helpful in relieving
colon, rectum, bladder, ureters, uterus, and adnexal structures) pass pain secondary to vertebral metastatic compression fracture.58
through the hyogastric plexus, which is located in the retroperito-
neum and overlies the anterior aspect of L5 to the superior sacrum.
Pain from the pelvic organs is often responsive to a blockade of this CONCLUSION
plexus. As in the celiac plexus, only visceral pain responds well to
this block. Approach is surgical via an open incision (intraopera- The pain associated with cancer should not continue to deny a
tive) or percutaneously through a posterior approach. Imaging stu- patient’s quality of life. Cancer pain can be controlled. Myriads
dies are used to guide and confirm appropriate needle placement agents and techniques are currently available. In addition, the
future holds great promises for improvements in the techniques, 25. Krames E. Interventional pain management: appropriate when less
routes, and agents. Research models are currently available that invasive therapies fail to provide adequate analgesia. Med Clin North
merge pain and cancer research, and there is hope for a synergistic Am 1999;83:787-808.
translational research and interdisciplinary collaboration. Cancer 26. Miguel R. Interventional treatment of cancer pain: the fourth step in
patients with pain deserve to have their pain controlled. the World Health Organization analgesic ladder? Cancer Control
2000;7:149-156.
Unrelieved pain can be devastating. Therefore, it is important not 27. Ferrente FM, Bedder M, Caplan RA, et al. Practice guidelines for
to delay excessively before consulting a pain management specialist cancer pain management. A report by the American Society of
when conventional pharmacologic therapy appears inadequate. Anesthesiologists Task Force on pain management, cancer pain
Many pain clinics today consider cancer pain as an ‘‘emergency’’ section. Anesthesiology 1996;84:1243.
that needs evaluation and treatment as soon as possible. We may 28. Reid C, Davies A. The World health Organization three step analgesic
not yet be victorious over cancer, but it is hopeful that we can ladder comes of age. Palliat Med 2004;18:175-176.
conquer much, if not all, of the pain associated with this dreaded 29. Eriator II. Opioid use in the United Sates. Fed Pract 2003;20:50-64.
disease. 30. Keskinbora K, Pekel AF, Aydinli I. Gabapentin and an opioid
combination versus opioid alone for the management of neuropathic
cancer pain: a randomized open trial. J Pain Symptom Manage
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JAMA 2004;291:1092-1099.
V
CHRONIC PAIN:
NONCANCER PAIN
Chapter 15 or premonitory phase, occurs in 20% to 60% of migraineurs and

may consist of a variety of symptoms from mild discomfort in the
MIGRAINE HEADACHES head to a change in mood or behavior to increased urination, yawn-
ing, and craving certain foods. When they experience these symp-
toms, many patients know hours before a migraine attack begins in
Eric M. Pearlman and Alan M. Rapoport earnest that it is coming. The migraine aura occurs in only 15% to
20% of migraineurs. Aura is a transient change in neurologic func-
tion that leads to focal neurologic symptoms. These symptoms can
be positive (a gain in function) or negative (a loss of function) and
usually precede the onset of pain but can accompany or, rarely,
follow the onset of the headache phase. Auras are usually visual,
but they can be sensory or motor or involve speech or coordination.
INTRODUCTION The more common visual auras take the form of colored spots, holes
in the visual field, bright-edged crescentic shapes that scintillate and
Headache is one of the most common complaints a physician will move slowly across the visual field, and photopsias or flashes of light.
hear, often sparking concern about ominous disease or illness. The presence or absence of these neurologic symptoms defines the
However, most headaches are not caused by serious medical con- two subtypes of migraine: migraine with aura (ICHD II 1.1) and
ditions or other systemic illnesses but are manifestations of a pri- migraine without aura (ICHD II 1.2). Postdrome, or resolution, is
mary headache disorder. This chapter focuses on one of the primary the final phase and can have features similar to those of the pro-
headache disorders, migraine; discusses strategies for distinguishing drome. Often as the headache is waning, the patient still feels tired
migraine from other primary headache disorders and other condi- and depressed and has trouble with executive functions like think-
tions that cause headache; and outlines migraine treatment ing, speaking, and writing. The postdrome can last for 1 to 2 days.
strategies.
EPIDEMIOLOGY
TAXONOMY
Migraine is a common, chronic disease, occurring in 18% of women
The International Headache Society developed a classification strat- and 6% of men in the United States and many Western countries.
egy for headaches in 1988 and subsequently revised the International With an overall prevalence of 12%, migraine is more common than
Classification of Headache Disorders (ICHD II) in 2004. There is no asthma and diabetes combined, with approximately 28 million suf-
objective test or biologic marker for migraine or other headache ferers in the United States. The gender difference appears around
disorders, so the diagnosis is made on clinical grounds, using history menarche and becomes somewhat less pronounced after 60 years of
and physical examination to elicit headache characteristics, associ- age, but still continues. Prevalence peaks during the 20s and 30s, the
ated symptoms, alleviating and exacerbating factors, degree of most productive years of one’s life, and appears to be greater in
impact and disability, and evidence of other underlying causes of groups with lower education and income. Around half of migrai-
headache. The most common headache disorders are tension-type neurs report severe disability or require bedrest during attacks, and
headache and migraine with or without aura (Table 15–1). Although 35% miss 1 or more days of work or school in a 3-month period.
tension-type headache is prevalent in Western societies, it rarely Sixty-two percent miss at least 1 day per year owing to migraine.
leads to a discussion with a physician. The great majority of indivi- Migraineurs also have decreased productivity at work/school. It is
duals who present to a physician complaining of headache suffer estimated that the direct and indirect costs of migraine approach
from migraine. Studies show that over 90% of patients presenting $13 billion annually in the United States.
to a primary care physician with headache are found to have
migraine. Migraine is characterized by discrete episodes of severe
head pain lasting from at least 4 hours to several days, often associ- PATHOPHYSIOLOGY
ated with photophobia (light sensitivity), phonophobia (sound sen-
sitivity), and nausea and vomiting. Migraine attacks are divided into Migraine is a genetically based disorder characterized by tran-
phases: prodrome, aura, headache, and postdrome. The prodrome, sient neuronal dysfunction in an otherwise healthy individual.
107
108 Chapter 15 MIGR AINE HEADACHES
Table 15^1. Classification of Migraine with and without Aura
Migraine without Aura Migraine with Aura

A. At least five distinct attacks
B. Headache attack lasting 4–72 hr (untreated or unsuccessfully E. Not attributable to another disorder
treated) F. Fulfills criteria for migraine without aura
C. Headache has at least two of the following: G. At least three of the following:
1. Unilateral location 1. One or more fully reversible aura symptoms indicating
2. Pulsating quality focal cortical and/or brainstem dysfunction
3. Moderate to severe intensity 2. At least one aura developing gradually over more than 4
4. Aggravation by routine physical activity min or two or more symptoms occurring in succession
D. During headache, at least one of the following: 3. No aura lasting > 60 min
1. Nausea and/or vomiting 4. Headache follows in < 60 min
2. Photophobia and phonophobia
The trigeminovascular system is the primary region involved in a rate of 2 to 3 mm/min. This wave does not respect vascular
migraine. The trigeminal nerve innervates the face, jaw, teeth, boundaries and seems to travel in the cortex. This wave is believed
scalp, sinuses, and intracranial structures including meninges and to correspond closely to the visual aura that some migraineurs
blood vessels. The trigeminal nerve contains sensory afferents that experience. This wave of excitation/suppression may also trigger
transmit electrical information, including pain from the face and migraine headache by local release of excitatory and inflammatory
head, to the brainstem where they synapse with second-order neu- substances from mast cells and other areas that act locally on blood
rons in the trigeminal nucleus caudalis in the medulla. This nucleus vessels, causing constriction followed by dilation, and activate tri-
extends down to the upper cervical spinal cord, connecting with geminal nerve terminals leading to pain perception.
inputs from the occipital and neck region. The trigeminal nerve
terminals lie peripherally on intracranial extracerebral blood vessels.
When activated, they release vasoactive peptides such as calcitonin CLINICAL FEATURES
gene–related peptide (CGRP) and substance P, which cause dilation
of the blood vessels and may be involved with breakdown in the As described previously, migraine attacks can be divided into four
blood-brain barrier leading to leakage of plasma and sterile neuro- phases: prodrome, aura, headache, and postdrome. The prodrome
genic inflammation. This, in turn, leads to additional activation of may consist of psychologic, neurologic, or constitutional symptoms
the trigeminal afferents, which activate pain pathways in the central and can last from hours to days. During this time, an individ-
nervous system and conscious sensation of pain in the head. Why this ual may feel depressed, irritable, drowsy, restless, hyperactive, or
cascade happens in migraineurs but not others is not fully under- euphoric. He or she may experience excessive thirst or hunger,
stood; however, it is clear that migraine is genetically based. food cravings, anorexia, sluggishness, and concentration difficulties.
Abnormalities in the P/Q-type calcium channel have been identified There may be yawning, enhanced sense of smell, photophobia,
in individuals who suffer from familial hemiplegic migraine, a phonophobia, neck stiffness, diarrhea, or constipation. Because
rare migraine subtype. Others have been found to have abnormalities the feeling is the same each time, some individuals just sense that
in an Na/K-ATPase pump on supporting astrocytes, and still a migraine is coming several hours before the attack.
others have a malfunctioning Na channel on neurons involved in The migraine aura consists of focal neurologic phenomena that
pain. These abnormalities lead to impaired glutamate release precede or accompany an attack. Aura symptoms usually arise over
and lack of reuptake, which may either predispose individuals to 5 to 20 minutes and typically last much less than 60 minutes, usu-
migraine attacks or impair a self-abortive mechanism that may ally only 20 to 30. Visual aura is the most common, occurring in
be present in nonmigraineurs. Serotonin receptors are also involved more than 90% of individuals with aura. It often is hemianoptic
in the process and are present on trigeminal nerve terminals on blood (occurring in half of the visual field), can be positive or negative
vessels, peripheral nerve terminals, and centrally in the trigemi- phenomena, and can vary in complexity. Simple visual disturbances
nal nucleus caudalis. Stimulating the 5-hydroxytryptamine1B/1D include scotoma (black spots), phosphenes (small sparkles or
(5-HT1B/1D) receptors on nerve terminals and blood vessels by treat- flashes), colors, or geometric forms. More complex visual auras
ing with a triptan prevents the release of CGRP and other peptides include teichopsia, or fortification spectra. These zigzag lines with
and constricts dilated vessels, playing an important role in stopping a scintillating edge begin near a point of fixation and spiral out or
an attack. These receptors are, therefore, critical targets for acute drift across the visual field. Other complex auras can include visual
treatment. distortions such as metamorphopsia, in which people or objects
Migraine aura also has a complex pathophysiology, but unco- become distorted, grow, or shrink in size. Sensory aura is the
vering this pathophysiology helps in understanding the clinical fea- next most common, occurring in about one third of migraineurs
tures of aura. In the 1940s, Lashley, a physiologist, described his who experience aura. These parasthesias are often cheiro-oral, with
own visual aura as moving across his visual field at a rate of 2 to 3 numbness and/or tingling starting in the hand, migrating up the
mm/min. At around the same time, Leáo, a Brazilian physiologist arm, and then jumping to involve the face, lips, and tongue. Motor
working on rabbit brain at Harvard, found that a noxious stimulus symptoms are much less common. Less than 20% of auras will
on the surface of rabbit cortex produced a decrease in electrical manifest as weakness or ataxia or other symptoms from the brain-
activity that spread across the cortex at a rate of 2 to 3 mm/min. stem and cerebellum.
Modern neuroimaging techniques have identified a sudden spike of The headache of migraine usually builds to moderate or severe
increased electrical activity followed by a longer wave of cortical intensity. The pain is often described as ‘‘throbbing,’’ ‘‘pounding,’’
spreading depression that moves across human cerebral cortex at or ‘‘pulsatile,’’ although some individuals will report ‘‘constant,’’
V CHRONIC PAIN: NONCANCER PAIN 109
‘‘sharp,’’ or ‘‘stabbing’’ pain. The onset is usually gradual, building angiography must be done to rule out vascular abnormalities
over the first 30 to 90 minutes; it then peaks and subsides, usually such as arteriovenous malformation, aneurysm, and arteritis. If
lasting less than 24 hours with a range of 4 to 72 hours. The pain is the history fulfills criteria for migraine based on ICHD II, no fur-
unilateral in 60% of attacks. It may always be on the same side, or it ther evaluation is warranted. In rare cases, coexisting tumors and
can alternate. Only 20% of individuals have attacks consistently on other abnormalities are found in migraineurs, and the physician
the same side. Pain may start unilaterally and become bilateral or must always have a high index of suspicion for secondary disease.
may radiate down into the neck. The pain of migraine is often
exacerbated by movement or routine physical activity such as bend-
ing, lifting, walking, and climbing stairs and will intensify with MANAGEMENT
coughing and sneezing.
In addition to the headache, migraine attacks often have asso- To be successful, one should take a comprehensive approach—
ciated features that contribute to the discomfort and disability expe- including diagnosis, patient education, and nonpharmacologic
rienced during an attack. Most migraineurs will experience and pharmacologic interventions—to migraine management for
photophobia and phonophobia during an attack. Less commonly, all patients. Effective migraine treatment begins with making an
osmophobia (sensitivity to odors) can occur. Nausea occurs in up accurate diagnosis. Not only should the clinician be comfortable
to two thirds of migraine attacks, and vomiting occurs in a little less with the diagnosis of migraine, she or he must also effectively com-
than half of attacks. Photophobia, phonophobia, nausea, and vom- municate this to the patient and make him or her comfortable with
iting are cardinal features that contribute to the diagnosis of the diagnosis. Unless the patient accepts the diagnosis, he or she will
migraine. Other associated symptoms that can occur include light- not accept a treatment plan. This may involve educating the patient
headedness, dizziness, blurred vision, anorexia, diarrhea, nasal con- on the features of migraine, including showing him or her the diag-
gestion, pallor, temperature intolerance, mood changes, and nostic criteria and explaining how his or her headaches fit.
difficulty concentrating, speaking, or writing. Gastric emptying is Supporting information such as family history, presence of
usually delayed, even when a migraineur is not in an attack, which migraine triggers, and a normal examination can also help.
can affect absorption of medications. Patient education begins with the diagnosis and should also
include lifestyle factors that contribute to migraine. Migraine can
be triggered under certain situations, some which are predictable
EVALUATION and others that are not. Common triggers are those that will lead to
migraine in many patients the majority of the time. These include
Diagnosis of migraine is a clinical diagnosis, not made by laboratory menses in women, sleep deprivation or change in the sleep/wake
findings. The ICHD II requires at least five recurrent attacks, pres- cycle, stress, letdown from stress, illness, and fasting or delaying
ent for at least 1 year, with normal function between attacks. In meals. Other triggers that occur less commonly include exertional,
order for an attack to qualify as migraine, according to the criteria, dietary, environmental, and hormonal factors. Exertional triggers
two of four pain features and one of two associated features must be include intense physical exertion, exercise beyond normal levels,
present. The four pain features include throbbing or pulsatile qual- and head trauma. Environmental triggers can be bright sunlight,
ity, unilateral location, moderate to severe intensity, and exacerba- fluorescent lights, glare, altitude, barometric pressure/weather
tion by routine physical activity. In addition, either nausea and changes, and odors such as perfumes or cleaning solutions.
vomiting or photophobia and phonophobia must be present. The There are many myths regarding diet and its influence on
history of attacks is all that is necessary to make a diagnosis of migraine. Dietary triggers only affect certain individuals, and each
migraine. Because most migraineurs are evaluated between attacks, patient has different sets of triggers. If it is determined that a
the general and neurologic examinations should be normal. The particular substance is not a trigger for a given individual, removing
presence of focal neurologic findings at any time other than that substance is not likely to alter headache frequency. Common
during aura should raise serious concern about organic causes of dietary triggers include alcohol, especially red wine; processed
headache. Evidence of systemic disease should also prompt other meats containing nitrites; monosodium glutamate; aspartame; cho-
evaluations for secondary causes of headache. colate; aged cheeses; citrous fruits; and acidic foods. Caffeine itself
If the history is consistent with migraine and there is no evi- as well as caffeine withdrawal is often a trigger and has to be dealt
dence for secondary causes, no additional diagnostic testing is with in a comprehensive treatment plan. One must be aware of
needed. Routine laboratory testing and imaging are not necessary dietary caffeine as well as the caffeine present in many headache
to diagnose migraine, but these would be helpful to rule out sec- medications. It should be explained that dietary triggers function
ondary causes of headache. Laboratory testing should be obtained via a chemical reaction and do not represent a true immunoglob-
only if there is suspicion for systemic illness or other pathology. If ulin E (IgE)–mediated allergic response.
neuroimaging is contemplated owing to evidence on history or The relationship between female hormones and migraine is
examination of intracranial pathology, magnetic resonance imaging complex. It is presumed that the drop in estrogen that leads to
(MRI) is often more revealing than computed tomography (CT) menses is the trigger for many women with menstrually related
scanning. CT scanning is helpful only to exclude processes that migraine. Estrogen-containing oral contraceptives have been
cause acute headache disorders such as hemorrhage, enlarged ven- shown to exacerbate migraine but also may alleviate migraine in
tricles, or increased cerebrospinal fluid pressure and should be some women. Migraine usually improves with pregnancy and
reserved primarily for urgent or emergency room evaluation. menopause, although some women will have worsening headaches
Evaluation with MRI is appropriate if the headache has unusual early in their pregnancy and many women will experience worsen-
features or a time course that suggests that a diagnosis of migraine ing headaches in the perimenopausal years, before their menses has
is in doubt. MRI provides significant benefit over CT in that it will been absent for a year.
identify small lesions, not visible on CT, allows for an evaluation of Basic education regarding headache hygiene is suggested for all
the brainstem and cervicomedullary junction to evaluate for patients. This includes encouraging regular sleep, regular meals, and
Chiari’s malformation, and also allows for evaluation of the arterial regular exercise. Triggers should be discussed and trigger avoidance
or venous systems. For an even better look at the vascular system, recommended once triggers have been identified. One excellent way
MR or CT angiography may be used if clinically appropriate. to identify triggers is with a headache diary or calendar. This pro-
Electroencephalography (EEG) has only a limited role in evaluation vides a means for a patient to record attacks of differing intensities
of headache. EEG is appropriate only if there is unusual aura such and duration. It should include information regarding circum-
that partial seizure is considered. On rare occasions, cerebral stances surrounding an attack, duration, severity, disability,
110 Chapter 15 MIGR AINE HEADACHES
treatments, and response to treatment. For menstruating women, it Table 15^2. Migraine-specific Medications
should also show the relationship of attacks to the menstrual cycle.
This not only allows the patient to identify triggers and be more Medications Available Doses
aware of her or his headache pattern but also gives the clinician an
objective tool for determining headache frequency and severity and Almotriptan 12.5 mg
a way to monitor response to treatments. Eletriptan 20 mg, 40 mg
Pharmacologic treatment can be divided into three types: acute, Frovatriptan 2.5 mg
rescue, and preventive. Acute treatment is taken at the earliest onset Naratriptan 2.5 mg
of an attack. The goal is to stop an attack as quickly as possible to Sumatriptan: tablet; intranasal; 25 mg, 50 mg, 100 mg; 5
limit pain, associated symptoms, and disability associated with the subcutaneous injection mg, 20 mg; 4 mg, 6 mg
attack. Choosing the appropriate acute medication should take into Rizatriptan: tablet; MLT (orally 5 mg; 10 mg
account previous medication use (including its effectiveness and disintegrating)
adverse events), characteristics of the patient’s attacks, and patient Zolmitriptan: tablet; ZMT (orally 2.5 mg; 5 mg; 5 mg
preference. In order to maximize the likelihood of success, patients
disintegrating); intranasal
should be stratified by severity of attacks and degree of disability 0.5 mg/spray (total
into mild, moderate, and severe disability, and appropriate treat- DHE 45: intranasal; subcutaneous
2 mg); 1 mg
ment strategies should be developed based on their stratum.
Individuals with mild impairment require less aggressive therapy, DHE 45, dihydroergotamine; MLT, rizatriptan orally disintegrating tablet;
whereas those with moderate to severe impairment require increas- ZMT, zolmitriptan orally disintegrating tablet.
ingly aggressive treatment strategies. For acute treatment, this
means choosing a therapy with the greatest likelihood of returning
the patient to normal functioning, taking into account the treat- formulations. Almotriptan, eletriptan, rizatriptan, sumatriptan, and
ment’s efficacy, safety, and side effects. zolmitriptan are all relatively fast-onset medications and, in general,
Acute treatments can be divided into nonspecific and migraine- will be effective in two thirds to three fourths of migraine attacks.
specific medications. Nonspecific medications include simple Frovatriptan and naratriptan have slightly slower onset of action
analgesics, nonsteroidal anti-inflammatory drugs, opiates, and but also seem to have low recurrence rates. Triptans are safe and
combination medications. Over-the-counter analgesics are effective effective for the acute treatment of migraine. They should be con-
for many migraineurs with mild attacks. Individuals who get sidered first-line therapy for patients with moderate to severe
effective relief from acetaminophen, ibuprofen, aspirin, and over- migraine. If nausea and vomiting are present early during an
the-counter combination analgesics are unlikely to seek medical attack, consideration should be given to intranasal or subcutaneous
attention for headaches unless the headaches are increasing in fre- routes of administration. Lack of response to one triptan does not
quency and/or the patient is developing medication-overuse head- mean that a patient will not respond to a different one. It is quite
ache or side effects. Many of these simple analgesics are combined reasonable to try several different triptans to obtain satisfactory
with caffeine and marketed specifically for migraine. Evidence sug- relief. This should be carried out using a headache diary and treat-
gests that these combination products containing aspirin, acetami- ing at least three different attacks to determine responsiveness. It is
nophen, and caffeine are effective for mild to moderate migraine not appropriate to give patients several different samples and expect
with little disability or vomiting. Prescription combination medica- them to sort out which works best, although it is commonly done.
tions containing butalbital (Fiorinal, Fioricet) and isometheptine Preventive medications should be considered for individuals
(Midrin) are often prescribed despite little evidence that they are who are significantly disabled by their headaches. The purpose of
effective for migraine. Some patients claim that these are the only preventive medications is to decrease the frequency, severity, and
medications that help them, and if used sparingly, they may remain disability of migraine attacks in order to improve the patient’s qual-
effective. Many experts believe that these are a significant source of ity of life. Prevention is also appropriate to avoid overuse of acute
dependence and medication-overuse headache, because patients medication leading to medication-overuse headache. The indication
usually escalate their use of these medications. Therefore, their for preventive medications must be tailored to an individual
chronic, frequent use is discouraged. For individuals with more patient’s needs but should be discussed when headaches are occur-
severe pain and associated symptoms, or for those who do not ring more than three times per month, are causing more than 3 days
respond to, or cannot tolerate, these nonspecific agents, migraine- of disability each month, are requiring multiple doses of acute
specific agents are more appropriate. medication, if there is intolerance or contraindications to acute
The migraine-specific medications include the ergots (ergotamine medication or if the patient requests medication for fewer attacks.
tartrate and dihydroergotamine) and the triptans. Ergotamine tar- There may also be specific circumstances, such as hemiplegic
trate, originally derived from a rye fungus, Claviceps purpurea, is a migraine or attacks with risk of permanent neurologic injury, that
serotonin receptor agonist, available in combination with caffeine as a would necessitate prevention even for infrequent headache.
tablet or suppository. Dihydroergotamine (DHE) can be adminis- Choosing a preventive medication should be individualized and
tered parenterally, subcutaneously, intramuscularly, intravenously, should take into account coexisting conditions whenever possible.
and intranasally. Ergotamine use is often limited by adverse events. Common coexistent conditions to consider include hypertension,
DHE has better tolerability. Both agents can exacerbate nausea and depression, anxiety, sleep disorders, asthma, allergies, epilepsy, and
can cause abdominal cramping, paresthesias, and chest tightness. obesity.
Both can induce uterine contractions and must be used with caution General principles with any medication include titrating the
in women of child-bearing potential, with counseling on adequate dose slowly to avoid adverse events, reaching an effective dose of
contraception. Women attempting to become pregnant and indivi- medication, and giving an adequate trial before deciding a treat-
duals with poorly controlled hypertension, renal or hepatic failure, ment is ineffective. An adequate trial is defined as an appropriate
coronary, cerebral, or peripheral vascular disease should avoid ergot- dose for 3 consecutive months, because most clinical trials showed
amine and DHE. These ergots do work on migraine and are less that it takes at least that long to show consistent efficacy on a pre-
expensive than triptans, but they do not seem to work as completely ventive medication.
or as quickly as triptans; their use has fallen off in the United States. There are currently five medications with U.S. Food and Drug
The triptans are selective 5-HT1B/1D receptor agonists marketed Administration (FDA) indication for migraine prevention, but
primarily for the acute treatment of migraine. Table 15–2 lists the only four are available in the United States: propranolol, timolol,
currently available migraine-specific therapies along with doses and topiramate, and divalproex sodium. Methysergide (Sansert) has
been approved for migraine prevention for many years but is no Topiramate is administered in doses of 25 to 200 mg, with most
longer available. Amitriptyline (not FDA approved for migraine people benefiting from doses of 25 to 100 mg. In clinical trials, it
prevention but frequently used) is a tricyclic antidepressant that was administered twice daily but many practitioners see benefit
can prevent migraine independent of underlying depression, but with daily dosing at night. Common side effects include weight
it would certainly be beneficial in individuals with coexisting loss, paresthesias, and taste disturbance (primarily with carbonated
depression or sleep disorders because of its sedating properties. beverages), with rare adverse events of nephrolithiasis, hypohydro-
Migraine prevention usually requires doses well below antidepres- sis, cognitive deficits, and increased eye pressure looking like
sant doses, ranging from 10 to 50 mg at bedtime. Rarely will doses glaucoma.
above 100 mg be necessary. Common side effects include sedation, Many other agents are used as preventive medications, including
weight gain, constipation, dry mouth, and orthostatic hypotension. other anticonvulsants, antidepressants, calcium channel blockers,
Of the FDA-approved preventives, the b-blocker antihyperten- angiotensin receptor blockers, memantine, and dietary supple-
sives were approved years ago and are effective, with propranolol ments. Data regarding their efficacy are either borderline or limited.
and timolol having indications for migraine prevention.
Propranolol is the most commonly used b-blocker for migraine
prevention, with doses ranging from 40 to 160 mg, rarely up to SUGGESTED READINGS
360 mg, usually given twice a day. This would be most appropriate Headache Classification Subcommittee of the International Headache
for individuals with hypertension, tremor, or performance anxiety. Society. The International Classification of Headache Disorders, 2nd ed.
Adverse events include fatigue, exercise intolerance, exacerbation of Cephalalgia 2004;24(suppl 1):1–150.
depression, and exacerbation of asthma. Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT
The anticonvulsants topiramate (Topamax) and divalproex 1B/1D agonists) in migraine: detailed results and methods of a meta-
sodium (Depakote) have been demonstrated effective for the pre- analysis of 53 trials. Cephalalgia 2002;22:633–658.
vention of migraine. Divalproex sodium dosing is usually between Lipton RB, Bigal ME, Diamond M, et al, and the AMPP Advisory Group.
Migraine prevalence, disease burden, and the need for preventive
250 and 1000 mg daily and comes in an extended-release prepara- therapy. Neurology 2007;68:343–349.
tion (Depakote ER) so it can be administered once daily. Common Sanchez-Del-Rio M, Reuter U, Moskowitz MA. New insights into
side effects include weight gain, tremor, and hair loss. Rrare but migraine pathophysiology. Curr Opin Neurol 2006;19:294–298.
serious side effects include hepatic failure, Pancreatitis, and platelet Silberstein SD, et al. Evidence-based guidelines for migraine headache (an
dysfunction. There is also a risk of neural tube defects in children of evidence-based review): report of the Quality Standards Subcommittee
mothers taking Depakote during pregnancy. If used in women of of the American Academy of Neurology. Neurology 2000;55:754–762.
child-bearing age, folic acid supplementation is recommended.
Chapter 16 with arrangements for an urgent computed tomography (CT)

scan of the head.
HEADACHES OTHER THAN Sudden onset of headache, or severe persistent headache that
reaches maximal intensity within a few seconds or minutes after
MIGRAINE the onset of pain, particularly warrants aggressive investigation.
Subarachnoid hemorrhage, for example, often presents with the
abrupt onset of excruciating pain and is often described by patients
Jan Kraemer, Joshua Pal, and Zahid H. Bajwa as ‘‘the worst headache in my life.’’ Cluster headache (CH) may
sometimes be confused with a serious headache because the pain
from a CH can reach full intensity within minutes. However, CH
usually lasts less than 1 to 2 hours and is associated with charac-
teristic ipsilateral autonomic signs such as lacrimation or
rhinorrhea.
The classification of (Table 16–1) and treatment for (Table 16–2)
INTRODUCTION headaches other than migraine are outlined.*
Chronic headache is a common reason for patients to present to

pain-management physicians. In the initial assessment of any head- TENSION-TYPE HEADACHE
ache, it is important to rule out serious underlying pathology, which
would necessitate more urgent and comprehensive management Tension-type headache (TTH) is the most common headache syn-
(Box 16–1). Whereas, normally, this has already been done by the drome, although the distinction between tension and migraine may
time the patient initially presents to the pain-management physician, not be based on a pathophysiologic difference.
it is important to remain vigilant when providing ongoing care in Many patients report daily headache symptoms for years and do
case new headache pathogenesis emerges in an established patient. not seek specialist consultation until very late in their course. There
It is important to pay attention to ‘‘danger signs’’ or clinical ‘‘red is a high correlation with analgesic abuse of over-the-counter
flags’’ because headaches may be the presenting symptom of a analgesics, muscle relaxants, acetaminophen, aspirin, opioids, bar-
space-occupying mass or vascular lesion, infection, metabolic dis- biturates, and benzodiazepines in these chronic headache sufferers.1
turbance, or systemic problem. The following pertinent positives in As a general rule, psychological factors play a more important role
the history and/or physical examination can serve as warning signs
of possible serious underlying disease (Box 16–2). Appropriate
transfer and management should be promptly initiated, possibly *Based on the International Headache Classification.
been approved for migraine prevention for many years but is no Topiramate is administered in doses of 25 to 200 mg, with most
longer available. Amitriptyline (not FDA approved for migraine people benefiting from doses of 25 to 100 mg. In clinical trials, it
prevention but frequently used) is a tricyclic antidepressant that was administered twice daily but many practitioners see benefit
can prevent migraine independent of underlying depression, but with daily dosing at night. Common side effects include weight
it would certainly be beneficial in individuals with coexisting loss, paresthesias, and taste disturbance (primarily with carbonated
depression or sleep disorders because of its sedating properties. beverages), with rare adverse events of nephrolithiasis, hypohydro-
Migraine prevention usually requires doses well below antidepres- sis, cognitive deficits, and increased eye pressure looking like
sant doses, ranging from 10 to 50 mg at bedtime. Rarely will doses glaucoma.
above 100 mg be necessary. Common side effects include sedation, Many other agents are used as preventive medications, including
weight gain, constipation, dry mouth, and orthostatic hypotension. other anticonvulsants, antidepressants, calcium channel blockers,
Of the FDA-approved preventives, the b-blocker antihyperten- angiotensin receptor blockers, memantine, and dietary supple-
sives were approved years ago and are effective, with propranolol ments. Data regarding their efficacy are either borderline or limited.
and timolol having indications for migraine prevention.
Propranolol is the most commonly used b-blocker for migraine
prevention, with doses ranging from 40 to 160 mg, rarely up to SUGGESTED READINGS
360 mg, usually given twice a day. This would be most appropriate Headache Classification Subcommittee of the International Headache
for individuals with hypertension, tremor, or performance anxiety. Society. The International Classification of Headache Disorders, 2nd ed.
Adverse events include fatigue, exercise intolerance, exacerbation of Cephalalgia 2004;24(suppl 1):1–150.
depression, and exacerbation of asthma. Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT
The anticonvulsants topiramate (Topamax) and divalproex 1B/1D agonists) in migraine: detailed results and methods of a meta-
sodium (Depakote) have been demonstrated effective for the pre- analysis of 53 trials. Cephalalgia 2002;22:633–658.
vention of migraine. Divalproex sodium dosing is usually between Lipton RB, Bigal ME, Diamond M, et al, and the AMPP Advisory Group.
Migraine prevalence, disease burden, and the need for preventive
250 and 1000 mg daily and comes in an extended-release prepara- therapy. Neurology 2007;68:343–349.
tion (Depakote ER) so it can be administered once daily. Common Sanchez-Del-Rio M, Reuter U, Moskowitz MA. New insights into
side effects include weight gain, tremor, and hair loss. Rrare but migraine pathophysiology. Curr Opin Neurol 2006;19:294–298.
serious side effects include hepatic failure, Pancreatitis, and platelet Silberstein SD, et al. Evidence-based guidelines for migraine headache (an
dysfunction. There is also a risk of neural tube defects in children of evidence-based review): report of the Quality Standards Subcommittee
mothers taking Depakote during pregnancy. If used in women of of the American Academy of Neurology. Neurology 2000;55:754–762.
child-bearing age, folic acid supplementation is recommended.
Chapter 16 with arrangements for an urgent computed tomography (CT)

scan of the head.
HEADACHES OTHER THAN Sudden onset of headache, or severe persistent headache that
reaches maximal intensity within a few seconds or minutes after
MIGRAINE the onset of pain, particularly warrants aggressive investigation.
Subarachnoid hemorrhage, for example, often presents with the
abrupt onset of excruciating pain and is often described by patients
Jan Kraemer, Joshua Pal, and Zahid H. Bajwa as ‘‘the worst headache in my life.’’ Cluster headache (CH) may
sometimes be confused with a serious headache because the pain
from a CH can reach full intensity within minutes. However, CH
usually lasts less than 1 to 2 hours and is associated with charac-
teristic ipsilateral autonomic signs such as lacrimation or
rhinorrhea.
The classification of (Table 16–1) and treatment for (Table 16–2)
INTRODUCTION headaches other than migraine are outlined.*
Chronic headache is a common reason for patients to present to

pain-management physicians. In the initial assessment of any head- TENSION-TYPE HEADACHE
ache, it is important to rule out serious underlying pathology, which
would necessitate more urgent and comprehensive management Tension-type headache (TTH) is the most common headache syn-
(Box 16–1). Whereas, normally, this has already been done by the drome, although the distinction between tension and migraine may
time the patient initially presents to the pain-management physician, not be based on a pathophysiologic difference.
it is important to remain vigilant when providing ongoing care in Many patients report daily headache symptoms for years and do
case new headache pathogenesis emerges in an established patient. not seek specialist consultation until very late in their course. There
It is important to pay attention to ‘‘danger signs’’ or clinical ‘‘red is a high correlation with analgesic abuse of over-the-counter
flags’’ because headaches may be the presenting symptom of a analgesics, muscle relaxants, acetaminophen, aspirin, opioids, bar-
space-occupying mass or vascular lesion, infection, metabolic dis- biturates, and benzodiazepines in these chronic headache sufferers.1
turbance, or systemic problem. The following pertinent positives in As a general rule, psychological factors play a more important role
the history and/or physical examination can serve as warning signs
of possible serious underlying disease (Box 16–2). Appropriate
transfer and management should be promptly initiated, possibly *Based on the International Headache Classification.
112 Chapter 16 HEADACHES OTHER THAN MIGR AINE
trigger points in the scalp, neck, trapezius, and superior oblique

Box 16^1 HEADACHES ASSOCIATED WITH SERIOUS muscle are found in similar proportions.
UNDERLYING PATHOLOGY The concept of a headache continuum has been proposed as a
unifying hypothesis that includes episodic and chronic TTH at one
Subarachnoid hemorrhage end and migraine at the other. In this view, the major distinction
Central venous thrombosis between migraine and TTH is the severity of headache, with TTH
Stroke being mild to moderate and migraine being moderate to severe.
Meningitis
Intracranial mass (tumor, infection) Both migraine and TTH could be considered different expressions
Carotid artery dissection of the same pathophysiologic processes, evinced by overlapping
Temporal arteritis symptomatic presentations and demonstrated clinical response to
Acute narrow angle glaucoma similar therapies.3 Unstable serotonergic neurotransmission and the
trigeminal neurovascular system may play important roles in the
pathogenesis of both disorders.
in these individuals than in patients with either migraine or CH, Another view is that chronic TTH encompasses at least two
whereas hereditary factors are less prominent.2 distinct mechanisms, one of which is indistinguishable from
In the revised International Headache Society (IHS) classifica- migraine. In this paradigm, very few patients encountered clinically
tion, the term tension-type headache replaces the previous terms have pure chronic TTHs, defined as frequent but always completely
‘‘muscle contraction headaches,’’ ‘‘tension headaches,’’ and featureless headache (e.g., without nausea, photophobia, phono-
‘‘chronic daily headaches.’’ Three subtypes are delineated: phobia, aggravation with movement, or throbbing qualities).
Most patients have chronic migraine, with some or all of the
n Infrequent episodic TTH with headache episodes less than 1 day
migraine-associated features listed previously; these same patients
a month.
also have frequent milder featureless headaches that are phenotypi-
n Frequent episodic TTH with headache episodes 1 to 14 days a
cally congruent with TTH.
month.
The general principles of TTH treatment are similar to those of
n Chronic TTH with headaches 15 or more days a month.
the prophylactic and abortive therapy of migraine. Simple analge-
TTHs feel like pressure or tightness around the head and have a sics such as acetaminophen, aspirin, and other nonsteroidal anti-
tendency to wax and wane in intensity. An easy clinical rule is that inflammatory drugs (NSAIDs) are the drugs of choice for abortive
TTHs are characterized as head pain devoid of typical migrainous therapy. Combination drugs containing ergotamine, caffeine, butal-
features (e.g., nausea, vomiting, photophobia, phonophobia, and bital, and codeine should be avoided owing to the potential for
aura). In addition, in patients with overlapping features of migraine drug dependency and analgesic-overuse (rebound) headaches.
and TTH, exacerbation by physical activity and food triggers is Prophylactic therapy is indicated for patients with chronic head-
more predictive of migraine than of TTH. aches requiring daily analgesics. Tricyclic antidepressants (e.g., ami-
Controversy exists regarding the pathophysiology of TTH. The tryptilline, nortryptilline) have been used most commonly and are
older concept of muscle contraction in the head and neck produ- effective in reducing headache activity, analgesic use, and headache-
cing vasoconstriction and ischemia as the most important factor related disability.4 Patients who have some features of migraine may
in the pathogenesis of TTHs is no longer widely held. benefit from b-blockers or calcium channel blockers, either alone or
Electromyographic studies have shown more muscle contraction in combination with an antidepressant.
with migraine than with TTH during the acute attack. Myofascial Biobehavioral techniques can be useful for managing chronic
TTHs, either alone or in combination with antidepressant medica-
tions. Psychotherapy, relaxation therapy, and biofeedback all may
be useful.5 Spinal manipulation did not have a positive effect in
Box 16^2 CLINICAL ‘‘RED FLAGS’’ IN HEADACHE patients with TTH in one study, but physical therapy also may
reduce the frequency of headaches in some cases. Possibly through
ASSESSMENT an enhanced placebo effect, both acupuncture and sham acupunc-
History
ture have been shown to be beneficial and superior to control
Sudden/rapid onset (‘‘first’’ or ‘‘worst’’ headache of patient’s life) treatments. Treatment of the periapical area of the maxillary
New, significant changes from patient’s preexisting headache pattern molars with the application of cold, anti-inflammatory agents,
Altered mental status/seizure/near-syncope and anesthetics has been shown to reduce both headache severity
Radiation of pain through neck, neck stiffness and frequency.
Immunosuppression/infectious disease
Onset during exertion
History of trauma
History of subarachnoid hemorrhage, polycystic kidney disease in first- CERVICOGENIC HEADACHE
or second-degree relatives
History suggestive of carbon monoxide poisoning (i.e., copresentation
Primary headache disorders can cause neck pain and cervical
with other patients with similar headache) muscle tenderness. In what has been termed cervicogenic headache,
Jaw claudication head pain can be referred from muscular, neurogenic, osseous,
vascular, or most likely, articular structures in the neck. The first
Physical Examination
three cervical spinal nerves and their rami are the primary periph-
Stiff neck, meningeal signs (head/leg raises)
Focal neurologic sign, local or lateralizing defect eral nerve structures that can refer pain to the head.
Alteration in mental status Cervicogenic headache can be characterized by unilateral head
Papilledema pain of fluctuating intensity that is increased by movement of the
Toxic appearance/fever head and radiates from occipital to frontal regions. The headache is
Periorbital or periauricular ecchymosis, hemotympanum, cerebrospi- precipitated by neck movement or sustained awkward head posi-
nal fluid drainage from facial orifice tioning or by external pressure over the upper cervical or occipital
Tenderness, swelling, diminished pulse in temporal artery region on the symptomatic side, and it typically does not shift from
Carotid artery bruit side to side. The pain is typically nonthrobbing, nonlancinating, of
Increased intraocular pressure
moderate to severe intensity, and of variable duration. Patients with
Severe hypertension
cervicogenic headaches may have restricted neck range of motion
Table 16^1. Current Diagnosis in Headache Other than Migraine*
Classification
TensionType Medication- Chronic Daily Paroxysmal

Characteristics Headache Cervicogenic Cluster Headache overuse Headache Sinus Headache Headache Hemicrania
Number of attacks At least 10 Variable One every other Headache1 present Related to the duration 15 or more More than five/
episodes day to eight per on 15 days/mo of the acute or chronic headache days day for more
occurring on day sinusitis per month than half of the
< 1 day/mo on time, although
average periods with
(<12 days/yr) lower frequency
may occur
Duration 30 min–7 days Variable 15–180 min if Variable Related to the duration 4 hr or more per 2–30 min
untreated of the acute or chronic day
sinusitis
Resolve within 7 days
after remission or
treatment of the
rhinosinusitis
Type of pain Pressing/tightening Pain referred from a Severe or very Variable with Frontal headache Variable Severe or very
(nonpulsating) source in the neck and severe unilateral characteristics accompanied by pain in severe unilateral
quality; mild or perceived in one or orbital, shifting, even one or more regions of orbital,
moderate more regions of the supraorbital, and/ within the same the face, ears, or teeth supraorbital,
intensity head and/or face or temporal pain day and/or temporal
pain
International Not aggravated by 1. Clinical or imaging 1. Ipsilateral 1. Regular overuse 1. Clinical, nasal 1. Same as cluster
Headache routine physical evidence of a disorder conjunctival for 3 mo of endoscopic, CT and/or headache
Classification activity such as or lesion within the injection and/or one or more MRI imaging and/or 2. Attacks
requirements walking or cervical spine or soft lacrimation drugs that can laboratory evidence of prevented
climbing stairs tissues of the neck. 2. Ipsilateral nasal be taken for acute or acute- completely by

2. Evidence that the pain congestion and/ acute and/or on-chronic therapeutic
can be attributed to or rhinorrhea symptomatic rhinosinusitis doses of
the neck disorder or 3. Ipsilateral eyelid treatment of 2. Headache and facial indomethacin
lesion based on at edema headache pain develop
least one of the 4. Ipsilateral 2. Headache has simultaneously with
following: forehead and developed or onset or acute
Demonstration of facial sweating markedly exacerbation of
clinical signs that 5. Ipsilateral worsened rhinosinusitis
implicate a source of miosis and/or during 3. Headache and/or facial
pain in the neck2 ptosis medication pain resolve within
Abolition of headache 6. Sense of overuse 7 days after remission
following diagnostic restlessness or 3. Headache or successful treatment
blockade of a cervical agitation resolves or of acute or acute-on-
structure or its nerve reverts to its chronic rhinosinusitis
supply previous pattern
Continued
Table 16^1. Current Diagnosis in Headache Other than Migraine*çcont’d

Classification
TensionType Medication- Chronic Daily Paroxysmal

Characteristics Headache Cervicogenic Cluster Headache overuse Headache Sinus Headache Headache Hemicrania
3. Pain resolves within within 2 mo
3 mo after successful after
treatment of the discontinuation
causative disorder or of overused
lesion medication
IHS 2.1—Infrequent 11.2.1—Cervicogenic 3.1.1—Episodic 8.2—MOH 11.5—Headache 1.5.1—Chronic 3.2—Paroxysmal
episodic TTH headache cluster headache attributed to migraine hemicrania,
rhinosinusitis 1.6.3—Probable subclass of
chronic migraine, cluster headache
transformed
migraine
2.3—Chronic
TTH, new daily
persistent
headache
3.2.2—Hemicrania
continua
*Based on the International Headache Classification.
CDH, chronic daily headache; CT, computed tomography; IHS, International Headache Classification; MOH, medication-overuse headache; MRI, magnetic resonance imaging; TTH, tension-type
headache.
Table 16^2. Current Therapy in Headache Other than Migraine
First-line/Abortive strategies
Pharmacologic PreventiveTreatment (Decreasing Order of Efficacy or
Type of Headache (Decreasing Order of Efficacy) NonpharmacologicTreatments Invasiveness) Second-line/Rescue Strategies
Tension type TCAs Biobehavioral techniques Acetaminophen, aspirin, and other Ergotamine, caffeine, butalbital,
Amitryptilline Physical therapy NSAIDs and codeine should be
Nortryptilline Acupuncture avoided or used sparingly
Mirtazapine Periapical molar intraoral application owing to the potential for
SSRIs of cold, anti-inflammatory, anesthetic drug dependency and MOH
TTH with migrainous features (either Botulinum toxin A
alone or in combination with an Myofascial trigger point release (if
antidepressant) present)
Calcium channel blockers
b-Blockers
Sinus Nasal corticosteroids and/or selective Referral to ENT surgeon Directed toward infectious etiology Nasal corticosteroids and/or
nasal antihistamines selective nasal antihistamines
Medication-overuse See text See TTH See TTH See TTH
Indomethacin- Indomethacin 75–250 mg daily in See TTH Indomethacin 75–250 mg daily in See TTH
responsive divided doses (initiate therapy divided doses (initiate therapy with
with 12.5 mg, two to three times/ 12.5 mg, two to three times/day;
day; titrate up dose every other titrate up dose every other day until
day until response elicited) response elicited)
Cluster (Consider discontinuing use during Surgical (complete or partial section 20 minutes of 6–15 L/min 100% Octreotide (SC) as
periods of remission) of the trigeminal nerve) oxygen alternative for patients with
Verapamil Continuous long-term DBS of the Sumatriptan (SC, intranasal) triptan therapy
Prednisone posterior hypothalamic gray matter Zolmitriptan (intranasal, PO) contraindications
Lithium (chronic form of cluster Prophylactic sphenopalatine ganglion DHE 45 (intranasal)
headaches) blocks
Ergotamine, methysergide,
cyproheptadine, and indomethacin

Temporomandibular No specific therapeutic strategy Low-level laser therapy Dietary measures, local heat, physical NSAIDs
joint Botulinum toxin A injections therapy, dental hygiene
Referral to experienced surgeon
Cervicogenic No specific therapeutic strategy Anesthetic block (if successful, Physical therapy, manipulative No specific therapeutic
subsequent percutaneous therapy strategy
radiofrequency neurotomy may
provide more sustained relief)
Intra-articular steroids
Referral to neurosurgeon (reserved for
compelling radiologic evidence for a
surgically correctable pathology in
patients who are refractory to all
reasonable nonsurgical treatments)
DBS, deep brain stimulation; DHE 45, dihydroergotamine; ENT, ear, nose, and throat; MOH, medication-overuse headache; NSAIDs, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin
reuptake inhibitors; TCA, tricyclic antidepressants; TTH, tension-type headache.
and may have ipsilateral neck, shoulder, or arm pain. Several sub- blocks of cervical structures or their nerve supply. Anesthetic block-
types of cervicogenic headache have been reported. Among these, ade of the zygapophyseal joints, cervical nerves, or medial branches
the best described are C2 neuralgia and third occipital nerve (C3) confirms the location and diagnosis and possibly predicts the
headache. treatment modalities that will most likely provide the greatest effi-
The first three cervical spinal nerves and their rami are the major cacy. Other headache etiologies should be pursued if the response to
peripheral nerve structures that can refer pain to the head. The C1 diagnostic blockade is incomplete. Imaging is primarily used
spinal nerve (suboccipital nerve) innervates the atlanto-occipital to search for secondary causes of pain that may require surgery
joint. Pathology or injury affecting this joint is a potential source or other, more aggressive forms of treatment.
for pain that is referred to the occipital region of the head. The C2 The natural course of cervicogenic headache is variable. The
spinal nerve and its dorsal root ganglion have a close proximity to majority of cervicogenic headaches occurring after whiplash will
the lateral capsule of the atlantoaxial (C1–2) zygapophyseal joint. resolve within a year of the trauma.10 There is no proven effective
Both this joint and C2–3 zygapophyseal joints are innervated by the treatment for cervicogenic headache. Physical therapy is the pre-
C2 spinal nerve. C2 neuralgia is typically described as a ‘‘deep or ferred initial treatment because it is noninvasive and may provide
dull pain’’ that radiates from the occipital to parietal, temporal, long-term improvement for cervicogenic headache. Manipulative
frontal, and periorbital regions. A paroxysmal sharp or shocklike therapy is also beneficial for cervicogenic headache at 5 weeks.11
pain centered in the occipital region is often superimposed over the However, combined treatment with manipulation and neck exercise
constant pain. Ipsilateral eye lacrimation and conjunctival injection was not significantly better than either treatment alone.12 The
are common associated signs. Arterial or venous compression of the intensity of headache may initially worsen during or after physical
C2 spinal nerve or its dorsal root ganglion has been implicated as a therapy, especially if it is vigorously applied. Physical treatment is
cause for C2 neuralgia in some cases. Meningioma has been rarely better tolerated when initiated with gentle muscle stretching and
implicated. Pathology and trauma to the C1–2 and C2–3 zygapo- manual cervical traction. Therapy can be slowly advanced as toler-
physeal joints can also refer head pain. The C2–3 zygapophyseal ated to include strengthening and aerobic conditioning. Using anes-
joint and the innervating third occipital nerve (dorsal ramus of thetic blockade for temporary pain relief may enhance patient
C3) appear most vulnerable to trauma from acceleration-decelera- tolerance of physical therapy.
tion ("whiplash") injuries of the neck. Pain from the C2–3 zygapo- Pharmacologic treatment options for chronic cervicogenic
physeal joint is referred to the occipital region of the head but is also headache include medications that are used for the preventive or
referred to the frontotemporal and periorbital regions. palliative management of neuropathic pain, such as tricyclic anti-
Occipital neuralgia causes pain in the distribution of the greater depressants, anticonvulsants, and others. However, these medica-
or lesser occipital nerves or of the third occipital nerve, sometimes tions have not been evaluated in controlled clinical trials for the
accompanied by diminished sensation or dysesthesia in the affected treatment of cervicogenic headache. Available evidence suggests that
area. The pain is often deep or burning, with superimposed parox- pharmacologic therapy does not provide substantial pain relief for
ysms of shooting pain. Anesthetic blockade of the nerve temporarily cervicogenic headache in most cases. In addition, patients with
reduces or abolishes the pain. Occipital neuralgia must be distin- chronic cervicogenic headache may overuse or become dependent
guished from occipital referral of pain from the atlantoaxial or on analgesics and develop medication-overuse headache (MOH).
upper zygapophyseal joints or from tender trigger points in neck Despite these observations, the judicious short-term use of analgesic
muscles or their insertions. This distinction may be difficult despite medication may provide enough pain relief to allow greater patient
careful evaluation of clinical features and thorough physical and participation in a physical therapy and rehabilitation program.
neurologic examination, and accurate diagnosis is achieved via Anesthetic injections can temporarily reduce or relieve pain and
image-directed anesthetic blockade. Occipital neuralgia that is may allow greater participation in physical treatments. Complete
refractory to medial therapy may be extremely difficult to control. relief of pain by diagnostic blockade of the cervical spinal nerve,
Long-term peripheral neurostimulation may be a safe and relatively medial branch, or zygapophyseal joint is likely to predict response
effective method for the treatment of intractable occipital neural- to radiofrequency neurotomy. Patients who have incomplete
gia.6,7 A positive analgesic response to occipital nerve block may not response to anesthetic blocks should not undergo radiofrequency
predict the therapeutic effect from occipital nerve stimulation in neurotomy or surgical procedures. Greater and lesser occipital
patients with medically refractory occipital neuralgia.8 nerve blockade may provide temporary but substantial pain relief
The anatomic locus of cervicogenic headache is the trigemino- in some cases, although the benefit of this treatment does not
cervical nucleus in the upper cervical spinal cord, where sensory appear to be specific for cervicogenic headache.
nerve fibers in the descending tract of the trigeminal nerve (trigem- Percutaneous radiofrequency neurotomy can be considered for
inal nucleus caudalis) are believed to interact with sensory fibers cervicogenic headache refractory to noninvasive therapy if diagnos-
from the upper cervical roots. This functional intersection of tri- tic anesthetic blockade of cervical nerve, medial branch, or zygapo-
geminal sensory and upper cervical pathways is believed to allow physeal joint blockade is temporarily successful in providing
the bidirectional transmission of pain signals between the neck and complete pain relief.13 After recurrence, headache relief could be
the trigeminal sensory receptive fields of the face and head. reestablished by repeating the procedure. Side effects of the proce-
The prevalence of cervicogenic headache in the general popula- dure are related to the denervation of the third occipital nerve and
tion is estimated to be 0.4% to 2.5%, but it may be as high as 20% include mild ataxia, numbness, and temporary dysesthesia; none of
in patients with chronic headache. The mean age of patients with these side effects required intervention.
this condition is 43 years, and the condition is four times more Small, uncontrolled, retrospective studies suggest that some
prevalent in women than in men. Third occipital headache appears patients may obtain relief from intra-articular steroid injections at
to be a common cause of cervicogenic headache. In a study of 100 the C2–3 zygapophyseal joint. Cervical epidural steroid injections
patients who had whiplash, the prevalence of third occipital nerve may give short-term pain relief in cases of multilevel disk or spine
headache was 27%. degeneration.14
Distinguishing cervicogenic headache from other headache types A variety of surgical interventions, such as neurectomy, dorsal
using clinical features can be difficult. Previous studies evaluating rhizotomy, and microvascular decompression of nerve roots or
patients with chronic neck pain and headache found no distinguish- peripheral nerves, have been performed for presumed cases of cer-
ing features on history or examination that confirmed a definitive vicogenic headache. The available data are limited to small observa-
diagnosis of third occipital headache before nerve blocks.9 The diag- tional studies, and these have generally reported that surgery
nosis can be established by demonstrating a cervical source of head is associated with only incomplete or temporary benefit for
pain. The diagnosis should be confirmed by controlled anesthetic pain relief. Case reports have suggested a benefit of surgical
decompression for patients with C2 neuralgia who have C2 root Table 16^3. Description of the IHS-CH-1 Group*
entrapment by a hypertrophied atlantoepistrophic ligament or me-
ningioma. Pain intensification or anesthesia dolorosa are potential IHS Criterion IHS-CH-1 Patients n (%)
adverse surgical outcomes. Given the uncertain and temporary ben-
efit, surgical procedures for cervicogenic headache are not recom- Attack Duration between 15 and 1808 min
mended unless there is compelling radiologic evidence for a Not fulfilling 194 (67)
surgically correctable pathology in patients who are refractory to <15 min 9 (3)
all reasonable nonsurgical treatments. >180 min 185 (64)
Attack Frequency between 1 and 2 to 8 per day
CLUSTER HEADACHE Not fulfilling 63 (22)
CHs are characterized by repetitive headaches that occur almost >8/day 17 (6)
daily for weeks to months at a time, followed by periods of remis- <1 or 2/days 46 (16)
sion. CH pain usually begins in or around the eye or temple; less
Severe Intensity of Attacks
commonly it may start in the face, neck, or ear. These headaches
begin quickly without warning, are unilateral, and reach maximal Not fulfilling 12 (4)
intensity within a few minutes. The headache is usually deep, excru-
Orbital/Temporal Location of Pain
ciating, continuous, and explosive in quality, although occasionally
it may be pulsatile and throbbing. It remains unilateral during a Not fulfilling (neck, occipital) 6 (2)
single cluster, but it can switch sides during the next cluster in a
small percentage of patients. Some patients report superimposed Unilateral Pain
paroxysms of stabbing ice pick–like pain in the periorbital region Not fulfilling 3 (1)
that last for a few seconds. Most patients with CH are restless and
may pace when an attack is in progress, in contrast to migraine 1 Ipsilateral Autonomic Symptoms
sufferers who tend to rest in a dark, quiet room. Not fulfilling 11 (4)
Nausea and vomiting may also be associated with CHs, although
less commonly than with migraines. Photophobia may occur ipsi- *N = 289. Patients were grouped by failing IHS criterion.
lateral to the pain. CHs are associated with ipsilateral lacrimation From van Vliet JA, Eekers PJE, Haan J, et al. Evaluating the IHS criteria for
and redness of the eye, stuffy nose, rhinorrhea, sweating, pallor, and cluster headache—a comparison between patients meeting all criteria and
Horner’s syndrome (otherwise, focal neurologic symptoms are patients failing one criterion. Cephalagia 2006;26:241–245.
rare). Over 50% of sufferers report that alcohol is a potent precip-
itant of CHs during a cluster bout; this sensitivity to alcohol ceases
when the cluster ends.
Whereas a typical CH lasts from 15 minutes to 3 hours, the
frequency of attacks depends upon the type of CH. Eighty percent
to 90% of patients suffer from episodic CHs. They are characterized
by one to three attacks of periorbital pain daily over a 6- to 12-week Table 16^4. Comparison of Clinical Characteristics of
period, followed by an average pain-free interval ranging typically IHS-CH and IHS-CH-1 Patients with
from 6 months to many years. The other type, chronic CHs, is Attacks Exceeding 3 Hr
characterized by the absence of sustained periods of remission.
Either form of CH can transform into the other. Most patients IHS-CH-1 Patients
experience one cluster per year, but this is not predictable. In with Attacks
80% of patients, attacks occur between 9 PM and 9 AM; most tend IHS-CH Exceeding 3 Hr
to recur at the same hour each day for the duration of a single
cluster. N 1163 185
It has been proposed that a CH represents a spectrum in which Male:female* 3.7:1 1.6:1
some patients may all have the (IHS) criteria minus one (IHS- Age at onset, years 32.3 ± (13.7), 31.5 ± (14.4),
CH-1) and still be considered to have a CH/‘‘cluster-like headache’’ (mean [SD]) 76% 64%
(Table 16–3).15 Typical CH features such as restlessness during Restlessness*
attacks and episodic attack pattern were frequently seen in the Smoking
IHS-CH-1 group. Furthermore, van Vliet and colleagues15 sug-
gested that attack frequency may not be a useful diagnostic criterion Current 70% 49%
and the upper limit of 3 hours for CH may be too restrictive (Table Stopped 20% 31%
16–4). In the IHS-CH-1 patients with attack duration longer than Never 9% 20%
3 hours (n + 185; 64%), attack duration ranged between 190 sec- Nausea* 27% 38%
onds and 5 days (median 5 hr).15 Ninety patients reported attacks Vomiting 12% 18%
lasting 6 hours or longer, with 36 reported attacks lasting longer
than 24 hours.15 This ‘‘spectrum hypothesis’’ is also supported by Photo-phonophobia* 54% 67%
the finding that 42% of the IHS-CH-2 patients with ‘‘long attacks’’ Circadian rhythm* 64% 49%
occasionally had attacks that completely fulfill the IHS-CH Nocturnal attacks* 78% 67%
criteria.15 Episodic pattern* 78% 65%
The prevalence of CHs is less than 1%, with men affected more
commonly than women and a peak age of onset of 25 to 50 years.16 *P .005.
The pathophysiology remains unclear; however, the three main CH, cluster headache; IHS, International Headache Classification.
characteristics include the trigeminal distribution of the pain, the From van Vliet JA, Eekers PJE, Haan J, et al. Evaluating the IHS criteria for
presence of ipsilateral cranial autonomic features, and the episodic cluster headache—a comparison between patients meeting all criteria and
and circadian pattern of attacks. The trigeminovascular system is patients failing one criterion. Cephalagia 2006;26:241–245.
likely the final common pathway for the pain of CH, as is also true United States. Methysergide had been linked with retroperitoneal
of migraine. With the exception of periodicity, all clinical features of fibrosis with long-term uninterrupted use and so was usually uti-
CH can be explained by a lesion involving the cavernous sinus lized ‘‘episodically.’’ Ergotamine, methysergide, cyproheptadine,
portion of the internal carotid artery (the only anatomic area and indomethacin may also be somewhat effective.
with coexisting nociceptive and autonomic eye innervation). Patients with chronic CHs that do not respond to medications
Neuroimaging studies suggest that neuronal changes in the inferior may be considered for trigeminal nerve surgical therapy. Although
posterior hypothalamus may be involved in contributing to patho- some patients may experience short-term pain relief from radiosur-
physiologic processes that occur in CH patients.17 Although CH has gery for refractory CHs, none had relief sustainable for longer
generally been considered a sporadic disorder, increasing evidence than 2 years.24 Thus, initial radiosurgery of the trigeminal nerve
supports a genetic role in the etiology. Other factors that may be does not yield long-term pain relief for medically refractory cluster
important include cigarette smoking and alcohol use. Cigarette headache (MRCH) patients,24 and repeat radiosurgery has also
smoking and alcohol use are found in the majority of those suffer- failed to provide long-term analgesia for MRCH.25 Therefore,
ing from CH, and an increased incidence of right-to-left cardiac trigeminal nerve radiosurgery should not be offered for MRCH.25
shunt has been identified. The majority of patients (male > female) Continuous long-term deep brain stimulation (DBS) of the
have a history of smoking prior to the onset of CHs. Red wine was posterior hypothalamus may be effective in certain patients with
the most common alcohol trigger for CHs, followed by beer intractable CH as well as short-lasting unilateral neuralgiform head-
(usually within an hour after drinking). ache attacks with conjunctival injection and tearing (SUNCT) syn-
Abortive therapy of CHs can be difficult because of the drome.26–29
short duration of each episode. Acute CHs can be aborted by inha- Encouraging results of open-label studies appear to justify larger
lation of 100% oxygen in the majority of patients. Oxygen inhala- prospective trials, but these do not yet justify widespread clinical
tion should be given for 20 minutes with the patient in an upright application of this technique.27 Occipital nerve stimulation (ONS),
sitting position at a rate of at least 7 L/min, with an increase in rate which may be effective for the treatment of refractory occipital
to 15 L/min in nonresponders. No absolute contraindications are neuralgia, may also be worthwhile evaluating for the treatment of
known for oxygen. intractable CHs.30,31 As with occipital neuralgia, a positive analgesic
Subcutaneous sumatriptan and intranasal sumatriptan are both response to occipital nerve block may not be predictive of the ther-
effective abortive treatments for CHs, usually within 30 min- apeutic effect from ONS in patients with medically refractory
utes.18,19 Subcutaneous sumatriptan has been reported to be the chronic headaches.8
most effective.15 Oxygen (100%) with a flow of at least 7 L/min
over 15 minutes and 6 mg subcutaneous sumatriptan are therapies
of first choice for the acute treatment of CH attacks.20 Intranasal SUNCT SYNDROME
zolmitriptan (5–10 mg) has been shown to be modestly effective at
30 minutes. Oral zolmitriptan (10 mg) is modestly effective for SUNCT syndrome is a rare but very disabling condition that sig-
acute episodic (but not chronic) CH.21 Whereas these are useful nificantly adversely affects quality of life. SUNCT syndrome is con-
first-line abortive agents, owing to their vasoconstrive properties, sidered in the spectrum of trigeminal-autonomic cephalgia. Patients
triptans are contraindicated in patients with ischemic cardiovascu- generally present with brief attacks of severe unilateral pain in the
lar disease. Octreotide (100 mcg subcutaneously) is an effective and orbitotemporal region, associated with ipsilateral cranial autonomic
well-tolerated alternative in these patients. Intranasal dihydroergo- disturbances, typically with ipsilateral conjunctival injection and
tamine (DHE 45; 1 mg) has been shown to relieve the pain of acute lacrimation.32 Patients with SUNCT syndrome usually have a
cluster attack, although the onset time of headache response is not mean age of onset around 50 years with a male predominance
well known, and it is also contraindicated in ischemic cardiovascu- and may be misdiagnosed as having trigeminal neuralgia or CHs.
lar disease. Primary and secondary forms exist, with the secondary form most
In contrast to migraine, most patients with CHs will require commonly associated with lesions of the posterior fossa or pituitary
both prophylactic and abortive treatment for the duration of the adenoma.32
cluster. Prophylactic therapy should be started as soon as possible at The treatment of SUNCT syndrome is generally refractory to
the onset of a cluster episode and can be tapered after the expected most commonly employed therapies. Large series suggest that
duration of the cluster has passed. The drugs can be restarted at the lamotrigine is the most effective preventive agent, with topiramate
lowest effective dose if symptoms recur during remission. As a gen- and gabapentin also being useful.20 Intravenous lidocaine may also
eral treatment consideration, care should be taken to avoid the be helpful as an acute therapy when patients are extremely dis-
overuse of analgesic medications, because patients with episodic tressed and disabled by frequent attacks.20
and chronic CH can develop MOH. CH patients are at a signifi-
cantly higher risk of developing MOH if they have a personal or
family history of migraine. MOH
A double-blind, cross-over comparison of lithium and verapamil
(120 mg three times a day) for CH prophylaxis showed both to be Chronic daily headache related to medication overuse has also been
equally effective, but verapamil had fewer side effects and a shorter referred to by the terms ‘‘analgesic rebound headache’’ and ‘‘drug-
latency period.22 Prophylaxis of CH with verapamil at a daily dose induced headache.’’ MOH may occur in patients who have tension,
of at least 240 mg (maximum dose depends on efficacy and/or migraine, and CHs. MOH is prevalent in about 1% of the popula-
tolerability) appears to be the agent of choice.20 Although there tion and is higher in women than in men. In a longitudinal study of
are no large well-designed class I or II trials available, steroids are 32,067 adults, individuals who used analgesics daily or weekly at
clearly effective in CHs. If steroids are utilized, the use of at least 100 baseline had significantly increased risk for the development of
mg methylprednisone (or equivalent corticosteroid) given orally or chronic migraine and chronic nonmigrainous headache 10 years
at up to 500 mg intravenously per day over 5 days (then tapering later.33
down) may be considered.20 Steroids are effective for prophylaxis, The diagnosis of MOH should be suspected in patients with
but they should not be used chronically owing to side effects. frequent or daily headaches despite, or because of, the regular use
Lithium may be reasonably effective for the chronic form of CHs.23 of headache medications. Medications such as acetaminophen,
Methysergide, lithium, and topiramate have been recommended butalbital-aspirin-caffeine (Fiorinal), and aspirin are the agents
as alternative treatments.20 Methysergide has been discontinued most commonly involved in MOH.34 Other medications com-
in the United States and, therefore, is clinically unavailable in the monly involved in MOH were analgesics (35%), ergots (22%),
opioids (12.5%), triptans (2.7%), and different combinations of n Recurrent, self-limited headaches associated with rhinogenic
medications (28%).35 symptoms are most likely migraine.
Clinicians debate whether frequent medication use is a cause n Prominent rhinogenic symptoms, with headache as one of
or consequence of chronic headache. Plausible mechanisms for several symptoms, should be evaluated carefully for otolar-
causality include two main schools of thought. The first is that yngologic conditions. The preferred standard is nasal endos-
continuous analgesic exposure causes antinociceptive tolerance copy. However, magnetic resonance imaging (MRI) and CT
along with diminishing medication effectiveness. The second can be substituted.
holds that medication tolerance and dependence result in repeated n Headache associated with fever and purulent nasal discharge
‘‘miniwithdrawals’’ and rebound headache with fluctuations in is likely rhinogenic in origin.
serum drug levels. n Referral to a headache specialist should be considered for
Prevention of MOH can be accomplished through limitation of new-onset headache, frequent (more than once a week) head-
acute medications to no more than 10 days per month. Preventive ache, headache associated with neurologic symptoms or signs,
therapies should be used as the mainstay in patients with frequent or headache that does not respond adequately to conven-
headaches. tional therapy.
Cessation of the offending drug should be combined with
limited rescue medication and preventive therapy. One option Patients with noninfectious rhinogenic symptoms who have
for patients with intractable and severe daily headaches who headache as a minor symptom should be given nasal corticosteroids
exhibit a clear pattern of analgesic abuse is inpatient treatment and/or selective nasal antihistamines. Migraine symptoms with no
with parenteral DHE 45. This is implemented while they are evidence of infection should be treated with a trial of migraine-
being detoxed from the analgesics of abuse and while building specific medication and scheduled for a follow-up evaluation.39
therapeutic levels of prophylactic medications. Silberstein and
coworkers36 demonstrated that 91% of 300 patients with refrac-
tory headache became headache-free after hospitalization and PAROXYSMAL HEMICRANIA
treatment with metoclopramide and repetitive injections of
DHE 45. The average duration of hospitalization was 7 days, Paroxysmal hemicrania is classified as a subset of the chronic form of
and most patients experienced headache relief within 2 to CHs, although in our view paroxysmal hemicrania is a different dis-
3 days.36 Subsequently, patients usually revert to having episodic order than CHs because of the age and sex of the patient population,
headaches while on prophylactic therapy. Recommendations for the frequency of daily attacks, and the shorter duration of individual
appropriate prophylactic therapy are similar in nature for episodes. However, other features of chronic paroxysmal hemicrania
patients with chronic daily headaches or TTHs. are similar to those of CHs, including nocturnal attacks and auto-
nomic symptoms such as ipsilateral tearing, rhinorrhea, conjunctival
injection, periorbital swelling, and Horner’s syndrome.40
SINUS HEADACHE The syndrome is characterized by 15 to 20 intense, brief, focal
headache attacks per day. The pain is primarily unilateral and loca-
Although sinus headache is commonly diagnosed by physicians and lizes to the forehead, eye, temple, or periaural area. It occurs pre-
self-diagnosed by patients, acute or chronic sinusitis appears to be dominantly in women. Unlike CHs, there is total responsiveness to
an uncommon cause of recurrent headaches. The prominence of indomethacin. This disorder is so rare that the diagnosis should not
‘‘sinus symptoms’’ often leads to a misdiagnosis of ‘‘sinus head- be made without a thorough evaluation, including an imaging study
ache’’ in patients who meet diagnostic criteria for migraine. In a of the brain that satisfactorily rules out an aneurysm or arteriove-
previous observational study that involved 2991 patients with a nous malformation in addition to other mass lesions.
history of physician or self-diagnosed sinus headache and no pre- Treatment consists of indomethacin (75–250 mg daily in divided
vious history of migraine; 88% fulfilled IHS criteria for migraine or doses), which stops the headaches associated with these syndromes.
migrainous headache.37 Sinus pain, pressure, and congestion com- The benefit is apparent within 3 to 4 days of an adequate dose. It is
monly occurred in these patients in association with typical a good strategy to begin with 12.5 mg, two to three times daily, and
migraine features such as pulsing head pain and sensitivity to activ- then increase the dose every other day until the beneficial effects are
ity, light, and sound. apparent. Other NSAIDs and corticosteroids do not significantly
True acute sinus headache is delineated by IHS criteria, but it benefit these patients.
occurs in conjunction with acute sinusitis, fever, and purulent dis-
charge. The absence of these features should prompt consideration
of migraine as an underlying etiology of headache associated with TEMPOROMANDIBULAR JOINT
sinus pain or pressure. Severity, extent, and location of sinus-related HEADACHE
pain do not correlate with the extent or location of mucosal disease
seen on imaging.38 Temporomandibular joint (TMJ)–associated headache is typically
Pain related purely to sinus conditions may have features that seen in young women in the third or fourth decade of life. It is often
aid in distinguishing it from migraine. Sinus-related pain or head- present as unilateral ear or preauricular pain that radiates to the
ache is typically described as a ‘‘pressure-like’’ or ‘‘dull’’ sensation jaw, temple, or neck. Patients often describe ‘‘deep,’’ ‘‘dull,’’ and
that is usually periorbital and bilateral. However, it can be unilateral ‘‘continuous pain,’’ usually worse in the morning. Physical exami-
with a deviated septum, middle or inferior turbinate hypertrophy, nation may reveal tenderness of the muscles of mastication and, less
or unilateral sinus disease. In addition, sinus-related pain is typi- commonly, clicking of the joint. It is usually associated with jaw
cally associated with nasal obstruction or congestion, lasts for days motion limitations and deviation of the jaw upon opening. Many
at a time, and is usually not associated with nausea, vomiting, cases are difficult to distinguish from TTHs.
photophobia, or phonophobia. The treatment of headache owing to TMJ syndrome primarily
A committee published guidelines in 200539 to address the evi- involves therapy of the joint disorder itself. Most cases can be trea-
dence from multiple disciplines that sinus headache (headache of ted with local heat, physical therapy, dental hygiene, NSAIDs, and
rhinogenic origin) and migraine may be confused with one another: dietary measures.41 Occasionally, patients may require referral to an
experienced surgeon. Arthroscopic approaches may be successful.
n A stable pattern of recurrent headaches that interfere with Initial studies support the use of some new therapeutic modal-
daily function is most likely migraine. ities. Botulinum toxin type A injected into the muscles of
mastication may be of benefit. In a randomized, double-blind, com- 21. Bahra A, Gawel MJ, Hardebo JE, et al. Oral zolmitriptan is effective in
parison with placebo, botulinum toxin was shown to significantly the acute treatment of cluster headache. Neurology 2000;54:1832–1839.
reduce pain in patients with chronic facial pain.42 Placebo-con- 22. Leone M, D’Amico D, Frediani F, et al. Verapamil in the prophylaxis
trolled evaluation of 15 sessions of low-level laser therapy in TMJ of episodic cluster headache: a double-blind study versus placebo.
syndrome revealed significant improvement in mouth opening and Neurology 2000;54:1382–1385.
23. Ekbom K. Lithium for cluster headache: review of the literature and
range of motion with the actively treated group and a significant preliminary results of long term treatment. Headache 1981;21:132–139.
reduction in pain with both groups.43 24. McClelland S, Tendulkar RD, Barnett GH, et al. Long-term results of
radiosurgery for refractory cluster headache. Neurosurgery
2006;59:1258–1262.
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2. Blanchard EB, Kirsch CA, Applebaum KA, Jaccard J. The role of 26. Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior
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for treatment of severe occipital neuralgia: a pilot study. Anesth Analg of eight patients. Lancet 2007;369:1099–1106.
2005;101:171–174. 32. Alore PL, Jay WM, Macken MP. SUNCT syndrome: short-lasting
8. Schwedt TJ, Dodick DW, Trentman TL, et al. Response to occipital unilateral neuralgiform headache with conjunctival injection and
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Chapter 17
DENTAL PAIN
OROFACIAL PAIN
Dentinal Pain (see Table 17–1)
Rafael Benoliel, Richard A. Pertes, and Eli Eliav
The pain originating in dentine is sharp, deep, and usually evoked
by external stimuli: hot, cold, sweet, sour, and sometimes, salty
foods and drinks. The pain generally subsides within a few seconds.
Extreme temperatures (hot soup or ice cream) may cause pain in
healthy or restored teeth, but this is often mild and transient.
The most common processes associated with dentine pain are
INTRODUCTION early dental caries, defective restorations, and areas of exposed den-
tine (e.g., abrasion or erosion of the enamel) and exposed roots
Orofacial pain includes, by definition, pain that originates from (due to gingival recession). Diagnosis is by direct observation and
oral structures accompanied by facial pain. The facial area examination with a sharp dental probe, augmented by the use of
includes the region demarcated as below the orbitomeatal line, dental radiographs.
above the neck, and anterior to the ears. However, the craniofacial
region has a high density of anatomic structures, and pain
The Cracked-tooth‘‘Syndrome’’
often radiates from one area to the other. As a result, the
patient with orofacial pain may seek help from a number of A cracked tooth induces sharp pain after biting that resolves imme-
specialists. diately after pressure on the tooth ceases. Localization to the
The prevalence of orofacial pain is around 17% to 26%, out of affected area of teeth is good, but identification of the exact tooth
which 7% to 11% is chronic.1 Most patients, therefore, suffer acute is imprecise. The patient may have pain and discomfort associated
pain that is in the most part secondary to dental or intraoral soft with cold and hot stimuli in the area. Diagnosis is by percussion or
tissue pathology. Epidemiologic data on dental pain are sparse and pressure on the cusps of the suspected teeth at different angles and
of poor quality, and its reported prevalence in community dwelling by asking the patient to bite on individual cusps using a Ene
adults ranges from 12% to 40%, depending on the description of wooden stick or a predesigned bite stick (available commercially).
dental pain used. Chronic orofacial pain is most frequently due to Probing of Essures and, if the tooth is restored, the margins of
musculoskeletal pain, but neuropathic and neurovascular pains are restorations may aid in identifying fractures.
also encountered.
Treatment of Dentinal Pain (see Table 17–1)
ACUTE OROFACIAL PAIN Removal of the carious lesion and restoration of the tooth with
plastic restorative materials generally resolve symptoms.
Most frequently, dental pain is due to dental caries, although a Sensitivity usually disappears within a day or two, but it may persist
broken filling or tooth abrasion may also cause dental sensitivity. (weeks) when the carious lesion is deep. Treatment of the cracked
Other oral pains are periodontal or gingival in origin (Tables 17–1 tooth depends on the state of the tooth (existing restorations, peri-
to 17–4). Acute dental and periodontal pain is moderate to odontal condition) and the extent of the fracture. Existing restora-
severe in intensity (6–10 on a 10-cm visual analog scale [VAS]). tions associated with tooth fractures can be replaced with adhesive
In about 60% of cases, pain is hard to localize but spreads into restorative materials; these may be successful but are associated with
remote areas of the head and face; periodontal pain, however, is postoperative sensitivity. Often, cracked teeth require crowning.
usually localizable. There is considerable overlap in pain referral Exposed cervical dentine may be hypersensitive to thermal stimuli
patterns for maxillary and mandibular sources, and the extent of and toothbrushing in the area. Acidic foods or beverages frequently
referral to adjacent facial structures positively correlates with pain enhance dentinal sensitivity. Desensitizing toothpastes with ingre-
intensity. dients such as stannous fluoride or potassium nitrate will improve
Generally, a connection exists between caries extent and the symptoms for most cases, or a variety of physical and chemical
presenting symptomatology. Initial caries, located in the superfi- agents applied by the dentist are able to induce a smear layer or
cial layer of the dentine, induces tooth sensitivity to various block the tubules. Tubule-blocking agents include resins, glass
stimuli such as change in temperature and sweet substances. ionomer cements and bonding agents; strontium chloride or
Pain is usually not spontaneous. As the lesion penetrates, pain acetate; aluminium, potassium, or ferric oxalates; silica- or calcium-
produced by these stimuli becomes both stronger and prolonged. containing materials; and protein precipitants.
Eventually, when the caries affects the tooth pulp, strong, spon-
taneous, paroxysmal pain develops that is usually intermittent in
nature. As the root apex is invaded by bacterial and tissue dis- Pulpal Pain (see Table 17–2)
integration by-products, the tooth becomes very sensitive to
chewing, touch, and percussion. At this point, pain generally Pulpal pain is spontaneous, strong, often throbbing, and exacer-
becomes continuous and the tooth is no longer sensitive to bated by changes in temperature, sweet foods, and pressure on
changes in temperature. In clinical practice, however, the demar- the carious lesion. Evoked pain outlasts the stimulus for a
cation between these various stages may overlap and the tooth number of minutes (unlike stimulus-induced dentinal pain) and
may be sensitive simultaneously to temperature changes and to can be excruciating. Localization is poor and becomes poorer as
chewing. pain severity increases. Pain originating from the pulp is not usually
122 Chapter 17 OROFACIAL PAIN
Table 17^1. Current Diagnosis and Therapy of Dentinal Pain
Primary Examination
Diagnosis Pain Intensity Location Referral Clinical Symptoms Findings Radiography Treatment
Caries Mild to Locally Adjacent Sensitivity to Faulty restorations, Caries, Removal of
moderate around teeth sweet and carious lesion exposed caries,
affected tooth thermal stimuli dentine restoration of
tooth
Exposed Mild to Locally Adjacent Sensitivity to cold Gingival recession, Not relevant Desensitization
cervical moderate around teeth and to exposed sensitive
dentine affected tooth toothbrushing dentine
Cracked Mild to Locally Localized Sensitivity to Pain on pressure to Not relevant Removal of
tooth moderate around biting on tooth tooth cusp fractured
affected tooth or chewing in material and
the area restoration or
tooth
crowning
continuous and abates spontaneously; the precise explanation for Depending on the diagnosis, treatment may aim at conserving
such abatement is unclear. Pain may increase and throb when the the pulp, extirpating it, or extracting the tooth. Pulpal pain nor-
patient lies down and, in many instances, wakes the patient from mally disappears immediately after treatment. Irreversible pulpitis
sleep. In some cases, pain may be continuous and dull, periodically dictates endodontic therapy or extraction. Normal pulpal vitality
exacerbated (by stimulation or spontaneously) for short (minutes) and no pain to percussion indicate that the diagnosis is reversible
or long (hours) periods. When the pain is episodic, sharp, and pulpitis. The tooth pulp may be preserved by caries removal with
paroxysmal, it may be confused with other conditions that mimic indirect pulp capping and the use of mild analgesics.
pain of pulp origin such as trigeminal neuralgia (TN).
Application of ethyl chloride on a pledget of cotton wool usually
induces a short, mildly painful response from intact teeth. The PERIODONTAL PAIN (see Table 17–3)
pulpal condition may be reversible or irreversible. In reversible
pulpitis, pain response is increased (hyperalgesia) and outlasts the The periodontal tissues include the alveolar bone, the periodontal
stimulus, usually by less than 10 seconds. In irreversible pulpitis, ligament, and the gingivae. A major feature of chronic periodontal
application of ethyl chloride results in excruciating pain that out- disease is that it is generally painless. Pain originating in the peri-
lasts the stimulus for well beyond 10 seconds. Percussion aids in odontal structures is easily localized; the affected teeth are very
localizing the tooth with painful pulpitis; 80% are tender to per- tender on chewing and are readily identified by percussion.
cussion. Nonvital pulps do not react to cold application. Periodontal pain usually results from an acute inflammatory
Table 17^2. Current Diagnosis and Therapy of Pulpal Pain
Primary Clinical Examination

Diagnosis Pain Intensity Location Referral Symptoms Findings Radiography Treatment
Reversible Moderate to Poorly localized Adjacent teeth Hypersensitive Large, faulty Restoration in Tooth may be
pulpitis severe to the affected to thermal restoration. Large proximity to amenable to
jaw stimuli carious lesion or dental pulp conservative
exposed pulp. therapy: new
Hypersensitive to restoration,
cold application. repair
Irreversible Severe Very poorly Opposing jaw, Severe Large, faulty Deep carious Pulp extirpation
pulpitis localized to temple continuous or restoration lesion. or tooth
the affected paroxysmal Large carious extraction
jaw pain lesion or exposed
Hypersensitive pulp
to cold and Extremely
sometimes to hypersensitive to
biting on the cold application
tooth with pain
outlasting
stimulus by
> 10 sec
Table 17^3. Current Diagnosis and Therapy of Periodontal Pain
Pain Primary
Diagnosis Intensity Location Referral Clinical Symptoms Examination Findings Radiography Treatment
Periapical Severe Localized Adjacent teeth, Pain on chewing or Affected tooth not Deep Débridement
periodontitis to tooth opposing approximating teeth vital restoration, of pulp
jaw, ipsilateral May be associated Extreme tenderness to deep caries chamber and
temple, with intra- or percussion on the Old root canal canals
regional extraoral swelling affected tooth therapy Redo root canal
lymph nodes (DAA) Hypersensitivity in May or may therapy
soft tissue overlying not be May require
apical area associated antibiotic
Swollen tender with a therapy
regional lymph periapical
nodes radiolucency
Lateral Severe Localized Adjacent teeth, Pain on chewing Tooth may be vital Usually Curettage and
periodontal to tooth opposing Intraoral swelling Deep periodontal generalized irrigation of
abscess jaw, ipsilateral pocket periodontal pocket
temple, Associated soft tissue disease If tooth pulp
regional swelling: usually A radiolucency affected, may
lymph nodes located more may be need
coronally than in observed in extirpation or
DAAs the lateral débridement
periodontal Antibiotic
space therapy
DAA, dentoalveolar abscess.
process of the gingivae, the periodontal ligament, and alveolar bone Whereas inflammation and pain originate from the periodontal
due to bacterial or viral infection. periapical tissues, the source of infection usually lies within the
pulp chamber and canal. In order to eliminate this source, the
pulp chamber is opened and the root canal débrided and dressed
Acute Periapical Periodontitis in accordance with current endodontic practice. Patients with
localized periapical pain or swelling generally recover quickly
Pain associated with acute periapical inflammation is spontaneous, with local treatment, and there is no demonstrable benefit
of moderate to severe intensity, and long lasting (hours). Pain from antibiotic supplementation. Apical abscess should be drained
increases with biting on the affected tooth and, in more advanced via the tooth or soft tissue incision, and antibiotics are usually of
cases, even with closing the mouth and bringing the tooth into no additional benefit. If cellulitis, fever, and malaise are present, or
contact with the opposing teeth. In these cases, the tooth feels the medical status of the patient requires this, systemic administra-
extruded and is very sensitive to touch. Frequently, the patient tion of antibiotics should be instigated.
reports symptoms of pulpal pain that preceded pain from the peri-
apical area. Localization of pain originating from the periapical area
is usually precise, and the patient is able to indicate the affected Lateral Periodontal Abscess
tooth.
The affected tooth is readily located by means of gentle tooth Pain characteristics of a lateral periodontal abscess are very sim-
percussion, and the periapical vestibular area may be tender to ilar to those of acute periapical periodontitis and usually result
palpation. The pulp of the affected tooth is nonvital (i.e., it does from a blockage of a deep periodontal pocket. Acute periodontal
not respond to thermal changes or to electrical pulp stimulation). abscesses may also be associated with dental implants. During
In more severe, purulent cases, swelling of the face associated with examination, tender swelling and redness of the gingivae may be
cellulitis is sometimes present and can be associated with fever and noticed, generally more coronally than in acute periapical
malaise. The affected tooth may be extruded and mobile, both lesions. The affected tooth is sensitive to percussion and may
vertically and horizontally. Usually, when facial swelling appears, be mobile and slightly extruded. In more severe cases, cellulitis,
pain diminishes in intensity, probably owing to rupture of the fever, and malaise may occur. A deep periodontal pocket is
local periosteum and the decrease in tissue pressure caused by generally located around the tooth and may exude pus. Acute
pus accumulation. The diagnosis of these advanced cases is referred lateral periodontal abscess causes rapid alveolar bone destruction,
to as dentoalveolar abscess. so a deep infrabony pocket is usually present on the radiograph.
Radiographs are of limited use in the diagnosis of acute periap- Irrigation and curettage of the pocket should be performed.
ical periodontitis because no periapical radiographic changes are A vertical incision for drainage is recommended when the
detected in the early stages. There is a lack of correlation between abscess is fluctuant and cannot be adequately approached
the periapical radiographic picture, the tooth symptomatology, and through the pocket. When cellulitis, fever, and malaise are pre-
the microbiology or histology of the periapical lesion. sent, systemic antibiotic administration may be recommended.
Table 17^4. Current Diagnosis and Therapy of Gingival/Mucosal Pain
Primary
Diagnosis Pain Intensity Location Referral Clinical Symptoms Examination Findings Imaging Treatment
ANUG Moderate to Localized When severe, may Pain around gingivae; Ulcerated interdental Not needed If possible,
severe spread to the face worse on brushing papilla, with antiseptic
and associated with destruction irrigation and
bleeding Fetid odor local
May report ‘‘tooth Painful débridement
tightness’’ or a lymphadenopathy Antibiotic therapy
metallic taste
PHGS Moderate Diffuse Lymph nodes may Increasingly seen in Erythematous Not needed Hydration,
throughout become very adults (third decade) gingivae, vesicles or infection
the mouth painful Malaise, fever ulceration control,
Vesicular eruption in Lymphadenopathy reduction of
oral mucosa fever
Vesicles may break May need antiviral
down and join to therapy
form ragged ulcers
Food Moderate to Localized to When severe, may Pain after chewing Swollen and red May show Curettage, if
impaction severe affected spread to the face Patient may complain interdental gingivae; fractured possible, and
quadrant of retained food easily bleed on restoration. irrigation
between teeth probing If longstanding Reestablishment of
Open contact point may be anatomic
between adjacent associated with contacts between
teeth; may be due to localized teeth with
fractured restoration periodontal adequate
Food debris may be disease and/or restoration
found interproximal
caries
Pericoronitis Moderate to Diffuse but When severe, may Spontaneous pain but Usually associated May show an Initially, drainage
severe located spread to the face may be aggravated with impacted, impacted third and irrigation
toward the by chewing or partially erupted molar may be needed
back of the swallowing third molars that are Usually not needed Antibiotics in
mouth partially covered by for initial selected cases
inflamed gingival diagnosis If molar impacted,
tissue extraction may
Limited mouth be needed
opening may be
present
ANUG, acute necrotizing ulcerative gingivitis; PHGS, primary herpetic gingivostomatitis.
As in periapical periodontitis, the need for antibiotic supplemen- strictly by b-lactamase–producing anaerobic microorganisms, and
tation, in addition to local treatment, is unclear. Pain generally the first-line treatment suggested is amoxicillin with clavulanic acid
subsides within 24 hours of treatment. (875 mg twice daily).
Interrelationships between Pulpal and Periodontal Diseases: Acute Necrotizing Ulcerative Gingivitis
‘‘Perio-Endo’’ Lesions
Acute necrotizing ulcerative gingivitis (ANUG) is an ulcerative gin-
Deep periodontal pockets can sometimes involve accessory canals gival disease characterized by pain, bleeding, and papillary necrosis.
(in the furcation or laterally) and, in extensive lesions, can reach the Soreness and pain are characteristically felt at the margin of the
root apex of the tooth and cause retrograde pulp inflammation. A gums. Pain is intensiEed by eating and toothbrushing; these activ-
second possibility is of an apical abscess that exudates through a ities are usually accompanied by gingival bleeding. In the early
periodontal pocket. Treatment for all these situations is initially stages, some patients may complain of a feeling of tightness
endodontic, followed by conventional periodontal treatment. The around the teeth. A metallic taste is sometimes experienced, and
prognosis of endodontic lesions causing periodontal symptomatol- generally, there is a fetid odor from the mouth. Pain is localized to
ogy is better than in periodontally initiated lesions. the affected areas, but in cases with widespread lesions, pain is
experienced throughout mouth. Low-grade fever and malaise are
sometimes present, and a regional lymphadenopathy is typical.
Vertical Root Fracture
Necrosis and ulceration are present on the marginal gingiva with
A fracture of the tooth that involves most of the root will induce different degrees of gingival papillary destruction. Fusiform bacillus
pain on biting. Root fractures are more common in endodontically and spirochetes are often isolated from gingival ulcers, and ANUG
treated teeth that have been restored with a post and core. The patients often demonstrate an anaerobic flora. An adherent grayish
fracture induces a periodontal pocket along its length and may slough represents the so-called pseudomembrane that is present in
also cause abscess formation. Currently, extraction is the only treat- the acute stage. Acute herpetic infection of the gums (herpetic
ment option for vertical root fractures. gingivostomatitis) can sometimes resemble ANUG, but the clinical
appearance and associated signs and symptoms are different. The
papillary necrosis typical for ANUG is absent in the herpetic infec-
Gingival Pain (see Table 17–4) tion, whereas herpetic lesions create a typically ‘‘punched-out’’
appearance located at the gingival margin.
Food Impaction Treatment includes swabbing and gentle irrigation of the ulcer-
ative lesions, preferably with chlorhexidine or an oxidizing agent
Food impaction results from food forced between teeth that causes (hydrogen peroxide), and scaling and cleaning the teeth. Systemic
pressure and inflammation of the gums. Localized pain develops antibiotics are recommended, especially when fever and malaise are
between two teeth, usually after meals and especially when food is present (amoxicillin/clavulanic acid 875 mg twice daily, metronida-
Ebrous (e.g., meat, celery). The pain is associated with a feeling of zole 250 mg three times daily).
pressure and discomfort but may sometimes become severe and
diffuse. The patient may report that pain gradually diminishes
until evoked again at the next meal or the pain may be relieved MUCOSAL PAIN
immediately by removing the food impacted between the teeth with
a toothpick or dental floss. Pain originating from the oral mucosa can be either localized or of a
Upon examination, there may be a faulty contact between two more generalized diffuse nature. Localized pain is usually associated
adjacent teeth so that food is frequently trapped between these with a detectable erosive or ulcerative lesion, whereas diffuse pain
teeth; the gingival papilla is tender to touch and bleeds easily. The may be associated with a widespread infection, a systemic disease,
two adjacent teeth are usually sensitive to percussion. Prompt treat- or other unknown factors. The localized pain associated with a
ment is essential to prevent cervical caries and interdental alveolar detectable lesion results from physical, chemical, or thermal
bone resorption. The cause of the faulty contact between the teeth is trauma, viral infection, or lesions of unknown origin. Pain is usually
often a carious lesion, and restoring the tooth will eliminate the mild to moderate, but when there is irritation, mechanically or by
pain. Faulty restorations may also lead to food impaction. In some sour, spicy, or hot foods, it may become quite severe and last for
cases, although the contacts are tight, food impaction may occur, some minutes.
and creating anatomic escape grooves adjacent to the marginal ridge Detailed descriptions of the various lesions of the oral mucosa
may eliminate food impaction. are beyond the scope of this chapter and only the most common
lesions, recurrent aphthous stomatitis, and acute herpetic gingivo-
stomatitis are briefly discussed.
Pericoronitis
Pain, which may be severe, is generally located at the distal end of
the arch of teeth in the lower jaw. Pain is spontaneous and exacer- Aphthous Lesions
bated by closing the mouth. In more severe cases, pain is aggravated
by swallowing, and limited mouth opening may occur. Acute peri- Recurrent aphthous ulcers represent a very common but poorly
coronal infections are common in teeth that are incompletely understood mucosal disorder. They occur in men and women of
erupted and partially covered by a flap or operculum of gingival all ages, races, and geographic regions. It is estimated that at least
tissue. The operculum is acutely inflamed (red, edematous), and one in five individuals has at least once been afflicted with aphthous
frequently, an indentation of the opposing tooth can be seen on ulcers.2 The condition is classified as minor, major, and herpetiform
the swollen gingival flap. Occasionally, fever and malaise are present. on the basis of ulcer size and number.
Irrigation between the operculum and the affected tooth with Recurrent aphthous stomatitis is characterized by a prodromal
saline or antibacterial agent will remove debris. Trauma can be burning sensation from 2 to 48 hours before an ulcer appears.
eliminated by grinding or extracting the opposing tooth. Systemic Although small in diameter (0.3–1.0 cm), this lesion may be quite
antibiotic administration is initiated when there is limited mouth painful and induces a painful regional lymphadenopathy. In the
opening or the patient is febrile or immunosuppressed. The infec- mild form, healing occurs within 10 days and pain is usually
tion in pericoronitis is multimicrobial, predominantly caused mild to moderate in severity. In the more severe forms (major
aphthous ulcers), deep ulcers occur that may be confluent, are atrophic glossitis. This is usually associated with observable atrophic
extremely painful, and interfere with speech and eating. Such changes of the tongue, in particular absence of Eliform and fungi-
lesions may last for months, heal slowly, and leave scars. form papillae. Atrophic glossitis and burning mouth sensations
Treatment is mostly symptomatic, including the application of a have also been associated with Helicobacter pylori colonization of
topical protective emollient for the mild form and the use of topical tongue mucosa and nutritional deficiency.
corticosteroids and tetracycline to decrease healing time for the
more severe form. Recently, cyanoacrylate has been used as an effec-
tive tissue adhesive for steroids and tetracycline. The use of diclo- PAIN FROM SALIVARYGLANDS
fenac, a topical nonsteroidal anti-inflammatory drug (NSAID), was
also found effective. Pain from the salivary glands is usually associated with salivary
gland duct blockage. Pain from salivary glands is localized to the
affected gland and is of moderate to severe intensity. The salivary
Acute Herpetic Gingivostomatitis gland is swollen and very tender to palpation. Salivary flow from
affected glands is reduced and sometimes completely abolished.
Oral infections caused by herpes simplex type 1 are widespread, Pain is intensified by increased saliva production, such as when
even among otherwise healthy people. Whereas most of these her- starting meals, and can be induced by applying an acidic stimulant
petic infections are mildly symptomatic, young children are at risk (citric acid is the standard stimulant) to the tongue. Many cases of
for developing extensive oropharyngeal vesicular eruptions when salivary gland blockage are associated with ascending bacterial
first infected with the virus. This initial outbreak is known as pri- infection of the gland. Pus may be secreted from the salivary duct
mary herpetic gingivostomatitis. There has been a general trend for when the gland is infected, and pain may be associated with fever
the mean age of patients with acute herpetic stomatitis to increase, and malaise.
and currently the majority of cases (>50%) suffer the first attack When blockage is diagnosed, surgical or endoscopic approaches
during their third decade.3 The incidence of oral herpes simplex are indicated to remove the blockage. In the acute bacterial infec-
infection is particularly high in immunocompromised patients and tion stage, antibiotic therapy is recommended. No antibiotics are
occurs in up to 50% of hospitalized patients with acute leukemia. recommended for mumps or recurrent parotitis.
Proper diagnosis and treatment are essential, particularly in elderly
and immunocompromised patients.
The appearance of oral lesions is preceded by a prodromal phase TEMPOROMANDIBULAR DISORDERS
(1–2 days) during which the patient feels unwell and may have
fever. Fever, lymphadenopathy, and difficulty eating and drinking Temporomandibular disorder (TMD) is an umbrella classification
are prominent during the active phase. Intraoral vesicles rarely that includes ailments of the temporomandibular joints (TMJs)
remain intact and rapidly rupture to form ulcers that may coalesce. and masticatory muscles. TMD-related facial pain has been found
The gingivae usually appear red and swollen, particularly at the to occur in 4% to 12% of the population, and severe symptoms are
margins. In immunocompetent patients, fever usually recedes reported by 10% of subjects. Some signs or symptoms of TMD are
within 4 days and the lesions disappear with 10 to 14 days. extremely common, joint clicking, for example, is found in 20% to
Although a self-limiting disease, intraoral symptoms may persist 30% of the population. However, only 3% to 11% are assessed
for up to 4 weeks, causing significant discomfort. Clinical diagnosis as needing treatment. These figures are compatible with the data
is usually sufficient but may confirmed by laboratory tests. on the percentage of individuals who seek treatment (1.4%–7%).
Young children, immunocompromised patients, or adults Masticatory muscle and TMJ tenderness were found in 15% and
unable to ingest fluids may require hospitalization to maintain 5%, respectively, of a large population examined.4 However, muscu-
fluid balance, prevent dehydration, control the infection, and pro- lar tenderness was self-reported by only about a third of these, sug-
vide pain control. A soft, bland diet preceded by a local anesthetic gesting that many patients have asymptomatic muscle tenderness.
mouth rinse is recommended. Oral hygiene may be maintained by Signs and symptoms of TMD have been found in all age groups,
rinsing with a mild bicarbonate or saline solution or a nonalcoholic peaking in 20- to 40-year-olds. Signs of TMD have been described
solution of 0.2% chlorhexidine. Antiviral agents such as acyclovir in children and adolescents but are usually mild. In a group of
and famciclovir should be considered part of early management of adolescents, treatment need was assessed at 7%.5 TMDs may also
primary herpetic gingivostomatitis. Providing supportive care and occur in edentulous patients. Accumulated evidence suggests that
educating parents about transmission of the virus are important. symptoms in the elderly may be lower than in the general popula-
tion, but some studies show a slight elevation in the prevalence of
some signs (e.g., joint sounds, limited mouth opening) in this age
Diffuse Mucosal Pain group.6 There is a female preponderance of TMD signs and symp-
toms, especially of muscular origin. Most studies also report that
When generalized diffuse pain is felt in the oral mucosa, it usually the vast majority of patients (up to 80%) who seek treatment are
has a burning nature and may be accompanied by a dysgeusia, females7 (Tables 17–5 and 17–6).
predominantly of a bitter metallic quality. This pain may result
from a direct insult to the tissues due to bacterial, viral, or fungal
infection, which can be identiEed by the characteristic appearance Masticatory Myofascial Pain
of the oral mucosa. Diagnosis is aided by microbiologic and other
laboratory examinations. In cases of chronic fungal infection (can- The diagnosis of masticatory myofascial pain (MMP) is based on
didiasis), possible underlying etiologic factors such as prolonged the history and clinical examination of the patient. MMP is char-
broad-spectrum antibiotic therapy, immunodeEciencies, and acterized by regional, unilateral pain around the ear, the angle/body
other debilitating factors should be investigated. Radiation therapy of the mandible, and the temporal region (see Table 17–5). Referral
to the head and neck region may result in acute mucositis with patterns include intraoral, auriculotemporal, supraorbital, and
severe generalized mucosal pain. Decreased salivary flow is a late maxillary areas, depending on the muscles involved and the inten-
sequela of radiation therapy that may result in chronic pain and sity of the pain. Pain is aggravated during jaw function, with tran-
discomfort of the oral mucosa. Burning sensation of the oral sient spikes of pain occurring spontaneously. In addition to pain,
mucosa, particularly the tongue, may result from systemic diseases, there may be deviation of the mandible on opening, fullness of the
such as chronic iron deEciency anemia, and may be associated with ear, dizziness, and soreness of the neck, particularly if muscle trigger
Table 17^5. Current Diagnosis of Temporomandibular Disorders
Diagnosis Pain Intensity Primary Location Referral Clinical Symptoms Examination Findings Imaging
MMP Moderate Angle of mandible, Depending on Continuous pain, Tender pericranial, masticatory and cervical Not relevant
temporal, involved muscles: exacerbated on chewing muscles
periauricular forehead, neck, and Difficulty in chewing Myofascial trigger points
intraoral regions Acute malocclusion: Deviation and limitation of mouth opening
clinically unverifiable Ethyl chloride spray onto muscle relieves
pain and increases mouth opening
ADDwR Moderate to Periauricular Ear, angle of mandible Pain on chewing Tender TM joint, associated with reciprocal MRI or arthrography:
severe Joint sounds clicking displaced articular
Deviation to affected side on mouth opening meniscus (reducing)
May have pain on loading the joint by biting
a hard stick contralaterally
ADDwoR Moderate to Periauricular Ear, angle of mandible Pain on chewing Very tender TM joint. Deviation to affected MRI or arthrography:
severe May report a history of joint side and limitation of mouth opening. Pain displaced articular
sounds on loading the joint by biting a hard stick menisus
Unable to fully open mouth contralaterally. (non-reducing)
DJD Moderate to Periauricular Ear, angle of mandible Pain and difficulty with Very tender TMJ; may occur bilaterally Plain radiographs or CT:
severe Muscles of chewing Usually associated with crepitation in the may be degenerative
mastication Stiffness of the jaws; usually affected joint changes with
Headache, neck pain worse in the evening but There may be no initial correlation between microcystes,
not particularly severe in clinical and imaging findings hypercortication and
the morning (if so, lasts Pain on loading the joint by biting a hard osteophyte formation
< 30 min) stick contralaterally.
IJD Moderate to Periauricular Ear, angle of mandible Pain and difficulty with Very tender, often swollen, TMJ
severe Headache, neck pain chewing Usually associated with crepitation in the Destruction of articular
Stiffness of the jaws and affected joint surfaces

pain in the muscles May occur bilaterally Often similar
Jaw stiffness is particularly TMJ involvement usually occurs in advanced radiographic picture as
severe in the morning and stages of generalized inflammatory in DJD
lasts > 30 min arthritides
Joint destruction may lead to an anterior
open bite
Depending on underlying disorder associated
with autoimmune or hematologic
abnormalities
ADDwR, anterior disk displacement with reduction; ADDwoR, anterior disk displacement without reduction; CT, computed tomography; DJD, degenerative joint disease; IJD, inflammatory joint disease;
MMP, masticatory myofascial pain; MRI, magnetic resonance imaging; TM, temporomandibular; TMJ, temporomandibular joint.
Table 17^6. Current Therapy of Temporomandibular Disorders
Diagnosis Treatment Options

MMP Physical: Home or institutional physiotherapy to maintain muscle strength and mobility and restore normal mouth
opening. Spray (with ethyl chloride) and stretch exercises. Biofeedback, soft laser, physical self-regulation program
(breathing training, postural relaxation, and proprioceptive reeducation).
Soft diet: For acute cases, a soft diet allows the muscles to rest.
Bite appliance: Flat occlusal appliance made of hard acrylic. Adjusted intraorally to maintain even contacts. Usually
worn only during sleep.
Pharmacologic: Acute cases may be treated with analgesics or NSAIDs: Paracetamol/acetaminophen 250–500 mg qid;
naproxen 500 mg bid; ibuprofen 200–400 mg qid. Chronic cases may require tricyclic antidepressants: amitriptyline
(10–35 mg daily), cyclobenzaprine (10–30 mg/day), clonazepam (0.5 mg daily), or gabapentin (2700–3600 mg daily).
Psychological: Cognitive behavioral therapy.
Trigger point injection: Lidocaine (2%), mepivacaine (3%), or procaine injection into muscle trigger points.
TMJ pain Physical: As above.
Bite appliance: Repositioning appliances have been advocated to recapture the disk; however, they fail to do so in the
long term, so we suggest flat appliances as above. Some data suggest that contacts on the posterior region of the bite
plate may lead to off-loading of the joint and may be used initially. Readjustment of the plate to allow full contacts
should be performed to prevent occlusal changes.
Pharmacologic: NSAIDs are usually required to reduce symptoms. Comorbid MMP should be treated concomitantly,
as above.
Arthrocentesis: Is able to restore mouth opening in disk displacement without reduction and may improve symptoms
in other intra-articular disorders.
Surgery: Either arthroscopic or open is reserved for resistant cases or cases with other clear indications for surgery
(hyperplasia, ankylosis).
MMP, masticatory myofascial pain; NSAIDs, nonsteroidal anti-inflammatory drugs; TMJ, temporomandibular joint.
points are present. Pain is dull, heavy, tender, and rarely, throbbing, approach. More rarely, the TMJ may be affected by infectious or
and the severity may fluctuate during the day but is moderate; the metabolic arthritides which are not be dealt with in this chapter.
average pain duration is about 5.5 hours. Some patients experience Internal derangement signifies an abnormal anatomic relation
the most intense pain in the morning (21%) or late afternoon between the condylar head and the articular disk when the teeth are
(79%), and others have no fixed pattern. Pain-free days may be in normal occlusion. In most cases, the disk is anteriorly displaced
reported, and fortunately, the pain rarely wakes the patient. MMP (see Fig. 17–1B).
has been clearly shown to be a chronic or fluctuating pain condi-
tion; over 5 years, 31% of patients suffered continuous MMP, 36%
AnteriorDiskDisplacementwithReduction (see Fig. 17–1B and C)
experienced recurrent pain, and 33% remitted.8
Examination usually reveals limited active mouth opening (<40 During mouth opening, the condyle on the affected side meets the
mm, interincisal). Forced (passive) opening by the examiner may posterior band of the anteriorly displaced disk, encounters some
reveal a slightly increased opening. Tenderness to palpation is usu- resistance, then moves under the disk proper (reduction). During
ally present in masticatory muscles unilaterally, and it is a distin- closing, the condyle will slip off the anteriorly positioned disk and
guishing feature of MMP patients. The masseter is the muscle most return into the glenoid fossa. The sound that the condyle makes on
commonly involved (>60%), the medial pterygoid and temporalis mounting the disk during opening and then slipping off during
muscles are tender in about 40% to 50% of cases, commonly uni- closing causes the characteristic reciprocal clicking of anterior
laterally. The sternocleidomastoid, trapezius, and suboccipital mus- disk displacement with reduction (ADDwR). Patients with
cles are usually tender in 30% to 45% of patients, very often ADDwR may be totally asymptomatic and report only joint clicking
bilaterally. Typically, there are localized tender sites and trigger or popping sounds that may or may not bother them. ADDwR may,
points in muscle, tendon, or fascia. A hypersensitive bundle or however, be symptomatic with pain that is associated with chewing,
nodule of muscle fiber of harder than normal consistency is the particularly hard foods. The affected TMJ may be tender to palpa-
physical finding most often associated with a trigger point. tion. Although pain is usually mild, it may become moderate to
Trigger points may be associated with a twitch response when sti- severe with VAS scores of 6 to 7. When the disk is displaced uni-
mulated. In addition, trigger point palpation may also provoke a laterally, the mandible will deviate to the affected side during open-
characteristic pattern of regional referred pain and/or autonomic ing until the first click occurs—this signifies ‘‘reduction’’ or a return
symptoms. Referral to the teeth may be prominent and may often to normal relationship. Mouth opening then continues undeviated
cause misdiagnosis as dental pathology. and is usually not limited; there may be some pain at maximal
opening.
Pain Associated with theTMJ Anterior Disk Displacement without Reduction

(see Fig. 17–1C and D)
The most common conditions associated with pain of the TMJ are
internal derangements, which may be painful when associated with In anterior disk displacement without reduction (ADDwoR), the
joint inflammation (Fig. 17–1 and Table 17–5). More rarely, degen- condyle is unable to mechanically pass under the disk, and there-
erative joint disease (DJD) or inflammatory arthritic diseases may fore, there is no reduction. Attempts to open the mouth further
affect the TMJ. Often, these TMJ entities are comorbid with muscle induce pain located over the joint and are usually associated with no
pain, usually MMP, and thus require a combined treatment increased opening. The joint is generally very tender to palpation.
Closed Maximal Opening Radiographic evidence of DJD is very common (14%–44%) in

asymptomatic individuals, but only 8% to 16% will have clinically
4 detectable disease. DJD affects women, particularly after the age of
40 to 50. Pain is located in the TMJ and periauricularly and may
2
spread to adjacent structures. Patients complain of difficulty in
3 1 chewing, jaw stiffness, and tiredness. Jaw stiffness is usually more
normal
severe in the evening. The TMJ and muscles of mastication are very
tender. Mouth opening is restricted and deviates to the affected
side; crepitation is generally present. Imaging often reveals sub-
chondral bone sclerosis, flattening, lipping (osteophyte formation),
and microcyst formation. DJD may occur after trauma to the TMJ
and may be more severe in its clinical presentation than its primary
wR
A AD
D
B counterpart.
Inflammatory Joint Disease

The TMJ may be involved in the clinical presentation of a number
of systemic arthritides including rheumatoid and psoriatic arthritis.
ADDwoR In most cases, the patient is already diagnosed, and TMJ involve-
ment is a sign of increasing disease severity. The management of
such cases, therefore, involves the addition of selected TMD-specific
therapies to the existing treatment. The TMJ may be very painful, at
times swollen, and will limit function. Imaging reveals joint destruc-
tion similar to that observed in DJD but often more rapid in its
progression. Laboratory findings may include a raised erythrocyte
C D sedimentation rate, anemia, leukocytosis, and the presence of
Figure 17^1. Internal derangements of the temporomandibular autoantibodies.
joint. A, Normally when the mouth is in the closed position, the
condyle lies below the articular disk.B, Mouth opening begins with
rotational movement followed by translation of the condyle over the
eminence to the maximal opening, which is usually 40 mm or more; Treatment
movementis fully coordinated with the disk.C, In ADDwR, the disk is Not all patients with acute TMDs will develop a chronic pain dis-
anteriorly located relative to normal, often the condyle is located order. Predictors of chronicity include high initial pain intensity,
under the posterior attachment.During opening, the condyle reduces high disability score, higher scores of emotional distress, the pres-
(resumes a normal position) under the disk and full opening is unlimited ence of myofascial pain (versus TMJ disorders), and female gender.
and characterized by a normal condyle/disk relation.D, In ADDwoR, Patients developing chronicity also differ significantly in numerous
the disk is anteriorly located relative to normal but is unable to reduce biopsychosocial variables (e.g., they suffer from more current anx-
during opening; mouth opening remains limited and the disk remains iety disorders, mood disorders, and somatization disorders).
anteriorly displaced, even at maximal opening (usually < 30mm). Treatment of TMDs with a variety of conservative methods
Movement is thus on the posterior attachment.1, condyle; 2, articular consistently results in high (75%–90%) success rates. In general,
disk, 3, posterior attachment; 4, fossa; 5, eminence; ADDwoR, anterior treatment is aimed at palliation and is based on clinical diagnosis;
disk displacement withoutreduction; ADDwR, anterior disk because the etiology is unclear, no treatment is curative. Extensive
displacement with reduction. research shows that there are no compelling data to support any
intervention as capable of TMD eradication or modification.
Moreover, conservative therapies are consistently successful and
Analysis of fluids obtained from the upper joint space during in no way inferior to more invasive or irreversible procedures
arthrocentesis reveals proinflammatory cytokines so that an active such as surgery, occlusal adjustment, and prosthetic rehabilitation.
inflammatory process is present. Pain in ADDwoR may become The data thus support a conservative approach to the management
quite severe with VAS scores of 7 to 9 and will severely affect the of TMDs. This is reinforced by findings that the natural history of
patient’s functional capabilities. The patient will present with TMD includes an extensive number of patients who will either
limited mouth opening (20–25 mm) and a sharp deviation to the substantially fluctuate or remit over time and rarely progress to
affected side when asked to open the mouth. Onset is usually acute severe pain.
and may be preceded by a history of ADDwR. In some patients, Treatment aims in TMD patients include reducing pain, restor-
there may be a slow transition from ADDwR to ADDwoR. The ing function and range of motion, decreasing or eliminating aggra-
patient has a consistent reciprocal click but reports that, at times, vating or contributing factors, and increasing bite comfort and
sudden-onset restricted mouth opening occurs with no click. muscle strength. In addition, we aim to reduce psychological
Mandibular movements often relieve this situation, and the patient distress, restore social functioning, and cease or prevent drug
returns to ADDwR; this condition is simply termed ADDwR with abuse. The assessment of treatment outcome is based on accurate
intermittent locking. If ADDwoR is untreated, a degree of physio- assessment of pain intensity and frequency and the evaluation of
logic adaptation occurs whereby the articular tissues are stretched changes in psychosocial comorbidity.
and the patient may therefore present with minimally limited Therapy for TMDs falls into a number of categories: physical,
mouth opening (30–35 mm) accompanied by a lesser degree of pharmacologic, psychological, trigger point injection (for MMP),
deviation. TMJ arthrocentesis, or TMJ surgery and is often multidisciplinary.
Treatment of TMD very often combines conservative interventions,
and different centers have variable protocols depending on patients’
DJD
signs and symptoms and clinician’s preferences. Treatment dura-
DJD is a chronic noninflammatory disease that affects the articular tion is generally 4 to 6 months but may be longer in selected cases
cartilages of synovial joints, particularly load-bearing ones. (see Table 17–6).
addressed. The assessment of psychological distress in MMP

Physical and Combined Modalities
patients may be performed with established questionnaires.
Most pain physicians with experience in the field of TMD will attest Cognitive-behavioral therapy (CBT) is an option that aims at
to the success of conservative physical therapy, including muscle altering negative overt behavior, thoughts, or feelings in chronic
exercise, thermal packs, and oral splints. However, few, if any, of pain patients and to diminish distress and suffering. Whether sepa-
these therapies have been subjected to controlled trials. Often, reas- rately or combined with other pain treatments, CBT produced sig-
surance and education of the patient combined with simple exer- nificantly decreased pain, emotional distress, and disability and is of
cises for the TMJ, masticatory, and neck muscles will result in pain proven efficacy in TMD patients.12 Biofeedback aims to teach the
alleviation and restored mandibular function. patient to control behavior that is possibly part of the pain etiology
Muscle tenderness may be also treated with vapocoolant sprays and is efficacious in regulating muscle tension in TMD patients with
and concomitant stretching—‘‘spray and stretch.’’ This usually good long-term results. Combination of biofeedback with CBT tech-
induces immediate relief and is often employed as a diagnostic niques significantly improves treatment outcomes versus CBT alone.
test. Other commonly used techniques such as ultrasound and ther-
mal packs have also not been rigorously assessed. Transcutaneous
Trigger Point Injections and Needling
electrical nerve stimulation (TENS), low-level laser, and physical
self-regulation (PSR) programs are sometimes effective in TMDs. Injections of local anesthetics into trigger points induce pain relief
Many studies indicate the importance of education and self-care in that may be prolonged beyond the effect of the anesthetic agent.
the management of TMDs.9 The technique for the head and neck muscles is simple and involves
the location and immobilization of the trigger point followed by
injection using a standard technique. In myofascial pain patients,
Occlusal Splints
bupivicaine (0.5%) is equiefficacious to botulinum toxin in the
Flat occlusal splints (relaxation or stabilizing splints) are in wide- relief of pain, and cost-effectiveness would suggest the former’s
spread use and provide even occlusal contacts; these may be con- preferential use. We initially use mepivacaine (3%) to test patient
structed for the upper or lower jaw. There seems to be no difference response. If the results are encouraging and the patient needs fur-
in effect between flat splints, anterior midline stop devices, and ther injections, we may then employ bupivacaine (0.5%), although
canine guidance splints. We do not recommend partial coverage there are reports of bupivicaine-induced damage to muscle fibers.
splints owing to the inherent potential to cause permanent occlusal Based on an extensive literature review, direct (or ‘‘dry’’) needling
changes and the lack of evidence for any advantage over flat splints. of myofascial trigger points appears to be an effective treatment,
Meta-analyses consistently demonstrate benefit for oral splints in most likely because of the needle or placebo rather than the injec-
TMDs in general: both TMJ arthralgia and MMP.10 The presence tion of either saline or active drug. Dry needling of trigger points is
of widespread pain reduces the effectiveness of oral splints and sug- very similar to some acupuncture techniques.
gests that these should be prescribed for patients with regional myo-
fascial face pain only. The number needed to treat (NNT) for occlusal
Arthrocentesis
appliances in the treatment of TMDs has been calculated: an NNT of
6 for TMJ pain and 4.3 for MMP.10 The relatively good success rate Arthrocentesis, or lavage, of the upper TMJ space is a very simple
and highly conservative nature of splints account for their extensive technique that involves the introduction of two large-bore hypo-
use. They do, however, entail higher costs than other therapies. dermic needles into the superior joint space and rinsing with 400 to
600 ml of sterile saline or lactated Ringer’s. This volume is the
minimum needed to eliminate proinflammatory cytokines that
Pharmacologic
have accumulated in the joint space. Arthrocentesis is commonly
NSAIDs are used extensively in the management of pain and dis- used to treat ADDwoR, particularly of sudden onset, but may also
ability associated with joint disease. Selective cyclooxygenase be employed to palliate pain in ADDwR, degenerative, or inflam-
(COX)-2 inhibitors and some of the older nonselective COX inhi- matory TMJ disease.
bitors have potentially serious side effects on the renal and cardio-
vascular system, and long-term therapy is contraindicated. For the
Surgery
treatment of TMDs, calculations of NNTs for drugs versus placebo
reveal encouraging figures of 2.7 to 3.5. Ibuprofen (400 mg three TMJ surgery may be performed with an arthroscope or via an open
times daily) and naproxen (500 mg twice daily) are good choices. In approach. In general, TMJ surgery is reserved for medically recal-
patients with gastrointestinal discomfort, we recommend the addi- citrant cases and is rarely employed for the control of TMJ pain.
tion of antacids (e.g., proton pump inhibitor; omeprazpole). Simple
analgesics or combination analgesics (e.g., codeine and paraceta-
Complementary and AlternativeTherapy
mol/acetaminophen) may also provide good analgesia and may be
safer than NSAIDs. Approximately 20% of facial pain patients in a referral center had
Amitriptyline at low doses (10–30 mg/day) provides consistent attended a complementary and alternative medicine (CAM) special-
benefit for patients with craniofacial myofascial pain, including ist previously, and up to 36% of TMD patients reported treating
predominantly muscular TMDs, and post-traumatic myofascial their symptoms with CAM techniques. The existing evidence sup-
pain. Clonazepam (0.5 mg daily), a long-acting benzodiazepine ports the value of acupuncture for the management of idiopathic
with anticonvulsant properties, or cyclobenzaprine (10–30 mg headaches and has shown promise in the management of TMDs.
daily), a muscle relaxant, is beneficial in predominantly muscular However, well-planned studies are needed to assess the clinical
TMDs. Gabapentin (2700–3400 mg daily) is effective for the treat- value and cost-effectiveness of acupuncture and other CAM thera-
ment of MMP with an NNT of 3.4.11 pies for facial pain.
Biobehavioral Therapy
FACIAL MIGRAINE, NEUROVASCULAR
Pain is a subjective experience with important affective, cognitive, OROFACIAL PAIN (Tables 17–7 and 17–8)
behavioral, and sensory components. Outcomes including restora-
tion of functional activity, eradication of drug abuse and depen- Aberrant migraine locations are not recognized by the International
dency, and rehabilitation of residual emotional distress need to be Headache Society (HIS) or the International Association for the
Table 17^7. Current Diagnosis of Neurovascular Orofacial Pain (NVOP)
Clinical Features:
Usually
Throbbing.
Variable autonomic
Diagnosis Pain Intensity Primary Location Referral activation Clinical Symptoms Examination Findings Imaging
Facial Moderate Intraorally. Infraorbitally, +/ Also pressing pain Important to exclude
migraine/NVOP to severe Middle and periauricular that may wake from dental pathology or
lower third of sleep. sinusitis. In selected
the face cases, brain imaging to
exclude pathology
Cluster headache Severe +++ Also neuralgic. Occurs Up to 4% of patients
(CH){ in cluster or chronic. with pituitary tumors
Lasts 15–180 have CH.
minutes and
may occur up to
8/day.* Restlessness
Paroxysmal Severe These entities Commonly to ++ More frequent (8–30/ Thorough examination to Chronic PH is often
hemicrania are usually temporal, frontal day) than CH but exclude dental pathology. associated with
(PH){ associated and cervical shorter lasting (2–30 Often mild pericranial/ systemic disease.
with a regions. Very min).* masticatory muscle
primarily commonly to tenderness is present.
periorbital intraoral regions Cranial nerve examination
location should be performed to
identify symptomatic cases.
SUNCT{ Severe ++ Sharp, stabbing lasts Most common mimics
2–240 seconds. of SUNCT are lesions
Extremely high in the posterior fossa
frequency (2–200/ or involving the
day). May have pituitary gland.

trigger areas similar
to trigeminal
neuralgia
Hemicrania Moderate Temporal, Upper 2/3 of the + Continuous
continua{ frontal, face and intraorally unremitting.
periorbital Exacerbations
resemble migraine
*In addition to the episodic form, a chronic form exists.
{
See Section V, Chapter 16, Headaches Other than Migraine.
SUNCT, short-lasting neuralgiform headache attacks with conjunctival injection and tearing.
Patients with atypical findings or symptomatology may require brain imaging to exclude pathology.
Table 17^8. Current Therapy of Neurovascular are observed. Patients may report dental hypersensitivity to cold,
Orofacial Pain leading to diagnostic confusion.
The onset of NVOP is around 35 to 50 years of age, and it affects
Diagnosis Treatment females more often than males (3–10:1). Time to diagnosis was, on
average, 34 to 101 months (range 1–528 mo), attesting to the diag-
Facial migraine/ Abortive{: Naproxen sodium (825 mg nostic difficulties presented by these patients.13 Often, patients have
NVOP* stat) a positive history of migraine. In 38% to 45% of cases, the pain was
Triptan therapy: No specific evidence diagnosed as secondary to dental pathology, and patients under-
base for facial migraine/NVOP but went dental treatment with no success. Some cases (36%) under-
works in selected cases went repeated extractions in the same quadrant.
Prophylactic{: b-Blockers (propranolol Low-dose amitriptyline, b-blockers, and ergotamine have been
SR 80–160 mg/day), antiepileptic drugs successful in NVOP or facial migraine. No trials with triptans have
(divalproex SR 500 mg/day), tricyclic appeared in the literature. The drugs and guidelines outlined in
Section V, Chapter 15, Migraine Headaches, are relevant for
antidepressants (amitriptyline
NVOP (see Table 17–8).
10–50 mg/day)
Cluster headache*{ Abortive{: Sumatriptan,
dihydroergotamine, oxygen TRIGEMINAL AUTONOMIC
Prophylactic: Verapamil, AEDs, CEPHALGIAS
prednisone, lithium§
Paroxysmal Indomethacin{ Pain quality in trigeminal autonomic cephalgias (TACs) and dental
hemicrania*{ pulpitis is similar, and dentists are often the first health care pro-
viders consulted. Incorrect diagnosis may lead to dental treatment
SUNCT{ Lamotrigine (currently considered drug that is both misguided and unjustified. Peak pain intensity in TACs
of choice), gabapentin, topiramate is classically felt periorbitally or in the eye. However, ‘‘lower’’ and
Hemicrania Indomethacin ‘‘upper’’ subtypes of cluster headache have been reported; pain in
continua{ ‘‘lower cluster headache’’ is ocular, temporal, and suboccipital with
radiation to the teeth, jaws, and neck and is therefore highly rele-
*Episodic and chronic forms that will dictate approach to therapy. vant. Intra- or perioral radiation of pain includes the jaws (37%),
{
{
See Section V, Chapter 16, Headaches Other than Migraine. teeth (maxillary 50%; mandibular 32%). and cheeks (45%).13 In
See Section V, Chapter 16, Headaches Other than Migraine. ‘‘upper cluster headache,’’ pain is periorbital but radiates to the
§
Effective for chronic cluster headache. forehead and temporal and parietal regions.
AED, antiepileptic drugs; NVOP, neurovascular orofacial pain; SR, Referral patterns of TACs often involve orofacial structures and,
sustained-release; SUNCT, short-lasting neuralgiform headache attacks at times, may primarily present in intraoral or unusual facial sites.
with conjunctival injection and tearing. Some TACs are characterized by short, repeated, and severe pain
that may be pulsatile and similar to the inflammatory symptoms of
pulpitis. Thus, patients with cluster headache (35%–45%), parox-
ysmal hemicrania (15%), and hemicrania continua (rarer) report
toothache-like pain, and many will undergo unnecessary dental
interventions. Thorough clinical and radiologic dental evaluation
Study of Pain (IASP). However, many patients present with a usually eliminates a dental cause in these cases. Referral patterns
primary lower facial pain characterized by classic neurovascular of migraines and cluster headaches include the areas over the para-
features, including autonomic signs, nausea, and photo- or phono- nasal sinuses, and migraine or cluster headache are common diag-
phobia. These may be termed neurovascular orofacial pain (NVOP), noses in otolaryngology settings.
or facial migraine. Up to 10% of patients with paroxysmal hemicrania have pain
Theoretically, migraine mechanisms may present in the facial or triggered by neck movement, causing confusion with musculoskel-
oral region, and primary orofacial pain of neurovascular origin is of etal pain syndromes. Some of the cases reported demonstrated
great diagnostic and therapeutic importance. NVOP patients often ipsilateral masticatory muscle tenderness, and although confusing,
present with dental symptomatology (thermal hypersensitivity), and this is consistent with findings in other primary neurovascular-type
the similarities with dental pulpitis have obviously caused diagnos- headaches such as migraine, particularly chronic migraine (see
tic difficulties. Section V, Chapter 15, Migraine Headaches). Hemicrania continua
patients may also describe pain that refers to the jaw, ear, and
mastoid and could be confused with pain arising from TMDs.
Clinical Features of Facial Migraine/NVOP However, although hemicrania continua and TMDs are both con-
tinuous, TMDs rarely wake the patient from sleep and are not
The vast majority of patients report unilateral pain. Pain occurs throbbing in character.
primarily at an intraoral site, usually around the alveolar process,
but may be associated with a mucosal site. Referral of pain is evenly
divided between perioral structures (e.g., lips, chin), the periorbital NEUROPATHIC OROFACIAL PAIN
region (usually infraorbital), and the periauricular region. Moderate (Tables 17–9 and 17–10)
to strong episodic pain characterizes NVOP. In about half the cases,
the pain throbs and, in one third, woke the patient from sleep. Pain Neuropathic pain may develop after a number of insults to the
may last from minutes to hours or, more rarely, continues for more peripheral or central nervous systems. Peripheral pain syndromes
than 24 hours. Many cases are characterized by a chronic high- include traumatic neuropathies, diabetic neuropathy, and posther-
frequency pattern. Pain can be accompanied by various local auto- petic neuralgia. These peripheral processes are almost invariably
nomic signs such as tearing, nasal congestion, a feeling of swelling complicated by dysfunction of nociceptive pathways in the central
or fullness of the cheek, and a complaint of excessive sweating. nervous system. Central pain may be caused by direct damage as in
Other phenomena such as photo- or phonophobia and nausea stroke and spinal cord trauma or after centrally occurring diseases
Table 17^9. Current Diagnosis of Neuropathic Orofacial Pain*
Primary
Diagnosis Pain Intensity Location Referral Clinical Symptoms Examination Findings Imaging
Post-traumatic Mild to severe Initially Adjacent May be associated with May be associated
Onset associated
neuropathy localized, structures, areas of scar tissue
with traumatic with skeletal
dermatomal may cross event Affected areas may fractures or other
midline Burning or demonstrate allodynia, pathology that
dysesthesia, analgesia,
lancinating, induces nerve
redness
electrical pain. damage
Temporal summation
may occur
BMD Moderate Tongue, lips Localized Idiopathic onset Primary or idiopathic Irrelevant
(severe in Very frequently BMD must not be due
some) observed in to any local or systemic
postmenopausal factor
women Secondary BMD may
Continuous occur in local mucosal
burning sensation disease and a number
May be associated of metabolic and
with taste and endocrine disorders
salivary secretion
disturbances
TN* Severe Second and Usually Short (seconds to Usually none Advanced techniques
third dermatomal 2–3 min), Quantitative sensory may show
dermatomes Referral to paroxysmal pain testing may reveal mild neurovascular
of CN 5 teeth very May be triggered sensory deficits contact at the CN
common by innocuous Focal neurologic findings 5 root TN may also
stimuli or may indicate pathology. occur secondary to
spontaneous Trigger area may be tumors and
May have identified that induces multiple sclerosis
background pain pain and subsequently
(atypical TN) or becomes refractory.
begin in an
uncharacteristic
fashion pre-TN
Postherpetic Moderate to Usually first Usually Burning, constant Scars, hypopigmented Irrelevant
TN{ severe dermatome of localized but pain regions
CN 5 may spread if Superimposed Scars may be
severe flashes of pain hyposensitive or
allodynic
*See Section V, Chapter 35, Trigeminal Neuralgia.
{
See Section V, Chapter 36, Postherpetic Neuralgia.
BMD, burning mouth disorder; CN, cranial nerve; TN, trigeminal neuralgia.
such as epilepsy, Parkinson’s disease, and multiple sclerosis (MS). effective in central poststroke pain (CPSP), and these should be
Pain due to MS may resemble TN (see Section V, Chapter 35, considered first. Gabapentin and the sodium channel blocker mex-
Trigeminal Neuralgia). ilitene are reasonable second choices. Short-term relief may be
obtained with intravenous lignocaine or propofol. Unfortunately,
some poststroke patients may not be good medical candidates for
Central Poststroke Pain tricyclic antidepressants (TCAs), and anticonvulsants are therefore
indicated.
Facial pain is common in brainstem lesions, particularly of the
lower medulla, and may cause constant burning or paroxysmal
sharp pain. About 50% of patients with lateral medullary infarcts TN
suffered ipsilateral facial pain with or without accompanying body
pain. Facial pain is located periorbitally and is burning or hot, TN is an excruciating short-lasting, unilateral facial pain with clear
stinging, and pressure-like. Persistent pain with superimposed classification criteria (see Section V, Chapter 35, Trigeminal
attacks occurs in 25% of patients, and 42% have only paroxysmal Neuralgia). In 16% to 18% of patients, the singly affected nerve in
pain lasting seconds to minutes. Ipsilateral sensory dysfunction and TN will be the maxillary or the mandibular branch, whereas the
corneal reflexes were not present in all facial pain patients.14 ophthalmic is affected singly in only about 2% of cases.14 Most
Amitriptyline as well as the anticonvulsant lamotrigine may be commonly, the maxillary and mandibular branches are affected
Table 17^10. Current Therapy of Neuropathic Unusual TN Presentations

Orofacial Pain*
Up to 30% of TN patients report atypical features: longer TN pain
Diagnosis Treatment Options attacks and a constant background pain. This is diagnostically and
therapeutically relevant; microvascular decompression provided
Post-traumatic Gabapentin (300 mg/day initial for 3 days; absolute postoperative pain relief in typical or classic TN (CTN)
neuropathy increase by 300 mg every 3 days until 300 mg for 80% of cases but for only 47% of atypical TN cases. Long-term
tid. If response is positive, titrate up to 2700 follow-up (>5 yr) revealed excellent results in 75% of CTN but in
mg/day) only 35% of atypical TN cases.14
Tricyclic antidepressants (amitriptyline 10 mg/ An early form of TN termed pretrigeminal neuralgia (PTN) has
day initially up to 50 mg/day) been described. PTN has been reported in 18% of TN patients and is
SNRIs (venlafaxine SR 37.5 mg/day initially up characterized by a dull continuous pain in one of the jaws that lasts
to 150 mg/day) from days to years. As the process continues, PTN becomes more
typical with characteristic flashes of pain. Thermal stimuli may cause
Pregabalin
triggering at a relatively higher rate, and a throbbing quality to PTN
Opioids pain is sometimes present, mimicking dental pathology. Indeed,
Combination therapies (gabapentin/venlafaxine; these qualities combined with the success of regional anesthesia
gabapentin/opioids) have led to misdiagnosis of PTN as pain of dental origin. PTN is,
Topical medications{: 5% lidocaine patches, however, highly responsive to anticonvulsant therapy. Our clinical
topical antiepileptic drugs, or tricyclic experience confirms that there are cases with highly atypical features
antidepressants in stents that respond to carbamazepine and develop into TN. However,
Burning Alpha lipoic acid (600 mg/day) the lack of clear and consistent diagnostic criteria makes this a prob-
mouth Topical clonazepam (1 mg; ‘‘suck and spit’’ tid) lematic entity to recognize; it is usually diagnosed when all other
possibilities are exhausted or in retrospect once CTN develops.
disorder Tricyclic antidepressants
TN* Carbamazepine
Oxcarbazepine
Burning Mouth Disorder
Baclofen
Lamotrigine{ Burning mouth disorder (BMD) is a poorly understood pain con-
Gabapentin. dition that is most probably neuropathic with a central component.
Surgical (best prognosis in typical TN early after The condition is also known as stomatodynia, oral dysesthesia, or
onset): stomatopyrosis and is often accompanied by dysgeusia and
Peripheral level xerostomia.
BMD may be subclassified into primary BMD, or essential/idio-
Ganglion level
pathic BMD for which a neuropathologic cause is likely, and
Trigeminal root level secondary BMD, resulting from local or systemic pathologic condi-
Postherpetic Topical lidocaine{ tions. By definition, primary BMD cannot be attributed to any
TN* Tricyclic antidepressants systemic or local cause.
Gabapentin BMD is, unfortunately, characterized by resistance to a wide
Opioids range of treatments and is one of the most challenging management
problems in the field of orofacial pain.
*See Section V, Chapter 35, Trigeminal Neuralgia, and Chapter 36, Owing to often vague criteria, the exact prevalence of BMD is
Postherpetic Neuralgia. unclear. However, it seems that BMD is most common in post-
{
Lamotrigine has been proven effective as an add-on therapy. menopausal women, and reported prevalence rates in general popu-
{
Topical medications may be unsightly on the face. Intraorally, they lations vary from 0.7% to 15%.
require construction of a carrier stent. The tongue, usually the anterior two-thirds, is the primary loca-
SNRI, selective serotonin-norepinephrine reuptake inhibitors; SR, tion of the burning complaint in the majority of cases. However,
sustained-release; TN, trigeminal neuralgia. usually more than one site is involved; in addition to the tongue, the
hard palate, lips, and gingivae are frequently affected. Pain intensity
varies from mild to severe; VAS scores reported range from 5 to 7
but may reach 8 to 10.14 The most common terms used to describe
the pain quality are ‘‘burning’’ or ‘‘hot.’’ BMD is typically of spon-
together (35%), and all three branches are involved in 14% of taneous onset and lasts from months to several years. Although a
patients. The jaws are, therefore, involved in most cases, explaining chronic unremitting pattern is usual, spontaneous or partial remis-
why TN patients so often seek help from dentists. Pain radiation is sion of BMD is reported in 3% to 50% of patients about 5 to 7 years
generally within the dermatome of origin. after onset.
TN may mimic dental pain, and a quarter of cases will initially A possible association to anxiety, depression, and personality
consult a dentist. Unfortunately, TN is often misdiagnosed, and disorders is described in the literature, particularly in postmeno-
33% to 65% of cases may undergo unwarranted dental interven- pausal women, but it is unclear whether pain initiated the psycho-
tions; up to 12% may be eventually rendered edentulous. The logical disorder or vice versa. Although a minority of BMD patients
numbers of TN cases with extensive and misguided dental interven- have significant distress, the vast majority cope better than most
tions suggest a lack of awareness of many dentists to the features chronic pain patients.
of TN. However, TN may occasionally present atypically and Secondary BMD may result from local or systemic factors or
resemble dental pathology; in these cases, it is more difficult diseases. Local factors and diseases known to induce secondary
to diagnose. Thorough clinical and radiographic dental examina- BMD include oral candidiasis, galvanism, lichen planus, allergies,
tions are essential, and invasive dental treatment must not be hyposalivation, and xerostomia. Systemic disorders known to
performed without positive anamnestic, clinical, and radiographic induce secondary BMD include hormonal changes, nutritional
findings. abnormalities (e.g., vitamin B12, folic acid, or iron deficiencies),
diabetes mellitus, drugs (directly or indirectly), autoimmune dis-

Atypical Odontalgia
eases, and emotional stress. Successful treatment aimed at the pri-
mary disease will usually (but not invariably) alleviate the burning Many atypical odontalgia cases present with neuropathic sympto-
sensation in secondary BMD patients. matology such as continuous, burning pain, and many report
trauma as the initiating event. There are some indications that
atypical odontalgia may be a subtype of ATP and that both are
Treatment (see Table 17–10)
neuropathic in origin. Other cases may have a throbbing character
Topical therapies may be useful, particularly in elderly, medically to the pain with no demonstrable pathology suggesting neurovas-
compromised patients. Topical clonazepam (sucking and spitting cular mechanisms. The lack of precise validated criteria is an obsta-
1 mg three times daily for 2 wk) was effective in reducing pain cle in the characterization of atypical odontalgia.
intensity in a subgroup of BMD patients, with some residual
effect at 6 months. Topical anesthetics may decrease or increase
Complex Regional Pain Syndrome
pain such that this is not a predictable mode of therapy.
Reduction in pain after treatment with benzodiazepines and low- Complex regional pain syndrome (CRPS) has been previously
dose TCAs or other antidepressants appear as case reports. Multiple termed sympathetically maintained pain, reflex sympathetic dystro-
studies consistently demonstrate the prolonged benefit of a phy, or causalgia. These early terms were based on observations of
2-month course of 600 mg daily of a-lipoic acid.15 Therapy-resis- the clinical phenotype that often suggested involvement of the sym-
tant BMD has been associated with underlying psychological dis- pathetic nervous system. However, the link between nociceptive
tress, and these patients may particularly benefit from CBT. neurons and postganglionic sympathetic activity is inconstant,
with sympathetic blocks sometimes altering the syndrome at least
temporarily and sometimes not. Adrenergic mechanisms in some
Traumatic TNs form do appear to be involved in some of these conditions, but
measurements of sympathetic responses have often shown normal
After zygomatic complex fractures, residual, mild hypoesthesia of results.14 CRPSs are painful disorders that develop as a consequence
the infraorbital nerve is common but chronic neuropathic pain of injury. Two subtypes have been defined: CRPS I (previously
developed in only 3.3% of patients. This compares with about 5% reflex sympathetic dystrophy) and CRPS II (previously causalgia).
to 17% in other body regions. Persistent pain after successful Both these entities present with spontaneous pain accompanied by
endodontics was found to occur in 3% to 13% of cases, whereas allodynia and hyperalgesia that are not limited to dermatomal
surgical endodontics resulted in chronic neuropathic pain in 5% of regions. Additional signs include edema, abnormal blood flow in
cases.14 Factors significantly associated with persistent pain were long the skin, and abnormal sudomotor activity. CRPS I may develop as
duration of preoperative pain, marked symptomatology from the a consequence of remote trauma or after relatively minor local
tooth, previous chronic pain problems or a history of painful treat- trauma such as sprains or surgery. These result in minor or no
ment in the orofacial region, and female gender. The fact that pre- identifiable nerve lesions with disproportionate pain. The less fre-
operative pain parameters were important suggests that some form quent form, CRPS II, is characterized by a substantiated injury to a
of sensitization may have occurred, predisposing to chronic pain. major nerve and is, therefore, a neuropathic pain syndrome by
definition. In both of these syndromes, there may be clinical evi-
dence to support the involvement of the sympathetic nervous
Atypical Facial Pain
system, in which case the term sympathetically maintained pain is
Atypical facial pain (AFP; previously known as persistent idiopathic added. The historical dependence on sympathetic involvement for
facial pain) is employed when no other diagnosis is feasible and has, the diagnosis of CRPS has probably prevented the identification and
therefore, tended to include a heterogeneous group of patients. documentation of head and neck cases. Thus, the cases reported in
Some AFP cases responded to triptans, suggesting migraine-like the literature have relied on cervical sympathectomy, clonidine,
mechanisms, whereas in others, triptans were ineffective. As knowl- guanethidine, and stellate ganglion blockade to confirm CRPS.14
edge and diagnostic skills accumulated, many AFP cases were However, some of the diagnostic criteria are rarely, if ever, observed
classified as chronic myofascial pain, traumatic neuropathy, pre- in post-traumatic orofacial pain. For example, trophic changes and
or atypical TN, facial migraine, or NVOP. It is likely that much atrophy of skin are unreported in the trigeminal region, and motor
of the collected data on AFP represent a neuropathic condition, and disturbances are rare. The other criteria listed are distinctly similar
many AFP patients demonstrate some degree of sensory to those described in ATF, atypical odontalgia, and clear post-
dysfunction. traumatic cases.
The latest International Headache Society criteria for AFP
include the presence of daily or near-daily pain that is initially
confined but may subsequently spread.14 The pain is not associated Treatment of Neuropathic Pain (see Table 17–10)
with sensory loss and cannot be attributed to any other pathologic
process. This is a rather loose definition that has not been field- The available evidence confirms that the mainstays of neuropathic
tested and may misleadingly allow the classification of a large pain treatment remain the AEDs and the TCAs. The usual end-
number of chronic facial pain disorders. Until specific data on point in drug trials has generally been a 50% reduction in pain
AFP accumulate, we describe in brief the features of AFP. intensity. However, research has shown that about a 30% reduction
Pain is usually poorly localized, radiating, and mostly unilateral, represents meaningful pain relief for neuropathic pain patients. The
although up to 40% of patients may describe bilateral pain.14 AFP role of surgery in the management of traumatic trigeminal neuro-
is commonly described as ‘‘burning,’’ ‘‘throbbing,’’ and often pathies is unclear. The literature reveals that some cases have been
‘‘stabbing.’’ Severity is mild to severe and rated approximately treated with peripheral glycerol injections with some success, but we
7 on a VAS. Most patients report long-lasting (years) chronic have found no prospective controlled trials. No prospective trials
daily pain, although there have been reports of pain-free periods. appear in the literature on central procedures aimed at the trigem-
Pain onset is often associated with surgical or other invasive pro- inal ganglion or the dorsal root entry zone for the treatment of such
cedures. Although there should be no sensory deficits, these have cases. Anecdotal evidence suggests that central procedures, such as
been reported in up to 60% of cases. The lack of a clear pathophy- dorsal root entry zone lesions, may be useful for recalcitrant cases.
siologic basis precludes the establishment of a treatment protocol. AEDs for the treatment of painful neuropathies exhibit varied
The use of TCAs and anticonvulsants may be beneficial. NNTs. Phenytoin (NNT = 2) is superior to both carbamazepine
(NNT = 3.3) and gabapentin (NNT = 3.8), but as a group, AEDs are 10. Forssell H, Kalso E. Application of principles of evidence-based medicine
inferior to the TCAs in the management of painful polyneuropa- to occlusal treatment for temporomandibular disorders: are there
thies. For TN, however, anticonvulsants remain the drugs of choice, lesssons to be learned? J Orofac Pain 2004;18(1):9–22; discussion 23-32.
particularly carbamazepine with an NNT for substantial relief of 11. Kimos P, Biggs C, Mah J, et al. Analgesic action of gabapentin on
chronic pain in the masticatory muscles: A randomized controlled
2.6. Based on the efficacy of pregabalin and gabapentin in periph-
trial. Pain 2006;127(1-2):151–160.
eral neuropathies, they may also be good treatment options in trau- 12. Turner JA, Holtzman S, Mancl L. Mediators, moderators, and
matic neuropathy. predictors of therapeutic change in cognitive-behavioral therapy for
Analgesic trials with TCAs reveal that drugs with mixed serotonin/ chronic pain. Pain 2006;127(3):276–286.
noradrenaline (e.g., imipramine and amitriptyline) or selective 13. Benoliel R, Sharav Y. The trigeminal autonomic cephalgias. In Sharav Y,
serotonin-norepinephrine reuptake inhibition are superior to the Benoliel R (eds): Orofacial Pain and Headaches. Edinburgh:
selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine or Mosby-Elsevier, 2008; pp 225–254.
paroxetine. In painful polyneuropathies, TCAs such as amitriptyline 14. Benoliel R, Heir G, Eliav E. Neuropathic orofacial pain cephalgias. In
have an NNT of 2.2. With dose titration of imipramine, an NNT of Sharav Y, Benoliel R (eds): Orofacial Pain and Headaches. Edinburgh:
1.4 for may be attained for traumatic neuropathies. SSRIs have an Mosby-Elsevier, 2008; pp 276–286.
15. Patton LL, Siegel MA, Benoliel R, De Laat A. Management of burning
NNT of 7 in painful polyneuropathies. In diabetic neuropathy, selec- mouth syndrome: Systematic review and management
tive serotonin-norepinephrine reuptake inhibitors (SNRIs) are effica- recommendations. Oral Surg, 2007;103(suppl 1):S39.e1-S39.e13.
cious, for example, venlafaxine (NNT = 4) or duloxetine (NNT = 4.1);
both have fewer side effects than the TCAs and may be attractive
alternatives. The sodium channel blocking agent mexilitene may SUGGESTED READINGS
be useful in traumatic neuropathies (NNT 2.2) but has been largely
Al-Ani Z, Gray RJ, Davies SJ, et al. Stabilization splint therapy for the
ineffective in other neuropathic pains.14 treatment of temporomandibular myofascial pain: a systematic review.
TCAs or gabapentin/pregabalin would be the first drugs indi- J Dent Educ 2005;69:1242–1250.
cated in peripheral neuropathy. The excellent NNTs for TCAs are Ashkenazi A, Levin M. Three common neuralgias. How to manage
counterbalanced by the excellent side effect profile of the newer trigeminal, occipital, and postherpetic pain. Postgrad Med 2004;
anticonvulsants. In patients initiated on amitriptyline with problem- 116:16–18, 21–24, 31–32 passim.
atic side effects, imipramine, desipramine, or the SNRI venlafaxine Barden J, Edwards JE, McQuay HJ, et al. Relative efficacy of oral analgesics
should be tried. If these fail or are contraindicated, the anticonvul- after third molar extraction. Br Dent J 2004;197:407–411. discussion 397.
sants gabapentin and pregabalin offer the best chances for success. Bender IB. Pulpal pain diagnosis—a review. J Endod 2000;26:175–179.
Benoliel R, Robinson S, Eliav E, et al. Hemicrania continua. J Orofac Pain
Similarly, in patients started on gabapentin, treatment failure is
2002;16:317–325.
an indication for a trial of TCAs/SNRIs. Alternatively, if TCAs/ Benoliel R, Sharav Y. Paroxysmal hemicrania. Case studies and review of
SNRIs or gabapentin is only partly successful, combination therapy the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
with their counterparts (e.g., venlafaxine and gabapentin, gabapen- 1998;85:285–292.
tin and morphine) should be considered. Third-line monotherapy, Benoliel R, Sharav Y, Tal M, et al. Management of chronic orofacial pain:
or add-on therapy, may be attained with opioids or tramadol. Based today and tomorrow. 922–924, 926–928 passim; quiz 932. Compend
on their efficacy in postherpetic neuralgia and diabetic neuropathy, Contin Educ Dent 2003;24:909–920.
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population: results of a population-based Study of Health in in the treatment of neuropathic pain of nonmalignant origin:
Pomerania. Quintessence Int 2004. systematic review and meta-analysis of randomized controlled trials.
5. Wahlund K. Temporomandibular disorders in adolescents. JAMA 2005;293:3043–3052.
Epidemiological and methodological studies and a randomized Finnerup NB, Otto M, McQuay HJ, et al. Algorithm for neuropathic pain
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6. Levitt SR, McKinney MW. Validating the TMJ scale in a national Fitzek S, Baumgartner U, Fitzek C, et al. Mechanisms and predictors of
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8. Rammelsberg P, LeResche L, Dworkin S, et al. Longitudinal outcome Gray A, Kehlet H, Bonnet F, et al. Predicting postoperative analgesia
of temporomandibular disorders: a 5-year epidemiologic study of outcomes: NNT league tables or procedure-specific evidence? Br J
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temporomandibular disorders. J Orofac Pain 2003;17:9–20. Herrera D, Roldan S, Sanz M. The periodontal abscess: a review. J Clin
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Martin MV, Longman LP, Hill JB, et al. Acute dentoalveolar infections: Suvinen TI, Reade PC, Kemppainen P, et al. Review of aetiological
an investigation of the duration of antibiotic therapy. Br Dent J 1997; concepts of temporomandibular pain disorders: towards a
183:135–137. biopsychosocial model for integration of physical disorder factors with
Matharu MS, Boes CJ, Goadsby PJ. Management of trigeminal autonomic psychological and psychosocial illness impact factors. Eur J Pain
cephalgias and hemicrania continua. Drugs 2003;63:1637–1677. 2005;9:613–633.
Pareja JA, Cuadrado ML. SUNCT syndrome: an update. Expert Opin Svensson P, Graven-Nielsen T. Craniofacial muscle pain: review of
Pharmacother 2005;6:591–599. mechanisms and clinical manifestations. J Orofac Pain 2001;15:117–145.
Penarrocha M, Bandres A, Penarrocha M, et al. Lower-half facial migraine: Swift JQ, Gulden WS. Antibiotic therapy—managing odontogenic
a report of 11 cases. J Oral Maxillofac Surg 2004;62:1453–1456. infections. Dent Clin North Am 2002;46:623–633, vii.
Polycarpou N, Ng YL, Canavan D, et al. Prevalence of persistent pain Tidwell E, Hutson B, Burkhart N, et al. Herpes zoster of the trigeminal
after endodontic treatment and factors affecting its occurrence in cases nerve third branch: a case report and review of the literature. Int
with complete radiographic healing. Int Endod J 2005;38:169–178. Endod J 1999;32:61–66.
Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Wiffen P, Collins S, McQuay H, et al. Anticonvulsant drugs for acute and
Database Syst Rev 2005;(3):CD005454. chronic pain. The Cochrane Database of Systematic Reviews. (2005).
Savage MG, Henry MA. Preoperative nonsteroidal anti-inflammatory Available at http://www.mrw.interscience.wiley.com/cochrane/clsysrev/
agents: review of the literature. Oral Surg Oral Med Oral Pathol Oral articles/CD001133/pdf_fs.html (accessed October 2005).
Radiol Endod 2004;98:146–152. Zakrzewska JM, Lopez BC. Trigeminal neuralgia. Clin Evid 2004:
Scala A, Checchi L, Montevecchi M, et al. Update on burning mouth 1880–1890.
syndrome: overview and patient management. Crit Rev Oral Biol Med
2003;14:275–291.
Chapter 18 magnetic resonance imaging (MRI) may not be associated with

symptomatology. Cervical cord impingement by protruding disks
NECK PAIN was seen in MRIs of the larynx in 26% of asymptomatic patients
over 64 years of age.
Susan Elizabeth Opper
PATHOPHYSIOLOGY
Neck pain may be spontaneous or traumatic in origin. Soft tissue
and cervical spine disease are the most common causes of neck
pain. Soft tissue structures include fascia, ligaments, tendons, and
INTRODUCTION muscles. Disorders of the synovial joints and intervertebral disks of
the cervical spine may contribute to neck pain as well as refer pain
Neck pain is a very common clinical malady with a lifetime prev- into the posterior head, the shoulder, and distally into the arm
alence of 40% to 70%. Less common than low back pain, neck pain (Table 18–1).
may be a challenging dilemma for the practitioner, especially in the Cervical radiculopathy refers to loss of neurologic function such
traumatic setting. Whiplash injuries may lead to severe disability as sensory or motor loss or impaired reflexes due to nerve root
despite a paucity of radiologic abnormalities and a lack of response compression or inflammation. The cause is often cervical disk her-
to treatment. Spontaneous neck pain is usually the result of cervical niation but may also be secondary to abnormalities of the vertebral
spine disease, but various organ structures in close proximity may column such as spinal stenosis and facet arthrosis. Diabetes and
cause referred neck pain. tumor may also cause secondary radiculopathy.
The therapy of neck pain is as varied as its etiology, with choices Visceral structures that may refer to the neck include the eso-
among pharmacologic, physical, interventional injection, and sur- phagus, thyroid, lymphatics, stomach, lung, and heart. The history
gical techniques. Newer treatments include botulinum toxin injec- and physical examination may provide important clues for deter-
tions and radiofrequency ablation, whereas the ancient technique of mining the etiology. Connective tissue and autoimmune diseases
acupuncture is gaining more acceptance for the treatment of refrac- such as polymyositis, ankylosing spondylitis, and rheumatoid
tory conditions. arthritis may affect the muscles and joints of the neck and shoulder
with resultant pain. Brachial plexus abnormalities and shoulder
impingement may also refer to the neck.
EPIDEMIOLOGY Whiplash injury was first described in 1928, referring to the cer-
vical spine’s lashlike effect after a rear-end motor vehicle accident.
Severe neck pain will be experienced by 10% of adults within a given The acceleration/deceleration incident causes extreme flexion and
year. Women are at increased risk, as are the elderly and those who subsequent extension of the neck. Damage to the ligaments, muscles,
have been involved in rear-end automobile accidents. Refractory and joints of the cervical area may ensue. Neck pain and stiffness may
cases are associated with work dissatisfaction and psychological stres- be accompanied by headache, dizziness, and memory and concen-
sors. Poor self-assessed health, a past history of lumbar pain, and tration disturbances. A chronic pain syndrome that is extremely
number of children are also correlated with neck pain. resistant to treatment may develop in over 10% of whiplash patients.
Cervical spine abnormalities increase with age. Thirteen percent Some pose that secondary monetary gain impedes recovery. The
of men over 20 years of age will have spondylosis, whereas 98% over effect of expectation may also play a role because those who do not
age 70 years will be affected. Abnormalities of the spine revealed on expect to become better usually do not.
Martin MV, Longman LP, Hill JB, et al. Acute dentoalveolar infections: Suvinen TI, Reade PC, Kemppainen P, et al. Review of aetiological
an investigation of the duration of antibiotic therapy. Br Dent J 1997; concepts of temporomandibular pain disorders: towards a
183:135–137. biopsychosocial model for integration of physical disorder factors with
Matharu MS, Boes CJ, Goadsby PJ. Management of trigeminal autonomic psychological and psychosocial illness impact factors. Eur J Pain
cephalgias and hemicrania continua. Drugs 2003;63:1637–1677. 2005;9:613–633.
Pareja JA, Cuadrado ML. SUNCT syndrome: an update. Expert Opin Svensson P, Graven-Nielsen T. Craniofacial muscle pain: review of
Pharmacother 2005;6:591–599. mechanisms and clinical manifestations. J Orofac Pain 2001;15:117–145.
Penarrocha M, Bandres A, Penarrocha M, et al. Lower-half facial migraine: Swift JQ, Gulden WS. Antibiotic therapy—managing odontogenic
a report of 11 cases. J Oral Maxillofac Surg 2004;62:1453–1456. infections. Dent Clin North Am 2002;46:623–633, vii.
Polycarpou N, Ng YL, Canavan D, et al. Prevalence of persistent pain Tidwell E, Hutson B, Burkhart N, et al. Herpes zoster of the trigeminal
after endodontic treatment and factors affecting its occurrence in cases nerve third branch: a case report and review of the literature. Int
with complete radiographic healing. Int Endod J 2005;38:169–178. Endod J 1999;32:61–66.
Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Wiffen P, Collins S, McQuay H, et al. Anticonvulsant drugs for acute and
Database Syst Rev 2005;(3):CD005454. chronic pain. The Cochrane Database of Systematic Reviews. (2005).
Savage MG, Henry MA. Preoperative nonsteroidal anti-inflammatory Available at http://www.mrw.interscience.wiley.com/cochrane/clsysrev/
agents: review of the literature. Oral Surg Oral Med Oral Pathol Oral articles/CD001133/pdf_fs.html (accessed October 2005).
Radiol Endod 2004;98:146–152. Zakrzewska JM, Lopez BC. Trigeminal neuralgia. Clin Evid 2004:
Scala A, Checchi L, Montevecchi M, et al. Update on burning mouth 1880–1890.
syndrome: overview and patient management. Crit Rev Oral Biol Med
2003;14:275–291.
Chapter 18 magnetic resonance imaging (MRI) may not be associated with

symptomatology. Cervical cord impingement by protruding disks
NECK PAIN was seen in MRIs of the larynx in 26% of asymptomatic patients
over 64 years of age.
Susan Elizabeth Opper
PATHOPHYSIOLOGY
Neck pain may be spontaneous or traumatic in origin. Soft tissue
and cervical spine disease are the most common causes of neck
pain. Soft tissue structures include fascia, ligaments, tendons, and
INTRODUCTION muscles. Disorders of the synovial joints and intervertebral disks of
the cervical spine may contribute to neck pain as well as refer pain
Neck pain is a very common clinical malady with a lifetime prev- into the posterior head, the shoulder, and distally into the arm
alence of 40% to 70%. Less common than low back pain, neck pain (Table 18–1).
may be a challenging dilemma for the practitioner, especially in the Cervical radiculopathy refers to loss of neurologic function such
traumatic setting. Whiplash injuries may lead to severe disability as sensory or motor loss or impaired reflexes due to nerve root
despite a paucity of radiologic abnormalities and a lack of response compression or inflammation. The cause is often cervical disk her-
to treatment. Spontaneous neck pain is usually the result of cervical niation but may also be secondary to abnormalities of the vertebral
spine disease, but various organ structures in close proximity may column such as spinal stenosis and facet arthrosis. Diabetes and
cause referred neck pain. tumor may also cause secondary radiculopathy.
The therapy of neck pain is as varied as its etiology, with choices Visceral structures that may refer to the neck include the eso-
among pharmacologic, physical, interventional injection, and sur- phagus, thyroid, lymphatics, stomach, lung, and heart. The history
gical techniques. Newer treatments include botulinum toxin injec- and physical examination may provide important clues for deter-
tions and radiofrequency ablation, whereas the ancient technique of mining the etiology. Connective tissue and autoimmune diseases
acupuncture is gaining more acceptance for the treatment of refrac- such as polymyositis, ankylosing spondylitis, and rheumatoid
tory conditions. arthritis may affect the muscles and joints of the neck and shoulder
with resultant pain. Brachial plexus abnormalities and shoulder
impingement may also refer to the neck.
EPIDEMIOLOGY Whiplash injury was first described in 1928, referring to the cer-
vical spine’s lashlike effect after a rear-end motor vehicle accident.
Severe neck pain will be experienced by 10% of adults within a given The acceleration/deceleration incident causes extreme flexion and
year. Women are at increased risk, as are the elderly and those who subsequent extension of the neck. Damage to the ligaments, muscles,
have been involved in rear-end automobile accidents. Refractory and joints of the cervical area may ensue. Neck pain and stiffness may
cases are associated with work dissatisfaction and psychological stres- be accompanied by headache, dizziness, and memory and concen-
sors. Poor self-assessed health, a past history of lumbar pain, and tration disturbances. A chronic pain syndrome that is extremely
number of children are also correlated with neck pain. resistant to treatment may develop in over 10% of whiplash patients.
Cervical spine abnormalities increase with age. Thirteen percent Some pose that secondary monetary gain impedes recovery. The
of men over 20 years of age will have spondylosis, whereas 98% over effect of expectation may also play a role because those who do not
age 70 years will be affected. Abnormalities of the spine revealed on expect to become better usually do not.
138 Chapter 18 NECK PAIN
FUNCTIONAL ANATOMYOF THE NECK Table 18^1. Current Diagnosis of Neck Pain
The neck is the most flexible part of the spine, which leads to a wide Diagnosis Characteristics
range of neck movements. The atlas and axis are unique vertebrae,
the atlas a ring structure and the axis with its elongated dens, that Myofascial No neurologic deficits, localized
confer increased rotation capabilities to the neck. The occipital ver- regional tender areas
tebral ligaments connect the occiput to the atlas and are very Cervical radiculopathy/ Radiation of pain down arm
important to the stability of this joint. secondary to disk disease Neuropathic description of pain
The zygapophyseal joints are true synovial joints that allow for or spinal stenosis Presence of neurologic abnormalities
motion of the vertebral spine while limiting excessive motion. These Axial pain/facet joint Pain more central, absence of
joints may be damaged in whiplash injury or succumb to degener- arthrosis neurologic deficits, occipital
ation with aging. Innervated by the medial branches of the dorsal
headaches
rami of the spinal nerves, painful joints may be treated with block-
ade of these nerves.
Referral patterns of pain from these joints have been described:
C2–3 may refer to the occipital region, C3–4 and C4–5 to the pos- HISTORYAND PHYSICAL
terior and lateral neck, C5–6 and C6–7 to the scapula and trapezius EXAMINATION INNECK PAIN
(Fig. 18–1).
The normal diameter of the spinal canal between C3 and C7 is Early in the evaluation of neck pain, one should be alert to ‘‘red
17 to 18 mm. The spinal cord at this level is uniform, with an flags’’ that signal the need for a more aggressive approach to the
average diameter of 10 mm. The diameter of the spinal canal is diagnosis and care of the individual patient. These include the pres-
decreased by up to 3 mm with extension of the head and neck. ence of fever, history of metastatic disease, and the rapid progres-
Central narrowing or stenosis of the canal may result in cervical sion of symptoms. These symptoms comprise loss of sensation,
myelopathy. Cervical spondylosis is a general term that refers to the weakness, and changes in bowel and bladder function.
degenerative changes brought about with ‘‘wear-and-tear’’ changes Myelopathy with long tract signs affecting the upper and lower
of the disks, joints, vertebral bodies, and/or soft/connective tissues extremities and trunk is suggested by hyperreflexia, clonus, loss of
of the cervical spine. Osteophytic spurring of the zygapophyseal balance, and a Babinski response. Potential compression of the
joints creates narrowing both laterally of the neuroforamen and spinal cord by a traumatic injury or severe spondylosis or cervical
centrally in the spinal canal. Spinal stenosis is diagnosed when the stenosis should be evaluated with radiologic studies and early sur-
canal diameter is less than 10 to 12 mm. gical consultation.
It is important to understand the relationship of the cervical Range of motion of the neck should be documented and can be
nerves and their vertebrae. The cervical nerve root passes above used as an ongoing measure of response to therapy. Ideally, forward
the numbered vertebra. For example, the C5 nerve passes in the flexion should result in the chin reaching the chest, lateral rotation
C4–5 foramen. This differs from the lumbar nerves that exit below should be 608 or greater, and lateral tilt should be 458.
the vertebra of the same number; therefore, the L5 nerve exits in the Chronic neck pain patients often have a distinctive posture of
L5–S1 foramen. forward head and slumped shoulders with kyphosis. Elicitation of
tender areas by palpation may identify trigger points and their
referral patterns. Muscle spasms and asymmetry of the neck and
shoulders should be noted. Patterns of cervical radicular radiation
with sensory, motor, and reflex changes are summarized in Table
18–2 and Figure 18–2.
In addition, several tests may elicit further information. The
Hoffman reflex is an involuntary flexion of the thumb and fifth
digit on quick flexion of the distal interphalangeal joint of the
long finger. This upper motor neuron test is similar to the
Table 18^2. Cervical Radicular Patterns
Level of
Nerve
Root Motor Sensory Reflex
C5 Shoulder Lateral arm Biceps
abduction
C6 Wrist extension Lateral forearm, Brachioradialis
thumb, and
index finger
C7 Wrist flexion and Middle finger Triceps
finger extension
C8 Finger flexion Medial forearm,
ring and small
fingers
T1 Finger abduction, Medial arm
Figure 18^1. Facet joint referral patterns. (From Bogduk N. adduction
Practice Guidelines for Spinal Diagnostic and Treatment Procedures. San
T2 Axilla
Francisco: International Spine Intervention Society, 2004; p 103.)
Figure 18^2. Neurologic examination findings of cervical radiculopathy. (Drawn by Deborah L. Martin.)
Babinski sign in the lower extremity and is associated with spinal suggestive of cervical radiculopathy if referred pain is elicited.
cord compression. The distraction test seeks the effects of neck Adson’s test is performed by abducting the arm while having the
traction on relieving neck pain caused by narrowing of the neural patient take a deep breath and turn the head to the affected side.
foramen or by increased pressure of the joint capsules. This test is The radial pulse will diminish in the presence of subclavian artery
performed by placing one hand under the chin and the other hand compression by a cervical rib or scalene muscle tightening.
under the occiput and lifting the head gradually. Conversely, the
compression test reproduces the pain caused by compressive disease
by placing the hands on top of the head and pressing downward. PHARMACOLOGIC THERAPYOF
Another useful sign of cervical compressive disease is that shoulder NECK PAIN
abduction with the arm placed on the head of the affected side
relieves nerve root pressure and pain. Many analgesic choices are available for the treatment of neck pain.
Spurling’s maneuver is performed by extending and rotating or Pharmacologic therapy is only one aspect of treatment and may
bending the cervical spine to the affected side and is strongly not be successful unless combined with other modalities such as
physical therapy, postural correction, and elimination of ongoing acetaminophen as a result of induction of microsomal detoxification
mechanical stresses. Treatment is ideally targeted to the underlying enzymes. Sympathomimetic agents (cold and allergy preparations,
pathophysiologic cause. Neck pain may be due to soft tissue injury caffeine) may increase acetaminophen’s liver and renal toxicity.
and respond readily to minimal analgesic therapy and rest. This
somatic nociceptive pain may be controlled with analgesics such
Anti-inflammatory Agents
as acetaminophen and anti-inflammatory agents. If muscle spasms
are problematic, a muscle relaxant may be added. If pain continues The nonsteroidal anti-inflammatory drugs (NSAIDS) can be extre-
to be severe, opiate therapy with short-acting agents can be mely helpful in acute neck pain. Their role in chronic conditions is
initiated. less clear, and currently, much controversy clouds the appropriate
When pain is not responsive to conservative therapy and the use of these agents. Long-term use may be associated with signifi-
diagnosis is unclear, one useful approach is to pay attention to cant risk to susceptible patients. Although touted as having less
the description of the pain for clues of a possible neuropathic com- adverse gastrointestinal effects, some of the cyclooxygenase-2
ponent. Lancinating, burning pain accompanied by symptoms of (COX-2) agents have had unique problems in those patients at
weakness and numbness, in addition to signs of loss of reflexes, cardiovascular risk. In addition to their anti-inflammatory effect,
motor strength, and sensation is characteristic of damage to the NSAIDs exert antipyretic and analgesic activity. The analgesic effect
nervous system. This neuropathic pain is often very challenging occurs at lower doses, with anti-inflammation more significant at
to manage and requires a different approach. Antidepressant and higher dosing. NSAIDs act to prevent the conversion of arachidonic
anticonvulsant therapy may be required as adjunctive therapy. acid to various prostaglandins by the inhibition of the cyclo-
oxygenase enzyme. Prostaglandins contribute to the inflammatory
response by increasing vascular permeability and sensitizing noci-
Analgesic Agents ceptors to bradykinin. Non–prostaglandin-mediated effects of
NSAIDS include inhibition of both phagocytosis and neutrophil
Acetaminophen activation, scavenging of superoxide radicals, and possibly inhibi-
tion of nitric oxide synthesis.
Acetaminophen (Tylenol) is a first-line treatment for musculoskel- Two types of cyclooxygenase enzymes exist, COX-1 and COX-2.
etal pain of the neck. This para-aminophenol compound exerts a The COX-1 ‘‘housekeeping’’ enzyme is found in most normal cells
potent antipyretic effect at the hypothalamic temperature regulatory and is important for maintaining gastric mucosal integrity and
center. The analgesic effect of acetaminophen also appears to be modulating renal blood flow. The COX-2 enzyme is inducible and
central. The blood-brain barrier is easily traversed because of acet- is expressed in inflammatory states. The selective COX-2 agents
aminophen’s low molecular weight and high lipid solubility. were developed to minimize gastrointestinal effects. However,
Although still being determined, its analgesic effect may involve recent developments have highlighted a heightened cardiovascular
descending serotonergic pathways. A spinal effect with inhibition risk of increased stroke and heart attack in susceptible patients.
of nitric oxide production with decreased N-methyl-D-aspartate Unlike the COX-1 agents, the COX-2 inhibitors do not suppress
(NMDA) activity has also been proposed. thromboxane production, potentially leading to increased throm-
Acetaminophen demonstrates some weak peripheral anti- botic risk. Rofecoxib (Vioxx) and valdecoxib (Bextra) have been
inflammatory effects with a suppression of prostacyclin and throm- removed from the market. Celecoxib (Celebrex) remains and may
boxane synthesis via cyclooxygenase inhibition. Anti-inflammation be relatively safe in those at risk for cardiovascular disease but should
is only accompanied in the setting of low peroxide levels, which is be avoided in those with sulfa allergy.
not normally the case in most inflammatory leukocyte-filled envir- Of the older agents, etodolac (Lodine) and meloxicam (Mobic)
onments. The recommended dose is 325 to 1000 mg every 4 hours, appear to have COX-2 selectivity. Arthrotec is a combination of
with a maximal daily dose of 4 g. Gastrointestinal absorption is diclofenac and misoprostol, the latter being a prostaglandin E1
almost totally complete. The onset of action is 10 to 30 minutes (PGE1) analogue, conferring gastrointestinal protection. The pro-
with a duration of effect of 3 to 4 hours. drugs sulindac (Clinoril) and nabumetone (Relafen) may also have
Liver toxicity may occur with acetaminophen overuse and a less gastrointestinal effects. Once-daily dosing such as with piroxi-
concurrent alcohol intake of greater than 3 drinks per day. A cam (Feldene) helps with compliance but may increase renal toxi-
low-protein diet also appears to contribute to increased toxicity city, particularly in the elderly.
secondary to decreased glutathione stores. The NSAIDs are metabolized in the liver by CYP2C9 of the
Acetaminophen is predominantly metabolized in the liver by cytochrome P-450 system. Care should be taken in those with
glucuronidation or sulfation. If these pathways are overwhelmed liver disease. Increased liver function studies may be seen with
by excessive acetaminophen, a reactive metabolite NAPQI NSAIDs. Sulindac has been associated with a high incidence of
(N-acetyl-p-benzoquinone imine) may accumulate and contribute reported liver problems. Bleeding time is increased with the non-
to hepatotoxicity. NAPQI may be eliminated by conjugation with selective NSAIDs. Platelet function is impaired, and these agents
glutathione. However, in acetaminophen overdose, glutathione may should not be used with warfarin. Salsalate (Disalcid) and choline
be diminished. Hepatocytes become more vulnerable to oxidative magnesium trisalicylate (Trilisate) have less antiplatelet effects. The
injury. NAPQI contributes to this damage, and in addition, cal- COX-2 agents do not prevent platelet thromboxane production and
cium-dependent catabolic activity may be activated. Renal tubular have no effect on the bleeding time (because, under normal circum-
necrosis and hypoglycemic coma are other adverse effects of aceta- stances, there is no COX-2 in platelets).
minophen overdose. NSAIDs have little effect on renal function in the healthy indi-
N-Acetylcysteine (Mucomyst) is the principal antidote of vidual. However, certain conditions may predispose to an overre-
acetaminophen overdose. Early treatment within 8 to 10 hours liance on the vasodilatatory effects of prostaglandins. These include
of ingestion is recommended at a dose of 140 mg/kg orally. hypovolemia, congestive heart failure, and hepatic disease. In these
N-Acetylcysteine acts to replenish glutathione stores and conjugates conditions, all NSAIDs should be avoided. In addition, NSAIDs
NAPQI, leading to detoxification. may promote edema formation with salt and water retention.
Acetaminophen in doses of 4 g/day or less is an excellent choice Abuse of NSAIDs may induce chronic interstitial nephritis.
for mild pain or as an adjunctive agent to other therapy in moderate Despite the risks associated with these drugs, the NSAIDs are the
to severe neck pain. Advantages include no effect on bleeding most commonly prescribed medications worldwide. They are good
and lack of irritative gastrointestinal effects. Green tea consump- choices for mild to moderate neck pain and are well suited for acute
tion may be hepatoprotective with long-term usage of 4 g/day of neck pain with an inflammatory or musculoskeletal component.
However, contradictory evidence exists regarding their efficacy in Table 18^4. Commonly Used Muscle Relaxants
various chronic pain states.
Drug Dose
Opioids Baclofen (Lioresal) 5 mg tid–20 mg qid
When pain is not adequately controlled with mild analgesics and Carisoprodol (Soma) 350 mg tid
their combination with muscle relaxants, the initial use of a short- Chlorzoxazone (Parafon Forte) 250–750 mg tid
acting opioid may be warranted. A great deal of controversy Cyclobenzaprine (Flexeril) 10 mg tid
surrounds opioid use, including fear of addiction, potential for Diazepam (Valium) 2–10 mg bid–tid
tolerance development, and opioid-induced hyperalgesia, a com-
plicated pain state characterized by a hypersensitivity to pain. Metaxolone (Skelaxin) 800 mg tid
However, the vast majority of patients with severe pain do benefit Methocarbamol (Robaxin) 750–1500 mg qid
from effective pain management with the rational use of opioid Orphenadrine (Norflex) 100 mg bid
therapy to facilitate movement and enhance function.
Many choices of short-acting opioids are available, although
most are combined with either acetaminophen or an anti-inflam- compared with placebo and diazepam. Its effect is central in the
matory agent. Unfortunately, these added agents limit the safe brainstem. Cyclobenzaprine has a structure very similar that of to
dosage and are the main reasons for organ damage. Abuse and amitriptyline and possesses anticholinergic effects. Dry mouth and
addiction may be more common with those medications with the sinus tachcardia may be worrisome. Recommendations are for
faster onset and shorter duration. If ongoing therapy is anticipated, short-term or intermittent use at an average dose of 10 mg three
a switch to the longer-acting agents is advised (Table 18–3). times a day, not to exceed 60 mg/day. Sedation, dizziness, and
dysrhythmias may occur. Avoidance of use with monoamine oxi-
dase (MAO) inhibitors and in those patients with angle-closure
Muscle Relaxants glaucoma is warranted.
Metaxolone (Skelaxin) is a muscle relaxant commonly used in
Muscle relaxants may be helpful in acute musculoskeletal injury of acute conditions but may rarely induce a hemolytic anemia and
the neck as well as chronic myofascial pain. These drugs exert their leukopenia. Carisprodol (Soma) is best limited to short-term use
effect centrally in the central nervous system instead of directly on because of the potential for abuse, particularly when combined with
the muscle fiber. Some of these medications, for example, baclofen, hydrocodone. Liver metabolism to several metabolites including
may aid in neuropathic pain control (Table 18–4). meprobamate may be the reason for its high abuse. High doses of
One of the most commonly used muscle relaxants for acute neck long-term carisprodol therapy should not be stopped abruptly.
pain is cyclobenzaprine (Flexeril). In randomized, controlled trials, Baclofen is a g-aminobutyric acidB (GABAB) agonist with inhib-
cyclobenzaprine demonstrated significant neck spasm relief when itory pre- and postsynaptic activity at the spinal level. Occurring as
Table 18^3. Current Therapy with Opioids
Interval of
Drug How Supplied Dosing
Propoxyphene/acetaminophen (Darvocet) 50/325, 100/500, 100/650 mg q4h
Codeine (plain) 15, 30, 60 mg q4h
With acetaminophen 15/300 (Tylenol No. 2)
30/300 (Tylenol No. 3)
60/300 (Tylenol No. 4)
Hydrocodone/acetaminophen 2.5/500, 5/325, 5/500, q4–6h
(Lortab, Vicodin, Norco) 7.5/325, 7.5/500, 7.5/650, 7.5/750,
10/325, 10/500, 10/650 mg
Hydrocodone/ibuprofen 7.5/200 mg
Oxycodone plain 5, 15, 30 mg q4–6h
With acetaminophen (Percocet, Tylox, Roxicet) 2.5/325, 5/325, 7.5/325, 7.5/500, 10/325, 10/650 mg
Oxycontin (long-acting) 10, 15, 20, 30, 40, 60, 80 mg bid
Hydromorphone (Dilaudid) 2, 4, 8 mg q4–6h
Fentanyl (Duragesic) patch 12, 25, 50, 75, 100 mcg/hr q72h
Methadone 5, 10 mg bid–qid
Morphine
Immediate-release 15, 30 mg q3–4h
Continuous-release
Oramorph 15, 30, 60, 100 mg bid–tid
MS Contin 15, 30, 60, 100, 200 mg bid–tid
Kadian 20, 30, 50, 60, 100 mg Once or twice/day
Avinza 30, 60, 90, 120 mg Once daily
Oxymorphone (Opana)
Immediate-release 5, 10 mg q4–6h
Extended-release 5, 7.5, 10, 15, 20, 30, 40 mg bid
a racemic mixture, the L-baclofen is active. Baclofen may be helpful patients with sleep disorders and coexistent depression. Tricyclic
in the setting of muscle spasms and has unique antinociceptive antidepressants (TCAs) are more commonly used for pain, because
effects. Decreased excitatory neurotransmitter release supports its the selective serotonin reuptake inhibitors (SSRIs) have not been as
use in neuropathic pain states. Baclofen is also useful in gastro- effective. The combination of both norepinephrine and serotonin
esophageal reflux disorders. suppression seems more beneficial for pain states. The effect on
Side effects of baclofen include dizziness and sedation. Baclofen pain is unique and not dependent on mood elevation. Anecdotal
also decreases seizure threshold. Abrupt discontinuance may be reports of a selective beneficial effect on burning pain have been
associated with tachycardia, hallucinations, and seizures. Baclofen advanced, but there have been no studies to support this belief.
should be tapered over a few weeks. Antidepressant therapy with the TCAs can be tailored to the
Baclofen undergoes partial liver metabolism and urinary excre- individual. More or less anticholinergic TCAs can be chosen
tion. Caution should be exercised with all the muscle relaxants in depending on treatment goals. If pain impairs sleep, the more sedat-
the setting of renal insufficiency. Baclofen has been associated with ing agents amitriptyline, imipramine, and doxepin may be helpful.
severe reactions in renal patients, with profound confusion occur- In elderly patients at risk for mental clouding, the less anticholin-
ring after single doses. ergic TCAs desipramine and nortriptyline may cause less confusion
Benzodiazepines such as diazepam act to increase chloride influx and sedation (Table 18–5).
with increased membrane potential. Problematic withdrawal and The TCAs induce sodium blockade of neuronal as well as cardiac
sedation limit their usefulness. Depressive symptoms may become channels. Heart block and arrythmias may occur in susceptible
magnified. Like baclofen, clonazepam is a GABAB agonist and may individuals. a-Receptor blockade may cause decreased sympathetic
also have analgesic effects. Concurrent use of baclofen with clonaz- response with postural hypotension contributing to a threefold risk
epam should be avoided. of hip fractures from falling in the elderly. Nortriptyline and dox-
epin are associated with less hypotension. However, nortriptyline
has been associated with some arrythmogenic properties.
Tizanidine
In addition to the sodium channel and a-receptor blockade,
Tizanidine (Zanaflex) is a centrally acting a2-agonist that reduces TCAs may demonstrate NMDA receptor antagonism in the spinal
muscle tone. Use of this drug has been approved for spasticity by cord. However, this property does not appear to contribute to the
the U.S. Food and Drug Administration (FDA). Myofascial neck pain oral effect of these agents. TCAs may also cause H1-receptor block-
and headache associated with muscle spasms may respond to tizani- ade with resultant sedation.
dine. The mechanism of effect is a presynaptic inhibition of alpha Other unwanted side effects include weight gain particularly
motor neurons within the spinal cord. Tizanidine is structurally associated with amitriptyline and sexual dysfunction with delayed
related to clonidine. Adverse side effects include dizziness, drowsi- orgasm. A potentially serious reaction may occur if antidepressants
ness, dry mouth, and hypotension that are worsened with clonidine are combined with MAO inhibitors. Serotonin syndrome symptoms
and other antihypertensive agents. Five percent of patients may include fever, confusion, and myoclonus. The use of SSRIs, weight
show increased aminotransferase levels, and several deaths from loss agents, and MAO inhibitors in combination is particularly
liver abnormalities have been reported. Therefore, it is recommended problematic. Of the newer agents, venlafaxine (Effexor) and dulox-
that aminotransferase levels be measured at 1, 3, and 6 months. etine (Cymbalta) may have advantages for neuropathic pain because
The initial dose is 4 mg with titration to 4 mg three times a day. of their combined serotonin and norepinephrine effects. Duloxetine
The maximum dosing is 36 mg/day. The peak effect is 1.5 hours has been FDA approved for diabetic peripheral neuropathic pain
with a 2.5-hour half-life. Tizanidine is metabolized in the liver with and fibromyalgia. Patients with preexisting liver disease may be at
urine (60%) and fecal (20%) excretion. Oral contraceptives cause increased risk of toxicity, and the use of this medication in those
decreased clearance. One beneficial effect of tizanidine is a possible with substantial alcohol consumption is discouraged. Paroxetine
gastroprotection with NSAIDs. (Paxil) and citalopram (Celexa) also have demonstrated some anal-
gesic effects but less than those of the TCAs. Paroxetine has been
used in panic disorder and may be helpful in the patient with whip-
Antidepressant Therapy lash injury associated with post-traumatic stress.
Slow tapering of the antidepressants is recommended because
For neuropathic neck pain, antidepressant therapy is a first-line withdrawal symptoms can occur with abrupt discontinuance. These
treatment. These agents are particularly good choices in those include malaise, gastrointestinal complaints, and headache.
Table 18^5. Commonly Used Antidepressants for Neuropathic Pain
Drug How Supplied (mg) Dosage Comments

Amitriptyline (Elavil) 10, 25, 50, 75, 100, 150 Start 10–25 mg hs, titrate up to Converted to nortriptylline,
50–300 mg/d predominantly serotonin effects
Desipramine 10, 25, 50, 75, 100, 150 Start 10–25 mg hs, up to 100–300 Predominantly norepinephrine effect
(Norpramin) mg/day
Doxepin (Sinequan, 10, 25, 50, 75, 100, 150 Start 10–25 mg, up to 75–300 mg/day Predominantly norepinephrine effects
Zonalon)
Duloxetine (Cymbalta) 20, 30, 60 Start 20–30 mg up to 60 mg/day Combined norepinephrine and serotonin
effects
Imipramine (Tofranil) 10, 25, 50, 75, 100, 125, Start 10–25 mg, up to 50–300 mg/day Converted to desipramine, both
150 norepinephrine and serotonin effects
Nortriptyline (Aventyl, 10, 25, 50, 75 Start 10–25 mg, up to 50–150 mg/day Comes in oral solution 10 mg/5 ml
Pamelor) Predominantly norepinephrine effect
Table 18^6. Anticonvulsant Therapy
Comparative
Drug Available Strengths (mg) Dosing Cost Notes
Carbamazepine 100, 200 200–400 mg bid–qid $$ Follow blood and liver function
(Tegretol) Extended-release tests
100, 200, 300, 400
Lamotrigine (Lamictal) 25, 100, 150, 200 50 mg/day to 150–200 $$$$ Rare but life-threatening rash
mg bid
Levetiracetam (Keppra) 250, 500, 750 500 bid to max $$$$$
3000 mg/day
Gabapentin (Neurontin) 100, 300, 400, 600, 800 100–300 hs increase to $$$$ Most commonly used
300–600 tid, max anticonvulsant for pain
3600 mg/day
Oxcarbamazepine 150, 300, 600 300 bid, increase to $$$$$
(Trileptal) 1200–2400 mg/day
Phenytoin (Dilantin) 100 100 bid–tid $$
Pregabalin (Lyrica) 25, 50, 75, 100, 150, 200, 50–75 bid–tid max 600/ $$$$ Excellent bioavailability and lack
225, 300 day of metabolites, becoming more
commonly used as first choice
Topiramate (Topamax) 25, 100, 200 25–50 hs $$$$$
Increased to 200 bid
Valproic acid 125, 250, 500 250 bid $$$$ Hepatotoxicity
(Depakote) Extended-release 250, 500
Zonisamide (Zonegran) 100 100/day to 300–400 qd $$$$ Contraindicated with sulfa allergy
Anticonvulsant Therapy Pregabalin (Lyrica) has been introduced to the U.S. market more
recently and is FDA approved for neuropathic pain due to diabetes,
Anticonvulsant therapy adds a new dimension to the treatment of postherpetic neuralgia, and for fibromyalgia. This drug has shown
neuropathic pain. These medications decrease the excitability of much promise when used for other types of neuropathic pain and
ectopic nerve impulses by inhibiting sodium and calcium channel has the advantage of less sedation with an earlier analgesic effect
activity with resultant membrane stabilization. while requiring less titration. Like gabapentin, pregabalin is a struc-
The older agents include phenytoin, carbamazepine, and val- tural derivative of GABA. Although no binding occurs at GABA
proic acid. Unfortunately, added vigilance is necessary when pre- receptors, GABA levels are increased. Pregabalin binds at the d2
scribing these drugs because of hematologic and liver toxicity. site of voltage-gated calcium channels in central nervous system
Blood counts and liver function testing should be performed rou- tissues, leading to normalization of calcium conductance. Release
tinely. Used in a number of pain conditions, phenytoin continues to of glutamate, substance P, and calcitonin gene–related peptide is
be popular for many practitioners but is associated with a number reduced. Few drug interactions occur, and uniquely, pregabalin has
of troublesome side effects such as gingival hyperplasia, coarsening a 90% oral bioavailabilty. Gabapentin’s bioavailability may vary and
of facial features, and hair growth. Fetal craniofacial abnormalities may be as low as 30% in some individuals. Pregabalin has little
render it a contraindicated drug in pregnancy. Phenytoin acts to metabolism and is almost totally excreted by the kidneys. Dosage
increase sodium efflux and stabilize neuronal membranes. adjustment is needed in those with renal insufficiency. Peripheral
Phenytoin may be dosed once a day but suffers from erratic absorp- edema may occur in up to 19% of patients. Other side effects
tion and numerous drug interactions. Decreased effectiveness of include dizziness, somnolence, and thinking abnormalities.
other drugs such as acetaminophen and contraceptives may Pregabalin has also been classified as a Schedule 5 drug because
occur. Typical phenytoin dosing is 100 mg three times a day. of patient ratings of a ‘‘good drug effect’’ (Table 18–6).
Dizziness is a common side effect.
Carbamazepine (Tegretol) is structurally similar to the TCAs
and may enhance their antidepressant effect. Particularly effective NONPHARMACOLOGIC MANAGEMENT
in trigeminal neuralgia, its use has been expanded to other neuro- OF NECK PAIN
pathic conditions with electric lancinating character. However,
because of its risk of aplastic anemia and the need for blood mon- Reassurance and education of the patient regarding the possible
itoring, this medication is rarely a first choice for cervical neuro- etiology of the problem while avoiding threatening labels should
pathic pain. be done as soon as neurologic compromise is ruled out. Bedrest
The most commonly prescribed anticonvulsant for cervical neu- should be limited to 2 days after acute onset of neck pain to avoid
ropathic pain is gabapentin (Neurontin). Gabapentin does not act muscle deconditioning. There appears to be little advantage of a
at the GABA receptor but at an N-type calcium channel at the a2d1- cervical collar with whiplash injury after the initial 24 to 48 hours. If
subunit. Modulation of the release of excitatory neurotransmitters neurologically stable, patients should be encouraged to return to
and an increase in the global GABA activity result. Because of the work as soon as possible despite some pain, although work mod-
lack of significant drug interactions or effect on the blood count, ifications may be needed.
gabapentin is the most commonly prescribed anticonvulsant in the Ice and moist heat should be tried. Correction of postural
United States for chronic pain. Dosing should be modified in those abnormalities and range of motion and strengthening exercises
with renal disease. are very important in the ongoing care of patients with cervical
pain. Exercises that stress retraction of the neck and shoulders are External occipital
beneficial. Extension and rotation exercises should be performed protuberance
with caution in those with radiculopathy.
Manipulative therapy includes myofascial release, massage, and
high-velocity, low-amplitude manipulation. Myofascial release impro-
ves flexibility and decreases pain perception. Osteopathic and chiroprac-
tic manipulation should be undertaken only by highly trained
individuals because neck manipulation carries the risk of spinal cord Greater
and vertebral artery occlusion. Cervical traction may reduce neck occipital n.
pain through myofascial stretching and improving neuroforaminal
and facet opening. Radicular pain may be diminished, but this therapy Lesser
should not be used alone. Cervical traction devices are available that, if occipital n.
felt to be beneficial, can be purchased and used at home. Finger finds
Transcutaneous electrical nerve stimulation is not indicated for occipital a.,
nerve medial
many acute neck pain conditions but may be tried for chronic pain
unresponsive to pharmacologic intervention. Electrical motor stim-
ulation utilizes high-voltage galvanic stimulation to stimulate Greater
muscle contraction and may be helpful to retrain muscles decondi- Superior auricular n.
nuchal line Posterior br.
tioned after injury.
Ultrasound is an effective form of deep heating that may
enhance range of motion but should be avoided in acute inflam-
matory conditions. This modality should be avoided at the antero-
lateral neck because of potential danger to the nerves of the brachial Figure 18^3. Occipital nerve block. (From Brown D. Atlas of
and cervical plexus owing to membrane destabilization. Ultrasound Regional Anesthesia. Philadelphia:WB Saunders,1999; p 145.)
is also contraindicated over the site of a prior laminectomy.
Psychological factors may pose barriers to improvement in pain
perception and function. The term ‘‘yellow flags’’ has been used to commonly used for surgical anesthesia of the neck, cervical plexus
predict poor outcome in chronic pain patients. These include the blockade is another option for chronic occipital and lateral neck
belief that the pain is disabling, fear-avoidance behavior that pain and has been used for metastatic pharyngeal pain control.
reduces activity, low mood and social withdrawal, and an overre- Cervical epidural steroid injections are commonly performed for
liance on passive treatment. Cognitive-behavioral techniques inte- cervical radicular pain with at least transient improvement in up to
grated into the overall care may help to overcome these obstacles. 70% of well-selected acute cases (Fig. 18–5). Axial neck pain has not
Acupuncture treatment is becoming more common for neck and been as responsive to this approach. The risks of epidural steroid
shoulder pain. The traditional Chinese approach emphasizes indivi- injections range from mild side effects to severe complications.
dual diagnosis of an energy and meridian imbalance that guides Neck stiffness, a transient increase in pain, and flushing may be
needle insertion. Both tongue and pulse diagnoses provide a very experienced. Infection with epidural abscess is less common than
individualized approach with a central rather than peripheral empha- in the lumbar area, but potential cord compression poses greater
sis in treatment. Western acupuncture is more conventional and danger. Similarly, an epidural hematoma may cause far more
relies more on needling of the area of discomfort or the trigger point.
INTERVENTIONAL INJECTION
TECHNIQUES
Trigger point injections with local anesthetic may be helpful for
myofascial neck and shoulder pain. Improvement in pain and
range of motion often lasts for long periods after the duration of
the local anesthetic has elapsed. The local anesthetic may lead to
vasodilatation and a decrease in muscle spasms with an enhance- Lesser
occipital n.
ment of physical therapy tolerance.
Botulinum toxins A and B act by inhibiting presynaptic acetyl- Greater C1
choline release and have been utilized for treatment in cervical dys- auricular n. C2
tonia and spasticity and other pain syndromes characterized by
muscle spasm. Large doses of botulinum A (>50 units) have C3
shown benefit for myofascial pain, but the effects of small but Cranial n. XI Transverse
more frequent dosing have not been as significant. (accessory n.) C4 cervical n.
Regional techniques with blockade of peripheral nerves have Ansa cervicalis
been employed for neck pain. Posterior head and neck pain may Phrenic n. complex
5
be treated with occipital nerve block, which is performed medial to
the occipital artery located one third of the distance from the
greater occipital protuberance toward the mastoid (Fig. 18–3).
The cervical plexus is formed by C1–4 ventral branches of the
cervical spinal nerves and innervates the posterior and lateral neck
and head (Fig. 18–4). The superficial cervical plexus is blocked Supraclavicular n.
posterior to the sternocleidomastoid muscle at its midpoint.
Branches of the superficial plexus include the lesser occipital (to
the lateral occipital area), the great auricular nerve, and the trans-
verse cervical and supraclavicular nerves. The deep cervical plexus is Figure 18^4. Cervical plexus. (From Brown D. Atlas of Regional
anesthetized at the level of the C2–4 transverse processes. More Anesthesia. Philadelphia,WB Saunders,1999; p 182.)
A B
Figure 18^5. A, Anteroposterior (AP) view of interlaminar cervical epidural steroid injection. B, Lateral view of interlaminar
cervical epidural steroid injection with contrast. (A, Reproduced with permission of Milton H. Landers, D.O., Ph.D.)
neurologic compromise because of the smaller and more contained Injections may be performed via an interlaminar or a trans-
space in the neck. foraminal approach. The midline interlaminar approach was the
Dural puncture may cause a spinal headache, and inadvertent most commonly used technique in the past. More recently, the
dural injection of local anesthetic may lead to severe hypotension transforaminal approach has been advocated to maximize the
and respiratory arrest. Paraplegia from intracord injection and delivery of the steroid to the targeted nerve and the dorsal root
quadriparesis from a theorized increase in cerebral fluid pressure ganglion (Fig. 18–6). Case reports detailing spinal cord and anterior
leading to a vascular insult during injection have been reported. The radicular artery and vertebral artery injection have led some to aban-
incidence of major complications is fortunately rare (0.4%). don this technique. Diligent fluoroscopic vigilance with multiple
C4 C5
R C5 SSNB
A B
Figure 18^6. A, Lateral view of transforaminal cervical epidural steroid injection with contrast. B, AP view of transforaminal
cervical epidural steroid injections with contrast. (A and B, Reproduced with permission of Milton H. Landers, D.O., Ph.D.)
C6
C7
T1
Figure 18^7. Intra-articular zygapophyseal joint Figure 18^8. Radiofrequency of medial branch to
injection. (Reproduced with permission of Milton H.Landers, D.O., Ph.D.) zygapophyseal joint. (Reproduced with permission of Milton H.
Landers, D.O., Ph.D.)
Table 18^7. Current Therapy of Neck Pain
Type Pharmacologic Nonpharmacologic InjectionTherapy

Mild/acute Acetaminophen NSAIDs Rest, immobilization
Muscle relaxants Cervical collar
Moderate Myofascial Short-acting opioids Physical therapy Trigger point injections
Lidoderm patch Chiropractic manipulation Botulinum toxin
Tizanidine TENS unit
Neuropathic Antidepressants Epidural steroid injections
Radicular Anticonvulsants
Axial Facet injections
Chronic and refractory Long acting opioids Behavioral medicine techniques (CBT) Surgery
Radiofrequency ablation
Dorsal column stimulation
Discography
Nucleoplasty
CBT, cognitive-behavioral therapy; NSAIDs, nonsteroidal anti-inflammatory drugs; TENS, transcutaneous electrical nerve stimulation.
views, real-time contrast injection, digital subtraction, nonparticu- SUGGESTED READINGS

late steroid use, and advanced technical expertise are advised.
Barnsley L. Percutaneous radiofrequency neurotomy for chronic neck pain:
The cervical zygapophyseal joint (often referred to as the facet outcomes in a series of consecutive patients. Pain Med 2005;6:282–286.
joint) is a common neck pain generator, and intra-articular injec- Bogduk N. The anatomy and pathophysiology of neck pain. Phys Med
tions may be tried (Fig. 18–7). Alternatively, the medial branch of Rehabil Clin N Am 2003;14:455–472.
the dorsal rami to these joints may be blocked with local anesthetic Bogduk N. Medical Management of Acute Cervical Radicular Pain.
to predict the response to radiofrequency ablation. This lesioning Newcastle, New South Wales, Australia: Newcastle Bone and Joint
technique is an effective palliative intervention for axial neck pain Institute, 1999.
(Fig. 18–8). Bogduk N. Practice Guidelines for Spinal Diagnostic and Treatment
For discogenic disease unresponsive to conservative therapy, Procedures. San Francisco: International Spine Intervention Society, 2004.
options include the evolving modality of lesioning of the disk itself. Devereaux MW. Neck pain. Prim Care 2004;31:19–31.
Ferrari R, Russell A. Neck pain. Best Pract Res Clin Rheumatol 2003;
Discography is used to determine suitable candidates. Nucleoplasty 17:57–70.
and intradiskal electrothermal therapy (IDET) are practiced in Honet J, Ellenberg M. What you always wanted to know about the history
advanced centers, but rigorous long-term results are as yet unknown. and physical examination of neck pain but were afraid to ask. Phys
In summary, the diagnosis and treatment of neck pain can be Med Rehabil Clin N Am 2003;14:473–491.
challenging. However, many therapeutic options are available. One Hoppenfeld S. Orthopaedic Neurology. Philadelphia: Lippincott Williams
simplified approach to treatment is summarized in Table 18–7. & Wilkins, 1997.
Huston C, Slipman C, Garvin C. Complications and side effects of Pelosa P, et al. Medicinal and injections therapies for mechanical neck
cervical and lumbosacral selective nerve root injections. Arch Phys Med disorders. Review. The Cochrane Collaboration, Cochrane Library,
Rehabil 2005;86:277–283. Issue 2. John Wiley & Sons, Ltd, 2006. Available at http://
Ma D, Gilula L, Riew KD. Complications of fluoroscopically guided www.thecochranelibrary.com
extraforaminal cervical nerve blocks. J Bone Joint Surg 2005;87:1025–1030. Phero J, Dionne R. Pharmacological management of head and neck pain.
Malanga G, Peter J. Whiplash injuries. Curr Pain Headache Rep 2005; Otolaryngol Clin North Am 2003;36:1171–1185.
9:322–325. Smith HS. Drugs for Pain. Philadelphia: Hanley and Belfus, 2003.
Ojala T, Arokoski J, Partanen J. The effect of small doses of botulinum Vas J, Perea-Milla E, Méndez C, et al. Efficacy and safety of acupuncture
toxin A on neck-shoulder myofascial pain syndrome: a double-blind, for chronic uncomplicated neck pain: a randomized controlled study.
randomized, and controlled crossover trial. Clin J Pain 2006;22:90–96. Pain 2006;126:245-255.
Chapter 19 (acute fractures excluded). The most common diagnoses were

impingement (2016 patients; 51% of patients with shoulder pro-
SHOULDER PAIN blems), calcific tendinitis (522 patients; 13%), and rotator cuff tear
(1059 patients; 26%).
Richard L.Uhl
PATHOPHYSIOLOGY
The shoulder is a highly mobile joint. According to American
Medical Association guidelines, a full range of motion is from 508
of adduction to 1808 of abduction, 508 of extension to 1808 of
INTRODUCTION flexion, and from 908 of external rotation to 908 of internal rota-
tion. However, a patient with considerably less shoulder motion can
Shoulder pain is a common complaint, affecting up to 66% of the still be functional for many tasks.
general population at some point during their lifetime. In many The shoulder joint is able to achieve this degree of motion
cases, the pain is limited in intensity and duration, resolving on because of the lack of bony constraints. The round humeral head
its own. In some cases, the pain persists and can become disabling. sits on the relatively flat glenoid, but it must be held in place with
The majority of these cases will resolve with accurate diagnosis and soft tissue constraints to maintain stability. The stabilizing struc-
appropriate treatment, with only a small percentage of patients tures include the glenoid labrum, the glenohumeral ligaments, the
going on to a chronic pain syndrome. rotator cuff, the biceps tendon, and the deltoid muscle. To maintain
stability, the static stabilizers (labrum and ligaments) must be
intact, and the dynamic stabilizers (muscles) must be balanced
TAXONOMY with each other. Injuries to the ligaments or muscle weakness will
lead to instability, and pain, of the shoulder joint. Contracture of
Impingement: General term used to describe pain-producing lesions the soft tissue stabilizers will lead to pain and stiffness of the nor-
of the bursa, rotator cuff, or biceps tendon due to tissue irritation mally mobile shoulder joint.
from the coracoacromial arch (acromion, acromioclavicular Irritation of the stabilizing structures (bursitis, tendinitis) will
[AC] joint, coracoacromial [CA] ligament, or coracoid) also lead to pain. Arthritis of the AC joint is a common cause of
Instability: Excess translational motion of the glenohumeral joint shoulder pain due to pain in the joint itself and due to irritation of
that produces pain in the shoulder joint. This may be from laxity the bursa, rotator cuff, and biceps tendon from the osteophytes that
of the tissues or from a labral tear after dislocation of the gle- form around the AC joint. True glenohumeral arthritis will present
nohumeral joint. with pain throughout the entire range of motion, rather than with
SLAP lesion: Superior labrum anterior posterior tear. The impingement pain at the end of motion.
biceps tendon is anchored to the superior labrum. If the If mechanical causes have been eliminated, other causes such as
biceps tendon tears the labrum from the glenoid, a SLAP cervical radiculopathy, avascular necrosis, infection, and tumor
lesion results. A SLAP lesion may also occur from repeated should be considered.
pinching of the superior labrum through excessive overhead
use of the arm.
Adhesive capsulitis: Tightening and scarring of the shoulder joint
capsule leading to profound glenohumeral stiffness and severe
CLINICAL FEATURES
pain. Commonly referred to as a ‘‘frozen shoulder.’’ Shoulder pain most often presents as a deep aching on the lateral
aspect of the arm, near the deltoid muscle insertion (shoulder pain
is commonly referred to this area). Patients will often notice pain
and weakness with overhead activities and difficulty sleeping on the
EPIDEMIOLOGY affected side. Patients complain of difficulty reaching up their back
(undoing a brassier for women and putting on a suit coat for men).
The true incidence of shoulder pain is difficult to determine, in part With time, the shoulder may become stiff, which leads to additional
owing to variation of the definition of shoulder pain. Of 60,131 new pain with attempted motion.
patient visits (or old patients with a new problem) seen in the Inflammation problems (bursitis or rotator cuff tendinitis) will
author’s orthopedic practice over a 2-year period, 4014 patients usually start after a period of overuse, but it may occur either
(7% of patients seen) had a diagnosis related to shoulder pathology suddenly or insidiously without any obvious aggravation.
Huston C, Slipman C, Garvin C. Complications and side effects of Pelosa P, et al. Medicinal and injections therapies for mechanical neck
cervical and lumbosacral selective nerve root injections. Arch Phys Med disorders. Review. The Cochrane Collaboration, Cochrane Library,
Rehabil 2005;86:277–283. Issue 2. John Wiley & Sons, Ltd, 2006. Available at http://
Ma D, Gilula L, Riew KD. Complications of fluoroscopically guided www.thecochranelibrary.com
extraforaminal cervical nerve blocks. J Bone Joint Surg 2005;87:1025–1030. Phero J, Dionne R. Pharmacological management of head and neck pain.
Malanga G, Peter J. Whiplash injuries. Curr Pain Headache Rep 2005; Otolaryngol Clin North Am 2003;36:1171–1185.
9:322–325. Smith HS. Drugs for Pain. Philadelphia: Hanley and Belfus, 2003.
Ojala T, Arokoski J, Partanen J. The effect of small doses of botulinum Vas J, Perea-Milla E, Méndez C, et al. Efficacy and safety of acupuncture
toxin A on neck-shoulder myofascial pain syndrome: a double-blind, for chronic uncomplicated neck pain: a randomized controlled study.
randomized, and controlled crossover trial. Clin J Pain 2006;22:90–96. Pain 2006;126:245-255.
Chapter 19 (acute fractures excluded). The most common diagnoses were

impingement (2016 patients; 51% of patients with shoulder pro-
SHOULDER PAIN blems), calcific tendinitis (522 patients; 13%), and rotator cuff tear
(1059 patients; 26%).
Richard L.Uhl
PATHOPHYSIOLOGY
The shoulder is a highly mobile joint. According to American
Medical Association guidelines, a full range of motion is from 508
of adduction to 1808 of abduction, 508 of extension to 1808 of
INTRODUCTION flexion, and from 908 of external rotation to 908 of internal rota-
tion. However, a patient with considerably less shoulder motion can
Shoulder pain is a common complaint, affecting up to 66% of the still be functional for many tasks.
general population at some point during their lifetime. In many The shoulder joint is able to achieve this degree of motion
cases, the pain is limited in intensity and duration, resolving on because of the lack of bony constraints. The round humeral head
its own. In some cases, the pain persists and can become disabling. sits on the relatively flat glenoid, but it must be held in place with
The majority of these cases will resolve with accurate diagnosis and soft tissue constraints to maintain stability. The stabilizing struc-
appropriate treatment, with only a small percentage of patients tures include the glenoid labrum, the glenohumeral ligaments, the
going on to a chronic pain syndrome. rotator cuff, the biceps tendon, and the deltoid muscle. To maintain
stability, the static stabilizers (labrum and ligaments) must be
intact, and the dynamic stabilizers (muscles) must be balanced
TAXONOMY with each other. Injuries to the ligaments or muscle weakness will
lead to instability, and pain, of the shoulder joint. Contracture of
Impingement: General term used to describe pain-producing lesions the soft tissue stabilizers will lead to pain and stiffness of the nor-
of the bursa, rotator cuff, or biceps tendon due to tissue irritation mally mobile shoulder joint.
from the coracoacromial arch (acromion, acromioclavicular Irritation of the stabilizing structures (bursitis, tendinitis) will
[AC] joint, coracoacromial [CA] ligament, or coracoid) also lead to pain. Arthritis of the AC joint is a common cause of
Instability: Excess translational motion of the glenohumeral joint shoulder pain due to pain in the joint itself and due to irritation of
that produces pain in the shoulder joint. This may be from laxity the bursa, rotator cuff, and biceps tendon from the osteophytes that
of the tissues or from a labral tear after dislocation of the gle- form around the AC joint. True glenohumeral arthritis will present
nohumeral joint. with pain throughout the entire range of motion, rather than with
SLAP lesion: Superior labrum anterior posterior tear. The impingement pain at the end of motion.
biceps tendon is anchored to the superior labrum. If the If mechanical causes have been eliminated, other causes such as
biceps tendon tears the labrum from the glenoid, a SLAP cervical radiculopathy, avascular necrosis, infection, and tumor
lesion results. A SLAP lesion may also occur from repeated should be considered.
pinching of the superior labrum through excessive overhead
use of the arm.
Adhesive capsulitis: Tightening and scarring of the shoulder joint
capsule leading to profound glenohumeral stiffness and severe
CLINICAL FEATURES
pain. Commonly referred to as a ‘‘frozen shoulder.’’ Shoulder pain most often presents as a deep aching on the lateral
aspect of the arm, near the deltoid muscle insertion (shoulder pain
is commonly referred to this area). Patients will often notice pain
and weakness with overhead activities and difficulty sleeping on the
EPIDEMIOLOGY affected side. Patients complain of difficulty reaching up their back
(undoing a brassier for women and putting on a suit coat for men).
The true incidence of shoulder pain is difficult to determine, in part With time, the shoulder may become stiff, which leads to additional
owing to variation of the definition of shoulder pain. Of 60,131 new pain with attempted motion.
patient visits (or old patients with a new problem) seen in the Inflammation problems (bursitis or rotator cuff tendinitis) will
author’s orthopedic practice over a 2-year period, 4014 patients usually start after a period of overuse, but it may occur either
(7% of patients seen) had a diagnosis related to shoulder pathology suddenly or insidiously without any obvious aggravation.
148 Chapter 19 SHOULDER PAIN
Instability may result from trauma, especially if there was a gle-

nohumeral dislocation, but may also be due to tissue laxity or
repetitive stretching trauma (baseball pitcher) over time. Medial AC joint Lateral
le Acr
EVALUATION Clavic om
ion
Evaluation of the patient with shoulder pain begins with a careful
Bice
history, including specific questions about the location and nature
p
of the pain, history of trauma or overuse, and previously attempted Del
s te
toid
treatments (Table 19–1). Injury to the AC joint (so-called separated
ndo
shoulder) often occurs after a direct blow to the shoulder, whereas
n
glenohumeral dislocation usually occurs from a fall on the out-
stretched arm. Repeated overhead activities may lead to impinge-
ment, rotator cuff tendinitis, or a SLAP lesion.
Most shoulder pain is referred to the outer arm region. When
pain is radiating below the elbow, especially when in a narrow,
dermatomal strip, cervical radiculopathy should be considered.
Examination begins with inspection of the shoulder region look- Figure 19^1. Begin the surface examination by palpating along the
ing for asymmetry, swelling, discoloration, or deformity. The clavicle to the acromioclavicular (AC) joint. Palpate the anterior,
patient is asked to raise the arm to the side (abduction) and elevate lateral, and posterior aspects of the acromion.The tendon of the long
in the forward plane (flexion). The patient is then asked to bring the head of the biceps lies inferior to the acromion, between the greater
arm up the back to evaluate internal rotation. and the lesser tuberosities.
Next, the shoulder region is palpated. Begin by following along
the clavicle to the AC joint. Tenderness, redness, swelling, and bony
prominence over the AC joint are indicators of AC joint arthritis have difficulty lowering the arm from a horizontal position to the
(Fig. 19–1). Tenderness of the biceps tendon when the bicipital side of the body (drop-arm test).
groove is palpated indicates biceps tendinitis. The apprehension test (Fig. 19–4), the Jobe relocation test, and
Various provocative tests have been described to help separate the sulcus sign indicate shoulder instability. The O’Brien test and
the mechanical causes of shoulder pain. The Neer and the Hawkins crank test load the biceps tendon and superior labrum, which causes
impingement tests look for bursa and rotator cuff impingement on pain in patients with a SLAP lesion.
the underside of the acromion or AC joint (Fig. 19–2). The cross- All patients presenting with shoulder pain should have radio-
body test compresses the AC joint, causing pain in patients with AC graphs. Standard views include an anteroposterior (AP) radiograph
arthritis (Fig. 19–3). Patients with a rotator cuff tear will have dif- (often with internal and external rotation of the humerus) and a
ficulty abducting the arm from the side of the body and also will lateral view (axillary or scapular Y view). In the absence of trauma
(and the need to rule out a dislocation), most information can be
gleaned from the AP radiograph. An acromial arch view is useful to
visualize the subacromial space.
Table 19^1. Current Diagnosis for Shoulder Pain The AP radiograph will visualize the AC joint, acromion, gle-
noid, and humeral head (Fig. 19–5). Spurs on the anterior acromi-
Diagnosis History Examination on can be seen on the AP view as a second shadow below the
Fracture Trauma Radiograph normal inferior cortex of the acromion (Fig. 19–6). AC joint
Dislocation Trauma Radiograph
Impingement Pain with overhead use Neer impingement test
Pain radiating down Hawkins impingement
the deltoid test
Pain when sleeping on
the shoulder
AC arthritis Pain over the AC joint Cross-arm test
Biceps Pain with elbow flexion Tenderness over the
tendinitis bicipital groove
Rotator cuff Difficulty raising the Drop arm test
tear arm
Instability History of dislocation Apprehension test
(traumatic) Relocation test
Tissue laxity Sulcus test (tissue
(nontraumatic) laxity)
SLAP lesion Pain or clicking with O’Brien’s test
overhead use Crank test
Frozen Stiffness and severe Markedly decreased
shoulder pain with motion glenohumeral motion Figure 19^2. The Neer impingement test (forward elevation of the
Cervical disk Pain radiating down Spurling’s test arm) and the Hawkins impingement test (shown) exacerbate the
the arm patient’s pain by moving the greater tuberosity under the spur on the
acromion or AC joint.The Hawkins test is performed by bringing the
AC, acromioclavicular; SLAP, superior labrum anterior posterior. arm to 908 of forward flexion and internally rotating the shoulder.
AC joint
Acromion
Greater
tuberosity
Figure 19^3. The cross-body test is performed by elevating the

arm and bringing it across the front of the body, which compresses Figure 19^5. Anteroposterior (AP) radiograph shows the AC joint,
the AC joint. acromion, glenoid, and humeral head.
arthritis and spurs (Fig. 19–7), degenerative cysts of the greater motion once the injury has healed. Many patients with traumatic
tuberosity (Fig. 19–8), calcific tendinitis (Fig. 19–9), and glenohu- dislocations will develop instability and recurrent dislocation and
meral arthritis (Fig. 19–10) can all be appreciated on the AP radio- will require surgical repair of the labrum.
graph as well. The initial treatment for nontraumatic shoulder problems
Magnetic resonance imaging (MRI) of the shoulder is useful to include
further confirm the diagnosis, especially if conservative treatment
1. Rest and medication (nonsteroidal anti-inflammatory drugs
has failed to provide relief. MRI is also useful for finding additional
[NSAIDs]) to decrease the pain and inflammation.
sources of pathology such as a labral tear, SLAP lesion, or rotator
2. Gentle range-of-motion exercise to restore motion to the joint.
cuff tear.
3. Gentle strengthening of the rotator cuff muscles to regain muscle
balance.
4. Generalized strengthening once motion and cuff balance are
MANAGEMENT restored.
Traumatic injuries (fractures and dislocations) are treated with Mild subacromial impingement (bursitits, rotator cuff tendini-
closed reduction and immobilization, or open reduction, if tis) may respond to rest, NSAIDs, range of motion, and strengthen-
needed (Table 19–2). Therapy is often needed to restore shoulder ing. The strengthened rotator cuff will depress the humeral head
into the glenoid, decreasing the pressure on the bursa and cuff from
osteophytes present on the undersurface of the acromion and AC
joint. However, if the bursa irritation is chronic, the tissue becomes
Figure 19^4. The apprehension test (shown) is performed by

abducting the shoulder to 908 and externally rotating the shoulder
while applying forward pressure on the humeral head. If the patient’s
shoulder is unstable, the maneuver will give the sensation of the
shoulder dislocating, and the patient will become apprehensive.The
relocation test is identical, except the pressure is applied from the Figure 19^6. A subacromial spur on the anterior acromion can be
front in an effort to stabilize the humeral head. Patients who are seen on the AP view as a second shadow (dotted line) below the
unstable will feel relief with this maneuver. normal inferior cortex of the acromion.
150 Chapter 19 SHOULDER PAIN
AC joint
arthritis
Bone spur
causing
impingement
Figure 19^7. AP radiograph of a patient with AC joint arthritis and

spurs, which may irritate the bursa and rotator cuff.
Figure 19^9. AP radiograph shows calcific tendinitis (arrow) within
the supraspinatus muscle.
thickened, and therapy and oral medication alone may not provide
sufficient relief. A subacromial injection of 20 mg of methylpred-
nisolone will help shrink the inflamed bursal tissue and facilitate often improve symptoms, but this may also lead to tendon rupture
rehabilitation. If injections fail to provide long-term relief, arthro- (which often occurs in the absence of any injection). If the tendon
scopic or open débridement of the anterior acromial spur (acro- does rupture, the symptoms will often improve. Repair of the
mioplasty) and bursa may be needed. tendon after rupture is rarely indicated, but a tenodesis of the
AC joint arthritis is often seen in conjunction with subacromial biceps tendon in conjunction with other surgery for impingement
impingement. Pain from AC joint arthritis is from the inflamed or rotator cuff tear may be considered prior to rupture.
joint itself and also from irritation of the bursa and rotator cuff Rotator cuff tears are usually chronic (from cuff attrition as the
caused by bony osteophytes that form on the undersurface of the greater tuberosity hits against the subacromial spur) but can occur
joint. Whereas subacromial injection is often helpful, direct injec- after an acute injury, especially after dislocation in an older
tion of the AC joint is sometimes needed. If this fails, removal of the patient. With chronic impingement, patients first develop a
distal 1 cm of the clavicle (Mumford’s procedure) will provide relief partial-thickness tear, which may heal with conservative treatment.
in most cases. Distal clavicle resection and acromioplasty are often Once the tear becomes full thickness, surgery is usually needed,
combined in the same procedure, because both problems often although some patients may have minimal symptoms if the full-
coexist. thickness tear is small. If untreated, the tear will usually enlarge, the
Biceps tendinitis usually occurs with impingement and AC joint rotator cuff will become incompetent, and the patient may progress
arthritis, but it occasionally occurs as an isolated problem. to rotator cuff arthropathy (superior migration of the humeral head
Conservative treatment to decrease inflammation (ultrasound with glenohumeral arthritis).
with phonophoresis) and to strengthen the rotator cuff may Instability is initially treated with rotator cuff strengthening. The
prove effective. Injection of steroid into the tendon sheath will strengthened cuff muscles act to stabilize the glenohumeral joint
Cystic changes
Figure 19^10. Spur formation on the inferior glenoid indicates

Figure 19^8. AP radiograph shows degenerative cysts of the greater glenohumeral arthritis.The humeral head is flattened from collapse
tuberosity from chronic impingement on the acromion. due to avascular necrosis.
Table 19^2. Current Therapy for Shoulder Pain
Diagnosis ConservativeTreatment Surgical Treatment

Fracture Closed reduction, sling Open reduction, internal fixation
Dislocation Closed reduction Arthroscopic labral repair
Impingement Therapy (rotator cuff strengthening) Acromioplasty (open or arthroscopic)
NSAIDs
Steroid injection
AC arthritis Steroid injection Distal clavicle resection (open or arthroscopic)
Biceps tendinitis Therapy (ultrasound, strengthening) Acromioplasty (with or without biceps tenodesis)
Steroid injection (may lead to rupture)
Rotator cuff tear Therapy Surgical repair (open or arthroscopic)
Steroid injection
Instability Therapy (rotator cuff strengthening) Arthroscopic labral repair
SLAP lesion Therapy (rotator cuff strengthening) Arthroscopic repair (<40 yr old) or débridement (>40 yr old)
NSAIDs
Frozen shoulder Therapy (stretching) Manipulation
Arthroscopic release of capsule
Cervical disk Therapy Cervical decompression
NSAIDs
Cervical traction
Cervical epidural
AC, acromioclavicular; NSAIDs, nonsteroidal anti-inflammatory drugs; SLAP, superior labrum anterior posterior.
when the labrum and capsule cannot. If a true labral tear exists Because impingement is a degenerative process, gradual worsen-
(especially after traumatic dislocation in a younger patient), ing of symptoms is expected over time. Surgical treatment can
Bankart’s repair may be inevitable to prevent recurrent dislocations. have profound results, but some patients will continue with
Currently, most surgeons repair the labrum arthroscopically, inflammation and pain despite surgery. A good postoperative
although the success rate (measured by recurrent dislocation after therapy program improves results. Occasionally, a postoperative
repair) may be somewhat better with an open repair. injection of steroid is needed to decrease residual inflammation.
SLAP lesions may respond to therapy aimed at stretching the Surgical treatment for instability will usually improve symp-
capsule followed by rotator cuff strengthening. If conservative treat- toms, but a careful postoperative therapy course and continued
ment fails, surgical treatment is indicated. Surgery is usually done maintenance of rotator cuff strength are essential.
arthroscopically and may include débridement, labral repair, and Some patients fail to respond to all reasonable treatment meth-
biceps tenodesis, depending on the SLAP lesion type. Débridement, ods. Various modalities, including trigger point injection and acu-
rather than repair, is usually preferred in patients over 40 years old puncture, can prove useful.
because of an increased risk of postoperative stiffness after repair in
the older patient.
Adhesive capsulitis, or frozen shoulder, is usually a self-limiting CONCLUSION
process, although it may take months to years for the shoulder to
regain motion. Gentle stretching in therapy may be of benefit, but Shoulder pain is a common presenting complaint. Many cases are
aggressive stretching may worsen the patient’s pain. Manipulation self-limited or respond to conservative treatment methods. If con-
under anesthesia had traditionally been used in cases of prolonged servative treatment fails to provide relief, surgical treatment is effec-
stiffness, but recently, arthroscopic release of the tightened capsule tive, but accurate diagnosis is essential. A careful postoperative
has proved more beneficial. therapy course, administered by an experienced therapist, is essen-
Cervical disk disease is treated first by NSAIDs and therapy to tial for good surgical results.
slowly stretch and mobilize the neck muscles. Traction can be help-
ful in some patients, but it can exacerbate the problem in others.
Surgery to remove a herniated disk or fuse an arthritic segment may SUGGESTED READINGS
be needed in select cases. Alternative treatments, such as acupunc- McFarland EG, Selhi HS, Keyurapan E. Clinical evaluation of
ture, can be helpful in many patients. impingement: what to do and what works. J Bone Joint Surg Am
2006;88:432–441.
Meislin RJ, Sperling JW, Stitik TP. Persistent shoulder pain: epidemiology,
COMPLICATIONS/OUTCOMES pathophysiology, and diagnosis. Am J Orthop 2005;34(12 suppl):5–9.
Pope DP, Croft PR, Pritchard CM, Silman AJ. Prevalence of shoulder
Aggressive therapy may worsen shoulder inflammation, stiffness, pain in the community: the influence of case definition. Ann Rheum
and pain. Operative treatment, especially in the older patient, Dis 1997;56:308–312.
may lead to stiffness. Axillary nerve injury may result from surgery Swanson GDG. The upper extremities. In Cocchiarella L, Anderson GBJ
(eds): Guides to the Evaluation of Permanent Impairment, 5th ed.
on the inferior portion of the labrum. Traction injuries to the bra- Chicago: AMA Press, 2000; pp 474–479.
chial plexus can occur when arthroscopic surgery is done using arm Yamaguchi K, Ditsios K, Middleton WD, et al. The demographic and
traction. morphological features of rotator cuff disease. A comparison of
Mild cases of impingement will often respond favorably to therapy, asymptomatic and symptomatic shoulders. J Bone Joint Surg Am
but patients must continue the rotator cuff strengthening exercises. 2006;88:1699–1704.
152 Chapter 20 ELBOW PAIN
Chapter 20
The lateral epicondyle gives origin to the common extensor
ELBOW PAIN tendon (extensor carpi radialis brevis and the extensor digitorum
communis). Repeated wrist extension (such as flicking the wrist in a
Richard L.Uhl poorly executed tennis backhand stroke) leads to microtears in the
muscle origin. Decreased blood flow to the area is common with
aging ( 40 yr), and this decreases the healing potential once the
microtears occur. A similar condition can affect the common flexor
origin at the medial epicondyle (Fig. 20–1).
The ulnar nerve crosses the elbow posterior to the medial epi-
condyle through the cubital tunnel. After it crosses the elbow, the
INTRODUCTION ulnar nerve passes between the ulnar and the humeral heads of the
flexor carpi ulnaris. The nerve can be compressed at the medial
The elbow is inherently more stable than the shoulder. The majority epicondyle or the flexor carpi ulnaris, leading to pain and numbness
of elbow problems come from lateral and medial epicondylitis, in the ulnar nerve distribution.
olecranon bursitis, and ulnar neuropathy. Less common causes of The radial nerve passes between the brachialis and the brachior-
elbow pain include instability, synovitis, and arthritis. Many pro- adialis muscles proximal to the elbow joint before splitting into the
blems are the result of overuse and can be addressed with rest, superficial radial nerve and the posterior interosseous nerve (PIN).
activity modification, and conservative treatment. The PIN passes between the superficial and the deep heads of the
supinator muscle into the dorsal forearm and can be compressed at
this location.
TAXONOMY The MCL is the major stabilizer of the elbow. The ligament can
be injured by acute trauma such as elbow dislocation, or by chronic
Epicondylitis: Lateral or medial epicondylitis is an avascular necro- stretching of the ligament, which is common in throwing athletes.
sis of the common extensor or flexor tendon origins rather than Fractures of the elbow are usually the result of a fall on the
a true inflammatory process, as the name would suggest. outstretched arm and may include supracondylar fractures of the
Olecranon bursitis: Inflammation of the bursa at the tip of the humerus, an avulsion fracture of the olecranon, and fracture of the
olecranon, causing an unsightly swelling at the posterior aspect radial head (Fig. 20–2).
of the elbow. Olecranon bursitis rarely has functional implica- Arthritis of the elbow is usually a result of fracture or chronic insta-
tions unless it becomes infected. bility (Fig. 20–3). Synovitis may occur from chronic instability, from
Intra-articular loose body: When a fragment of bone or cartilage is inflammatory arthritis (such as rheumatoid arthritis [RA]), and from
floating freely within the joint, it can become lodged between the repeated intra-articular bleeding seen in patients with hemophilia.
articular surfaces, causing intermittent locking and pain with Olecranon bursitis occurs from local trauma to the bursa over-
joint motion. lying the olecranon. The process is usually self-limiting, but the
bursa may become infected after skin trauma or aspiration to
drain the bursa. A spur may develop on the tip of the olecranon
in chronic cases (Fig. 20–4).
EPIDEMIOLOGY
Of 60,131 new patient visits (or old patients with a new problem) CLINICAL FEATURES
seen in a general orthopedic practice over a 2-year period, 2219
patients (3.7% of patients seen) had elbow-related diagnoses Lateral epicondylitis and medial epicondylitis present as local ten-
(acute fractures excluded). The most common diagnoses were lat- derness at the muscle origins. The pain is often worse in the morn-
eral epicondylitis (918 patients; 41% of patients with elbow pro- ing, with patients describing a tearing sensation when they first
blems), olecranon bursitis (307 patients; 14%), medial epicondylitis move the wrist after awakening (Table 20–1).
(214 patients; 10%) and ulnar neuropthy (194 patients; 9%). Ulnar neuropathy often presents with medial elbow pain and
tenderness and associated hand numbness in the ulnar nerve dis-
tribution (ulnar half of the ring finger and the little finger). More
PATHOPHYSIOLOGY advanced cases of ulnar neuropathy have weakness and atrophy of
the hand’s intrinsic muscles. With subluxation of the ulnar nerve,
The elbow is made up of the ulnohumeral joint, which is a hinge- patients complain of a snapping sensation as the nerve crosses over
type joint, and the radiocapitellar joint, which allows rotation. The the medial epicondyle with elbow flexion and extension. The snap-
elbow has considerably more bony stability than the shoulder, but it ping is accompanied by an electric shock sensation along the course
still requires ligamentous support, especially from the medial col- of the ulnar nerve in the forearm and into the hand.
lateral ligament (MCL). The radiocapitellar joint acts as a secondary Compression of the PIN causes a deep aching pain in the dorsal
stabilizer of the ulnohumeral joint. Normal elbow range of motion forearm muscles. Symptoms of PIN compression can coexist with
is from full extension (08) to 1408 of flexion. lateral epicondylitis and may account for continued symptoms after
The annular ligament of the elbow wraps around the radial treatment of lateral epicondylitis.
head, allowing rotation while preventing translation. Normal Instability of the elbow results in an increase in motion in the
supination is 808, and normal pronation is 808. Fractures of the varus/valgus plane that leads to inflammation, pain, and eventually
radial head and arthritis of the radiocapitellar joint may limit degeneration of the joint. Chronic instability can be difficult to
this motion. detect because of the inherently stable bony architecture of the
Medial
Lateral epicondyle
Radial head
epicondyle
Tip of the
olecranon
Figure 20^1. Anteroposterior(AP)(left)andlateral(right)radiographs Figure 20^3. Severe diffuse arthritis of the elbow joint shows
ofanormalelbow.Thelateralandmedialepicondylesarebony multiple osteophyte formation (arrows) without significant narrowing
prominencesonthehumerus.Thelateralepicondyleservesas theorigin of the joint space. Arthritis in this patient was due to previous
to thecommonextensor tendon.Themedialepicondyleis theoriginof trauma. Severe narrowing of the joint space may indicate rheumatoid
thecommonflexor tendon.Theotherreadilypalpablebonylandmarkis arthritis, hemophilia, infection, and other causes.
thetip of theolecranon.Theradialheadisdistalto thelateralepicondyle.
The patient is asked to extend and flex the elbow, and the motion
elbow joint and because the symptoms often occur under extreme is noted.
loading circumstances (such as pitching a fastball). Next, the elbow is systematically palpated over the lateral and
Fractures about the elbow will present with pain and swelling. medial epicondyle, along the ulnar nerve at the cubital tunnel
Most fractures are easily discernible on plain radiographs, but and the tip of the olecranon, noting areas of tenderness. To evaluate
occult fractures of the radial head and neck may not be apparent the radial head and radiocapitellar joint, the examiner places a
on the initial radiographs. Diagnosis in this case is made by the finger over the lateral aspect of the joint, 2 to 3 cm distal to the
history of elbow trauma and local tenderness at the radial head. lateral epicondyle, while pronating and supinating the wrist. The
Arthritis of the elbow causes pain with elbow motion and a motion of the radial head should be free without popping or
restriction of motion as osteophytes begin to form about the grinding.
joint. Patients with an intra-articular loose body will complain of Passive wrist flexion while the patient attempts to extend the
intermittent locking of the joint as the fragment moves in and out wrist will exacerbate the pain of lateral epicondylitis. Passive wrist
of the joint space. extension while actively resisting will increase the pain of medial
epicondylitis.
Examination of the ulnar nerve includes palpation along course
EVALUATION of the nerve and sensory and motor examination of the hand.
Tinel’s sign may be elicited by light percussion on the skin over
Examination of the elbow begins with visual observation, looking the nerve. Flexion of the elbow produces tension along the nerve,
for areas of swelling, deformity, atrophy, and discoloration. which can reproduce the symptoms in cases of ulnar neuritis.
Free
fragment
Radial
head
fracture
Figure 20^2. AP and lateral radiographs demonstrate a fracture of

the radial head after a fall on the outstretched arm. In this patient,
approximately 40% of the radial head is depressed, and there is a Figure 20^4. Bone spur formation at the tip of the olecranon after
loose fragment in the anterior portion of the elbow joint. Surgery repeated episodes of olecranon bursitis. At this point, the spur is
would usually be performed to remove the loose fragment and to likely to cause additional irritation of the bursa, and surgical removal
repair the large depressed portion of the radial head. should be considered.
154 Chapter 20 ELBOW PAIN
Table 20^1. Current Diagnosis for Elbow Pain
Diagnosis History Examination

Lateral epicondylitis Repetitive wrist extension Tender over lateral epicondyle
Pain with passive wrist flexion while the patient resists
Medial epicondylitis Repetitive wrist flexion Tender over medial epicondyle
Pain with passive wrist extension while the patient resists
Ulnar neuropathy Aching pain along the medial forearm Tinel’s sign over the ulnar nerve
Tender along the ulnar nerve Numbness with pressure over the ulnar nerve
Ulnar-sided hand numbness Numbness with elbow flexion
Radial nerve/PIN Deep aching pain over the extensor Tender along PIN
entrapment musculature Pain with attempted supination against resistance
Instability History of dislocation (traumatic) Pain and laxity with valgus stress
Repetitive injury (throwing)
Fracture Trauma Localized tenderness
Pain with attempted motion
Synovitis Swelling Crepitus, popping with ROM
Painful ROM
Arthritis Trauma Generalized swelling
History of inflammatory arthritis (RA) Restricted painful motion
Intra-articular loose body History of locking while moving the elbow Elbow may lock and pop during examination
Olecranon bursitis/cellulitis Swelling Soft, fluctuant mass
Pain Red streak up the arm
History of scrape over elbow
PIN, posterior interosseous nerve; RA, rheumatoid arthritis; ROM, range of motion.
The diagnosis of radial nerve/PIN entrapment is made by con- Early cases of ulnar neuropathy (several weeks to several months
firming deep aching pain in the dorsal musculature, tenderness to duration) can initially be managed conservatively if there is no
deep palpation along the course of the nerve (between the extensor profound numbness or intrinsic muscle atrophy. Initial treatment
carpi radialis brevi and extensor digitorum communis muscle bel- in early and mild cases of ulnar neuropathy includes rest, avoiding
lies), and increased pain with attempted supination while the exam- pressure on the nerve from resting the elbow on desks and
iner holds the wrist in pronation. unpadded armrests, and sleeping with a pillow to avoid flexing
Instability due to laxity of the MCL is tested in 308 of elbow the elbow when asleep. Formal therapy with ulnar nerve gliding
flexion, by applying a valgus stress while the examiner’s fingers are and phonophoresis can provide relief in mild cases. If conservative
on the medial joint line at the MCL. treatment is not effective, or if there is evidence of intrinsic muscle
Evaluation for an intra-articular loose body is difficult if the weakness or atrophy, operative treatment should be considered. In
symptoms are very intermittent, but sometimes the patient can situ decompression, medial epicondylectomy, subcutaneous trans-
reproduce the locking (and unlocking) maneuvers, and on rare position, and submuscular transposition all have an essentially
occasion, the fragment can be palpated at the joint surface. equivalent success rates according to published reports.
Patients presenting with elbow pain should have anteroposterior In acute cases of ulnar nerve subluxation, an initial period of
(AP) and lateral radiographs of the elbow to evaluate for fractures, rest, while avoiding flexion, may allow the nerve to heal within
arthritis, and radiopaque fragments (loose bodies) within the joint. the cubital tunnel. For chronic ulnar nerve subluxation, medial
epicondylectomy, subcutaneous transposition, or submuscular
transposition should be considered. Chronic ulnar neuritis not
MANAGEMENT responding to these measures may require medication (pregabalin,
gabapentin, or amitriptyline) or alternative treatments such as
Lateral and medial epicondylitis are initially treated in a similar acupuncture.
fashion (Table 20–2). Conservative treatment includes rest, nonster- Radial nerve/PIN entrapment is initially treated conservatively.
oidal anti-inflammatory drugs (NSAIDs), and therapy including Repetitive activities involving supination should be avoided.
gentle stretching and ultrasound with or without phonophoresis, Therapy should include radial nerve gliding to help mobilize the
followed by gentle strengthening. Steroid injections usually provide nerve. If there has been no improvement after 3 months of therapy,
substantial relief, which can last weeks to months. When injecting surgical decompression should be considered.
steroid around the superficial epicondyles, care should be taken to Instability from acute MCL injury can heal with early protected
avoid subcutaneous injection. Because these conditions are usually motion. If instability remains, ligament reconstruction can restore
self-limited, steroid injections can provide relief while waiting for stability. In chronic cases, strengthening of secondary stabilizers
the condition to heal over time. (flexor/pronator group) can restore stability. In a competitive
The standard surgical procedure for both lateral and medial thrower, surgical reconstruction, using a tendon graft, may be
epicondylitis has been débridement, partial epicondylectomy, and needed.
repair of the tendon. Medial epicondylectomy may be combined Minimally displaced radial head fractures, including depressed
with ulnar nerve decompression if the patient also has symptoms of fractures involving 30% of the articular surface or less, are treated
ulnar neuropathy. A newer procedure for lateral epicondylitis uses a with a short period of immobilization followed by early motion.
radiofrequency (RF) probe to provide a controlled burn to the Displaced fractures of the elbow benefit from open reduction and
tendon. This injury stimulates neovascularization and healing. internal fixation with early motion.
Table 20^2. Current Therapy for Elbow Pain
Diagnosis ConservativeTreatment Surgical Treatment

Lateral epicondylitis Rest, ice, splinting, NSAIDs, therapy Lateral epicondylectomy
Steroid injection Extensor tendon origin release
RF ablation therapy (Topaz)
Medial epicondylitis Rest, ice, splinting, NSAIDs, therapy Medial epicondylectomy
Steroid injection Flexor origin release
Ulnar neuropathy Rest, therapy, ulnar nerve gliding Ulnar nerve decompression
Ulnar nerve transposition
Medial epicondylectomy
Radial nerve/PIN entrapment Rest, therapy, radial nerve gliding Radial nerve/PIN decompression
Instability Therapy Ligament reconstruction
Fracture Immobilization ORIF
Synovitis Rest, ice, splinting, NSAIDs, therapy Synovectomy
Steroid injection
Arthritis Rest, ice, splinting, NSAIDs, therapy Débridement
Steroid injection Radial head excision
Total elbow replacement
Intra-articular loose body Minimal role for conservative treatment Arthroscopic removal of loose body
Olecranon bursitis/cellulitis Observation of bursitis I&D with bursectomy
Antibiotics for cellulitis
I&D, incision and drainage; NSAIDs, nonsteroidal anti-inflammatory drugs; ORIF, open reduction and internal fixation; PIN, posterior interosseous
nerve; RF, radiofrequency.
Synovitis is treated with rest, therapy, steroid injection, and then percentage of patients will develop a chronic ulnar neuritis requir-
arthroscopic, or open, synovectomy if conservative treatment fails. ing pain management treatment methods.
Arthritis may respond to NSAIDs and steroid injection. Outcomes after procedures for arthritis are less successful. Joint
Occasionally, débridement may help with pain, but it usually will débridement with removal of osteophytes may help pain at the end-
not restore motion. Total elbow replacement is occasionally indi- points of motion, but this rarely improves motion.
cated but has a high complication rate, especially in younger, high-
demand patients.
Intra-articular loose bodies will usually require removal because CONCLUSIONS
continued incarceration of the fragment within the joint can lead to
arthritis. Careful diagnosis and appropriate conservative treatment, com-
Olecranon bursitis is usually a self-limiting process. Attempts at bined with activity modification, will help most patients with lateral
aspiration are rarely successful and may lead to infection. If or medial epicondylitis. Ulnar neuropathy often requires surgical
infected, surgical drainage and intravenous antibiotics are needed. treatment.
Chronic, painful olecranon spurs benefit from surgical removal. Conservative and surgical treatment results for synovitis and
arthritis of the elbow are less successful than results for the other
elbow conditions.
COMPLICATIONS/OUTCOMES
Therapy that is too aggressive can worsen inflammation, stiffness, SUGGESTED READINGS
and pain. Briggs CA, Elliott BG. Lateral epicondylitis: a review of structures
Steroid injections can cause atrophy of the overlying skin if given associated with tennis elbow. Surg Radiol Anat 1985;7:149–153.
in the subcutaneous layer. Coleman SH, Altchek DW. Arthropscopy and the thrower’s elbow. In
Ulnar nerve fibrosis can occur after transposition if the support- Green DP, et al (eds): Green’s Operative Hand Surgery, 5th ed.
ing neural tissue is stripped from the nerve during mobilization. Philadelphia: Elsevier Churchill Livingtone, 2005; pp 959–972.
Aspiration of an olecranon bursitis can result in infection, Field LD, Altchek DW. Chronic elbow pain, overuse, and tendinitis. In
requiring operative drainage and intravenous antibiotics. Peimer C (eds): Surgery of the Hand and Upper Extremity. New York:
McGraw-Hill, 1996; pp 491–506.
Most elbow problems will improve with rest, activity modifica- Swanson GDG. The upper extremities. In Cocchiarella L, Anderson GBJ
tion, therapy, and steroid injection. Surgical treatment of lateral and (eds): Guides to the Evaluation of Permanent Impairment, 5th ed.
medial epicondylitis will usually result in improvement, but pro- Chicago: AMA Press, 2000; pp 470–474.
blems may recur if the patient does not modify her or his activity.
Ulnar nerve decompression, medial epicondylectomy, and trans-
position all have a success rate ranging from 80% to 90%. A small
156 Chapter 21 HAND PAIN
Chapter 21 proximal to the wrist (radiating toward the shoulder) has been
frequently reported as well.1 The presence of proximal pain may
HAND PAIN represent a clinical marker of mild median nerve damage and
appears to be related to ‘‘extramedian spread of symptoms in the
Joseph M. Bellapianta, William F. Lavelle, Elizabeth hand, from peripheral or central nervous system mechanisms.’’1 A
Demers Lavelle, Ike Onyedika, Demetri Economedes, careful history and physical examination should be performed with
the addition of certain specific tests to reveal median nerve neurop-
and Richard Whipple athy (Box 21–2). Electromyography/nerve conduction velocity stu-
dies can be helpful in confounding cases in which other causes for
symptoms need to be ruled out, such as compression at a higher
level. In some cases of CTS, the only complaints are deep hand pain
and aching, but no numbness.
Treatment for CTS should always begin with conservative mea-
sures. Conservative therapy includes splinting the wrist in a neutral
INTRODUCTION position, oral anti-inflammatory drugs to reduce synovitis, diuretics
to reduce edema, and treatment of any underlying medical condi-
The hand is a complex anatomic structure that has been in part tion. Corticosteroid injections can also be tried; however, only a
credited with the development of modern people. Tendons, nerves, small percentage of patients will be symptom-free 12 months later.
blood vessels, and small bones allow for the seemingly fluid func- Noninvasive treatment approaches for mild to moderate CTS
tion of the hand, yet all of these structures may fall victim to pathol- with median motor nerve distal latencies of more than 4.2 msec
ogy and become sources of hand pain. The diagnosis of hand pain but less than 7.0 msec have been advocated with mixed results. The
requires a working knowledge of functional hand anatomy and an use of laser therapy for mild to moderate CTS may be beneficial2–4
understanding of the processes that may lead to pain. Hand pain or without dramatic success.5 Differences in treatment technique
may be primary or referred from other areas. may be at least partly responsible for varied results. Another non-
invasive treatment strategy for CTS that may be beneficial is the use
of the lidocaine 5% patch.6,7
Injections can also be used for diagnostic purposes to predict
NERVE ETIOLOGIES OF HAND PAIN surgeon outcome. Patients with typical symptoms but normal nerve
tests, who improve with injections, may be candidates for surgical
Carpal Tunnel Syndrome release. Injections may also be used for atypical patients with only
hand pain but no numbness. Injections can help to distinguish fixed
Carpal tunnel syndrome (CTS) is the most common compression neuropathy versus compressive neuropathy. The steroid, if placed
neuropathy of the upper extremity. It is caused by compression of in the carpal tunnel, will shrink the synovium and lower the carpal
the median nerve at the wrist through the carpal tunnel. It may be tunnel pressure. If noninvasive measures fail, surgical release of the
acute or chronic in nature. Any space-occupying lesion in the carpal transverse carpal ligament is generally recommended. Sectioning of
tunnel or a reduction of the space inside the tunnel from external the transverse carpal ligament decompresses the median nerve, thus
compression will result in reduced space for the median nerve. relieving the symptoms. The point of compression on the median
Pressure on the nerve may result from swelling of the lining of nerve can often be seen with a hyperemic epineurium and changing
the flexor tendons, joint dislocations, fractures, and inflammatory nerve diameter in the carpal tunnel. This procedure can be done
arthritis (Box 21–1). The root cause of the compression is often open or endoscopically with similar long-term results.
unknown. Occupational hazards such as keeping the wrist bent for
long periods of time have also been speculated to cause CTS. Wrist
and distal radius fractures can often produce acute CTS because of Guyon’s Canal or UlnarTunnel Syndrome
swelling or immobilization of the wrist in a flexed position.
Repetitive flexion/extension of the wrist, repetitive motion of the In the palm, the ulnar nerve passes under the pisohamate ligament,
fingers, the repetitive and forceful squeezing and releasing of a tool, which is a fascial band between the pisiform and the hamate. This
and vibration exposure have all been implicated. Patients will often tunnel is called Guyon’s canal. Guyon’s canal contains the ulnar
complain of symptoms when driving a car or reading a newspaper. artery and vein and the ulnar nerve. Patients with ulnar tunnel
Swelling and symptoms can also develop from pregnancy, thyroid syndrome complain of paresthesias and decreased sensation in the
disorder, and diabetes. little finger and half of the ring finger. Unlike CTS, it is not caused
CTS may present with paresthesia, hypothesia, anesthesia, or directly by tendinitis because no tendons run through the tunnel.
pain on the surfaces of the hand innervated by the median nerve, Compression may be induced by activities such as using the palm of
which includes the palmar and the dorsal distal phalangeal aspects the hand as a hammer or with repetitive use of tools such as a
of the lateral three and a half digits (Fig. 21–1). With prolonged screwdriver or pliers. Ulnar tunnel syndrome is also more
median nerve compression, weakness and atrophy will be seen in common in long-distance cyclers. The compression may be the
the thenar muscles as a result of denervation. The pain, paresthesia, result of a cyst in the canal, swelling of the ulnar artery, or a fracture
hypothesia, and anesthesia associated with CTS tend to be more of the hook of the hamate. Hamate fractures are seen in golfers as
severe at night and often interrupt sleep. This is due to elevated the result of hitting the firm ground instead of the golf ball while
carpal tunnel pressures and lower systemic blood pressures causing swinging. These are also seen in racquet sports.
acute ischemia. Patients will often awake with pain and dangle or Treatment options for ulnar neuropathy at the wrist include
shake out the hand to increase blood flow. Patients with CTS usu- avoiding provocative activities, splinting, anti-inflammatory medi-
ally complain of pain and paresthesia in the hand or wrist, but pain cation, steroid injections, and occupational therapy. If these are
Box 21^1 CAUSES OF CARPAL TUNNEL SYNDROME

Anatomic Causes Due to Decreased Size
Carpal bone abnormalities
Thickened transverse carpal ligaments
Anatomic Causes Due to Increased Contents of Canal
Neuroma, lipoma, myeloma, persistent median artery, anomalous
muscles in the tunnel
Hypertrophic synovium, distal radial fractures, post-traumatic
osteophyte, hematoma
Neuropathic Causes
Diabetes, alcoholism, proximal lesion of median nerve Median nerve
Inflammatory Causes
Tenosynovitis, rheumatoid arthritis, infection, gout
Ulnar nerve
Alteration of Fluid Balance
Pregnancy, eclampsia, myxedma, long-term hemodialysis, horizontal
position and muscle relaxation, Raynaud’s disease, obesity
Congenital
Mucopolysaccharidosis, mucolipidosis, Down’s syndrome,
achondroplasia
Transverse carpal
unsuccessful, surgery to decompress the nerve may be needed. The ligament
tunnel may be directly decompressed for isolated ulnar nerve symp-
toms or in combination with a release of the carpal tunnel.
Cubital Tunnel Syndrome A

Cubital tunnel syndrome is the most common site of ulnar nerve Median nerve
entrapment and the second most common peripheral compression
neuropathy. Cubital tunnel syndrome affects men more often than
women. The ulnar nerve enters the cubital tunnel by passing deep to
the arcuate ligament (Osborne’s ligament), which connects the
ulnar and the humeral heads of the flexor carpi ulnaris (FCU)
muscle. The nerve then passes between the two heads of the FCU
before heading deep to the flexor pronator aponeurosis.
Compression or injury may develop because of repetitive elbow
motion, prolonged elbow flexion, direct compression, or childhood Radial nerve
elbow fractures with subsequent abnormal growth and alignment
(tardy ulnar nerve palsy) (Box 21–3). Patients with this condition
commonly exhibit symptoms of intermittent pain on the medial
side of the elbow and paresthesias of the fourth and fifth digits.
An associated aching discomfort along the inner forearm or elbow
may be present. If nerve damage persists, there is loss of sensation in
the fourth and fifth digits. Eventually, there is loss of pinch and grip
strength owing to atrophy of the muscle of the hand because the
Ulnar nerve
ulnar nerve is responsible for innervation of most of the intrinsic
hand muscles.
The major diagnostic tests for cubital tunnel syndrome include
an elbow flexion test, Tinel’s test, and the pressure provocative test.
In the elbow flexion test, patients are positioned with their arms at
their side, and elbows flexed approximately 1208. The patient main-
tains that position for 3 minutes in an attempt to reproduce the
symptoms. In Tinel’s test, the groove between the olecranon process
and the medial epicondyle through which the ulnar nerve passes is
palpated and tapped. Similarly to a Tinel test at the carpal tunnel, a B
positive test is characterized by a tingling sensation in the ulnar
Figure 21^1. A, Nerves of the palm of the hand. B, Nerves of
distribution of the forearm and hand distal to the tapping point
the dorsal hand.
(see Fig. 21–2). The pressure provocative test for cubital tunnel
syndrome involves applying pressure proximal to the cubital
tunnel, with the elbow flexed 208 and the forearm in a supine posi- activities with repetitive elbow movements. The use of nonsteroidal
tion. Anterior subluxation of the ulnar nerve should also be identi- anti-inflammatory drugs may be beneficial. Steroid injections are
fied by direct palpation with flexion of the elbow. rarely used.
Nonoperative treatment of cubital tunnel syndrome includes If nonoperative treatments are ineffective, surgical procedures
immobilization with long arm splints to prevent elbow flexion at may be entertained. The goal of surgery is to relieve compression
night, a padded elbow brace during the day, and avoidance of of the ulnar nerve. The methods used to decompress the ulnar nerve
Box 21^2 TESTS USED TO CONFIRM THE DIAGNOSIS OF Box 21^3 CAUSES OF CUBITAL TUNNEL SYNDROME
CARPAL TUNNEL SYNDROME
Compression of the ulnar nerve
*Phalen’s test: Patient places elbow on table, forearm vertical, wrists Entrapment in distal humeral fracture or elbow dislocation
flexed. The test is positive when paresthesias develop on the radial side Cubitus valgus, cubitus varus, malunion, nonunion
digits within 60 sec (Fig. 21^2). Reverse Phalen’s with wrist extended can Aberrant or abnormal musculature of forearm musculature
also be done. Osteoarthritis
*Tinel’s test: Examiner lightly taps along median nerve at the wrist, Inflammatory arthritis
proximal to distal. Positive if tingling develops in fingers at site of Synovial chondromatosis
compression. Bands, vascular and fascial, musculotendinous variations around the
*Carpal tunnel compression test: Examiner compresses median medial epicondyle, aberrant muscle anomalies. The ulnar nerve may
nerve. If paresthesias develop within 30 sec, test is positive. be compressed at different levels including the medial intermuscular
Hand diagram: Patient marks signs of pain or paresthesias on dia- septum or posterior compartment of the arm (e.g., arcade [or liga-
gram of hand. ment] of Struthers) and soft tissue of bony abnormalities of the cubital
Hand-volume stress test: Measure hand volume by water displace- tunnel (e.g., epitrochleoanconeus muscle [anconeus epitrochlearis
ment, repeat after stress test and10 min rest. muscle], thick arcuate ligament of Osbourne [‘‘Osborne’s band’’]).
Measurement of carpal tunnel pressure: Measure carpal tunnel Space-occupying lesions, e.g., tumors
pressure via infusion catheter. Positive if pressure reaches 25 mm Hg or
more.
Static two-point discrimination: Determine minimum separation
of two points on the palmer aspect of the hand. Test is positive if one include in situ decompression, in situ decompression with medial
fails to discriminate points more than 6 mm apart. epicondylectomy, and anterior transposition. Transpositions may
Moving two-point discrimination: Similar to static two-point dis- be completed in a subcutaneous or submuscular fashion.
crimination. Positive if patient fails to discriminate points more than 5 Decompression of the nerve usually leads to symptom resolution.
mm apart.
Vibrometry: Head of vibrometer is placed on palmar side of the
digit. An amplitude of 120 Hz is increased to threshold of perception. It
is then compared with the median and ulnar nerves in both hands. Test Radial Tunnel Syndrome
is positive if there is asymmetry with contralateral hand or between
radial and ulnar digits. Proximal radial compression neuropathy occurs infrequently and is
Semmes-Weinstein monofilament test: Monofilaments of diagnosed correctly even less frequently (Rinker, 2004). The radial
increasing lengths are touched to the palmar side of digit until patient nerve emerges from the intermuscular septum on the lateral arm
can tell which digit is touched. Positive if value is greater than 2.83 in and descends distally along the border of the brachialis muscle
radial digit. (Rinker, 2004). Roughly 2 cm distal to the elbow, the radial nerve
*Electromyogaphy: Needle electrodes placed in muscle.Fibrillation divides into the posterior interosseous nerve (PIN) and the super-
potentials, sharp waves, increased insertional activity. Nerve conduction
ficial sensory divisions.8 The PIN courses under the fibrous proxi-
velocities can also be useful.
mal margin of the supinator muscle, known as the arcade of Frohse,
*Commonly used tests. and bifurcates to innervate the extensor carpi ulnaris muscle and
the digital extensor muscles.8
Figure 21^2. Tinel’s test.

Table 21^1. Dorsal Compartment Tendons
Compartment I II III IV V VI
Tendons 1. Extensor pollicis 1. Extensor carpi Extensor pollicis 1. Extensor Extensor digiti Extensor carpi
longus (EPL) radialis brevis longus (EPL) digitorum minimi (EDM) ulnaris (ECU)
2. Abductor (ECRB) communis (EDC)
pollicis brevis 2. Extensor carpi 2. Extensor indicis
(APB) radialis longus proprius (EIP)
(ECRL)
In 1979, Lister and colleagues9 suggested four possible sites of Scalenotomy or first rib resections may be done to relieve symp-
radial nerve compression: (1) the fibrous bands anterior to the toms, although the prognosis is guarded.
radial head; (2) the ‘‘radial recurrent fan’’ of vessels described by
Henry; (3) the tendinous margin of the extensor carpi radialis brevis
(ECRB); and (4) the arcade of Frohse.8,9 Symptoms and signs Double Crush
depend on the site of compression, however; the most common
symptoms were deep aching pain in the lateral forearm (from com- Carpal tunnel and cervical root compression may coexist, causing
pression of the PIN), pain radiation to the neck and shoulder, and a what is frequently called the double crush. CTS may cause pain
‘‘heavy’’ sensation of the affected arm.8 above the hand but never numbness above the carpal tunnel. If
The most common physical findings were tenderness over the the work-up reveals a double crush, injections of the carpal
radial nerve at the supinator muscle level, pain on resisted supina- tunnel may help to determine the more primary lesion. Generally
tion, and the presence of Tinel’s sign over the radial forearm.8 speaking, the carpal tunnel is released prior to a cervical procedure
Furthermore, the radial nerve may be compressed between the bra- because the risk of disability is much less.
chialis and the brachioradialis muscles (e.g., in a manual worker)10;
may mimic epicondylitis lateralis humeri (‘‘tennis elbow’’); or
present with lateral upper arm pain, local tenderness, and tingling Cardiac Disease
sensations at the distal end of the upper arm when the radial
nerve is percussed in the mid third of the upper arm (Tinel’s Do not forget that acute and chronic cardiac disease may present
sign), without clinical muscular weakness.11 Surgical decompres- with hand and arm pain. The patient may describe tingling in the
sion in cases refractory to conservative therapy may yield good hand with activity. Do not be misled. Family history and risk factors
results.8 should always be assessed.
REFERRED HAND PAIN

TENDON DISORDERS OF THE HAND
Cervical Entrapment Diagnosing and treating tendon related disorders of the hand
require an understanding of the anatomy, course, and function of
More proximal nerve compression may produce hand pain. both the volar and the dorsal tendons of the hand. The dorsal aspect
Cervical disk disease or stenosis may produce pain radiating of the hand has six compartments as described in Table 21–1. A
down the arm into the hand. Numbness and pain typically follow helpful memory aide is ‘‘2-2-1-2-1-1.’’
a radicular pattern based on the root that is compressed. Reflexes The volar, or flexor, aspect of the hand is not as neatly com-
may be diminished along with proximal strength. Diagnosis is con- partmentalized; however, zones of injury are often discussed to
firmed with magnetic resonance imaging (MRI). Conservative treat- describe injuries and develop a treatment plan. Anatomic land-
ment with traction therapy, steroids, and pain management marks divide the zones from distal to proximal. Table 21–2
injections may help initially. Decompression with fusion may be describes the flexor zones and their boundaries.
indicated for intractable pain or progressive weakness. Symptoms Of highest regards is zone 2, which is often referred to as ‘‘No
may be relieved by placing the hand above the head. man’s land.’’ This name developed owing to the difficulties encoun-
tered by the pioneers of hand surgery. Surgical interventions within
the fibro-osseus sheath of the palm resulted in large numbers of
Thoracic Outlet Syndrome postsurgical complications, particularly adhesions. Through
improved surgical techniques and postoperative hand therapy pro-
Thoracic outlet syndrome may produce arm pain and numbness, tocols, hand surgeons have realized better functional outcomes after
especially on the ulnar side of the hand. Symptoms are exacerbated zone 2 injuries. Zone 2 injuries present this management difficulty
by overhead activity. Diagnosis may be difficult because nerve test- because both the flexor digitorum superficialis (FDS) and the flexor
ing may be inconclusive. Pancoast’s tumors of the lung should be digitorum profundus (FDP) tendons enter the fibro-osseous tunnel
ruled out because they can mimic thoracic outlet syndrome. at the midpalm level, making repair difficult. The primary
Table 21^2. Flexor Zones of the Hand and Their Respective Landmarks
Zone 1 2 3 4 5
Landmarks Flexor digitorum Distal palmar crease Distal edge of Carpal tunnel Proximal to carpal
superficialis to insertion of flexor transverse carpal (transverse carpal tunnel
insertion to tip digitorum ligament to distal ligament)
of finger superficialis palmar crease
postoperative complication of repair is formation of adhesions to the must be considered. This is a syndrome by which the tendons of
flexor tendon sheaths. Physicians managing hand pain after an oper- the first dorsal compartment cross over the tendons of the second,
ative repair should emphasize aggressive occupational therapy with causing a site of irritation proximal to the extensor retinaculum.
passive range of motion. A balance between therapies that protect the This occurs proximal to the wrist in the distal forearm. This con-
repaired tendons from the forces of active flexion yet allow for excur- dition commonly affects patients who do repeated wrist actions
sion of the tendon in the fibro-osseous sheath is necessary. such as shoveling or raking. Conservative management is again
first-line treatment. Hand surgeons will typically recommend activ-
ities that emphasize neutral wrist alignment. Corticosteroid injec-
Extensor Compartment Hand PainçExtensor tion within the second dorsal compartment at the intersection point
Tenosynovitis may be offered. Surgery is rarely necessary to treat intersection
syndrome. In extremely difficult cases, a hand surgeon may
Compartment1 remove some of the thickened tenosynovium around the irritated
tendons.
The most common etiology of pain within this compartment is due
to DeQuervain’s tenosynovitis. This is caused by inflammation and
Compartments 3 to 6
stenosis of the synovial sheath surrounding the extensor pollicis
longus (EPL) and abductor pollicis brevis (APB) tendons. Patients The EPL tendon is alone in the third extensor compartment. It
may experience an acute exacerbation, but symptoms are far more deviates sharply around Lister’s tubercle to provide extension of
commonly chronic in nature and caused by repetitive motion. The the thumb. Lister’s tubercle is a palpable bony landmark on the
Finklestein test is used for confirmation of diagnosis (Fig. 21–3). In dorsal radius. It acts as a fulcrum to prevent radial subluxation of
this test, the patient flexes the thumb of the affected hand while the EPL tendon. Tendinitis can occur in this compartment and is
making a fist around ther thumb. The patient then ulnarly deviates usually treated without surgery. Rupture of the EPL can also occur
the hand. A positive test elicits increased pain over this compart- and is discussed further in the section ‘‘Degenerative Joint Disease
ment. Local injection of corticosteroids into this compartment may of the Wrist and Hand,’’ later. The fourth compartment has the
confirm the diagnosis. Rest and nonsteroidal anti-inflammatory extensor digitorum communis (EDC) and extensor indicis proprius
drugs (NSAIDs) are a first line of treatment. Immobilization tech- (EIP) tendons. It is a broad compartment that is often violated
niques include thumb spica casting or bracing for up to 1 month; during dorsal approaches to the wrist. Distally, the EDC can be
however, shorter durations of immobilization are more common. avulsed off of the distal phalynx, which is called ‘‘mallet finger.’’
Surgical decompression of the first dorsal compartment is reserved This injury to the distal extensor tendon insertion is usually treated
for recalcitrant pain but has an excellent prognosis. Persistent pain with immobilization of the distal interphalangeal (DIP) joint in
after surgery may be due to inadequate release, subluxation of the extension for approximately 8 weeks. Compartment 5 has the ex-
tendons, or radial nerve injury. tensor digiti minimi (EDM) tendon, which provides independent
fifth finger extension. Compartment 6 contains the extensor carpi
ulnaris (ECU) tendon, which is closely associated with the triangu-
Compartment 2
lar fibrocartilage complex (TFCC) of the ulnar wrist. The ECU
Far less common than pain within the first dorsal compartment is tendon can sublux with wrist motion, leading to tendinitis and
pain within the second. If the patient is experiencing pain within ulnar wrist pain. Treatment is initially conservative with rest and
this compartment, however, intersection or cross-over syndrome anti-inflammatory medication.
Figure 21^3. Finklestein’s test.

Tendon Lacerations Table 21^3. Classification of Flexor Digitorum

Profundus Avulsion Injuries
Lacerations to the extensor tendons that are less than 50% of the
tendon substance generally do not have to be repaired, and early Type 1 Type 2 Type 3
gentle motion can be started. Tendon lacerations that are greater
than 50% are usually repaired. There are a variety of suture tech- Location of Palm Proximal Distal
niques for tendon repair. Of the utmost importance, however, is retracted interphalangeal interphalangeal
the number of strands of suture that cross the repair site, with tendon joint joint
increasing number of sutures providing a stronger repair. Tendon Timing of Within 7–10 4 wk 4 wk
repair has been proved to be strongest when four to six sutures cross repair days
the repair site. Protected gentle active motion may be started with
multisuture repairs, which lessen adhesions and increase mobility.
avulsion, classically known as ‘‘Jersey finger,’’ injuries are classified

based on the location of tendon retraction, as illustrated in Table
FLEXOR ASPECT HAND PAIN 21–3. This is most common in the ring finger and is diagnosed by
lack of flexion at the DIP joint.
Anatomy
The two extrinsic flexors of the fingers are the FDS and the FDP. As Complications of Treatment
the FDS approaches the metacarpophalangeal (MCP) joint, it bifur-
cates, with the FDP passing through the bifurcation. Just proximal Adhesions are by far the most common complication of flexor
to the bifurcation lies the entrance of the digital flexor sheath. It is tendon surgery, regardless of the appropriateness of therapy. In
within the tendinous sheath that one can find the annular and the case of active flexion restriction, tenolysis is the appropriate
cruciate pulleys. These pulleys provide both a mechanical advantage treatment of adhesions when active motion is poor and tendons
and flexibility to the tendons they support. Whereas annular pulley are well healed. Tendon repair rupture is the second most common
A1 is the strongest, A2 and A4 are the most important pulleys to complication of surgical tendon repair. It may also occur after te-
provide the mechanical advantage of the tendons. Unlike the exten- nolysis. If the diagnosis is made acutely, the tendons may be
sor compartment, there are many etiologies of flexor tendon hand repaired back together without resection of their ends. If the diag-
pain, which include tenosynovitis and avulsion and complications nosis is made at a later date, tendon resection and graft or staged
from their subsequent treatment. repair is often the treatment of choice. Bowstringing is another
complication of surgical therapy, particularly in flexor tenosynovi-
tis. If the A2 and/or A4 pulleys are disrupted, the tendons will
FlexorTenosynovitis (Trigger Finger, consequently lose their mechanical advantage, and therefore,
TriggerThumb) active flexion strength will be diminished.
Flexor tendon tenosynovitis is a very common diagnosis character-

ized by pain in the area of the A1 pulley. Triggering digits are more DEGENERATIVE JOINT DISEASE OF THE
common in women than in men. Triggering will be more common WRISTAND HAND
early in the day and becomes less bothersome with increased use of
the fingers and hand. Patients often report a palpable nodule located The wrist functions as a connection between the distal radius and
in the same area, although this is not necessary for the diagnosis. The ulna and the metacarpal bones of the hand. It is a complex structure
affected digit is typically ‘‘stuck’’ or locked in flexion after forceful made of eight carpal bones, which precisely articulate with one
flexion and may require use of the opposite hand to bring the digit another to increase the motion and strength of the hand in space
back into extension. As the nodule passes under the pulley during (Fig. 21–4). Pain in the wrist is often difficult to localize because the
extension, the finger will suddenly fully extend. For mildly symptom- sensory innervations are relatively nonspecific. X-rays are also chal-
atic patients, NSAIDs and nighttime extension splinting may be lenging to critically evaluate because many of the bones overlap.
done. Clinicians may also elect to place a corticosteroid injection When evaluating radiography, it is important to realize that the
into the tendon sheath. This may be repeated a few times if symptoms wrist is dynamic with multiple bones that change their individual
return. Refractory flexor tenosynovitis may require surgical release of positions depending on hand position.
the A1 pulley, with care taken not to disrupt the A2 pulley. This is a An initial approach to wrist pain should always begin with a
minor procedure with excellent results. thorough history and physical examination. The patient should be
asked about a history of recent trauma, the duration and location on
the pain, and any movement that makes the pain worse or better.
Wrist FlexorTenosynovitis Also important is whether the pain is worse during the day or night, if
it is localized or if it radiates, and if sensory or motor symptoms are
Acute flexor carpi radialis tendinitis may be precipitated by acute present. One method when obtaining a history is to organize the
use of the wrist. It presents with pain and tenderness ulnar to the history by system (e.g., nervous, tendinous, bony). A physical exam-
scaphoid tuberosity. Longitudinal swelling may exist along this ination should compare the painful side with the normal side when
tendon. This may be confirmed with MRI and responds to bracing possible. Range of motion of the wrist should include flexion, exten-
or steroid injection. Calcific tendinitis may also be seen at the wrist sion, ulnar deviation, radial deviation, supination, and pronation.
but is more common on the ulnar side. The hand should be examined for asymmetry such as swelling or
eccymosis and whether any muscular atrophy is present, which
would be suggestive of disuse or denervation. Tendon function can
Avulsion Injuries be systematically checked with resistance against active motion to
elicit pain. All joints should also be palpated to localize the pain. It is
The most common etiology of an avulsion comes from a forced often helpful to get comparison x-rays of the other side to detect
extension in an already actively flexed digit. In the case of an FDP subtle differences in the symptomatic limb.
tendon ruptured, followed by the EDC of the ring and small

finger, finally followed by the EPL. New pharmacologic therapies
for the inflammatory arthridites have reduced these debilitating
conditions and are reviewed extensively in Section V, Chapter
33, Rheumatoid Arthritis.
Trapezoid Post-traumatic arthritis of the wrist may also present as pain due
Capitate to altered biomechanics of the hand and forearm. The distal radius
Trapezium
normally absorbs approximately 80% of the load of the hand and
Hamate wrist, with the ulna responsible for 20%. If the radius is shortened
Scaphoid by 2.5 mm, the load approaches 50% for both bones. This abnormal
Pisiform loading of the ulnar side of the wrist may lead to what is known as
Triquetrum
Lunate ‘‘abutment, or impaction, syndrome.’’ This causes a breakdown of
the TFCC. Damage here can cause pain with ulnar deviation of the
wrist or with pronation and supination. This is common with distal
radius malunions and may result in early arthritis of the wrist.
Classic osteoarthritis of the hand and wrist affects the DIP and
PIP joints. Signs of osteoarthritis on x-ray include joint space nar-
rowing, sclerosis, osteophytes, and subchondral cysts. Fusion of the
finger joints is the most common treatment for advanced disease.
PIP joint replacement may be done in the middle, ring, and little
fingers but has a limited life expectancy. Excellent hand function
may be expected if the PIP and DIP joints are fused in positions of
function. Many techniques have been described for IP fusion.
Figure 21^4. Carpal bones.
Compression screws and tension band wiring techniques are most
common (Fig. 21–6).
Arthritis of the wrist can be due to a number of causes includ- The most common painful joint in the hand is the thumb
ing inflammatory disease and trauma. Rheumatoid arthritis is an carpometacarpal (CMC) joint. CMC arthritis (which is largely
inflammatory synovitis that classically affects the proximal inter- osteoarthritis) causes pain with thumb motion. As with other
phalangeal (PIP) and MCP joints. With an advanced disease pro- arthridites of the hand and wrist, conservative therapy with
cess, the fingers usually deviate ulnarly as the wrist goes radially NSAIDs, steroid injections, ice, heat, rest, and splinting should
(Fig. 21–5). The synovitis also affects the wrist, causing capsular be attempted. Surgery is the last alternative. Fusion of the CMC
laxity and volar and ulnar instability. This is most common with joint at the base of the thumb is a surgical option for pain relief
extensor tendinitis lasting greater than 6 months. It can also lead that is typically reserved for heavy laborers. It severely limits dex-
to tendon ruptures. Patients may present with an atraumatic terity. Good pain relief, preservation of length, and stability are
inability to extend a finger. The EDM is the most common usually achieved with a CMC fusion; however, motion is limited.
Figure 21^5. X-ray of a rheumatoid hand. Figure 21^6. Tension band fusion technique.
The articulation of the trapezium with the thumb metacarpal has

classically been described as a ‘‘saddle joint’’ because of its shape.
Several operations have been described to reduce pain and main-
tain motion. CMC arthritis is a relatively common problem attrib-
uted to the large amount of motion and force that cross this small
surface area. The most common arthroplasty procedure for first
CMC arthritis is ligament reconstruction and tendon interposition
(LRTI). The trapezium is removed and the space is filled with a
tendon graft. Numerous tendons have been used, but the flexor
carpi radialis has the advantage of being already attached to the
second metacarpal base and can be used to stabilize the first meta-
carpal base along with filling the void. LRTI has been shown to be
as effective in eliminating the pain of CMC arthritis as synthetic
implants and does not have the long-term failure rates. The LRTI
has a greater than 95% satisfaction rate. Stability is not as good as
with the fusion; however, motion is better preserved and the little
shortening that can result does not compromise patient
satisfaction.
*
FRACTURES OF THE WRISTAND HAND
Fractures of the Carpal Bones

The diagnosis of fractures of the carpal bones requires a careful
physical examination including palpation of the individual carpal Figure 21^7. Snuffbox tenderness.
bones. Any area of tenderness should be imaged with anteroposte-
rior (AP), lateral, and oblique images. Computed tomography
(CT), MRI, and bone scan are often useful if the x-rays are difficult Tunnel Syndrome,’’ earlier. Pain is often localized to the volar and
to interpret and injury is suspected. The most common fractured ulnar palm, however, many times it will present with dorsal pain
carpal bone is the scaphoid (70%–80%) followed by the triquetrum over the hamate. Ulnar nerve symptoms may be present. This frac-
(7%–20%) and trapezium (5%). ture is best diagnosed by CT scan. If conservative measures such as
Scaphoid fractures pose one of the greatest challenges to ortho- immobilization or steroid injection fail, excision of the fragment
pedic surgeons owing to both the difficulty in diagnosis and the will usually result in pain relief.
tenuous blood supply to this bone. Much like the odontoid process Fractures of the remaining carpal bone fractures are rare. The
of the second cervical vertebrae, the scaphoid possesses a watershed fracture type, age of the patient, handedness, activity level, and
region in its vascular supply. The primary blood supply arises from employment are just a few of the considerations that must be
a branch of the radial artery that enters the scaphoid at the dorsal taken into account when discussing treatment with the patient.
aspect of its waist. A separate, more distal branch is also typically Carpal fractures are usually cared for when possible by either an
present and supplies the distal pole of the scaphoid; therefore, frac- orthopedic surgeon or a hand surgery subspecialist owing to the
tures at the waist of the scaphoid leave the proximal fragment prone complex anatomy and interrelationships of the carpus.
to nonunion as well as avascular necrosis (AVN).
Scaphoid fractures should be suspected in any patient with wrist
pain. A classically described presentation is pain with palpation of Fractures of the Metacarpal Bones
the anatomic snuffbox, or radial fossa. The anatomic snuffbox is a
triangular deepening on the radial dorsal aspect of the hand (Fig. Metacarpal fractures are relatively common fractures of the hand.
21–7). The snuffbox is bordered above by the tendon of the EPL They can be fractured at the base, shaft, neck, or head and may be
and below by a pair of parallel and intimate tendons (the extensor the result of axial loading, a direct blow, or torsional loading.
pollicis brevis [EPB] and the abductor pollicis longus [APL]). Fractures of the fifth metacarpal neck are among the most
Fractures of the scaphoid that are nondisplaced may be treated common fractures in the hand. The ‘‘boxer’s fracture’’ most often
with cast immobilization. This is usually a long arm thumb spica refers to a fracture at the neck of the fifth metacarpal bone just
cast to control rotation of the forearm and possible displacement of proximal to the MCP joint. It is usually the result of a person
the fracture. Displaced fractures should be treated with surgery to punching a hard object with poor skill. Metacarpal neck fractures
prevent AVN and restore alignment. Surgery is also an option in rarely require surgery. As much as 408 to 508 of angulation defor-
nondisplaced fractures to reduce the period of cast immobilization mity may be tolerated for a boxer’s fractures because the fifth meta-
for the athlete or laborer. Fractures with any degree of displacement carpal is a border digit and will usually result in no functional
are best treated surgically with open reduction and internal fixation deficit. Patients are typically treated by some form of cast or
(Fig. 21–8). In patients with an injury and positive examination splint immobilization, with the most common complaint being
findings but normal x-rays, immobilize the patient’s painful limb cosmetic because the knuckle of the hand with a clenched fist is
in a thumb spica splint or cast for 10 to 14 days. Repeat the x-rays if often less prominent. Surgery is rarely indicated.
the patient is still symptomatic. If pain is still present but x-ray The fourth metacarpal neck is also at risk as the result of the
continues to be normal; consider MRI or a bone scan. same mechanism as the fifth metacarpal. As the digits become
The hamate is also susceptible to fracture at the volar process more central, deformity is not as well tolerated. Only small
(‘‘hook of the hamate’’) due to a fall on an outstretched hand or amounts of deformity, typically less than 108, are acceptable for
classically participation in racquet sports (Fig. 21–9). Hamate hook shaft fractures of the second and third metacarpals. Shaft fractures
fractures were also discussed in the section ‘‘Guyon’s Canal or Ulnar of the fourth and fifth metacarpals may accept angulations of
208 618 and 308, respectively. The index finger through little finger should be considered potentially open and treated as a human
metacarpal neck and shaft fractures are usually treated conserva- bite unless proved otherwise.
tively with splinting unless the fractures are irreducible or unstable. The first metacarpal is unique because it is much more mobile to
Rotational alignment is the most important factor in the assess- allow for the oppositional function of the thumb. Approximately
ment of fracture reduction. Malrotation will lead to finger overlap 25% of all metacarpal fractures occur in the thumb metacarpal, with
and an abnormal arch of finger motion if not addressed. Intra- 80% of those occurring at the base. The ligamentous structures at
articular fractures of the head of the metacarpals should be the first CMC joint are very important to thumb stability. Bennett
addressed similar to other joint fractures. If the articular surface and Rolondo fractures are the two main variants of thumb meta-
is displaced, reduction and K-wire fixation should be attempted to carpal base fractures. Extra-articular or minimally displaced frac-
restore joint congruity. Stiffness of the MCP joints should be tures of thumb metacarpal base can be treated with a thumb spica
avoided with initiation of range of motion exercises as soon as cast; however, displaced fractures into the CMC joint need to be
possible. Motion of the PIP joints should begin immediately to surgically reduced and internally fixed using plates and screws or
avoid permanent stiffness. Any laceration over the MCP joints K-wire fixation.
B
Figure 21^8. A, Scaphoid fracture. B,Open reduction and internal fixation of a scaphoid fracture.
Figure 21^9. Computed tomography (CT) of a fracture of the

hook of the hamate.
Figure 21^10. Fracture with dorsal angulation and
Fractures of the Phalanges
comminution.
Fractures of the middle and proximal phalanges are usually buddy-
taped to the adjacent digit, which acts a protective splint. This If the fracture is intra-articular or unable to be kept corrected in
obviates the need for a bulky accessory splint that can interfere a cast, surgery is often indicated. This is especially the case with
with hand function and necessary joint motion. Compression frac- dorsal comminution because this pattern is classically unstable
tures, vertical shear fractures, and unstable or displaced/irreducible (Fig. 21–10). Measurements are often made on a reduction x-ray
fractures should be treated surgically with closed reduction and to determine whether length, volar tilt, and radial inclination are
pinning or open reduction and internal fixation. Displaced intra- acceptable (Fig. 21–11). Near-anatomic alignment is preferred in
articular fractures should also be surgically reduced and stabilized to the younger, more active patient to avoid future arthritis and pain.
restore articular congruity. Care must be taken during surgical For articular fractures, the treatment goal is reconstruction of an
exposure to prevent injury to the complex extensor and flexor anatomic joint surface.
mechanisms in addition to the digital artery and nerve, which
travel on either side of the fingers. Of paramount importance is
early motion to prevent joint stiffness. Distal phalynx fractures Ligament Injuries
rarely require opened reduction. The nail should be carefully exam-
ined with distal finger trauma, and the patient should be educated After a fall, if pain persists and radiographs remain normal, one
on the possibility of abnormal nail growth or nail loss depending on should suspect ligament injuries. The most common devastating
the severity of the injury. ligament injury is a torn scapholunate ligament. Initial radiographs
may be normal, but over time, these carpal bones begin to shift
apart and the scaphoid rotates. This will lead to very early arthritis.
Fractures of the Distal Radius It is similar to a tire being way out of alignment and causing exces-
sive wear. Early diagnosis with MRI and acute surgical treatment
Fractures of the distal radius were first described in the literature by give the best prognosis.
an Irish surgeon and anatomist, Abraham Colles in 1814. The
Colles’ fracture typically occurs in patients over 60 years old due
to osteoporosis. As a fracture of fragility, relatively minor trauma Carpal Avascular Necrosis
such as a fall from a standing position causes the fracture. As a sign
of osteoporosis, either medical management or referral for an The lunate has an unusual blood supply and may be prone to
osteoporosis evaluation is warranted. The most common demo- avascular necrosis if the ulna is shorter than the radius. It presents
graphic is an older postmenopausal woman. Women who sustain with dorsal pain in the central aspect of the wrist with swelling from
this injury outnumber men by ratio of 4:1. synovitis. This may be associated with repetitive trauma to the
The position (alignment) of the fracture and the extent of articular wrist. Diagnosis in the earliest stage via MRI will have the best
involvement dictate fracture management. For most distal radius prognosis with the most treatment options. Casting, radial short-
fractures, a splint is usually used for the first few days to allow for ening, and bone graft revascularization are all viable options. Late
swelling. For extra-articular fractures with little dorsal comminution, diagnosis with fragmentation and associated arthritis has the worst
immobilization may be all that is needed to achieve a good result. The prognosis, often requiring carpal wrist fusion.
splint can be replaced by a cast a few days to a week later, after the
swelling goes down. X-rays are taken at regular weekly intervals for
3 weeks and then at 6 weeks. The cast is typically removed at about
6 weeks. Protective bracing is then applied. Physical therapy is often PAINFUL HAND TUMORS
started to help improve motion and function of the injured wrist if
needed. If at 2 weeks the patient does not have full digital motion in Benign Hand Tumors
the cast, therapy should begin in order to avoid permanent stiffness
and the risk of complex regional pain syndrome type I [CRPS I] Ganglions are the most common of all hand tumors. They are
(formerly known as reflex sympathetic dystrophy). commonly found on the volar radial side of the wrist and cause
10 deg
25 deg. 10 mm
A B C
Figure 21^11. Normal measurements for a distal radius. A, Radial inclination (208 ^308).B, Radial length (8 ^18 mm).C, Radial tilt (08 ^288).
pain when they are under pressure or compress tendons or nerves. malignant tumor of the hand is a squamous cell carcinoma, which
Dorsal ganglions, which are very visible, do not always produce pain rarely causes pain.
unless they are entrapped during wrist extension. Smaller ganglions
are not always seen clinically but are a common cause of dorsal
pain, often picked up on an MRI. These can be removed arthro- Ischemia of the Hand
scopically or via an open procedure. Volar flexion sheath tumors of
the digits, also called retinacular cysts, are commonly found near Small or large vessel occlusion may produce hand pain.
the A1 and A2 pulleys. They produce pain during grasping activities Scleroderma, a connective tissue disorder, often causes painful non-
as they become compressed. Such activities include lifting weights healing ulcerations. These patients frequently have Raynaud’s phe-
and using the steering wheel of a vehicle. nomenon with cold-induced vasospasm. Sympathetic blockade may
Vascular tumors can be extremely painful. Glomus tumors, be helpful as well as vasodilators. Digital artery sympathectomy may
which arise from the thermoregulatory system near the finger improve microarterial flow. Amputation may also be offered as a
tips, are often difficult to diagnose. They are very well localized last resort to alleviate symptoms.
and may be seen under the nail bed. On the pulp side of the digit,
they are often not seen but localized to a specific spot of tender-
ness. Bone scan or MRI may or may not identify them. CONCLUSION
Exploration and excision may be required to diagnose and alleviate
the symptoms. Patients may see several physicians who may not be The hand and wrist are complex structures that can cause pain,
knowledgeable about glomus tumors before someone familiar with severely limiting a person’s quality of life. A careful history and
these tumors surgically explores the area. Glomus tumors should physical examination should be combined with imaging studies to
be suspected with extreme localized pain and temperature elucidate the patient’s pathology. Treatment usually begins with
sensitivity. conservative measures; however, with problems such as scaphoid
Terminal neuromas secondary to trauma may also cause severe fractures and FDP avulsions, surgical treatment may be the first line
local pain and hypersensitivity with distal loss of sensation. A lo- of therapy. Comparison to the unaffected extremity when possible
calized Tinel test over the nerve is often seen. Excision and/or mobi- is a useful tool to help make an accurate diagnosis and guide
lization to a less exposed or traumatized area may be a solution. treatment.
There are numerous other benign tumors that cause pain such as an
inclusion cyst in the finger tip pulp, giant cell tumor, which may
compress nerves, or schwannomas, which may cause neurogenic REFERENCES
symptoms.
1. Zanette G, Marani S, Tamburin S. Proximal pain in patients with
carpal tunnel syndrome: a clinical-neurophysicological study.
J Peripher Nerv Syst 2007;12:91–97.
Malignant Hand Tumors 2. Naeser MA. Photobiomodulation of pain in carpal tunnel syndrome:
review of seven laser therapy studies. Photomed Laser Surg 2006;24:101–110.
Although they are very rare in the hand, malignant tumors can 3. Naeser MA, Hahn KA, Lieberman BE, et al. Carpal tunnel syndrome
cause cortical erosions and subsequent fracture and pain. Because pain treated with low-level laser and microamperes transcutaneous
of the relatively minimal overlying soft tissue in the hand, these electric nerve stimulation: A controlled study. Arch Phys Med Rehabil
tumors can be picked up when they are small. The most common 2002;83:978–988.
4. Elwakil TF, Elazzazi A, Shokeir H. Treatment of carpal tunnel 8. Rinker B, Effron CR, Beaslet RW. Proximal radial compression
syndrome by low-level laser versus carpal tunnel release. Lasers Med neuropathy. Ann Plast Surg 2004;52:174–180.
Sci 2007 (in press). 9. Lister GD, Belsole RB, Kleinert HE. The radial tunnel syndrome.
5. Irvine J, Chong SL, Amirjani N, et al. Double-blind randomized J Hand Surg 1979;4:52–59.
controlled trial of low-level laser therapy in carpal tunnel syndrome. 10. Lee YK, Kim YI, Choy WS. Radial nerve compression between the
Muscle Nerve 2004;30:182–187. brachialis and brachioradialis muscles in a manual worker: a case
6. Nalamachu S, Crockett RS, Gammaitoni AR, et al. A comparison of report. J Hand Surg 2006;31:744–746.
the lidocaine patch 5% vs naproxen 500 mg twice daily for the relief of 11. Adolfsson LE, Nettleblad H. Radial nerve entrapment in the upper
pain associated with carpal tunnel syndrome: a 6-week, randomized, arm as a cause of lateral arm pain: a report of four cases. Scand
parallel-group study. Med Gen Med 2006b;9:33. J Plast Reconstr Surg Hand Surg 2001;35:217–220.
7. Nalamachu S, Crockett RS, Mathur D. Lidocaine patch 5 for carpal
tunnel syndrome: how it compares with injections: a pilot study. J Fam
Pract 2006a;55:209–214.
Chapter 22 vertebrae at the spinous and transverse processes, which arise

from the dorsal aspect of the vertebra.
BACK PAIN
William F. Lavelle, Allen L. Carl, Elizabeth Demers MOTION SEGMENTS
Lavelle, and Aimee Furdyna
The vertebrae link together through facet joints on the posterior
side of the spinal column. The facet joints are formed between the
superior articular processes of one vertebra and the inferior articu-
lar processes of the vertebra directly above.
Between each of the lumbar vertebrae is a thick, spongy disk
made up of various types of cartilage. The three major constituents
INTRODUCTION of the disk are water, fibrillar collagens, and aggrecan (a large aggre-
gating proteoglycan [PG]) with highly sulfated glycosaminoglycan
The majority of patients will experience spine-related pain at some (GAG) chains that attract and hold water. The annulus fibrosus is
time in their lives. Low back pain, in particular, is most common in the outer ring that forms the border of the disk. It is composed of
patients between the ages of 35 and 55 years. Fortunately, the 15 to 25 distinct layers of concentric collagenous lamellae (made of
majority of acute back pain is self-limited, with over 90% of patients bundles of collagen fibers running obliquely from one vertebrae to
recovering within 6 weeks. Back pain has a high recurrence rate, the next, thereby anchoring the disk to bone or cartilaginous end-
with symptoms returning within the year in two thirds of patients. plate, highest in the outer annulus fibrosus and lowest in the inner
The majority of sciatic pain is also self-limiting. Certain aspects of annulus fibrosus). With aging and/or degeneration of the disk, the
lifestyle, such as a lack of physical activity, obesity, and smoking, relative content of collagen increases owing to a loss of water and
predispose patients to recurrent episodes of back pain and sciatica. aggrecan. At a pressure of 0.25 megapascals (Mpa; 36 pounds/inch2
[psi]) a 37-year-old disk is hydrated with approximately 4 g water
per gram of dry weight, whereas a 91-year-old disk is hydrated to
LUMBAR SPINE ANATOMY about 1.8 g water per gram of dry weight with four- to fivefold less
aggrecan. This may be due in part to actions of matrix metallopro-
The spine is composed of three anatomic sections, the cervical, teinases (MMP; collagenases from connective tissue cells [MMP-1]
lumbar, and thoracic spine. The pain conditions discussed and from polymorphonuclear leukocyte [MMP-8], and stromelysin
within this chapter involve primarily the lumbar spine. The five [MMP-3]). Stromelysin may degrade multiple connective tissue
lumbar vertebrae are characterized by their relatively large size matrix components (including aggrecan and type IX collagen
compared with the cervical and thoracic vertebrae. This increased activating procollagenase; also referred to as aggrecanase).
size is necessary to support the patient’s body weight from succes- The nucleus pulposus forms the center of the disk and functions
sive vertebral levels. The outer portion of each vertebra is composed to resist compressive loads. The nucleus pulposus largely consists of
of dense cortical bone. The cortical bone is narrower in the center PGs, water, collagen, and cells. PGs have gained the most attention
of the vertebra and flares at the superior and inferior ends in an with respect to nerve irritation secondary to herniated nucleus
hourglass pattern. On the dorsal side of the vertebral body are the pulposus material; however, cells may produce MMPs, cytokines
laminae, two short, broad plates of bone that cover and protect (interleukin [IL]-6), and prostaglandin E2. Each disk is approxi-
the dural sac. These plates join medially at the spinous processes mately 1=4 to 3=4 inch thick. Furthermore, the cartilaginous endplate
(Fig. 22–1). separates the nucleus from the adjacent vertebral bone. Together,
The pedicles are also found on the posterior side of the vertebral these layers form a strong disk, capable of absorbing the shock
body and act to join the posterior bony structures to the anterior produced from the movement of the spine. When weight is put
vertebral body (Fig. 22–2). From the confluence of the laminae and on the spine, the disks compress; when the weight is lifted, the
the pedicles protrudes the articular processes that form the facet disks return to their original shape and size. The loads on an L3
joints. This particular confluence of bone is referred to as the pars disk in a 70-kg person are approximately: lying prone 0.10 Mpa
interarticularis. The transverse processes, which extend laterally, also (14 psi), lying lateral 0.12 Mpa (17 psi), free sitting 0.3 Mpa
protrude from this junction. Together, the pedicles and processes (43 psi), sitting unsupported 0.46 Mpa (67 psi), relaxed stand-
form the vertebral arch. Muscles and ligaments connect to the ing 0.5 Mpa (72 psi), lifting a 20-kg weight close to the body
4. Elwakil TF, Elazzazi A, Shokeir H. Treatment of carpal tunnel 8. Rinker B, Effron CR, Beaslet RW. Proximal radial compression
syndrome by low-level laser versus carpal tunnel release. Lasers Med neuropathy. Ann Plast Surg 2004;52:174–180.
Sci 2007 (in press). 9. Lister GD, Belsole RB, Kleinert HE. The radial tunnel syndrome.
5. Irvine J, Chong SL, Amirjani N, et al. Double-blind randomized J Hand Surg 1979;4:52–59.
controlled trial of low-level laser therapy in carpal tunnel syndrome. 10. Lee YK, Kim YI, Choy WS. Radial nerve compression between the
Muscle Nerve 2004;30:182–187. brachialis and brachioradialis muscles in a manual worker: a case
6. Nalamachu S, Crockett RS, Gammaitoni AR, et al. A comparison of report. J Hand Surg 2006;31:744–746.
the lidocaine patch 5% vs naproxen 500 mg twice daily for the relief of 11. Adolfsson LE, Nettleblad H. Radial nerve entrapment in the upper
pain associated with carpal tunnel syndrome: a 6-week, randomized, arm as a cause of lateral arm pain: a report of four cases. Scand
parallel-group study. Med Gen Med 2006b;9:33. J Plast Reconstr Surg Hand Surg 2001;35:217–220.
7. Nalamachu S, Crockett RS, Mathur D. Lidocaine patch 5 for carpal
tunnel syndrome: how it compares with injections: a pilot study. J Fam
Pract 2006a;55:209–214.
Chapter 22 vertebrae at the spinous and transverse processes, which arise

from the dorsal aspect of the vertebra.
BACK PAIN
William F. Lavelle, Allen L. Carl, Elizabeth Demers MOTION SEGMENTS
Lavelle, and Aimee Furdyna
The vertebrae link together through facet joints on the posterior
side of the spinal column. The facet joints are formed between the
superior articular processes of one vertebra and the inferior articu-
lar processes of the vertebra directly above.
Between each of the lumbar vertebrae is a thick, spongy disk
made up of various types of cartilage. The three major constituents
INTRODUCTION of the disk are water, fibrillar collagens, and aggrecan (a large aggre-
gating proteoglycan [PG]) with highly sulfated glycosaminoglycan
The majority of patients will experience spine-related pain at some (GAG) chains that attract and hold water. The annulus fibrosus is
time in their lives. Low back pain, in particular, is most common in the outer ring that forms the border of the disk. It is composed of
patients between the ages of 35 and 55 years. Fortunately, the 15 to 25 distinct layers of concentric collagenous lamellae (made of
majority of acute back pain is self-limited, with over 90% of patients bundles of collagen fibers running obliquely from one vertebrae to
recovering within 6 weeks. Back pain has a high recurrence rate, the next, thereby anchoring the disk to bone or cartilaginous end-
with symptoms returning within the year in two thirds of patients. plate, highest in the outer annulus fibrosus and lowest in the inner
The majority of sciatic pain is also self-limiting. Certain aspects of annulus fibrosus). With aging and/or degeneration of the disk, the
lifestyle, such as a lack of physical activity, obesity, and smoking, relative content of collagen increases owing to a loss of water and
predispose patients to recurrent episodes of back pain and sciatica. aggrecan. At a pressure of 0.25 megapascals (Mpa; 36 pounds/inch2
[psi]) a 37-year-old disk is hydrated with approximately 4 g water
per gram of dry weight, whereas a 91-year-old disk is hydrated to
LUMBAR SPINE ANATOMY about 1.8 g water per gram of dry weight with four- to fivefold less
aggrecan. This may be due in part to actions of matrix metallopro-
The spine is composed of three anatomic sections, the cervical, teinases (MMP; collagenases from connective tissue cells [MMP-1]
lumbar, and thoracic spine. The pain conditions discussed and from polymorphonuclear leukocyte [MMP-8], and stromelysin
within this chapter involve primarily the lumbar spine. The five [MMP-3]). Stromelysin may degrade multiple connective tissue
lumbar vertebrae are characterized by their relatively large size matrix components (including aggrecan and type IX collagen
compared with the cervical and thoracic vertebrae. This increased activating procollagenase; also referred to as aggrecanase).
size is necessary to support the patient’s body weight from succes- The nucleus pulposus forms the center of the disk and functions
sive vertebral levels. The outer portion of each vertebra is composed to resist compressive loads. The nucleus pulposus largely consists of
of dense cortical bone. The cortical bone is narrower in the center PGs, water, collagen, and cells. PGs have gained the most attention
of the vertebra and flares at the superior and inferior ends in an with respect to nerve irritation secondary to herniated nucleus
hourglass pattern. On the dorsal side of the vertebral body are the pulposus material; however, cells may produce MMPs, cytokines
laminae, two short, broad plates of bone that cover and protect (interleukin [IL]-6), and prostaglandin E2. Each disk is approxi-
the dural sac. These plates join medially at the spinous processes mately 1=4 to 3=4 inch thick. Furthermore, the cartilaginous endplate
(Fig. 22–1). separates the nucleus from the adjacent vertebral bone. Together,
The pedicles are also found on the posterior side of the vertebral these layers form a strong disk, capable of absorbing the shock
body and act to join the posterior bony structures to the anterior produced from the movement of the spine. When weight is put
vertebral body (Fig. 22–2). From the confluence of the laminae and on the spine, the disks compress; when the weight is lifted, the
the pedicles protrudes the articular processes that form the facet disks return to their original shape and size. The loads on an L3
joints. This particular confluence of bone is referred to as the pars disk in a 70-kg person are approximately: lying prone 0.10 Mpa
interarticularis. The transverse processes, which extend laterally, also (14 psi), lying lateral 0.12 Mpa (17 psi), free sitting 0.3 Mpa
protrude from this junction. Together, the pedicles and processes (43 psi), sitting unsupported 0.46 Mpa (67 psi), relaxed stand-
form the vertebral arch. Muscles and ligaments connect to the ing 0.5 Mpa (72 psi), lifting a 20-kg weight close to the body
168 Chapter 22 BACK PAIN
Spinous process Vertebral body
Lamina
Dural sac with
Articular facet CSF
Pedicle
Transverse Nerve roots
process
Transverse process
Cortical bone of
vertebral body Spinal process
Cancellous bone
of vertebral body Figure 22^3. Axial MRI of the lumbar spine at the level of the
vertebral body.
Figure 22^1. Model of a lumbar vertebra.
and matrix degradation remain relatively constant (with minor

1.1 Mpa (159 psi), and lifting a 20-kg weight around a flexed back decreases).2,3
2.3 Mpa (333 psi). Significant diurnal disk shrinkage occurs
during a working day, with rapid recovery with lying down
(e.g., at night). Thus, with awakening in the early morning, we are NEUROLOGIC STRUCTURES
taller than at the end of a day spent on our feet. Forward flexion
causes higher bending stresses in the early morning than later in the The spinal cord extends from the base of the brain, through the
day (about 300% for the disks and 80% for the ligaments of the cervical and thoracic vertebrae, and ends at the top of the first
neural arch), leading to a greater risk of injury (especially from flex- lumbar vertebra (L1). The terminal end of the solid spinal cord is
ion) and higher intradiskal/pressures in the early morning. (Thus, if called the conus medullaris. At this point, the spinal cord divides
one is in the practice of doing 10 ‘‘toe touches’’ every day; doing them into a series of nerve rootlets, called the cauda equina owing to the
upon awakening is probably not ideal for the back.) The disk is resemblance to a horse’s tail (Fig. 22–3). These neural fibers are
believed to remain reasonably healthy when the rates of macromo- suspended in spinal fluid within the dural sac of the spinal canal
lecular synthesis and breakdown are in balance. Disk degeneration and exit the spine through foramen between vertebrae (intervertbral
may result from failure of the disk’s cells to produce, maintain, and foramen); extending to the legs and buttocks.
repair the matrix. Disks are among the largest avascular tissues in the
body. Disk cells in the center of an adult lumbar disk are 6 to 8 mm
from the nearest blood supply and, consequently, receive oxygen CAUSES OF BACK PAIN
largely via diffusion. Multiple factors including atherosclerosis,
smoking, vibration, and calcified endplates may contribute to dimin- Subaxial spine pain is often caused by either muscular spasm or a
ished nutrient/transport into disks. Disk cells utilize oxygen (despite failure of the joints that compose the complex anatomy of the spine.
the fact that disk metabolism is largely via glycolysis) to synthesize As stated in the ‘‘Lumbar Spine Anatomy’’ section, each level of the
PGs at the center of the nucleus pulposus at around 5% oxygen.1 spine below C2 is composed of several joints. Four facet joints are
As the pH of the nucleus pulposus center falls (largely from lactic associated with each vertebra—one pair of facet joints that faces
acid accumulation) or oxygen levels in the nucleus pulposus center upward and another pair that faces downward. The vertebral bodies
fall below 5%, PG synthesis decreases dramatically, but MMP activity are separated by intervertebral disks that act as cushions between
the bones. Each disk is made up of two parts—the hard, tough
outer layer called the annulus, which surrounds a pliable, aqueous
center termed the nucleus (Fig. 22–4). Mechanical failure of any of
these motion segments may result in back pain.
An examination of the causes of isolated back pain in patients
who presented to a primary care physician revealed that 4% had a
compression fracture, 3% spondylolisthesis, 0.7% a tumor or
metastasis of another tumor, 0.3% ankylosing spondylitis, and
Invertebral disc 0.01% an infection.4 Therefore, most patients who present with
the complaint of low back pain will leave their primary care physi-
Vertebral body cian’s office without a definitive diagnosis. It is our suspicion that
this nonspecific back pain is attributable in part to the degenerative
Nerve root processes that occur with aging.
In spinal degeneration, disk degeneration seems to occur first.
Changes to the biologic structure of the disk lead to the mechanical
Pedicle
failure of that disk. Aged disks have decreased stiffness and strength.
The accumulated products of the failing disk affect the metabolism
of the remaining viable cells. This causes further failures in the disk
and changes that may be seen on magnetic resonance imaging
(MRI). These MRI changes include decreased water content and
are termed dark disk disease (Fig. 22–5).
Figure 22^2. Sagittal magnetic resonance imaging (MRI) of Disk failure is often the beginning of a series of failures in the
the lumbar spine. spine. Disk failure causes the spinal ligaments to buckle and
Table 22^1. Meyerding Classification

Nucleus pulposis
Grade 1 1%–25% slippage
Annulus fibrosis
Exiting nerve root Grade 4 76%–100% slippage
Grade 5 >100% slippage
Facet joint
Degenerative spondylolisthesis rarely exceeds 35%. Patients are

typically treated with nonsteroidal anti-inflammatory drugs
(NSAIDs) and bracing. Nerve root decompression and fusion are
Figure 22^4. Axial MRI of the lumbar spine at the level of the employed if conservative measures fail. These techniques are
disk. detailed later in the chapter.
The posterior elements of the vertebra may be disrupted by a
stress fracture of an area of the spine called the pars interarticularis.
hypertrophy from being exposed to excessive forces including new The pars interarticularis is the lateral part of the posterior element
torsion forces. This combined instability results in facet joint degen- that connects the superior and inferior facets. By definition, pars
eration. The facet joints may then hypertrophy, leading to nerve interarticularis means ‘‘part between the articulations.’’ Repetitive
compression and sciatica. As is witnessed in the hip and knee, flexion/extension and rotation lead to microtrauma at this junction
although joints may be degenerative, they may or may not be pain- and thereby fracture. In the athletic adolescent, spondylolysis is one
ful. Patients with significant radiographic degenerative changes of the most common causes of back pain and should be investigated
could potentially have little to no pain. by spot radiographs and/or lumbar spine single-photon emission
The areas of the degenerating spine may fail at different rates, computed tomography (SPECT) images on nuclear bone scans (in
leading to different clinical pictures of back pain, leg pain, or insta- addition to usual bone scintigraphy) in this population. Activity
bility. If the anterior disk and ligaments fail at the same rate as the limitation and bracing are usually the first line of care. Recalcitrant
posterior structures such as the facet joints, anterior subluxation of pain and instability may require either a posterior fusion or an
one vertebra is a possible result. This is termed spondylolisthesis. The attempt at an operative repair of the pars interarticularis.
Marchetti-Bartolozzi classification system of spondylolysis/spondy- Back pain may also be due to disk dysfunction. Internal disk
lolisthesis is divided into derangement (IDD) is a term coined by Crock in 1970.5 This term
was coined to describe a large group of patients whose disabling
I. Developmental (high-dysplastic, low-dysplastic) spondylolisthesis
back and leg pain worsened after an operation for suspected disk
II. Acquired spondylolisthesis
prolapse. IDD was intended to describe a condition marked by an
IIA. Traumatic (acute pars fracture, stress fracture/reaction) alteration in the internal structure and metabolic functions of disk
IIB. Postsurgical (direct or indirect surgery) that were believed to be attributable to an injury or series of injuries
IIC. Pathologic (local or systemic) that may even have been subclinical. Annular tears are believed to
IID. Degenerative (primary or secondary) be either the major manifestation of IDD or a contributor to IDD.
The clinical hallmark of ‘‘discogenic pain’’ due to IDD is sitting
Degenerative spondylolisthesis is most common at the L4–5 level intolerance. Measures to improve discogenic pain/IDD may pro-
and occurs here 6 to 10 times more than at any other level. The long sitting tolerance. The diagnostic criteria for discogenic pain
increased motion caused by disk degeneration combined with attributable to IDD are outlined in Table 22–2 and are primarily
decreased shear resistance allows for the anterior slip. Degenerative based on diskography. Diskography involves injection of contrast
spondylolisthesis at the L4–5 levels may result in central stenosis into the disk center and evaluating its morphology on computed
combined with lateral recess stenosis that compresses the traversing tomography (CT) and plain x-ray as well as monitoring the patient
L5 nerve roots. Spondylolisthesis may be unstable and therefore for a pain response reproducing his or her pain (Fig. 22–6).
painful. The degree of spondylolisthesis is classified as shown in Monitoring of baseline pressures as well as the pressure response
Table 22–1. to a volume bolus may be useful. The specificity of diskography
may be improved if a positive disk is defined as one in which (1)
evoked concordant or similar/‘‘familiar’’ pain on a numerical rating
scale-11 (NRS-11) is 6 or greater at a pressure above opening pres-
sure of 50 psi or lower and total volume injected is 3 ml or less, and
(2) the morphology is significantly abnormal (i.e., high-grade
annual disruption [grade 3]). It is conceivable in the future
Normal disk
Table 22^2. Internal Disk Derangement Diagnostic

Tests5
1 CT diskography reveals annular tear

Dark disk 2 Pain should be reproduced on diskogram
3 As control, stimulation of at least one other disk should fail to
reproduce pain
Figure 22^5. Sagittal MRI shows dark disk disease. CT, computed tomography.
in the elderly. With an annual incidence of 700,000, vertebral com-

pression fractures occur more frequently than hip and wrist frac-
tures combined. Vertebral compression fractures account for
150,000 hospital admissions, 161,000 physician office visits, and
more than 5 million restricted-activity days annually.
Vertebral compression fractures frequently result in both acute
and chronic back pain, as well as leading to progressive vertebral
collapse. Patients sustaining osteoporotic compression fractures
also face increased risks for multiple comorbidities such as weight
loss due to early satiety and poor psychological well-being. More
commonly, elderly patients who were independent prior to their
injury find themselves dependent on their adult children.
Along with disks and joints, muscles and ligaments also experi-
ence degenerative disease and inflammation, making them potential
sources for pain. Molecular biology and genetics have yet to yield
conclusive information about the true precise etiology of spine-
related pain.
Figure 22^6. Diskography. CONSERVATIVE TREATMENT FOR

ISOLATED BACK PAIN
that the use of ex vivo high-resolution magic angle spinning
(HR-MAS) nuclear magnetic resonance (NMR) spectroscopy to Activity versus Bedrest
assess disk PG/lactate ratios may aid in identifying disks that may
be contributing to discogenic pain.5 Persistent activity is always the first line of treatment for patients
Facet joint degenerative changes are often the next area of failure with either acute or chronic back pain. Although it is true that
in the degenerative process. When pain arises from this area, placing a patient on bedrest when there is concern about a fracture
patients often complain of greater discomfort with spine extension or a ligamentous injury is advisable, once an unstable injury to the
or hyperextension positioning. Once muscles weaken, any position spine has been excluded, it is of prime importance to begin to
can cause discomfort. As a minimally invasive diagnostic and ther- mobilize the patient. The current literature has demonstrated that
apeutic modality, facet joint injections may be offered (Fig. 22–7). when patients are advised to stay active, they have significantly
However, the diagnosis of facet joint failure remains a clinical one. reduced sick leave and reduced chronic disability.7 A subsequent
Physical therapy as well as facet joint injections are the first line of randomized, controlled trial that included 211 people examined a
treatment in facet joint disease. self-management program that included advice to minimize bedrest
Despite the fact that scoliosis is classically described as a painless and stay active.8 This study found significant improvement in func-
condition, up to 30% of patients with adolescent idiopathic scoli- tional status at 12 months compared with ‘‘usual care’’(Roland
osis complain of back pain. It would seem intuitive that spinal disability questionnaire: 12 mo; P = .009). Patients should be
deformity would alter spine biomechanics and lead to increased advised to continue to remain mobile rather than stay in bed.
stress, degeneration, and therefore, pain. However, studies have Walking and light exercise should be emphasized.
found no difference in pain scores between patients with scoliosis
that were treated with either a brace or surgery compared with a
control group.6 Physical Therapy
The hallmark of osteoporosis is fractures of fragility. A fragility
fracture occurs as a result of a fall from standing height. The three Physical therapy is often a good option for these patients becauses
sites that are typical of fragility fractures are the vertebra, hip, therapy provides both a motivational and an educational advantage
and wrist. Vertebral body fractures may be another source of pain to the patient. Physicians should have a low threshold for beginning
physical therapy regimes in this population. In addition, education
about back pain is critical in its treatment. Studies show that the
patient’s understanding of her or his pain significantly predicts
treatment success.9
NSAIDs
A number of reviews and randomized, controlled trials have shown
that NSAIDs provide better pain control and improved function
even after only 1 week compared with placebo.10 The literature has
not shown a difference in the effectiveness of one NSAID over
another, and it has also been unable to demonstrate an advantage
of an NSAID over a muscle relaxant or opioid analgesia in terms of
pain relief.
Muscle Relaxants
Muscle relaxants have been found to decrease pain and improve
Figure 22^7. Facet injection. overall clinical assessment compared with placebo. Literature reviews
have failed to show a significant difference among different types performed by a percutaneous technique or used to augment other
of muscle relaxants. Most reviews have shown that benzodiaze- percutaneous procedures.
pine and nonbenzodiazepine muscle relaxants have increased Fusion techniques are designed to specifically address either the
adverse effects including drowsiness, dizziness, and nausea com- posterior facet joints or the anterior disk. A combined approach in
pared with placebo. Use of these medications should be limited which both the anterior and the posterior motion segments are
to those patients noting a particularly significant spasm compo- fused may also be utilized. As with most fusion procedures used
nent to their pain. Muscle relaxants should also be limited to the in orthopedic surgery, the fusion procedure should excise or
acute phase of a flare of back pain. denude the joint that has been painful. Paramount to durability
as well as functionality of the fusion is for the procedure to restore
the patient to an anatomic and functional position. In the case of
Spinal ManipulativeTherapy the spine, patients are typically fused in a position of normal relative
lordosis or kyphosis. Any extreme in the fusion position may leave
No published series have demonstrated that spinal manipulative the joints above and below the fused segment exposed to great
therapy is threatening; however, as with any treatment, there have extremes of load and shear. Fusing a patient in a nonanatomic
been isolated and anecdotal reports of injury. One review showed position also places greater demands on the muscles and ligaments
that spinal manipulative therapy reduced short- and long-term pain about the fused segment, possibly increasing the back pain the
and improved short-term function compared with sham therapy. fusion procedure was meant to treat. Loss of balance in the sagittal
This difference was not sustained long term, and significant differ- plane can lead to a loss of normal contour and subsequently to flat
ences in function were not seen after 6 weeks. As with most con- back alignment complications such as fatigue and back pain after
servative treatments, spinal manipulation has been shown in some standing for extended periods of time.
reports to increase the number of patients who return to work Clinicians should also be aware that the field of spine surgery has
within a year compared with those without treatment. This may seen greater successes in the surgical treatment of sciatica-type pain
suggest effectiveness or possibly an increased interest in the patients rather than isolated back pain. Turner and associates13 found that
who seek care in getting well.7,10 satisfactory outcomes after fusion for all indications were not as
high as physicians would have hoped (mean 68%; range 16%–
95%). Bono and Lee14 found similar positive results for fusion
Injections studies of degenerative disk disease that were published in the
1980s (78%) and the 1990s (74%), despite the advent of more
Facet joint injections offer a means to diagnose as well as to treat modern surgical procedures and instrumentation. However, the
facet joint arthritis; however, some clinicians doubt the utility of last few decades have seen some fascinating advances including
this modality. Large studies with a high level of evidence that exam- pedicle screw instrumentation and interbody cage systems.
ined the true efficacy of facet injections are not common. One study Several of the most recent advances have been in the direction of
failed to find a statistically significant difference at 1 and 3 months minimally invasive surgery. One of these advances has been percu-
between patients injected with corticosteroid and those who taneous pedicle screws. Percutaneous pedicle screw placement
received saline injections; however at 6 months, the patients treated begins with accurate identification of the levels to be instrumented.
with steroids had a marked improvement in their pain.11 Currently, In a manner similar to that for performing vertebroplasty or kypho-
there are no large multicenter, well-designed, randomized, con- plasty, 22-gauge spinal needles are inserted under lateral fluoros-
trolled trials attesting to the effectiveness or detriment of epidural copy in a paramedian approach so that they bisect the superior and
injections for isolated back pain. inferior pedicles. The medial to lateral position of the needles is
confirmed on the anteroposterior (AP) fluoroscopic image. A
K-wire is then placed through the cannulated needle followed by
Intradiskal Electrothermal Therapy needle removal. Sequential dilators are placed over the K-wire to
develop a soft tissue corridor. The final dilator is left in place and
Percutaneous intradiskal electrothermal therapy (IDET) is a the pedicle is tapped under fluoroscopic guidance. Finally, a cannu-
treatment that has been developed for patients with imaging lated, polyaxial screw is placed over the K-wire and, with the screw,
and diskographic evidence of IDD. This minimally invasive tech- is inserted under fluoroscopic guidance. Care is taken to avoid
nique uses a navigable catheter to provide targeted thermal inadvertent advancement of the K-wire. This process is repeated
energy within the disk. This procedure has the advantage of for each screw.
preserving the native disk structure. As a result, undergoing After both screws are inserted, screw extenders are then manipu-
the IDET procedure does not eliminate the possibility for sur- lated and mated, and a rod is passed via a guide through a separate
gery at a later time. Although the literature on this technique is stab incision.
limited, studies in the current literature have found that between Disks may also represent a painful motion segment. Posterior
50% to 65% of appropriately selected patients reported a signif- fusions alone may not alleviate pain at a particular vertebral level,
icant reduction in their back pain after an IDET procedure thus anterior fusion may be necessary. This was originally per-
followed by a specific ‘‘post-IDET’’ long-term physical therapy formed through a second approach using an anterior or anterolat-
program.12 eral exposure. The ability to accomplish similar stabilization
procedures of the anterior column through a single posterior expo-
sure was the next logical step. Posterior lumbar interbody fusion
SURGERY FOR PAINFUL MOTION (PLIF) and subsequently transforaminal lumbar interbody fusion
SEGMENTS (TLIF) approaches were soon popularized.15
PLIF was first performed by Cloward in 1943.16 The PLIF tech-
As with other joints in the body, painful spinal motion segments nique may be applied either through two small paramedian skin
may be treated by either arthroplasty or fusion. Both currently and incisions made at the level to be fused or through a midline dissec-
historically, fusion remains the standard of care for painful motion tion that has been used for an open diskectomy or decompression.
segments that have failed conservative treatment. These fusion tech- The interlaminar space is accessed with any interposing soft tissue
niques have now been supplemented with structural support sys- removed. Bilateral hemilaminotomies and medial facetectomies are
tems in the form of rods, hooks, wires, and screws. The advent of then performed, with the excised bone saved as bone graft. A com-
pedicle screws allowed for shorter fusion masses and may be plete diskectomy is performed with the endplates prepared using
was devised. Being a more recent development, kyphoplasty was

first performed in 1998. The procedure seemed to herald the
same type of pain relief. The topics of vertebroplasty and kypho-
plasty are extensively reviewed in Section XIII, Chapter 86.
‘‘SCIATICA’’ OR LUMBOSACRAL
RADICULAR PAIN
The condition of spine-related pain or paresthesia that radiates into
the legs or buttocks has been referred to by various names including
the general term sciatica or the more precise terms lumbosacral
radicular pain or radiculagia, if the symptoms are dermatomal or
myotomal. Although the term sciatica is discouraged by many
thought leaders, it may serve a useful purpose as a term to include
spine-related back pain radiating into the lower extremities that is
nondermatomal and nonmyotomal. Sciatica-type pain may occur in
the legs or buttocks. Patients often describe it as a ‘‘shooting’’ type
of pain that progresses distally. Lumbosacral radicular pain can be
attributed to a number of causes, but in general, it is due to extrin-
sic nerve compression. The pressure may be the result of a herniated
disk, stenosis, facet, and/or ligament hypertrophy. The inflamma-
tory process that is occurring around the nerve root likely is the
common thread. The intervertebral disk contains material (e.g.,
Figure 22^8. Interbody fusion. phospholipase A2) that has been found to cause inflammation
and excite nerve roots, thereby causing pain.17,18
decorticating instruments such as rasps and curettes. The anterior How Disks Fail
disk space as well as an interbody cage are packed with bone graft or
a bone graft substitute. The fusion level is then further instrumented Each vertebral level of the spine sees numerous forces imparted
with pedicle screws (Fig. 22–8). A TLIF is similar to the PLIF pro- from the levels above and below. Repetitive mechanical loading,
cedure except the TLIF device is inserted through a unilateral at least in part, is believed to cause intervertebral disk degeneration.
approach, theoretically minimizing nerve root retraction. This mechanical loading causes a disruption that affects both the
Unfortunately, the approach does sacrifice a facet joint. physical and the biologic properties of the disk. The mechanical
destruction is accompanied by a cascade of nonreversible cell-
mediated responses causing cell death. Cadaveric experiments and
PERCUTANEOUS VERTEBRAL computer models have shown how various combinations of com-
AUGMENTATION FOR VERTEBRAL pression, bending, and torsion can cause the morphologic features
BODY FRACTURES of disk degeneration such as endplate disruption, fissure formation
in the annulus, radial bulging, disk prolapses, and internal collapse
After the initial investigations in Europe, vertebroplasty was intro- of the annulus.2 As the repetitive trauma continues, nucleus pulpo-
duced in the United States by interventional neuroradiologists at sus material is slowly pushed into and sometimes through the annu-
the University of Virginia. The technique involves the percutaneous lar ring of the disk. The added structural support and configuration
injection of cement into a fracture site. In this technique, a small of the posterior longitudinal ligament typically deflects the pro-
incision is made and an 11-gauge cannulated trocar and bone truded disk material to either side; however, central protrusions
biopsy needle are advanced through the posterior aspect of the may be seen. This disk failure often develops as the result of additive
vertebra, through the pedicle, and into the vertebral body being microtraumas patients see in their activities of daily living.
treated. Both lateral and AP projections provide necessary visual- As with most disease processes, one element of failure does not
ization of the path of the needle. adequately explain the extent of our knowledge on disk degenera-
The most common approach involves accessing and injecting tion. As the disk ages, studies have shown that the number of blood
cement through both pedicles. With single-plane fluoroscopic vessels in the vertebral endplates decreases, with a majority disap-
equipment, actual injection of the cement should be visualized pearing by the 3rd decade of life.2 The number of viable cells at the
with lateral fluoroscopy. Vertebroplasty has gained increasing pop- core of the disk declines at this time as well. The chemical structure
ularity with patients reporting rapid pain relief. The typical patient of the disk and organization of the disk, including the collagen fibril
who is offered percutaneous vertebral augmentation is one who has organization, begin to change and eventually disappear. Questions
already failed a number of weeks of conservative therapy consisting remain as to whether all of these changes are the predecessors to
of oral NSAIDs and/or opioid analgesics for mild to moderate pain degeneration or if they result from the mechanical stresses described
in addition to a supportive orthosis. earlier.
The possibility of injecting highly viscous cement into fractured
trabecular bone was worrisome to clinicians. The fear that cement
extravasation could have devastating neurologic consequences from Evaluation of Lumbosacral Radiculopathy
intrusion was of particular concern. Clinicians were also concerned
that the high pressures used to introduce the cement could poten- A detailed evaluation of the patient with concerns of sciatica-type
tially lead to the bolus embolization of cement through the venous pain is required. This normally consists of a complete history of
channels in the vertebral bodies to the lungs. In addition, vertebro- symptoms and events that led to the onset of these symptoms. The
plasty was believed to be an inadequate means of fracture reduction. review should include a systemic questioning to exclude other
As an answer to all these concerns, the kyphoplasty technique potential causes of leg pain and/or neurologic problems.
Table 22^3. Pertinent Physical Examination Findings for Patients with Back Pain
FABER Patrick’s or FABER (flexion, abduction, external rotation) test is screening test for pathology of hip joint or
sacrum. Foot of affected side is placed on opposite knee.
Pain in groin area indicates problem with hip and not spine.
Pain in sacroiliac area indicates problem with sacroiliac joints.
Straight leg raise Lasegue’s straight leg raise is performed by having patient positioned supine. Knee or tested limb is kept
straight and passively raised as far as possible. This action will usually move L4, L5, and S1 nerve roots 1–
4 mm. In positive test, patient will report reproduction of sciatica symptoms. Examiner should record
degree of hip flexion that reproduces sciatica symptoms.
Sciatic stretch test Perform straight leg raise test. At conclusion of test, lower affected leg a few degrees below point at which
pain is being produced.
1. Apply compression to popliteal fossa. This tethers sciatic nerve and produces symptoms at lower angle of
hip flexion. This aids in distinguishing hamstring tightness from sciatica.
2. Severe dorsiflexion at ankle will also increase sciatic nerve tension and produce symptoms at lower degree
of hip flexion.
Reverse sciatic stretch Test is completed in conjunction with straight leg raise as well as sciatic stretch test. Ankle is maximally
test plantarflexed, which should alleviate sciatica symptoms produced by sciatic stretch test.
Contralateral straight leg Test is performed in manner identical to straight leg raise test, except asymptomatic leg is elevated. In
raise positive test, symptoms will develop in symptomatic leg (not leg being elevated).
Femoral stretch test Patient is positioned prone. Knee is flexed and hip is lifted into extension. Pain along anterior thigh signifies
irritation of lumbar nerve roots above L4.
Hoover’s test Patient is asked to lie supine and raise limb that has suspected weakness. Patient will involuntarily exert
counterpressure with heel of opposite (untested) leg. If individual attempts to lift paralyzed leg,
counterpressure is still made with heel of untested leg.
The physical examination aims to exclude other causes of leg Physical therapy is often begun after a short period of convales-
pain and to document any evidence of tension on the nerve, ten- cence for the acute disk herniation. One popular method is the
derness to the spine, and neurologic change in the sciatic nerve dis- McKenzie method, developed by a New Zealand–based phy-
tribution (Table 22–3). The neurologic examination of the legs siotherapist, Robin McKenzie. It consists of a comprehensive
examines sensation, strength, and any change in reflexes (Table mechanical evaluation that assesses the effect of repetitive move-
22–4). The clinician should inquire about symptoms relating to ments and/or provocative positioning on the patient’s symptoms.
abnormal function of the bladder or bowel, which may indicate The patient’s self-management skills are integral to the McKenzie
compression of the terminal nerve roots of the spinal cord, method. Therapists teach patients how to perform the specific
termed cauda equina syndrome or myelopathy (Table 22–5). exercises, positions, and static/dynamic posture corrections
Cauda equina syndrome is a surgical emergency requiring emergent shown in the mechanical evaluation to have a direct therapeutic
decompression. A series of specific tests, termed Waddell’s signs benefit. Patients are also taught to avoid specific movements, pos-
(Table 22–6), have been proposed to aid in determining whether tures, and activities that clearly exacerbate their condition. Manual
a nonorganic cause of leg or spine pain is present.2 therapy techniques, such as mobilization and manipulation, are
introduced if the self-treatment strategies fail to fully resolve the
problem.
ConservativeTreatment
NSAIDs
Activity versus Bedrest
A large component of the pain caused by disk herniation is inflam-
A short period of bedrest is often employed during the early con- matory. As outlined earlier, herniated disk material incites an
valescence period after an acute disk herniation. Prolonged periods inflammatory response. NSAIDs offer a clear treatment option for
of bedrest are ill advised because patients may decompensate. When the component of lumbosacral radicular pain that may be attribu-
they attempt to return to their daily activities, they are at increased ted to inflammation.
risk for muscular strain. Patients who have been at bedrest often
suffer increased psychological ailments, succumbing to a feeling of
Muscle Relaxants
depression and hopelessness. Symptoms will improve and/or
resolve in about half of patients. This may be due to a decrease in Lumbosacral radiculopathy may cause back as well as leg spasms.
the inflammatory response or reabsorption of the material causing Short-term treatments that involve muscle relaxants are appropriate
compression. It may also be attributable to good patient education and often provide symptomatic relief. As stated earlier, most
and the early return to light physical activity. reviews have shown that benzodiazepine and nonbenzodiazepine
muscle relaxants have increased adverse effects including drowsi-
ness, dizziness, and nausea compared with those of placebo.
Physical Therapy
Physical therapy is an excellent option providing both a motiva-
Spinal ManipulativeTherapy
tional and an educational service to the patient. Studies concerning
lumbosacral radicular pain also reveal that the patient’s under- Spinal manipulation cannot reverse the pathology of disk hernia-
standing of his or her pain significantly predicts treatment success. tion. Massage techniques may provide support for associated back
Table 22^4. Neurologic Examination
Spinal
Nerve Root Dermatome Muscle Reflex
C5 Lateral arm (especially over lateral Deltoid muscle; test resistance to Biceps reflex: Flexion at elbow
aspect of deltoid) abduction of arm at shoulder/test upon striking biceps tendon
resistance to elbow flexion with forearm
supinated (C5&6)
C6 Lateral forearm, thumb, index, and Test resistance to wrist extension (C6&7) Brachioradialis reflex: Reflex
half of middle finger [ECRL (C6), ECRB (C6), ECU (C7)]/ supination upon striking
test resistance to elbow flexion with brachioradialis insertion
forearm supinated (C5&6)
C7 Middle finger Triceps (extension of arm at elbow)/wrist Triceps reflex: Extension at
flexors/finger extensors elbow occurs upon striking
triceps insertion
C8 Fourth and fifth digits of hand and Finger flexors (FDS flexes PIP joint; FDP No reflex
distal half of medial forearm flexes DIP joint)
L4 Medial leg Tibialis anterior Patellar: Knee extends upon
Test resistance to dorsiflexion and striking patellar tendon
inversion of foot
L5 Lateral leg and dorsum of foot Extensor hallucis longus No reflex
Test resistance to dorsiflexion of great toe
S1 Lateral malleolus/lateral aspect and Peroneus longus and brevis Ankle jerk reflex:
plantar surface of foot Test resistance to plantar flexion and Gastrocnemius/soleus
eversion of foot complex fires upon striking
Achilles tendon
DIP, distal interphalangeal; ECRB, extensor carpi radialis brevis; ECRL, extensor carpi radialis longus; ECU, extensor carpi ulnaris; FDP, flexor digitorum
profundus; FDS, flexor digitorum superficialis; PIP, proximal interphalangeal.
pain and spasm. Leg pain due to nerve compression is more diffi- Surgical Treatment for Painful Lumbosacral
cult to treat with manipulation. Radiculopathy
Those patients who have failed conservative measures such as
Injections
oral analgesia, physical therapy, epidurals, or nerve root injections
Selective nerve root injections as well as central epidural injections for 6 to 12 weeks may go on to surgical interventions. Dandy,
are common treatments for lumbosacral radiculopathy. The aim of Mixter, and Barr20 were among the first pioneers of surgical decom-
the injection is to reduce the inflammation around the nerve root, pression for a disk herniation. This surgical decompression involves
which may be a substantial contributor to the pain these patients removal of ligamentum and lamina followed by retraction of the
experience. This technique may be very effective, but it is somewhat dural sac to access the disk material compressing the nerve root.
unpredictable. In some patients, it is not beneficial, although the As time has passed, the size of the laminar resection has become
risks are relatively low. Despite the fact that a handful of studies smaller, and the soft tissue dissection has been minimized.
have found injection procedures to be effective,19 it remains con- Minimally invasive techniques have hopefully decreased scar
troversial whether or not this option has a role in the long-term tissue formation as well as decreased the incidence of creation of
treatment of patients with lumbosacral radicular pain. iatrogenic instability.
Table 22^5. Physical Examination Findings for the Myelopathic Patient
Babinski’s response Babinski’s response is elicited by scratching lateral and plantar foot with hand or reflex hammer. Normal
response is flexion of great toe, whereas abnormal response involves extension of great toe.
Finger-escape sign Hand is held with fingers extended and adducted (held together). Positive response: Ring and small finger
will flex and abduct. Occasionally, middle finger will adopt this position as well. Negative response: No loss
of position of ulnar digits.
Grip-and-release test Patient is asked to make a closed fist repetitively as quickly as possible. Positive response: Myelopathic patient
will be able to complete < 20 repetitions in 1 min before fatiguing. Negative response: Normal patient will
be able to complete > 20 repetitions in 1 min.
Hoffmann’s sign Distal phalanx of patient’s middle finger is snapped. This elicits flexion stretch reflex. Positive response:
Flexion of other digits of hand, particularly thumb and index finger, denotes a pathologic response.
Negative response: No reflexive flexion of any digits of hand.
Table 22^6. Waddell’s Signs*
Superficial tenderness Skin discomfort on light palpation over a wide area.

Nonanatomic tenderness Tenderness crossing multiple anatomic boundaries not localized to one structure. Pain often extends to
thoracic spine, sacrum, or pelvis.
Axial loading Back pain is elicited when pressing down on top of patient’s head. This may cause neck pain but should not
cause low back pain.
Pain on simulated Shoulders and pelvis are rotated together as unit. This should not be painful because it does not stretch
rotation structures of back.
Distracted straight leg If patient complains of pain on straight leg raise while supine, confirm test with patient seated. This may be
raise done while testing for Babinski’s response.
Regional sensory change Stocking sensory loss, or sensory loss in entire extremity or side of body.
Regional weakness Weakness that can be overpowered smoothly. Organic weakness will be jerky, with intermittent resistance,
which may be described by some as ‘‘cogwheeling.’’
Overreaction Exaggerated painful response to stimulus that is not reproduced when same stimulus is given later.
*Waddell and associates,23 in 1984, described indicators of a nonorganic or a psychological component to back pain. The presence of three or more of
these signs is highly correlated with a nonorganic or psychological cause of back pain.
Microdiskectomy by any method has become the operation of relieved by rest. This is referred to as neurogenic claudication.
choice owing to decreased hospital costs, diminished postoperative Patients will report that bending forward diminishes the pain. A
pain, and fewer days missed from work. The rate of recurrent disk common report is that the patients find their symptoms are
herniation is variable and perhaps more related to surgeon skills improved walking up stairs and worsened walking down. This is
than choice of operation. Studies have shown no difference in the due to the relative increase in the size of the spinal canal that occurs
rate of recurrent disk herniation treated by open diskectomy or with a flexed posture. Similarly, patients note improved symptoms
microdiskectomy.21 Despite the fact that patients who undergo while pushing a shopping cart. Lower back pain and radiating scia-
decompression will have a more rapid resolution of symptoms, tica-type leg pain may be concurrent with the symptoms of lumbar
long-term results are no different from those of nonoperative man- spinal stenosis. A detailed spine and neurologic examination is
agement as demonstrated by Henrik Weber in 1983.22 More necessary, as described previously.
recently, Peul and colleagues9 randomly assigned 283 patients
with severe sciatica for 6 to 12 weeks to early surgery versus pro-
longed conservative treatment (with eventual surgery, if needed) ConservativeTreatment
and concluded that the 1-year outcomes were similar for patients
assigned to early surgery. With this being the case, attempts at Treatment with conservative measures may provide relief for
injections rather than surgery would seem a logical choice. patients with mild symptoms. This may consist of NSAIDsS, phys-
Percutaneous disk depression options include automated percu- ical therapy, and education. Central epidural steroid injections are
taneous diskectomy (APD; Nucleotome [Clarus-medical, offered to treat the component of the patient’s leg pain attributed to
Minneapolis, MN], DeLompressor [Stryker Instruments, nerve inflammation. The results of studies in the literature vary as
Kalamazoo, MI]), percutaneous laser diskectomy (PLD; LASE cath- to the true long-term usefulness of central epidural steroids for
eter [Clarus-medical, Minneapolis, MN]), and radiofrequency lumbar stenosis.19
plasma ablation, Coblation, or DISC Nucleoplasty Perc-D catheter
(Arthrocare Spine, Sunnyvale, CA). However, rigorous long-term
results from large, multicenter, well-designed studies comparing Surgical Treatment
these various treatments with conservative as well as traditional
surgical approaches are not available. Treatment is often surgical, with the entirety of the offending areas
of compression removed. This typically entails a posterior spine
approach with excision of the lamina and a portion of the facet
SPINAL STENOSIS joints. Instability may result from the decompression, necessitating
spinal fusion along with instrumentation. Dynamic spinal instabil-
All of the previously described degenerative processes such as disk ity may also cause stenosis.
failure, spinal ligament buckling and hypertrophy, facet joint degen- The X Stop device is an alternative method to decompressive
eration, and spondylolesthesis may result in central spinal canal lumbar surgery. The mode of action of the device reflects the change
narrowing. Whereas isolated compression along with inflammation in size of the spinal canal with normal flexion and extension. The
may cause irritation of an individual nerve root, lumbar spinal cross-sectional area at one segment can increase as much as 50%
stenosis describes constriction of all of the nerve roots that pass a from extension to flexion. By placing a spacer device between the
larger area of constriction. Spinal stenosis is most common at L3–4, spinous processes of the affected segment, the isolated motion seg-
L4–5, and L5–S1. ment is held in a relatively flexed position while the adjacent levels
Lumbar spinal stenosis is a clinical entity. It is diagnosed pri- are allowed to freely flex and extend (Fig. 22–9).
marily by history and confirmed by imaging such as an MRI or CT The primary advantage of the device is its minimally invasive
myelogram. A stenosis, or constriction, may simply be viewed on an approach for implantation. The device is useful if the stenotic area
imaging study like an MRI. The clinical entity ‘‘lumbar spinal ste- of the spine encompassed one or two spinal levels. Early clinical
nosis’’ requires symptoms along with the radiographic evidence of trials found good efficacy and excellent safety profiles12; however,
decreased cross-sectional area of the spinal canal. data are limited to 2 years. Patients who have undergone an X Stop
Patients with lumbar stenosis typically present with radiating leg procedure are still candidates for surgical decompression if their
pain or cramping associated with walking that is immediately symptoms persist or recur.
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16. Harms J, Rolinger H. A one-stage procedure in operative treatment of
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B (author’s transl). Z Orthop Ihre Grenzgeb 1982;120:343–347.
17. Cornefjord M, Olmarker K, Farley DB, et al. Neuropeptide changes in
Figure 22^9. A and B, X Stop Interspinous Process compressed spinal nerve roots. Spine 1995;20:670–673.
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SUMMARY back and leg pain: mechanisms of action and efficacy. Spine
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The treatment of spine-related pain is an ever-evolving area that 20. Dandy WE. Loose cartilage from intervertebral disk simulating tumor
requires a multidisciplinary focus. Current therapy techniques still of the spinal cord. By Walter E. Dandy, 1929. Clin Orthop Relat Res
emphasize conservative care such as patient education, physical 1989;(238):4–8.
therapy, and NSAIDs. These techniques are effective for both 21. Barrios C, Ahmed M, Arrotegui J, et al. Microsurgery versus standard
back pain and lumbosacral radicular pain. Surgical treatments are removal of the herniated lumbar disc. A 3-year comparison in 150
evolving, with decompression of neural elements for lumbosacral cases. Acta Orthop Scand 1990;61:399–403.
radicular pain and fusion techniques for painful motion segments 22. Weber H. The natural history of disc herniation and the influence of
intervention. Spine 1994;19:2234–2238.
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invasive techniques such as IDET and percutaneous instrumenta- physical disease or illness behaviour? Br Med J 1984;289:739–741.
tion are evolving, with the hopes of less invasive and more biologic
solutions on the horizon.
Chapter 23 sacroiliac joint disease. Sacroiliac joint disease maybe tested by the flex-
ion, abduction, and external rotation (FABER) test.2,4-7
HIP PAIN Most hip problems manifest themselves during ambulation;
however, a physical examination is still required. Information
Rakesh Ramakrishnan, Michael A. Krieves, may be obtained by simply observing the patient’s gait. Testing
William F. Lavelle, Elizabeth Demers Lavelle, and the range of motion of the hip is another valuable component of
a thorough hip examination. Passive internal and external rotations
Marc D. Fuchs are important indicators of the extent of joint irritation. Loss of
articular cartilage and outgrowth of osteophytes can reduce internal
and external rotation. Severe osteoarthritis, acute synovitis, and
septic arthritis can all result in decreased hip range of motion.
Finally, tests should be performed to look for sources of referred
pain from the sacroiliac joint, lumbar spine nerves, lateral femoral
cutaneous nerve, and lower abdominal vascular structures.2,7
INTRODUCTION Observation of gait is a very simple way to test hip function. Gait
can be evaluated when the patient first enters the examination room.
There are many possible causes for hip pain. In addition to pathology Toe and heel walking can add further detail for the examiner. The
affecting the hip joint itself, conditions involving soft tissues, nerves, patient’s gait and ability to change positions are an indication of
and adjacent bones can all cause a patient to experience hip pain. The generalized hip function. However, meralgia paresthetica, mild hip
location and type of pain combined with the physical examination arthritis, and most cases of bursitis do not affect ambulation greatly.1,7
can be used to differentiate among the many possible etiologies.1 Certain abnormalities can cause specific gait patterns. A gluteus
medius lurch or ‘‘Trendelenburg gait’’ may be observed in a patient
with an arthritic hip. With this gait pattern, the patient shifts his or
ANATOMY her torso over the affected hip during the single limb stance phase of
gait. This prevents firing of the hip abductor muscles, which would
It is necessary to understand the anatomy of the hip joint in order normally fire to prevent the pelvis from dropping toward the side of
to correctly diagnose and treat hip pain. The hip joint is known as a the limb that is off of the ground. Were the abductors to fire, the
ball-and-socket joint. The rounded head of the femur articulates affected and arthritic joint would experience greater than five times
with the acetabulum, which is formed by the junction of the ilium, the typical forces imparted by body weight. Placing the center of
ischium, and pubis. The nature of the joint and its innervations may gravity over the painful hip results in less total force on the hip and,
result in primary pain conditions of the hip. Pain symptoms arising therefore, decreases the pain. This is also why placing a cane in the
from the hip may be felt in the groin or referred distally to the knee. opposite hand from the painful and arthritic hip is recommended.1,7
Conversely, primary conditions of the lumbar spine can cause An antalgic gait refers to a gait that allows the patient to lessen
symptoms in the hip.1-3 pain by spending a shorter time weight-bearing on the affected side.
Patients with painful hip conditions including arthritic conditions,
infection, avascular necrosis (AVN), and fracture may demonstrate
APPROACHES TO DIAGNOSIS this gait pattern.2,7
Plain x-rays should be obtained in all patients with acute hip pain
History and physical examination help determine the etiology of a to rule out fracture. Plain radiographs are also indicated in patients
patient’s hip pain. The pattern of the pain is a key component in the with moderate chronic hip pain. If the plain radiograph combined
formation of a differential diagnosis. A structural joint problem can with a thorough history and physical examination is inconclusive,
result in pain that is increased with use and improves with rest, further imaging studies may be indicated. Plain x-rays allow the
whereas an infectious etiology will typically result in constant pain, physician to assess the articular width of the joints, pelvic obliquity
especially at night. Location is also a major indicator of the etiology. (to assess limb length), general bone morphology, and integrity of
Lateral hip pain is unlikely to be caused by a process occurring the sacroiliac joints. Characteristic findings of osteoarthritis are
in the hip joint. True intra-articular hip pathology presents as groin marked joint space narrowing, sclerosis of the joint space margins,
pain. Lateral hip pain, especially when aggravated by direct pres- and periarticular osteophyte formation. Magnetic resonance imag-
sure, is classically associated with trochanteric bursitis. ing (MRI) is indicated when a suspected fracture is not demonstrated
Groin pain or anterior hip pain generally suggests direct invol- by plain radiograph, for early diagnosis of osteonecrosis, for assessing
vement of the hip joint. Gradual groin pain with progressive loss of labral pathology, and in evaluation for infection and malignancy.
range of motion is indicative of an arthritic condition such as Soft tissue inflammation and osteoblastic activity are better visua-
osteoarthritis. When combined with impaired weight-bearing, the lized when MRI is enhanced with gadolinium.1,2
differential diagnosis for anterior hip pain should also include
osteoarthritis, osteonecrosis, occult fracture, acute synovitis, and
septic arthritis. Pain that is not exaggerated by hip motion or COMMON CAUSES AND TREATMENTS
weight-bearing suggests lower abdominal or retroperitoneal pathol-
ogy. Pain associated with flexion and external rotation of the hip FOR HIP PAIN
may represent a psoas abscess.
Posterior hip pain may represent an intra-articular process but Trochanteric Bursitis
often requires extensive testing to rule out spinal pathology. Irritation
of the L4 or L5 nerve roots may cause posterior hip or buttock Inflammation of the trochanteric bursa is a common cause of hip
pain. This uncommon presentation for hip pain may also represent pain. The greater trochanteric bursa is located between the greater
178 Chapter 23 HIP PAIN
Illiotibial band
Trochanteric
bursa
Figure 23^2. Hip arthritis.
Figure 23^1. Trochanteric bursitis.

on standing x-rays (Fig. 23–2). There may also be osteophyte for-
mation along the acetabulum and subchondral cyst formation.
Every attempt is made to treat arthritis of the hip nonoperatively.
trochanter and the fascia lata (Fig. 23–1). Underlying gait abnorm- The main goals of nonoperative treatment are to relieve pain and to
alities may lead to increased friction and uneven contraction of the preserve function. Regardless of the severity of the arthritis, most
gluteus medius tendon, which causes irritation of the bursa. It is patients respond to a period of rest, physical therapy, medication,
important to note that the pain is localized over the trochanter and and the use of an assistive device. Nonsteroidal anti-inflammatory
not in the groin. If this bursitis is left untreated, the walls of the drugs (NSAIDs) and mild weight loss are indicated for early arthri-
bursa may fibrose and fail to function. Treatment for trochanteric tis. Even modest weight loss in an obese patient can significantly
bursitis is local physiotherapy, anti-inflammatory drugs, and rest. reduce the amount of forces on the hip joint. Physical therapy can
Local anesthetic and steroid injections may be useful for recalcitrant be considered as an additional treatment and includes stretching of
pain.1,2 the adductors, rotators, and gluteus muscles. The use of a cane in
the opposite hand decreases hip joint loading by as much as 40%.
Significant pain relief can be obtained with the aggressive use of
Arthritis of the Hip nonoperative techniques. However, these effects are usually tempo-
rary and may eventually require surgical intervention.5,6
Hip arthritis can result from several causes. Conditions such as Total hip replacement may be indicated for advanced disease
osteonecrosis, trauma, sepsis, rheumatoid arthritis, and infre- that is recalcitrant to conservative measures. Ideal candidates are
quently, Paget’s disease can all produce degeneration of the hip healthy, thin patients over 65 years of age. The procedure involves
joint. Predisposing anatomic abnormalities that can later result in removing the femoral head by dislocating it from the acetabulum
osteoarthritic changes include developmental dysplasia of the hip and cutting through the femoral neck. Once the head is removed,
and slipped capital femoral epiphysis. If any preexisting conditions the cartilage from the acetabulum is removed and the bone is
can be identified, the hip arthritis is termed secondary osteoarthritis. reamed into a hemispherical shape to fit the acetabular component
When a preexisting anatomic abnormality or a specific disease of the hip prosthesis. Two types of acetabular components can be
process cannot be identified, the condition is termed primary used: cemented and uncemented. With a cemented component,
osteoarthritis.5 bone cement is used to anchor the acetabular component to the
The main complaint in a patient with osteoarthritic change is bone. With the uncemented component, the acetabular part is held
pain exacerbated by ambulation and relieved by rest. Eventually, as in place by the tightness of the fit and can be further reinforced by
the disease progresses, the pain will occur at rest and at night. As screws. Bone grows into the beaded surface of the component to
opposed to the lateral pain of trochanteric bursitis, osteoarthritis of anchor it down (Fig. 23–3). After the acetabular component is
the hip typically presents with groin pain. Decreased internal rota- inserted, the femoral canal is broached for the metal stem of the
tion, decreased flexion, and pain on rotation are also key physical femoral component. The femoral component can also be cemented
findings suggestive of hip osteoarthritis. Standing anteroposterior or uncemented. The cemented component requires a larger-
(AP) and frog-leg x-rays of the hip are indicated for hip joint diameter canal than the femoral stem; the cement is then used to
disease. A pelvic x-ray is often necessary as well, and it allows bond the metal stem to the surrounding bone. In the uncemented
for comparison of both hips, screens for sacroiliac disease, and component, the metal stem is held into place by the friction of
assesses leg length discrepancy. The decreased joint space seen the surrounding bone as the stem is driven into a canal slightly
between the femoral head and the acetabulum is most prevalent smaller than the stem itself. Current therapy favors uncemented
Meralgia Paresthetica
Meralgia paresthetica is a chronic neurologic disorder involving the
lateral femoral cutaneous nerve. This sensory nerve may be com-
pressed at any point along its course from the lumbosacral plexus to
its eventual target in the subcutaneous tissue of the thigh. The most
common site of compression is at the anterior superior iliac spine
owing to ill-fitting clothing or direct trauma. There is no indication
for advanced imaging or electrodiagnostic testing because this diag-
nosis can be made entirely on its characteristic presentation. The
patient will often complain of pain in the anterolateral thigh. On
examination, the sensory function of the upper thigh in the area of
the pain is impaired or lost. Otherwise, the lower extremity neuro-
logic examination is normal. In addition, the back, hip, and sacro-
iliac joints are normal. This disease is self-limited in most cases.
Eliminating the offending clothing or activity is the initial treat-
ment. Counseling the patient on weight loss and suggesting
abdominal toning exercises may also be helpful. If symptoms are
persistent for several months, an oral medication may be indicated.
Carbamazepine or phenytoin may be considered to reduce the dys-
esthetic pain. A local nerve block may also be considered.
Neurolysis may be considered as a last resort.
AVN
AVN is a pathologic process that is associated with many conditions
and orthopedic interventions. In the United States, approximately
15,000 new cases of AVN are reported annually.8 Hip osteonecrosis
Figure 23^3. Total hip arthroplasty. may be due to a vascular occlusion or an intravascular coagulation.
A hip that has been affected by AVN has decreased strength and is
susceptible to collapse. The etiology of AVN is largely unknown;
however trauma, corticosteroid use, and excessive alcohol use have
acetabular components because cemented components seem to fail been known to contribute to this disease. Patients affected by sickle
faster owing to torsional forces seen at the acetabulum.5,6 cell disease, hemoglobin S disease, or hemoglobin SC disease also
As with any surgical procedure, there is a risk of complications have a higher rate of AVN. A patient with AVN may complain of
due to the anesthesia, the surgical procedure itself, and a variety of groin pain or present with a limp. X-rays and MRI are the most
postsurgical risks. With total hip replacement, some of the most useful tests. In the early stages, x-ray may be completely normal
common complications include deep venous thrombosis (DVT), whereas an MRI may reveal decreased signal intensity on T1- and
infection, dislocation, and loosening. DVT can occur with any T2-weighted imaging in the region of the subchondral bone (Table
operation, but orthopedic procedures involving the long bones 23–1). Crutches and anti-inflammatory medications can be helpful
carry a higher risk. Preventive measures include encouraging activ- early in the course of the disease. However, treatment is difficult
ity as soon as possible, pressure stockings, and anticoagulation because this disease may progress quickly despite intervention.
medications. The probability of infection after a total hip replace- The treatment for AVN is largely surgical. In the early stages, hip
ment is less than 1%. Infections involving the incision are treated core decompression may be performed to help relieve increased
with antibiotics. The infections of concern are a result of bacteria pressure in the femoral head. Some groups have advocated the
invading the bone with the prosthesis. This risk is lessened by anti- use of a vascularized fibular bone graft as a method to both decom-
biotic use whenever bacteremia is a concern, such as during surgical press the femoral head as well as increase the blood flow to the
procedures on the bladder, colon, and dentition. There is a low
incidence of dislocation that is usually the result of noncompliance
with the postoperative restrictions. Muscle imbalance around the Table 23^1. Stages of Hip Avascular Necrosis
hip joint can also cause dislocation. The primary reason an artificial (Steinberg)
joint may fail is loosening of the bone-to-cement or bone-to-metal
attachment. Loosening of the implants will require a total hip revi-
Stage Findings
sion. Postoperatively, a patient is given many restrictions on posi-
tion to avoid dislocation. This is required because there are no 1 X-rays and CT scan normal
longer any ligamentous attachments to hold the components of Radionuclide scan positive and/or MRI positive
the artificial joint.6 2 X-ray abnormalities without collapse (sclerosis, cysts,
For younger patients who will likely place greater demands on a osteopenia)
total hip prosthesis, a hip fusion should be considered. During a hip 3 Crescent sign seen on x-ray (Fig. 23–4)
fusion procedure, the cartilage is denuded from both the acetabu-
lum and the proximal femur. The hip joint is then stabilized in 4 Flattening or evident collapse, may be initially seen on
neutral abduction, 08 to 308 of external rotation, and 208 to 258 CT scan
of flexion. Although a hip fusion eliminates the complication of 5 Same findings as stage 4 with narrowing of joint space
early total hip prosthesis failure, it is often associated with a greater on x-ray
than 50% incidence of low back pain and a significant nonunion 6 Same as stage 5 with destruction of the joint
rate. Gait analyses of patients who have undergone a hip fusion
reveal excessive motion in the lumbar spine.8 CT, computed tomography; MRI, magnetic resonance imaging.
180 Chapter 23 HIP PAIN
Figure 23^5. Hip labrum tear.

Figure 23^4. Crescent sign.
affected hip.6 The most successful surgical treatment of end-stage of the hip joint. The hip may also feel unstable or give way. MRI
AVN is total hip replacement. Once collapse occurs, decompressive may show the abnormality.
procedures are no longer effective.6 If inflammation is contributing to the pain, a short course of
anti-inflammatory medications or possible a cortisone injection
may be useful. Avoidance of extensive activity and even physical
Occult Hip Fracture therapy may be useful for stretching the muscles and tendons caus-
ing the snapping sensation. Surgery is rarely necessary and is con-
Osteoporotic hip fractures in elderly women are common. A history sidered only for patients who have chronic, severe symptoms even
of a fall followed by an inability to bear weight with a leg after an adequate trial of nonoperative treatments. In the case of a
length discrepancy and an externally rotated leg on the affected labral tear of the hip, the torn labrum may be addressed arthrosco-
side is diagnostic of a displaced fracture. A nondisplaced frac- pically (Fig. 23–5). Surgical release of the causative tendons is rarely
ture may also present as hip or groin pain and leave a patient indicated but may be considered if symptoms are truly recalcitrant
unable to bear weight. In cases in which a fracture is not seen on to conservative therapy.1,2
initial hip radiographs, a follow-up with repeat films, a bone scan,
or MRI may be necessary. Treatment is surgical stabilization of
the femoral head, typically with cannulated screws. Patients Paget’s Disease
should also be referred for medical management of their underlying
osteoporosis.1 Paget’s disease, osteitis deformans, is a disorder or abnormal bone
formation and turnover that may result in enlarged and deformed
bones. It is rarely diagnosed in people younger than 40 years of age.
Snapping Hip Both genders are affected equally. This disorder has many systemic
effects, but in terms of hip pain, the distorted bone may cause joint
Snapping hip refers to a condition characterized by a snapping surfaces to undergo excessive wear. Bone remodeling itself may lead
sensation, usually associated with pain when the hip is moved. to pain. Treatment of this disease with bisphosphonates may reduce
There are three primary causes for a snapping hip: iliotibial band intense bone pain. Joint replacement of the hips of a patient affected
snap, iliopsoas tendon snap, and hip labral tear. The iliotibial band by Paget’s disease may be considered if disability is severe and med-
is a thick tendon over the outside of the hip joint. The iliotibial ication is no longer helpful.1
band may snap over the greater trochanter during extension of the
hip and may ultimately cause trochanteric bursitis from the irrita-
tion of the bursa in this region. The iliopsoas is the primary flexor Malignancy
of the hip. The tendon of this muscle passes in front of the hip joint
and may snap over the pectineal eminence. The discomfort felt is Metastases in the pelvis or proximal femur can cause hip pain. The
produced from the tendon impinging anteriorly on the capsule of peritrochanteric region of the femur is a common site of bony
the hip. metastases. The proximal femur may also be a site for a primary
A hip labral tear is the least common cause of a snapping hip. bone malignancy. A history of a previous malignancy along with
The labrum of the hip is the fibrous cartilage that surrounds the hip pain should increase suspicion of bony metastasis to the hip.
bony rim of the acetabulum. The labrum deepens the socket, adding Treatment with local radiotherapy or bisphosphonates may slow
stability to the hip joint as well as cushioning the joint itself. Labral progression and improve pain symptoms. Surgery for metastasis
tears may be degenerative or traumatic. Traumatic injuries may to the hip is aimed at stabilization of impending fractures. In
occur with rapid hip motion, especially associated with sudden 1989, Mirels9 developed a scoring system to quantify the risk of
stops and turns. A labral tear may produce groin pain on rotation pathologic fracture (Table 23–2). This system uses four criteria
Table 23^2. Mirels Scoring System child has septic arthritis. The probability decreases as fewer criteria
are met: 93% for three of four, 40% for two of four, and 3% for one
Score of four.1,2
This diagnosis is best made by joint aspiration. Analysis of the
Variable 1 2 3 synovial fluid is the best method for definitive diagnosis of septic
Site Upper limb Lower limb Peritrochanteric arthritis. Several analyses can be performed on the fluid: appear-
ance, cell count with differential, Gram stain, and culture. A puru-
Pain Mild Moderate Severe lent or turbid (or both) appearance to the fluid suggests a septic
Lesion Blastic Mixed Lytic process. The joint fluid in nongonococcal septic arthritis generally
Size < 1/3 1/3 2/3 > 2/3 has greater than 50,000 WBC/mm3. In addition, the predominant
WBCs in infected fluid are neutrophils. A Gram stain of the syno-
vial fluid is a highly specific test for septic arthritis; however, it is
and allots 1, 2, or 3 points to each risk factor depending upon the not sensitive enough to rule out an infected joint. The Gram stain is
degree of risk (out of a total score of 12). The combination of these used to guide antibiotic therapy. Bacterial culture can also support
four features of bone lesions creates a more reliable risk assessment. the diagnosis and is positive in 70% to 90% of cases. Surgical joint
Displaced fractures of the femoral neck may require prosthetic drainage serves three purposes: removes bacteria from the joint,
replacement. Surgical treatment is often palliative with fixation reduces pressure in the joint, and allows for identification of the
methods directed toward returning patients to functional status as causative organism. Antibiotics are also used in the treatment; ini-
early as possible. Primary bone tumors are a rare cause of hip pain tially intravenous broad-spectrum antibiotics are used and then
and should be referred to an orthopedic oncologist.9 switched to oral once the organism is identified. However, antibio-
tics do carry a risk of side effects and allergic reactions. Appropriate
pain medications can be administered to reduce the acute pain:
Infection NSAIDs, codeine, or morphine are all acceptable depending upon
the patient’s allergies and level of pain. Once the infection is con-
Primary septic arthritis of the hip in adults is rare. However, it may trolled, movement is encouraged to preserve joint function and
present suddenly in immunocompromised patients. Classic clinical increase blood flow to facilitate the healing process.1,2
signs and symptoms include solitary joint pain, marked restriction
of both passive and active range of motion, inability to bear weight,
and temperature elevation (although this increase may not be pro- SUMMARY
nounced). It is important to differentiate the source of the pain
between articular and periarticular (skin, bursae, or tendons). The Hip pain is associated with a multitude of etiologies. Proper diag-
latter does not cause joint effusions, and passive range of motion nosis of hip pain requires an extensive history and physical exam-
generally does not elicit pain. Because septic arthritis can involve ination as well as radiographic imaging. The most common causes
more than one joint, all joints should be examined. Peripheral white of pain at the hip joint include trochanteric bursitis, arthritis, me-
blood cell (WBC) counts are elevated in most cases of septic arthri- ralgia paresthetica, AVN of the femoral head, occult fractures, infec-
tis. The erythrocyte sedimentation rate and C-reactive protein are tion, and malignancy.
generally elevated and can be useful in monitoring the disease pro-
cess. There can be an associated bacteremia in about 40% to 50% of
the patients with septic arthritis; therefore, blood cultures should be REFERENCES
obtained before the administration of antibiotics. Plain film find- 1. Anderson B. Hip. In Anderson B (ed): Office Orthopedics for
ings of acute septic arthritis are not diagnostically useful but are Primary Care: Diagnostics and Treatment, 3rd ed. Philadelphia:
obtained as a baseline and to rule out other pathologies. In septic Saunders Elsevier, 2006; pp 126–145.
arthritis, the findings mainly include joint effusion and soft tissue 2. Greene W, Griffin Y. Hip and thigh. In Greene W, Griffin Y (eds):
swelling. Periarticular osteoporosis, joint space narrowing, and Essentials of Musculoskeletal Care, 3rd ed. Rosemont, IL: American
bony ankylosis can also be seen on plain films. Computed tomog- Academy of Orthopaedic Surgeons, 2005; pp 292–338.
3. Thompson J. Netter’s Concise Atlas of Orthopaedic Anatomy.
raphy is more sensitive than plain films for the detection of early
Teterboro, NJ: Icon Learning Systems, 2002; pp 199–242.
bone destruction and effusion. Kocher and coworkers10 developed 4. Hoaglund FT, Criswell LA, Seldin MF. Gender and racial differences in
clinical criteria for the diagnosis of septic arthritis in a child with a rates of total hip replacement. J Bone Joint Surg Am 2003;85:569–570.
painful hip based on four criteria: history of fever, non–weight- 5. Hoaglund FT, Steinbach LS. Primary osteoarthritis of the hip: etiology
bearing, an erythrocyte sedimentation rate of 40 mm/hr or greater, and epidemiology. J Am Acad Orthop Surg 2001;9:320–327.
and a serum WBC count greater than 12,000/mm3 (Box 23–1). 6. Hochberg M, Altman R, Brandt K, et al. Guidelines for the medical
When all four criteria are met, there is a 99% chance that the management of osteoarthritis. Arthritis Rheum 1995;38:1535–1540.
7. Hoppenfeld S. Examination of the hip and pelvis. In Hoppenfeld S
(ed): Physical Examination of the Spine and Extremities. New York:
Prentice Hall, 1976; pp 143–170.
8. Lawrence RC, Hochberg MC, Kelsey JL, et al. Estimates of the
prevalence of selected arthritic and musculoskeletal diseases in the
Box 23^1 KOCHER CRITERIA (FOR A CHILD WITH United States. J Rheumatol 1989;16:427–441.
9. Mirels H. Metastatic disease in long bones: a proposed scoring system
PAINFUL HIP)
for diagnosing impending pathologic fractures. Clin Orthop
History of fever > 388C 1989;249:256–264.
Non ^weight-bearing 10. Kocher MS, Mandiga R, Murphy JM, et al. A clinical practice
Erythrocyte sedimentation rate 40 mm/hr guideline for treatment of septic arthritis in children: efficacy in
Peripheral white blood cell count > 12,000/mm3 improving process of care and effect on outcome of septic arthritis of
the hip. J Bone Joint Surg 2003;85:994–999.
182 Chapter 24 KNEE PAIN
Chapter 24 pain should be determined. Meniscus pain is often localized at the

joint line and may give a locking sensation to the knee.
KNEE PAIN The physical examination begins with observation of the
patient’s gait and resting position. If the patient sits with the knee
Michael A. Krieves, Rakesh Ramakrishnan, joint in extension, there may be an effusion. On inspection, the
alignment of the knee should be noted, with 88 to 128 of a valgus
William F. Lavelle, and Elizabeth Demers Lavelle
Q-angle considered normal. The Q-angle is defined as the angle
formed by a line drawn from the anterior superior iliac spine or
top of the hip to the central patella and a second line drawn from
the central patella to the tibial tubercle. Q-angles greater than 208
increase the likelihood of patellofemoral pain syndromes. The
patella should face anteriorly and both should be at the same
level bilaterally. A medially positioned patella is associated with
INTRODUCTION patellofemoral pain syndromes, as is atrophy of the vastus medialis
oblique. Therefore, these pain syndromes warrant careful inspection
In humans, the knee is the largest joint in the body, based on the of the quadriceps. The clinician should also inspect for an effusion,
surface area of the articular cartilage and volume of the joint space. marked by the loss of soft tissue dimples at the knee. An enlarge-
Owing to its complex nature, the knee joint has great susceptibility ment of the insertion of the patellar tendon in adolescents may
to injury, age-related degeneration, and arthritis. An extensive dif- indicate Osgood-Schlatter disease (Fig. 24–1). An inability to fully
ferential diagnosis of knee pain makes determination of the under- extend the knee indicates an intra-articular pathology such as
lying cause challenging. A careful history correlated with the meniscus tear, arthritis, loose body, or large effusion. Inability to
patient’s age and the anatomic site of the pain is important in walk in a squatting position, or a duck walk, may be due to a
achieving an accurate diagnosis. meniscal tear.
Palpation of the knee can demonstrate an effusion as well as
localize the pain symptoms. With a large effusion, a floating patella
ANATOMY can be felt. Palpation for tenderness can help define the pathology.
Pain on palpation of the superior pole of the patella is seen with
The knee is a hinge joint between the femur and the tibia consisting quadriceps tendinitis. Prepatellar bursitis presents with warmth,
of three compartments, medial tibiofemoral, lateral tibiofemoral, erythema, and swelling upon palpation of the anterior patella.
and patellofemoral. The three compartments share a common sy- Tenderness over the medial or lateral retinaculum or medial and
novial cavity. The patella is a sesamoid bone in the quadriceps lateral facets of the patella is seen with patellar subluxation and
tendon that acts as a pulley to increase the mechanical advantage patellofemoral pain syndrome. The patella should be checked for
of the quadriceps as it articulates with the trochlear groove of the intrinsic stability by gently pushing it medially and laterally.
femur. The head of the fibula is within the knee capsule but is not a Subluxation of more than 50% of the patella’s width is abnormal.
weight-bearing surface. The femoral condyles and tibial plateaus Tenderness on palpation of the joint line is indicative of a
form the weight-bearing surfaces. The meniscal cartilage provides meniscal injury. Palpation of the medial and lateral aspect of the
shock absorption in the space between the tibial plateaus and the knee may illicit pain in a damaged MCL or LCL. The pes anserine
femoral condyles. The collateral ligaments provide stabilization of complex should be palpated for tenderness from tendinitis or bur-
the joint. The anterior cruciate ligament (ACL) and the posterior sitis. The iliotibial band should be followed from the lateral thigh
cruciate ligament (PCL) stabilize the knee in flexion and extension. and knee to its insertion on the anterolateral aspect of the tibia. The
The medial collateral ligament (MCL) stabilizes the knee against a Ober test can demonstrate iliotibial band tightness. With the patient
valgus stress, and the lateral collateral ligament (LCL) stabilizes the in the lateral decubitus position with the painful knee up, the leg
knee against a varus stress. should be abducted as far as possible and then flexed at the knee
to 908. The symptomatic leg is then released into adduction. If the
iliotibial band is contracted, the thigh will remain in the abducted
APPROACH TO DIAGNOSIS position when the leg is released.
Palpation of the posterior aspect of the knee may demonstrate
A careful history is imperative for the accurate diagnosis of knee a popliteal, or Baker, cyst. The posterior tibial pulse should be
pain. The history should not be limited to the knee, because an palpated to rule out vascular damage in the event of multiplanar
evaluation of the hip and back may reveal patterns of referred instability.
pain. A review of systems should be performed, looking for systemic Stability testing should be performed in the mediolateral, ante-
illness such as Lyme disease, lupus, and rheumatoid arthritis, as well roposterior, and rotational planes. To test MCL stability, gentle
as a sexual history for gonococcal arthritis. The temporal nature of valgus force is applied to the joint line in full extension and at
the pain should be established. The pain may be either acute or 308 of flexion. If there is instability in full extension, the MCL is
chronic in nature. If acute, an injury should be suspected. Ligament likely torn. If there is instability at 308 of flexion, a partial injury to
tears often present with an acute hemarthrosis (collection of blood the MCL is more likely. Applying varus forces to the extended and
in the knee) and instability that inhibit continued activity. If the the 308 flexed knee will evaluate the stability of the LCL.
pain is chronic, the initial onset of symptoms and cause of the pain To assess the ACL and PCL, the anterior and posterior drawer
should be investigated. An increase in activity levels, such as exercise tests are performed. With the knee flexed 908 and the patient’s foot
or climbing stairs, can often lead to chronic patellofemoral pain. neutrally aligned on the table, the knee is grasped and the tibia is
The location of the pain as well as specific complaints such as pulled forward for the anterior drawer test and pushed posterior for
swelling, locking, giving out, instability, numbness, weakness, and the posterior drawer test. The amount of displacement as well as the
Quadriceps tendonitis
Prepatellar bursitis
Pain from a medial

meniscus tear
Patellar tendon
Osgood-Schlater
Figure 24^1. Knee pain on palpation.
character of the end-point are assessed. Lack of a clear end-point should bounce back. For a smaller effusion, the medial side of the
and increased displacement in comparison with the patient’s other patellar tendon can be milked; then the lateral retinaculum should
knee indicate damage to the ACL or PCL. In addition, the Lachman be tapped while palpating for a fluid wave on the medial side. The
test may be performed for assessment of the ACL. The Lachman test fluid should be examined for crystals from gout or pseudogout. A
is performed with the knee flexed to 208 and the examiner stabiliz- cell count and differential as well as routine and gonococcal cultures
ing the thigh above the patella with one hand while grasping the should be done.
proximal tibia in the other, pulling the tibia forward. Excessive For direct visualization of the intra-articular structures, arthros-
displacement and lack of a clear end-point are signs of an incom- copy can be done with the patient under local anesthesia.
petent ACL.
Rotational stability can be assessed by repeating the drawer tests
with the foot rotated internally or externally. This allows testing of
the secondary stabilizers of the knee as the lateral structures of the DIFFERENTIAL DIAGNOSES OF
knee are tightened with internal rotation and the medial structures COMMON INJURIES TOTHE KNEE
of the knee are tightened with external rotation of the foot.
The provocation test for meniscus injury is the McMurray test.
The McMurray test is performed with the knee in full flexion, and Children and Adolescents
internal and external rotational forces are applied. The knee is then
Patellar Subluxation
fully extended. A positive test is indicated by joint line pain or
palpable click. Patellar subluxation is the most likely diagnosis in an adolescent girl
Radiographic evaluation of the knee is almost always required to who presents with a knee that is ‘‘giving out.’’ Owing to the
evaluate complaints of knee pain. A standing anteroposterior view increased Q-angle in women, this is a common injury in girls and
of bilateral knees with a lateral view of the affected knee will elucidate young women. A mild effusion is usually present and subluxation of
most pathologies, including fractures, loose bodies, arthritis, osteo- the patella laterally elicits patellar apprehension. Extensive swelling
chondritis dessicans, and chondrocalcinosis. When an ACL injury is may indicate hemarthrosis from a patellar dislocation with osteo-
suspected, a tunnel view may be useful to show small bone chips chondral fracture and bleeding. Tenderness may be elicited along
from the tibial spine. Sunrise views of the patella are helpful in the the medial retinaculum and medial facet of the patella. Sunrise view
evaluation of patellofemoral tracking and subluxation. radiographs assist in the evaluation of patellar subluxation.
Evaluation of intra-articular soft tissue injuries, such as menis- Treatment initially is ice, compression, elevation of the knee
cus injuries or ACL and PCL injuries, can be visualized with mag- splinted in full extension, and nonsteroidal anti-inflammatory
netic resonance imaging (MRI). An MRI or a bone scan can drugs (NSAIDs) for pain. Rehabilitation should be done to
confirm epiphyseal injuries, avascular necrosis lesions, stress frac- strengthen the quadriceps, especially the vastus medialis. A neo-
tures, and early osteochondritis. An arteriogram should be done in prene patellar stabilization brace may be beneficial during sporting
an acutely injured knee with multiplanar instability to access the activities. If functional impairment remains after adequate rehabi-
competency of the vasculature. litation, surgical intervention may be considered.
Knees with effusions should be aspirated and synovial fluid ana-
lyzed. Aspiration with an 18-gauge needle through the medial or
PatellarTendinitis (Jumper’s Knee)
lateral patellar retinaculum is easily performed. With the knee
extended, the patella should be pressed into the trochlear groove Patellar tendinitis commonly occurs in teenage boys, especially
and gently tapped. When a large effusion is present, the patella during their period of maximal growth velocity. It can also occur
in any patient who repeatedly performs jumping activities, such as moving the patella back and forth across the femoral groove with
basketball players. The most common presentation is persistent the leg in an extended position. X-rays including a sunrise, standing
anterior knee pain that increases after walking down stairs, running, posterolateral, lateral, and tunnel views are useful to assess patello-
or jumping. femoral alignment. A bone scan or MRI can be used to evaluate the
The patellar tendon is tender upon palpation, and pain is elicited degree of osteochondral injury.
with resisted knee extension. Chronic inflammation can increase the The treatment goals for patellofemoral pain syndrome include
risk of tendon rupture at its insertion to the patella. improvement of patellofemoral tracking, decreasing the patient’s
If diagnosed within the first 3 weeks, rest, ice, and NSAIDs for pain, and reducing the risk for the development of arthritis.
pain are the recommended therapeutic interventions. If the condi- Initial treatment involves icing and elevating the knee while avoid-
tion is chronic, complete restriction of activity with possible casting ing aggravating factors, such as squatting and kneeling. Straight leg
may be necessary. Rehabilitation with strengthening of the quadri- raising with the leg externally rotated to improve the strength of the
ceps is important. NSAIDs, ice after activity, and bracing may help vastus medialis is recommended. Treatment with NSAIDs typically
control the symptoms, allowing for earlier return to activity. In last 3 to 4 weeks, after which the medication should be tapered.
refractory cases, surgical débridement may be indicated. For cases that persist beyond 3 to 4 months, a local corticoster-
oid injection with 1 to 2 ml of anesthetic and 1 ml of triamcinolone
acetonide (Kenalog, K40) may be useful. The techniques and a
Tibial Apophysitis (Osgood-Schlatter Disease)
review of intra-articular injections are provided in Section XIII,
The most likely diagnosis for anterior knee pain localized to the Chapter 81. The injection can be repeated at 4 to 6 weeks if symp-
tibial tuberosity in teenage boys is tibial apophysis, or Osgood- toms have not decreased by 50%. If symptoms persist despite a
Schlatter disease. The patient is usually active and has recently expe- strong quadriceps for over 6 months, surgical intervention, such
rienced a period of maximal velocity growth. The pain often waxes as a lateral retinacular release, tibial tubercle transposition, or
and wanes for months, increasing with squatting, walking down arthroscopic débridement, should be considered. Patellofemoral
stairs, or forceful contraction of the quadriceps. The tibial tuberos- pain syndrome can be particularly difficult to treat.
ity is often swollen and tender and may be warm. No effusion is
present, and the knee pain is reproducible with resisted extension or
QuadricepsTendinitis
passive hyperflexion of the knee.
Treatment is symptomatic for pain. For moderate pain, restric- Quadriceps tendinitis presents with pain superior to the patella. It is
tion of physical activity decreases symptoms. In the presence of an the result of repetitive quick acceleration or quick deceleration
acute episode or evidence of a ‘‘flake fracture,’’ the knee may be movements causing microtrauma to the tendon.
immobilized in a cast for 4 to 6 weeks. A Chopart strap may be used Treatment is rest, ice, restoration of flexibility, and quadriceps
to unload the tendon insertion. Knee padding may prevent contu- strengthening with straight leg raises daily. A patellar-stabilizing
sions to the tibial tubercle. brace may be useful during rehabilitation, and NSAIDs can be
used for pain control.
Osteochondritis Dissecans
Medial Plica Syndrome
Osteochondritis dissecans is an intra-articular osteochondrosis that
is believed to be an avascular necrosis of the subchondral plate. It is Medial plica syndrome is a frequently overlooked cause of medial
characterized by degeneration and recalcification of articular carti- knee pain. The plica, a redundancy in the synovium, can become
lage and the underlying bone. It is common in the medial femoral inflamed with repetitive overuse. The patient usually presents with
condyle in the knee. Morning stiffness, recurrent effusion, and acute knee pain after an increase in activity.
poorly localized pain are common patient complaints. Locking A tender, mobile nodularity may be present at the medial aspect
and catching of the knee may be present if there is a loose body. of the knee just anterior to the joint line on physical examination.
Tenderness along the involved chondral surface and atrophy of There is no effusion, and the remainder of the examination is
the quadriceps may be present. Recommended radiographs are normal.
anteroposterior, lateral, tunnel, and sunrise (merchant) view. Treatment is NSAIDs for pain control, activity modification,
Radiographs may demonstrate osteochondral lesions or loose and strengthening of quadriceps with straight leg raises. A cortisone
bodies. MRI is very sensitive in detecting these abnormalities. injection may be indicated to decrease the inflammation if conser-
Treatment is conservative with protective weight-bearing if the vative therapy is unsuccessful. If the pain is refractory to treatment,
physis are open. With a closed physis, the prognosis for healing is an arthroscopic débridement may be necessary.
poor. If the fragment is detached, débridement and possible replace-
ment of the osteochondral lesion are preferred. If acute reattach-
Pes Anserine Bursitis
ment is not possible, chondral resurfacing with autologous
osteochondral grafts can be done. Pes anserine bursitis is another cause of medial knee pain. It is an
inflammation of the bursa located between the attachment of the
MCL at the medial tibial plateau and the conjoined tendon of the
Overuse in Adults gracilis, sartorius, and semitendinosus. It is most commonly caused
by an abnormal gait leading to an increase in tension at the inser-
Patellofemoral Pain Syndrome (Chondromalacia Patellae) tion of the pes anserinus tendons; but it can also happen as the
result of trauma. The patient presents with pain localized to a well-
Patients with patellofemoral pain syndrome usually complain of defined area on the anteromedial aspect of the knee (Fig. 24–2).
moderate anterior knee pain that increases after long periods of On physical examination, there is local tenderness medial to the
sitting, commonly referred to as the ‘‘theater sign.’’ Patellofemoral tibial tubercle, and valgus stress testing of the MCL does not cause
pain syndrome results from direct trauma, chronic overuse, or more pain. Radiographs are unnecessary for diagnosis, but they may be
commonly, repetitive irritation from patellofemoral misalignment. helpful in identifying associated osteoarthritis.
It is more common in women owing to an increased Q-angle. Treatment is directed at any underlying gait disturbance. Ice,
On physical examination, a palm is placed over the patella as the restrictions on squatting and repetitive bending, and avoiding
knee is passively flexed and extended to demonstrate a patellar click. direct pressure are recommended. NSAIDs may be prescribed for
In addition, retropatellar crepitation may be detected by passively pain and to decrease inflammation; however, oral medications may
* Figure 24^3. Prepatellar bursitis.
Figure 24^2. Pes anserine bursitis. cases lasting over 4 to 6 weeks, reaspiration and injection can be
done if the symptoms have not decreased by 50%. The remaining
5% to 10% of patients progress to chronic bursitis and may require
not concentrate sufficiently in this structure. If there has not been a bursectomy.
sufficient improvement in 6 to 8 weeks, an injection of 1 to 2 ml of
anesthetic and 0.5 ml of methylprednisolone acetate (Depo-Medrol,
Iliotibial Band Tendinitis
D80) is indicated. Surgical treatment with bursectomy is rarely
required for refractory cases. Excessive friction between the lateral femoral condyle and the ilio-
tibial band can lead to iliotibial band tendinitis that presents as
lateral knee pain. It is an overuse syndrome commonly seen in
Prepatellar Bursitis
runners and cyclists as a result of inadequate stretching.
Patients with prepatellar bursitis typically present with complaints Inadequate stretching results in a tight iliotibial band that rubs
of knee swelling and anterior knee pain. Prepatellar bursitis is an over the posterolateral corner of the knee causing inflammation
inflammation of the bursa between the patella and the overlying and pain. In addition to a tight iliotibial band, excessive foot pro-
skin. It is commonly caused by trauma or direct pressure from nation, genu varum, and tibial torsion are predisposing factors.
repetitive kneeling (‘‘housemaid’s knee,’’ ‘‘bricklayer’s knee’’). The On physical examination, tenderness is present at the lateral
bursa can become infected or inflamed by urate crystals. epicondyle of the femur. There is no effusion, but soft tissue swell-
On physical examination, there is swelling and inflammation ing and crepitus may be present. A positive Ober test confirms the
superficial to the patella (Fig. 24–3). The range of motion of the diagnosis. An Ober test is performed with the patient in the lateral
knee should be normal unless there is an underlying articular con- decubitus position with the painful knee up. The leg is maximally
dition. Radiographs are not necessary for the diagnosis. Aspiration abducted and then flexed to 908. The symptomatic leg is released
and fluid analysis of the bursa should be done to rule out infection into adduction. If the iliotibial band is contracted, the thigh will
or crystal-induced arthropathy. remain in the abducted position when the leg is released. Noble’s test
Treatment includes aspiration and drainage combined with pro- is used to reproduce the pain in iliotibial band tendinitis. The
tection of the bursa for acute cases. A compression dressing for 24 examiner places a thumb over the lateral femoral epicondyle as
to 36 hours after aspiration should be used to encourage the walls of the patient repeatedly flexes and extends the knee. Pain is most
the bursa to reapproximate. Ice and NSAIDs can be used to control commonly reproduced at 308 of flexion.
the pain and decrease inflammation. The patient should avoid
direct pressure on the bursa and avoid squatting or flexing the
knee more than 908. If fluid analysis shows infection, empirical Trauma in Adults
antibiotics that cover Staphylococcus aureus should be prescribed
while waiting for culture results. When fluid culture results are ACL
available, antibiotic therapy should be directed toward the specific
pathogen. If urate crystals are present, gout treatment should be Injury to the ACL is usually due to noncontact deceleration forces,
initiated. such as sharply changing direction on a planted foot. Stress on the
Approximately 50% to 60% of traumatic bursitis resolves spon- knee from the deceleration force leads to anterior displacement of
taneously with aspiration and protective padding. Thirty percent to the tibia and sprain or rupture of the ligament. Patients usually
40% of patients require corticosteroid injections to control swelling report feeling or hearing a ‘‘pop’’ at the time of injury and are
and pain. If the diagnosis of infection and gout has been eliminated unable to continue activity. Swelling within 2 hours after the
by fluid analysis, reaspiration and local corticosteroid injection with injury indicates hemarthrosis from rupture of the ligament.
1 to 2 ml of anesthetic and 1 ml of triamcinolone acetonide Damage to the MCL and medial meniscus commonly accompanies
(Kenalog, K40) can be used to treat the bursitis. For persistent ACL injury and should be thoroughly evaluated.
the PCL. In addition, arthroscopy can be done to directly view

damage, in efforts to obtain a definitive diagnosis.
Treatment for mild sprains is NSAIDs and avoidance of weight-
bearing on the joint. For less severe PCL tears, rehabilitation with
strengthening exercises as well as knee bracing can allow return to
activity after the initial pain and swelling have been controlled.
Surgical treatment is recommended if supporting structures in
addition to the PCL are also damaged. As with ACL replacement,
a piece of tendon or ligament is used to replace the torn PCL.
MCL
Injury to the MCL is commonly caused by acute trauma. There is
history of a trauma that places valgus stress on the knee. Usually, an
immediate onset of pain and swelling occur at the medial aspect of
the knee. The patient complains of medial knee pain and difficulty
pivoting, twisting, and walking.
There is point tenderness on the medial aspect of the knee on
physical examination. Valgus stress testing should be performed
with the leg extended and at 308 of flexion. The MCL is likely
torn if there is instability in full extension. If there is instability at
only 308 of flexion, a partial injury to the MCL is more likely. In
addition, medial knee pain may be reproduced by externally rotat-
ing the tibia on the femur with the knee flexed at 908. Effusion may
be present, as well as damage to the medial meniscus and ACL.
Radiographs are not necessary for diagnosis, but calcification of
the ligament can occur months to years after the initial injury
and is visible on radiographs. An MRI is indicated if there is sus-
picion of damage to other structures.
Figure 24^4. Magnetic resonance imaging (MRI) of an
Treatment for MCL sprains is immobilization with straight leg
anterior cruciate ligament (ACL) tear.
brace, non–weight-bearing, ice, and NSAIDs for inflammation and
pain. Strengthening exercises for the quadriceps, such as straight leg
raises, are recommended as soon as the acute pain subsides. Use of a
hinged knee brace offers support to the injured MCL. Sprains that
On physical examination, joint effusion will limit the range of are persistent at 6 to 8 weeks can be treated with local injection of
motion. Both the anterior drawer test and Lachman’s test may be 1 to 2 ml of anesthetic and 1 ml of methylprednisolone acetate.
positive, but they can be negative owing to hemarthrosis and guard- Treatment for third-degree separations with completely disrupted
ing by the hamstring muscles. Radiographs are useful to detect a ligaments and gross instability is surgical and usually accompanied
tibial spine avulsion fracture on tunnel view. An MRI of the knee by surgical correction of damage to additional structures such as the
will show the extent of intra-articular soft tissue damage (Fig. 24–4). ACL and medial meniscus.
Treatment of mild ACL sprain is relief of pain with NSAIDs, ice,
and restriction of activities. Moderate sprains should be treated with
LCL
complete resting of the knee without weight-bearing, leg elevation,
and ice for the first 48 to 72 hours after the injuries. The joint Injury to the LCL is much less common than injury to the MCL.
should be aspirated if there is a moderate effusion. Strengthening Injury to the LCL usually results from varus stress to the knee
of the quadriceps and hamstrings will help increase stability of the causing an acute onset of lateral knee pain that requires cessation
knee joint. Knee braces can be used to provide support for a of activity. Damage to the LCL is associated with damage to other
damaged ACL. Treatment of severe ligamentous tears and resulting ligaments and peroneal nerve injuries.
instability can be managed by prolonged conservative treatment. If Physical examination demonstrates point tenderness at the lat-
reestablishment of stability is desired, surgical treatment may be eral joint line and instability or pain with varus stress testing with
necessary. Surgical reconstruction of the ACL with a piece of the knee flexed at 308. Radiographs are not necessary for diagnosis
tendon or ligament can be done arthroscopically. Grafts are com- but may be ordered to rule out other causes of symptoms.
monly taken from the patellar tendon or the semitendinosis muscle Treatment for isolated LCL injuries is primarily nonoperative
of the hamstrings, or an allograft is used. and can be treated in a fashion similar to that for MCL sprains,
discussed previously. For third-degree separations, which are usu-
ally a combination injury, surgical treatment is indicated. Surgical
PCL
repair of the LCL can be done by suturing the damaged ligament
Injuries to the PCL are less common than injuries to other liga- ends together or reattaching the ligament to the bone. Surgical
ments of the knee. Injury from a direct blow to the front of the knee reconstruction with a tendon or ligament graft may be necessary
while the knee is bent is the most common mechanism for injury of to replace a damaged ligament.
the PCL. If the tibia moves too far backward in relationship to the
femur, the PCL can rupture. The PCL as well as other structures can
MeniscusTear
also be damaged from violent hyperextension. Patients may com-
plain of instability and giving out of the knee as well as stiffness and Injury of the meniscus can occur acutely with a sudden twisting
some swelling. injury on a partially flexed knee. It is a common sports injury, but it
Swelling and tenderness are present on physical examination. can also happen during simple activities that cause rotation of the
The posterior drawer test may be positive with damage to the knee. Meniscal tears can also be due to a prolonged degenerative
PCL. An MRI is the most accurate test to visualize damage to process, especially in a patient with an ACL-deficient knee.
Treatment for septic arthritis is aspiration of joint fluid and

hospitalization for parenteral antibiotic therapy. Antibiotics are
directed at the causative organism. Treatment is continued for
1 to 2 weeks after resolution of symptoms, 3 to 4 weeks for
gram-negative organisms, or 6 to 8 weeks if the joint was previously
diseased. If a joint prosthesis is present, the infection is difficult to
eradicate without removal of the prosthesis. If antibiotics fail,
arthrotomy is indicated.
Crystal-induced Inflammatory Arthropathy

Gout or pseudogout should be suspected in patients who present
with acute inflammation, pain, and swelling in the absence of
trauma. In pseudogout, calcium pyrophosphate crystals precipitate
in the knee causing an intense inflammatory response. More
common in the first metatarsophalangeal joint than in the knee,
gout is caused by deposition of sodium urate crystals.
The knee is erythematous, warm, swollen, and tender on phys-
ical examination. The joint is painful with even minimal motion.
Aspirated fluid shows a white blood cell count of 2000 to 75,000/
mm3, protein content greater than 32 g/dl, and a glucose concen-
tration approximately 75% of the serum glucose concentration.
Polarized light microscopy of synovial fluid will show positively
birefringent rhomboids in patients with pseudogout and negatively
birefringent rods in patients with gout.
Treatment for pseudogout is rest and elevation of the affected
Figure 24^5. Meniscus tear on MRI. joint as well as straight leg raises to maintain quadriceps strength.
NSAIDs at anti-inflammatory doses are the medication of choice
The patient complains of loss of smooth motion, giving out of the for an acute attack.
knee, or less commonly, locking. Symptoms are usually more prev- Treatment for gout is an NSAID at full dose for 2 to 5 days
alent with squatting or twisting of the knee. followed by a taper. Patients should be tested for uric acid excretion
Mild effusion is usually present on physical examination, as well to establish whether they are hypoexcreting uric acid or whether
as tenderness at the medial or lateral joint line. The McMurray test there is excess uric acid production. For patients who have
may be positive, but a negative test does not rule out a tear. The decreased uric acid excretion, probenacid (Benadryl) at 500 mg/
knee is internally and externally rotated at full flexion and then day can be started for chronic prevention and increased by
extended to elicit joint line pain or a palpable click. Routine radio- 500 mg at monthly intervals until the uric acid level is within the
graphs may be ordered to rule out other causes of symptoms or normal range (<2 mg/dl). For excessive uric acid production, allo-
loose body, but they are not diagnostic for meniscal injury. An MRI purinol (Aloprim, Zyloprim) 100 mg/day can be initiated and
will demonstrate most significant meniscal tears (Fig. 24–5). increased by 100 mg weekly to a maximum of 600 mg/day for
Initial treatment is the control of inflammation with ice, chronic prevention. For definite severe acute gout that is not
NSAIDs, and rest with the knee immobilized in a comfortable responding to NSAIDs, treatment with steroids and/or intravenous
position. As pain subsides, straight leg raises should be done to colchicines may be beneficial.
strengthen the quadriceps. If effusions are present, aspiration is
indicated for pain relief. Arthroscopic repair or resection is the
preferred treatment for symptomatic patients. Repair of the menis- Older Adults
cus is preferred over resection to preserve as much meniscus as
possible, decreasing the probability of developing arthritis. The Osteoarthritis
severity of the tear and the patient’s age and general health are
considered when determining whether repair or removal of the Osteoarthritis of the knee is a common complaint in advanced-aged
meniscus is the appropriate treatment. patients. The patient typically complains of morning stiffness that
decreases with activity and knee pain that is aggravated with activity
and relieved with rest. The patient has no systemic complaints.
Septic Arthritis
Osteoarthritis is due to ‘‘wear and tear’’ with mild inflammation
Infection of the knee joint may occur at any age but it is more of the knee joint. There is asymmetrical wear of the articular carti-
common in those patients with weakened immune systems. The lage, osteophyte formation, subchondral sclerosis, and cyst forma-
patient presents with an abrupt onset of pain and swelling without tion. Patients are predisposed to osteoarthritis from family history,
a history of trauma. obesity, genu valgum and genu varum, meniscal injury, and previ-
On physical examination, the joint is tender, swollen, and warm. ous trauma to the knee joint. Radiographs show narrowing of the
Motion of the knee is exquisitely painful. Aspiration of fluid and articular cartilage between the femur and the tibia (Fig. 24–6).
fluid analysis will show a white blood cell count greater than 50,000/ Osteoarthritis is most common in the medial compartment because
mm3, with more than 75% neutrophils, a low glucose concentration it is the main weight-bearing compartment of the knee joint.
(<50% of serum glucose concentration), and an elevated protein Tenderness at the joint line, especially on the medial side, is
above 3 g/dl. Common pathogens are S. aureus, Streptococcus spe- found on physical examination. There is a loss of smooth motion
cies, Haemophilus influenzae, and Neisseria gonorrhoeae. Gram stain (crepitation) with passive or active motion of the knee. There is a
and culture of fluid are imperative to appropriate antibiotic treat- decrease in range of motion, palpable osteophytes, and commonly,
ment. Hematologic laboratory tests show elevated white blood cells, knee effusion. Standing posteroanterior, lateral, sunrise, and tunnel
a left shift (increased band cells), and an elevated erythrocyte sed- view radiographs are recommended. The distance between the
imentation rate. medial tibial plateau and the medial femoral condyle is normally
aspect of the knee, loss of motion, and a sensation of fullness in the

popliteal fossa.
On physical examination, a palpable mass may be felt at the
medial aspect of the popliteal space. Definitive diagnosis can be
made with ultrasonography, arthrography, computed tomography,
or MRI. Aneurysm in the popliteal space must be ruled out in older
patients.
Treatment is directed at the underlying source of the knee effu-
sion, which will usually resolve the popliteal cyst. For a cyst that
does not resolve or is causing venous obstruction, surgical excision
is necessary.
Spontaneous Osteonecrosis
Osteonecrosis is an acute vascular insufficiency of the femoral con-
dyle or tibial plateau that causes a spontaneous onset of pain. It is
most common in patients in their 5th to 8th decade. The most
common sites are the femoral condyle or tibial plateau in the
medial compartment.
On physical examination, there is usually an effusion and a
Figure 24^6. Knee arthritis. decrease in range of motion as well as point tenderness over the
involved area of the joint. Radiographs are often normal at onset of
symptoms, but increased activity can be detected by technetium
bone scan. MRI can also be used to diagnose acute osteonecrosis.
6 to 8 mm and is gradually narrowed in osteoarthritis. If there is Treatment is symptomatic with rest, ice, NSAIDs, and protected
significant mechanical impairment, an MRI is indicated to evaluate weight-bearing with support. Pain relief has been reported with core
for a degenerative meniscus tear or intra-articular loose body. decompression. Surgical reconstruction is indicated if arthritis
Treatment is aimed at relieving pain, decreasing effusion, and develops. Patients with involvement of more than 50% of weight-
preserving function. Ice and elevation, restrictions on bending and bearing surface in the involved compartment often require knee
impact, and straight leg raises to strengthen the quadriceps are the replacement surgery.
treatment for mild disease. Pharmacologic treatment with 1500 mg
glucosamine sulfate daily may be started as well as NSAIDs at
full dose for 3 weeks, with possible tapering in the 4th week. If CONCLUSION
significant symptoms persist after a 3- to 4-week NSAID trial, dis-
continue the initial NSAID, and consider a course of a second, The extensive differential diagnosis of knee pain makes a thorough
different NSAID, adding a different analgesic, or local corticosteroid history and physical examination imperative to determine the cor-
injection. Measures can be taken in efforts to alleviate pressure from rect diagnosis. For many causes of knee pain, conservative therapy
the medial compartment of the joint, such as heel wedges or a with rest, ice, NSAIDs, and rehabilitation with quadriceps-strength-
knee-unloading brace. Measures to decrease joint impact, including ening exercises is adequate. For other causes of knee pain, correc-
shock-absorbing insoles, may also be effective. Patients are consid- tion of the underlying pathology through the use of physical
ered for surgical treatment if pain is intractable, function is severely therapy, braces, or surgical correction can often offer patients
compromised, 80% to 90% of the articular cartilage is worn away, relief. Many injuries can be prevented by strengthening the support-
or progressive angulation of the lower extremity has occurred. ive musculature of the knee joint, especially the quadriceps.
Patients with severe osteoarthritis who have medical contraindica-
tions for surgery can be treated with a restraining brace, a walker, or SUGGESTED READINGS
a wheelchair.
Surgical treatment is varied for osteoarthritis. Arthroscopy can Anderson B. Knee. In Anderson B (ed): Office Orthopedics for Primary
be used to irrigate the joint with saline solution and remove loose Care: Treatment, 3rd ed. Philadelphia: Saunders Elsevier, 2006;
pieces of cartilage as well as using a burring tool to roughen badly pp 146–177.
worn cartilage in efforts to encourage fibrocartilaginous growth. Metcalf MH, Larson RV. Painful disorders of the thigh and knee. In
Loeser J (ed): Bonica’s Management of Pain, 3rd ed. Philadelphia:
Another surgical option is a proximal tibial osteotomy to realign Lippincott Williams & Wilkins, 2001; pp 1603–1613.
the angles of the lower leg, which takes pressure off the damaged Calmbach W, Hutchens M. Evaluation of patients presenting with knee
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patients over 60 years of age, because younger, more active patients syndrome in runners. Clin J Sports Med 2006;16:261–268.
may put excessive stresses on the prosthesis. Hochberg M, Altman R, Brandt K, et al. Guidelines for the medical
management of osteoarthritis. Arthritis Rheum 1995;38:1541–1546.
McMahon P, Kaplan L. Sports medicine. In Skinner H (ed): Current
Popliteal Cyst (Baker’s Cyst) Orthopedics. New York: McGraw-Hill, 2006. Available at
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terior fossa due to increased synovial pressure secondary to recur- Musculoskeletal Primary Care. Philadelphia: Lippincott Williams &
rent effusions. The increased pressure causes a distention of the Wilkins, 1999; pp 217–249.
medial aspect of the posterior capsule and subsequent cyst forma- Thompson J. Netter’s Concise Atlas of Orthopaedic Anatomy.
tion. The patient reports mild to moderate pain in the posterior Teterboro, NJ: Icon Learning Systems, 2002; pp 199–242.
Chapter 25 is a common and effective remedy. A rigid, flat-bottom shoe is an

additional technique.Whereas union of fracture segments typically
FOOT PAIN occurs in 3 to 8 weeks, tissue injury and trauma may be a source of
chronic pain. Treatment should focus on desensitization therapy.
William F. Lavelle, Joseph M. Bellapianta, and Nonunions are a rare but persistent source of chronic pain that may
Elizabeth Demers Lavelle require orthopedic referral for surgical procedures to supplement
the fracture’s rigidity and biologic potential for healing.
Metatarsal Fractures
Minimally displaced or nondisplaced fractures are again best treated
conservatively. A firm, flat-bottom shoe suffices for most fractures.
INTRODUCTION Typical healing times are 6 to 8 weeks, but pain should persist for
greater than 3 months before a nonunion is suspected. Fractures of
Foot pain is a common cause of pain and disability. Causes of foot the first metatarsal are rare; however, fractures of the second, third,
pain include fractures, ligamentous injuries, tendon injuries, nerve or fourth metatarsal are very common.
entrapment, and plantar fasciitis. All of these pain sources require March fractures are the first stress fractures discussed in this
skill in diagnosis and treatment. Owing to the large differential review. A march fracture is a fracture of the second and/or third
diagnosis of localized musculoskeletal pain, an organized approach metatarsal that was named for the soldiers in whom this type of
and skillful evaluation, combined with comprehensive knowledge of fracture was initially described. Today, these injuries are more
the possible causes of musculoskeletal pain, aid in the diagnosis and common in joggers and are believed to be due to repetitive trauma.
treatment of foot pain. As with all stress fractures, x-rays are often negative. The diagnosis is
principally clinical, but it may be reinforced with a bone scan to
confirm the diagnosis. The ideal treatment is cessation of the offend-
TRAUMATIC INJURY ing activity for 6 weeks, with a gradual return to preinjury activity.
Fractures of the fifth metatarsal deserve a special discussion.
Any discussion about pain in the foot to the ankle would have to There are three types of proximal fifth metatarsal fractures that
begin with a discussion of foot trauma. Ten percent of all fractures are divided into three zones of the metatarsal. As illustrated in
in the body occur in the foot alone. Ankle fractures are even more Figure 25–1, zone I injuries involve an avulsion that occurs at the
common. However, fractures are not the only trauma seen at the attachment of the peroneus brevis tendon. This type of fracture
foot and ankle. Only 15% of patients who present to an emergency heals well with the patient left weight-bearing as tolerated.
room will leave diagnosed with a fracture. The rest will have suf- The Jones fracture occurs at zone II and represents a fracture of
fered sprains or other soft tissue injuries the metaphyseal and diaphyseal junction. This injury often is the
result of an acute adduction of the forefoot. Management consists
of casting, but surgical treatment has been advocated for the athlete
Fracture Evaluation owing to the prolonged healing time for this fracture.
Zone III injuries occur at the proximal diaphysis. This type of
As is often quoted in medical texts, good diagnosis begins with a good injury also occurs in the athlete, but represents our second stress
history. Patients with a traumatic foot injury will provide valuable fracture to be discussed in this chapter. Patients with this fracture
information as to how that injury was sustained. Certain fracture often (35%–50%) develop persistent nonunions requiring bone
types and ligamentous injuries are the result of specific mechanisms. grafting and internal fixation. Initial therapy may include immobi-
A careful physical examination is the next logical step. lization without weight bearing.
Ecchymoses or deformities are strong indicators of traumatic
injury. The range of motion of all the joints should be observed,
after which all the bones of the foot and up into the ankle should be Sesamoid Fractures
palpated. As a general rule, any area of point tenderness, ecchymo-
sis, or deformity should be imaged with an x-ray. The sesamoids of the foot are located under the metatarsal heads.
The Ottawa foot and ankle rules1 (Box 25–1) were developed by The most commonly discussed sesamoid is that under the first
a team of physicians at the department of emergency medicine in metatarsal. Sesamoid fractures may result from overuse, excessive
Ottawa, Canada, as an aid in determining whether a patient will pressure on the plantar foot, or an acute traumatic injury.
require an x-ray of a foot or ankle injury. Symptoms include pain, which may be either severe and throbbing
A complete review of all foot and ankle fractures would fill an or intermittent and dull. Treatment includes rest, nonsteroidal anti-
entire textbook. This review discusses common injuries and those inflammatory drugs (NSAIDs), casting, steroid injection, or exci-
that are often missed by clinicians. sion. All of these methods have been successful, with each having its
advocates in the literature.
Phalanx Fractures
Lisfranc’s Injury
Phalanx fractures typically occur after an object has been dropped
on the toes. These fractures often heal well with benign neglect. The Lisfranc joint, the tarsometatarsal articulation of the foot,
Buddy taping of a fractured phalanx to an adjacent, uninjured toe is named for Jacques Lisfranc, a surgeon in Napoleon’s army.
190 Chapter 25 FOOT PAIN
Undiagnosed lateral process fractures of the talus may be a source

Box 25^1 THE OTTAWA FOOT AND ANKLE RULES of chronic lateral foot pain. Treatment should include immobiliza-
tion with strict avoidance of weight-bearing. Calcaneus fractures are
X-rays are required only if there is any pain in the malleolar or midfoot associated with a fall from a height with patients landing on their
area and any one of the following: heels. These fractures are often associated with lumbar compression
Bone tenderness along the distal 6 cm of the posterior edge of the tibia fractures. A high index of suspicion must be maintained. Calcaneus
or tip of the medial malleolus. fractures are almost always associated with chronic pain. Operative
Bone tenderness along the distal 6 cm of the posterior edge of the interventions are indicated for severe joint incongruity and a
fibula or tip of the lateral malleolus. widened heel. Surgery may have a significantly high rate of compli-
Bone tenderness at the base of the fifth metatarsal (for foot injuries). cation, especially for smokers and diabetics. The most common
Bone tenderness at the navicular bone (for foot injuries).
An inability to bear weight, both immediately and in the emergency complications are infections and wound related issues. The risks
department, for four steps. and benefits of surgery must be seriously considered prior to under-
taking a surgical intervention.4,5
Injuries to this area are usually caused by high-energy forces in Ankle Injuries
motor vehicle crashes, industrial accidents, and falls. The Lisfranc
ligament spans the articulation of the medial cuneiform and the A proper discussion of ankle injuries far exceeds the scope of this
second metatarsal base. Transverse ligaments connect the bases of chapter. True fractures of the ankle are diagnosed by x-ray.
the other lateral four metatarsals. A transverse ligament is not pres- Treatment is based on the ability to maintain a well-reduced and
ent between the first and the second metatarsal bases. Injuries in stable ankle joint. Surgical intervention is typically indicated for
this region may be purely ligamentous or involve a series of bony failure of casting or for fractures whose mechanics provide for
avulsion fractures, with the latter having a better prognosis of heal- such an unstable ankle joint that casting would be prohibitively
ing. A high degree of suspicion must be maintained, because these difficult or unreliable. Ankle sprains are a more common source
fractures are commonly missed and may lead to chronic pain and of pain that would be seen by a nonorthopedic surgeon. Sprains are
arthritis. Any midfoot ecchymosis should raise suspicion. Pain can classified by their severity, as shown in Table 25–1. Nonoperative
localize to the medial or lateral aspect of the foot at the tarsometa- treatment is typical. Chronic instability and pain as manifested by
tarsal region on direct palpation, or it can be produced by abduc- recurrent ankle sprains may necessitate a ligamentous repair versus
tion and pronation of the forefoot while the hindfoot is held fixed. reconstruction; however, any surgical reconstruction would be con-
An inability to bear weight while standing on the tiptoe is another sidered only after exhaustive physical therapy and proprioceptive
diagnostic clue. Management is nearly always surgical with open training.
reduction and internal fixation of the fracture/dislocation.
Anatomic reduction is necessary in an attempt to avoid chronic
pain and arthritis.2,3 NERVE ENTRAPMENT
Understanding the nervous system anatomy of the ankle and foot is
Tarsal Fractures important in order to help diagnose and treat foot pain caused by
nerve entrapment. There are five main nerves, as shown in Figure
A detailed discussion of tarsal fractures is beyond the scope of this 25–2, that cross the ankle before branching into their terminal
chapter. Cuneiform, cuboid, and navicular fractures are typically branches (clockwise lateral to medial): (1) sural nerve, (2) superfi-
treated with non–weight-bearing cast immobilization for 6 weeks. cial peroneal nerve, (3) deep peroneal nerve, (4) saphenous nerve,
There are operative indications for these fractures, particularly if and (5) posterior tibial nerve. The sural nerve curves posterior to
joint incongruity and stability are in question. Fractures of the neck the lateral malleolus and supplies sensation to the lateral aspect of
of the talus necessitate anatomic reduction because the blood the heel and foot. The superficial peroneal nerve exits the deep
supply of the talus is tenuous.4,5 These more often than not require fascia of the leg approximately 10 cm above the tip of the fibula
open reduction and internal fixation. Talar neck fractures are often anterolaterally and supplies sensation to the dorsal foot. The deep
accompanied by dislocations of the ankle or subtalar joint. Lateral peroneal nerve descends the limb anterior to the ankle, passing
process fractures of the talus are becoming common owing to between the extensor digitorum longus and the extensor hallucis
snowboarding injuries.6 This is also an often overlooked fracture. longus tendons. It sends a motor branch to the extensor digitorum
brevis before supplying sensation to the first dorsal web space.
The saphenous nerve supplies sensation to the dorsomedial skin
of the ankle and foot. Lastly, the posterior tibial nerve courses
Table 25^1. Classification of Ankle Sprains

II III
Class Description
Partial ligament Mild tenderness and swelling. Patients will
I tear be able to walk with minimal pain.
Incomplete More significant pain at the site of injury.
ligament tear Patients will still be able to walk, but with
noticeable pain.
Complete Profound pain and instability. Patients will
ligament tear be unable to ambulate.
Figure 25^1. Fifth metatarsal fractures.
nodules or point tenderness. Comparison with the other side can

often be helpful. A careful motor and sensory examinaiton is also
Deep peroneal important. Stretching the nerve with certain ankle and/or foot
nerve motion may also elicit symptoms. Laboratory studies, x-rays, com-
Branches of puted tomography (CT) scans and magnetic resonance imaging
the superficial (MRI) can also be useful. Electromyography (EMG) and nerve con-
peroneal nerve duction studies should also be considered because they are very
helpful when combined with a good history and physical
examination.
Entrapment of the posterior tibial nerve in the tarsal tunnel can
have the most devastating sequelae, given the importance of this
nerve to foot function. The tarsal tunnel is created by a fibrous band
of tissue posterior to the medial malleolus called the laciniate liga-
ment. Many tendons run in this space, along with the posterior
Sural tibial vein, artery, and nerve. Compression of the nerve can result
nerve from a space-occupying lesion in the tunnel or constriction of the
A fibrous tunnel itself. The nerve can be compressed before or after it
divides into its terminal branches. The location of compression
would dictate the distribution of symptoms. The lateral plantar
nerve is believed to be trapped more often and more severely
than the medial plantar nerve because of its oblique anatomy.
Pain beginning at the arch of the foot and radiating to the medial
plantar foot is often seen in long-distance runners and is classically
referred to as ‘‘jogger’s foot.’’ The point of lateral plantar nerve
entrapment is believed to be the junction of the abductor hallucis
with the medial border of the navicular bone.8
Posterior As would be expected, treatment for tarsal tunnel syndrome
tibial nerve involves increasing the space available for the nerve. When conser-
vative methods of treatment (such as cortisone injection, shoe mod-
ification, and possibly NSAIDs) fail, a formal release of the nerve
may be indicated. If distal compression is suspected, the release may
need to be extended to the terminal branches of the nerve. Isolated
lateral plantar nerve entrapment can often be confused with plantar
fasciitis and should be suspected when plantar fasciitis persists
despite treatment. Swelling of a nerve proximal to the area of
entrapment is seen.
Another rare but classically described area of entrapment is the
anterior tarsal tunnel. The deep peroneal nerve and artery travel
under the extensor retinaculum anterior to the ankle. Often, an
osteophyte is the cause of deep peroneal nerve impingement.
Symptoms include pain, weakness, and sensory changes of the
foot and ankle. Burning and tingling at the first dorsal web space
may also be present, which may be exacerbated by certain footwear.
B The deep peroneal nerve may also be trapped under the extensor
Figure 25^2. Nerves of the foot and ankle. A, Lateral view. hallucis brevis muscle. As for the superficial peroneal nerve, the
B, Medial view. usual site of entrapment is where the nerve exits the lateral com-
partment 10 cm above the tip of the fibula. Symptoms include
burning or tingling over the dorsal aspect of the foot and lateral
behind the medial malleolus, sending off a calcaneal sensory distal leg. This is usually associated with trauma.9 Sural nerve
branch, and terminating as the medial and lateral plantar nerves entrapment can be the result of recurrent ankle sprain, fractures
of the foot, which are responsible for plantar sensation and intrinsic of the calcaneus or fifth metatarsal, or chronic inflammation of the
muscle function.7 Achilles tendon. A trial of steroid injection followed by decompres-
Whereas most nerve entrapment occurs at characteristic loca- sion and possible proximal resection may be necessary.10
tions, nerve pain can occur at any location along the nerve, which is
why it is important to get a detailed history to elucidate any trauma
that may be aggravating a nerve, such as repeated use of certain MORTON’S NEUROMA
footwear. Before making the diagnosis of nerve entrapment of the
foot, it is also important to rule out any pathology proximally in the The most frequent location of pain for patients with Morton’s neu-
leg or lumbar spine. These proximal problems can present with roma is between the third and the fourth metatarsals. At the level of
isolated distal symptoms. Nerve dysfunction or injury associated the metatarsal heads, the interdigital nerve traverses inferior to the
with neuropathy, metabolic disorders, drug interactions, reflex sym- intermetatarsal ligament. At this site, the nerve may be compressed
pathetic dystrophy (now known as complex regional pain syndrome or stretched from repetitive toe motion. Poorly fitting and con-
[CRPS] type I), and other coexisting conditions must also be constricting shoes or shoes with high heels often contribute to
sidered when making the diagnosis. Nerve pain is classically Morton’s neuroma. This makes women who wear high-heeled
described as a ‘‘tingling’’ or ‘‘burning’’ pain that may be ‘‘shooting’’ shoes or constricting shoes for a number of years at greatest risk
in nature. It can be well or poorly defined. Diagnosis involves a of developing this condition.
careful history and physical examination including inspection for Morton’s neuroma is not a true or classic neuroma. Histology
clawing or atrophy and palpation of the length of the nerve for typically reveals perineural fibrosis and nerve degeneration of the
192 Chapter 25 FOOT PAIN
common digital nerve. Patients will often report numbness in the either acute or chronic. Chronic irritation is common because the
toes adjacent to the neuroma, which occur along with episodes of tendon passes through the complex mucous sheath and bony
pain. Some patients describe the sensation as walking with a small grooves described earlier. The most common complaint is pain at
stone in their shoe. the posteromedial foot. Pain may also be noted with resisted flexion
The examination of patients with Morton’s neuroma frequently of the great toe or with great toe hyperextension. Treatment is often
is unremarkable. Firm squeezing of the metatarsal heads with one conservative with rest, ice, and NSAIDs. Longitudinal arch supports
hand while applying direct pressure to the dorsal and plantar as well as a firm-soled shoe are often recommended. Refractory pain
interspace with the other hand may elicit radiating neuropathic or triggering may be treated by release of the fibrous tunnel
pain. This squeezing may also result in a perceivable ‘‘click’’ as described earlier.
the neuroma moves between the metatarsal heads.
Imaging studies are often unnecessary because the diagnosis is
usually made clinically through the patient’s history. MRI may be Peroneal Tendons
utilized to confirm the diagnosis of Morton’s neuroma. EMG stu-
dies are often not used owing to the difficulty in obtaining them so The peroneus brevis and longus tendons are common sources of
far distal in the appendage. pain in the foot and ankle. The peroneus brevis arises from the
Treatment begins with conservative measures. Footwear modi- lower two thirds of the lateral surface of the body of the fibula,
fication is the best first step. Offending footwear should not be medial to the peroneus longus. The peroneus longus is attached
worn. Soft-soled shoes with a wide toe box and low heel are best proximally to the head of the fibula and its ‘‘belly’’ runs down
for symptomatic relief. A plantar pad may be used to elevate the most of the bone. Both tendons pass posterior to the fibula and
metatarsal head adjacent to the neuroma, possibly preventing irri- are held in place by the superior peroneal retinaculum and a notable
tation. Surgical excision of the fibrotic nerve is often curative. The sulcus in the fibula.
entire area of injury should be resected. Surgeons will often release A frank dislocation of the peroneal tendons is diagnosed by pain
the intermetatarsal ligament so as to resect the common digital at the posterior and inferior aspect of the fibula. The examiner may
nerve at its most proximal extent. be concerned that this diagnosis may be confused with an ankle
fracture or sprain. Because this is a possibility, x-rays should always
be obtained. An avulsion fracture of the lateral ridge of the distal
TENDON DISORDERS fibula raises the suspicion of dislocated peroneal tendons.
Treatment is typically surgical with reconstruction of the injured
As with any component of the musculoskeletal system that sees retinaculum. Some authors advocate conservative treatment with a
motion, all of the tendons about the foot and ankle may act as a well-molded cast that places pressure over the peroneal tendons and
source of pain. Within this review, we discuss some of the more the superior peroneal retinaculum.11,12
common tendons that, when injured either acutely or chronically, Painful tears of the peroneal tendons may be acute or chronic.
cause patients pain. Chronic tears are believed to occur when the tendon partially sub-
luxes and is abraded by the sharp posterior ridge of the fibula. The
peroneus brevis is most commonly affected in this manner. Patients
AnteriorTibial Tendon complain of pain at the distal and posterior aspect of the fibula.
Surgical treatment is often necessary with tightening of the superior
The tibialis anterior tendon acts to dorsiflex and invert the foot. peroneal retinaculum. The injured tendon is either repaired or déb-
This tendon originates in the upper two thirds of the lateral surface rided, depending on the extent of the tendinopathy.
of the tibia and inserts into the medial cuneiform, the tarsal navi- Injury to an os peroneum may also cause peroneal pain. An os
cula, and first metatarsal of the foot. Along this course, the tibialis peroneum is an oval or round accessory ossicle located within the
anterior passes under the superior extensor retinaculum. An over- substance of the distal peroneal longus tendon near the cuboid. It is
use syndrome or tendinitis is rare but diagnosed by tenderness found in roughly 25% of all feet. Patients with pain in this region
along the course of the tendon, particularly under the superior often report a history of direct trauma or a supination and inver-
retinaculum. As with all degenerative or inflamed tendons, a partial sion injury to the ankle. This injury may cause a fracture of the
tendon injury results in painful motion for the patient, whereas a ossicle that is either acute or goes on to a nonunion owing to con-
complete rupture is often painless. Complete tendon injuries should tinued use. Treatment may be conservative with cast immobiliza-
be surgically repaired because the tibialis anterior supplies 80% of tion. Some physicians elect to inject the area with steroid, whereas
the power of dorsiflexion at the ankle. Partial injuries may benefit others advocate surgical excision.11,12
from orthotic immobilization.11
AchillesTendon
Flexor Hallucis LongusTendon
The Achilles tendon is the tendinous insertion of two muscles. The
This tendon originates from the inferior two thirds of the posterior first is the gastrocnemius, which originates from both the lateral
and lateral fibular surface. A portion of the muscle also arises from and the medial femoral condyles. The second is the soleus, which
the intermuscular septum between the tibia and the fibula. The originates from the posterior surface of the tibia and the fibula as
flexor hallucis longus tendon lies in a groove that crosses the pos- well as the interosseous. The tendon itself inserts on a tuberosity of
terior surface of the lower end of the tibia, the posterior surface the calcaneus. A watershed area in the vascular supply is located 3 to
of the talus, and the undersurface of the sustentaculum tali of 6 cm above the insertion on the calcaneus. In addition to acute
the calcaneus. In the sole of the foot, it runs forward between traumatic ruptures, chronic tendon degradation may occur.
the two heads of the flexor hallucis brevis and inserts into the Achilles tendinosis is the result of microscopic failure from accu-
base of the last phalanx of the great toe. The grooves on the mulated and repetitive microtrauma. Central tissue necrosis fol-
talus and calcaneus, which contain the tendon of the muscle, are lowed by mucoid degeneration is often the final result. The
converted by tendinous fibers forming distinct canals, lined by a damage to the tendon itself may be asymptomatic, but the inflam-
mucous sheath. mation of the peritendon sheath is not. Treatment is typically con-
This is the most frequently injured tendon in athletes such as servative with a non–weight-bearing cast and NSAIDs. Failure of
ballet dancers who push off of their great toe. This injury may be extensive conservative treatment necessitates surgical intervention
with débridement of the peritendon sheath as well as the mucoid may be treated with NSAIDs, colchicines, or intra-articular injec-
area of the tendon. Patients should be warned of the risk of tendon tions of corticosteroids. Probenecid, sulfinpyrazone, and allopuri-
rupture after the procedure. Patients are typically immobilized and nol can be used to prevent recurrent attacks. The crystals that cause
kept non–weight-bearing for 6 weeks.11,13,14 pseudogout are composed of calcium pyrophosphate. These crystals
appear rhomboid and positively birefringent using polarized light
microscopy. Both cause pain by accumulation of crystals that trig-
PosteriorTibial Tendon ger an immune response.
OA of the foot and ankle most commonly involves the navicu-
The posterior tibial tendon originates on the inner posterior locuneiform, intercuneiform, and metatarsocuneiform joints as well
borders of the tibia and fibula as well as the interosseous membrane. as the first MTP joint. It is believed that these joints are susceptible
The tendon passes behind the medial malleolus and inserts on to arthritis because of the large forces that they are subjected to as
the navicular, the first and third cuneiforms, the cuboid, and well as their limited motion. Conservative therapy includes pain
the second, third, and fourth metatarsals. Irritation of this tendon control, NSAIDs, and shoe modification. OA progression can
typically occurs at the point where the tendon and posterior only be slowed and not stopped or reversed. Fusion with bone
medial malleolus come in contact. Microtrauma may cause the grafting and hardware fixation is the mainstay of surgical treatment.
tendon to become inflamed, leading to degeneration. Patients Obesity is believed to have a negative effect on degenerative joint
typically complain of pain at the posterior and inferior ankle into disease of the foot and ankle.
the medial malleolus. Early inflammation may be treated conserva- OA of the first MTP joint is a common problem that has
tively with rest and NSAIDs as well as orthotics. Surgical treatment successful surgical options. Typical changes of OA that are found
is dependent on the degree and rigidity of foot deformity. The in other joints such as the knee (joint space narrowing, sclerosis,
typical deformity is hindfoot valgus with forefoot abduction and osteophyte formation, and subchondral cysts) are seen as the
pronation. For a supple deformity, tendon reconstruction may disease progresses in the foot. For milder cases of OA of the
be considered. Rigid deformity requires the consideration of an first MTP joint, a dorsal cheilectomy can help to improve motion
arthrodesis procedure.11 and relieve some pain caused by bone-on-bone contact present
dorsally. When the disease has progressed further, fusion is
more likely to be successful in relieving pain and improving
ARTHRITIC CONDITIONS function.
Arthritis of the foot and ankle can be divided into two main groups:
inflammatory arthritis and osteoarthritis (OA). Inflammatory PLANTAR FASCIITIS
arthritis includes rheumatoid arthritis (RA), gout or pseudogout,
seronegative spondyloarthropathies, and ankylosing spondylitis. Plantar fasciitis is inflammation of the plantar fascia of the foot. It
Foot and ankle involvement in rheumatoid arthritis may be as has been associated with obesity, middle age, and biomechanical
high as 85% to 90%. OA of the foot and ankle is a degenerative abnormalities of the foot such as a tight Achilles tendon, pes
process commonly seen in hips and knees and can be accelerated by cavus, and pes planus. The plantar fascia of the foot extends from
traumatic injury.15,16 the medial tubercle of the calcaneus to the base of the toes (plantar
RA is an immune-mediated inflammatory disease with a genetic to the intrinsic musculature and neurovascular structures). It helps
predisposition that leads to vasculitis, synovitis, and cartilage to maintain the arch of the foot and resists widening of the toes and
destruction. Once the diagnosis of RA is made, special foot care the calcaneus, the windlass effect. It also helps to give the foot
principles similar to those followed by diabetic patients should be rigidity when the toes are dorsiflexed during the push-off phase
observed. Valgus deformity of the hindfoot and flattening of the of walking. Plantar fasciitis can occur bilaterally in 20% to 30%
arch are common findings. Once foot biomechanics are altered, of patients.18,19
there is a domino effect of progressive disease usually ending with There are many causes of heel and foot pain; therefore, a careful
forefoot pain and deformity. Conservative treatment should begin history and physical examination are once again very important to
early with good foot care habits, comfortable shoes, stretching, make the diagnosis. One characteristic sign of plantar fasciitis is
braces, rest, and occasional steroid injections to relieve acute epi- pain that is worse in the morning or after a period of rest just
sodes of inflammation. Many new disease-modifying drugs specif- distal to the heel pad at the origin of the plantar fascia on the
ically target inflammatory mediators. Management of RA involves a calcaneus. This area may be sorer on days of increased activity.
multidisciplinary approach.16 The pain will also likely worsen with dorsiflexion of the toes because
Synovitis of the metatarsophalangeal (MTP) joint is a most this puts tension on the plantar fascia and irritates the inflamed
common finding in RA. Destruction of the soft tissue support area. Repetitive stress on this fascia, as seen with long-distance
around this joint causes the head of the proximal phalanx to runners, is believed to contribute to the irritation and inflamma-
sublux dorsally with respect to the metatarsal head. With progres- tion. The presence of a heel spur on x-ray has not been shown to
sion of this altered foot biomechanics, a claw-toe deformity devel- have a direct link to plantar fasciitis. A bone scan or MRI may be
ops. This can lead to proximal interphalangeal joint irritation useful in refractory cases to help confirm the diagnosis if improve-
against shoes. Kinematics are altered, which changes the plantar ment is not seen with early treatment.
weight-bearing pressure points causing pain and possible ulcera- Most cases of plantar fasciitis will resolve with conservative
tions.17 Posterior tibial tendon insufficiency also develops. Once treatment. As Dr. Gill18 pointed out in his review of this topic,
conservative measures are exhausted, the most common and suc- there are many treatments for this problem because no one treat-
cessful forefoot procedure is fusion of the first MTP joint with ment has stood out as the most beneficial. Casting is a common
resection of the lesser metatarsal heads. Claw-toe deformities can treatment that has good results because it allows the inflamma-
also be surgically addressed. tion to subside. Stretching exercises have also been shown to help
Gout and pseudogout are also common sources of pain. In gout, decrease pain. NSAIDs, orthotics, and steroid injections have
monosodium urate crystals are deposited on the articular cartilage also been used with varying degrees of success. LowDye taping
of joints and in the periarticular tissue (e.g., tendons). Definitive combined with 5% acetic acid iontophoresis to the site of maxi-
diagnosis involves joint aspiration with fluid inspection. mal tenderness on the plantar aspect of the foot (6 treatments
Monosodium urate crystals appear needle-shaped and are nega- over a 2-wk period) appears to be a viable therapeutic option
tively birefringent using polarized light microscopy. Acute attacks as well.20
194 Chapter 26 THOR ACIC PAIN
CONCLUSION Nerve Entrapment

7. Beskin JL. Nerve entrapment syndromes of the foot and ankle. J Am
The vast majority of foot pain is treated conservatively. Pain after Acad Orthop Surg 1997;5:261–269.
trauma may represent a fracture or ligamentous injury. The clini- 8. Keck C. The tarsal tunnel syndrome. J Bone Joint Surg 1962;44:180–182.
9. DiDomenico LA, Masternick EB. Anterior tarsal tunnel syndrome.
cian should pay careful attention to midfoot pain and ecchymosis
Clin Podiatr Med Surg 2006;23:611–620.
because this may represent a Lisfranc injury. All fractures should 10. Pringle RM, Protheroe K, et al. Entrapment neuropathy of the sural
initially be treated with immobilization. Fractures may cause nerve. J Bone Joint Surg 1974;56:465–486.
chronic pain owing to soft tissue and nerve injury as well as fracture Tendon Disorders
nonunion. Pain mediated by tendon dysfunction typically repre- 11. Jones DC. Tendon disorders of the foot and ankle. J Am Acad
sents mechanical irritation that is often relieved by rest. Chronic Orthop Surg 1993;1:87–94.
irritation may require operative débridement. Nerve entrapment is 12. Brage ME, Hansen ST Jr. Traumatic subluxation/dislocation of the
rare in the foot. Occasionally, a compressed nerve may require peroneal tendons. Foot Ankle 1992;13:423–431.
operative release. Finally, plantar fasciitis is also treated conserva- 13. DuVries HL (ed): Surgery of the Foot, 2nd ed. St Louis: CV
tively with rest, NSAIDs, and orthotics. The treatment of foot pain Mosby, 1965.
14. Saltzman CL, Thermann H. Achilles tendon problems. In Pfeffer GB,
represents a clinical challenge. Knowledge of painful foot conditions Frey (eds): Current Practice in Foot and Ankle Surgery, Vol 1. New
is truly a useful tool for clinicians. York: McGraw-Hill, 1993; pp 194–218.
Arthritic Conditions
15. Richardson EG. Disorders of the foot and ankle. In Miller M
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injuries. Ann Emerg Med 1992;21:384–390. 17. Khazzam M, Long JT, et al. Kinematic changes of the foot and ankle
2. Haapamaki V, Kiuru M, Koskinen S. Lisfranc fracture-dislocation in in patients with systemic rheumatoid arthritis and forefoot deformity.
patients with multiple trauma: diagnosis with multidetector computed J Orthop Res 2007;25:319–329.
tomography. Foot Ankle Int 2004;25:614–619. Plantar Fasciitis
3. Englanoff G, Anglin D, Hutson HR. Lisfranc fracture-dislocation: a 18. Gill LH. Plantar fasciitis: diagnosis and conservative management. J
frequently missed diagnosis in the emergency department. Ann Emerg Am Acad Orthop Surg 1997;5:109–117.
Med 1995;26:229–233. 19. Bolgla A, Malone TR. Plantar fasciitis and the windlass mechanism: a
4. Early JS. Fractures and dislocations of the midfoot and forefoot. In biological link to clinical practice. J Athl Train 2004;39:77–82.
Bucholz RW, Heckman JD (eds): Rockwood and Green’s Fractures in 20. Osborne HR, Allison GT. Treatment of plantar fascilitis by LowDye
Adults, 5th ed. Philadelphia: Lippincott-Raven, 2002; pp 2182–2245. taping and iontophoresis: short term results of a double blinded,
5. Karasick D: Fractures and dislocations of the foot. Semin Roentgenol randomized, placebo controlled clinical trial of dexamethasone and
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Chapter 26 common, underreported, and less studied in the literature. The

biggest reason for this is that the thoracic region of the spine has
THORACIC PAIN less mobility and flexibility than the cervical or lumbar regions
owing to the anchoring effect of its articulation to the ribs and
Pradeep Chopra sternum. Thoracic spine pain is sometimes referred to other regions
of the spine or other areas of the body, where it is likely to be
misdiagnosed
Thoracic spine pain falls under the rubric of thoracic pain,
which encompasses pain that takes place in and around the thoracic
cavity. Pain related to the structures within the thoracic cavity
INTRODUCTION is referred to as intrathoracic pain. These structures—which are
enclosed by the ribs, spinal column, and sternum and separated
Thoracic pain is often synonymous with chest pain. It is a common from the abdominal cavity by the diaphragm—include vital
symptom that patients present with, especially when it is confused organs and tissues such as the lungs, bronchi, esophagus, trachea,
with cardiac pain. Thoracic pain may be due to intrathoracic (heart, heart and major blood vessels, and the visceral and parietal pleura.
lungs, esophagus, mediastinum) or extrathoracic structures (Table Thoracic pain related to structures outside the thoracic cavity
26–1). In this chapter, I discuss primarily pain due to extrathoracic is referred to as extrathoracic pain. These structures include the
structures. Readers are referred to specific literature for pain due to thoracic spine, the ribs, and the anterior and posterior muscles in
intrathoracic structures. the thoracic area. The purpose of this chapter is to
1. Increase awareness of thoracic spine pain by discussing the dis-

THORACIC PAIN STRUCTURES eases and conditions associated with the structures of the tho-
racic spine, and
Although thoracic spine pain can be as chronic and disabling as 2. Describe respective diagnostic procedures and therapy options.
pain in the cervical or lumbar regions of the spine, it is less The extrathoracic structures most likely to be associated with
CONCLUSION Nerve Entrapment

7. Beskin JL. Nerve entrapment syndromes of the foot and ankle. J Am
The vast majority of foot pain is treated conservatively. Pain after Acad Orthop Surg 1997;5:261–269.
trauma may represent a fracture or ligamentous injury. The clini- 8. Keck C. The tarsal tunnel syndrome. J Bone Joint Surg 1962;44:180–182.
9. DiDomenico LA, Masternick EB. Anterior tarsal tunnel syndrome.
cian should pay careful attention to midfoot pain and ecchymosis
Clin Podiatr Med Surg 2006;23:611–620.
because this may represent a Lisfranc injury. All fractures should 10. Pringle RM, Protheroe K, et al. Entrapment neuropathy of the sural
initially be treated with immobilization. Fractures may cause nerve. J Bone Joint Surg 1974;56:465–486.
chronic pain owing to soft tissue and nerve injury as well as fracture Tendon Disorders
nonunion. Pain mediated by tendon dysfunction typically repre- 11. Jones DC. Tendon disorders of the foot and ankle. J Am Acad
sents mechanical irritation that is often relieved by rest. Chronic Orthop Surg 1993;1:87–94.
irritation may require operative débridement. Nerve entrapment is 12. Brage ME, Hansen ST Jr. Traumatic subluxation/dislocation of the
rare in the foot. Occasionally, a compressed nerve may require peroneal tendons. Foot Ankle 1992;13:423–431.
operative release. Finally, plantar fasciitis is also treated conserva- 13. DuVries HL (ed): Surgery of the Foot, 2nd ed. St Louis: CV
tively with rest, NSAIDs, and orthotics. The treatment of foot pain Mosby, 1965.
14. Saltzman CL, Thermann H. Achilles tendon problems. In Pfeffer GB,
represents a clinical challenge. Knowledge of painful foot conditions Frey (eds): Current Practice in Foot and Ankle Surgery, Vol 1. New
is truly a useful tool for clinicians. York: McGraw-Hill, 1993; pp 194–218.
Arthritic Conditions
15. Richardson EG. Disorders of the foot and ankle. In Miller M
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Traumatic Injury pp 309–357.
1. Stiell IG, Greenberg GH, McKnight RD, et al. A study to develop 16. Abdo RV, Iorio LJ. Rheumatoid arthritis of the foot and ankle. J Am
clinical decision rules for the use of radiography in acute ankle Acad Orthop Surg 1994;6:326–333.
injuries. Ann Emerg Med 1992;21:384–390. 17. Khazzam M, Long JT, et al. Kinematic changes of the foot and ankle
2. Haapamaki V, Kiuru M, Koskinen S. Lisfranc fracture-dislocation in in patients with systemic rheumatoid arthritis and forefoot deformity.
patients with multiple trauma: diagnosis with multidetector computed J Orthop Res 2007;25:319–329.
tomography. Foot Ankle Int 2004;25:614–619. Plantar Fasciitis
3. Englanoff G, Anglin D, Hutson HR. Lisfranc fracture-dislocation: a 18. Gill LH. Plantar fasciitis: diagnosis and conservative management. J
frequently missed diagnosis in the emergency department. Ann Emerg Am Acad Orthop Surg 1997;5:109–117.
Med 1995;26:229–233. 19. Bolgla A, Malone TR. Plantar fasciitis and the windlass mechanism: a
4. Early JS. Fractures and dislocations of the midfoot and forefoot. In biological link to clinical practice. J Athl Train 2004;39:77–82.
Bucholz RW, Heckman JD (eds): Rockwood and Green’s Fractures in 20. Osborne HR, Allison GT. Treatment of plantar fascilitis by LowDye
Adults, 5th ed. Philadelphia: Lippincott-Raven, 2002; pp 2182–2245. taping and iontophoresis: short term results of a double blinded,
5. Karasick D: Fractures and dislocations of the foot. Semin Roentgenol randomized, placebo controlled clinical trial of dexamethasone and
1994;29:152–175. acetic acid. Br J Sports Med 2006;40:545–549.
6. Nicholas R, Hadley J, Paul C. "Snowboarder’s fracture": fracture of the 21. Schepsis AA, Leach RE. Plantar fasciitis: etiology, treatment, surgical
lateral process of the talus. J Am Board Fam Pract 1994;7:130–133. results, and review of the literature. Clin Orthop 1991;266:185–196.
Chapter 26 common, underreported, and less studied in the literature. The

biggest reason for this is that the thoracic region of the spine has
THORACIC PAIN less mobility and flexibility than the cervical or lumbar regions
owing to the anchoring effect of its articulation to the ribs and
Pradeep Chopra sternum. Thoracic spine pain is sometimes referred to other regions
of the spine or other areas of the body, where it is likely to be
misdiagnosed
Thoracic spine pain falls under the rubric of thoracic pain,
which encompasses pain that takes place in and around the thoracic
cavity. Pain related to the structures within the thoracic cavity
INTRODUCTION is referred to as intrathoracic pain. These structures—which are
enclosed by the ribs, spinal column, and sternum and separated
Thoracic pain is often synonymous with chest pain. It is a common from the abdominal cavity by the diaphragm—include vital
symptom that patients present with, especially when it is confused organs and tissues such as the lungs, bronchi, esophagus, trachea,
with cardiac pain. Thoracic pain may be due to intrathoracic (heart, heart and major blood vessels, and the visceral and parietal pleura.
lungs, esophagus, mediastinum) or extrathoracic structures (Table Thoracic pain related to structures outside the thoracic cavity
26–1). In this chapter, I discuss primarily pain due to extrathoracic is referred to as extrathoracic pain. These structures include the
structures. Readers are referred to specific literature for pain due to thoracic spine, the ribs, and the anterior and posterior muscles in
intrathoracic structures. the thoracic area. The purpose of this chapter is to
1. Increase awareness of thoracic spine pain by discussing the dis-

THORACIC PAIN STRUCTURES eases and conditions associated with the structures of the tho-
racic spine, and
Although thoracic spine pain can be as chronic and disabling as 2. Describe respective diagnostic procedures and therapy options.
pain in the cervical or lumbar regions of the spine, it is less The extrathoracic structures most likely to be associated with
Table 26^1. Diseases and Conditions Associated withThoracic Pain
Pain Symptoms and Signs

Extrathoracic
Postherpetic neuralgia Constant, severe, lancinating, or burning pain. Itching. History of herpes zoster rash. Allodynia,
hyperalgesia, hyperpathia, or dysesthesia.
Intercostal neuralgia Constant, superficial burning pain in the distribution of the intercostal nerve.
Peripheral neuropathy Spontaneous, diffuse, burning pain involving several segments.
Myofascial pain Localized over the area of the muscle, achy turning to sharp pain with use of muscle. Discrete tenderness.
Relieved by trigger point injections.
Degenerative disk disease Axial or radicular band-like pain along the course of an intercostal nerve.
Facet joint syndrome Discrete, sharp pain and tenderness localized to joints. Exacerbated by movement, especially
hyperextension and axial rotation. Relieved by localized injection to the joint or forward flexion.
Costovertebral joint pain Deep aching pain, not as severe as facet joint pain. Localized tenderness. Aggravated by movement and
relieved by local injection to the joint.
Costochondritis Localized pain and tenderness over the ribs. Exacerbated by deep breathing and coughing.
Thoracic outlet Pain in upper shoulders and arms, exacerbated by abduction of arms. Pectoral muscle tenderness,
syndrome hyperalgesia, and parasthesias. Supraclavicular fullness and tenderness.
Sternoclavicular joint Localized joint swelling, which is tender on palpation. Pain over the joint radiating to the shoulder and
pain upper chest.
Slipping rib syndrome Localized to lower costal margin, unilateral, sharp pain exacerbated by extension and raising of arms.
Relieved by forward flexion. Clicking noise and tenderness on hooking a finger under the costal margin
and applying anterior pressure.
Postsurgical Sharp lancinating pain with significant tenderness. Hyperalgesia, dysesthesia.
thoracotomy pain
Thoracolumbar Low back pain over the lumbosacral region. Reproduction of pain with pressure over the thoracolumbar
syndrome junction.
Vertebral compression Localized adult achy pain in the anterior part of the chest. Exacerbated with movement. Constant burning
fracture pain, in a segmental distribution if associated with nerve compression. Paroxysms of sharp pain. Usually
worse at night. Tenderness over the paravertebral region.
Rib fracture Sharp pain localized to the area of the fracture. Exacerbated by coughing. Significant tenderness over the
rib in a patient with a history of trauma or a bout of severe coughing.
Referred pain from Neck, upper shoulders, arms, and anterior chest pain. Exacerbated by lateral flexion. Positive
cervical spine Spurling’s test.
Abdominal pain Symptoms and signs of pain due to gas in the bowel, peptic ulcer (pain in epigastrium), biliary colic
(severe pain radiating in to the back or subcostal region), acute cholecystitis (pain right upper quadrant,
nausea, and vomiting), acute pancreatitis (severe pain radiating to the back, hypotension, and
hypovolemia), subphrenic abscess (fever, shortness of breath, lower chest pain radiating to the shoulder).
Intrathoracic
Coronary artery disease Varying degree severity of anterior chest pain radiating to either arm, neck, or epigastrium. Tight band-like
sensation. May have electrocardiographic changes.
Pneumonia Moderate pain with deep breathing and coughing. Cough, fever, and blood-stained sputum.
Trachea and bronchial Burning, retrosternal pain. Associated with upper respiratory infection, fever, cough, and malaise.
Diaphragmatic/pleuritis Sharp pain along the posterior aspect of the neck and shoulder. Exacerbated by deep breathing or
coughing.
Esophagitis Burning pain in the retrosternal and epigastric area, dysphagia, regurgitation, and odynophagia.
Dissecting aneurysm Sharp, severe, sudden onset of anterior and posterior chest pain. Associated with nausea, vomiting, and
hypotension.
Pericarditis Sharp chest pain, exacerbated by lying supine and deep breathing. Partially relieved by sitting
Pneumothorax Sudden, sharp severe chest pain. Absent breath sounds, dyspnea, and tympani on percussion.
Pleuritis Sharp, stabbing pain exacerbated by breathing. Pleural rub on auscultation.
Hiatal hernia Mostly asymptomatic and occasional epigastric discomfort. Diagnosed radiographically.
pain are those derived from the thoracic spine: the thoracic absorbers and create space for nerve roots to exit the spinal canal.
vertebrae, thoracic intervertebral disks, thoracic facet joints, cos- The functional anatomy of thoracic intervertebral disks includes the
tovertebral and costotransverse joints, thoracolumbar junction, nucleus pulposus (the gelatinous core, composed largely of water
ribs, and muscles of the thoracic spine. and proteoglycans), the annulus fibrosus (the concentric rings of
dense, fibroclastic collagen that surrounds the core and serves as the
outer portion of the disk), and vertebral end-plates (which aid in
transferring nutrients to the disks).
CLINICAL ANATOMYOF THE Thoracic intervertebral disks are smaller in volumetric dimen-
sion and more centrally located than their lumbar counterparts.
THORACIC SPINE They also have a lesser proportionate vertical dimension than in-
tervertebral disks in the cervical and lumbar regions, making up
Thoracic Vertebrae approximately one sixth of the height of the thoracic region of
the spine. Their thinner anterior and thicker posterior portions
Twelve vertebrae (T1–12) make up the thoracic region of the spine. create a wedge that contributes in part to the normal kyphotic
The thoracic vertebrae are intermediate in size to the smaller ver- curvature of the thoracic spine. Another contributor to the kyphotic
tebrae in the cervical region and the larger vertebrae in the lumbar curve is the anatomy of the thoracic vertebral body, discussed else-
region. A variation in vertebral size is seen also within the thoracic where in this chapter.
region itself: the vertebrae in the upper segment of the region are The diminished height dimensions of the disks in the upper
much smaller than the vertebrae in the lower segment of the region, segment of the thoracic region are believed to contribute to the
such that the beginning and ending vertebrae of the thoracic spine relative stiffness of that segment, whereas an increase in height
resemble the ending vertebra of the cervical spine and the beginning dimension in the lower segment tends to decrease stiffness. The
vertebra of the lumbar spine, respectively. lower segments are not constrained by attachment to the thoracic
Another variation within the thoracic spine is that mobility pro- rib cage, allowing for a gradual increase in range of motion.
gressively increases from the upper to the lower vertebrae. Even Another unique feature of thoracic intervertebral disks is the
though the upper thoracic vertebrae resemble the cervical vertebrae variation of their sagittal shape from elliptical in the upper segment
with respect to size, the attachment of the ribs to the sternum of the region to a rounded triangle in the midthoracic region to a
greatly impairs the respective ranges of motion of the thoracic ver- larger ellipse flattened posteriorly in the lower segment. Overall, the
tebrae. Unlike the movements of mobility and motion, which are disks in the midthoracic region show a more circular horizontal
most restricted by the anchoring effect of the rib cage, rotation is cross-section than any other disks in the spine.
the movement that is least restricted, owing to the circumferential Because of its architectural design, the thoracic spine is geared
arc of the plane of articular facets. The entire vertebral column has toward axial loading and support, offering only limited mobility,
been shown to rotate approximately 908 to either side of the sagittal which is governed by the thoracic intervertebral disk that permits
plane, with most of this traversing accomplished in the cervical and vertebral mobility; the thoracic facet joint restrains rotational
thoracic regions. However, flexion and extension become freer in motion.
the lower thoracic region as the disks and vertebral bodies increase
in size. It is important to note that the last few vertebrae in the
lower segment of the thoracic region are transitional with respect to Thoracic Facet (Zygapophyseal) Joints
the surfaces of the articular facets, which begin to turn more toward
the sagittal plane, limiting rotation and permitting greater extension The vertebrae of the thoracic spine are connected posteriorly
Besides the differences in size, mobility, and range of motion by paired synovial joints, commonly referred to as facet joints or
between the thoracic vertebrae and their cervical and lumbar coun- zygapophyseal joints. A facet joint is formed when two articular
terparts, the thoracic vertebrae are distinguished by the presence of processes (which emerge from the anterior and posterior surfaces
facets on the sides of the vertebral bodies. The facets articulate with of two ‘‘stacked’’ vertebrae where the lamina and pedicle meet)
the heads of the ribs and facets on the transverse processes of all extend and overlap each other. Each pair of vertebrae is joined
except the 11th and 12th bodies, for articulation with the tubercles by two facet joints, one on each side of the vertebra, behind the
of the ribs. spinal nerves as they emerge from the spinal canal. The surfaces
Like other vertebrae, each thoracic vertebra consists of three of facet joints are covered with articular cartilage, and a tough,
basic functional parts: fibrous, watertight capsule is present on the posterolateral aspect
of the joint. The alignment of the two facet joints and the interver-
1. The drum-shaped vertebral body (the anterior segment), which
tebral disk at each vertebral level of the thoracic spine facilitates
is composed of hard cortical bone on the outside and less dense
freedom of movement (e.g., when we twist back and forth or lean
cancellous bone on the inside. It is designed to bear weight and
side to side).
withstand compression.
Facet joint orientation varies at different levels of the spine.
2. The vertebral arch (posterior segment), which is composed of
In the thoracic spine, the articular processes face posteriorly;
the lamina, pedicles, and facet joints and encloses the small,
the angle of inclination to the horizontal of the different levels of
round vertebral foramen.
facet joints is 608; and the freedom of movement at each vertebral
3. The transverse processes to which the spinal muscles are
level is largely governed by the orientation of its respective facet
attached. The thoracic vertebral bodies are taller posteriorly
joints.
than anteriorly, which contributes in part to the anterior con-
cavity and normal thoracic kyphosis. Also contributing to the
kyphosis is the shape of the thoracic intervertebral disk, dis-
cussed elsewhere in this chapter. Costovertebral and Costotransverse Joints
The costovertebral joint in the thoracic spine is the juncture at
which the head of a rib articulates with the vertebral body of a
Thoracic Intervertebral Disks thoracic vertebra. The costotransverse joint is the juncture at
which the neck and tubercle of a given rib are united with the
Like the other vertebrae, thoracic vertebrae are separated from each transverse process of its corresponding thoracic vertebra. Closely
other by intervertebral disks that act as cushions and shock related to the costovertebral and costotransverse joints, which
articulate the ribs posteriorly with the thoracic vertebrae, are the muscles, are positioned in many directions, running vertically up
costosternal and costochondral joints, which articulate the ribs and down the lower ribs and the rib cage and across to the back.
anteriorly with the sternum. Both pairs of joints are synovial (dia- The third and deepest layer of muscles, levatores costarum, attaches
throdial) in that their makeup includes a fibrous outer capsule that to bones on the back of the spine, connecting the vertebrae. The
limits their excursion and surrounds articular cartilage that is lubri- intercostal muscles connect one rib to the next. They are composed
cated with synovial fluid. Both pairs of joints are supported by of three layers, from outside to inside, they are external, internal,
ligaments that strengthen the bone junctions and limit the and intimi intercostal.
motion of joints in the upper back. It is worth noting that the gradual increase in size of the verte-
brae from the top of the spinal column to the bottom provides
balance and supports the layers of muscles that connect to the
Thoracolumbar Junction lower parts of the spine
The thoracolumbar junction is a spine segment known for its vul-

nerability to traumatic injury. This vulnerability is strongly associ- DISEASES AND MEDICAL CONDITIONS
ated with the junction’s location, the segment between T12 and L1, ASSOCIATED WITH THORACIC
which is the transition zone between the lumbar region of the spine SPINE PAIN
(where there is virtually no rotation) and the thoracic region of the
spine (which has a rotational function). Because the design of the thoracic spine (i.e., to provide stability
Also contributing to this junction’s vulnerability to traumatic and structural support to the upper back and to protect vital
injury are its biomechanical features, which can be explained by organs and tissues in the thoracic cage) allows only minimal move-
the difference in alignment of the facet joints. In the thoracic and ment and flexibility, the frequency of injury and consequent pain to
lumbar regions of the spine, that alignment is in the coronal plan; in this spinal region owing to mechanical causes is much lower than
the lumbar spine, it is the sagittal plane. The thoracic facet joints are that associated with the cervical or lumbar regions. Similarly, the
angled at 608 and the lumbar facet joint at 908 in a horizontal medical literature is abundant with information on cervical and
orientation. At the T12–L1 junction, the superior facet joints of lumbar pain, whereas such information on thoracic spine pain is
the T12 are shaped like those of thoracic vertebrae and the inferior sparse.
ones have the pattern of the lumbar vertebrae, breaking the harmo- The vast majority of cases of thoracic spine pain will fit into
nious movement of the spine and making it especially susceptible to these two classes:
rotational injuries. This is also a common site for compression
1. Simple thoracic pain in which pain is due to problems with the
fractures.
muscles, ligaments, and joints of the thoracic spine, or
2. Complex thoracic pain in which pain arises from more compli-
cated causes, such as age-related changes and irritation of the
Ribs spinal nerve roots. Uncommon causes of thoracic spine pain are
the ones associated with mechanical causes, such as degenerative
The ribs, whose anatomy includes relatively flat elastic arches of
disk disease or degenerative facet joint disease. Diagnosis and
bone, make up a large part of the thoracic skeleton. In most
treatment of diseases and medical conditions associated with
cases, 12 ribs occur bilaterally in matched pairs. Of these, ribs
thoracic spine pain can be challenging, owing to the myriad of
two through seven are connected posteriorly to the spine (i.e., the
signs and symptoms and the instances of referred pain. A
heads of the ribs to thoracic vertebral bodies and the tubercles of
number of diseases and medical conditions that cause or con-
the ribs to the transverse processes) and anteriorly to the sternum
tribute to thoracic spinal pain have been identified.
(i.e., via synovial joints). The first rib is flattened above and below;
its anterior cartilage is fused to the manubrium, forming a rigid ring
referred to as the thoracic outlet. Of the five remaining ribs, the first
three have cartilages that are fused to the cartilage of the rib above; Thoracolumbar Junction Syndrome
the last two, which do not articulate anteriorly, are referred to as
floating or vertebral ribs. Patients with thoracolumbar junction syndrome usually present
The ribs, each of which includes a head, neck, tubercle, body, with pain in the lower lumbar region. They may present with
and costal cartilage, vary in directional orientation. The upper ribs pain in the lower abdomen, pelvis, and/or over the lateral hip. It
are less oblique than the lower ribs. Between each rib is an inter- is common in patients over 45 years of age and often confused with
costal space. The ribs are of varying lengths, with graduated pain of lumbosacral origin.
increases in length in the first seven. The 12th ribs (one on each Thoracolumbar junction syndrome is a result of the unique ana-
side) are usually the shortest. The 11th and 12th ribs are also known tomic and physiologic features of the T12 and L1 vertebrae. The
as floating ribs. syndrome is usually caused by painful minor intervertebral dysfunc-
The articulations of the ribs allow them to move upward and tion (PMID) at T12–L1. In rare instances, the cause may be a
downward during inspiration, increasing anterior, posterior, right, prolapsed intervertebral disk. The medial cutaneous branch of L1
and left diameters of the thorax. The thoracic outlet is fixed during and L2 is cutaneous approximately 7 to 8 cm lateral to the midline
respiration after perforating the latissismus dorsi near the iliac crest.
This syndrome’s most frequent symptom is low back pain, the
same kind that originates in the lumbosacral or sacroiliac regions of
Muscles of theThoracic Spine the spine. Pain that may sometimes radiate posteriorly or laterally
into the thigh, abdominal, groin, and pubic regions has been
The muscles associated with the thoracic spine are arranged in reported alone or accompanying low back pain.
layers. The first layer contains the muscles closest to the surface There is tenderness to palpation approximately 7 to 8 cm lateral
of the skin, which run from the back of the vertebrae to the shoul- to the midline. If a skinfold over the iliac crest is pinched lightly
der blades (i.e., the trapezius) at the upper thoracic back. The between the index finger and the thumb, it is very tender.
muscles that wrap around the rib cage (midthoracic back) and In most cases, treatment involves manipulation of the thoraco-
connect to the shoulders are the latissimus dorsi. The erector lumbar segment or infiltration of the T11–12 or T12–L1 facet joints
spinae, strap-shaped muscles that belong to the middle layer of with a local anesthetic.
Thoracic Outlet Syndrome Sometimes described as a combination of kyphosis (the exaggerated,

rounded-back curve) and scoliosis (a lateral or sideways curve),
Thoracic outlet syndrome refers to a condition in which vascular or this disorder is believed to be potentially more serious than sco-
neurologic symptoms are produced as a result of neurovascular liosis alone because its curves can progress rapidly and deformi-
compression in up to nine different anatomic locations. The three ties can lead to spinal cord compression and paraplegia as well
most common syndromes and their locations are as respiratory failure (when curves exceed 708) and hypoxemia
and cor pulmonale (when curves exceed 1008). Respiratory failure
1. Costoclavicular syndrome (between the first rib and the clavicle).
and hypoxemia occur when thoracic kyphosis is extreme because
2. Scalenus anticus syndrome (interscalene triangle).
it reduces available visceral space, compromising lung capacity
3. Pectoral syndrome (between the pectoralis minor and the tho-
and venous return to the heart.
racic cage).
Most cases are idiopathic but can be caused by bad posture,
Reports vary, but overall the syndrome is more common in muscle spasms, or psychogenic factors. Many patients are
women than in men. It occurs mostly in the 2nd or 4th decade. asymptomatic.
Thoracic outlet syndrome is common in people who work as com- Diagnosis involves a review of the patient’s medical history, a
puter workers and people who work at a bench for long hours. It is physical examination (i.e., back, chest, pelvis, legs, feet, and skin—
also common in workers who do heavy lifting and abduct their for characteristic café-au-lait spots [e.g., neurofibromatosis]), x-ray
arms. evaluation (view of the entire spine with 36-inch film), and mea-
Common symptoms include pain in the supraclavicular region surement of the angle of curve. Curves with angles greater than
radiating into the shoulder and medial aspect of the upper 208 usually require treatment.
arm, forearm, and fourth and fifth fingers. Neurologic symptoms Treatment consists of back braces (e.g., the Milwaukee brace) to
(e.g., pain, paresthesias, dysesthesia, loss of dexterity, cold intoler- control moderate deformities. However, reports of patient compli-
ance, and headache) are produced by the compression of the C8 ance in the use back braces have been disappointing. Surgery is
and T1 spinal nerve roots and commonly affect the ulnar side of the attempted in some cases to repair or readjust the spine and to
hand but can also occur in the upper back and chest, neck, and ear. arrest the progression of deformity. Long-term use of oxygen may
Vascular symptoms (e.g., [venous] pain, edema, cyanosis, and dis- be necessary in patients experiencing significant hypoxemia.
tended superficial veins in the shoulder and chest; [arterial] clau-
dication, pallor, pulselessness, low blood pressure in the affected
arm, and embolization of hand and finger), which are related to DegenerativeThoracic Disk Disease
compression of the subclavian or axillary artery, commonly affect
the radial side of the hand. Degenerative thoracic disk disease occurs when accelerated or
Patients usually present with hand weakness and cold intoler- advanced aging causes pain in a thoracic intervertebral disk that
ance. Movement of the neck increases their pain. They may present has undergone structural failure and cell-mediated changes. The
with atrophy of the first dorsal interosseous and hypothenar underlying cause of disk degeneration is tissue weakening, occur-
muscles of the hand. Adson’s test (the radial pulse disappears as ring primarily from genetic inheritance, aging, nutritional compro-
the arm is abducted beyond 908 and the head is turned to the mise, and loading history. The precipitating cause is structural
ipsilateral side) and Wright’s test (the patient develops paresthesias disruption, which occurs from injury or fatigue failure.
or has diminished pulses on the ipsilateral side when the arm is The most common disk pathology presented to spine surgeons
progressively hyperabducted and externally rotated) are positive. for treatment is the herniated or prolapsed intervertebral disk
The Roos test is performed by positioning the patient’s shoulders (i.e., when the nucleus pulposus is forced outside the disk wall or
in abduction and external rotation of 908 with elbow flexion at 908. bulges out from its position between two disks, respectively). Other
The patient then opens and closes her or his hands for several disk pathologies include annular tears, end-plate degeneration, and
minutes. If the patient reproduces her or his symptoms or develops radiculopathy (i.e., irritation or compression of a spinal nerve root).
heaviness, she or he most likely suffers from thoracic outlet As was emphasized earlier, the least common location for disk
syndrome. pathology is the thoracic spine. Symptomatic thoracic disk hernia-
Diagnostic procedures include imaging tests (e.g., x-ray; mag- tions are very rare relative to disk herniations in other spine regions,
netic resonance imaging [MRI], computed tomography [CT], and with an estimated incidence of one in one million persons per year.
angiography) for revealing anatomic abnormality. Ultrasound anal- Asymptomatic thoracic disk herniations, conversely, are relatively
ysis is indicated for suspected vascular involvement. Arteriography common in the general population with prevalence rates ranging
and venography are used to test for suspected arterial and venous from 7% to 10%, according to reports from autopsy studies.
involvement, respectively. Nerve root stimulation is used to detect Pain is the most common presenting symptom of symptomatic
nerve involvement. thoracic disk herniations. It can be manifested in two ways: axially
Treatment should be directed toward the underlying cause of and as bandlike radicular pain along the course of the intercostal
neurovascular compression. Postural retraining, physical therapy, nerve (thoracic radiculopathy). On rare occasions, upper or lower
and weight reduction are important first steps. A soft cervical herniated thoracic disks can manifest as cervical or lumbar pain,
collar and a cervical neck pillow will help reduce traction of the respectively. The pain can be referred to visceral or inguinal areas,
brachial plexus. Scalene injections of local anesthetics and steroids resulting in misdiagnoses as such myocardial infarction or
may help relieve some of the symptoms. Patients with symptoms of cholecystitis.
complex regional pain syndrome may benefit from stellate ganglion Diagnosis is based on CT scan, myelography, and MRI, with
blocks. Conservative management must be attempted for at least MRI being the most-used imaging mode. A word of caution is in
8 to 12 weeks. Surgical options for treatment of thoracic outlet order regarding the use of MRI in making this diagnosis. In spite of
syndrome include myotomy of the scalene muscles and resection the advantages it offers, MRI has been shown to underestimate
of the first rib. thoracic disk herniation when it has low signal intensity on T1
and T2 sequences. Other tests include electrodiagnostic studies
(e.g., nerve conduction study, needle electromyography, and pro-
Thoracic Kyphoscoliosis vocative diskography for patients who are considering surgical
intervention).
Thoracic kyphoscoliosis is a disorder of the spine that involves abnor- Conservative treatment includes fluoroscopically guided epidu-
mal curvature of the spine in both coronal and sagittal planes. ral steroid injections, and anti-inflammatory agents are often
effective when continued for at least 6 to 12 weeks. Surgery is usu- painful upon deep inspiration, coughing, or sneezing. Pain may
ally recommended if conservative measures are unsuccessful. be exacerbated by passive or active thoracolumbar flexion, rotation,
and lateral flexion. Palpation elicits tenderness and pain of the
involved costotransverse joint and rib angle. Movement in the adja-
DegenerativeThoracic Facet (Zygapophyseal) cent thoracic vertebral and rib segments is usually restricted and
Joint Disease may stimulate or exacerbate protective muscle spasm.
To diagnose this dysfunction, physicians rely on clinical findings
Degenerative thoracic facet joint disease occurs when thoracic facet and patient presentation. Fluoroscopically guided costovertebral
joints become irritated or stressed. Causes include misalignment, and costotransverse joint injections are used to confirm the diag-
everyday wear-and-tear, and trauma (e.g., motor vehicle accidents). nosis and treat the pain.
Although the role of thoracic facet joints in thoracic spine pain has
received little attention in the literature, a recent study showed these
joints to be responsible pain generators in 48% of patients suffering Chronic Postsurgical Thoracic
with thoracic spine pain. (Post-thoracotomy) Pain
Symptoms include stiffness in the morning and after prolonged
sitting and pain that may be felt paravertebrally or referred laterally Chronic post-thoracotomy pain is seen in approximately 50% of
to the paravertebral region. It is important to point out that referred patients after thoracotomy, with about 30% of patients experien-
pain patterns are less frequent in the thoracic region of the spine cing the pain chronically—for as long as 4 to 5 years after surgery.
than in the cervical and lumbar regions. Pain due to thoracic facet The incidence of this condition ranges from 22% to 67%, depend-
joint disease usually emanates from and remains localized over the ing on the surgical approach. Although the exact pathogenesis
affected facet joint or from the one below it. Pain may also be remains unclear, cumulative evidence suggests neuropathic and
referred to the chest along the rib at the level of the abnormal nociceptive causes, the most likely of which is trauma to the inter-
facet joint, both anteriorly and posteriorly. Typical areas for pain costal nerve during thoracotomy. Persistent pain at the site of inci-
include the upper back, chest, and (rarely) the arm. sion may also be due to recurrent tumor in the thoracotomy scar or
Diagnosis includes a combination of medical history, physical a neuroma.
examination, and imaging studies such as x-ray, CT scan, and MRI, Symptoms include persistent chest wall pain that can be con-
which enable physicians to look for other signs of spinal distress stant as well as recurrent. Occasionally, patients report numbness at
(e.g., herniated disk) that often accompany degenerative facet joint the site of incision, shoulder pain, and limited range of motion. The
disease. intensity of pain varies from mild to severe, such that it causes
Facet joint injections with steroids have been very valuable in disability.
treating this condition. Radiofrequency denervation of the facet Management is conservative unless the pain is severe or causing
joints provides long-term relief. significant disability. Local anesthetic infiltration may help relieve
neuroma pain. Posterior, multilevel intercostal nerve blocks, tho-
racic paravertebral blocks or thoracic epidural injections are good
Costochondritis techniques for pain relief.
Recommendations for preventive measures include choosing the
Costochondritis is the inflammation and associated tenderness of most appropriate, least traumatic surgical approach, avoiding inter-
the costochondral joints, which are associated with the articulation costal nerve trauma, and adopting an aggressive, perioperative pain
of the anterior end of the lower six to seven ribs to the sternum. management that begins before the surgical incision. In addition,
Closely related to the costochondral joints are the costosternal patients should be warned preoperatively about the possibility of
joints, which are associated with the articulation of the anterior the condition and how it might affect their quality of life.
end of ribs one through five to the upper aspect of the sternum.
Although any of the seven costochondral junctions can become
inflamed, the third or fourth ribs are more frequently affected. Most Thoracic Myofascial Pain
likely causes include injury, repetitive minor trauma, and unusual
physical activity. Thoracic myofascial pain involves the muscles associated with the
The primary symptom is severe chest wall pain, which is usually thorax or chest and the thoracic spine. The muscles of the thorax
felt in the lower rib area or upper breast bone. Sitting or reclining consist of the diaphragm and the intercostal muscles (e.g., sternalis,
positions and trunk movement tend to intensify the pain, which has pectoralis major), which are arranged in three layers. The muscles of
been described as ‘‘pressure-like,’’ ‘‘sharp,’’ or ‘‘nagging.’’ the thoracic spine (e.g., levator scapulae, rhomboideus), explained
Diagnosis is based on palpation of the affected joints and exclu- elsewhere in this chapter, are also arranged in three layers. The
sion of other possible causes, including heart attack, bacterial infec- muscles in the anterior chest that are likely to be affected are pec-
tions, or pain occurring after postoperative thoracic surgery. toralis major and minor, sternocleidomastoid, subclavius, sternalis,
Treatment usually includes nonsteroidal anti-inflammatory and scalene muscles. Myofascial pain in the upper and midthoracic
drugs (with ibuprofen being the drug most commonly utilized), region is usually due to the trapezius, multifidis, latissimus dorsi,
supplemented by local heat, biofeedback, and gentle stretching of serratus posterior, superior and inferior, rhomboids, and levator
the pectoralis muscles. Local injections with steroids have been scapulae.
helpful. Myofascial pain in the chest can be caused by acute overload
(eccentric greater than concentric), repetitive movements, or
trauma of a muscle and can develop gradually or as a sudden
Costovertebral and Costotransverse Joint onset. Prompt identification of myofascial pain in this context is
Dysfunction crucial in order to avoid the emotional and financial costs of cardiac
evaluation. Predisposing factors include short leg syndrome, poor
Costovertebral and costotransverse joint dysfunction is an often- posture, prolonged immobility, vitamin/mineral deficiencies, endo-
overlooked condition in which the costovertebral and costotrans- crine dysfunctions, and injury to an intervertebral disk.
verse joints become inflamed. Patients usually present with localized Myofascial pain symptoms usually involve muscle pain with
pain to the posterior thorax that may radiate to the anterior chest or specific trigger points. The pain is often exacerbated with activity
along the associated rib. Symptoms are usually unilateral and or physical or emotional stress and with changes in temperature and
barometric pressure. Some patients present with impaired strength, the intrascapular area is the presenting symptom of a Pancoast
endurance, and flexibility, which result in impairment of mobility, tumor in 39% of cases. This example illustrates how easy it can
activities of daily living, work performance, recreation, sex, and be for practitioners who concentrate on the area of referral
sleep. (the thoracic spine area in this case) to miss the actual problem
Diagnosis of myofascial pain includes evaluation of posture, (a Pancoast tumor) or to take a longer time to make the correct
range of motion of affected limbs and areas, and strength. diagnosis while disease progression continues.
Palpation of the muscle is positive for taut bands, twitch or jump Visceral problems can also refer pain to the intrascapular area.
response, and reproducibility of patient’s symptoms. Such a pain referral occurs because of a shared sympathetic nerve
Treatment is conservative. These patients respond very well to supply between the spinal structures and the affected visceral
trigger point injections and stretching exercises. This helps relieve organ(s) (e.g., esophagus, stomach, liver, gallbladder, and pan-
muscle spasm of the affected muscle. creas). Pancreatitis, cholecystitis, or a dissecting aortic aneurysm
are among some of the visceral medical conditions that may present
with referred pain to the interscapular region.
Thoracic Radiculopathy
Thoracic radiculopathy occurs when the roots of spinal nerves CONCLUSION
emanating from the thoracic spine become pinched or trapped
because of such conditions as intervertebral disk disease, degener- Chest pain can be due to a multitude of reasons. Physicians must be
ative disk disease, diabetes mellitus, and infections like diskitis. able to identify life-threatening conditions. The thoracic region
Thoracic radiculopathy is relatively uncommon because (as pre- is also one of the most common sites of pain. Diagnosis and treat-
viously discussed) the thoracic spine lacks the flexibility and mobil- ment of a patient’s thoracic pain can be difficult because it can stem
ity of the lumbar or cervical regions from the effects of disease, trauma, and aging on both intrathoracic
Symptoms of segmental sharp, burning pain, numbness, weak- and extrathoracic structures. To further compound this difficulty,
ness, and paresthesia are usually felt in arms, chest, abdomen, or physicians must consider the possibility of referred pain. That
pelvis. Patients have described this pain as ‘‘burning,’’ ‘‘shooting,’’ is, pain may be referred from the thoracic spine to other regions
or ‘‘tingling.’’ It is aggravated by sneezing, coughing, or straining of the spine or to other areas of the body and pain may be referred
and any movement of the thoracic spine. to the thoracic spine from other regions of the spine or from vis-
Diagnosis is based on the patient’s symptoms with the use of ceral causes.
MRI or electromyography to confirm the diagnosis.
Initial treatment is often conservative. These patients often
respond well to thoracic epidural steroid injections and thoracic SUGGESTED READINGS
transforaminal injections. The exercise prescribed by a physical
therapist is designed to strengthen the thoracic spinal muscles Adams MA, Roughley PF. What is intervertebral disc degeneration, and
and tissues to relieve pressure on the affected spine nerve roots. what causes it? Spine 2006;31:2151–2161.
When conservative treatment fails, surgery may be performed to Arguello F, Baggs RB, Duerst RE, et al. Pathogenesis of
minimize pressure on the affected nerve roots and the blood vessels vertebral metastases and epidural spinal cord compression.
Cancer 1990;65:98–106.
that serve them and/or to stabilize spinal structure. Australian Acute Musculoskeletal Pain Guidelines Group. Acute thoracic
spinal pain. Evidence-based Management of Acute Musculoskeletal
Pain. Brisbane: Australian Academic Press, 2003.
OtherThoracic Pain Conditions The Thoracic Cage. Available at http://www.med.mun.ca/anatomyts/
thorax/cage.htm (accessed March 21, 2007).
Other extrathoracic spine pain conditions include vertebral com- Canale ST. Campbell’s Operative Orthopaedics, 10th ed. Mosby, 2003.
pression fracture, rib fracture, and referred pain from cervical spine Cohen SP, Sireci A, Wu CL, et al. Pulsed radiofrequency of the dorsal
disease, abdominal pathology, postherpetic neuralgia, intercostal root ganglia. 2006;9:236–277.
Dajczman E, Gordon A, Kreisman H, et al. Long-term postthoracotomy
neuralgia, peripheral neuropathy, sternoclavicular joint pathology,
pain. Chest 1991;99:270–274. Available at http://chestjournals.org/cgi/
vertebral metastases, and metastatic spine disease. content/abstract/99/2/270 (accessed March 31, 2007).
Edmondston SJ, Singer KP. Thoracic spine: anatomical and biomechanical
Referred Thoracic Pain considerations for manual therapy. Man Ther 1997;2:132–143.
Fruth SJ. Differential diagnosis and treatment in a patient with posterior
Although the focus of this chapter is on pain within the ana- upper thoracic pain. Phys Ther 2006;86:254–268. Available at
tomic confines of the thoracic spine, a few references were made www.ptjournal.org/cgi/content/full/86/2/254 (accessed March 28, 2007).
with respect to the referral of thoracic spine pain to other parts Gerwin RD. Myofascial and visceral pain syndromes: visceral-somatic pain
of the spine and other locations. Consequently, a simple and representations. J Musculoskel Pain 2002;10:165–175.
brief discussion of how thoracic spine pain is referred is war- Gilman L. Radioculopathy. 2007. Available at www.answers.com/topic/
radiculopathy. (accessed March 31, 2007).
ranted. Pain referrals from the thoracic spine occur because the Gray H. The thoracic vertebrae. In Anatomy of the Human Body.
spinal nerve of an affected structure of the spine is shared with Available at http://www.bartleby.com/107/22.html (accessed: March
the area to which the pain is being referred. For example, spinal 20, 2007).
nerves originating from vertebrae T2 to T12 have been known to Hoffberg J, Rosen NB. Myofascial pain and dysfunction syndrome. In
refer pain to the chest and abdomen, whereas the pain referred Frontera (ed): Essential of Physical Medicine and Rehabilitation, 1st ed.
by the spinal nerve originating at T1 refers pain down the ulnar Hanley & Belfus, 2002.
side of the arm (as mentioned in the section on ‘‘Thoracic Outlet James JIP. Kyphoscoliosis. J Bone Joint Surg Br 1955;37:414–424.
Syndrome’’). Karmakar MK. Postthoracotomy pain syndrome. Thorac Surg Clin
Pain can also be referred to the thoracic spine from other parts 2004;14:345–352.
Koehler RP. Management of postthoracotomy pain: acute and chronic.
of the spine or from structures in multiple visceral areas. For exam- Thorac Surg Clin 2006;16:287–297.
ple, pain may be felt in the interscapular area while its source may Lillegard WA. Medical causes of pain in the thoracic region.
be C7–T1 or T12–L1 spinal nerve dysfunction. Pain may also be felt In Flynn TW (ed): The Thoracic Spine and Rib Cage:
in the intrascapular area because of a Pancoast tumor (i.e., cancer Musculoskeletal Evaluation and Treatment. Boston: Butterworth-
near the apex of the lung). According to some sources, pain in Heinemann, 1996; pp 107–120.
Loeser J, et al. General considerations of pain in the chest. Bonica’s O’Connor RC, Andary MT, Russo RB, et al. Thoracic radiculopathy. Phys
Management of Pain, 3rd ed. Philadelphia: Lippincott Williams & Med Rehabil Clin North Am 2002;13:623–644.
Wilkins, 2001; pp 1113–1148. Parziale J, et al. Thoracic outlet syndrome. Am J Orthop 2000;3353–3359.
Manchikanti L, Singh V, Vidyasagar P, et al. Evaluation of the prevalence Schiller L. Effectiveness of spinal manipulative therapy in the treatment of
of facet joint pain in chronic thoracic pain. 2002;5:354–359. mechanical thoracic spine pain: a pilot randomized clinical trial. J Man
Maigne R: Diagnosis and Treatment of Pain of Vertebral Origin, 2nd ed. Manipulative Ther 2001;24:394–401.
Philadelphia: Lippincott Williams & Wilkins, 2006; pp 308–315. Singer K. Thoracic and chest pain. In Brukner P, Khan K (eds): Clinical
Malanga GA, McLean JP, Alladin I, et al. Thoracic discogenic pain Sports Medicine, 3rd ed. Australia: McGraw-Hill, 2006.
symptoms. EMedicine from WebMD. Available at www.emedicine.com/ Sims J. Costochondritis. In Gale Encyclopedia of Medicine, updated ed.
sports/topic129.htm (accessed March 24, 2007). Gale Group, 2006. Available at www.healthatoz.com (accessed March
Markman JD, Philip A. Interventional approaches to pain management. 28, 2007).
Med Clin North Am 2007;2. Singh V. Thoracic discography. Pain Physician 2004;7:451–458.
McMaster MJ, Singh H. The surgical management of congenital kyphosis University of Queensland Faculty of Health Sciences. Acute thoracic spinal
and kyphoscoliosis. Spine 2001;2146–2154. pain: Evidence-based management. Draft. 2002. Available at http://
McRae M, Cleland J. Differential diagnosis and treatment of upper www.uq.edu.au/health/pdf/thoracic.pdf (accessed March 24, 2007).
thoracic pain: a case study. J Man Manipulative Ther 2003;11:43–48. Urban JPG, Roberts S. Degeneration of the intervertebral disc. Arthritis
Nadalo LA, Jones K. Rib, Fractures. EMedicine 2003. Available at: http:// Res Ther 2003;5:120–130.
www.emedicine.com/radio/topic609.htm (accessed March 21, 2007). Walker RS. Thoracic pain. In The Pain Clinic. 2007. Available at http://
North American Spine Society (NASS). Definition of parts and what they www.painclinic.org/spinalpain-thoracicpain.htm (accessed March 31,
do. Available at http://www.spine.org/fsp/anatomy-functions.cfm 2007).
(accessed March 20, 2007).
Chapter 27 CLASSIFICATION
ABDOMINAL PAIN The perception of abdominal pain is determined by anatomic, phy-
siologic, psychological, and social factors. Despite the variability in
Carl Rosati and Steven C. Stain etiology and clinical manifestation, specific diagnoses remain
grounded in meticulous history taking, physical examination, and
the use of appropriated adjunctive laboratory and imaging studies.
A sound knowledge of anatomy and physiology is required to syn-
thesize these data into a working diagnosis upon which to base a
management strategy.
Abdominal pain may be classified as visceral, somatic, and
referred pain types. The neuroanatomic organization for both vis-
INTRODUCTION ceral and somatic begins with primary sensory neurons. Unlike the
somatic sensory system, however, visceral afferent fibers are fewer in
Abdominal pain is one of the most common presenting problems to number and diverge over many more spinal segments and the same
the primary care physician, emergency department, gastroenterolo- dorsal nerve roots may receive nociceptive impulses from varied
gist and general surgeon. This chapter will discuss the epidemiology abdominal locations. This contributes to the poorly localized,
and clinical presentation of both acute and chronic abdominal pain, deep, aching, and vague qualities of visceral pain. Visceral afferents
examine the classification and present an anatomically based differ- travel within the trunks of the autonomic nervous system, princi-
ential diagnosis with which to formulate a plan of investigation and pally sympathetic trunks for the abdominal organs and parasympa-
management. thetic trunks for the thorax and pelvis. The visceral afferents enter
the spinal cord via the dorsal horn, decussate, and ascend via the
lateral spinothalamic and spinoreticulothamic tracts to the thala-
EPIDEMIOLOGY mus. Visceral pain stimuli include ischemia, inflammation, and
elevated tension in the wall of a hollow viscus from distention or
The U.S. Centers for Disease Control and Prevention National contraction and capsular distention of solid viscera.4
Hospital Ambulatory Medical Care Survey 2004 Emergency Somatic afferent nerve fibers receive nociceptive impulses from
Department Summary1 identified stomach and abdominal pain, the parietal pleura and peritoneum, root of the mesentery, and
cramps, and spasms as the most common symptoms responsible abdominal wall. Somatic afferents enter the dorsal roots of the
for emergency room visits, accounting for over 7.5 million emer- spinal cord, decussate, ascend the anterolateral spinothalamic
gency visits annually. Abdominal pain ranks within the most tract, and then to the thalamus and somatic sensory cortex.4
common three illness-related diagnoses in the emergency depart- Somatic afferents more closely correspond to specific dermatomes
ment between the ages of 13 and 65 and over. No specific etiology is and, therefore, are more well localized. The quality of somatic pain
identified in 35% to 51% of patients, and up to one third of patients is typically sharper and lateralized.
have diagnoses that may require surgical intervention.2,3 It is appar- Referred pain is discomfort perceived at a site remote from
ent that abdominal pain is a common presenting complaint, and the source of pain. The neuroanatomic organization for referred
physicians should be familiar with the common disorders that pres- pain is less well understood but generally follows the embryologic
ent with abdominal pain. The evaluation and treatment of patients dermatome. At times, pain may be referred to the site of previous
with abdominal pain require an efficient diagnostic and therapeutic trauma or scar. Common examples of referred pain include shoulder
framework because significant resources are often consumed to care tip pain corresponding with dermatomes C3, C4, and C5 in associ-
for these patients. ation with diaphragmatic irritation from subphrenic, splenic, or
Loeser J, et al. General considerations of pain in the chest. Bonica’s O’Connor RC, Andary MT, Russo RB, et al. Thoracic radiculopathy. Phys
Management of Pain, 3rd ed. Philadelphia: Lippincott Williams & Med Rehabil Clin North Am 2002;13:623–644.
Wilkins, 2001; pp 1113–1148. Parziale J, et al. Thoracic outlet syndrome. Am J Orthop 2000;3353–3359.
Manchikanti L, Singh V, Vidyasagar P, et al. Evaluation of the prevalence Schiller L. Effectiveness of spinal manipulative therapy in the treatment of
of facet joint pain in chronic thoracic pain. 2002;5:354–359. mechanical thoracic spine pain: a pilot randomized clinical trial. J Man
Maigne R: Diagnosis and Treatment of Pain of Vertebral Origin, 2nd ed. Manipulative Ther 2001;24:394–401.
Philadelphia: Lippincott Williams & Wilkins, 2006; pp 308–315. Singer K. Thoracic and chest pain. In Brukner P, Khan K (eds): Clinical
Malanga GA, McLean JP, Alladin I, et al. Thoracic discogenic pain Sports Medicine, 3rd ed. Australia: McGraw-Hill, 2006.
symptoms. EMedicine from WebMD. Available at www.emedicine.com/ Sims J. Costochondritis. In Gale Encyclopedia of Medicine, updated ed.
sports/topic129.htm (accessed March 24, 2007). Gale Group, 2006. Available at www.healthatoz.com (accessed March
Markman JD, Philip A. Interventional approaches to pain management. 28, 2007).
Med Clin North Am 2007;2. Singh V. Thoracic discography. Pain Physician 2004;7:451–458.
McMaster MJ, Singh H. The surgical management of congenital kyphosis University of Queensland Faculty of Health Sciences. Acute thoracic spinal
and kyphoscoliosis. Spine 2001;2146–2154. pain: Evidence-based management. Draft. 2002. Available at http://
McRae M, Cleland J. Differential diagnosis and treatment of upper www.uq.edu.au/health/pdf/thoracic.pdf (accessed March 24, 2007).
thoracic pain: a case study. J Man Manipulative Ther 2003;11:43–48. Urban JPG, Roberts S. Degeneration of the intervertebral disc. Arthritis
Nadalo LA, Jones K. Rib, Fractures. EMedicine 2003. Available at: http:// Res Ther 2003;5:120–130.
www.emedicine.com/radio/topic609.htm (accessed March 21, 2007). Walker RS. Thoracic pain. In The Pain Clinic. 2007. Available at http://
North American Spine Society (NASS). Definition of parts and what they www.painclinic.org/spinalpain-thoracicpain.htm (accessed March 31,
do. Available at http://www.spine.org/fsp/anatomy-functions.cfm 2007).
Chapter 27 CLASSIFICATION
ABDOMINAL PAIN The perception of abdominal pain is determined by anatomic, phy-
siologic, psychological, and social factors. Despite the variability in
Carl Rosati and Steven C. Stain etiology and clinical manifestation, specific diagnoses remain
grounded in meticulous history taking, physical examination, and
the use of appropriated adjunctive laboratory and imaging studies.
A sound knowledge of anatomy and physiology is required to syn-
thesize these data into a working diagnosis upon which to base a
management strategy.
Abdominal pain may be classified as visceral, somatic, and
referred pain types. The neuroanatomic organization for both vis-
INTRODUCTION ceral and somatic begins with primary sensory neurons. Unlike the
somatic sensory system, however, visceral afferent fibers are fewer in
Abdominal pain is one of the most common presenting problems to number and diverge over many more spinal segments and the same
the primary care physician, emergency department, gastroenterolo- dorsal nerve roots may receive nociceptive impulses from varied
gist and general surgeon. This chapter will discuss the epidemiology abdominal locations. This contributes to the poorly localized,
and clinical presentation of both acute and chronic abdominal pain, deep, aching, and vague qualities of visceral pain. Visceral afferents
examine the classification and present an anatomically based differ- travel within the trunks of the autonomic nervous system, princi-
ential diagnosis with which to formulate a plan of investigation and pally sympathetic trunks for the abdominal organs and parasympa-
management. thetic trunks for the thorax and pelvis. The visceral afferents enter
the spinal cord via the dorsal horn, decussate, and ascend via the
lateral spinothalamic and spinoreticulothamic tracts to the thala-
EPIDEMIOLOGY mus. Visceral pain stimuli include ischemia, inflammation, and
elevated tension in the wall of a hollow viscus from distention or
The U.S. Centers for Disease Control and Prevention National contraction and capsular distention of solid viscera.4
Hospital Ambulatory Medical Care Survey 2004 Emergency Somatic afferent nerve fibers receive nociceptive impulses from
Department Summary1 identified stomach and abdominal pain, the parietal pleura and peritoneum, root of the mesentery, and
cramps, and spasms as the most common symptoms responsible abdominal wall. Somatic afferents enter the dorsal roots of the
for emergency room visits, accounting for over 7.5 million emer- spinal cord, decussate, ascend the anterolateral spinothalamic
gency visits annually. Abdominal pain ranks within the most tract, and then to the thalamus and somatic sensory cortex.4
common three illness-related diagnoses in the emergency depart- Somatic afferents more closely correspond to specific dermatomes
ment between the ages of 13 and 65 and over. No specific etiology is and, therefore, are more well localized. The quality of somatic pain
identified in 35% to 51% of patients, and up to one third of patients is typically sharper and lateralized.
have diagnoses that may require surgical intervention.2,3 It is appar- Referred pain is discomfort perceived at a site remote from
ent that abdominal pain is a common presenting complaint, and the source of pain. The neuroanatomic organization for referred
physicians should be familiar with the common disorders that pres- pain is less well understood but generally follows the embryologic
ent with abdominal pain. The evaluation and treatment of patients dermatome. At times, pain may be referred to the site of previous
with abdominal pain require an efficient diagnostic and therapeutic trauma or scar. Common examples of referred pain include shoulder
framework because significant resources are often consumed to care tip pain corresponding with dermatomes C3, C4, and C5 in associ-
for these patients. ation with diaphragmatic irritation from subphrenic, splenic, or
202 Chapter 27 ABDOMINAL PAIN
hepatic pathology; right subscapular pain associated with gallbladder renal colic, pelvic inflammatory disease, benign and malignant
pathology; thoracolumbar back pain associated with pancreatic adenexal masses, ectopic pregnancy, endometriosis, psoas
pathology; and sacral pain associated with rectal pathology. abscess, aortic aneurysm.
HISTORYAND PHYSICAL
EXAMINATION EXTRAGASTROINTESTINAL
DIAGNOSES
It is well known that the greatest yield to the medical diagnosis co-
mes from the contribution made by the combination of history and A number of nonabdominal and nonsurgical disorders may present
physical examination. Care must be taken to include potential con- as acute or chronic abdominal pain. A combined anatomic and phys-
founding variables such as extremes of age, comorbidities, and med- iologic paradigm helps the clinician to consider these entities when
ications in addition to psychosocial influences. A thorough history the more common gastrointestinal diagnoses are ruled out. One such
and physical examination combined with a common sense working paradigm includes consideration of thoracic, retroperitoneal, pelvic,
paradigm that takes into account common illnesses is, therefore, functional, inflammatory, infectious, vascular, hematologic, meta-
important in formulating a differential diagnosis. For example, bolic, and toxic etiologies. It is also important to develop a frame-
abdominal pain that begins as a vague central abdominal discomfort work in which one considers the risk of morbidity and mortality
that localizes to the right lower quadrant with evidence of peritoneal should important diagnoses be missed. Utilizing this methodology
irritation would suggest acute appendicitis in North America; may generate a differential diagnosis that could include myocardial
however, in sub-Saharan Africa, it may suggest acute typhus. infarction, septic emboli from endocarditis, thoracoabdominal
Elements of the history should include onset, duration, quality, aortic dissection or aneurysm, pulmonary embolism, pneumonia,
radiation, character, associated symptoms, aggravating and relieving empyema, spinal cord or nerve root compression (benign or malig-
factors, similar previous illnesses, and exposures. In addition, a thor- nant), spontaneous retroperitoneal hematoma, psoas abscess, ectop-
ough review of systems, medications, allergies, and family and social ic pregnancy, pelvic inflammatory disease, gynecologic malignancy,
history may provide valuable clues to formulating a working diagnosis. endometriosis, adenexal torsion, sickle cell disease, acute leukemia,
Physical examination of the abdomen must include inspection hemolytic-uremic syndrome, adrenal insufficiency, diabetic ketoaci-
and inspection with cross-illumination, light and deep palpation, dosis, porphyria, and toxic drug and environmental exposure.
percussion, and auscultation. Attention must be paid to search for
hernias as well as to performing a rectal and vaginal examination.
LABORATORYAND IMAGING STUDIES
DIFFERENTIAL DIAGNOSIS Adjunctive studies should be based on the clinician’s working and
differential diagnoses. A discussion of the sensitivity, specificity,
Whereas, in many respects, the abdomen is a black box, combining positive and negative predictive values, accuracy, and likelihood
the physical examination with knowledge of the underlying anat- ratios of the multitude of laboratory and imaging studies is well
omy and standard pathophysiologic mechanisms—inflammatory, beyond the scope of this chapter. However, knowledge about some
obstructive, vascular—is a rational approach that can assist with of the properties of the adjunctive test along with an idea of the
formulating a more specific differential diagnosis and provide the prevalence of a disease will assist the clinician by confirming or
basis upon which to utilize appropriate adjunctive studies. Utilizing rejecting a diagnosis. Since the late 1990s, there have been dramatic
this framework, the following differential diagnoses may be gener- improvements in numerous imaging and laboratory test technolo-
ated based on acute abdominal pain by anatomic location: gies, most notably in imaging. Ultrasonography is now considered
by many physicians as an extension of the physical examination.
n Generalized pain: Perforated viscus, intestinal obstruction, Helical computed tomography (CT) now provides noninvasive and
intestinal ischemia, colitis, pancreatitis, early appendicitis, detailed imaging data of the head, neck, chest, abdomen, and pelvis
constipation, ruptured abdominal aortic aneurysm, gastroen- in seconds. A number of authors suggested that with the widespread
teritis, diabetic ketoacidosis, sickle cell crisis, uremia, leuke- use of CT has come an improvement in diagnostic certainty of 40%
mia, porphyria, Munchausen’s syndrome. to 50%.5,6 The most common initial tests for the patient with acute
n Left upper quadrant pain: Splenic injury, splenic infarction, abdominal pain are complete blood count, electrolytes, blood urea
subphrenic abscess, peptic ulcer, intestinal obstruction, intes- nitrogen, creatinine, serum amylase, serum lipase, liver function
tinal ischemia, colitis, pancreatitis, pancreatic psuedocyst, tests, electrocardiogram, and urinalysis. These are often followed
abdominal wall hernia, pyelonephritis, renal colic, renal neo- by radiographic studies, such as abdominal ultrasonography and
plasm, aortic dissection, pulmonary embolism, left lower lobe abdominal and pelvic CT. Among all the diagnostic tests, studies
pneumonia, herpes zoster, myocardial infarction. have suggested that the highest yields in terms of improved diag-
n Left lower quadrant pain: Abdominal/inguinal hernia, diver- nostic accuracy and in directing patient disposition (admission or
ticular disease, benign and malignant colonic obstruction, discharge home) were seen from the use of urinalysis and CT.7,8
ischemic colitis, renal colic, renal neoplasm, pelvic inflamma-
tory disease, benign and malignant adenexal masses, ectopic
pregnancy, endometriosis, psoas abscess, aortic aneurysm. ACUTE PAIN MANAGEMENTAND
n Right upper quadrant pain: Subphrenic abscess, liver abscess,
hepatobiliary and pancreatic neoplasms (benign and malignant),
EVALUATION
biliary colic, cholecystitis, cholangitis, Fitz-Hugh-Curtis syn- The issue of whether to administer analgesic medications to patients
drome, peptic ulcer disease, renal colic, pyelonephritis, pulmo- with acute abdominal pain prior to surgical evaluation remains
nary embolism, pneumonia, pericarditis, myocardial ischemia/ somewhat controversial. At issue is the potential that analgesic
infarction, thoracoabdominal aneurysm/dissection. medications may alter the patient’s pain perception and physical
n Right lower quadrant pain: Abdominal/inguinal hernia, findings, resulting in erroneous diagnosis and/or delay in appropri-
appendicitis, inflammatory bowel disease (Crohn’s disease, ul- ate therapy. Authoritative resources including textbooks of physical
cerative colitis), gastroenteritis, diverticulitis, cholecystitis, diagnosis and surgery have, in the past, rigorously supported the
peptic ulcer disease, intestinal ischemia, intestinal obstruction, position that analgesic medications should be withheld in those
patients awaiting surgical evaluation. In addition, improvements in Functional Abdominal Pain

diagnostic imaging such as ultrasonography, high-speed CT, and
magnetic resonance imaging have influenced or changed practice The definitions of functional abdominal pain in adults and in chil-
patterns and, in some situations, may have deemphasized the role of dren differ somewhat but share common themes. In children, pain
the careful history and physical examination. Reliance on diagnostic exceeding 1 to 2 months in duration, and in adults in whom abdomi-
testing is not justification for the use of analgesic medications in nal pain is continuous or nearly continuous for 6 months, and inter-
this setting. Over the past decade, a considerable body of research feres with function, satisfies the definition of chronic or functional
has been generated to examine the influence of analgesic adminis- abdominal pain. Importantly, however, there should be no evidence
tration, in the setting of acute abdominal pain, on diagnostic accu- of underlying pathologic disorder resulting from anatomic, neoplas-
racy and the morbidity and mortality resulting from delay in tic, inflammatory, infectious, metabolic, or toxic etiology.12,13
surgery or unnecessary surgery. A number of interesting hypotheses
have been generated as they related to the history and physical
examination when analgesics were given in the setting of the eval- Pathophysiology of Chronic Abdominal Pain
uation of the patient with acute abdominal pain. Some of these
include the possibility that on the one hand, analgesics may make The pathophysiology of chronic abdominal pain is much less well
the patient’s clinical history unreliable; on the other hand, the anal- understood than that of acute abdominal pain. Current neurophy-
gesic effect may also relieve the patient’s distress sufficiently to siologic and neuropharmacologic research have provided useful
improve the clinical history. Some clinicians believe that abdominal insights into the pathophysiologic characteristics of this problem.
muscular rigidity in response to peritoneal irritation (involuntary Abnormalities in pain perception may be rooted in peripheral and
guarding) is a spinal reflex mediated by somatic spinal afferents and central hypersensitivity. It is postulated that inciting events such as
should not be affected by opiate analgesics. However, neuroana- surgery or inflammation may induce sensitization of peripheral
tomic evidence suggests that opiate receptors m and k in the periph- nerves, and in certain patients, this hypersensitivity persists.
ery may modulate pain stimuli at their site of origin, and together Overexpression of peripheral nerve receptors responsible for modu-
with the m-, k-, and d-receptors in the brain and spinal cord may lation of noxious stimuli may then result in ongoing nociceptive
indeed exert a blunting effect on involuntary guarding.9 stimuli or interference with local inhibitory responses. Alteration
A recent meta-analysis of 12 placebo-controlled trials (9 adult in the expression of several genes in the spinal cord dorsal horn
and 3 pediatric trials) to evaluate the affect of opiates on the clinical has been identified in chronic inflammation disorders such as
evaluation of patients with acute abdominal pain revealed a number osteoarthritis. The reduced efficacy of opioid analgesics, as is fre-
of interesting findings.10 The risk of changes in the physical exam- quently observed in patients with neuropathic pain, may be the
ination was significantly greater among patients receiving opiates result of a reduction in the sensitivity of the opioid receptor.14 It is
versus placebo (risk ratio 2.13; 95% confidence interval [CI] 1.14– further postulated that peripheral sensitization results in central sen-
3.98). Patients receiving opiate analgesic medication had no signif- sitization. This phenomenon is clinically supported by the increased
icant association with management errors (risk difference –0.2%; frequency of clusters of other potentially functional disorders such as
95% CI –4.0% to +3.6%), and there was a trend toward a reduction nonulcer dyspepsia, noncardiac chest pain or fibromyalgia.12
in unnecessary surgeries. All of the studies in the meta-analysis
evaluated the patients’ perception of pain; however, none of the
studies evaluated the effect of opiate analgesic on the accuracy History and Physical Examination
of the clinical history. There were notable methodologic limitations
of the studies in this meta-analysis. Few of the studies indicated Functional abdominal pain syndromes are most often characterized by
adequate blinding in either treatment allocation or outcomes assess- a neuropathic quality with overlying emotional features and little
ment. The same physician examined the patients before and after to no relationship to gut function. Symptoms tend to be protracted,
administration of the study medication, and the specific analgesic often constant, aggravated by minimal stimulus, and debilitating with
medications varied considerably and included some analgesic med- pervasive emotional features that may include depressed mood, anhe-
ications not commonly used for the management of acute pain donia, and abulia. In a recent study,11 quality of life indices identified
in the emergency department. Recognizing the potential bias intro- risk factors for postsurgical chronic pain as younger age, female gender,
duced by these methodologic limitations, this meta-analysis and surgery for benign disease. The absence of alarm symptoms often
suggested that despite the finding that analgesic administration referred to pediatric literature portend a functional etiology. Alarm
does alter the physical examination, there does not appear to be symptoms and signs include pain that awakens the patient from
any significant impact on clinical management in terms of manage- sleep, anorexia, involuntary weight loss or significant change in the
ment errors. The authors further concluded that no patient suffered growth chart of children, vomiting, diarrhea, constipation, and changes
major morbidity or mortality owing to opiate analgesic administra- in bowel and bladder function. Frequently, the history taking is influ-
tion.10 Judicious use of analgesics would seem reasonable and enced by the search for organic diagnoses; however, a comprehensive
justified to relieve pain, although not to the point of affecting the evaluation of the psychosocial issues is important to consider for a
patient’s ability to provide a valid history. functional diagnosis and in the formulation of a management plan.
Much like the comprehensive history taking, the physical exam-
ination should employ the same thorough and meticulous method-
CHRONIC ABDOMINAL PAIN ology as is used in the evaluation of the patient with acute pain.
Signs that may suggest a functional etiology of abdominal pain
The diagnosis and management of chronic abdominal pain present include hypervigilance; absence of stress state; autonomic signs
a significant clinical challenge, particularly in the differentiation of such as hypertension, tachycardia, tachypnea, multiple surgical inci-
organic and functional etiologies. The following discussion deals sions, distractibility, and Carnett’s sign (increased tenderness when
primarily with chronic functional abdominal pain. The prevalence abdominal muscles are tensed).
of chronic abdominal pain varies, ranging from 18% chronic post-
operative pain after gastrointestinal surgery to less than a 2% rate in
a U.S. population-based survey.11,12 Authorities recommend a mul- Diagnostic Investigation
tidisciplinary approach to the management of these patients to
ensure that the biopsychosocial aspects of the patient’s care are No laboratory or imaging studies, over and above those used for
considered. the evaluation of acute abdominal pain, are of proven benefit
204 Chapter 27 ABDOMINAL PAIN
for the diagnosis of chronic abdominal pain. A number of neuro- barbiturate medications should be avoided. Reduced opioid sensi-
physiology- and metabolism-based studies have been used in the tivity is commonly observed among patients with chronic pain in
research arena, but as yet, these have not demonstrated utility in the general, which is supported by biologically plausible pathophysio-
day-to-day evaluation of these patients. Some of these studies logic changes (discussed earlier). In addition, avoidance of opioid
include cortical evoked potentials, positron-emission tomography, analgesics will also reduce the risk of drug dependency and opioid
functional magnetic resonance imaging, and magnetoencephalo- bowel syndrome.12,14
graphy.12 Diseases are, however, not static. To ensure that a thor-
ough diagnostic evaluation has been performed, repeat studies are
commonly done and may help in providing patients with functional SUMMARY
gastrointestinal pain with reassurance that treatable disorders have
been ruled out. Disorders that present as either acute or chronic abdominal pain are
not static entities. What may appear confusing or cryptic early in
the presentation may become clear as the disease process evolves.
Differential Diagnosis The clinician’s diagnostic accuracy will, therefore, change with var-
iations in presentation. The clinical evaluation firmly rooted in the
The differential diagnosis for chronic abdominal pain is extremely meticulous history and physical examination complemented by
broad. Once common etiologies have been ruled out, a number of judicious diagnostic investigation will help distinguish competing
unusual, infrequent, and at times, serious diagnoses should be diagnoses.
entertained. These diagnoses may be variously classified; a partial
list of organic and functional diagnoses would include thoracoab-
dominal aneurysm, myocardial ischemia, pulmonary neoplasm, REFERENCES
thoracolumbar disk disease, costal chondritis (Tietze’s syndrome) 1. U.S. Centers for Disease Control and Prevention. National hospital
and intercostal neuralgia, postherpetic neuralgia, myofacial pain ambulatory medical care survey 2004 emergency department
syndrome, porphyria, adrenal insufficiency, chronic renal insuffi- summary. Available at http://www.cdc.gov/nchs/data/ad/ad372.pdf
ciency, abdominal migraine, sickle cell disease, Henoch-Schönlein (accessed December 5, 2007).
purpura, inflammatory bowel disease, intestinal ischemia, intestinal 2. Irvin T. Abdominal pain: a surgical audit of 1190 emergency
volvulus, Meckel’s diverticulum, opportunistic infections in immu- admissions. Br J Surg 1989;76:1121–1125.
nocompromized patients, and adverse effects of drugs and toxins. 3. Klinkman MS. Episodes of care for abdominal pain in a primary care
practice. Arch Fam Med 1996;5:279–285.
4. Barkow R (ed). Acute abdomen and surgical gastroenterology:
abdominal pain. The Merck Manual, 14th ed. Rahway, NJ: Merck
Therapy Sharp & Dohme, 1982; pp 736–740.
5. Esses D, Birnbaum A, Shah S, et al. Ability of CT to alter decision
Outlining a plan of management requires a working diagnosis. making in elderly patients with acute abdominal pain. Am J Emerg
Therefore, a working diagnosis of chronic functional abdominal Med 2004;22:270–272.
pain syndrome must be discussed with the patient, including the 6. Tsushima Y, Aoki J, Endo K. Contribution of the diagnostic test to
current hypotheses of pathophysiology and the multidisciplinary the physician’s diagnostic thinking: new method to evaluate the effect.
approach to symptom management. Acad Radiol 2003;10:751–755.
7. Naqurney JT, Brown DF, Chang Y, et al. Use of diagnostic testing in
Intra-abdominal adhesions are frequently implicated as a caus- the emergency department for patients presenting with non-traumatic
ative factor in chronic postoperative abdominal pain. Whereas this abdominal pain. J Emerg Med 2003;25:363–371.
remains a controversial subject, it is postulated that lysis of adhe- 8. Sandler G. Do emergency tests help in the management of acute
sions should result in improvement or resolution of abdominal medical admissions? Br Med J (Clin Res Ed) 1984;289:973–977.
pain. Prospective studies evaluating this question, including a mul- 9. Yaksh TL. Pharmacology and mechanisms of opioid analgesic activity.
ticenter randomized clinical trial, have failed to demonstrate mean- Acta Anaesthesiol Scand 1997;41:94–111.
ingful benefit to lysis of adhesions for chronic abdominal pain.15,16 10. Ranji SR, Goldman LE, Simel DL, Shojania KG. Do opiates affect the
Nonoperative treatement for functional abdominal pain syn- clinical evaluation of patients with acute abdominal pain? JAMA
2006;296:1764–1774.
dromes includes cognitive, behavioral, physical, occupational,
11. Bruce J, Krukowski Z. Quality of life and chronic pain four years
recreational, and medical therapies. Detailed discussion about after gastrointestinal surgery. Dis Colon Rectum 2006;49:1362–1370.
the role of cognitive and behavioral therapies is beyond the scope 12. Matthews PJ, Aziz Q. Functional abdominal pain. Postgrad Med J
of this report. However, clinical evidence has demonstrated that 2005;81:448–455.
these therapeutic modalities are superior to education alone.17 13. Subcommittee on Chronic Abdominal Pain. Chronic abdominal pain
The subcommittee of chronic abdominal pain of the American in children. Pediatrics 2005;115:812–815.
Academy of Pediatrics and the North American Society for 14. Przewlocki R, Przewlocka B. Opioids in chronic pain. Eur
Pediatric Gastroenterology, Hepatology, and Nutrition outlines J Pharmacol 2001;429:79–91.
medication recommendations based on classes of medication that 15. Swank D, Swank-Bordewijk S, Hop W, et al. Laparoscopic
may also be generalized to adult populations. This body also recom- adhesiolysis in patients with chronic abdominal pain: a blinded
randomized controlled multicenter trial. Lancet 2003;361:1247–1251.
mends that medications be used as part of a multimodal and indi- 16. Dunker MS, Bemelman WA, Vijn A, et al. Long-term outcomes and
vidualized management plan. Judicious use of some of the following quality of life after laparoscopic adhesiolysis for chronic abdominal
medications were recommended: acid-reducing agents, spasmoly- pain. J Am Assoc Gynecol Laparosc 2004;11:36–41.
tics and smooth muscle relaxants, low-dose psychotropic agents 17. Drossman DA, Toner BB, Witehead WE, et al. Cognitive-behavior
(particularly tricyclic antidepressants), antidiarrheal agents, and therapy versus education and desipramine versus placebo for
nonstimulating laxatives.13 Anticonvulsants, notably gabapentin moderate to severe functional bowel disorders. Gastroenteroloy
(Neurontin) and pregabulin (Lyrica) have proved useful for 2003;125:19–31.
the relief of neuropathic pain. Generally, narcotic (opioid) and
Chapter 28 propagation of pelvic pain syndromes. In addition, we have to be

prepared to offer our patients who suffer from debilitating chronic
GENITOURINARY PAIN pelvic pain and the associated bladder, bowel, and sexual disorders
the special care needed to help relieve them of the burden of years of
SYNDROMES: INTERSTITIAL invalidation and abandonment by family members and caregivers.
In the end, the good news is that safe and adequate pain relief and
restoration of function are currently available to most of these
CYSTITIS, CHRONIC patients, using strategies involving pharmacologic and electronic
neuromodulation and that even better treatments are just over
PROSTATITIS, PELVIC FLOOR the horizon.
The urogenital pain syndromes encompass a wide variety of
disorders including chronic prostatitis, vulvodynia, pelvic floor dys-
DYSFUNCTION, AND RELATED function, urethral syndrome, and orchialgia. A reasonable ‘‘model’’
syndrome for this group of urogenital pain disorders is interstitial
DISORDERS cystitis. Interstitial cystitis and related disorders may be responsible
for generating the majority of cases of ‘‘chronic pelvic pain,’’ even
Daniel Brookoff those attributed to other structural disorders such as endometriosis,
uterine adenomyosis, and pelvic adhesions. Whereas the lifetime
incidence of chronic pelvic pain in American women is estimated
to be as high as 33%, fewer than 1% of these patients are ever seen
by pain specialists. Developing neuromodulatory strategies for
interstitial cystitis and related syndromes such as chronic prostatitis,
pelvic floor dysfunction, and chronic genital pain also holds the
INTRODUCTION promise of developing effective treatments for the functional urin-
ary, bowel, and sexual disorders that often accompany them.
It is testimony to the importance and complexity of chronic uro- Interstitial cystitis has long been characterized as a ‘‘urologic’’
genital and pelvic pain disorders that this volume contains three disease, but it may be better understood as a ‘‘complex visceral pain
separate chapters dealing with chronic pelvic pain. This chapter syndrome.’’ Indeed, interstitial cystitis has been likened to ‘‘reflex
aims to present an integrative approach to some of the common sympathetic dystrophy’’ of the bladder or ‘‘chronic regional pain
urogenital pain disorders, placing them in the ‘‘neurovisceral’’ con- syndrome (CRPS) I of the pelvis.’’ The epidemiology, pathology,
text of painful disorders, such as fibromylagia or irritable bowel and pattern of response to treatment in interstitial cystitis overlap
syndrome, that we commonly associate with other end-organs. so closely with those in chronic prostatitis, pelvic floor dysfunction,
Whereas there may be some disagreements and differences among and frequency-urgency syndrome (‘‘overactive bladder’’) that it is
different authors addressing a similar subject, I hope that this will reasonable to conclude that these syndromes represent different
prove complementary to the anesthesiologic and rehabilitative expressions of the same disease process.
approaches discussed in Section V, Chapter 29, Pelvic Pain, and The prevalence of interstitial cystitis and related syndromes has
Chapter 30, Female Perineal/Pelvic Pain: The Rehabilitation. long been underestimated. Data from the Nurse’s Health Study
One factor that has made urogenital pain disorders particularly found that over 6% of American women have ‘‘classic’’ interstitial
difficult to manage is that many of the traditional treatments— cystitis, defined by urologists as a syndrome characterized by
ranging from caustic bladder instillations to short-lived denervation ‘‘chronic irritative voiding symptoms, sterile and cytologically neg-
procedures to the excision of the presumptively ‘‘diseased’’ end- ative urine, characteristic cystoscopic findings along with failure
organs in the form of unnecessary hysterectomies, prostatectomies, to find a more objective cause for the clinical picture.’’ In addition,
and cystectomies—often do more to ingrain and accelerate these the prevalence of ‘‘chronic pelvic pain syndrome’’ in American
painful conditions than to relieve them. Recent insights from the women between the ages of 18 and 50 is estimated to be over
study of these syndromes suggest that we should be directing our 10%. The estimated prevalence of chronic abacterial prostatitis,
treatments toward modulating the neurologic generators of noci- which is the diagnosis most commonly given to adult males in
ception and dysfunction rather than removing or destroying the the United States with the symptom complex consistent with inter-
visceral organs that were once presumed to be responsible for stitial cystitis, is over 5%. Moreover, ‘‘overactive bladder’’ syndrome
chronic pelvic pain or the nerves that innervate them. I tell my (urgency, frequency, nocturia often accompanied by pelvic pain)
patients with chronic urogenital and pelvic pain that I have two may also represent a form of interstitial cysitits and is estimated
equally important obligations to them. On the one hand, I must to affect over 33 million Americans, amounting to over 15% of the
make sure that they get all the treatments they need, but on the adult population. The prevalence for overactive bladder syndrome
other hand, I must often expend just as much effort to make sure does not vary by gender, and the burden of this disorder is highest
that they are not subjected to treatments they do not need. in the elderly, in whom it is associated with pressure ulcers, urinary
One of the most difficult tasks that we as physicians need to tract infections, falls, and fractures.
accomplish in reconsidering our treatment of painful urogenital
disorders involves the ‘‘unlearning’’ of long-held beliefs rather
than the acquisition of new knowledge. Many of the assumptions BLADDER DYSFUNCTION AND
we have carried with us for years (e.g., that the uterine cervix serves PELVIC PAIN
only as a potential source for cancer that should be removed at the
earliest opportunity rather than as the ‘‘keystone’’ for the muscu- Interstitial cystitis is essentially hypersensitivity of the urinary blad-
lature of the pelvic floor) have contributed to the iatrogenic der. The hallmarks of this disorder are exaggerated and abnormal
206 Chapter 28 GENITOURINARY PAIN SYNDROMES
sensory and motor reactions to the presence of urine in the blad- In a large survey of female patients with interstitial cystitis, 92%
der that often progress to debilitating hyperalgesia and allodynia. reported urinary urgency, 91% urinary frequency, 70% pelvic pain,
Interstitial cystitis often starts out as ‘‘irritable bladder,’’ with the 60% dysuria, 37% pain for days after intercourse, and 22% hema-
urgency to urinate accompanied by small urinary volumes. At the turia (usually microscopic). Fifty-five percent of these patients
extreme, patients with interstitial cystitis may experience the com- reported daily or constant pelvic pain, with 57% of them character-
pelling urge to urinate up to 80 times per day, suffering with izing the pain as ‘‘severe’’ or ‘‘excruciating.’’ Pelvic pain was often
constant disabling pelvic pain and intractable insomnia. (but not always) increased by stress, ingestion of alcohol, tomatoes,
Interstitial cystitis and its associated syndromes such as chronic acidic or carbonated beverages, disturbances in sleep, and long car
nonbacterial prostatitis are the most disabling disorders seen by rides. Most patients with interstitial cystitis report that the disease
urologists. has caused significant disruptions in family relationships.
Female predominance among patients with interstitial cystitis, Many patients with interstitial cystitis believe that they can
estimated at up to 90%, was noted early on in the study of this pinpoint the day their symptoms started. They often associate the
syndrome. Soon thereafter, interstitial cystitis came to be associated onset of irritative voiding symptoms with a specific event such as a
with psychiatric and emotional disturbance. A 1958 paper entitled urinary tract infection or pelvic surgery. Most of these patients are
‘‘Masochism and Interstitial Cystitis’’ talked about the etiology of initially treated with antibiotics for acute bacterial cystitis despite
interstitial cystitis being ‘‘repressed hostility toward parental figures negative urinalyses and cultures. In general, patients will suffer with
handled masochistically via bladder symptoms.’’ Interestingly, progressive symptoms for 3 to 7 years and undergo work-up by
whereas many urologists subscribed to a psychiatric etiology of more than four physicians before the diagnosis of interstitial cystitis
interstitial cystitis, they continued to advocate for surgical treat- is finally made.
ment, most of which worsened the illness. One standard urology
textbook, which strongly advocated for early cystectomy in the
treatment of interstitial cystitis, described the syndrome as ‘‘the ASSOCIATION WITH TRAUMATO
end-stage of a bladder that has been made irritable by emotional PELVIC NERVES
disturbance—a pathway for the discharge of unconscious hatreds.’’
Although originally believed to be a disease of the elderly, epide- The majority of women diagnosed with interstitial cystitis have a
miologic studies show that the onset of interstitial symptoms gen- history of antecedent pelvic surgery. The most common procedure
erally occurs between the ages of 30 and 50 years. An increasing is hysterectomy, which is already known to be a common cause of
number of sufferers are found to have had urinary symptoms and bladder dysfunction. In an epidemiologic study in the United States,
pelvic problems (e.g., severe dysmenorrhea causing them to miss 44% of women with interstitial cystitis had undergone hysterectomy
days of work or school, severe constipation) dating back to within 6 months preceding the onset of symptoms. The rate for the
childhood. control group was 17%. Vaginal delivery also puts women at
increased risk of developing urge incontinence and nocturia.
Women with urge incontinence 3 months after their first vaginal
COMMON SYMPTOMS (Box 28–1) delivery have a very high risk of developing long-lasting urinary
symptoms. This risk is further increased by episiotomy or
Interstitial cystitis and associated urogenital pain syndromes com- vacuum extraction. Another study found that the majority of
monly present with progressive urinary frequency and urgency. Half males diagnosed with interstitial cystitis had undergone transureth-
of patients initially report dysuria and nocturia. Male patients will eral prostatectomy within 6 months preceding diagnosis. This his-
often describe perineal, scrotal, and groin discomfort and pain at tory of surgery does not necessarily imply causation because many
the base of the penis without penile tenderness. Although patients of these surgeries may have been carried out to relieve preexisting
often have a combination of voiding symptoms and pelvic pain, in chronic urogenital pain.
most cases one of the two symptom complexes tends to predomi-
nate. Fifty percent to 75% of women with interstitial cystitis report
dyspareunia, with spasmodic pelvic pain typically worst toward the ARE CHRONIC PROSTATITIS AND
end or even after intercourse. By the time of diagnosis, many INTERSTITIAL CYSTITIS THE
patients have chosen to abstain from sexual intercourse entirely. SAME DISEASE?
Incontinence is not a usual feature of interstitial cystitis, but
when present, it is of the urgency type. Certain continence disor- Interstitial cystitis is rarely diagnosed in men, but it probably is not
ders, such as urgency-frequency syndrome and primary urge incon- rare. Males presenting with irritative voiding symptoms and pelvic
tinence, are probably forms of interstitial cystitis. Many patients pain with no evidence of infection are most commonly diagnosed
with interstitial cystitis and chronic prostatitis report symptoms with chronic abacterial prostatitis (also called type III chronic pros-
consistent with neurogenic bladder, such as urinary hesitancy or tatitis or prostadynia). The overall prevalence of chronic prostatitis
retention, difficulty maintaining their urinary stream, or the need among adult males in the United States has been estimated at
to apply pressure to their lower abdomen or ‘‘sit forward’’ on the between 5% and 8%, with abacterial prostatitis accounting for
toilet in order to urinate. more than 90% of these cases.
Although abacterial prostatitis is a common condition, its
pathophysiology, like that of interstitial cystitis, is enigmatic. One
prominent urologist called the condition a ‘‘wastebasket of clinical
Box 28^1 CURRENT DIAGNOSIS ignorance.’’ In fact, the pathologic evidence linking chronic abac-
terial prostatitis to any abnormality of the prostate gland per se is so
Urinary frequency with low urinary volumes scant that recently revised National Institutes of Health diagnostic
Pain with voiding classifications have renamed chronic abacterial prostatitis as chronic
Pain during and following intercourse pelvic pain syndrome.
Chronic pelvic, urethral, or genital pain The epidemiology of chronic abacterial prostatitis is similar to
Nocturia that of interstitial cystitis. Up to 70% of men with chronic non-
Flares of pelvic or genital pain with exercise or car rides or after the bacterial prostatitis and prostadynia have the cystoscopic appear-
ingestion of certain foods
ance of interstitial cystitis when hydrodistended under anesthesia,
although the reliability of this finding is now open to question All of the pelvic muscles are regulated via the S2–4 nerves. The
(see later). These and other significant overlaps in the epidemiology, parasympathetic motor nuclei in S3 and S4 provide the principle
pathophysiology, and response to therapy in the two syndromes motor input to the bladder, which is modulated by inputs from
have led many urologists to conclude that interstitial cystitis and other dorsal roots and descending supraspinal pathways. Chronic
chronic abacterial prostatitis represent different manifestations of pelvic floor dysfunction is often combined with lower urinary
the same disease. tract dysfunction, and both can end up being maintained by up-
regulated sacral reflex arcs.
HIGH-TONE PELVIC FLOOR

DYSFUNCTION THE RELATIONSHIP OF OTHER PELVIC
PAIN SYNDROMES AND INTERSTITIAL
High-tone pelvic floor dysfunction is a common source of chronic CYSTITIS
pelvic pain, and many of its manifestations are mistakenly attrib-
uted to dysfunction of the painful end-organ, such as the bladder, Many women presenting to gynecologists or family physicians
bowel, prostate, or external genitalia. The pelvic floor is composed with undifferentiated chronic pelvic pain have interstitial cystitis.
of two muscular layers. The deeper layer is composed of the levator In a large study of unselected patients presenting to gynecology
and its various components (a hammock-like structure attached to practices for chronic pelvic pain, 84% had urinary symptoms
the pelvic brim supporting the internal pelvic organs). Contraction and 81% had positive potassium tests (a putative clinical marker
of the levator muscles lifts the pelvic organs upwards and anteriorly for interstitial cystitis). Positivity rates were comparable across
toward the pubic bone and compresses the bladder neck. This is all diagnoses including endometriosis, vulvodynia, and chronic
dependent upon stimulation of the S3 and S4 roots. The second pelvic pain of unknown etiology. None of the control patients
layer is composed of the transversus perinei, the ischiocavernosus (e.g., those without chronic pelvic pain) tested positive for potas-
and bulbocavernosus muscles, the urethral sphincter, and the super- sium sensitivity. Repeat studies have borne this out, leading to the
ficial anal sphincter. These muscles are innervated by the pudendal recommendation that screening for interstitial cystitis should
nerve, which is primarily derived from S2 and which also mediates be undertaken in all women presenting with chronic pelvic pain.
perineal skin sensation. Stimulation of the pudendal nerve produces In one study, 75% of female patients presenting to gynecologists
an anteroposterior squeezing. Pelvic floor dysfunction occurs when with chronic pelvic pain had interstitial cystitis but less than 3%
contractions of these muscle layers are dysynergic relative to each were correctly diagnosed.
other or to the bladder. Patients with pelvic pain attributed to endometriosis have a
In many cases, all or part of the pelvic pain in interstitial cystitis, high incidence of interstitial cystitis. These patients are often mis-
chronic prostatitis, and related syndromes can be generated by diagnosed and do not respond completely to specific treatments
dysfunction of the pelvic floor muscles. Spasm or hypertonia of for endometriosis. Interstitial cystitis should be considered in
the pelvic floor can also give rise to urinary urgency, constipation, women with chronic pelvic pain who fail treatment for other
and dyspareunia. Myofascial trigger points in the muscles of the causes such as endometriosis or pelvic adhesions. Interstitial cys-
pelvic floor can generate bladder pain and voiding symptoms. titis and related pelvic muscle dysfunction can even generate the
This muscle dysfunction can manifest as spasm or abnormal con- ‘‘dermatologic’’ abnormalities of the external genitalia seen in vul-
tractions when the bladder fills or when voiding is initiated. In vodynia and vulvar vestibulitis. This occurs as chronic neurogenic
addition, hypertonus of pelvic floor muscles can also trigger neu- inflammation of the bladder is allowed to progress, leading to
rogenic inflammation of the bladder via antidromic reflexes con- extravasation of plasma from cutaneous vessels in the vulva enhan-
tributing to bladder-related symptoms. cing cutaneous sensitivity and resulting in trophic changes, such as
Visceral pain from pelvic organs and myofascial pain from mus- thickening of subcutaneous tissue. This bears striking similarities
cular trigger points can share common characteristics. Referred pain to the trophic changes characteristic of other chronic regional pain
from myofascial trigger points can commonly mimic visceral pain syndromes.
syndromes. Conversely, visceral pain syndromes can induce the A strong association exists between interstitial cystitis, chronic
development of these trigger points. Many patients with interstitial pelvic pain, and irritable bowel syndrome. In large subgroups of
cystitis have certain elements of their pain referable to an inflamed patients with interstitial cystitis, vulvar vestibulitis, prostodynia/
bladder lining (e.g., burning after consuming certain foods such as prostatitis, and loin pain/hematuria syndrome, inflammatory
alcohol) and other components related to pelvic floor dysfunction bowel changes are observed for which no etiology can be identified.
(e.g., positional pain, urinary hesitancy, and dyspareunia). The clinical features of many of these syndromes are consistent with
A careful history of exacerbating factors can help identify the the type of chronic neurogenic inflammation that is associated with
generators of pelvic pain. For example, hypertonus of the bulbo- interstitial cystitis.
spongiosus and ischiocavernosus muscles (vaginal constrictors,
muscles that mediate penile and clitoral tumescence) can lead to
tension myalgias of the pelvic floor. Premature contractions of OVERLAP WITHOTHER CHRONIC PAIN
detrussor muscles surrounding the bladder (termed ‘‘detrussor SYNDROMES
instability’’) can cause pelvic pain associated with voiding.
Triggers in the oblique transversus muscles can cause pelvic, Interstitial cystitis, chronic prostatitis, and related urogenital pain
groin, and perineal pain. Triggers in the rectus abdominis muscles syndromes are also associated with other poorly defined extrapelvic
can cause pelvic pain associated with increased intra-abdominal pain syndromes. A large survey of patients with interstitial cystitis
pressure. Spastic dysfunction of the pyramidalis muscles (spinal found a strong association with irritable bowel syndrome (64%)
flexion and trunk rotation) can also cause detrussor spasm. and high frequencies of atopia, fibromyalgia, and migraine head-
Iliopsoas dysfunction (hip flexion, spinal extension on standing) ache. When Clauw and colleagues compared aged-matched patients
can lead to groin pain. Dysfunctional hip adductor magnus mus- with fibromyalgia, interstitial cystitis, and healthy controls, a com-
cles can trigger pelvic pain with thigh extension or gluteal monality of reported symptoms was seen between the fibromyalgia
contraction. Pelvic hypertonus can be assessed by a careful physi- and the interstitial cystitis groups, leading to the conclusion that
cal examination (including a rectal examination) and pelvic similar disorders in pain processing were present. Compared with
electromyography. normal controls, individuals with interstitial cystitis are 100 times
more likely to have inflammatory bowel disease and 30 times more permeability of the bladders of interstitial cystitis patients and
likely to have systemic lupus. In addition, allergies, atopia, and those of normal controls to 99mTc-diethylenetriaminepenta-acetic
fibromyalgia are all found in increased incidences among patients acid (DTPA), a solute comparable with urea.
with interstitial cystitis. One important clinical indicator of a ‘‘permeability defect’’ driv-
ing pelvic pain is the association of flares of pelvic pain associated
with the ingestion of certain foods, notably alcohol, chili peppers,
ANATOMIC PATHWAYS OF BLADDER tomatoes, and fruit juices. The latter probably cause pain owing to
PAIN the release of high concentrations of potassium into the urine. The
pain flares usually start within an hour of ingesting the offending
There are several potential anatomic pathways for the pain of food and can last for hours or days. Some patients do not report
interstitial cystitis. Whereas classic neuroanatomy would implicate these sensitivities but will report flares of pelvic pain related to the
the pelvic nerves, fibers coming off the dome of the bladder join- ingestion of caffeine or chocolate, and these appear to be related
ing the hypogastric nerve probably carry much of the burning more to pelvic floor dysfunction than to irritation of the bladder
sensation and dysesthetic pain. The hypogastric nerve carries sym- lining per se.
pathetic preganglionic input to the pelvic ganglia and afferent
input from the bladder to the thoracolumbar spinal cord. These
pathways can explain how some patients with cord transections ABNORMALITIES OF EPITHELIAL
can still feel pain due to bladder infections. The afferents in PROLIFERATION
this pathway are either lightly myelinated A-d- or unmyelinated
C-fibers. These A-d-fibers generally function as mechanoreceptors, Bladder epithelial cells in patients with interstitial cystitis appear to
but in certain situations, they can transmit nociceptive input to the make a specific antiproliferative factor (APF), which may be a bio-
spinal cord. marker of the disease. Patients with interstitial cystitis also have
There are apparently different pathways for different types of decreased urinary levels of heparin-binding epidermal growth
bladder pain. For example, overdistention pain may be transmitted factor and increased levels of other epidermal growth factors. APF
via hypogastric nerves (with referral pattern in dermatomes of T10– may cause the epithelial thinning or denudation sometimes associ-
12). This can explain some of the abnormal bladder sensations ated with interstitial cystitis.
reported by patients with low thoracic cord transections. The
sensation of mucosal irritation, conversely, may be conducted via
the pelvic nerves, with referred pain to the rectum, vagina, and ABNORMALITIES OF THE
perineum when there is bladder irritation. This certainly reflects BLADDER WALL
the pattern of pain that is reported by patients with interstitial
cystitis (and is often disbelieved by their physicians). Whereas urothelial ulcers (Hunner’s ulcers) are the pathologic
finding historically most commonly associated with interstitial
cystitis, they are generally rare and found in only 5% to 10% of
PATHOPHYSIOLOGYOF INTERSTITIAL patients with this syndrome. Biopsies of the bladder wall in people
CYSTITIS: INCREASED BLADDER with interstitial cystitis typically show normal epithelial and mus-
PERMEABILITY cularis layers with submucosal edema and vasodilatation. Classical
inflammatory changes are rare and are usually limited to the lamina
Pathologic clues to the causes of interstitial cystitis have been propria. This pattern is reminiscent of the changes seen in biopsies
elusive. A popular concept holds that interstitial cystitis develops of the colons of patients with ulcerative colitis. Eighty percent of
when the watertight layer overlying the bladder epithelium has bladder biopsies in interstitial cystitis will show perineural lympho-
become dysfunctional and leaky. Normal bladder mucosa is lined cytic infiltrates. Although nonulcerated patients may have severe
by a layer of negatively charged sulfonated glycosaminoglycans symptoms, they may have very meager histopathologic findings.
(GAGs). This GAG layer maintains the permeability barrier between This may be because the actual disease process operates proximal
urine and the bladder wall, preventing the back-diffusion of water, to the bladder wall (e.g., in the nerve roots or spinal cord).
potassium, and other solutes. This layer probably also plays an
important role in protecting the bladder from invasive bacterial
infections. Interestingly, in a study in which protamine sulfate EVIDENCE FOR PERIPHERAL NEURAL
(which will combine with and precipitate negatively charged REMODELING
GAGs) was instilled into the bladders of normal volunteers, the
subjects quickly developed the symptoms of interstitial cystitis. In Biopsies from bladders of people with interstitial cystitis and other
these cases, the permeability barrier could be restored and symp- urogenital pain syndromes often show increased nerve density in
toms relieved by instilling a sulfated polysaccharide, such as the bladder wall, specifically sympathetic nerves and fibers contain-
heparin, into the bladder. ing substance P. An increase in mast cells in the bladder walls of
Based on these findings, synthetic polysaccharides such as patients with interstitial cystitis has been described,but this has not
sodium cromoglycate (cromolyn sodium) and pentosan polysulfate been a consistent finding. Nonetheless, this has led to the wide-
(Elmiron, Ortho Women’s Health), an orally bioavailable hepari- spread use of antihistamine medications in the treatment of uro-
noid compound, have become mainstays in the treatment of inter- genital pain syndromes, the efficacy of which has been questionable
stitial cysititis and urogenital pain syndromes. These compounds at best. Whereas data on the density of mast cells vary, consistent
may be more effective early on in the course of the disease but are evidence exists for increased mast cell degranulation in the bladder
probably not as effective once the process of continuous, self- walls of patients with interstitial cystitis. Peptide-secreting nerve
reinforcing neurogenic inflammation has become established. fibers are often seen in close apposition to degranulating mast
There is also some evidence that pentosan polysulfate may be cells, which also release nerve growth factor (NGF). NGF is found
acting by other means, (e.g., as an anti-inflammatory agent or as in high concentrations in the urine of many patients with interstitial
an inhibitor of nerve growth or angiogenesis). The reports of cystitis and chronic prostatitis. Similar findings are commonly seen
abnormalities in urinary GAG levels in interstitial cystitis patients in inflammatory diseases of the gastrointestinal tract such as ulcer-
are variable but may point to chemical differences among patients. ative colitis and Crohn’s disease and other chronic inflammatory
One large study showed that there was no difference in the states such as psoriasis and chronic arthritis.
THE ROLE OF NEUROGENIC Physical Examination

INFLAMMATION IN INTERSTITIAL
CYSTITIS Assessment of patients with urogenital pain syndromes requires a
careful and thorough physical examination, which should include
Neurogenic inflammation, the process by which central stimulation detailed pelvic, rectal, and musculoskeletal examinations and a
of sensory nerves elicits antidromic impulses causing vasodilatation, detailed assessment of the spine, coccyx, and bony pelvis. This is
plasma extravasation, and other inflammatory changes in peripheral well described in Section V, Chapter 30, Female Perineal/Pelvic Pain.
tissue, can explain many of the pathologic features of interstitial
cystitis, chronic prostatitis, and related urogenital pain syndromes.
Although we have been taught that sensory nerve fibers function Voiding Diaries
only as carriers of messages to the central nervous system, we now
understand that in certain disease states, they can also act as efferent Voiding diaries can be useful in gauging frequency and nocturia and
fibers in the periphery, causing neurogenic inflammation through assessing the response to treatment. Frequent small-volume voids
the release of neuropeptides from their dendritic terminals. For reflect bladder instability, hyperreflexia, hypersensitivity, or poor
example, edema of the bladder wall can be elicited by stimulation compliance with treatment. Two validated survey instruments, the
of lumbar roots or pelvic nerves. These findings provide an impor- Interstitial Cystitis Symptom Index’’ and the Interstitial Cystitis
tant rationale for the utility of neuromodulation in selected cases of Problem Index,’’ are useful in the evaluation and management of
interstitial cystitis and related syndromes. patients with interstitial cystitis.
Studies linking the release of neuropeptides to inflammation of
the bladder wall and the development of urinary symptoms suggest
that patients with interstitial cystitis possess altered afferent inner- Cystoscopy
vation and that their symptoms are, to some extent, generated by
neurogenic inflammation. With persistent neurogenic inflamma- Cystoscopic examination of the bladder, although of questionable
tion, new nerve pathways are recruited, potentiating the transmis- value, has been a standard maneuver in the diagnosis and assess-
sion of bladder and pelvic pain. These pathways can include sacral ment of interstitial cystitis and related urogenital pain syndromes
dorsal root ganglion neurons, which carry afferent inputs from the ever since Guy Hunner described the ‘‘characteristic bladder ulcer’’
bladder. These fibers are small and quiescent and normally possess in 1914. Based on cystoscopic findings, interstitial cystitis has tra-
high thresholds for firing. Because of this, they are called ‘‘silent C- ditionally been classified as either ulcerative (marked by the cys-
fibers.’’ With persistent bladder inflammation, these once-silent toscopic observation of Hunner’s ulcers) or nonulcerative. This
neurons become activated, expressing new sodium channels and may represent different stages of the same disease or different
new receptors for neuropeptide pain mediators, such as the NK-1 pathologic processes. Even though many practitioners still consider
receptor for substance P. bladder ulcerations to be a sine qua non of interstitial cystitis,
The role of inflammatory neuropeptides in interstitial cystitis estimates of the incidence of ulcerative interstitial cystitis range
and chronic prostatitis may explain the relief that patients experi- from only 5% to 20%. At first, Hunner himself advocated for
ence after intravesicular instillation of capsaicin or resiniferatoxin. the resection of the ulcerated tissue, but the high recurrence rate
The decrease in interstitial cystitis pain soon after hydrodistention eventually led him to abandon this surgical approach, which he
of the bladder may also be due to depletion of neuropeptides caused detailed in a paper with the interesting title ‘‘Neurosis of the
by transient damage to peripheral nerve fibers. Unfortunately for Bladder.’’ In fact, Hunner’s ulcers are not even true ulcers but
many patients, the pain returns and intensifies soon after this rather areas of inflamed granulation tissue that are probably
treatment. better referred to as ‘‘Hunner’s patches.’’
Another cystoscopic finding that is often regarded as character-
istic of interstitial cystitis is the presence of strawberry-like hemor-
CLINICAL ASSESSMENTOF PATIENTS rhages called ‘‘glomerulations.’’ Typically, glomerulations are
not seen on first filling of the bladder but are found on redisten-
WITHUROGENITAL PAIN SYNDROMES tion. Although glomerulations are widely considered to be specific
and sensitive for the diagnosis of interstitial cystitis, they are prob-
History ably neither. A recent study of asymptomatic women undergoing
tubal ligation showed that most of them had glomerulations
A careful history is the most important tool for assessing the gen- on repeated cystoscopic distention of their bladders. It has repeat-
erators of chronic urogenital pain. This should include a careful edly been shown that the presence or absence of ulcers or glomer-
history of problems in childhood including voiding disorders, uri- ulations is not correlated with symptoms. In light of this, the value
nary tract infections, pain related to defecation, menstrual disor- of cystoscopic examination in the assessment of interstitial cystitis
ders, and chronic constipation. Eliciting a careful family history for and related urogenital syndromes is questionable at best. Some
these symptoms can also be helpful and can sometimes serve to urologists maintain that every patient with symptoms of interstitial
reveal that the patient’s pelvic dysfunction may be a manifestation cystitis should undergo cystoscopy in order to rule out bladder
of a congenital disorder, such as structural urologic disorders that cancer, but the incidence of concurrent interstitial cystitis and
may have been missed such as incompetent ureteral valves, redun- bladder cancer is so vanishingly small as to call this rationale
dant ureters, ‘‘partial’’ Hirschprung’s disease, or an immune disor- into question.
der (e.g., immunoglobulin G3 [IgG3] deficiency), leading to repeat
infections.
In my experience, I have found that it is important to be very PotassiumTesting
specific and detailed when considering congenital abnormalities
because families will tend to ‘‘normalize’’ shared disorders. For Potassium sensitivity is sometimes used by urologists as a clinical
example, I have come across many patients who have vigorously marker for interstitial cystitis. The potassium test assesses bladder
maintained that having a bowel movement only two or three times discomfort after intravesicular instillation of 0.4 M KCl. This test
per month is ‘‘normal for them’’ because this is the way it has been can be extremely painful for patients with interstitial cystitis
since childhood—and not only for them but also for their mothers and prostatitis, although some patients with proven interstitial
and siblings. cystitis may not experience discomfort. The rationale behind this
test is that the bladder wall in interstitial cystitis is abnormally GOALS OF TREATMENT
permeable to solutes. Some practitioners have tried to redesign
the test using lower concentrations of potassium. In my experience, Patients with debilitating urogenital pain syndromes usually present
potassium sensitivity is so often correlated with certain food to pain specialists, physiatrists, or anesthesiologists after months
sensitivities (e.g., bladder pain after ingesting alcohol or high- or years of suffering with debilitating pain. Nonetheless, many phy-
potassium foods such as orange juice) that the need to subject sicians continue to advise that we withhold effective analgesics
patients to this painful test can safely be obviated by taking a careful except as a ‘‘last resort.’’ This is where I part ways with many of
history. my colleagues in this area. These patients deserve pain relief as
quickly as possible, and the fact of the matter is that many of
them can obtain significant relief safely and quickly with opioid
UrodynamicTesting analgesics. Once some analgesia is obtained, it becomes much
easier to specifically address the generators of pain and possibly
Urodynamic testing provides objective measures of the function of ‘‘unravel’’ the disease process, leading to sustained relief and
the lower urinary tract. I think that this is the most important test improved function. Even those physicians who support the use of
in assessing the generators of chronic pelvic pain. This is not uni- opioids often believe that it should be considered only after the
versally accepted by urologists and gynecologists, who rarely use failure of other therapies that have been shown to have less success
urodynamic testing in the evaluation of chronic pelvic pain. and greater toxicity.
Unfortunately, many pain specialists, anesthesiologists, and neurol- One of the issues we have to address when we treat chronic
ogists are only beginning to develop familiarity with this modality. urogenital and pelvic pain is that there are indeed discrete neuro-
An innovative approach to the use of urodynamic testing (including physiologic generators of these syndromes and that the use of med-
pudendal nerve evoked potentials and anorectal manometry) pro- ications or therapies that augment these drivers of pain and
mises to advance the diagnosis and assessment of a wide variety of dysfunction is a design for failure. An obvious example is the
painful syndromes involving the genitourinary system, pelvis, the common use of medications or therapies in patients with high-
lower bowel, and even the lower spine. tone pelvic floor dysfunction who are treated with medications that
Urodynamic testing has several components. Cystometry mea- increase pelvic muscle tone. This can include the commonly used
sures the sensation of fullness with different bladder volumes. The tricyclic antidepressants and urinary antispasmodics (e.g., oxybuti-
bladder is filled with warm water at a rate of 50 ml/min with nin) when more rational medications are available that can reduce
the patient lying down. A normal adult should be able to hold abnormally high tone, such as judicious use of a-blockers, certain
500 ml without much more than a sense of fullness. Uroflow benzodiazepines, or tamsulosin (Flomax), which insurors will
testing measures pressures and flows during micturation and resid- sometimes deny to female patients because it is a ‘‘prostate drug.’’
ual volumes to assess for voiding dysfunction. With detrussor over- Other undermining treatments can include misguided physical
activity, a rapid supernormal flow with abrupt cessation or therapy carried out by therapists who are unfamiliar with the com-
intermittent flow due to detrussor spasm can be seen. The cysto- plex urogenital pain syndromes. For example, the pelvic floor mus-
metrogram evaluates the compliance and stability of the detrussor cles are the only muscles whose ‘‘default’’ position is contraction.
muscles. Electromyography evaluates the electrical activity of the This means that neurologic damage generally causes spasticity
sphincter muscle. Urethral pressure readings assess pelvic floor rather than flaccidity (and hence the symptoms of neurogenic blad-
hypertonus. der and sphincter-mediated constipation, similar to those seen in
A strong correlation exists between daytime, nighttime, and our patients with spinal cord injuries). In these cases, the goal of
24-hour frequency and the urodynamic end-points ‘‘volume at pelvic floor physical therapy should be relaxation rather than
first sensation to void’’ (VFSV) and ‘‘volume at maximal cysto- strengthening. These patients need the training or treatment to
metric capacity’’ (VMCC). Urgency symptoms are correlated with relax their pelvic floors and restore coordination. This can be
uninhibited detrussor contractions. Urodynamics can also assess the done through specialized physical therapy, biofeedback, muscle sti-
response to neuromodulation and guide the response to medical mulation, or neurostimulation.
treatments or to the programming of neurostimulators. Urgency- It has to be understood that more than 95% of the process of
frequency syndrome, which is often painful, is invariably accompa- urination and defecation involves muscle relaxation and that the
nied by urodynamic evidence of detrussor instability. The expanded abdominal ‘‘pushing’’ contributes very little to the function of mic-
use of urodynamic testing holds great promise for developing pro- turition or defecation. I tell our patients with high-tone pelvic floor
tocols for effective functional neurostimulation in urogenital pain dysfunction that they are stuck pushing against a ‘‘locked door.’’
syndromes. For example, severe symptomatic high-tone pelvic floor When their dysfunction is seen in this light, it helps us to under-
dysfunction is often accompanied by increased urethral pressures. stand why strengthening exercises such as Kegel maneuvers or
The pressure normally needed to maintain urinary continence is destructive procedures such as presacral neurectomies or unneces-
approximately 15 cm H2O, but patients with severe urogential sary hysterectomies could be expected to make them worse. This
pain due to pelvic floor dysfunction may have urethral pressures also explains why something as simple as fiber laxatives are often
measured at over 105 cm H2O. unsuccessful because they only add to the already excessive bulk of
In the past, these high urethral pressures were interpreted to stool in a locked rectum. It is interesting to note that we have had
mean that the pain was generated by urethral stricture— excellent evaluative tests for these conditions for years that are
even when the patients were young girls in whom the incidence rarely used. Some of them are complex and require the involvement
of urethral stricture is infinitesimally small—when in fact it of a specialist, such as anorectal manometry and defecography,
was due to constriction of the urethra by dysfunctional pelvic but others are simple to obtain and interpret, such as Sitzmark
muscles. Nonetheless, many of these patients underwent destruc- tests for localizing the source of constipation that can be obtained
tive urethrotomies or mechanical distentions that served only to through any radiology department.
worsen their pelvic pain and pelvic floor dysfunction. Through In addition to analgesics, specific therapies for selected patients
the use of urodynamic guidance to reduce abnormally elevated can decrease pelvic pain by helping to restore and protect the blad-
pelvic muscle tone, neuromodulation can reduce abnormally der lining, relaxing hypertonic pelvic muscles, and improving bowel
elevated urethral pressures, increase total bladder capacity, and function. Another major component in relieving the suffering of
increase volume at first sensation and mean volume at ‘‘normal chronic urogenital pain is the restoration of disrupted sleep. In
desire to void,’’ decreasing total daily voids and total nighttime selected patients in whom infections seem to be a driver of pelvic
voids. pain, antibiotic suppression can be a mainstay of therapy.
Ultimately, if neurogenic inflammation or neuropathy is driving the In some of our patients, the traditional ‘‘neuropathic pain’’
illness, neuromodulatory approaches can be successfully applied. drugs can be helpful, but their utility is often limited by cognitive
side effects. Compounding these drugs into vaginal suppositories
can sometimes allow us to confer the pain-relieving benefits while
SPECIFIC MODALITIES OF TREATMENT minimizing the side effects. For our female patients, we have seen
some positive results with vaginal suppositories using combinations
(Box 28–2) of local anesthetics (e.g., lidocaine or bupivicaine), amitriptyline, or
gabapentin. These medications do not appear to be well absorbed
Analgesic Medications through the vaginal mucosa and can apparently confer pain relief
with minimal side effects. Certain medications that we have tried in
Many patients who present with chronic urogenital and pelvic pain these formulations, such as clonidine and ketamine, appear to be
will have gone through enough years of trial-and-error treatments highly absorbed and have not been practical for intravaginal use.
that they will be able to tell us what has worked and what has not. It should be noted that rectal use of these medications is not
They deserve to be listened to and believed. Many patients who have analogous to intravaginal delivery, the rectum being a highly
not had success with tricyclics, antiepileptic drugs, nonsteroidal, absorptive surface that carries medications directly into the systemic
and ‘‘urologic’’ pain drugs will often report having had relief with circulation through the hemorrhoidal veins, bypassing the portal
opioids. In fact, one of the first and most successful studies of the circulation. Because of this, a rectal dose of a medication can
use of sustained-release oxycodone was conducted in patients with often be expected to deliver up to 50% more than the same dose
interstitial cystitis. administered orally. The only analgesic that has appeared to have
Patients with chronic moderate to severe urogenital pain deserve had a specific benefit in our practice when administered rectally has
a timely trial of opioid medications. Brookoff outlined a structured been belladonna and opium (B&O) suppositories, which generally
approach to opioid therapy in these patients. It is important to note come in doses of 30 or 60 mg (these doses are often designated
that the different opioid medications have different side effect pro- ‘‘15A’’ and ‘‘16A’’) and can give good relief of prostate pain and
files. For example, an opioid that may be ‘‘energizing’’ during urethral spasm when used up to three times per day. Whereas B&O
the day, such as oxycodone, may prove disruptive to sleep at suppositories are commercially available, their rarity sometimes
night. In some patients, this can rationalize the use of combinations makes it necessary to have them compounded. In my experience,
of opioids (e.g., oxycodone during the day with a more sedating when these suppositories prove useful, they generally cause few
long-lasting opioid such as methadone used in single doses of 10–20 systemic side effects and have not been subject to abuse.
mg at bedtime at night to promote sleep).
A nonopioid medication that has been helpful with severe break-
through pain for some of our patients has been ketamine, which Benzodiazepenes
should soon be commercially available as a nasal spray. In the
meantime, it can be compounded as a fast-acting nasal spray (100 Benzodiazepene medications—particularly diazepam
mg/ml H2O or 4% lidocaine in a 0.1-ml metered-dose spray bottle (Valium)—have long been known to be effective pelvic muscle
used in doses of 2 to 3 sprays up to every 3 hr). Because of the relaxants, working on both the striated and the smooth muscle
possible side effects of agitation, we usually have our patient’s try elements of the dystonic pelvic floor. The action of diazepam on
the first few doses in the office. If they get significant pain relief, striated muscle is believed to be mediated through CNS pathways,
many pharmacies can compound ketamine into oral lozenges or and because of this sedating, doses are often needed to relieve
troches (50–100 mg up to four times a day), which can give more ‘‘voluntary’’ muscle spasms. In addition to this, diazepam in par-
sustained relief without the side effects related to rapidly peaking ticular appears to have a direct relaxing effect on unstriated detrus-
serum levels. sor muscle surrounding the bladder, which has been demonstrated
Some patients with neurogenic pain will benefit from medica- in studies using urodynamic end-points.
tions that specifically treat neural inflammation (analogous to the The specific action of diazepam on detrussor muscle appears to
experience in the CRPS syndromes). These patients will often report be mediated via a specific benzodiazepene receptor unique to blad-
relief with a brief trial of a highly central nervous system (CNS)– der smooth muscle. This has been demonstrated in both animal and
penetrating steroid such as dexamethasone. Our usual approach in human experiments. When used orally or intravenously, the con-
nondiabetic patients that we believe may be suitable for this is a trial centrations of diazepam needed to reduce bladder and pelvic floor
of dexamethasone 8 mg every morning for 1 week, then 4 mg every spasticity will often cause significant drowsiness. Oral ingestion will
morning for 1 week. The patients are informed about potential side also lead to the rapid hepatic metabolism of the diazepam to des-
effects including agitation, increased appetite, and sleep disruption methyldiazepam, which may have a higher potency and longer half-
and are told that they can discontinue this medication at any time life than the parent compound, augmenting its toxicity and limiting
without the need to taper. If the patients report significant relief its usefulness in elderly patients.
with this trial, we will often try a combination of a highly CNS- In patients whose sleep has become severely disrupted by fre-
penetrating nonsteroidal ant-iinflammatory medication such as quent nocturia and pelvic spasm, a single bedtime dose of diazepam
indomethacin (75–225 mg/day) combined with a leukotriene- will often provide significant nighttime pain relief and allow for
inhibitor such as zileuton (Zyflo) 600 mg four times a day to restorative sleep. Relatively high doses of 10 mg or even 20 mg at
attempt to replicate the neuro–anti-inflammatory effects of the bedtime are usually needed to achieve this effect. If nociceptive pain
steroids while minimizing the side effects. is an important component in undermining sleep, we will some-
times couple this with a judicious single bedtime dose of a sedating
opioid such as methadone.
In many of my female patients, I have been able to use diazepam
Box 28^2 CURRENT THERAPY to relieve detrussor spasm without causing sedation by formulating
the medication into a vaginal suppository. In my experience, many
Adequate analgesic medications women will experience pelvic floor relaxation without sedation at
Pelvic muscle relaxants intravaginal doses of up to 20 mg three times per day. For many of
Medications that restore the bladder lining our patients, this formulation will allow them to exercise without
Tailored bowel regimen
pelvic spasm and prevent postcoital dyspareunia. Up to 10% of
Therapies aimed at correcting pelvic floor dysfunction
female patients will experience some apparent systemic absorption
of intravaginal diazepam, and I instruct patients to try this medi- urologists will periodically instill heparinoids or heparin itself
cation at first only under circumstances in which sedation would directly into the bladder on a periodic basis, usually in a
not be dangerous. Because vaginal suppository formulations of ‘‘cocktail’’ containing sodium bicarbonate and a steroid.
diazepam are not commercially available in the United States, Because this involves frequent catheterization, the risk of infec-
they have to be custom-compounded. Some of my patients have tion and the pain of catheterization may outweigh the benefit of
gotten relief of pelvic floor spasm by inserting oral diazepam tablets this type of therapy for many patients. Urinary anesthetics such
intravaginally. It should be noted that, for these purposes, diazepam as phenazopyridine (Pyridium; up to 200 mg three times a day)
cannot be used rectally because it is very well absorbed systemically or the combination of methenamine, phenyl salicylate, atropine
and is even available as a high-peaking rectal gel (Diastat, X-Cell sulfate, methylene blue, hyoscyamine sulfate, and benzoic acid
Pharmaceuticals) for the treatment of epileptic seizures. (Urised) can sometimes be helpful in relieving the urethral
pain in these situations.
MedicationsThat Restore the Bladder Lining

PRIMARY PREVENTIONOF INFECTION
Patients in whom flares of pelvic or urogenital pain are related to
the ingestion of alcohol, highly spiced foods, or foods that quickly Many patients with chronic urogenital pain syndromes are initially
increase the urinary concentration of potassium (e.g., fruit juices) diagnosed as having either prostatic or bladder infections but have
are probably telling us that some of their pain is triggered by a persistently negative results on bacterial cultures of urine or pros-
deficiency in the protective GAG lining of their bladder. These tatic secretions. It is important to note that these cultures are not
appear to be the patients that have the greatest chance of benefitting ‘‘absolute measures’’ of the presence of pathogenic organisms but
from treatment with heparinoid medications. The mainstay of this are rather assessed using arbitrary thresholds. For example, a urine
class of medications is pentosan polysulfate. Whereas the putative sample with less than 100,000 bacterial colony-forming units
mechanism of this medication is that it ‘‘fills in the gaps’’ in the (CFUs)/ml will generally be reported as ‘‘negative.’’
defective bladder lining, pentosan polysulfate has long been known Patients with chronic urogenital pain syndromes may be more
to have unique anti-inflammatory and antiangiogenic properties. In sensitive to the presence of bacteria or fungus than average subjects,
fact, it was originally trialed in the United States in the late 1960s for paralleling the case of other types of patients with urothelial
breast cancer, and its antigliosis properties have sparked interest in abnormalities such as pregnant patients in whom a urinary bacterial
its use as a useful medication to combat neurodegenerative illnesses. concentration as low as 10,000 CFUs/ml can cause symptoms and
Its chemical similarities to chondroitin and glucosamine have also medical problems such as fetal wastage. Because of this, whenever
led to its use in some countries as an antiarthritic. I send a urine culture on a patient with chronic urogenital pain,
Because pentosan polysulfate was originally introduced into the I ask the laboratory to assess for and speciate lower concentrations
American market as an orphan drug, it did not undergo extensive of organisms (this can usually be most easily done by writing
pharmacodynamic and phamacokinetic testing. and many of its ‘‘pregnant patient’’ on the laboratory slip).
basic properties remain unknown. Its current indication calls for Many patients with chronic urogenital pain will have undergone
a dosing protocol of 100 mg three times per day, but over years of empirical therapy with antibiotics or antifungals despite negative
use, I have found that it is much more effective in doses of 300 mg cultures, and a small proportion of them will report significant
twice daily taken on an empty stomach (e.g., first thing in the relief while on therapy. Others will report flares in certain situa-
morning and last thing at night). I have had many experiences in tions, such as instrumentation or sporadic intercourse, in which
which this latter high-dose protocol provided significant improve- they may be subject to transient bacteruria. I will often trial these
ment and even sustained remission of pelvic pain symptoms in patients on a month or two of suppressive antibiotics that do not
patients for whom the standard dosing had failed. I am convinced evoke much bacterial resistance, such as mandelamine or nitrofu-
that taking this medication on an empty stomach improves its oral rantoin (Macrobid) 100 mg twice daily. Some of these patients will
bioavailability, which in various studies has been found to be as low respond to tetracycline analogues such doxycycline or minocycline,
as 3%. The onset of the action of pentosan polysulfate is generally whose actions may be more anti-inflammatory than anti-infective.
delayed, and I tell my patients that, even if it successful, it may take Another class of anti-infective medications that may be worthy of a
8 to 12 weeks to experience a decrease in urinary frequency and a brief trial is the antifungals. I have had a small group of patients
significant reduction in food-induced pelvic pain. with chronic interstitial cystitis, prostatitis, or other urogenital pain
Because pentosan polysulfate is a heparinoid, it does carry syndromes who have had impressive responses to ketoconozole
some risk of anticoagulation, but this has generally not been a (Nizoral) orally at doses of 200 mg once per day. Because ketoco-
problem in routine use (although we will discontinue the med- nazole has a variety of endocrinologic and anti-inflammatory effects
ication 1 week before surgery). Other side effects can include (e.g., it is often used in the emergent treatment of prostate cancer
headaches and nausea, which can usually be relieved by breaking because of its antitestosterone effects), success with this medication
the capsules open and pouring the contents into a glass of water does not necessarily imply that the patient had an active fungus
and drinking this mixture. A rare but particularly worrisome side infection.
effect of pentosan polysulfate is hair loss. I have seen only this
three or four times in over 10 years of frequent use. It appears to
be an idiosyncratic reaction (e.g., not related to dose) and man- TAILORED BOWEL REGIMEN
ifests as hair on the pillow or in the shower before it becomes
noticeable to others and stops very soon after discontinuation of In patients in whom pelvic pain is triggered by rectal distention
the medication. owing to a dysfunctional anal sphincter, it is imperative that
Some patients will experience benefits similar to those of pen- they adhere to a bowel regimen that will address this particular
tosan polysulfate using high-dose oral heparinoid-like drugs such problem. As mentioned previously, the use of fiber laxatives will
as chondroitin, glucosamine, cromolyn, and certain oral aloe vera usually serve only to add bulk to these patients and slow rectal
preparations. Because the GAG layer of the bladder may provide transit time, often making matters worse. Because of this, our main-
a natural barrier against infection, there is some reason to think stays in controlling bowel function are standing doses of osmotic
that oral heparinoids may prevent or reduce recurrent bladder laxatives such as routine doses of magnesium-containing laxatives,
infection, although this has not been specifically studied. Because MiraLax or lactulose. Another very useful treatment for this type
of the low oral bioavailability of these medications, some of constipation includes emollient laxatives, such as mineral oil,
which by itself can often relieve a lot of pelvic pain by promoting Several investigators noted increased sympathetic activity in the
regular bowel movements without pelvic spasm. Although it is often lower extremities of interstitial cystitis patients compared with
hard to convince some patients to give these emollients an adequate controls, and this led to the use of lumbar sympathetic blocks,
trial (which usually involves a ‘‘loading period’’ of taking 3–4 tbsp which have been reported to ease the pain of interstitial cystitis
of mineral oil four times per day until they feel that their anus is in rare cases.
‘‘greasy’’), the resulting ease in defecation and relief in pain often In the 1930s, cystodistention under general anesthesia came into
proves more than worth the effort. vogue. This is still a standard urologic treatment for interstitial
cystitis and related syndromes, although nowadays, it is usually
done without the anesthesia. Hydrodistention and many of the
HORMONAL MANIPULATION early treatments for interstitial cystitis can be seen as primitive
attempts at neuromodulation, which worked by causing temporary
Some female patients will report flares of urogenital pain associated damage to sensory fibers in the bladder wall. This would explain the
with certain phases of their hormonal cycles or during menses. For temporary effectiveness of these treatments and others, such as the
these patients, hormone-replacement therapy aimed at avoiding instillation of solvents including dimethyl sulfoxide or caustic
cycling and periods can be very useful. In addition, many patients agents. The process of neural remodeling would explain why, in
on chronic opioid medications will have significant secondary most cases, the symptoms would generally return with greater
hypogonadotrophic hypogonadism, which can exacerbate their intensity in the weeks or months after standard therapy and often
pain. Judicious hormone replacement can often provide significant became refractory to treatment. As has been the case for other dif-
relief. For example, in mine and others’ published experience, more ficult chronic pain syndromes, many of the medical treatments for
than 60% of males on chronic opioids have testosterone levels interstitial cystitis ultimately promoted neurogenic inflammation
below the National Institutes of Health standard for hypogonadism and neural remodeling. Until recently, when these treatments
and can benefit from hormone supplementation, provided there is stopped working, many patients with interstitial cystitis, prostatitis
no contraindication to testosterone treatment such as prostate or genital pain underwent resective treatments such as cystectomy,
cancer. It has been estimated that the chronic use of opioids is prostatectomy, or vulvectomies, which also failed to relieve the pain
the most significant cause of hypogondism among men in the in most cases.
United States.
SACRAL NERVE STIMULATION FOR

MODALITIES AIMED AT NEUROPATHY CHRONIC UROGENITAL PAIN
AND PELVIC FLOOR DYSFUNCTION SYNDROMES
As outlined in Section V, Chapter 30, Female Perineal/Pelvic Pain: Sacral nerve stimulation is an effective approach to modulating the
The Rehabilitation, detailed assessment and physical therapy aimed activity of the bladder and pelvic floor muscles. Sacral nerve stimu-
at pelvic floor dysfunction can often prove helpful in the relief of lators were first implanted for intractable urge incontinence and
pelvic floor dysfunction. This therapy can include myofascial urgency-frequency syndrome over 30 years ago by Drs. E. A.
release, biofeedback, and pelvic floor physical therapy, which, Tanagho and R. A. Schmidt. In the years since, sacral nerve stim-
although often very effective, are difficult to undertake with the ulation has become the standard of care for refractory overactive
frequency needed to provide sustained relief. Relief of myofascial bladder, proving to be both effective and cost efficient. S3 neuro-
trigger points that kindle pelvic pain, using iontophoresis or trigger modulation can change sensory parameters in patients with urge
point injections, can also be helpful in selected patients, as can incontinence, increasing the bladder volume at which the urge to
physical manipulation and injection therapies aimed at sacroiliac void is triggered. Sacral neuromodulation can also reestablish pelvic
joint dysfunction. Whereas some of the blocks mentioned in floor muscle awareness and reduce pelvic floor hypertonus, reliev-
Section V, Chapter 29, Pelvic Pain, such as superior hypogastric ing the symptoms of interstitial cystitis such as pelvic pain, daytime
blocks and ganglion impar blocks, can confer temporary relief for frequency, and nocturia. There is also evidence that sacral neuro-
urogenital pain, we have not had sustained success with these tech- modulation promotes the resolution of vestibulitis and vulvodynia
niques. Using neurolytic approaches in these blocks, such as ther- and normalizes bowel function, which is often disrupted in patients
mocoagulation, cryoablation, or chemical denervation with alcohol with interstitial cystitis and related syndromes.
or phenol, has generally led to a worsening of the syndrome after a
period of transient relief, and we have essentially abandoned these
ablative approaches. Low-frequency Sacral Nerve Stimulation
Many of the studies of the mechanisms of neurostimulation in
NEURODESTRUCTION VERSUS interstitial cystitis and related syndromes involve low-frequency
NEUROMODULATION (5–50 Hz) stimulation of S3 via one or both sacral roots. S3 is
generally targeted because approximately 70% of the closure pres-
Whereas the bladder provides a promising target for neuromodula- sure of the external urethral sphincter is due to somatic fibers that
tion, the history of the treatment of interstitial cystitis and related emanate from this root. Sacral neurostimulation may directly affect
urogenital syndromes chronicles over 100 years of neurodestruc- both sensory and motor fibers. In some cases, S3 stimulation may
tion. Soon after the first medical reference to interstitial cystitis have a direct effect on striated sphincter function.
was published in 1836, the use of intravesicular caustic silver nitrate Low-frequency sacral neurostimulation has been successfully
was promoted as a treatment, one that unfortunately continues to used to treat both urinary retention and urge incontinence. One
be used to this day. Presacral neurectomy for the pain of interstitial explanation for this apparent contradiction is that stimulation of
cystitis was first described in 1926 and was commonly done for over the posterior sacral roots supports the continence (storage) phase
40 years, although any positive results were, at best, transient. by reducing detrussor contraction and increasing bladder neck
Another neurosurgical approach recommended for the pain and activity. Termination of stimulation can trigger bladder emptying
‘‘sympathetic overactivity’’ of interstitial cystitis was surgical excision through contraction of the detrussor vesicae muscles via the mic-
of the superior hypogastric plexus. In 1951, more selective neurec- turation reflex, increasing detrussor contraction and reducing blad-
tomies were described, although they too were generally unsuccessful. der neck activity.
Low-frequency sacral nerve stimulation may also work by inhi- stimulate sacral nerve roots transforaminally for the syndrome of
biting somatic afferents in the pelvic floor. In addition to evoking urge incontinence (a symptom complex that undoubtedly includes
a bellows-type contraction of the perineum owing to direct stimu- cases of interstitial cystitis). Interstim generates low-frequency
lation of the levator muscles, stimulation of S3 can block abnormal impulses (10–50 Hz, pulse width of 200 msec) that stimulate
C-fiber activity through suppression of interneuronal mechanisms, pelvic floor muscles. This device has been most effective in patients
which do not have an inhibitory effect on voluntary voiding. This with associated detrussor instability but cannot generate the fre-
effect may only hold in hyperreflexic bladders through direct quencies that may be necessary for the control of neuropathic pain.
supraspinal excitatory input by the pelvic ganglion neurons. Studies of the long-term use of Interstim showed sustained
There is a high degree of variability in the reported responses to clinical benefit, including significant relief of pelvic pain, in
sacral neuromodulation, which may be related to the high incidence patients with urgency-frequency syndrome. A large multicenter
of intradural bridging between adjacent sacral roots. trial of low-frequency sacral nerve stimulation showed decreases
In addition to its action on peripheral nerves, sacral nerve stim- in symptoms, including pain, and increases in voided volumes in
ulation may operate in higher neural centers. Low-frequency stim- patients with interstitial cystitis that had been unresponsive to
ulation of S3 generates impulses in the sensory cortex, which may standard urologic therapies. Urodynamic testing showed that
not be consciously felt by the patient. This indicates that some of its low-frequency S3 nerve stimulation did not adversely affect void-
effects may be mediated through a supraspinal site of modulation. ing function or cause nerve damage. Complications of Interstim
S3 stimulation also has pharmacologic effects on the bladder wall, implantation have included pain at the site of the pulse generator,
increasing urinary concentrations of heparin-binding epidermal lead site pain, and lead migration. In one study, surgical revision
growth factor–like growth factor and reducing concentrations was required in 32% of patients. Patients with preexisting perineal
of antiproliferative factor, the urinary marker correlated with pain have an increased incidence of device-related pain. Low-
symptoms of interstitial cystitis. Long-term, low-frequency stimu- frequency neurostimulation has been successful in older (> 55
lation at the intensity needed to alleviate voiding symptoms does yr) patients with urge incontinence, but response rates were
not induce neural damage. This has been the case even when lower than those in younger patients. Some of the effects of
the stimulators have been implanted in childhood and have been Interstim may be mediated by stimulation of pudendal afferents
left operating for years. arising from S2.
Sacral Neurostimulation for Pelvic Pain Sacral Nerve and Pelvic Floor Muscle Stimulation
Using External Interferential Stimulators
Sacral nerve stimulation is a very effective means of reducing pain
related to longstanding interstitial cystitis, chronic prostatitits, and In the mid 1990s, external interferential stimulators have become
other pelvic disorders as well as the associated irritative voiding available that appear to provide the same pattern of sacral
symptoms. In a prospective study of women with refractory inter- nerve stimulation and pelvic floor relaxation as the implanted
stitial cystitis having a mean duration of symptoms of more than Interstim devices without the need for surgery or the attendant
5 years, low-frequency S3 stimulation increased voiding volumes, complications. These devices often confer pelvic floor relaxation
decreased both daytime and nocturnal frequency, and significantly and relief of urinary urgency and/or prostatic pain within a week
reduced pelvic pain scores. Additional studies have shown that of use and can eventually prevent exercise-induced pain and dys-
low-frequency S3 stimulation can reduce pelvic pain and improve pareunia. Studies of similar devices in specific conditions such as
measured quality of life in patients with longstanding urogenital overactive bladder syndrome have shown that these have been sig-
pain syndromes. Sacral neuromodulation can decrease opioid nificantly more effective than treatment with medications such as
requirements in patients with severe chronic pain due to refractory oxybutinin.
urogenital pain. The first clinical use of interferential stimulation is attributed
Clinical improvement of interstitial cystitis symptoms in to Dr. Hans Nemec, an Austrian physicist, who, in 1949, super-
response to low-frequency stimulation has generally been greater imposed two medium-frequency (1000–5000 Hz) alternating cur-
in patients with a predominance of voiding symptoms (e.g., fre- rents of slightly different frequencies and found that, as he
quency and dysuria) over those with constant pelvic pain. A large increased the frequencies, there was a sharp drop in skin and
study showed that low-frequency sacral stimulation relieved chronic organ resistance to the currents. This eliminated the superficial
pelvic pain in males as well as females, suggesting that it is a useful pain and ‘‘tingling’’ sensations associated with lower-frequency
modality for the treatment of chronic prostatitis. In this study, external stimulators such as transcutaneous electrical nerve stimu-
success was related to urodynamic proof of dysfunctional voiding lators units and allowed for deep penetration of the signal. When
and inversely related to the degree of neuropathic pain. This led the two interferential streams were properly calibrated, they gen-
the investigators to conclude that the success of low-frequency erated a third stream of nonpainful electrical impulses originating
stimulation was linked to the degree of demonstrated pelvic deep inside the body that could directly stimulate nerves and
floor dysfunction. There may be some utility in combining neuro- muscles. By aiming the currents at right angles to each other,
modulation with medical treatments for interstitial cystitis, such as the stimulation could be localized to the point of intersection of
intravesicular instillation of heparin. In patients with urinary symp- the currents without causing extraneous muscle stimulation or
toms due to detrussor instability, use of a low-frequency sacral paresthesias.
nerve root stimulator can obviate the need for more invasive With proper adjustment and programming, externally placed
surgery. interferential stimulators can directly stimulate sacral nerve roots,
causing pelvic floor relaxation. With enough intensity, this stimu-
lation could transiently paralyze pelvic floor muscles leading to
Mechanisms of Sacral Nerve Stimulation incontinence and, someday soon, to the development of new
devices such as a ‘‘noninvasive Foley catheter’’ and ‘‘electronic laxa-
Whereas sacral nerve stimulation has been proved to be effective in tives.’’ As is the case with implanted sacral nerve stimulators, inter-
the treatment of pelvic floor dysfunction, there is still some question ferential stimulators appear to function better with prolonged use.
about its utility in the treatment of pelvic pain per se. In 1997, the This could be due to the fact that repeated stimulation of a dystonic
U.S. Food and Drug Administration (FDA) approved an implan- or chronically spasmodic area of muscle will reduce muscular
table pulse generator (Interstim, Medtronic, Minneapolis, MN) to edema and improve venous outflow.
European studies have shown that ‘‘treatment of detrussor insta- SUGGESTED READINGS
bility using devices that deliver interferential current is a reliable Brookoff D, Bennett DS. Neuromodulation in intractable interstitial
technique which is effective in cases of instability refractory to cystitis and related pelvic pain syndromes. Pain Med
anticholinergic drugs.’’ Whereas these devices have been available 2006;7(suppl 1):S66–S84.
for several years in Europe and Japan, they have only been recently Brookoff D. Chronic pain as a disease: the pathophysiology of disordered
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duced a portable interferential stimulator into the American Management. Philadelphia: American College of Physicians, 2005; pp 1–33.
market specially programmed for pelvic floor relaxation, which Brookoff D. Chronic pain: the case for opioids. Hosp Pract 2000;
delivers sequences of incremental alternating currents to the areas Sept 15):69–84.
subserved by the S3 roots, resulting in reduction in pelvic pain Brookoff D. Chronic pelvic pain. In Abram SE, Haddox JD (eds): The
Pain Clinic Manual. Philadelphia: Lippincott Williams & Wilkins, 2000;
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ter function (‘‘IF3WAVE,’’ Empi Technologies, St. Paul, MN). Brookoff D. The battle for the bladder in interstitial cystitis: neurodestruction
When this device is properly applied, an examiner can feel a versus neuromodulation. Pain Forum 1999;8:151–153.
slight ‘‘fluttering’’ of the pelvic floor muscles, as is the case with Brookoff D. The causes and treatment of pain in interstitial cystitis. In Sant G
the implanted Interstim device. In my practice, the use of these (ed): Interstitial Cystitis. New York: Raven, 1997; pp 219–240.
external devices has essentially eliminated the need to implant Butrick CW. Discordant urination and defecation as symptoms of pelvic
low-frequency sacral nerve stimulators and has reduced our use floor dysfunction. In Howard F, Perry CP, Carter JE (eds): Pelvic Pain:
of other implanted stimulators for urogenital and pelvic pain Diagnosis and Management. Philadelphia: Lippincott Williams &
Wilkins, 2000; pp 279–299.
(e.g., high-frequency dorsal column or peripheral sacral nerve
Clemons JL, Arya LA, Myers DL. Diagnosing interstitial cystitis in women
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Collins MM, MacDonald R, Wilt TJ. Diagnosis and treatment of chronic
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significant component of neuropathic pain may benefit from sacral Eisenberg ER, Moldwin RM. Etiology: where does prostatitis stop and
nerve stimulation at higher frequencies than those that can be gen- interstitial cystitis begin? World J Urol 2003;21:64–69.
erated by the currently available interferential or Interstim devices. Feler CA, Whitworth LA, Fernandez J. Sacral neuromodulation for
chronic pain conditions. Anesthesiol Clin North Am 2003;21:785–795.
Using a spinal cord stimulator and bilateral S2 and S3 leads placed via Feler CA, Whitworth LA, Brookoff D, Powell R. Recent advances: sacral
a retrograde lumbar approach, Feler and colleagues reported signif- nerve root stimulation using a retrograde method of lead insertion for
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treatment of interstitial cystitis and related syndromes. Many 2002;22:187–196.
pain specialists maintain that S2, S3, and S4 should be covered Kream RM, Carr DB. Interstitial cystitis. Pain Forum 1999;8:143–150.
in these patients. Unlike the transforaminal systems, leads applied Mauroy B, Goullet E, Bonnal JL, et al. Long term results of interferential
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combination of high and low frequencies, patients experience pelvic pain syndrome. Curr Urol Rep 2002;3:313–318.
more complete relief of pain and other symptoms and soon Pettit PD, Thompson JR, Chen AH. Sacral neuromodulation: new
progress to needing their stimulators only intermittently (e.g., sev- applications in the treatment of female pelvic floor dysfunction. Curr
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with which the retrograde systems can be trialed and implanted traditions and new concepts. Adv Intern Med 1999;44:19–57.
and their apparent effectiveness suggest that neuromodulation Siegel S, Paszkiewicz E, Kirkpatrick C, et al. Sacral nerve root stimulation
in patients with chronic intractable pelvic pain. J Urol 2001;166:
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216 Chapter 29 PELVIC PAIN
Chapter 29 PELVIC NEUROANATOMYAND

PATHOPHYSIOLOGY
PELVIC PAIN Many potential areas of pathologic involvement exist in patients
Paul J. Christo and Greg Hobelmann with CPP, and despite extensive diagnostic investigation, the symp-
toms often remain puzzling. The pelvis is a complex, neurophysio-
logic region, and sources of pain may arise from somatic, visceral,
and/or neurogenic structures. Somatic sources include muscles,
pelvic bones and joints, ligaments, and fascia. Visceral sources of
CPP include the reproductive, gastrointestinal, and urologic sys-
tems (Fig. 29–1). Broadly, dual projections from the thoracolumbar
INTRODUCTION AND TAXONOMY and sacral portions of the spinal cord innervate the pelvis and then
(Box 29–1) coalesce into neuronal plexuses that send fibers throughout the
pelvis. The pelvic viscera receive neurons from the sympathetic
Chronic pelvic pain (CPP) of nonmalignant origin may be defined (thoracolumbar) and parasympathetic (craniosacral) systems.
as nonmenstrual pelvic pain of 6 months or more duration that is More specifically, visceral afferent fibers that travel in the sympa-
severe enough to cause functional disability or require medical or thetic trunk contain their cell bodies in the dorsal root ganglia
surgical treatment. Acute pelvic pain and CPP may be localized between T10 and L2. Similarly, visceral afferents traveling with
or referred and can be present in all age groups. Further, CPP parasympathetic fibers contain their cell bodies in the dorsal root
may be divided into syndromes of the pelvic cavity (diffuse pain ganglia between S2 and S4. The lateral pelvic region transmits pain
with no particular pelvic structure identified or hypothesized organ through parasympathetic neurons arising from S2–S4, whereas the
involvement such as irritable bowel syndrome/interstitial cystitis) or midline structures of the pelvis receive most of their input from
pelvic floor (prostatodynia, orchialgia, vulvodynia, urethral syn- sympathetic fibers arising from T10–L1. These fibers coalesce to
drome). Pelvic pain is one of the most challenging problems form the superior hypogastric plexus (SHP or presacral nerve),
faced by health care practitioners because it is difficult to identify which lies immediately anterior to sacral promontory at the L5–
both an etiology and, subsequently, a treatment. It is often associ- S1 level. The SHP transmits sensory input from the descending and
ated with other problems such as voiding difficulty or sexual dys- sigmoid colon, rectum, vaginal fundus, bladder, prostate, prostatic
function. Before intervening, a comprehensive evaluation and urethra, testes, seminal vesicles, uterus, and ovaries. This plexus
work-up are necessary. Practitioners involved in the treatment of then divides into hypogastric nerves that eventually form the infe-
pelvic pain include family physicians, internists, gynecologists, gas- rior hypogastric plexus (IHP). The IHP is the primary neural,
troenterologists, psychiatrists, neurologists, urologists, and pain autonomic coordinating center in the pelvis that integrates both
medicine specialists. parasympathetic and sympathetic output. Efferent fibers that
The pelvis contains several anatomic structures including mus- derive from the IHP innervate the clitoris, vagina, and urethra in
cles that form the pelvic diaphragm and the urogenital diaphragm, women and the prostate, seminal vesicles, vas deferens, epididymus,
the urinary bladder, distal ureters, sigmoid colon, rectum, some and penis in men.
small intestine, internal genitalia, blood vessels, lymph vessels, The termination of the paired paravertebral sympathetic chains
lymph nodes, and nerves. occurs at the sacrococcygeal junction and is called the ganglion
impar (ganglion of Walther). The neuronal interconnections of
this ganglion are poorly understood, although blocking this gan-
EPIDEMIOLOGY glion can provide relief of pain originating from the perineum or
distal pelvic structures. Other regions believed to be subserved by
Pelvic pain is a common disorder in women, especially in the repro- the ganglion impar include the distal rectum and anus, distal ure-
ductive age group, with an estimated prevalence of 3.8% in women thra, vulva, and distal third of the vagina. Note that the sympathetic
aged 15 to 73, resulting in about 10% of all referrals to gynecolo- nervous system is contiguous; therefore, there may be overlap and
gists. This prevalence rate parallels those rates reported for asthma, variation of innervation among ganglia (e.g., lumbar ganglia, hypo-
low back pain, and migraine headaches. Approximately 15% to gastric plexus, ganglion impar).
20% of women aged 18 to 50 years have CPP of greater than Painful sensations from the pelvis to the brain travel through
1 year’s duration. In fact, the lifetime occurrence rate of CPP may dorsal root ganglion cells (sensory neurons) located in the thora-
be as high as 33%. Patients with CPP may exhibit pathology that columbar and sacral portions of the spinal cord. Animal studies
fails to correlate with the pain, and one third to one half of cases suggest that pelvic sensations are carried within the sacral parasym-
may exist with no identifiable pathology. Signs and symptoms of pathetic system to a greater extent than the thoracolumbar sympa-
CPP may be evident in at least 50% of patients with preexisting thetic system.3 Certain CPP syndromes such as interstitial cystitis,
sexual or physical abuse. The psychological literature suggests that irritable bowel syndrome, and prostatodynia (prostatitis) may be
women with CPP report greater psychological distress.1 For associated with neurogenic inflammation. This process is initiated
instance, women with CPP have elevated rates of depression, anxi- by neuropeptides such as substance P, calcitonin gene–related
ety, hostility, and somatic complaints. The direct health care– peptide (CGRP), and neurokinin A and B, which are released by
related costs owing to CPP are estimated to be $880 million per primary afferent neurons. Primarily C-fibers and some Ad-fibers are
year.2 Both direct and indirect costs potentially amount to greater believed to be the primary afferent fibers involved in the process of
than $2 billion per year. The individual burden of CPP ranges neurogenic inflammation. Within the pelvis, neurogenic inflamma-
from years of personal suffering to missed or lost work, marital tion has been described in the digestive, genitourinary, and repro-
or relationship disruption, and multiple medical and/or surgical ductive systems. Some researchers have hypothesized that referred
interventions. pain associated with interstitial cystitis and vulvodynia or interstitial
T10-L1
Box 29^1 CURRENT DIAGNOSIS CEL
1. Pelvic pain has been defined as nonmenstrual pelvic pain of 6 months

or more that is severe enough to cause functional disability or require G SCG
DR
medical or surgical treatment. Aorta
2. Before intervening, a comprehensive clinical evaluation is necessary.

3. Practitioners involved in the treatment of pelvic pain include family phy- SHP
sicians, internists, gynecologists, urologists, psychiatrists, and pain
medicine physicians. Chronic pelvic pain (CPP) is often associated with S2-S4
voiding difficulty or sexual dysfunction.
Uterus
P
4. Many areas of CPP pathology exist, and the etiology is frequently puz-
HG
zling. In one third to one half of cases, pelvic pain persists without evi-
DRG
dent pathology. Even when pathology exists, it may not correlate with
C N
painful symptomatology. SA
PS Bladder
5. Imaging is often nonrevealing because many CPP conditions fail to pres- P
IH
ent on film. SA
6. Over 40% of diagnostic laparoscopies are performed for CPP and may Rectum
reflect a reasonable approach to treating refractory pelvic pain PU
7. Specific nerve blocks in the pelvis such as superior hypogastric plexus D
(SHP) and ganglion impar may aid in identifying the region of pain. C
cystitis and prostatodynia may represent certain mechanisms of

neurogenic inflammation when patients report referred pain in A
the urogenital floor (referred area) of the bladder.4 Further,
animal studies suggest that a neurogenic inflammatory mechanism T10-L1
CEL
may explain edema and trophic alterations in the skin, muscle, and
subcutaneous tissue of patients reporting discomfort in referred
zones from chronic visceral pain.
SCG
Psychological disorders such as somatization, psychosexual dys- DR
G
Aorta
function, and depression can contribute to CPP and merit a com-
prehensive evaluation by trained mental health professionals. More
SHP
often, diseases of several systems in the body may account for
symptoms of CPP, and sometimes, disorders of more than one SS
system may contribute to ongoing pelvic discomfort (Table 29–1). S2-S4 P
These disorders can cause a constellation of symptoms ranging in V88
P
severity from producing no pain to causing debilitating, persistent HG ISP
pain. Such disparate responses may result from changes in visceral DR
G Bladder
SA
nerve function or from altered central nociceptive processing; how- C N
SA PS SA
ever, precise mechanisms remain unclear. P
IH SA
Rectum SA Penis
Prostate
CLINICAL FEATURES PU
D
A careful and detailed history and physical examination are essential
in the diagnosis and treatment of CPP. Demographic profiles sug- Epid.
gest that women with CPP are no different from women without
pelvic pain in terms of age, race, ethnicity, education, socioeco- Testis
nomic status, or employment status. Certain factors, however, can
increase the risk of developing pelvic pain, which a thorough history B
can elicit. For example, in addition to assessing typical pain descrip- Figure 29^1. Pelvic neuroanatomy of females (A) and
tors such as location, severity, quality, and timing, clinicians should males (B). Animal data have provided much of the anatomic
include an obstetric history that details the patient’s menstrual information about human pelvic innervation. CEL, celiac plexus; DRG,
cycle, dysmenorrhea, dyspareunia, and any voiding dysfunction. dorsal root ganglion; HGP, hypogastric plexus; IHP, inferior
Moreover, pregnancy and childbirth are specific events from hypogastric plexus; ISP, inferior spermatic plexus; PSN, pelvic
which CPP may arise. In particular, patients with lumbar lordosis, splanchnic nerve; PUD, pudendal nerve; Epid., epididymis; SA, short
delivery of a large infant, pelvic muscle weakness, poor physical adrenergic projections; SAC, sacral plexus; SCG, sympathetic chain
conditioning, and a difficult delivery represent a group at higher ganglion; SHP, superior hypogastric plexus; SSP, superior spermatic
risk of developing CPP. In nulliparous patients, several conditions plexus. (FromWesselmann U, Burnett A, Heinberg L, et al.The urogenital
may predispose them to developing CPP. For instance, diseases and rectal pain syndromes. Pain 1997;73:269^294. Used with permission.)
such as endometriosis, chronic pelvic inflammatory disease, inter-
stitial cystitis, and irritable bowel syndrome may lead to complaints
of CPP. Although a detailed psychosocial evaluation is best per-
formed by a psychiatrist or psychologist, the pain specialist can with depression tend to benefit less from treatment strategies than
elicit a brief psychological history. Focusing on depressive sympto- those without depression. Finally, a comorbid history of abuse is
matology is important and constitutes one of several predictors of important to uncover owing to the association between physical
pain severity in women suffering from CPP. Coexisting depression and sexual abuse and the subsequent development of CPP.
also serves as an indicator of response to treatment; that is, patients The International Pelvic Pain Society has designed a comprehensive
Table 29^1. Systems Associated with Potential Sources of Pelvic Pain
Gynecologic Urologic Gastrointestinal Musculoskeletal Neurologic

Endometriosis Interstitial cystitis Irritable bowel syndrome Pelvic floor dysfunction Postherpetic neuralgia
Adenomyosis Malignancy Inflammatory bowel Myofascial pain Incisional neuroma
disease syndromes
Pelvic congestion Radiation cystitis Chronic constipation Adhesions Visceral hyperalgesia
syndrome
Adhesions Acute recurrent cystitis Colon malignancy Fibromyalgia Pudendal neuralgia
Ovarian remnant Chronic urinary tract Colitis Muscular sprains (rectus Entrapment neuropathy
syndrome infection muscle)
Pelvic inflammatory Urolithiasis Hernia Piriformis syndrome
disease
Malignancy Uninhibited bladder Diverticular disease Spondylosis
contractions
Leiomyomata Urethral syndrome Diarrhea Chronic coccygeal pain
or back pain
Symptomatic pelvic Urethral caruncle
relaxation
Cervical stenosis Urethral diverticulum
Adnexal cyst
Postoperative peritoneal
cyst
Tuberculous salpingitis
Gärtner’s cyst
Benign cystic
mesothelioma
history and physical examination document that targets CPP The physician should focus on locating foci of tenderness and cor-
patients.5 The website may be accessed at www.pelvicpain.org. relating them with areas of pain.
Physicians may view the clinical presentation of patients with There are no standard diagnostic tests that should be ordered on
CPP as confusing and often enigmatic. CPP patients (women and all patients with CPP. Rather, the history and physical examination
men) often struggle in describing and localizing their pelvic pain, should direct relevant testing. There is an array of imaging and
and clinicians feel limited in examining and quantifying CPP. blood testing that clinicians may order, and a partial list of tests
Furthermore, the differential diagnosis of CPP is vast because that correlate with suspected diagnosis and symptomatology is pre-
patients report symptoms that appear diffuse and nonspecific. In sented in Table 29–2. Laparoscopy may be of value as well. Actually,
part, CPP reflects a visceral pain condition, and patients generally over 40% of diagnostic laparoscopies are performed to help clarify
describe visceral pain as ‘‘deep,’’ ‘‘dull,’’ ‘‘squeezing,’’ ‘‘crampy,’’ the etiology of CPP. Endometriosis and adhesions encompass the
and ‘‘oppressive.’’ In contrast to somatic pain, mechanical stimula- vast majority of laparoscopic diagnoses, whereas therapeutic
tion, ischemia, and chemical irritation may induce visceral pain. removal of endometrial lesions or lysis of adhesions can be per-
Visceral pelvic pain displays three characteristics: (1) true vis- formed during laparoscopic surgery. A newer, state-of-the-art diag-
ceral pain: experienced deep in the pelvis; (2) referred visceral pain: nostic laparoscopic technique has emerged in which the patient is
sensed in somatic regions such as muscle and skin; and (3) referral awake for the procedure and can provide feedback about pain
site hyperalgesia: the site of referred pain may demonstrate intensity while the surgeon gently probes specific pelvic regions.2
increased sensitivity to a painful stimulus. Some have suggested The value of this test has not been demonstrated, however.
that both visceral and somatic primary afferent neurons may con-
verge on similar neurons in the spinal cord and thereby cause the
phenomenon of referred pain.6 This overlapping segmental afferent MANAGEMENT
innervation may explain why patients report referred pelvic pain to
the perineum, abdomen, thighs, legs, and back. In fact, the process Although a single pathologic process may be responsible for a spe-
of referred pain may manifest itself as a sensation that several organs cific CPP syndrome and can be treated, most CPP is caused by a
of the pelvis feel affected during the course of CPP states. number of factors for which multiple treatments are needed. The
mainstays of treatment include noninvasive, pharmacologic, and
surgical interventions (Box 29–2).
EVALUATION
The physical examination should be thorough and evaluate the Complementary/Alternative Medicine
musculoskeletal, gastrointestinal, and urinary systems in addition
to the reproductive tract. Ideally, the examination should be per- Noninvasive treatments consist of exercise/physical therapy, cogni-
formed while the patient is standing, sitting, in the prone position, tive-behavioral techniques, massage, dietary modification, and acu-
and in the lithotomy position to fully evaluate all of these systems. puncture. These modalities may be beneficial in many chronic pain
Table 29^2. Imaging or Laboratory Testing That May Be Appropriate to Support a Specific Diagnosis of
Chronic Pelvic Pain
Suspected Diagnosis/Symptom Tests

Adenomyosis US, hysterosalpingography, MRI
Chronic urethral syndrome Urodynamic testing
Entrapment neuropathy EMG/nerve conduction studies
Constipation Thyroid function tests, renal function tests, hepatic function tests, electrolytes
Diarrhea Test for ova and parasites in stool, stool guaiac, stool culture, barium enema, upper GI series, CT
Diverticular disease Barium enema
Dyspareunia Gonorrhea and chlamydia cultures, vaginal and urine cultures, vaginal wet preparation, vaginal pH
Endometriosis CA 125, US, barium enema, CT, MRI, laparoscopy
Hernia Abdominal wall US, CT, herniography
Interstitial cystitis Cystourethrography, KCl bladder challenge test, urine cultures, urine cytology, urodynamic testing,
bladder biopsy
Ovarian remnant syndrome FSH, estradiol, GnRH stimulation test, US, barium enema, CT
Ovarian retention syndrome US, CT
Pelvic congestion syndrome Pelvic venography, US, MRI
Tuberculous salpingitis Chest x-ray, PPD
Urethral diverticulum US, voiding cystourethrography, MRI
Gärtner’s cyst US, MRI
CA, cancer; CT, computed tomography; EMG, electromyography; FSH, follicle-stimulating hormone; GI, gastrointestinal; GnRH, gonadotropin-releasing
hormone; MRI, magnetic resonance imaging; PPD, purified protein derivative; US, ultrasound.
conditions. Exercise, physical therapy, and massage can ease the small study by Engel and associates8 examined sertraline (Zoloft), a
severity of CPP, given that many CPP patients display coexisting selective serotonin reuptake inhibitor (SSRI) for the treatment of
myofascial dysfunction and may even develop kinesophobia. CPP. This was a double-blinded, placebo-controlled, cross-over
Dietary modifications may help control certain painful symptoms study using 50 mg of sertraline once a day. The researchers found
if they are associated with conditions such as irritable bowel syn- no difference in pain scores between the two groups. The SSRI
drome or interstitial cystitis. Cognitive-behavioral techniques may group of antidepressants appears to possess the least analgesic prop-
not alter the disease process, but they certainly help reframe the role erties versus TCAs and selective serotonin and norepinephrine re-
CPP has taken in an individual’s life and move patients toward uptake inhibitors (SNRIs). Despite the lack of convincing evidence
healthy, functional living.
PharmacologicTreatment Box 29^2 CURRENT THERAPY

Evidence supports the use of nonopioid analgesics such as nonster- Therapy is achieved through a multimodal approach with a goal of func-
oidal anti-inflammatory drugs (NSAIDs) and acetaminophen in tional restoration.The mainstays of treatment include noninvasive, phar-
treating a variety of pain conditions. Many agents are recom- macologic, surgical, and nonsurgical interventions.
1. Noninvasive treatments consist of exercise/physical therapy, cognitive-
mended for initial treatment in cancer pain by the World Health
behavioraltechniques,massage,dietarymodification,andacupuncture.
Organization, and we can apply their benefit in this broad group of 2. Pharmacologic therapies for CPP include these types of medications
cancer patients to the nonmalignant pain population. Moreover, a. Nonsteroidal anti-inflammatory durgs (NSAIDs; e.g., acetamino-
certain neuropathic agents such as gabapentin (Neurontin) and phen, ibuprophen, celecoxib).
the tricyclic antidepressants (TCAs) have demonstrated value in b. Tricyclic antidepressants (TCAs; e.g., amytriptyline, nortriptyline,
treating neuropathic pain states (postherpetic neuralgia, diabetic desipramine).
painful neuropathy) and, by extension, may be helpful in control- c. Anticonvulsants (e.g., gabapentin, pregabalin, topirimate)
ling CPP. There are no clinical trials addressing the efficacy of d. Opioids (e.g., methadone, oxycodone, morphine, trandermal fen-
NSAIDs in CPP, although clinicians may consider them as reason- tanyl, oxymorphone); focus on long-acting opioids short-acting
agents for breakthrough pain.
able first-line medications given their proven, moderate analgesic
e. Hormone agonists (gonadotropin-releasing hormone [GnRH]
efficacy in cancer pain conditions. agonists, progestins).
TCAs and other antidepressants are frequently used in the treat- 3. Surgical interventions
ment of neuropathic pain and other chronic pain states. Clinicians a. Evidence suggests that laparoscopic excision or destruction of en-
should consider the TCAs as useful agents for patients suffering dometriotic tissue reduces pain compared with diagnostic laparos-
from CPP. TCAs (amytriptyline, nortriptyline, desipramine, imi- copy alone.
pramine, and doxepin.) in particular may be effective. However, b. Denervation procedures: Presacral neurectomy: excision of the
only one study has documented the effectiveness of TCAs in CPP. superior hypogastric plexus (SHP; presacral nerve), or laparoscopic
Walker and coworkers7 studied 14 women with CPP and treated uterosacral nerve ablation (LUNA)
them with increasing doses of TCAs to a maximum dose of 100 mg 4. Nonsurgical options
a. SHP blocks or neurolysis (chemical or thermal).
per day. Seven of the women dropped out owing to adverse effects, b. Ganglion impar blocks or neurolysis (chemical or thermal).
although 6 of the remaining 7 remained pain free at 1 year. Another
for the use of antidepressants in CPP, these remain a rational and after adhesiolysis.16 Conversely, a randomized trial of 48 women
safe option for CPP sufferers. with laproscopically diagnosed adhesions receiving either conserva-
Anticonvulsant medications have shown efficacy in treating neu- tive management or laproscopic adhesiolysis showed no significant
ropathic pain such as diabetic neuropathy and postherpetic neural- difference in pain relief at 1 year.17 Thus, the efficacy of this pro-
gia. Their pain-relieving properties are applied to other neuropathic cedure remains unclear. Hysterectomy remains an option for
pain states including CPP. Practitioners may consider several antic- women suffering from intractable CPP. Approximately 10% to
onvulsants such as gabapentin, pregabalin (Lyrica), lamotrigine 12% of hysterectomies are performed for CPP. Results of the
(Lamictal), topiramate (Topomax), and tiagabine (Gabitril). Maryland Women’s Health study and the U.S. Collaborative
Gabapentin may be particularly useful in treating CPP because Review of Sterilization suggest that 75% to 90% of women report
researchers have demonstrated its effectiveness in controlling pain pain relief for greater than a year after hysterectomy.18 These data
related to the genitourinary tract.9 indicate that woman with CPP of gynecologic origin may respond
Opioids for the treatment of nonmalignant chronic pain remain well to hysterectomy.
controversial. Opioid maintenance therapy should be considered For patients without a definable disease, surgical denervation
after failure of other reasonable therapies and if pain is impeding may offer pain reduction. This procedure consists of surgical tran-
all efforts for improved function. Some clinical trials suggest a section or excision of peripheral nerves. Lesioning of the central
good analgesic response to opioids in chronic pain, but not neces- nervous system has been performed, but in only extreme cases of
sarily a functional or psychological improvement.10 In contrast, CPP and without convincing data to support its routine use. A
clinical experience in pain centers suggests that opioid therapy more common procedure, presacral neurectomy, involves excising
may improve function without significant adverse effects when phy- the SHP (presacral nerve). Surgeons incise the pelvic peritoneum
sicians have exhausted other treatment modalities.11 Prior to initi- over the sacrum and identify and transect the SHP. The SHP sup-
ating opioids, clinicians should strongly consider implementing an plies the cervix, uterus, and proximal fallopian tubes; consequently,
informed consent for opioid therapy that details risks and benefits SHP neurectomy may be more useful for patients affected with
of treatment, mandates only one prescriber, and highlights the severe dysmenorrhea or endometriosis. Nonetheless, this surgical
process as a trial of opioid therapy that can be discontinued at approach has been used to treat CPP of unknown origin. Clinical
the physician’s or patient’s discretion. Close and regular follow- experience suggests a better response in patients with midline pelvic
up to assess treatment effectiveness in terms of pain relief, improved pain than with lateral pelvic pain. In a retrospective review exam-
function, enhanced quality of life, and adverse effects along with ining 655 patients undergoing presacral neurectomy for dysmenor-
proper urine drug monitoring is essential to responsible opioid rhea or chronic pain of unknown origin, 72% of the 392 patients
therapy. with a diagnosis of dysmenorrhea reported significantly decreased
Hormone therapy in the form of oral contraceptives, gonado- pain.19 Sixty-two percent of the 135 patients with CPP of unknown
tropin-releasing hormone (GnRH) agonists, and progestins has origin also reported significantly decreased pain. SHP blockade
been incorporated with some success in select CPP states. For prior to presacral neurectomy may offer good predictive value. In
instance, oral contraceptives are recommended for pelvic pain one report, 10 of 11 patients who underwent successful SHP block
associated with endometriosis by the American College of experienced greater than 50% pain relief after neurectomy.20
Obstetricians and Gynecologists, even though supportive evidence Laproscopic uterosacral nerve ablation (LUNA) represents
is lacking. Oral contraceptives suppress ovulation, markedly reduce another surgical option. This procedure involves the excision of
uterine activity, and reduce the pain associated with menses; hence, the IHP (a coalescence of sympathetic and parasympathetic
they may reduce pain related to other gynecologic conditions. nerves at the base of the broad ligament). Although few studies
GnRH agonists (nafarelin, goserelin, and leuprolide) down-regulate have evaluated this procedure and no randomized trials have
hypothalamic-pituitary gland production resulting in decreased been performed, preliminary data are promising. For example, a
estradiol levels. Numerous trials demonstrate that these medications small study showed that 81% of 21 patients with CPP experienced
are effective in treating pelvic pain caused by endometriosis,12 and decreased pain after a uterovaginal ganglion excision.21
observational data suggest that GnRH agonists are effective in treat- A final approach is neurosurgical and creates lesions in the cen-
ing pelvic pain resulting from ovarian retention syndrome and tral nervous system. Several case reports demonstrate success in
ovarian remnant syndrome. Principal adverse effects include bone treating incapacitating pelvic pain.2 However, risks are high, and
density loss, which can be reversed with progesterone replacement it is unlikely that large clinical studies will be performed to evaluate
with or without estrogen.13,14 Finally, progestins (medroxyproges- its efficacy because surgeons rarely resort to this technique.
terone acetate) are effective in the treatment of pain associated with
endometriosis as well as pelvic congestion syndrome.
Neuromodulation (Sacral Nerve Stimulation)
The previously mentioned medications may have deleterious
effects; therefore, clinicians must carefully select patients before Sacral stimulation has been used to successfully treat voiding dys-
beginning any of these medications. function for several years. For instance, some patients suffering
from interstitial cystitis have benefited from electrical modulation
of the sacral nerves and report improvement in pain and urinary
Surgical Interventions urgency. Recently, pain physicians have applied the technique for
the treatment of CPP. The transforaminal approach consists of a
Surgical options either treat the primary problem or strive to alle- trial stimulation in which an electrode is placed percutaneously into
viate the pain, although the latter is usually of unknown origin. the S3 or S4 foramen in the area of the nerve roots (Fig. 29–2). If the
Surgery typically treats pain resulting from endometriosis or adhe- trial is successful, the patient is taken to the operating room, where
sions. Evidence suggests that laparoscopic excision or destruction of the permanent lead is placed and tunneled subcutaneously to an
endometriotic tissue reduces pain compared with diagnostic lapa- implanted pulse generator. In an observational study of 10 patients
roscopy alone.15 Unfortunately, recurrence rates approach 100%, undergoing sacral nerve stimulation for intractable pelvic pain,
with an average time to recurrence of 40 to 50 months.15 9 reported a decrease in pain severity for at least 19 months.22 In
Recurrence may be reduced with thorough excision of endometrial another study, 11 patients were followed for 36 months after under-
tissue and proper medical management. Because adhesions are going sacral stimulator placement; 9 experienced extended and sig-
commonly believed to cause CPP, adhesiolysis remains an option nificant reduction in their pelvic pain, and 2 failed the therapy soon
for patients with known suspected adhesions. One observational after implantation.23 This failure was likely due to a false-positive
study suggested that up to 85% of women report reduced pain result during the trial. These preliminary studies suggest that
(need to change to a fixed rate), specific needs for magnetic reso-

nance imaging (MRI; spinal cord stimulation [SCS] equipment is
incompatible with MRI).
Neuromodulation (SCS)
SCS has been used for the treatment of lumbosacral radicular pain
after spine surgery, intractable cardiac ischemia, peripheral vascular
disease, occipital neuralgia, and complex regional pain syndrome.
There is emerging evidence that a midline dorsal column pathway
exists that may mediate the perception of visceral pelvic pain; there-
fore, dorsal column stimulation may serve an effective means of
treating CPP (Fig. 29–3). For instance, Kapural and colleagues24
reported that six female patients with severe CPP undergoing
dual-lead implantation with the lead tip between the levels of
T11–12 described significant improvement in pain scores and activ-
ities of daily living during an average follow-up of 2.6 years.
Although the study was retrospective and small, it provided a
framework for other researchers to clarify the efficacy of SCS in
visceral pelvic pain with randomized, controlled trials.
Nonsurgical Interventions
Figure 29^2. Anteroposterior (AP) fluoroscopic view of sacral
stimulation: bilateral leads over the sacral nerves. Neurolysis
Neurolysis refers to the intentional injury of a nerve or nerves with
the intent of reducing pain. Pain physicians may offer nonsurgical
neurolytic treatments with chemicals (alcohol or phenol), cryoabla-
sacral stimulation may be helpful in reducing pelvic pain among tion, or thermocoagulation. Many practitioners reserve these treat-
properly chosen patients who undergo a successful stimulator trial ments for cancer-related pain because of the associated risks such as
excessive neurologic injury, damage to nonnervous tissue, and
spotty relief owing to tumor or scar tissue. For example, SHP abla-
Technique
tion has demonstrated a 69% percent success rate for 6 months in
Psychiatric comorbidities, substance misuse/abuse, and issues of cancer patients with intractable pelvic pain. In patients with
secondary gain should be assessed prior to implementation. This
examination is usually performed by a licensed psychologist. Test
stimulation with a temporary lead is performed under fluoroscopic
guidance. The lead is placed through the sacral hiatus and
advanced in an anterograde fashion toward the sacral foramen
or inserted through the low lumbar vertebrae and advanced retro-
grade toward the sacral foramen. The lead is then positioned with
contacts placed inside the S3 or S4 foramen, and test stimulation
is performed to ensure coverage over the intended pelvic region.
A dressing is placed over the insertion site to anchor the lead as
well as to prevent infection. A trial of stimulation is then per-
formed on an outpatient basis for 3 to 5 days. If the patient reports
a significant reduction in pain during the trial (typically consid-
ered at least a 50% reduction), a permanent stimulator implanta-
tion is offered. The implantation is performed in an operating
room. During the surgery, the percutaneous leads are anchored
to underlying fascia, tunneled underneath the skin, and attached
to the pulse generator (battery), which is placed in a subcutaneous
pocket. Several locations are suitable for placement of the pulse
generator including the upper buttock or inferior to the last rib
anteriorly.
Complications
Spinal cord injury or nerve injury, cerebrospinal fluid leak, infec-
tion, bleeding, lead migration/malposition, lead fracture, epidural
abscess, and generator failure may occur.
Contraindications
Patient refusal, sepsis, coagulapathy, pregnancy, untreated psychi- Figure 29^3. AP fluoroscopic view of the thoracolumbar spine with
atric comorbidities (anxiety, depression), substance abuse/misuse, two leads positioned midline fromT10 ^12 in anticipation of spinal cord
inability to cooperate, secondary gain, demand cardiac pacemaker stimulator implantation.
Sacrum
L1
L2
L3 L5
L4
A
Bifurcation of
iliac vessels
B Superior hypogastric Psoas major

plexus muscle
Superior
hypogastric
plexus
Superior Psoas major muscle

rectal
artery
Internal iliac
artery and vein
External
iliac artery
and vein
C
Figure 29^4. Anatomic approach to the superior hypogastric plexus block. A. Patient positioned prone with the needle positioned to
the infero-lateral portion of the L5 vertebral body and the needle tip directed to the L5-S1, interspace. B. Cross-sectional view of the SHP with
bilateral needle tips inserted toward the anterolateral aspect of L5, through the psoas major, and medial to the iliac vessels. C. Anterior and
oblique view of the lumbar spine and pelvis demonstrating bilateral needle approach to the SHP and associated anatomy. (From Cousins MJ,
Bridenbaugh PO [eds.] Neural Blockade, 3rd ed. Philadelphia, Lippincott-Raven,1998.)
nonmalignant pain, sequential SHP blockade with local anesthetics one needle in the transdiskal approach. If patients report meaning-
may attentuate central sensitization and sympathetically maintained ful relief (at least 50% pain reduction) and chemical neurolysis
pain, resulting in prolonged relief. Ganglion impar denervation has is desired, 6 to 10 ml of 6% to 10% phenol or 50% to 80% alco-
been performed in cancer patients with persistent perineal or rectal hol is injected through each needle. If a lateral approach is pre-
pain, but randomized, controlled trials to support this therapy have ferred, two needles are required to achieve adequate coverage of
not yet been performed. Pain physicians treating CPP due to cancer the plexus with local anesthetic or chemical neurolytic (Figs. 29–8
should consider pretreatment with local anesthetics prior to injec- and 29–9).
tion of alcohol for neurolysis owing to significant pain on injection
and burning or shooting sensations after injection. Unlike alcohol,
Complications
phenol exhibits local anesthetic properties that render the injection
painless. Somatic nerve injury, cerebrospinal fluid leak, infection, vascular
puncture of common iliac vessels, disk trauma, diskitis, hypoten-
SHP Block sion, intrathecal/epidural injection, bladder and ureteral trauma
may occur.
Indications
Contraindications
Pelvic pain related to nonmalignant conditions or cancer can be
reduced by blocking the SHP. Patients suffering from CPP associ- Patient refusal, sepsis, coagulapathy, pregnancy, untreated psychi-
ated with endometriosis, adhesions, inflammation, interstitial cysti- atric comorbidities (anxiety, depression), inability to cooperate are
tis, irritable bowel syndrome, and chronic pain related to the contraindications.
bladder, prostate, testes, uterus, ovaries, descending/transverse
colon, vagina, rectum, postsurgical pelvic pain, or neoplasms of Ganglion Impar Block
the pelvis should be considered candidates. Afferent fibers innervat-
ing the pelvic viscera travel with the sympathetic nerves, trunks,
Indications
ganglia, and rami; thus, a sympathectomy can produce analgesia
from painful pelvic structures. SHP blocks can be used for either Visceral or sympathetically maintained perineal pain from the
diagnostic or therapeutic purposes. For instance, the block may help rectum, anus, distal urethra, vulva, and distal third of the vagina
differentiate between low back pain referred from chronic pelvic of malignant or nonmalignant origin are indications. Patients may
disease and low back pain from myofascial, facet, disk, or other report burning sensations and urgency.
primary lumbar pathology.
Anatomy
Anatomy (Fig. 29-4)
The ganglion impar is a semicircular, solitary, retroperitoneal struc-
The SHP lies in the retroperitoneum, anterior to the sacral pro- ture often positioned midline at the level of the sacrococcygeal
montory, in proximity to the bifurcation of the common iliac ves- junction and marks the end of the bilateral sympathetic chains.
sels, and extends from the lower third of the fifth lumbar vertebral The impar contains gray rami communicantes that travel to sacral
body to the upper third of the first sacral vertebral body (L5–S1 and coccygeal nerves, although the precise neural interconnections
interspace). It exists as a weblike convergence of interconnecting are incompletely understood. The impar seems to lack while rami
fibers that carry both sympathetic fibers and parasympathetic fibers communicantes. Visceral afferents that innervate the perineum,
(S2–4). The ureter is located close to the anterolateral aspect of the rectum, anus, distal urethra, vulva, and distal third of the vagina
L5 vertebral body. travel to the ganglion impar.
Technique Technique
The patient is positioned prone in a comfortable position with Most often, the patient is positioned prone on the fluoroscopy
pillows beneath the abdomen to flatten the lumbar lordosis. The table. The anococcygeal region is prepared and draped in a sterile
low back is prepared and draped in a sterile fashion. The SHP can fashion. A 22-gauge, 3.5-inch needle is manually bent about 1 inch
be accessed through a posterior paravertebral (lateral), transdiskal, from its hub to form a 258 to 308 angle. This bend facilitates needle
transvascular, or transvaginal approach under fluoroscopic or position toward the anterior aspect of the sacrococcygeal concavity.
computed tomography (CT) guidance. The more common paraver- Lateral fluoroscopic imaging is used to identify the coccygeal area,
tebral and transdiskal approaches are described. In the lateral and the needle is introduced under local anesthesia through the
approach, the L4–5 interspace is identified by palpating iliac anococcygeal ligament or an intercoccygeal space (Fig. 29–10). If
crests and confirmed with fluoroscopy. The skin and subcutaneous the intercoccygeal space is used, the needle tip may require only
tissues are anesthetized with local anesthetic 5 to 7 cm lateral to the a slight bend around its tip. The needle tip is then directed anterior
midline on each side at the L4–5 level. Two, 7-inch, 22-gauge nee- to the coccyx but close to the anterior surface of the bone
dles are directed 458 medially and 308 caudally under image guid- until it reaches the sacrococcygeal junction. The interventionalist
ance until the tips lie anterolateral to the L5–S1 interspace. Biplanar should pay close attention to needle depth to avoid rectal
fluoroscopy (anteroposterior [AP] and lateral images) is needed to trauma because this structure lies close to the sacrum (Fig. 29–11;
confirm proper placement. If the transdiskal approach is used (Fig. see also Fig. 29–10). Midline position is confirmed with an AP view
29–5), one 7-inch, 22-gauge needle is typically inserted through the (Fig. 29–12). After negative aspiration of blood or stool, 2 to 3 ml
L5–S1 disk to approximate the L5–S1 junction anteriorly or slightly of contrast is injected to confirm retroperitoneal location
anterolaterally. After negative aspiration, 2 to 3 ml of radiographic (see Fig. 29–11). Laterally, the contrast should appear smoothly
contrast is injected through each needle to verify proper needle contoured and hug the coccygeal concavity like a teardrop (see
position and spread of material along the anterior surface of the Fig. 29–11). For diagnostic or therapeutic purposes, 4 to 6 ml of
lumbosacral junction and at the midline region under AP view 0.25% bupivicaine or 1% lidocaine is injected. For neurolytic
(Figs. 29–6 and 29–7). A total of 6 to 8 ml of 0.25% bupivicaine blockade, 4 to 8 ml of 6% to 10% phenol or 50% to 80% alcohol
is then injected through each of two needles or 12 to 15 ml through is injected.
Figure 29^5. Transdiskal, single-needle approach to the superior hypogastric plexus under fluoroscopy. Images show AP and lateral views
depicting the proper spread of contrast.
Figure 29^6. Two-needle approach to the superior hypogastric Figure 29^7. Lateral fluoroscopic view of two needles positioned at
plexus and the proper spread of contrast material in the AP the L5^S1 junction with proper spread of contrast along the region of
fluoroscopic view. the superior hypogastric plexus.
Figure 29^8. Bilateral needle approach to the superior hypogastric

plexus under AP fluoroscopic imaging.
Figure 29^9. Two needles inserted bilaterally and approaching the
region of the superior hypogastric plexus at the L5^S1 junction under
the lateral fluoroscopic view.
Rectum
Anus
Figure 29^10. Schematic of the ganglion impar and relevant anatomy. (From Benzon HT, Raja SN, Borsook D, et al [eds.]. Essentials of Pain Medicine
and Regional Anesthesia. Philadelphia: Elsevier,1999; p330.)
Levator Ani Syndrome

Patients exhibit dull, aching, or pressure-like sensations in the
rectum that may last for hours. Diagnosis is made if patients
report chronic (at least 3 mo) or recurrent bouts of rectal pain
that last 20 minutes or longer without identifiable causes such as
coccydynia, hemorrhoids, anal fissures, sphincter abscess, cryptitis,
ischemia, or inflammatory bowel disease. Methods of treatment
include sitz baths, digital massage three to four times a week, and
muscle relaxants (diazepam or methocarbamol).
Proctalgia Fugax
Symptoms include episodes of severe, sudden, stabbing, cramping,
or aching rectal pain that lasts from seconds to minutes. The pain
usually lasts less than 5 minutes and rarely as long as 30 minutes.
Women tend to be more affected than men. Diagnosis requires the
absence of anorectal conditions that could produce rectal pain.
Treatments that have been utilized include caudal epidural block-
ade, clonidine, nitrates, diltiazem, and inhaled salbutamol.
Pudendal Nerve Entrapment (Pudendal

Figure 29^11. Lateral fluoroscopic image of a needle through the
intercoccygeal joint and retroperitoneal contrast spread resembling a Neuralgia)
teardrop. Note the presence of bowel gas anterior to the contrast The pudendal nerve derives from the sacral plexus (S2–4) and
medium. enters the gluteal region via the greater sciatic foramen. The nerve
travels through the pelvis around the ischial spine, between the
sacrospinous and the sacrotuberous ligaments. Finally, it divides
Complications
into three branches: anal/rectal, perineal, and clitoral/penile.
Sacral nerve root injury (neurolysis), rectal perforation, periosteal Pudendal neuralgia is often attributable to mechanical or inflam-
injection, and epidural spread may occur. matory damage to the nerve caused by pressure or trauma. Pudendal
nerve entrapment is sometimes referred to as cyclist’s syndrome.
Symptoms may include a stabbing, burning, or pinpricking sensa-
Contraindications
tion in the penis, scrotum, labia, perineum, or anorectal region.
Patient refusal, sepsis, coagulapathy, pregnancy, untreated psychi- Sometimes, the pain may refer to the groin, medial thigh, buttock,
atric comorbidities (anxiety, depression), inability to cooperate, and abdomen. Patients report that sitting and other flexion
local infection are contraindications. activities of the hip (sitting, squatting, cycling, exercising) exacerbate
the pain whereas standing or lying down relieves the discomfort. The
distribution may be ipsilateral or even bilateral, and patients may
demonstrate allodynia and hyperalgesia in the affected region. There
may be associated urinary, anal, or sexual dysfunction.
Treatments consist of using a doughnut-shaped pillow to reduce
the pressure on the pudendal nerve, antiepileptic or TCA medica-
tions, image and nerve stimulator-guided pudendal nerve blocks
positioned at the ischial spine or Alcock’s canal (pudendal canal)
with local anesthetic/steroid, and surgical decompression of the pu-
dendal nerve.
Coccygeal, Ilioinguinal, Genitofemoral Blocks

These blocks may be performed owing to pain from coccygeal
trauma or abdominal surgery.
CONCLUSIONS
CPP remains obscure in its diagnosis and treatment modalities.
Because the pelvis is complex neuroanatomically and neurophysio-
logically, pelvic pain may exhibit mixed characteristics of somatic,
autonomic, visceral, and neuropathic origin. Underlying patho-
genic pain mechanisms in CPP require a variety of treatment
strategies including medications, physical restoration, behavioral
medicine techniques, surgery, neuromodulation, and SHP and gan-
Figure 29^12. AP fluoroscopic view of contrast spread at the glion impar blocks/neurolysis. A thorough systematic evaluation
midline and moving superiorly. with proper screening for coexisting diseases is critical to
formulating a rational treatment plan. Furthermore, a multidisci- 11. Portenoy RK, Foley KM. Chronic use of opioids in non-malignant
plinary approach to patients with CPP aids in coordinating the pain: a report of 38 cases. Pain 1986;25:171–186.
assessments of primary care physicians and specialists in pain med- 12. ACOG Practice Guidelines Bulletin. Clinical management guidelines
icine, urology, gynecology, gastroenterology, physiotherapy, and for obstetrician-gynecologists. Chronic Pelvic Pain 2004;103:589–605.
13. Siddall-Allum J, Rae T, Rogers V, et al. Chronic pelvic pain caused by
psychology. In fact, a randomized clinical trial by Peters and cow-
residual ovaries and ovarian remnants. Br J Obstet Gynaecol
orkers25 compared the effectiveness of a focused organic approach 1994;101:979–985.
to CPP and a multidisciplinary approach consisting of surgical, 14. Carey MP, Slack MC. GnRH analogue in assessing chronic pelvic pain in
psychological, social, and dietary interventions. Patients in the mul- women with residual ovaries. Br J Obstet Gynaecol 1996;103:150–153.
tidisciplinary treatment group reported greater improvement in 15. Sutton CJ, Ewen SP, Whitelaw N, Haines P. Prospective, randomized,
self-reported pain scores. double-blind, controlled trial of laser laparoscopy in the treatment of
pelvic pain associated with minimal, mild and moderate
endometriosis. Fertil Steril 1994;62:696–700.
REFERENCES 16. Steege JF, Stout AL. Resolution of chronic pelvic pain after laparoscopic
lysis of adhesions. Am J Obstet Gynecol 1991;165:278–281.
1. Walling MK, Reiter RC, O’Hara MW, et al. Abuse history and 17. Peter AAW, Trimbos-Kemper GCM, Admiral C. A randomized
chronic pain in women. I. Prevalences of sexual and physical abuse. clinical trial of the benefit of adhesiolysis in patients with
Obstet Gynecol 1994;84:193–199. intraparitoneal adhesions and chronic pelvic pain. Br J Obstet
2. Howard FM. Chronic pelvic pain. Clinical gynecologic series. An Gynaecol 1992;99:59–62.
expert’s view. 2003;101:594–611. 18. Kjerulff KH, Langenberg PW, Rhodes JC, et al. Effectiveness of
3. Jänig W, Koltzenburg M. Pain arising from the urogenital tract. In hysterectomy. Obstet Gynecol 2000;95:319–326.
Maggi CA (ed): Nervous Control of the Urogenital System. Harwood 19. Chen F-P, Soong Y-K. The efficacy and complications of laparoscopic
Academic, 1993; pp 525–578. presacral neurectomy in pelvic pain. Obstet Gynecol 1997;90:974–977.
4. Wesselmann U. Neurogenic inflammation and chronic pelvic pain. 20. Bourke DL, Foster DC, Valley MA, Robinson JC. Superior hypogastric
World J Urol 2001;19:180–185. plexus block as predictive of presacral neurectomy success: a
5. The International Pelvic Pain Society. www.pelvicpain.org (Accessed preliminary report. Am J Pain Manage 1996;6:9–12.
April 2008). 21. Perry CP. Laproscopic uterovaginal ganglion excision (LUVE) for
6. Cervero F. Sensory innervation of the viscera: peripheral basis of chronic pelvic pain. J Gynecol Surg 1996;12:89–93.
visceral pain. Physiol Rev 1994;74:95–138. 22. Siegel S, Paszkiewicz E, Kirkpatrick C, et al. Sacral nerve stimulation in
7. Walker EA, Sullivan MD, Stenchever MA. Use of antidepressants in patients with chronic intractable pelvic pain. J Urol 2001;166:1742–1745.
the management of women with chronic pelvic pain. Obstet Gynecol 23. Everaert K, Devulder J, De Muynk M, et al. The pain cycle:
Clin North Am 1993;20:743–751. implication for the diagnosis and treatment of pelvic pain syndromes.
8. Engel CC Jr, Walker EA, Engel AL, et al. A randomized double-blind Int Urogynecol J Pelvic Floor Dysfunct 2001;12:9–14.
crossover trial with sertraline in women with chronic pelvic pain. 24. Kapural L, Narouze SN, et al. Spinal cord stimulation is an effective
J Psychosom Res 1998;44:203–207. treatment for the chronic intractable visceral pelvic pain. Pain Med
9. Sasaki K, Smith CP, Chuang YC. Oral gabapentin (neurontin) treatment 2006;7:440–443.
of refractory genitourinary tract pain. Tech Urol 2001;7:47–49. 25. Peters AA, van Dorst E, Jellis B. A randomized clinical trial to
10. Moulin DE, Iezzi A, Amireh R, et al. Randomized trial of morphine compare two different approaches in women with chronic pelvic pain.
for chronic non-cancer pain. Lancet 1996;347:143–147. Obstet Gynecol 1991;77:740–744.
Chapter 30 physiology is what clears the path for accurate diagnosis and treat-
ment of pelvic pain. In the past, visceral etiologies and psychogenic
FEMALE PERINEAL/PELVIC causes topped the list. Current thinking incorporates musculoskel-
etal diagnoses predominated by dysfunction of the pelvic floor
musculature. Whether the initial insult is visceral or not, the
PAIN: THE REHABILITATION somatic response can become the ultimate culprit, particularly in
the persistance of pelvic pain. Perhaps if acute pelvic pain muscu-
APPROACH loskeletal diagnoses were made more definitively, chronic pelvic
pain (CPP) would not be as rampant. Some research supports
Colleen M. Fitzgerald and Christina K. Hynes that pregnancy- and postpartum-related pelvic pain can be the ini-
tial insult for those who develop chronic issues. This chapter
explores the role of the musculoskeletal system in the diagnosis of
pelvic pain, reviews pelvic musculoskeletal anatomy, identifies
physical examination techniques in making the pelvic pain diagno-
sis, and proposes effective rehabilitation treatment options in the
management of pelvic pain.
INTRODUCTION
Physiatrists since the early days of physical medicine and rehabili-
tation have often been the physicians who take over where others PELVIC ANATOMYAND FUNCTION
have left off. They are doctors who need to formulate treatment
strategies for those patients whose diagnoses leave others confused Muscle/Fascia
and frustrated. Certainly, persistent pelvic pain has fallen into
this category. Often considered the ‘‘black box’’ of medicine, it is The pelvic floor is composed of layers of muscles connecting the
this author’s belief that understanding the pelvic anatomy and anterior and posterior pelvic ring and surrounding the urethra,
formulating a rational treatment plan. Furthermore, a multidisci- 11. Portenoy RK, Foley KM. Chronic use of opioids in non-malignant
plinary approach to patients with CPP aids in coordinating the pain: a report of 38 cases. Pain 1986;25:171–186.
assessments of primary care physicians and specialists in pain med- 12. ACOG Practice Guidelines Bulletin. Clinical management guidelines
icine, urology, gynecology, gastroenterology, physiotherapy, and for obstetrician-gynecologists. Chronic Pelvic Pain 2004;103:589–605.
13. Siddall-Allum J, Rae T, Rogers V, et al. Chronic pelvic pain caused by
psychology. In fact, a randomized clinical trial by Peters and cow-
residual ovaries and ovarian remnants. Br J Obstet Gynaecol
orkers25 compared the effectiveness of a focused organic approach 1994;101:979–985.
to CPP and a multidisciplinary approach consisting of surgical, 14. Carey MP, Slack MC. GnRH analogue in assessing chronic pelvic pain in
psychological, social, and dietary interventions. Patients in the mul- women with residual ovaries. Br J Obstet Gynaecol 1996;103:150–153.
tidisciplinary treatment group reported greater improvement in 15. Sutton CJ, Ewen SP, Whitelaw N, Haines P. Prospective, randomized,
self-reported pain scores. double-blind, controlled trial of laser laparoscopy in the treatment of
pelvic pain associated with minimal, mild and moderate
endometriosis. Fertil Steril 1994;62:696–700.
REFERENCES 16. Steege JF, Stout AL. Resolution of chronic pelvic pain after laparoscopic
lysis of adhesions. Am J Obstet Gynecol 1991;165:278–281.
1. Walling MK, Reiter RC, O’Hara MW, et al. Abuse history and 17. Peter AAW, Trimbos-Kemper GCM, Admiral C. A randomized
chronic pain in women. I. Prevalences of sexual and physical abuse. clinical trial of the benefit of adhesiolysis in patients with
Obstet Gynecol 1994;84:193–199. intraparitoneal adhesions and chronic pelvic pain. Br J Obstet
2. Howard FM. Chronic pelvic pain. Clinical gynecologic series. An Gynaecol 1992;99:59–62.
expert’s view. 2003;101:594–611. 18. Kjerulff KH, Langenberg PW, Rhodes JC, et al. Effectiveness of
3. Jänig W, Koltzenburg M. Pain arising from the urogenital tract. In hysterectomy. Obstet Gynecol 2000;95:319–326.
Maggi CA (ed): Nervous Control of the Urogenital System. Harwood 19. Chen F-P, Soong Y-K. The efficacy and complications of laparoscopic
Academic, 1993; pp 525–578. presacral neurectomy in pelvic pain. Obstet Gynecol 1997;90:974–977.
4. Wesselmann U. Neurogenic inflammation and chronic pelvic pain. 20. Bourke DL, Foster DC, Valley MA, Robinson JC. Superior hypogastric
World J Urol 2001;19:180–185. plexus block as predictive of presacral neurectomy success: a
5. The International Pelvic Pain Society. www.pelvicpain.org (Accessed preliminary report. Am J Pain Manage 1996;6:9–12.
April 2008). 21. Perry CP. Laproscopic uterovaginal ganglion excision (LUVE) for
6. Cervero F. Sensory innervation of the viscera: peripheral basis of chronic pelvic pain. J Gynecol Surg 1996;12:89–93.
visceral pain. Physiol Rev 1994;74:95–138. 22. Siegel S, Paszkiewicz E, Kirkpatrick C, et al. Sacral nerve stimulation in
7. Walker EA, Sullivan MD, Stenchever MA. Use of antidepressants in patients with chronic intractable pelvic pain. J Urol 2001;166:1742–1745.
the management of women with chronic pelvic pain. Obstet Gynecol 23. Everaert K, Devulder J, De Muynk M, et al. The pain cycle:
Clin North Am 1993;20:743–751. implication for the diagnosis and treatment of pelvic pain syndromes.
8. Engel CC Jr, Walker EA, Engel AL, et al. A randomized double-blind Int Urogynecol J Pelvic Floor Dysfunct 2001;12:9–14.
crossover trial with sertraline in women with chronic pelvic pain. 24. Kapural L, Narouze SN, et al. Spinal cord stimulation is an effective
J Psychosom Res 1998;44:203–207. treatment for the chronic intractable visceral pelvic pain. Pain Med
9. Sasaki K, Smith CP, Chuang YC. Oral gabapentin (neurontin) treatment 2006;7:440–443.
of refractory genitourinary tract pain. Tech Urol 2001;7:47–49. 25. Peters AA, van Dorst E, Jellis B. A randomized clinical trial to
10. Moulin DE, Iezzi A, Amireh R, et al. Randomized trial of morphine compare two different approaches in women with chronic pelvic pain.
for chronic non-cancer pain. Lancet 1996;347:143–147. Obstet Gynecol 1991;77:740–744.
Chapter 30 physiology is what clears the path for accurate diagnosis and treat-
ment of pelvic pain. In the past, visceral etiologies and psychogenic
FEMALE PERINEAL/PELVIC causes topped the list. Current thinking incorporates musculoskel-
etal diagnoses predominated by dysfunction of the pelvic floor
musculature. Whether the initial insult is visceral or not, the
PAIN: THE REHABILITATION somatic response can become the ultimate culprit, particularly in
the persistance of pelvic pain. Perhaps if acute pelvic pain muscu-
APPROACH loskeletal diagnoses were made more definitively, chronic pelvic
pain (CPP) would not be as rampant. Some research supports
Colleen M. Fitzgerald and Christina K. Hynes that pregnancy- and postpartum-related pelvic pain can be the ini-
tial insult for those who develop chronic issues. This chapter
explores the role of the musculoskeletal system in the diagnosis of
pelvic pain, reviews pelvic musculoskeletal anatomy, identifies
physical examination techniques in making the pelvic pain diagno-
sis, and proposes effective rehabilitation treatment options in the
management of pelvic pain.
INTRODUCTION
Physiatrists since the early days of physical medicine and rehabili-
tation have often been the physicians who take over where others PELVIC ANATOMYAND FUNCTION
have left off. They are doctors who need to formulate treatment
strategies for those patients whose diagnoses leave others confused Muscle/Fascia
and frustrated. Certainly, persistent pelvic pain has fallen into
this category. Often considered the ‘‘black box’’ of medicine, it is The pelvic floor is composed of layers of muscles connecting the
this author’s belief that understanding the pelvic anatomy and anterior and posterior pelvic ring and surrounding the urethra,
228 Chapter 30 FEMALE PERINEAL/PELVIC PAIN: THE REHABILITATION APPROACH
vagina, and anus. Any layer of the pelvic floor musculature can be pubic symphysis inflammation, which is typically seen in associa-
the pain generator or the source of dysfunction. These muscles, with tion with a pelvic obliquity, can often lead to a chronic, painful,
their differing degrees of fast-twitch (30%) and slow-twitch (70%) noninfectious inflammatory condition known as osteitis pubis.
fibers, facilitate sphincter closure1 and support the intra-abdominal Osteitis pubis has been described as a complication of various
organs to prevent pelvic organ prolapse. Their combined optimal obstetric and gynecologic procedures, including vaginal deliveries.7
function as a neuromuscular unit is integral to maintaining urinary, Any patient with a history of traumatic labor and delivery may be at
flatal, and fecal continence. The pelvic floor muscles also contract risk for this entity. Plain films are the imaging method of choice;
during orgasm to provide sexual appreciation. They can be however, radiographic findings often lag behind clinical symptoms.
damaged during childbirth, after gynecologic or urologic instru- Real-time ultrasound is investigational in assessing pubic symphysis
mentation, after repetitive minor trauma from activities such as injuries. Typically, x-ray changes seen include loss of smooth cor-
dance and gymnastics, or after incidents of sexual abuse. tical bone and reactive sclerosis.
The superficial pelvic floor or urogenital diaphragm includes the Coccydynia is defined as pain in and around the coccyx without
bulbocavernosus, ischiocavernosus, and transverse perinei. The significant symptom referral. Sitting and arising from the seated to
deep pelvic floor or levator ani includes the puborectalis, pubococ- the standing positions are common exacerbating influences. A his-
cygeus, iliococcygeus, and coccygeus (Fig. 30–1). The piriformis and tory of coccyx pain or complaints of very low back pain or tailbone
obturator internus muscles are considered associated muscles, and pain warrant consideration of this diagnosis. The coccyx is evalu-
the deep transversus abdominis, lumbar multifidi, and diaphragm ated most fully with digital rectal examination. The coccyx is heavily
are considered synergistic groups. The pelvic floor works dynami- supported by ligamentous structures and serves as the attachment
cally in conjunction with these other muscles to maintain core sta- point for pelvic floor musculature. The combination of laxity and
bility. The pelvic floor is considered the ‘‘floor of the core.’’ asymmetry can create abnormal motion at the level of the coccyx
Innervation of the pelvic floor posteriorly is by direct efferents similar to that of the SI joint. Often, coccygeal pain may be sec-
from the S2–4 nerve roots, whereas the anterior pelvis is innervated ondary to or seen in conjunction with pelvic floor muscle myofas-
by the pudendal nerve and its three branches, the dorsal nerve to the cial pain and dysfunction.
clitoris, the perineal branch, and the inferior hemorroidal nerve.
BONY PELVIS
Sacroiliac Joint Dysfunction and Pelvic Obliquity
Lumbar Spine and Hip
The pelvis is a ring comprising two innominate bones that are
connected anteriorly by the pubic symphysis and posteriorly to Contribution of the lumbar spine and hip must be considered in
either side of the sacrum by the sacroiliac (SI) joints. The female patients complaining of pelvic pain, because each of these entities
pelvis has more joint space surface area and a higher center of may refer pain to the pelvic area or be the primary diagnosis in the
gravity compared with males (Fig. 30–2). Pelvic joint pain and setting of a pelvic obliquity. Pain from lumbar spondylosis
dysfunction are often associated with a pelvic obliquity or subtle or degenerative change should be explored in patients who com-
asymmetry of the bony pelvis, which itself can be secondary to tight plain of back pain, numbness, and tingling or with neurologic
or weak muscles. The pelvic obliquity may lead to the SI joint findings on examination. A thorough examination will differentiate
dysfunction and change in joint mechanics or vice versa. the symptoms of degenerative disk disease from radiculopathy
Asymmetry of any part of the ring will cause dysfunction on the from pain referred from the SI joint. Patients can have SI joint
opposite side (e.g., dysfunction of the posterior pelvis will result in dysfunction concurrently with an S1 radiculopathy. If there is
asymmetry and dysfunction of the anterior pelvis). These typically progressive weakness or bowel or bladder incontinence associated
do not occur in isolation. In turn, pelvic floor muscles may react to with back pain, cauda equina syndrome must be ruled out.
pelvic obliquity with increased tension, pain, or weakness. Often, Immediate imaging with magnetic resonance imaging (MRI) and
determining primary joint versus primary muscle dysfunction can surgical referral is warranted.
be difficult, especially when the pain is chronic in nature. Osteoarthritis of the hip, hip fracture, and avascular necrosis
The SI joint is a true joint consisting of a synovial component (AVN) of the femoral head are hip conditions that may present
inferiorly. It is auricular-shaped, with the thinner sacral side lined with nonspecific groin pain or anterior pelvic pain. Range of
with hyaline cartilage and the thicker ilial side with fibrocartilage. motion testing of the hips will aid in making a diagnosis. Often,
Primary innervation to this joint is believed to be from S1.2 in osteoarthritis, hip internal rotation is severely limited. AVN pre-
Sturesson and coworkers3 in 1989 described true movement of sents typically with pain on weight-bearing.
the SI joint measuring approximately 18 to 38 of rotation. The SI
joint has also been shown in the literature to be a generator of
low back pain.4 Suspicion should be raised for SI joint pain when MUSCULOSKELETAL CAUSES OF
the patient complains of pain below L5 in the region of the PELVIC PAIN
posterior pelvis.5,6 Clinically, patients typically report pain over
the sacrum or the sacral sulcus, but they may also describe back Many of the potential causes of pelvic pain are listed in Table 30–1.
pain and pain radiating into the legs, which can be confused Physiatrists typically classify the diagnoses into the area of dysfunc-
with a radiculopathy. Transitional motions, particularly while tion or pain (e.g., muscular/fascial, skeletal/joint, visceral, neurolo-
turning in bed and arising from the seated to the standing posi- gic, or psychogenic). Pelvic floor or piriformis pain was found
tion, frequently trigger or exacerbate the presenting symptoms. in over 20% of women in CPP referral clinics.8 Pelvic floor myo-
SI joint dysfunction is the leading cause of pregnancy-related fascial pain can be associated with other musculoskeletal findings,
pelvic pain. most notably pelvic obliquity. This fact points to the importance
of a complete musculoskeletal evaluation of the entire kinetic chain.
The kinetic chain describes the coordinated activation of body
Pubic Symphysis and Coccyx segments to perform a function optimally. A physiatry examination
will evaluate the level above and below the lesion or area of symp-
Pubic symphysis asymmetry or inflammation may be seen in toms. For the pelvis, this involves examining the lumbar spine
patients and simultaneously precipitate pelvic or low back pain. above and the lower extremity below for any pain, muscle imbal-
Patients typically complain of anterior pelvic or pubic pain. Acute ances, or mobility issues.
Bulbospongiosus
muscle with investing Suspensory ligament
(Gallaudet’s) fascia of clitoris
partially
Clitoris Ischiocavernosus
Superficial muscle
perineal space
(pouch or compartment) Vestibular bulb
Ischiopubic ramus Greater vestibular

with cut edge of (Bartholin’s) gland
superficial perineal
(Colles’) fascia Bulbospongiosus
muscle (cut away)
Inferior fascia Superficial
of urogenital transverse
diaphragm perineal muscle
Ischial
tuberosity Obturator
internus fascia
Sacrotuberous
ligament Tendinous arch
of levator ani
muscle
Gluteus
maximus
muscle
Inferior fascia
of pelvic
diaphragm (cut)
Ischiorectal
fossa
External anal Levator ani

sphincter muscle Anococcygeal Coccyx Central tendon muscle
ligament of perineum
Figure 30^1. Pelvic floor musculature. (From Netter FA. Atlas of human anatomy. In Colacino S (ed): Netter’s Anatomy. Philadelphia: Elsevier,1989.)
PHYSICAL EXAMINATION IN THE rotators). These muscles are integral to the functioning of the pelvis,
PATIENT WITH PELVIC PAIN may become weak and imbalanced, and are potential sources for
pelvic pain. The gluteus maximus is the primary hip extensor and
Recent investigations suggest that there are specific abnormal mus- can be evaluated by having the patient lie prone and asking her or
culoskeletal physical examination findings more commonly seen in him to extend her or his leg off the table against resistance. The
CPP patients, and these warrant further investigation of somatic gluteus medius is most easily evaluated on gait assessment and, if
pain generators. Tu and associates in 20079 performed a masked, weak, results in the classic Trendelenburg gait (i.e., weakness causes
prospective, cross-sectional study of abnormal pelvic, abdominal, contralateral hip drop).11 The piriformis is tested for tightness in
and back examination findings in 19 women with CPP versus 20 the prone position. With the knee flexed 908, the lower leg is moved
healthy controls. The results showed that women with CPP had medially, causing hip internal rotation. If range of motion is less
more frequent abnormal musculoskeletal findings than did controls than 408 to 508, the piriformis may be tight. In the standing posi-
(asymmetrical iliac crests (61% vs. 25%), pubic symphysis heights tion, patients typically assume a posture of lower extremity external
(50% vs. 10%), and positive posterior pelvic provocation testing rotation with the toe out if the piriformis is tight, short, and weak.
(37% vs. 5%; all had P <.05). Pain patients exhibited more tender- It can also be painful to palpation in standing. The iliopsoas is
ness at several abdominal muscle sites, had higher median total tested with the patient in the supine position, raising one leg to
pelvic floor tenderness scores (3/24 vs. 0/24; P <.05), and less con- the chest and dropping the contralateral thigh off the examining
trol of the pelvic floor (unable to maintain 10 sec of relaxation, 78% table (Thomas’s test). This will show tightness in the hip flexors.11
vs. 20%; P <.001). Another similar study of pelvic pain patients Typically, these patients have postural problems, including an ante-
revealed that the presentation of patients with pelvic floor muscle riorly tilted pelvis.
dysfunction and a positive forced (FABER) test in addition to core In a patient complaining of pelvic pain, the pelvic floor mus-
weakness should prompt the clinician to suspect a musculoskeletal cles should be evaluated manually for both relaxation and con-
basis of CPP.10 tractile dysfunction. Intrapelvic muscle assessment is done using a
one finger technique both vaginally and rectally. Female patients
are examined while lying supine on an examining table with their
Muscle AssessmentçExternal Evaluation and legs in the dorsal lithotomy position. Pelvic floor muscles are
Internal Evaluation assessed for tone, strength, conditioning, coordination, tender/
trigger points, and anatomic deficits such as prolapse. The mus-
External examination of the pelvic musculature in both men and cles function as a group, so isolating a specific muscle can be
women includes evaluating the gluteus complex (pelvic stabilizers/ difficult; however, separating superficial from deep dysfunction is
hip extensors), iliopsoas (hip flexors), and piriformis (hip external possible.
FEMALE PELVIS/FEMALE PELVIC OUTLET: INFERIOR VIEW
Pubic
symphysis
Transverse
diameter of pelvic
outlet (~11 cm)
Ischial
tuberosity
Anteroposterior
Ischial spine
diameter of pelvic outlet
(varies 9.5–11.5 cm)
because of mobility
of coccyx
Tip of coccyx
Figure 30^2. Female pelvis/female pelvic outlet: inferior view. (From Netter FA. Atlas of human anatomy. In Colacino S (ed): Netter’s Anatomy.
Philadelphia: Elsevier,1989.)
Initially, the patient’s ability to lift the pelvic floor function is Maigne and Chatellier18 and is the only way to access the pelvic
assessed by requesting that the patient voluntarily contract and relax floor muscles in males. Most commonly, the examination is per-
the pelvic floor and visualizing perineal body lift and descend. Pain formed with the patient in the side-lying position. A finger is
patients typically have a nonrelaxing pelvic floor that also lacks inserted into the rectum and the coccyx can be palpated by gradu-
optimal contractile function. Q-tip testing for pain/hyperesthesia, ally pushing the finger posteriorly until contact is made with the
reflex testing of the anal wink, and palpation of the external uro- coccyx.18 This technique also allows for palpation of the pelvic floor
genital diaphragm for pain are performed. Tender or trigger points because the coccyx is the anatomic insertion for most of these
are noted and documented by location. To date, there is no vali- muscles, including the iliococcygeus, pubococcygeus, and coccyge-
dated objective assessment for this portion of the examination, but us. Palpation and mobilization of the coccyx using Mennell’s tech-
pelvic pressure sensory testing is being researched with use of a nique19 can be performed. The coccyx can be grasped between
pelvic palpometer/pressure algometer.12 the external thumb and the internal index finger while flexion,
General contractile strength is evaluated including sustained iso- extension, and rotation are applied, noting pain and range of
metric holds to evaluate endurance slow-twitch muscle fibers and motion. Using voluntary contraction and relaxation cues with the
‘‘quick flicks’’ to evaluate fast-twitch muscle fibers.13 Manual finger inserted in the rectum, the examiner may also be able to
muscle strength testing is scored using the modified Oxford scale evaluate for any dyssynergia of the puborectalis and external sphinc-
(Table 30–2).14 Although the general interrater reliability is shown ter musculature and relate these finding to a patient’s complaints of
to be fair to poor for pelvic floor muscle testing using this scale, fecal incontinence or constipation.20 Again, typically the pain
Isherwood and Rane15 and Frawley and colleagues16 found good patient will have a nonrelaxing pelvic floor, which also makes
agreement between digital assessment of pelvic floor strength passage of stool difficult and control of bowel movements tenuous.
using the Oxford scale and vaginal perineometry readings. Digital Specific physical examination maneuvers, including the forced
internal examination is currently the best-documented test avail- FABER test,11 posterior pelvic pain provocation test,21,22 active
able. It is suggested that the same examiner perform both the initial straight leg raise with compression,23 and the compression test24
and the follow-up evaluations. The obturator internus can also be are specific for SI joint pathology. Often, examination for tender-
palpated on internal examination and is activated with hip external ness of the pubic symphysis is also an important part of a pelvic
rotation. As the patient’s knee presses against the examiner’s exter- pain evaluation. Measuring for subtle pelvic obliquities can also be
nal hand with external rotation of the hip, the internal hand can helpful in directing the physical therapy (PT) prescription. An array
appreciate ipsilateral obturator internus muscle contraction and of nomenclature exists to describe a given obliquity. A problematic
evaluate the muscle for tightness and tenderness. hemipelvis can be rotated anteriorly or posteriorly, sheared super-
Rectal examination, first described by Theile in 1937,17 can be iorly (up-slip) or inferiorly (down-slip), in-flared or out-flared.
done using several techniques reviewed in detail in an article by Sacral positioning can be similarly described.25
Table 30^1. Differential Diagnosis of Pelvic Pain
Category Diagnoses
Muscular/fascia Pelvic floor myofascial pain/levator ani syndrome/tension myalgia
Myofascial pain syndromes of the piriformis or iliopsoas muscles
Dyssynergia of the pelvic floor muscles
Vaginismus
Vulvodynia
Skeletal/joint Pelvic insufficiency/stress fracture
Sacroiliac joint dysfunction
Pelvic obliquity or derangement, pelvic asymmetry
Pubic symphysitis/osteitis pubis
Coccydynia
Lumbar degenerative disk disease/spondylosis or spondylolisthesis
Hip osteoarthritis
Hip fracture
Avascular necrosis of the femoral head
Bony metastasis
Neurologic Radiculopathy
Plexopathy
Peripheral neuropathy—pudendal neuropathy
Visceral Urogynecologic Cystitis
Urethritis
Urolithiasis
Pelvic inflammatory disease
Endometriosis
Interstitial cystitis/Bladder pain syndrome
Urethral syndrome
Tumor of urogynecologic organs
Urologic Interstitial cystitis/Bladder pain syndrome
Neoplasm of urogenital organs
Gastroenterologic Irritable bowel syndrome
Infectious enterocolitis
Diverticular disease
Hernia
Appendicitis
Ischemic bowel disease
Inflammatory bowel disease
Intestinal neoplasm
Vascular Hypoxemia/necrosis
Pelvic congestion syndrome
Pelvic varicosities
Psychogenic Depression
Physical or sexual abuse
Post-traumatic stress disorder
appreciation, and activities of daily living. It can affect one’s

REHABILITATION FOR PELVIC PAIN social life, vocational capacity, and leisure activity, not to mention
future pregnancy decisions. Therapeutic goals for the pelvic pain
The rehabilitation team in treating the pelvic pain patient comprises patient are realistically set based on the severity of disability and
the physiatrist as the team leader, the physical therapist, the occu- patient preference.
pational therapist, the psychologist, and the nurse educator. A com- In rehabilitation, PT is often the mainstay of treatment for mus-
bination of treatments including medication management, culoskeletal disorders of both the external and the internal pelvis.
hormonal therapies, pelvic injections, PT, OT, biofeedback, and This treatment carries little risk and no long-term side effects,
modalities is often employed in the context of an interdisciplinary unlike others such as medications, injections, and procedures.
pain program. Acute and subacute pelvic pain patients may need a Pelvic floor PT is more than just Kegel maneuvers. In fact, strength-
lesser combination of these; however, in the setting of chronic pain, ening of these muscles is often the last step in a PT program
typically all treatment options are utilized. because strengthening too soon may increase pain. Primary
Pelvic pain has a significant impact on a patient’s ability to muscle dysfunction is often concomitantly seen with joint dysfunc-
function. This includes the effect on bowel and bladder, sexual tion, and physical therapists will address all musculoskeletal issues.
Table 30^2. Modified Oxford Scale [Laycock]* activation of pelvic floor muscles during activities such as lifting,
squatting, and coughing is then taught.
Unfortunately, few studies objectively evaluate the efficacy of PT
in pelvic pain patients. Weiss and coworkers27 showed that myo-
fascial trigger point therapy that lasted on average for 8 to 12 weeks
for 10 interstitial cystitis patients resulted in a 70% moderate to
marked improvement.
A chronic pain program with a focus on functional recovery,
not just pain relief, has been shown to be effective in low back
pain. Interdisciplinary pain programs have also been found to be
beneficial in CPP.28 Psychological support in the context of pain
program versus psychology alone or in combination with internal
PT is also not well studied but is currently being assessed in our
institution.
CONCLUSION
Accurate diagnosis and treatment of pelvic pain is possible with a
comprehensive rehabilitation approach. This includes exploring
musculoskeletal causes of pelvic pain by identifying somatic pain
From Laycock J. Pelvic muscle exercises: physiotherapy for the pelvic floor. generators via a thorough and specialized physical examination of
Urol Nurs 1994;14:136-140. the internal pelvic floor musculature. Although better research is
needed to define a specific algorithm of PT treatments, clinical
experience has shown that patients benefit from therapeutic exercise
A PT evaluation begins with a good history followed by a thorough to include all pelvic musculoskeletal structures along with more
skilled examination. This includes external musculoskeletal exami- traditional medical therapies.
nation in standing, sitting, supine, and prone positions. An evalu-
ation of posture, spinal mobility, spinal and extremity range of
motion, flexibility, and strength is performed. Pelvic alignment
including iliac crests, SI, pubic symphysis, and coccyx joints is
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judged, and soft tissues around the pelvis and specific muscle 1. Travell J, Simons DG. Myofascial pain and dysfunction. In the Trigger
groups including the piriformis, iliopsoas, gluteals, adductors, Point Manual, vol 2, The Lower Extremities. Baltimore, Williams &
and hamstrings are assessed. Intravaginal and/or intrarectal pelvic Wilkins, 1992; pp 110–131.
floor examination is completed as described previously. The phys- 2. Fortin JD, Kissling RO, O’Connor BL, Vilensky JA. Sacroiliac joint
ical therapist will differentiate between primary dysfunction and innervation and pain. Am J Orthop 1999;28:687–690.
3. Sturesson B, Selvik G, Uden A. Movements of the sacroiliac joints.
pain.26 A roentgen stereophotogrammetric analysis. Spine 1989;14:162–165.
The physical therapist will recommend a plan of care typically 4. Schwarzer AC, Aprill CN, Bogduk N. The sacroiliac joint in chronic
including both internal or vaginal/rectal PT and external PT with a low back pain. Spine 1995;20:31–37.
home exercise program. For patients with significant soft tissue 5. Bernard TN Jr, Kirkaldy-Willis WH. Recognizing specific
impairments and/or pain, the therapist may provide manual thera- characteristics of nonspecific low back pain. Clin Orthop
pies such as massage, myofascial release, joint mobilization, and 1987;217:266–268.
manual stretching, Patients must be actively involved in their care 6. Maigne JY, Aivaliklis A, Pfefer F. Results of sacroiliac joint double
and participate in treatments including stretching, posture training, block and value of sacroiliac pain provocation tests in 54 patients
with low back pain. Spine 1996;21:1889–1892.
and therapeutic exercise. They learn self-correction techniques for
7. Lentz SS. Osteitis pubis: a review. Obstet Gynecol Surv 1995;50:310–315.
pelvic obliquity. Frequency and duration of PT treatment may be 8. Tu FF, As-Sanie S, Steege JF. Musculoskeletal causes of chronic pelvic
anywhere from one to two treatments per week for 6 to 10 weeks, pain: a systematic review of diagnosis: part I. Obstet Gynecol Surv
although this varies among therapists. 2005;60:379–385.
Internally, the PT provides neuromuscular reeducation for 9. Tu FF, Holt J, Gonzales J, Fitzgerald CM. Physical therapy evaluation
proper activation and relaxation of pelvic floor muscles. of chronic pelvic pain patients: a controlled study. Am J Obstet
Relaxation training of the pelvic floor muscles with manual and Gynecol 2008;198:272e1–7.
surface electromyography biofeedback is utilized, and monitoring 10. Neville CE, Fitzgerald CM, et al. Musculoskeletal dysfunction in
electrical activity of muscles is employed. The patient visualizes female chronic pelvic pain: a blinded study of examination findings.
activity on a liquid crystal display or computer screen and learns Presented at World Congress in Physical Therapy, Vancouver, June
2007.
to control the activity. This is similar to external forms of biofeed- 11. Magee DJ. Orthopedic Physical Assessment, 3rd ed. Philadelphia: WB
back; however, an internal probe may be used. Perineal massage/ Saunders, 1997.
stretching along with internal myofascial release of the pelvic floor 12. Tu FF, Fitzgerald CM, Kuiken T, et al. Comparative measurement of
musculature is done by the therapist, and instruction of self-mas- pelvic floor pain sensitivity in chronic pelvic pain. Obstet Gynecol
sage techniques using dilators is taught. Often, electrical stimulation 2007;110:1244–1248.
devices are added as modalities that may be used for both pain 13. Theofrastous JP, Swift SE. The clinical evaluation of pelvic floor
management (similar to a transcutaneous electrical nerve stimula- dysfunction. Obstet Gynecol Clin North Am 1998;25:783–804.
tion unit) and to facilitate pelvic floor muscle contraction. Both 14. Laycock J. Pelvic muscle exercises: physiotherapy for the pelvic floor.
home biofeedback and electrical stimulation units can be ordered. Urol Nurs 1994;14:136–140.
15. Isherwood PJ, Rane A. Comparative assessment of pelvic floor
Pelvic floor muscle training is usually the last step in PT once pain is strength using a perineometer and digital examination. Br J Obstet
under better control and muscles are in their optimal positioning. Gynaecol 2000;107:1007–1011.
Patients are taught to do pelvic floor muscle contractions, holding 16. Frawley HC, Galea MP, Phillips BA, et al. Reliability of pelvic floor
for 5 to 10 seconds, then relaxing for 10 seconds, 10 to 20 repeti- muscle strength assessment using different test positions and tools.
tions, three to six times per day, in multiple positions. Functional Neurourol Urodyn 2006;25:236–242.
17. Thiele G. Coccygodynia and pain in the superior gluteal region. 23. Mens JM, Vleeming A, Snijders CJ, et al. The active straight leg raising
JAMA 1937;109:1271–1275. test and mobility of the pelvic joints. Eur Spine J 1999;8:468–473.
18. Maigne JY, Chatellier G. Comparison of three manual 24. Laslett M, Williams M: The reliability of selected pain provocation
coccydynia treatments: a pilot study. Spine 2001;26:E479–E483; tests for sacroiliac joint pathology. Spine 1994;19:1243–1249.
discussion E484. 25. Isascs EB, Mark R: Bourdillon’s Spinal Manipulation, 6th ed. London:
19. Mennell JM. Manipulation and the treatment of low back pain. Clin Butterworth Heinemann, 2002; pp 125–155.
Orthop 1955;5:82–96. 26. Messelink B, Benson T, Berghmans B, et al. Standardization of
20. Oyama IA, Rejba A, Lukban JC, et al. Modified Thiele massage as terminology of pelvic floor muscle function and dysfunction: report
therapeutic intervention for female patients with interstitial from the pelvic floor clinical assessment group of the International
cystitis and high-tone pelvic floor dysfunction. Urology Continence Society. Neurourol Urodyn 2005;24:374–380.
2004;64:862–865. 27. Weiss JM, et al. Pelvic floor myofascial trigger points: manual therapy
21. Ostgaard HC, Zetherstrom G, Roos-Hansson E. The posterior pelvic for interstitial cystitis and the urgency-frequency syndrome, J Urol
pain provocation test in pregnant women. Eur Spine J 1994;3:258–260. 2001;166:2226–2231.
22. Albert H, Godskesen M, Westergaard J. Evaluation of clinical tests 28. Kames LD, Rapkin AJ, Naliboff BD, et al. Effectiveness of an
used in classification procedures in pregnancy-related pelvic joint interdisciplinary pain management program for the treatment of
pain. Eur Spine J 2000;9:161–166. chronic pelvic pain. Pain 1990;41:41–46.
Chapter 31 Pain in FMS is consistently felt in the musculature and is related

FIBROMYALGIA SYNDROME to sensitization of CNS pain pathways. The pathogenesis of FMS is
not fully known, but abnormal concentrations of CNS neuropep-
tides, biogenic amines, and alterations of the hypothalamic-pitui-
Roland Staud tary-adrenal (HPA) axis have been described. There is a large body
of evidence for a generalized lowering of pressure pain thresholds in
FMS patients. The mechanical pain hypersensitivity (allodynia) of
FMS patients, however, is not limited to tender points and appears
to be widespread. In addition, almost all studies of FMS patients
have shown abnormalities of pain sensitivity while using different
methods of sensory testing.
INTRODUCTION Although relevant for many clinical pain syndromes like FMS,
nociception alone cannot explain the human pain experience.
Fibromyalgia syndrome (FMS) pain is frequent in the general popu- Peripheral pain impulses always undergo modulation in the CNS
lation, and its pathogenesis is increasingly better understood. by conscious and unconscious mental activity. In addition, socio-
Many recent studies have emphasized the role of central nervous cultural influences, beliefs, or biases, particularly those related
system (CNS) pain processing abnormalities in FMS, including cen- to cause, control, duration, outcome, and blame, can strongly influ-
tral sensitization and inadequate pain inhibition. However, increas- ence pain. These beliefs are frequently linked to negative emotions,
ing evidence points toward peripheral tissues as relevant contributors such as anger, fear, and depression. Generally, pain has several
of painful impulse input that might either initiate or maintain central emotional components including the unpleasantness of the sensa-
sensitization or both. It is well known that persistent or intense notion (primary pain affect) as well as negative feelings such as depres-
ciception can lead to neuroplastic changes in the spinal cord and sion, anger, and fear (secondary pain affect). This relationship
brain, resulting in central sensitization and pain. This mechanism of emotions to pain is bidirectional because modulation of negative
represents a hallmark of FMS and many other chronic pain syn- feelings can powerfully alter the pain experience. Owing to the fact
dromes, including irritable bowel syndrome, temporomandibular that pain is a personal (first-person) experience, it can be only
disorder, migraine, and low back pain. In addition, abnormalities partially captured by definitions. Nevertheless, the International
of the autonomic nervous system and hypothalamus-pituitary- Association for the Study of Pain (IASP) has defined pain as an
adrenal axes seem to play an important role in peripheral and central ‘‘unpleasant sensory and emotional experience associated with
sensitization of FMS patients. Importantly, after central sensitization actual and potential tissue damage or describe in terms of such
has been established, only minimal nociceptive input is required damage.’’ This definition of pain, however, has significant short-
for the maintenance of the chronic pain state. Additional factors, comings because it is not encompassing all aspects of pain.
including pain-related negative affect and poor sleep, have also In general, abnormalities of pain processing appear to play an
been shown to significantly contribute to clinical FMS pain. Better important role for FMS pain, particularly those abnormalities
understanding of these mechanisms and their relationship to central related to deep tissue impulse input, central sensitization, and
sensitization and clinical pain will provide new approaches for the mood abnormalities. Some of the important contributions of
prevention and treatment of FMS and other chronic pain syndromes. abnormal central pain mechanisms to clinical FMS pain include
FMS is a chronic pain syndrome that can be defined as widespread temporal summation of pain (or wind-up [WU]) and central
pain for more than 3 months and the presence of 11 or more out sensitization.
of 18 tender points. In addition, most FMS patients complain of
disturbed sleep, emotional distress, and pronounced fatigue. FMS
represents the extreme end of the spectrum of musculoskeletal TAXONOMY
pain in the general population and is a chronic illness that dispropor-
tionately affects women (9:1 ratio of women to men affected). As with FMS was defined by the American College of Rheumatology in
many other clinical syndromes, FMS has no single specific feature but 1990. The classification criteria include a history of chronic wide-
represents a symptom complex of self-reported or elicited findings. spread pain and the presence of 11 or more out of 18 tender points.
17. Thiele G. Coccygodynia and pain in the superior gluteal region. 23. Mens JM, Vleeming A, Snijders CJ, et al. The active straight leg raising
JAMA 1937;109:1271–1275. test and mobility of the pelvic joints. Eur Spine J 1999;8:468–473.
18. Maigne JY, Chatellier G. Comparison of three manual 24. Laslett M, Williams M: The reliability of selected pain provocation
coccydynia treatments: a pilot study. Spine 2001;26:E479–E483; tests for sacroiliac joint pathology. Spine 1994;19:1243–1249.
discussion E484. 25. Isascs EB, Mark R: Bourdillon’s Spinal Manipulation, 6th ed. London:
19. Mennell JM. Manipulation and the treatment of low back pain. Clin Butterworth Heinemann, 2002; pp 125–155.
Orthop 1955;5:82–96. 26. Messelink B, Benson T, Berghmans B, et al. Standardization of
20. Oyama IA, Rejba A, Lukban JC, et al. Modified Thiele massage as terminology of pelvic floor muscle function and dysfunction: report
therapeutic intervention for female patients with interstitial from the pelvic floor clinical assessment group of the International
cystitis and high-tone pelvic floor dysfunction. Urology Continence Society. Neurourol Urodyn 2005;24:374–380.
2004;64:862–865. 27. Weiss JM, et al. Pelvic floor myofascial trigger points: manual therapy
21. Ostgaard HC, Zetherstrom G, Roos-Hansson E. The posterior pelvic for interstitial cystitis and the urgency-frequency syndrome, J Urol
pain provocation test in pregnant women. Eur Spine J 1994;3:258–260. 2001;166:2226–2231.
22. Albert H, Godskesen M, Westergaard J. Evaluation of clinical tests 28. Kames LD, Rapkin AJ, Naliboff BD, et al. Effectiveness of an
used in classification procedures in pregnancy-related pelvic joint interdisciplinary pain management program for the treatment of
pain. Eur Spine J 2000;9:161–166. chronic pelvic pain. Pain 1990;41:41–46.
Chapter 31 Pain in FMS is consistently felt in the musculature and is related

FIBROMYALGIA SYNDROME to sensitization of CNS pain pathways. The pathogenesis of FMS is
not fully known, but abnormal concentrations of CNS neuropep-
tides, biogenic amines, and alterations of the hypothalamic-pitui-
Roland Staud tary-adrenal (HPA) axis have been described. There is a large body
of evidence for a generalized lowering of pressure pain thresholds in
FMS patients. The mechanical pain hypersensitivity (allodynia) of
FMS patients, however, is not limited to tender points and appears
to be widespread. In addition, almost all studies of FMS patients
have shown abnormalities of pain sensitivity while using different
methods of sensory testing.
INTRODUCTION Although relevant for many clinical pain syndromes like FMS,
nociception alone cannot explain the human pain experience.
Fibromyalgia syndrome (FMS) pain is frequent in the general popu- Peripheral pain impulses always undergo modulation in the CNS
lation, and its pathogenesis is increasingly better understood. by conscious and unconscious mental activity. In addition, socio-
Many recent studies have emphasized the role of central nervous cultural influences, beliefs, or biases, particularly those related
system (CNS) pain processing abnormalities in FMS, including cen- to cause, control, duration, outcome, and blame, can strongly influ-
tral sensitization and inadequate pain inhibition. However, increas- ence pain. These beliefs are frequently linked to negative emotions,
ing evidence points toward peripheral tissues as relevant contributors such as anger, fear, and depression. Generally, pain has several
of painful impulse input that might either initiate or maintain central emotional components including the unpleasantness of the sensa-
sensitization or both. It is well known that persistent or intense notion (primary pain affect) as well as negative feelings such as depres-
ciception can lead to neuroplastic changes in the spinal cord and sion, anger, and fear (secondary pain affect). This relationship
brain, resulting in central sensitization and pain. This mechanism of emotions to pain is bidirectional because modulation of negative
represents a hallmark of FMS and many other chronic pain syn- feelings can powerfully alter the pain experience. Owing to the fact
dromes, including irritable bowel syndrome, temporomandibular that pain is a personal (first-person) experience, it can be only
disorder, migraine, and low back pain. In addition, abnormalities partially captured by definitions. Nevertheless, the International
of the autonomic nervous system and hypothalamus-pituitary- Association for the Study of Pain (IASP) has defined pain as an
adrenal axes seem to play an important role in peripheral and central ‘‘unpleasant sensory and emotional experience associated with
sensitization of FMS patients. Importantly, after central sensitization actual and potential tissue damage or describe in terms of such
has been established, only minimal nociceptive input is required damage.’’ This definition of pain, however, has significant short-
for the maintenance of the chronic pain state. Additional factors, comings because it is not encompassing all aspects of pain.
including pain-related negative affect and poor sleep, have also In general, abnormalities of pain processing appear to play an
been shown to significantly contribute to clinical FMS pain. Better important role for FMS pain, particularly those abnormalities
understanding of these mechanisms and their relationship to central related to deep tissue impulse input, central sensitization, and
sensitization and clinical pain will provide new approaches for the mood abnormalities. Some of the important contributions of
prevention and treatment of FMS and other chronic pain syndromes. abnormal central pain mechanisms to clinical FMS pain include
FMS is a chronic pain syndrome that can be defined as widespread temporal summation of pain (or wind-up [WU]) and central
pain for more than 3 months and the presence of 11 or more out sensitization.
of 18 tender points. In addition, most FMS patients complain of
disturbed sleep, emotional distress, and pronounced fatigue. FMS
represents the extreme end of the spectrum of musculoskeletal TAXONOMY
pain in the general population and is a chronic illness that dispropor-
tionately affects women (9:1 ratio of women to men affected). As with FMS was defined by the American College of Rheumatology in
many other clinical syndromes, FMS has no single specific feature but 1990. The classification criteria include a history of chronic wide-
represents a symptom complex of self-reported or elicited findings. spread pain and the presence of 11 or more out of 18 tender points.
234 Chapter 31 FIBROMYALGIA SYNDROME
Definition of Chronic Widespread Pain govern the HPA axis, the activity of which is reflected in blood
concentrations of corticosteroid hormones. Central abnormalities
Pain is considered widespread when all of the following are present: of FMS patients appear to be related to increased levels of substance
P, excitatory amino acids, and neurotropins in the CNS fluid as well
n Pain in the left side of the body.
as blunting of the HPA axis responses to stressors.
n Pain in the right side of the body.
Although previous FMS studies did not show consistent periph-
n Pain above the waist.
eral tissue abnormalities, more recent evidence points to possibly
n Pain below the waist.
relevant alterations in skin and muscles. These abnormalities
n In addition, axial skeletal pain must be present.
include increased substance P in muscle tissue, DNA fragmentation
n Duration of pain for more than 3 months.
of muscle fibers, muscle perfusion deficits, and increased interleu-
kin-1 (IL-1) concentrations in cutaneous tissues. These peripheral
changes may contribute to increased tonic nociceptive input into
Location of 18 Tender Point Sites the spinal cord that results in augmented WU and central sen-
sitization. There is compelling evidence for the contribution of
n Occiput: bilateral, at the suboccipital muscle insertion. peripheral pain to overall clinical pain in FMS. In a large study
n Low cervical: bilateral, at the anterior aspects of the inter- of FMS patients, ratings of peripheral pain areas accounted for
transverse spaces at C5–7. 27% of the variance of overall clinical pain, thus emphasizing
n Trapezius: bilateral, at the midpoint of the upper border. the important role of peripheral impulse input for FMS pain.
n Supraspinatus: bilateral, at origins, above the scapula spine These findings represent a possible link between peripheral input
near the medial border. and FMS pain. Importantly, nociceptive activity in peripheral
n Second rib: bilateral, at the second costochondral junctions, tissues of FMS patients does not necessarily have to be extensive
just lateral to the junctions on upper surfaces. because central sensitization requires little sustained input for the
n Lateral epicondyle: bilateral, 2 cm distal to the epicondyles. maintenance of the sensitized state and chronic pain.
n Gluteal: bilateral, in the upper outer quadrants of the but- Despite increasing evidence emphasizing the role of sensory
tocks in the anterior fold of muscle. abnormalities in chronic widespread pain and FMS, the contribu-
n Greater trochanteric: bilateral, posterior to the trochanteric tion of psychological factors to FMS pain must also be recognized.
prominence. Several psychological risk factors for FMS, including somatic symp-
n Knee: bilateral, at the medial fat pad proximal to the joint. toms, negative life events, psychological distress, increased focus on
bodily symptoms, and passive pain-coping mechanisms, are
A tender point is considered positive when pain can be elicited common in Western populations. Both community and clinic
by pressures of 4 kg or less. A dolorimeter or thumb pressure can be patients with FMS are also more likely than the general population
used. For tender points to be considered positive, the patient must to have a diagnosis of psychiatric disorders, particularly depression
perceive the palpation as painful; tenderness to palpation is not and anxiety. In a prospective study of 214 women with self-reported
sufficient. pain, 39 (18%) were diagnosed with FMS at study entry, and 33%
satisfied FMS criteria after 5.5 years of follow-up. Self-reported
depression at baseline was associated with a more than sixfold
EPIDEMIOLOGY increased likelihood of reporting FMS symptoms at follow-up and
was found to be the strongest independent predictor. In addition,
FMS has been described in 2% to 3% of persons in the general psychosocial factors including high levels of distress, fatigue, and
population, indicating that this condition is frequently encountered frequent health care–seeking behavior are strong predictors for
by general practitioners and rheumatologists. Most FMS patients chronic widespread pain and FMS.
are female (80%) with a mean age of 49 years. FMS affects an In this context, several studies have reported FMS to be
estimated 3.4% of adult women and 0.5% of adult men. The prev- comorbid with major depressive disorder (MDD). A recent large
alence of FMS rises steadily with age from less than 1% in women family study of FMS subjects showed that FMS and MDD are char-
aged 18 to 30 years to almost 8% in women 55 to 64 years of age. acterized by shared, familial risk factors, thus emphasizing the
Chronic musculoskeletal pain syndromes such as FMS are fre- strong relationship between negative affect and FMS pain.
quently encountered not only by rheumatologists but also by
other pain specialists. Thirty-six percent of patients hospitalized
on internal medicine wards can be diagnosed with chronic regional Peripheral and Central Sensitization
pain, 21% with chronic widespread pain; 15% of all patients
fulfill FMS criteria. Thus, FMS is one of the most common diag- Although heightened pain sensitivity is a hallmark of FMS, little is
noses among patient consultations across the United States and known about the genetic and other factors that contribute to this
Canada. abnormality. Tissue sensitization after injury has long been recog-
nized as making an important contribution to pain. This form of
sensitization is related to changes of the properties of primary no-
PATHOGENESIS OF FMS PAIN ciceptive afferents (peripheral sensitization), whereas central sensi-
tization requires functional changes in the CNS (neuroplasticity).
FMS is a pain-amplification syndrome of patients who are highly Such CNS changes related to central sensitization can manifest
sensitive to painful and nonpainful stimuli, including touch, heat, themselves in several ways, including increased excitability of
cold, chemicals, light, sound, and smell. The cause for the heigh- spinal cord neurons after injury, enlargement of the receptive
tened sensitivity of FMS patients is only partially understood, but it fields of these neurons, reduction in pain threshold, or recruitment
likely involves abnormalities in CNS stress responses, sensory proof novel afferent inputs. Behaviorally, centrally sensitized patients
cessing, and peripheral tissues. such as FMS sufferers report abnormal or heightened pain sensitiv-
When a situation is perceived as stressful, the brain activates ity with spreading of hypersensitivity to uninjured sites and the
many neuronal circuits to adapt to the demand. Two neuropep- generation of pain by low threshold mechanoreceptors that are
tides, corticotropin-releasing hormone (CRH) and vasopressin normally silent in pain processing. Thus, tissue injury might
(AVP), are essential for coordinating the behavioral and metabolic cause not only pain but also an expansion of dorsal horn receptive
responses to stress. The hypothalamic release of CRH and AVP fields and central sensitization.
Central sensitization can occur as an immediate or delayed phe- Does not return to baseline
nomenon resulting in increased sensitivity of wide dynamic range during stimuli of ≥0.33 Hz
and nociception-specific neurons of the spinal cord. Whereas
Pain sensitivity
delayed central sensitization depends mostly on transcriptional
and translational neuronal changes during afferent barrage, imme-
diate central sensitization relies mainly on dorsal horn neuron
receptor mechanisms, including the N-methyl-D-aspartate
(NMDA) and neurokinin-1 receptors.
Baseline
Peripheral and Central Pain Amplification

Time axis
Peripheral nociceptors can become increasingly sensitive after tissue Stimuli of equal
trauma and/or after up-regulation of nociceptor expression in intensity and duration
peripheral nerve endings. Subsequent activation of these receptors
Figure 31^1. Temporal summation of C-fiber pain (wind-up [ WU]) is
can lead to increased firing rates and pain. This mechanism
relevant for clinical pain and central sensitization.WU testing can be
(peripheral sensitization) seems to play an important role for
used to noninvasively assess central sensitization of chronic pain
FMS pain, although only indirect evidence supports this assump-
patients, like fibromyalgia syndrome (FMS).When identical stimuli are
tion at this time. Impulses from peripheral nociceptors are trans-
applied to normal subjects at frequencies of 0.33 Hz or greater, pain
mitted to the CNS by myelinated Ad-fibers (first pain) and
sensations will summate and not return to baseline during the
unmyelinated C-fibers (second pain). Ad-fiber–mediated pain
interstimulatory interval.WU is strongly dependent on stimulus
signals are rapidly conducted to the CNS (10 m/sec), whereas
frequency and is inversely correlated with interstimulatory interval.
C-fiber impulses travel relatively slowly (1.6 m/sec). When the
distance of pain transmission is sufficiently long (such as the
length of the arm or leg), the slowly conducted C-fiber impulses
can be easily detected by study subjects. An important test of central increase by experimental stimuli (mechanical, heat, cold, or electri-
pain amplification relies on summation of C-fiber pain, or WU. city) is greater for FMS patients than for control subjects, as is the
This technique reveals not only sensitivity to input from unmyeli- amount of temporal summation or WU within a series of stimuli
nated (C-fiber) afferents but also the status of the NMDA receptor (Fig. 31–2). Following a series of stimuli, WU after-sensations
systems that are implicated in a variety of chronic pain conditions. are greater in magnitude, last longer, and are more frequently painful
Thermal, mechanical, or electrical WU stimuli can be applied to the in FMS subjects. These results indicate both augmentation and
skin or musculature of patients, and commercial neurosensory prolonged decay of nociceptive input in FMS patients and provide
stimulators are readily available for WU testing. convincing evidence for a role for central sensitization in the patho-
genesis of this syndrome. Several important points appear rele-
vant for clinical practice. As previously mentioned, when central
Temporal Summation of C-Fiber Pain or WU sensitization has occurred in chronic pain patients, including FMS
patients, little additional nociceptive input is required to main-
In 1965, Mendell and Wall1 described for the first time that repet- tain the sensitized state. Thus, seemingly innocuous daily activities
itive C-fiber stimulation can result in a progressive increase of elec- might contribute to the maintenance of the chronic pain state. In
trical discharges from second-order neurons in the spinal cord. This addition, the decay of painful sensations is very prolonged in FMS,
important mechanism of pain amplification in the dorsal horn and patients do not seem to experience drastic changes of their pain
neurons of the spinal cord is related to temporal summation of
C-fiber pain, or WU. First pain, which is conducted by myelinated
Ad pain fibers, is often described as ‘‘sharp’’ or ‘‘lancinating’’ and
can be readily distinguished from second pain by most study sub- 90
jects. In contrast, second pain (transmitted by unmyelinated NC-2s
80
C-fibers), which is strongly related to chronic pain states, is most NC-5s
frequently reported as ‘‘dull,’’ ‘‘aching,’’ or ‘‘burning.’’ Second pain 70 FM-2s
increases in intensity when painful stimuli are applied more often 60 FM-5s
Pain (0–100)
than once every 3 seconds (Fig. 31–1). This progressive increase

50
represents temporal summation or WU and has been demonstrated
to result from CNS rather than peripheral nervous system mechan- 40
isms (see Fig. 31–1). Animal studies have demonstrated similar WU 30
of C afferent–mediated responses of dorsal horn nociceptive neu-
rons, and this summation has been found to involve NMDA recep- 20
tor mechanisms. Importantly, WU and second pain can be 10
inhibited by NMDA receptor antagonists, including dextromethor-
phan and ketamine. 0
T1 T10 AS15s AS120s
Figure 31^2. WU pain ratings of normal control (NC) and FMS
Abnormal WU of FMS Patients patients during 10 identical heat stimuli (508C) to the hands at
interstimulatory intervals (ISIs) of 2 sec and 5 sec. FMS patients
Recent investigations in FMS patients have focused on WU and cen- showed thermal hyperalgesia during the first tap and greater
tral sensitization because this chronic pain syndrome is associated temporal summation than NC at both ISIs. In contrast to NC, FMS
with extensive secondary hyperalgesia and allodynia. Several studies patients’ WU at ISI greater than 3 sec and require lower stimulus
provided psychophysical evidence that input to central nociceptive intensities. A numerical pain scale was used (0 ^100).The shaded area
pathways is abnormal in FMS patients. When WU pain is evoked represents pain threshold. AS15s, after-sensations at 15 sec; AS120s,
both in FMS patients and in normal controls, the perceived pain after-sensations at 120 sec; T1,1st heat tap; T10,10th heat tap.
levels during brief therapeutic interventions. Many frequently used relationship between tissue events and pain is necessary for under-
analgesic medications do not improve central sensitization, and standing the clinical context of these pathologies, defining the rela-
some medications, including opioids, have been shown to maintain tionship between injury and specific and relevant nociceptive
or even worsen this CNS phenomenon. responses is crucial for understanding the central mechanisms of
persistent pain in FMS. It must be emphasized, however, that
specific abnormalities in persons with FMS have not been identified
WU Measures as Predictors of FMS Pain Intensity that might produce the prolonged impulse input necessary to ini-
tiate the events underlying the development of central sensitization
The important role of central pain mechanisms for clinical pain is and/or spinal glia cell activation. After central sensitization has
also supported by their usefulness as predictors of clinical pain occurred, low-threshold Ab afferents, which normally do not
intensity of FMS patients. Thermal WU ratings correlate well with serve to transmit a pain response, are recruited to transmit spon-
clinical pain intensity (Pearson’s r = 0.53), thus emphasizing the taneous and movement-induced pain. This central hyperexcitability
important role of this pain mechanism for FMS. In addition, hier- is characterized by WU, expanding receptive field areas, and spinal
archic regression models that include tender point count, pain- neurons taking on properties of wide dynamic range neurons.
related negative affect, and WU ratings have been shown to account Ultimately, Ab-fibers stimulate postsynaptic neurons to transmit
for 50% of the variance in FMS clinical pain intensity. pain where these Ab-fibers previously had no role in pain transmis-
sion, all leading to central sensitization. Nociceptive information is
transmitted from the spinal cord to supraspinal sites, such as the
Mechanisms Underlying Abnormal Pain thalamus and cerebral cortex by ascending pathways.
Sensitivity
The mechanisms underlying the central sensitization that occurs in MuscleTissue as a Source of Nociceptive Input
patients with FMS rely on hyperexcitability of spinal dorsal horn
neurons that transmit nociceptive input to the brain. As a conse- A likely source of nociceptive input that may account for FMS pain
quence, low-intensity stimuli delivered to the skin or deep muscle is muscle tissue. Several types of muscle abnormalities have been
tissue generate high levels of nociceptive input to the brain as well reported in FMS patients, including the appearance of ragged red
as the perception of pain. Specifically, intense or prolonged impulse fibers, inflammatory infiltrates, and moth-eaten fibers. Possible
input from Ad and C afferents sufficiently depolarizes dorsal mechanisms for such muscle changes may include repetitive
horn neurons and results in the removal of the Mg2 + block of muscle microtrauma, which could contribute to the postexertional
NMDA-gated ion channels. This is followed by the influx of extra- pain and other painful symptoms experienced by these patients. In
cellular Ca2 + and production of nitric oxide, which diffuses out of addition, prolonged muscle tension and ischemia have been
the dorsal horn neurons. Nitric oxide, in turn, promotes the exag- detected in muscles of FMS patients. Changes in muscle pH related
gerated release of excitatory amino acids and substance P from to ischemia can provide powerful mechanisms for the sensitization
presynaptic afferent terminals and causes the dorsal horn neurons of spinal and supraspinal pain pathways. Investigations using 31P
to become hyperexcitable. Subsequently, low-intensity stimuli nuclear magnetic resonance (NMR) spectroscopy have shown that
evoked by minor physical activity may be amplified in the spinal FMS patients display significantly lower phosphorylation potential
cord, resulting in painful sensations. and total oxidative capacity in the quadriceps muscle during rest
and exercise. FMS patients also exhibit significantly lower levels of
muscle phosphocreatine and ATP, as well as a lower phosphocrea-
Role of Glia in Central Sensitization tine–to–inorganic phosphate ratio. Because nociceptive input from
muscles is very powerful in inducing and maintaining central
Accumulating evidence suggests that dorsal horn glia cells might sensitization, muscle abnormalities may strongly contribute to
have an important role in producing and maintaining abnormal this important mechanism of pain amplification.
pain sensitivity. Synapses within the CNS are encapsulated by glia
that do not normally respond to nociceptive input from local sites.
Following the initiation of central sensitization, however, spinal glia Abnormal Muscle Perfusion in FMS
cells are activated by a wide array of factors that contribute to
hyperalgesia, such as immune activation within the spinal cord, Investigations of tissue perfusion during exercise have usually
substance P, excitatory amino acids, nitric oxide, and prostaglan- involved isometric contractions to study blood flow within a con-
dins. Once activated, glia cells release proinflammatory cytokines, tracting muscle. Although sympathetic activation correlates with the
including tumor necrosis factor, IL-6 and IL-1, substance P, nitric intensity and duration of muscular contraction, the vascular effects
oxide, prostaglandins, excitatory amino acids, adenosine triphos- differ for active and passive muscles. To maintain blood pressure
phate (ATP), and fractalkine that, in turn, further increase the and preferentially distribute blood flow to active muscles, vasocon-
discharge of excitatory amino acids and substance P from the Ad striction of nonexercising muscles increases in proportion to
and C afferents that synapse in the dorsal horn and also enhance the the magnitude and duration of muscular activity. For exercising
hyperexcitability of the dorsal horn neurons. Recent evidence also muscles, however, vasoconstriction is inhibited (functional sym-
points toward a possible role of NMDA receptors in glial activation patholysis) in favor of local vasodilatation, thus optimizing perfu-
and pain. sion and supporting the metabolic demands of tissues. As a result,
blood flow to exercising muscles is greatly increased in normal
subjects, but not in FMS patients. When muscle contractions are
Possible Causes of Central Sensitization maintained at 30% of maximum or greater, nociceptors are acti-
vated in normal pain-free subjects. Pain from such contractions is
As a normal response to tissue trauma, injury is followed by repair enhanced for FMS subjects, most likely because of muscular
and healing. Inflammation occurs, which results in a cascade of hypoxia, deficient relaxation between contractions, and increased
electrophysiologic and chemical events that resolve over time and muscle tone of nonexercising muscles. Also, the low exercise capac-
the patient becomes pain free. In persistent pain, however, the local, ity of FMS patients seems to be a factor in worsening these abnor-
spinal, and even supraspinal responses are considerably different mal physiologic responses. These relationships can account for
from those that occur during acute pain. Whereas defining the some of the deleterious effects of strenuous exercise on FMS pain.
Receptor Up- and Down-regulation testing (QST), are often used to confirm the diagnosis. The patho-
genesis of chronic musculoskeletal pain frequently varies in large
Several lines of evidence suggest that nociceptor signaling from population studies. Because FMS is a syndrome of heightened pain
peripheral tissues represents an important mechanism for FMS sensitivity, it can also be detected in many other chronic conditions,
pain. Studies showed that FMS pain and tender point hyperalgesia including osteoarthritis, rheumatoid arthritis, systemic lupus
can be abolished by epidural lidocaine application. Similarly, stellate erythematosus, human immunodeficiency virus, and cancer.
ganglion blockade and regional sympathetic blockade have been Many patients referred for rheumatologic consultation receive an
demonstrated to reduce FMS pain as well as the tender point inaccurate diagnosis of FMS. Common rheumatologic conditions
counts. These studies not only emphasized the relevance of pain are often overlooked and incorrectly labeled as only FMS.
input from peripheral tissues but also highlighted the importance of Conversely, the diagnosis of FMS is often missed. Thus, it appears
the autonomic system for FMS pain. There is convincing evidence prudent to use the diagnostic label of ‘‘FMS’’ exclusively in patients
for the role of a-adrenergic input in many chronic pain conditions with diffuse musculoskeletal symptoms only after a rigorous eval-
that results in down-regulation of b-adrenergic receptors. uation. Physicians need to consider a wide spectrum of diagnostic
Accordingly, FMS patients exhibit a reduction of b-adrenergic possibilities in patients presenting with ill-defined aches and pains.
receptors and diminished vasodilatation during adrenergic stimula-
tions. In contrast, FMS patients show up-regulation of receptors for
noradrenaline and neuropeptide Y, the latter is coreleased with
norepinephrine (NE) from sympathetic nerve terminals. Both fac- MANAGEMENT
tors produce vasoconstriction that has been described as more
pronounced in females than in males. Changes in a- and b-adre- NonpharmacologicTreatments
nergic as well as neuropeptide Y receptor density have been detected
in FMS patients, and this could provide a mechanism for muscular The majority of nonpharmacologic FMS treatments have included
ischemia. These receptor changes enhance vasoconstriction in FMS low to moderate levels of aerobic exercise or strength training. Most
patients and are expected to increase the sensitivity of muscle noci- exercise studies have reported reductions of clinical pain or tender
ceptors to catecholamines and to contraction-related hypoxia. The points compared with control groups. Duration of reported studies
relevance of these mechanisms for FMS patients has been demon- ranged between 3 months and 4 years, and almost all studies found
strated by NE injections into the skin that resulted in local pain, a long-term reduction of clinical pain or tender points or both.
an effect not seen in control subjects. Furthermore, muscular Thus, the benefits of exercise for FMS pain appear to be long last-
contractions produce more pain and fatigue for FMS subjects ing. Although frequently used for treatment, the effects of exercise
than for controls. Therefore, pharmacologic treatments directed at on FMS symptoms and function are difficult to explain. Although
peripheral blood flow and ischemia appear to be beneficial for FMS. exercise improves cardiovascular function of FMS patients, this
improvement does not correlate with FMS pain reductions.
Owing to pain and fatigue, even mild exercise is often difficult
CLINICAL FEATURES for FMS patients. Strenuous exercise can result in activation of
sensitized muscle nociceptors and pain. Accordingly, several studies
FMS has been defined by the 1990 Criteria of the American College showed that high exercise levels can increase FMS pain over time,
of Rheumatology, which include chronic widespread pain for more in contrast to the beneficial effects of most protocols using only
than 3 months and the presence of more than 10 out of 18 tender moderate or light exercise.
points. Tender points are areas of mechanical hyperalgesia at The therapeutic benefits of low levels of exercise for FMS appear
specific sites of the body, including the back of the head, upper to result from normalizing of muscular perfusion during exercise
back and neck, upper chest, elbows, hips, and knees. People with and long-term improvements in the oxidative capacity of muscle,
FMS often wake up tired and unrefreshed even though they seem to both of which would help FMS patients reduce the negative con-
get plenty of sleep. Some studies suggest that this sleep problem is sequences of muscular activity. Abnormal blood flow to active and
the result of ad-wave electroencephalogram intrusions, a condition passive muscles during static contractions emphasizes the need for
in which deep sleep is frequently interrupted by bursts of brain exercise modifications that optimally produce generalized vasodila-
activity similar to wakefulness. Thus, people with FMS may lack tation. For example, aqua therapy in warm water can be prescribed
the restorative stages of deep sleep (stages III and IV). FMS is also to help increase peripheral blood flow. Several studies showed
associated with increased distress, including anxiety, depression, immediate as well as long-term benefits of warm water exercises
anger, and fear. Irritable bowel syndrome is common in people on FMS pain. Simple warm water immersion without exercise has
with FMS, as are headaches and facial pain. Many people with also been found to improve FMS pain. These findings seem to
FMS also complain of chronic fatigue. indicate that interventions that improve blood flow and/or tension
of muscle tissues appear to have significant benefits for FMS pain.
EVALUATION Pain-management Strategies

Most FMS patients report musculoskeletal pain with diffuse rather The majority of FMS patients progress from local to widespread
than localized onset and complain equally of upper and lower body pain over time. However, no long-term prospective studies have
discomforts. Objective limitations in spinal mobility are not a been conducted regarding the prevention or treatment of progres-
prominent finding in the FMS patients, although cervical and sive FMS pain. In contrast, a large number of studies have evaluated
lumbar spinal movements are frequently limited in older FMS the role of physical and cognitive-behavioral therapy for FMS
patients similar to those in age-matched controls. The FMS diag- symptoms. Most study procedures have consistently included
nosis requires exclusion of other serious health problems, and there pain-management strategies (self-efficacy), usually in combination
is no single blood test or imaging procedure that is diagnostic. with exercise and/or techniques for reduction of stress and muscu-
Chronic widespread pain syndromes, like FMS, are most often lar tension. These strategies consistently appear to improve FMS
associated with hyperalgesia to mechanical, thermal, electrical, subjects’ ratings of overall well-being and self-efficacy. Pain-
and chemical stimuli. Although the most frequently used evaluation management strategies, however, do not reliably reduce FMS pain
for FMS is the tender point examination, other psychophysical tests, ratings, tender point count, or pain sensitivity at tender points.
including thermal, mechanical, and electrical quantitative sensory Treatment effects of self-efficacy training on FMS pain, compared
with pretraining values, showed no efficacy in two studies and a Table 31^1. Antidepressant Medications
small but significant decrease in clinical pain and increase in tender
point thresholds in another. The study showing positive effects Medication Dose
trained subjects for a prolonged period (2 mo) appeared to place
more emphasis on compliance and specifically addressed stress Amitriptyline (Elavil) 50 mg qd
reduction. Adding stretching exercises to self-efficacy training, how- Mirtazapine (Remeron) 15 mg qd
ever, has not substantially improved FMS study outcomes. In con- Fluoxetine (Prozac) 20–60 mg qd
trast, electromyography biofeedback procedures were more Venlafaxine XR (Effexor) 150 mg qd
successful in reducing clinical pain and tender point counts. Duloxetine (Cymbalta) 60 mg qd
Thus, attenuation of muscle tension appears to be more effective
than self-efficacy training for FMS pain. Milnacipran (not FDA approved) 100–200 mg qd
FDA, U.S. Food and Drug Administration.
Patient Education
Several randomized, controlled trials provided evidence for exten-
sive patient education as an effective treatment for FMS. Most single-drug therapy. SNRIs are quite similar to some TCAs (e.g.,
interventions included didactic lectures, group discussions, and amitriptyline) in increasing the levels of both NE and 5-HT.
written materials. Trial outcomes were often compared with wait- Unlike TCAs, however, SNRIs show greatly improved side effect
listed or untreated controls or with mild exercises (stretching and profiles and general tolerability. Currently, only two SNRIs—
movement). Education given during multiple sessions improved venlafaxine (Effexor) and duloxetine (Cymbalta)—are on the
pain, sleep, fatigue, self-efficacy, quality of life, and physical func- market in the United States, although several others are in clinical
tioning for extended periods (more than 1 yr). trials. Interestingly, data suggest that venlafaxine primarily affects
the 5-HT system at low doses; NE effects are apparent only at high
doses. Venlafaxine and duloxetine have been shown to be effica-
Pharmacotherapy of FMS Pain cious in FMS and other pain paradigms. The SNRIs milnacipran
and duloxetine demonstrated efficacy for FMS symptoms in sev-
Some of the most successful treatments for FMS symptoms include eral trials. Milnacipran, an SNRI widely used in Europe, has been
medications with predominant central activity like antidepressants, shown to improve FMS pain and other outcome measures in con-
muscle relaxants, and anticonvulsants. Through activation of many trolled trials.
receptor sites in the periphery, spinal cord, and brain, these drugs
can modulate hyperalgesia/allodynia and pain sensations.
Analgesic Drugs
Lidocaine (Xylocaine) is frequently used for localized pain relief,
Tricyclic Antidepressants
and multiple injections into tender/trigger points may offer some
Tricyclic antidepressants (TCAs) inhibit the neuronal reuptake of benefit to FMS patients. Multiple tender/trigger point injections
serotonin (5-hydroxytryptamine [5-HT]) and NE at the presynaptic with lidocaine in patients with FMS have been found to result in
membrane. Because 5-HT is involved in pain modulation, abnorm- significant improvements of pain intensity and range of motion for
alities of 5-HT metabolism were assumed to play important roles more than 2 weeks. However, studies have also shown that benefits
in the pathogenesis of FMS. Therefore, several trials evaluated from tender/trigger point injections with lidocaine are small,
the benefits of those drugs for patients with FMS. In general, and patients with FMS frequently experienced postinjection sore-
many trial results support the efficacy of TCA medications, in par- ness. It is unclear whether the analgesic effects of lidocaine injec-
ticular cyclobenzaprine (Flexeril) and amitriptyline (Elavil), for the tions into tender/trigger point are strongly influenced by patients’
treatment of FMS symptoms. Despite its indication as a muscle expectations because no statistical difference between injections
relaxant, cyclobenzaprine is chemically very similar to tricyclic com- with lidocaine, saline, or dry needling could be detected.
pounds and has comparable efficacy with that of other TCAs. Generally, nonsteroidal anti-inflammatory drugs (NSAIDs) are
Several meta-analyses demonstrated that TCAs are more effective ineffective as monotherapy in FMS, but they may improve analgesia
than placebo for pain, sleep, fatigue, and sense of well-being in when combined with TCAs.
FMS. However, no detectable improvement in mechanical tender- When therapies with commonly used analgesics fail, opioid
ness (tender point count) was noted. Importantly, the efficacy of analgesics are a recommended option for persistent, moderate to
TCAs for treatment of FMS symptoms appears to be time-limited. severe nonmalignant pain syndromes. However, concerns about
Although TCAs are effective for up to 12 weeks, a meta-analysis opioid abuse, dependency, tolerance, and toxicity are common
reported that they become less effective after 6 months in FMS. and have resulted in opioid underutilization by physicians and
Side effects of TCAs, such as weight gain, constipation, orthostatic patients. Tramadol (Ultram) is a weak m-opioid agonist that can
hypotension, and agitation, occur in up to 20% of patients and be used with or without acetaminophen for FMS pain. This anal-
often limit the use of these agents. gesic is effective and well tolerated in patients with FMS, resulting in
lowered pain and FIQ scores compared with patients receiving pla-
cebo. Tramadol has also been found to be effective in treating the
Other Antidepressant Medications
pain of osteoarthritis, a condition that can coexist with FMS in
Growing evidence indicates that selective 5-HT reuptake inhibitors elderly persons.
(SSRIs) and selective 5-HT–NE reuptake inhibitors (SNRIs) are Although narcotic medications are frequently used by FMS
effective for the treatment of FMS symptoms. Therapy with the patients, there is no sufficient trial experience to support their use
SSRI fluoxetine (Prozac) resulted in improvement of pain (Table in this chronic nonmalignant pain population at this time.
31–1), fatigue, and depression as well as Fibromyalgia Impact
Questionnaire (FIQ) total scores. Tender point counts and total
Anticonvulsant Medications
myalgic scores, however, did not significantly improve.
Importantly, these effects were not dependent on improvement of Antiepileptic drugs act on several mechanisms that may be relevant
depression. Combination of fluoxetine (20 mg/day) with cycloben- to pain, but the precise mechanisms of their analgesic effects remain
zaprine (10 mg/day) over a 12-week period was more effective than unclear. These agents limit neuronal excitation, enhance inhibition,
and act on voltage-gated ion channels (i.e., sodium and calcium of guaifenesin found no significant effects on FMS pain or other
channels), ligand-gated ion channels, the excitatory receptors symptoms or laboratory measures over 12 months.
for glutamate and NMDA, and the inhibitory receptors for
g-aminobutyric acid (GABA) and glycine. Antiepileptic drugs may
Future Pharmacologic Approaches to FMS
be categorized as first or second generation. First-generation anti-
epileptics include carbamazepine (Tegretol) and phenytoin Adrenergic agents that attenuate peripheral vasoconstriction would
(Dilantin). The second-generation agents, including gabapentin be candidates for pharmacologic management of FMS pain. An
(Neurontin) and pregabalin (Lyrica), are better tolerated, cause agonist for a2-adrenergic receptors might be employed to attenuate
less sedation, and have fewer CNS side effects. Pregabalin and gab- peripheral vasoconstriction, and/or agonists for b-adrenergic recep-
apentin are anticonvulsants that bind to the a2d-subunit of the tors might be useful to enhance vasodilatation. An alternative
voltage-gated calcium channel in the CNS and have shown moder- approach would be to antagonize peripheral vascular actions of
ate effectiveness for FMS symptoms. During a multicenter trial, neuropeptide Y.
pregabalin (450 mg/day) significantly reduced FMS pain compared Most current pharmacologic treatments for FMS rely on sero-
with placebo. Other reported benefits included significant improve- tonergic and noradrenergic reuptake inhibitors such as TCAs. These
ments in sleep, fatigue, and health-related quality of life. drugs, however, do not seem to substantially attenuate FMS pain,
In 2007, the U.S. Food and Drug Administration (FDA) and they gradually lose effectiveness relative to placebo. These
approved the indication of FMS for pregabalin (making it the agents may have negative effects on tissue perfusion and resulting
first FDA-approved agent for FMS). The efficacy of pregabalin in muscular ischemia that has been detected in FMS. a-Adrenergic
FMS was established in two double-blind, placebo-controlled, mul- agonists used as decongestants are also contraindicated on the
ticenter trials. In these trials, a total of 2246 FMS patients were basis of peripheral vasoconstriction. Inflammation likely contri-
screened, with 1311 being randomly assigned to treatment taking butes little to FMS pain because anti-inflammatory agents have
at least 1 dose of study medication. Doses of pregabalin ranged from been utilized clinically with minimal success. FMS pain is likely
300 to 600 mg/day (administered as 150, 225, or 300 mg twice secondary to widely distributed ischemia within deep tissues,
daily). The approved dose range of pregabalin for FMS is 300 to which could become a promising target for therapeutic action.
450 mg/day (600 mg/day is not FDA approved for use in FMS). For example, antagonists to acid-sensing ion channel 3 (ASIC3)
Furthermore, Mease and coworkers2 conducted a randomized, receptors could be used to effectively reduce FMS pain. ASIC3
double-blind, placebo-controlled trial of pregabalin in the treat- receptors are sensitive to lowered pH and ischemia, are present
ment of patients with FMS and concluded that pregabalin at 300, on nociceptors in muscle tissue, and may be critical for enhance-
450, and 600 mg/day was efficacious and safe for treatment of pain ment of central responsiveness after intramuscular injection of
associated with FMS (Table 31–2). acidic saline. In addition, ASIC3 receptors are located on ergore-
ceptive afferents supplying muscles. These metaboreceptor afferents
respond to metabolites produced by working muscles to signal
Other Medications
effort or fatigue. Thus, sensitization of ASIC3 receptors by chronic
Tropisetron, a 5-HT3 receptor antagonist, and 5-hydroxytryptophan, muscular ischemia renders nociceptors and ergoreceptors highly
an intermediate metabolite of L-tryptophan, were more effective sensitive to muscular contractions, lowering thresholds for muscu-
than placebo in several controlled FMS trials. S-Adenosyl-methionine, lar pain and fatigue. Not only does pain produce sympathetic vaso-
an agent with both anti-inflammatory and antidepressant effects, constriction, but input from ergoreceptor afferents to brainstem
was found helpful in one study but performed no better than cardiovascular centers also activates the sympathetic nervous
placebo in a second study in patients with FMS. There has been system. Therefore, activation of ASIC3 receptors on nociceptive
no evidence that benzodiazepines or other sedatives are effective and ergoreceptive afferents in ischemic muscle can contribute to
in patients with FMS other than as treatments for sleep distur- the vasoconstriction that has established ischemia and sensitization
bances. Potential dependence and withdrawal seizures associated of these receptors. Thus, treatment with ASIC3 receptor antagonists
with benzodiazepine therapy suggest caution in the long-term use could attenuate ischemic pain, fatigue, and peripheral vasoconstric-
of benzodiazepines for chronic conditions such as FMS. tion in FMS.
Hormones and Supplements

CONCLUSIONS
One controlled study of corticosteroids in FMS patients reported
that 10 mg of prednisone daily was ineffective for pain. FMS is a chronic pain syndrome characterized by widespread pain
Administration of growth hormone to female FMS patients with in peripheral tissues, psychological distress, dysfunction, and central
low levels of insulin-like growth factor-1 showed significant sensitization. Whereas the role of chronic stress and psychological
increases in global improvement and FIQ and tender point scores. factors for FMS patients’ pain has been well established, little is
There are no data from controlled trials to support the use of thy- known about the origin of the sensory abnormalities for pain.
roid hormone, dehydroepiandrosterone, melatonin, or calcitonin in Deep tissue impulse input is most likely relevant for the initiation
the treatment of FMS. Dietary modifications, nutritional supple- and/or maintenance of abnormal central pain processing and repre-
ments, magnesium, herbal, and vitamin therapy have not been sents an important opportunity for new treatments and prevention
adequately evaluated in FMS. One randomized, controlled study of this chronic pain syndrome. Abnormalities of stress response
systems lead to increased sympathetic tone and may result in
perfusion abnormalities of peripheral tissues, particularly muscles.
Table 31^2. Anticonvulsant Medications Three important strategies for FMS therapy appear useful at this
time: (1) reduction of peripheral nociceptive input, particularly
from muscles, (2) improvement or prevention of central sensitiza-
Medication Dose tion, and (3) treatment of negative affect, particularly depression.
Phenytoin (Dilantin) 300 mg qd The first strategy is most likely relevant for acute FMS pain exacer-
Carbamazepine (Tegretol) 800 mg qd bations and includes physical therapy, muscle relaxants, muscle
Gabapentin (Neurontin) 800 mg tid injections, and anti-inflammatory analgesics. Central sensitiza-
tion can be successfully ameliorated by cognitive behavioral
Pregabalin (Lyrica) 450 mg qd
therapy, sleep improvement, NMDA receptor antagonists, and
antiseizure medications. The pharmacologic and behavioral treat- Raphael KG, Janal MN, Nayak S, et al. Familial aggregation of depression
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targets for analgesic development. Curr Top Med Chem 2005;5:557–567.
treatment of FMS pain is currently unknown because of insufficient
Sluka KA, Price MP, Breese NA, et al. Chronic hyperalgesia induced by
trial experience. repeated acid injections in muscle is abolished by the loss of ASIC3, but
not ASIC1. Pain 2003;106:229–239.
Staud R. Evidence of involvement of central neural mechanisms in
ACKNOWLEDGMENTS generating fibromyalgia pain. Curr Rheumatol Rep 2002;4:299–305.
Staud R, Domingo M. Evidence for abnormal pain processing in
The author is supported by NIH grants NS-38767 and AR-053541. fibromyalgia syndrome. Pain Med 2001;2:208–215.
Staud R, Domingo M. New Insights into the pathogenesis of fibromyalgia
syndrome. Med Aspects Hum Sex 2001;1:51–57.
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Chapter 32 THE JOINT

OSTEOARTHRITIS: ETIOLOGY, The joint is a multicomponent system consisting of bone, cartilage,
and connective tissue. Subchondral bone is covered by hyaline
PATHOGENESIS, AND (articular cartilage) that consists of type II collagen, chondrocytes,
and proteoglycans (high-molecular-weight glycoproteins that retain
water and thereby increase resiliency of the cartilage). The arcade
TREATMENT arrangement of the specific collagen fibrils provides tensile strength,
and the proteoglycans provide distensibility by retaining adequate
Lee S. Simon hydration. The synovial cell layer lining the joint produces a viscous
synovial fluid, which provides lubrication, facilitating joint motion.
Superficial to the synovial membrane is a flexible joint capsule
associated with ligaments and tendons. In strategic spots, such as
bone prominences outside the joint, bursae provide a smooth sur-
face for muscles, tendons, and ligaments to pass over roughened
bone surfaces. These joint components provide for both motion
INTRODUCTION and load-bearing across nearly frictionless surfaces, and any or all
of these joint components are involved in the osteoarthritic process,
Arthritis is a generic description of inflammation and pain around depending on the extent of the disease.10–13
the joint. It does not refer to a single specific disease; instead, it is OA is primarily a disease of the cartilage that progressively pro-
associated with more than 100 different disease states. Osteoarthritis duces a local tissue response, a mechanical change that may then
(OA) is one of the most common of these diseases and one of the manifest in change in subchondral bone and, ultimately, failure
most common disabling diseases in developed countries. Estimates of function of the joint.14–18 The disease typically affects weight-
are that approximately 10% of men and 18% of women aged over bearing joints asymmetrically. Historically, OA was not considered
60 years have symptomatic OA; 80% of patients with OA have an inflammatory process, which then led to a general understanding
limitations of movement, and 25% cannot perform their major that it is a degenerative joint disease. However, an association has
daily activities of living.1–7 been established between OA and local low-grade inflammation
with few systemic effects. This inflammatory response is explained
in some experimental models as a response to joint debris of various
DEFINITION types. Thus, it is a secondary phenomenon; however, other inves-
tigators suggest it may represent the primary process leading to
OA is not itself a single disease entity; it represents a disease group progressive disease.
with different underlying pathophysiologic mechanisms. For exam- The inflammatory process is characterized by increased levels of
ple, primary OA should be distinguished from secondary forms of inflammatory markers, such as high-sensitivity C-reactive protein
the disease, which may be due to joint trauma, congenital abnorm- (CRP) and serum amyloid protein A (SAA) observed in the sera
alities, developmental abnormalities, or a result secondary to other of OA patients.19–26 Elevated serum levels of CRP have also been
joint diseases such as rheumatoid arthritis or crystal-induced associated with rapidly progressive OA of the knee, measured radio-
arthropathies, diabetes, acromegaly, hemochromatosis, Wilson’s graphically.23 There are also data that support the role of the
disease, and neuropathic disorders.2–6 proinflammatory cytokines derived from the synovium and chon-
The etiology of primary OA remains a mystery, but the interac- drocytes in the destruction of the cartilage.12,13,19,20 The cytokines
tion of overuse syndromes (including the effects of chronic obesity produced in the joint tissues are released into the synovial fluid
on weight-bearing joints) with a subsequent ongoing inflammatory where they act on cells in an autocrine-paracrine manner. The
response, leading to fundamental changes in the integrity of the imbalance between the proinflammatory cytokines, such as inter-
cartilage, the chondrocyte, subchondral bone, and the soft tissues, leukin-1 (IL-1a), IL-1b, tumor necrosis factor-a (TNF-a), IL-6,
is important. This complicated series of events clinically leads to leukemia inhibitory factor, oncostatin M, IL-8, IL-17, and IL-18,
progressive pain as well as loss of joint function, resulting in a and the anti-inflammatory cytokines such as IL-4, IL-10, IL-11, IL-
significantly reduced quality of life for patients suffering from 3, IL-1 Ra, and interferon-g may well result in the development of
the disease. The enormous frequency of this disease establishes OA.19,20 An increase in the expression of IL-1b leads to the activa-
OA-related joint disease as one of the most expensive conditions tion of proteolytic enzymes and inhibition of the synthesis of col-
in the Western world, in terms of both direct and indirect costs.3,8 lagen type II and proteoglycans. All of this is in response to the
So far, the treatment options have been limited and mostly degeneration of cartilage and serves as an inflammatory reaction to
restricted to those that improve signs and symptoms of the disease the generation of particles. Thus, this is a chain reaction leading to a
until, ultimately, the joint needs to be replaced by endoprosthetic cascade effect of more and more inflammation followed by more
joint surgery. Thus, there is a significant need to develop disease- and more damage. The process is quite variable, which leads to the
modifying therapies in order to improve health-related quality of clinical heterogeneity characteristic of the disease.
life and function and to reduce the enormous socioeconomic Although the inflammatory components may exacerbate the
burden of the disease. However, despite intensive efforts over process, the fundamental etiology is likely to be multifactorial. In
several decades, the success of disease-modifying approaches have some patients, an osteoarthritic process can result from excessive or
so far had limited success. Likely, this frustrating progress is repetitive loading of the normal joint including work-related repet-
related to the heterogeneity of the disease and poor ability to predict itive activities damaging cartilage or subchondral bone; trauma; or
which patient may have more progressive disease.9 increased load to the joint from chronic obesity. This process may
242 Chapter 32 OSTEOARTHRITIS: ETIOLOGY, PATHOGENESIS, AND TREAT MENT
occur in the context of either inherently abnormal cartilage or a tests are not. Local inflammation may be present, yet there is a
specific insult to the structure of cartilage leading to increased sus- normal erythrocyte sedimentation rate (ESR), hematocrit, and
ceptibility. Alternatively, minimal structural stress may be applied white blood cell (WBC) counts. Recently, very sensitive tests for
to inherently abnormal cartilage leading to failure of the tissue to CRP have shown some elevations in some patients with OA. This
withstand normal wear and tear. has partially led to the reconsideration of inflammation as an
As cartilage is damaged, it becomes thinner and develops fissures important component to this process. Radiographs commonly
or large clefts, and proteoglycan synthesis decreases. That process reveal joint space narrowing, increased subchondral bony sclerosis,
leads to further decreased cartilagenous load-bearing capacity. The and sometimes, subchondral cyst formation and osteophytes. Small
chondrocyte in cartilage can respond initially by attempting to synovial effusions are typically noninflammatory or minimally
repair its surrounding extracellular matrix, but as it is overwhelmed, inflammatory; typically WBC counts are less than 2000 and most
there is increased release of neutral metalloproteinases and lysoso- cells are mononuclear.27
mal proteases, leading to further matrix loss and, ultimately, The syndrome is most characterized by chronic intermittent
increasing the destructive cascade. These altered stress forces are episodes of pain with or without evidence of significant inflamma-
now transferred directly to subchondral bone, which then leads tion, usually beginning in one or a few weight-bearing joints.
to small microfractures according to some hypotheses of As time goes by, there is progressively more pain with increasing
pathogenesis.14,16,17,18 loss of function but usually only within a few joints.27
INCIDENCE TREATMENT
Eighty percent of the population develops radiographic evidence of Pain is a major determinant of quality of life for people with OA.
OA in at least one joint site such as the hands, feet, spine, knees, or Despite receiving appropriate treatment for the underlying disease,
hips by age 65.7 The incidence of OA of the hips and knees has been many people continue to experience pain that impairs physical and
reported to be 47.3 per 100,000 person-years and 163.8 per 100,000 psychological function. Both pharmacologic and nonpharmacologic
person-years in age- and sex-adjusted rates, respectively.1–4 The therapies (e.g., occupational therapy [OT], physical therapy [PT],
incidence of OA of the hands, hips, and knees increases with age. cognitive-behavioral therapy), accompanied by patient education,
Women have a higher incidence rate than men, especially after the are important components of a treatment plan for arthritis.
age of 50. The incidence rate plateaus for both men and women at Education about the disease and the rationale for therapy may
all joint sites at approximately age 80.1–3 enhance patients’ adherence to the therapeutic regimen. Patients
should participate in establishing goals and be informed about
the risks and benefits of therapy and its functional impact.28–30
PREVALENCE The goals of optimal care for people with OA are to determine
what can be done to slow or correct the underlying disorder and
The prevalence of radiographic OA increases with age at all joint to identify pain as an issue to be addressed as soon as the disease is
sites.6,7 One study has shown that a total of 75% of women aged diagnosed.
between age 60 and 70 have OA of the distal interphalangeal (DIP) Several different guidances have been developed since the late
joints. Ten percent to 20% of individuals have evidence of severe 1990s. These have reflected a multimodal approach to therapy,
radiographic OA of the hands and feet by the age of 40. Knee including education; cognitive-behavioral interventions; physical
involvement is less frequent than that of the hands and feet.7 modalities; and assistive devices along with simple analgesics, non-
Population-based studies in the United States and Europe show steroidal anti-inflammatory drugs (NSAIDs), including the cycloox-
prevalence rates of 30% in individuals aged 75 years or above and ygenase-2 (COX-2)–selective drugs, tramadol, topical therapies, and
1% in individuals aged 25 to 34 years. OA of the hands and knees the applicability of neutraceuticals.
appears to be more frequent among women than men. Hip OA is Overall, no effective disease-modifying therapies are available at
less common than OA of the knees.1–6 present in the United States. Recently, several attempts to modulate
either articular cartilage or subchondral bone have failed to develop
a successful disease-modifying approach.31 Thus, the goal is to pro-
CLINICAL PRESENTATION vide improvement in signs and symptoms for the short term and
ultimately to lead to replacement of a severely damaged eburnated
The joints most commonly involved in OA include knees, hips, feet, and chronically painful joint.
ankles, DIP joints, proximal interphalangeal joints, first carpometa- Most patients who seek medical care have already tried over-
carpal joints, cervical spine, and lower spine. Involvement of the the-counter simple analgesics or NSAIDs and probably have either
wrists, elbows, and shoulders is uncommon unless there is trauma observed failed benefit or had an adverse event. Clearly, nonphar-
to those areas or the patient has generalized OA. Typically, people macologic therapy is critical, as is weight loss for those obese
describe feeling stiffness (a result of soft tissue reaction to change in patients whose weight-bearing joints are symptomatic. It is not
the physical and mechanical properties of joints) in the involved clear that the natural history will be altered but pain may be
joints when arising in the morning, with the symptoms lasting no reduced.28 The next choice for therapy probably should represent
longer than 20 to 30 minutes. While sitting or driving, people may more substantial pain control than that afforded by simple analge-
experience a ‘‘gel’’ phenomenon, described as a feeling of stiffness sics or over-the-counter NSAIDs. A highly controversial question
that disappears when the person begins to move again. This gel in the management of OA is whether NSAIDs are superior to sim-
phenomenon lasts no longer than about 20 minutes. If the symp- ple analgesics with respect to pain relief.32–37 This question is
toms of morning stiffness or the gel phenomenon last longer, there important, given the potential adverse effects of NSAIDs, espe-
may be more joint inflammation than is normally associated with cially in older patients, including both risk for gastrointestinal
OA and other diagnoses should be considered. Morning stiffness (GI) events or cardiovascular (CV) thromboembolic events.
improves with the use of the joints, but most people experience Unfortunately, NSAIDs do not seem to affect the pathophysiology
increased pain as the joints continue to bear weight throughout of joint destruction in OA such as reducing osteophyte formation,
the day.27 protecting cartilage, or preventing mechanical malalignment.
The diagnosis of OA is based largely on clinical presentation and However, NSAIDs reduce pain, decrease gel phenomenon, and
physical findings. Radiographic evaluation can be useful, but blood improve function in OA patients.29,30 Whether this is due to their
anti-inflammatory or analgesic effects remains unknown. In this injections with hyaluronic acid supplementation, which in animals
population of patients, the balance of positive effects measured have shown structural effects but have not been corroborated in
against the potential adverse effects is particularly critical, given the humans.56,57 For an acute inflammatory flare, an intra-articular
increased potential for NSAID-induced toxic effects mediated par- injection of glucocorticoid may be very useful.
tially by age. Pincus and coworkers34,35 in two important trials revis- Many patients have tried glucosamine and/or chondrotin sul-
ited the question of the importance of NSAIDs in the treatment fate.58 There is little evidence of benefit in humans, but if it is
of patients with OA of the hip or knee. These double-blinded, ran- tolerable to a patient and she or he derives benefit, there is little
domized, controlled cross-over trials were designed to study the reason to not use it or other neutraceuticals.59 However, the FDA
effects of either an NSAID with inherent gastroprotection compared does not review these agents for safety or efficacy.
with acetaminophen at full dose nonselective (Arthrotec 75 mg twice Ultimately, the patient with progressive disease may benefit from
daily [diclofenac/misoprostol] or acetaminophen at 1000 mg four surgical replacement of a joint. This is highly successful, but owing
times daily)34 or celecoxib 200 mg/day compared with acetamino- to longevity issues, delay until the patient has intractable pain
phen 4000 mg/day.35 Each patient serve as his or her own control, in would be appropriate.
that these studies were identical cross-over designs with each patient Future therapies may include anticytokine therapies as well as
receiving one drug for 6 weeks followed by a wash-out period and directed disease-modifying interventions, which might include car-
then starting the other agent. In all circumstances including the tilage-implant therapy.
concept of patient preference as well as standard U.S. Food and
Drug Administration (FDA)–required outcome measures of a
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39. Singh G, Mithal A, Triadafilopoulos G. Both selective COX-2 Altman RD, Hochberg MC, et al (eds): Osteoarthritis, 4th ed.
inhibitors and non-selective NSAIDs increase the risk of acute Philadelphia: Walters Kluwar, 2006; pp 287–302.
myocardial infarction in patients with arthritis: selectivity is with the 58. Goggs R, Vaughan-Thomas A, Clegg P. Nutraceutical therapies for
patient, not the drug class. Ann Rheum Dis 2005;64:S85–86. degenerative jJoint diseases: a critical review. Crit Rev Food Sci Nutr
40. Hernandez-Diaz S, Varas-Lorenzo C, Garcia Rodriguez LAS, 2005;45:145–164.
Hernandez-Diaz A. Non-steroidal antiinflammatory drugs and the 59. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin
risk of acute myocardial infarction. Basic Clin Pharmacol Toxicol sulfate and the two in combination for painful knee osteoarthritis. N
2006;98:266–274. Engl J Med 2006;354:795–808.
Chapter 33 rheumatoid factor in an early study done by pulmonologists. One

European study examined the incidence of RA in monozygotic
RHEUMATOID ARTHRITIS twins. It concluded that when one twin was diagnosed with RA,
the relative risk of the other twin of developing RA was increased by
Lori A. Lavelle,William F. Lavelle, and 30%, especially if they smoked. Other studies have also shown an
Elizabeth Demers Lavelle increased incidence of RA in those people who smoke.12
Exposure to certain infections has been linked to the develop-
ment of RA. Studies that have examined synovial tissue for the
presence of active bacterial infection have been negative. Some
experts speculate that bacteria activate toll-like receptors and thus
start the proinflammatory pathway that can lead to RA.
Infections with certain viruses have been investigated as a direct
INTRODUCTION cause of RA.13 Levels of these viruses have been higher and have
lasted months longer in patients with RA than in those without the
According to the Arthritis Foundation, rheumatoid arthritis (RA) disease. Studies have suggested that patients who have RA have
affects about 1% of the population, or approximately 2.1 million difficulties removing lymphocytes that have been activated by
people in the United States. It is one of the most common causes of Epstein-Barr virus. Some speculate that these lymphocytes could
disability in the United States. Between the cost for office visits, contribute to RA.12
prescriptions, joint replacements, and hospitalizations, RA is one
of the most costly chronic diseases to the nation’s health care
system. PATHOGENESIS
To date, the exact trigger that stimulates the immune system to be
EPIDEMIOLOGY activated in RA remains unidentified. The current belief is that an
‘‘unknown’’ antigen is engulfed in macrophages or dendritic cells in
RA can affect any ethnic group. According to statistics, arthritis has the area of the synovial lining.14 The macrophage or dendritic cell is
a female predominance with a ratio of about 3:1. The cause for a then labeled the antigen-presenting cell (APC). The antigen is pha-
higher incidence of RA in women is largely unknown, but it is gocytized into smaller segments enzymatically inside the macro-
speculated that hormones such as estrogen play a role. The diagno- phage. Segments of the ‘‘unknown antigen’’ are then presented to
sis of RA peaks in the 4th to 6th decades of life. receptors on the surface of macrophages. These unknown antigens
Commonly, women who are pregnant have a remission of are then recognized by specialized CD4+ T-cells. Close examination
their disease. Although the cause of this remission remains of the T-cells activated in RA reveal that they possess CD28 ligands
unproved, the production of anti-inflammatory cytokines, such as on the cell surface. The CD28 ligand on the T-cell interacts with
interleukin-10 (IL-10), which is produced in higher concentrations either the CD80 or the CD86 ligand located on the APC. In order
during pregnancy, can suppress RA symptoms. Also, the possession for a T-cell to be fully activated, a connection must be formed
of certain antibodies that protect the pregnant mother from between these two ligands for proinflammatory cytokines to be
exposure to the father’s human leukocyte antigens (HLAs) can sup- produced, thus contributing to RA.
press the inflammatory processes from the RA. Postpartum, a Once the T-cell is activated, various cytokines are released into
majority of these patients will develop a flare of their arthritis.1-3 the extracellular environment. These cytokines perform several
activities, such as activating other CD4+ T-cells in the area of the
synovial lining, stimulating the growth of new synovial blood ves-
ETIOLOGY sels, and activating endothelial cells in the endothelium of blood
vessels to produce adhesion molecules to attract other cell lines into
The exact etiology of RA is currently unknown. However, certain the synovial membrane. These activities provide the framework
factors have been linked to the predisposition for RA.4-11 Possession upon which synovitis can occur.
of certain HLA alleles can increase the risk of having RA, including One cytokine produced by activated T-cells is tumor necrosis
factor (TNF). TNF-a is the principal cytokine responsible for the
n Caucasian: HLA-DRB1*0401 and HLA-DRB1*0404.
production of synovitis. This cytokine acts through activating other
n Japanese: HLA-DR4*0405.
T-cells; activating B-cells and encouraging them to mature and
n Chinese: HLA-DRB1*0404 and HLA-DRB1*0405.
differentiate; stimulating the production of enzymes such as
n Israeli: HLADRB1*0102.
matrix metalloproteinase-3 and collagenase, which break down car-
n Spanish: HLADRB1*0405 and HLA-DR10.
tilage in the joint; stimulating osteoclasts to resorb bone in the joint,
A recent study looked at gene alleles in the African American thus causing erosions; and stimulating new blood vessel growth
population. The study concluded that there was not one particular inside the synovial lining.
HLA subtype that predominated, but the study did show that those IL-17 is another cytokine produced by activated T-cells. This
participants who possessed the HLA-DR4 gene more frequently had cytokine promotes the destruction of cartilage and stimulates
a positive rheumatoid factor. To date, the use of genetic typing is osteoclasts, thus causing erosive changes in the bones. IL-1 is
beneficial only in the research setting—this is not used in everyday also produced by T-cells during an inflammatory reaction. This
practice. cytokine stimulates the activation of other T-cells, recruits other
Smoking has been shown to increase the relative risk for the inflammatory cells into the joint, and inhibits new blood vessel
development of RA. Smoking was initially found to produce growth.
246 Chapter 33 RHEUMATOID ARTHRITIS
Summary of Interactions of Cytokines in RA Assessment Questionnaire (HAQ) and is used to monitor the
patient’s response to medical treatment.
In summary, cytokines such as IL-1, IL-6, IL-18, and TNF-a direct Other diseases must be excluded from the differential diagnosis
other inflammatory cells into the synovial space. The T-cells already when evaluating for RA. Because RA can present as either a poly-
activated in the synovium have alterations in their genetic structure articular arthritis or swelling of a single joint, many other diseases
(p53) that prevents apoptosis. Cytokines such as TNF-a and IL-15 must be eliminated as the source for the symptoms. Some examples
keep the inflammatory cells in the synovial space. IL-17 and TNF-a include systemic lupus erythematosus, septic arthritis, Lyme disease,
stimulate the production of enzymes that degrade cartilage and sarcoidosis, ankylosing spondylitis, viral arthritis, Reiter’s syn-
stimulate osteoclasts to degrade bone. drome, hepatitis, and hemochromatosis.
B-CELLS AND RHEUMATOID FACTOR LABORATORY FEATURES

B-cells also play a role in the development of RA. B-cells are To date, there is no single laboratory test that can detect RA. Rather,
often activated by TNF. B-cells produce IL-6, interferon-g the diagnosis of RA is determined by the presence of four of six
(INF-g), and TNF-a, which activate other B- and T-cells. B-cells criteria set forth by the American College of Rheumatology.
also differentiate into memory cells, which produce immunoglobu- The presence of inflammation in the joints can be evaluated
lins such as rheumatoid factor. Molecules of rheumatoid factor can systemically with a complete blood count (CBC). Typically, the
link to form immune complexes that can accumulate in joint spaces white blood cell count is elevated. In rare instances, the white
and various tissues. blood cell (WBC) count can be low. Felty’s syndrome is defined
The production of rheumatoid factor often conveys a worse by leukopenia noted in association with splenomegaly, lung invol-
prognosis, including the production of rheumatoid nodules, vement, and other symptoms.
extra-articular manifestations of RA, vasculitis, and the presence Anemia and thrombocytosis are often seen in patients with RA.
of erosive disease on x-rays. Also, acute-phase reactants, such as the erythrocyte sedimentation
rate and C-reactive protein, can be elevated. In about 85% of
patients with RA, the rheumatoid factor is positive.
CYCLIC CITRULLINATED PROTEIN If synovial fluid is aspirated from a joint and analyzed, the WBC
ANTIBODIES count is often between 2000 and 50,000/mm3. No crystals are seen
under a polarized microscope. In cases in which the WBC count is
The cyclic citrullinated protein (CCP) antibody is a test that has greater than 50,000/mm3, the possibility of a septic joint must be
been used commercially for the past few years as a blood test to evaluated and ruled out. If the WBC count is above 75,000/mm3,
determine the presence of early RA. This kit tests for citrullination the joint may require irrigation and débridement by an orthopedic
in a process catalyzed by peptidyl arginine deaminase. This CCP test surgeon.
is specific but not sensitive for the detection of RA. Citrullinated Prior to the use of magnetic resonance imaging (MRI) for the
proteins were also found in bronchoalveolar lung fluid in smokers detection of early erosions, synovial biopsies were performed to look
but not in nonsmokers. Thus, a patient who smokes and has joint for synovial thickening. In cases in which the diagnosis of joint swell-
pain may have a positive CCP antibody but yet not have RA. No ing is unclear, synovial biopsies may still be used for diagnosis.
studies have been performed to determine whether RA patients who
have a positive CCP antibody also have worse prognosis as do those
who have a positive rheumatoid factor. EXTRA-ARTICULAR MANIFESTATIONS
Rarely, patients with RA who possess a positive rheumatoid factor
CRITERIA AND DIFFERENTIAL can also develop symptoms outside of the joint space. RA can affect
DIAGNOSIS almost every major organ system.
According to the 1987 American College of Rheumatology criteria,15

the diagnosis of RA is made by having at least four of the following Ocular
criteria:
The most common ocular symptom in patients with RA is dry eyes.
n Morning stiffness lasting at least 45 minutes.
Keratoconjunctivitis sicca occurs in between 20% and 30% of
n Synovitis or swelling of three or more joints lasting at least
patients with RA (Fig. 33–1). Most patients who suffer from dry
6 weeks.
eyes believe that the symptoms are just a natural part of getting
n Synovitis or swelling of the metacarpophalangeal or proximal
older, so they rarely complain. Thus, practitioners who treat RA
interphalangeal joints or wrists lasting at least 6 weeks.
must specifically inquire about dry eyes. Treatment with either arti-
n Symmetrical swelling of the joints.
ficial tears or ophthalmic cyclosporine is used to combat kerato-
n Presence of rheumatoid nodules.
conjunctivitis sicca.
n Presence of erosions on x-rays of the hands or feet.
Episcleritis is another common self-limiting ocular disease asso-
n Presence of a positive rheumatoid factor.
ciated with RA. Scleritis is a rare but serious inflammation of the eye
When a patient presents to the office with symptoms of joint pain requiring immediate treatment with steroid eye drops. If the symp-
and swelling, a detailed history and a physical examination are toms of scleritis are ignored, the inflammation can spread and cause
necessary for the diagnosis of RA. Often, x-rays of the affected swol- blindness from scleromalacia perforans.16
len joints are obtained to examine for either periarticular osteopenia
or erosions. Also, blood work is obtained to evaluate for the presence
of rheumatoid factor, CCP antibodies, and other diseases. Skin
When patients present to the office for routine visits, they
should also be interviewed about their ability to perform various About 30% of rheumatoid factor–positive patients develop rheu-
activities of daily living, such as dressing, walking, eating, toileting, matoid nodules. These nodules develop in areas including tendon
and opening jars. The scoring of these activities is called the Health sheaths (such as the Achilles), bursae (such as on the olecranon),
Figure 33^1. Keratoconjunctivitis sicca.
and subcutaneous areas (Fig. 33–2). When the nodules are excised A
and examined under the microscope, they appear to have a central
area of necrosis surrounded by a zone of elongated histiocytes and
an outer layer of connective tissue. Medications such as methotrex-
ate can increase the likelihood of developing nodules.17
Ulceration of the skin is another problem that can occur in
rheumatoid-positive patients. These patients typically have a disease
state that is not well controlled with medications. The ulcerations
develop from leukocytoclastic vasculitis, whereby the small blood
vessels become irritated and cause palpable purpura that can
develop into ulcers. Treatment of RA will also treat the ulcers.
Musculoskeletal
RA can result in significant joint inflammation and destructive pro-
cesses that may lead to a myriad of bony deformities and disloca-
tions (Fig. 33–3).
B
Nervous System
Leukocytoclastic vasculitis can affect the small blood vessels that feed
to the nerves, causing necrosis of the sensory and motor nerves. RA
patients can develop foot drop or loss of motor control to the hands.
This vasculitis can also affect the spinal cord and brain and cause
serious complications including paralysis, blindness, or even death.
Inflammation of the joints causes destruction of the bones in the
wrists and feet and leads to impingement on nerves. This can cause
carpal tunnel or tarsal tunnel syndrome. Patients with RA often
require surgery to remove the inflamed synovium, realign bones,
and free the entrapped nerves.
Long-standing RA can also place patients at risk for spinal cord
instability, especially in the cervical spine. Inflammation of the liga-
mentous structures, particularly the transverse ligaments, that con-
nect C1 and C2 causes the ligaments to fail. Disruption of the
transverse ligament causes atlantoaxial subluxation, which is defined
as an increase in the distance between the posterior aspect of the C1
arch and the dens of greater than 2.5 mm in adults (Fig. 33–4). When
this occurs, instability may develop, causing neurologic symptoms.
An MRI is indicated in a RA patient for evaluation of neck pain, C
numbness, or tingling. These patients need immediate surgical inter- Figure 33^2. Examples of rheumatoid nodules.
vention to prevent permanent disability or possibly death.
can lead to heart attacks, conduction system abnormalities, and
valvular problems.
Cardiac
Some of the cardiac manifestations of RA include pericardial effu- Pulmonary
sions as well as arrhythmias from rheumatoid nodules growing in
the region of the conduction system. Patients with RA are also at The medications used to control RA, such as methotrexate and TNF
increased risk for development of coronary artery disease, which inhibitors, can weaken the immune system and place the patient at
248 Chapter 33 RHEUMATOID ARTHRITIS
Figure 33^3. Examples of ulnar

deviation and dislocation caused by
rheumatoid arthritis.
increased risk for infections. If patients develop bronchitis or pneu- fluid are high. The pH of the pleural fluid is frequently low, and
monia, they should hold their RA treatment medications while often, an empyema needs to be ruled out.
taking antibiotics.
Another pulmonary complication of RA is lung nodules. The
nodules are benign in nature. RA patients have a higher incidence of Kidney and Gastrointestinal System
interstitial lung disease. Imaging with computed tomography (CT)
scan shows fibrosis of the lower lobes. Cases in which the fibrosis Renal problems as a direct result of RA are rare. If kidney function
progresses rapidly are called Hamman-Rich syndrome and can be deteriorates faster than expected, it is often due to the overuse of
life-threatening. nonsteroidal anti-inflammatory drugs (NSAIDs). Proteinuria could
Patients with RA can also develop pleural effusions. If the pleural be due to amyloidosis, a rare secondary effect from RA.
fluid is drained and analyzed, it would show a low glucose level Problems with the gastrointestinal system such as esophagitis,
owing to a defect of the transport of glucose across the pleura. gastritis, and bleeding ulcers are again likely due to a side effect
The protein and the lactate dehydrogenase levels in the pleural from using NSAIDs and/or prednisone.
A B
Figure 33^4. C1 and C2 instability.
TREATMENT Infliximab is a chimeric monoclonal antibody that binds to

TNF-a and prevents TNF from binding to cell receptors. This med-
Many medications are used in the treatment of RA. These medica- ication is mixed into saline and is administered intravenously over 2
tions are used for relief of symptoms, decrease of the inflammatory hours. The amount of medication administered is based on body
response, and prevention of the progression of the disease. weight (3–5 mg/kg) and is usually given about every 8 weeks.
Steroids, such as prednisone, are commonly used to quickly Adalimumab is a recombinant human monoclonal antibody that
reduce the swelling, stiffness, and pain from inflammation. They binds to TNF-a extracellularly. It also binds to cell surface receptors
are effective in controlling the inflammatory process, but steroids and prevents TNF from binding to the receptor. Adalimumab
also lead to side effects such as weight gain, mood swings, elevated is administered as a 40-mg dose in a prefilled syringe or pen
blood pressure, hyperglycemia, cataracts, glaucoma, and an increased every 2 weeks.
risk of osteoporosis. For patients who are expected to require a The TNF inhibitors all share the same side effects, including:
prolonged course of glucocorticoids, it is recommended that they
n Risk of serious infections including sepsis and from oppor-
consume 1500 mg of calcium and 400 IU of vitamin D daily.
tunistic organisms.
Hydroxychloroquine is an antimalarial agent used to treat RA.
n Risk of tuberculosis (thus, a purified protein derivative [PPD]
The mechanism of action of hydroxychloroquine is broad, but it is
test is given prior to initiation).
likely is through binding of antigens to cell surface. The common
n Nervous system infections including multiple sclerosis and
dosage of hydroxychloroquine is twice daily. Common side effects
optic neuritis.
include nausea, lack of appetite, and altered vision owing to depo-
n Congestive heart failure in patients with class III/IV heart disease.
sition of the medication on the retina. It is recommended that
n Lupus-like syndrome.
patients taking hydroxychloroquine receive an eye examination
n Malignancies such as lymphoma, breast, and colon.
biannually to evaluate for retinal toxicity.18
Methotrexate is the medication most commonly used to treat Anakinra is a daily subcutaneous injection that works by inhi-
RA. Originally used as a chemotherapeutic agent, methotrexate has biting IL-1, which degrades bone and cartilage. The medication is
been shown to delay the progression of damage from RA. This supplied in a 100-mg prefilled syringe. Anakinra should not be
medication may be administered as a pill or as an injectate once administered simultaneously with TNF inhibitors because the com-
per week. Side effects include nausea, mouth sores, alopecia, loss of bination further increases the risk of infections. A PPD test is admi-
appetite, and diarrhea. Rare side effects include elevated liver nistered prior to the initiation of anakinra. Malignancies such as
enzymes, nodulosis, pneumonitis, and aplastic anemia. Because of lymphoma, breast, lung, and colon have been associated with
the risk of elevated liver enzymes, alcohol consumption and the use anakinra.
of antibiotics such as trimethoprim-sulfamethaxozole should be Abatacept was approved by the U.S. Food and Drug
avoided. Administration (FDA) in December 2005 for the treatment of mod-
Leflunomide is a medication specifically designed to treat RA. It is erate to severe RA. The medication’s mechanism of action is at the
available in 10-, 20- and 100-mg pills. The 100-mg pills are taken APC. Abatacept prevents the binding of the second signal between
for 3 days as a loading dose, followed by a 10- or 20-mg pill once the APC and the T-cell. By blocking the attachment of the second
daily. Common side effects include nausea, abdominal pain, signal, the inflammatory cascade seen in RA is halted. Abatacept is
diarrhea, and elevated liver enzymes. The half-life of leflunomide is administered intravenously as several loading doses over the first
about 2 weeks. If elevated liver enzymes develop, cholestyramine month, and then every 4 weeks. Side effects of abatacept include the
should be prescribed for stimulation of leflunomide elimination.19,20 increased risk of serious infections and tuberculosis, infusion reac-
Sulfasalazine is a medication distributed in 500-mg tablets. tions, and malignancies.
Patients with RA are often administered this medication as 2 pills Rituximab was approved for use in moderate to severe RA in
taken either two or three times a day. Nausea, abdominal pain, early 2006. This is a monoclonal antibody that binds to and inhibits
leukopenia, anemia, and kidney stones are common side effects. the CD20 antigen on B-cells. This binding causes cell apoptosis. It is
This medication often takes several months to work effectively. given after intravenous corticosteroids are administered to reduce
Azathioprine, originally used as an antirejection medication in the chance of infusion reactions. Common side effects can include
organ transplant patients, was found to be beneficial in RA. This hypotension, nausea, abdominal pain, diarrhea, anemia, and neu-
medication is used in patients who have failed other disease- tropenia. Redosing of rituximab varies depending upon return of
modifying antirheumatic drugs (DMARD) therapies. Distributed RA symptoms, but it is generally every 6 months.
in 50-mg tablets, an effective dose is approximately 1 to 1.5 mg/
kg. Possible side effects include nausea, vomiting, rash, and REFERENCES
pancreatitis.
Other medications rarely used in treating mild to moderate RA 1. Nelson JL, Hughes KA, Smith AG, et al. Maternal-fetal disparity in
include cyclosporine, gold shots, and D-penicillamine. Patients who HLA class II alloantigens and pregnancy-induced amelioration in
have been taking ‘‘gold’’ for the treatment of RA for many years and rheumatoid arthritis. N Engl J Med 1993;329:466.
are doing well should probably continue on this therapy. 2. Silman A, Kay A, Brennan P. Timing of pregnancy in relation to the
onset of rheumatoid arthritis. Arthritis Rheum 1992;35:152.
The treatment of moderate to severe RA typically consists of 3. Nepom GT, Byers P, Seyfried C, et al. HLA genes associated with
methotrexate with the addition of a biologic agent where appropri- rheumatoid arthritis. Arthritis Rheum 1989;32:15.
ate. Currently, the categories of biologic agents are TNF inhibitors, 4. Fries JF, Wolfe F, Apple R, et al. HLA-DRB1 genotype associations in
anakinra, abatacept, and rituximab. 793 white patients from a rheumatoid arthritis inception cohort:
TNF inhibitors have been used to treat RA since their introduc- frequency, severity and treatment bias. Arthritis Rheum 2002;46:2320.
tion in 1998. These medications have been shown to virtually halt 5. Ohta N, Nishimura YK, Tanimoto K, et al. Association between HLA
the progression of the disease state in RA. This class of medications and Japanese patients with rheumatoid arthritis. Hum Immunol
includes etanercept, infliximab, and adalimumab. 1982;5:123.
Etanercept was originally packaged in a powder form that was 6. Molkentin J, Gregersen PK, Lin X, et al. Molecular analysis HLA-DR
beta and DQ beta polymorphism in Chinese with rheumatoid
mixed with a diluent and injected subcutaneously twice a week. The arthritis. Ann Rheum Dis 1993;52:610.
medication was then reformulated in 2003 and was packaged in 7. Seglias J, Li EK, Cohen MG, et al. Linkage between rheumatoid
a prefilled syringe given subcutaneously once a week. In 2006, arthritis susceptibility and the presence of HLA-DR4 and DR beta
etanercept was distributed in a penlike syringe. Etanercept is a allelic third hypervariable region sequences in southern Chinese
fusion protein that binds to TNF extracellularly. persons. Arthritis Rheum 1992;35:163.
250 Chapter 34 PAINFUL DIABETIC PERIPHER AL NEUROPATHY
8. de Vries N, Ronningen KS, Tilanus MG, et al. HLA-DR1 and 14. Fuchs HA, Callahan LF, Kaye JJ, et al. Radiographic and joint count
rheumatoid arthritis in Israeli Jews: sequencing reveals that DRB10102 findings of the hand in rheumatoid arthritis: related and unrelated
is the predominant HLA-DR1 subtype. Tissue Antigens 1993;41:26. findings. Arthritis Rheum 1988;31:44–51.
9. Yelamos J, Garcia-Lozano JR, Moreno I, et al. Association of HLA- 15. Arnett FC, Edworthy SM, Bloch DA, et al. The American
DR4-Dw15 (DRB010405 and DR10) with rheumatoid arthritis in a Rheumatism Association 1987 revised criteria for the classification of
Spanish population. Arthritis Rheum 1993;36:811. rheumatoid arthritis. Arthritis Rheum 1988;31:315–324.
10. McDaniel DO, Alacron GS, Pratt PW, et al. Most African-American 16. Matteson EL, Conn DL. Extra-articular manifestations of rheumatoid
patients with rheumatoid arthritis do not have the rheumatoid arthritis. In Weinsman MH, Weinblatt ME, Louie JS (eds) Treatment of
antigenic determinant (epitiope). Ann Intern Med 1995;123:181. the Rheumatic Diseases. Philadelphia: WB Saunders, 1995; pp 236–248.
11. van der Heijden IM, Wilbrink B, Tchetverikov I, et al. Presence of 17. Mellbye OJ, Forre O, Mollnes TE, et al. Immunopathology of
bacterial DNA and bacterial peptidoglycans in joints of patients with subcutaneous rheumatoid nodules. Ann Rheum Dis 1991;50:909–912.
rheumatoid arthritis and other arthridities. Arthritis Rheum 18. Fox RI, Kang H. Mechanism of action of antimalarial drugs: inhibition
2000;43:593. of antigen processing and presentation. Lupus 1993;2(suppl 1):S9.
12. Silman AJ, MacGregor AJ, Thompson W, et al. Twin concordance 19. Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the
rates for rheumatoid arthritis: a nationwide study. Br J Rheumatol efficacy and safety of leflunomide and methotrexate for the treatment
1993;32:903. of rheumatoid arthritis. Rheumatology (Oxford) 2000;39:655–665.
13. Blaschke S, Schwarz G, Moneke D, et al. Epstein-Barr virus infection 20. Fox RI. Mechanisms of action of leflunomide. J Rheumatology
in peripheral blood mononuclear cells, synovial fluid cells, and 1998;(suppl 53):20.
synovial membranes of patients with rheumatoid arthritis.
J Rheumatol 2000;27:866.
Chapter 34 neuropathy to be referred by the primary care physician to the pain

specialist.
PAINFUL DIABETIC As the global burden of diabetes and its complications rises, it
behooves the conscientious health care practitioner to learn more
PERIPHERAL NEUROPATHY about PDPN in order to better serve this growing patient popula-
tion. Pain-management physicians, in particular, have a definitive
and necessary role in the care of these patients, who are at risk for
Vania E. Fernandez and Salahadin Abdi medical and psychological comorbidities. Thus, it is incumbent
upon the pain specialist to properly identify and to adequately
manage PDPN early in order to slow the progression of symptoms,
avoid permanent disability, and enhance the patient’s quality of life.
This chapter focuses on the understanding and treatment of this
possibly devastating complication of diabetes.
INTRODUCTION
EPIDEMIOLOGY
Diabetes remains the most common cause of neuropathy world-
wide. Diabetic neuropathies encompass a myriad of syndromes with Despite advances in the understanding and treatment of diabetes, it
diverse clinical manifestations. Consequently, these presentations remains a substantial medical and economic burden. By 2010, it is
can often be overlooked or misdiagnosed. In fact, subclinical neu- estimated that globally 220 million people will have diabetes.4
ropathy, without signs or symptoms, is much more common than Currently, diabetes is the fifth leading cause of death in the
clinical neuropathy. The resultant delay in the recognition and United States, accounting for billions of health care dollars annu-
treatment of diabetic neuropathy can lead to irreversible end- ally.5 The precise epidemiology of diabetic neuropathies is difficult
organ damage resulting in unnecessary morbidity and mortality. to establish owing largely to the inconsistency of definitions, meth-
Diabetic neuropathies affect patients with either type 1 or type 2 odology, and diagnostic criteria used among studies and also to the
diabetes with equal frequency.1 As with any other diabetic compli- lack of population-based reviews. The prevalence of neuropathy in
cation, the major culprit is poor glycemic control. diabetic patients is considered to be 10% at diagnosis, and it rises to
The broad groups of diabetic neuropathies include sensory neu- greater than 50% after 5 years.2 The Rochester Diabetic Neuropathy
ropathies, which can be acute or chronic; focal or multifocal neu- Cohort,6 one of the largest population-based trials to date, demon-
ropathies; and lastly, autonomic neuropathy, which encompasses strated that distal symmetrical polyneuropathy was the most
effects to the cardiovascular, gastrointestinal, and genitourinary sys- common neuropathy (50%), followed by median nerve mononeu-
tems (Fig. 34–1). Distal symmetrical sensorimotor polyneuropathy, ropathy (> 30%), and finally, by visceral autonomic neuropathy
often referred to as diabetic peripheral neuropathy, is the most (> 5%). The incidence of neuropathy in individuals with either
common neuropathy found among diabetic patients. It generally insulin-dependent diabetes mellitus (66%) or non–insulin-depen-
results in the insensate ‘‘diabetic foot.’’ In contrast to this well- dent diabetes mellitus (59%) was similar in proportion. Whereas
described lack of sensation, studies have found that up to 50% of the study noted that 15% of patients experienced some form of
patients with diabetes experience painful neuropathic symptoms.2 symptoms at the time of assessment, the true incidence of PDPN
Ten percent to 20% of diabetic patients endure severe neuropathic was not specifically determined. It is important to note that 10% of
pain requiring treatment.3 Although painful diabetic peripheral the patients studied had nerve damage unrelated to diabetes. These
neuropathy (PDPN) shares some of the characteristics of other other forms of neuropathy can represent serious medical conditions
types of neuropathic pain, it is poorly described and can be more that are often unrecognized in this patient population or incorrectly
difficult to treat. As a consequence, PDPN is the most likely diabetic attributed to diabetes, such as a cerebrovascular accident.
8. de Vries N, Ronningen KS, Tilanus MG, et al. HLA-DR1 and 14. Fuchs HA, Callahan LF, Kaye JJ, et al. Radiographic and joint count
rheumatoid arthritis in Israeli Jews: sequencing reveals that DRB10102 findings of the hand in rheumatoid arthritis: related and unrelated
is the predominant HLA-DR1 subtype. Tissue Antigens 1993;41:26. findings. Arthritis Rheum 1988;31:44–51.
9. Yelamos J, Garcia-Lozano JR, Moreno I, et al. Association of HLA- 15. Arnett FC, Edworthy SM, Bloch DA, et al. The American
DR4-Dw15 (DRB010405 and DR10) with rheumatoid arthritis in a Rheumatism Association 1987 revised criteria for the classification of
Spanish population. Arthritis Rheum 1993;36:811. rheumatoid arthritis. Arthritis Rheum 1988;31:315–324.
10. McDaniel DO, Alacron GS, Pratt PW, et al. Most African-American 16. Matteson EL, Conn DL. Extra-articular manifestations of rheumatoid
patients with rheumatoid arthritis do not have the rheumatoid arthritis. In Weinsman MH, Weinblatt ME, Louie JS (eds) Treatment of
antigenic determinant (epitiope). Ann Intern Med 1995;123:181. the Rheumatic Diseases. Philadelphia: WB Saunders, 1995; pp 236–248.
11. van der Heijden IM, Wilbrink B, Tchetverikov I, et al. Presence of 17. Mellbye OJ, Forre O, Mollnes TE, et al. Immunopathology of
bacterial DNA and bacterial peptidoglycans in joints of patients with subcutaneous rheumatoid nodules. Ann Rheum Dis 1991;50:909–912.
rheumatoid arthritis and other arthridities. Arthritis Rheum 18. Fox RI, Kang H. Mechanism of action of antimalarial drugs: inhibition
2000;43:593. of antigen processing and presentation. Lupus 1993;2(suppl 1):S9.
12. Silman AJ, MacGregor AJ, Thompson W, et al. Twin concordance 19. Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the
rates for rheumatoid arthritis: a nationwide study. Br J Rheumatol efficacy and safety of leflunomide and methotrexate for the treatment
1993;32:903. of rheumatoid arthritis. Rheumatology (Oxford) 2000;39:655–665.
13. Blaschke S, Schwarz G, Moneke D, et al. Epstein-Barr virus infection 20. Fox RI. Mechanisms of action of leflunomide. J Rheumatology
in peripheral blood mononuclear cells, synovial fluid cells, and 1998;(suppl 53):20.
synovial membranes of patients with rheumatoid arthritis.
J Rheumatol 2000;27:866.
Chapter 34 neuropathy to be referred by the primary care physician to the pain

specialist.
PAINFUL DIABETIC As the global burden of diabetes and its complications rises, it
behooves the conscientious health care practitioner to learn more
PERIPHERAL NEUROPATHY about PDPN in order to better serve this growing patient popula-
tion. Pain-management physicians, in particular, have a definitive
and necessary role in the care of these patients, who are at risk for
Vania E. Fernandez and Salahadin Abdi medical and psychological comorbidities. Thus, it is incumbent
upon the pain specialist to properly identify and to adequately
manage PDPN early in order to slow the progression of symptoms,
avoid permanent disability, and enhance the patient’s quality of life.
This chapter focuses on the understanding and treatment of this
possibly devastating complication of diabetes.
INTRODUCTION
EPIDEMIOLOGY
Diabetes remains the most common cause of neuropathy world-
wide. Diabetic neuropathies encompass a myriad of syndromes with Despite advances in the understanding and treatment of diabetes, it
diverse clinical manifestations. Consequently, these presentations remains a substantial medical and economic burden. By 2010, it is
can often be overlooked or misdiagnosed. In fact, subclinical neu- estimated that globally 220 million people will have diabetes.4
ropathy, without signs or symptoms, is much more common than Currently, diabetes is the fifth leading cause of death in the
clinical neuropathy. The resultant delay in the recognition and United States, accounting for billions of health care dollars annu-
treatment of diabetic neuropathy can lead to irreversible end- ally.5 The precise epidemiology of diabetic neuropathies is difficult
organ damage resulting in unnecessary morbidity and mortality. to establish owing largely to the inconsistency of definitions, meth-
Diabetic neuropathies affect patients with either type 1 or type 2 odology, and diagnostic criteria used among studies and also to the
diabetes with equal frequency.1 As with any other diabetic compli- lack of population-based reviews. The prevalence of neuropathy in
cation, the major culprit is poor glycemic control. diabetic patients is considered to be 10% at diagnosis, and it rises to
The broad groups of diabetic neuropathies include sensory neu- greater than 50% after 5 years.2 The Rochester Diabetic Neuropathy
ropathies, which can be acute or chronic; focal or multifocal neu- Cohort,6 one of the largest population-based trials to date, demon-
ropathies; and lastly, autonomic neuropathy, which encompasses strated that distal symmetrical polyneuropathy was the most
effects to the cardiovascular, gastrointestinal, and genitourinary sys- common neuropathy (50%), followed by median nerve mononeu-
tems (Fig. 34–1). Distal symmetrical sensorimotor polyneuropathy, ropathy (> 30%), and finally, by visceral autonomic neuropathy
often referred to as diabetic peripheral neuropathy, is the most (> 5%). The incidence of neuropathy in individuals with either
common neuropathy found among diabetic patients. It generally insulin-dependent diabetes mellitus (66%) or non–insulin-depen-
results in the insensate ‘‘diabetic foot.’’ In contrast to this well- dent diabetes mellitus (59%) was similar in proportion. Whereas
described lack of sensation, studies have found that up to 50% of the study noted that 15% of patients experienced some form of
patients with diabetes experience painful neuropathic symptoms.2 symptoms at the time of assessment, the true incidence of PDPN
Ten percent to 20% of diabetic patients endure severe neuropathic was not specifically determined. It is important to note that 10% of
pain requiring treatment.3 Although painful diabetic peripheral the patients studied had nerve damage unrelated to diabetes. These
neuropathy (PDPN) shares some of the characteristics of other other forms of neuropathy can represent serious medical conditions
types of neuropathic pain, it is poorly described and can be more that are often unrecognized in this patient population or incorrectly
difficult to treat. As a consequence, PDPN is the most likely diabetic attributed to diabetes, such as a cerebrovascular accident.
Diabetic
nonpainful ischemic mononeuropathies accounting for less than
neuropathy 1% of all diabetic neuropathies. These patients present with an
acute onset of transient symptoms. The most common presentation
is diplopia, ptosis, and ipsilateral headache seen with ischemia of
the third cranial nerve. In some cases, ipsilateral, retro-orbital pain
can precede these findings, which typically resolve within 6 weeks to
Sensory Autonomic 6 months.13 Consequently, these patients are less likely to be seen in
• acute • cardiovascular the pain clinic.
-painful • gastrointestinal Peripheral mononeuropathies can either be the result of neuronal
-rapid reversal • genitourinary
ischemia or develop more indolently from nerve entrapment.
• chronic • sudomotor
Ischemic nerve damage is characterized by neuropathic pain.
Focal Multifocal Nerve compression results in the gradual onset of neuropathic
• cranial • amyotrophy pain that persists without treatment. Entrapment neuropathies,
• peripheral • distal symmetric such as carpal and tarsal tunnel syndromes, are relatively
• radicular -small fiber common in diabetes and occur more frequently in diabetic patients
-large fiber than in the general population.14,15 The most common nerves
• radiculopathies involved in diabetic peripheral neuropathy are the median nerve,
Figure 34^1. Classification of diabetic neuropathies.
common peroneal nerve, and lateral cutaneous nerve of the thigh.
Burning pain, paresthesias, and hyperalgesia spread throughout the
involved limb overshadowing motor weakness, if any. Obesity is
also associated with meralgia paresthetica, the painful compression
PATHOPHYSIOLOGY of the lateral cutaneous nerve of the thigh. Mononeuritis multiplex is
the term used to describe neuropathies involving several isolated
Persistent hyperglycemia is the leading factor in the incidence of nerves on the same side of the body.
negative outcomes in diabetic patients, including those with Radiculoneuropathies are usually very painful. They affect mainly
PDPN.7–10 Thus, early detection and maintenance of normoglyce- older, diabetic men and can be either focal or multifocal.16 The pain
mia is key to the prevention of diabetic complications such as of a monoradiculoneuropathy is described as ‘‘burning’’ and
PDPN. The body derives glucose from three sources: intestinal ‘‘aching’’ with a ‘‘lancinating’’ or ‘‘stabbing’’ quality. Patients
absorption of carbohydrates, glycogenolysis from glucose stores, often experience cutaneous hyperesthesias with nocturnal exacerba-
and gluconeogenesis from metabolic precursors, amino acids, and tions. On rare occasions, they present with motor weakness. Clinical
glycerol. The liver and kidneys are the primary organs involved in examination may reveal hyperesthesia in a dermatomal pattern.
glucose homeostasis along with the hormones insulin, glucagon, These symptoms generally resolve within 6 months. Diabetic tho-
and epinephrine.11 Diabetes results when this complex regulatory racoabdominal neuropathy is characterized by thoracic and
system is tilted in favor of a hyperglycemic state, whether by resis- abdominal pain produced by injury to several thoracic nerve
tance to insulin, insulin deficiency, or both. Autoimmune or infec- roots. This can present concomitantly with abdominal muscle
tious destruction of insulin-secreting pancreatic islet b-cells is weakness, producing a protruding abdomen. Initially, the pain of
known as diabetes type 1. The more common diabetes type 2 thoracoabdominal neuropathy can be mistaken for ischemic disease
begins with decreased insulin action and progresses to inadequate of the visceral organs.5
compensatory insulin secretion. In either case, chronic hyperglyce- Diabetic amyotrophy is a lumbosacral plexus neuropathy seen
mia causes a host of biochemical changes that result in end-organ most commonly in older, type 2 diabetic patients. It is often
damage, namely ophthalmic, renal, cardiac, neural, and vascular discovered during a time of weight loss when poorly controlled
dysfunction. Although a single definitive explanation for the cause diabetes is first treated. The onset of pain can be acute or subacute
of diabetic complications does not exist, microvascular damage is with an asymmetrical distribution in the proximal muscles of the
common among all of these problems. pelvis and thighs, the iliopsoas, quadriceps, and adductors. It can
It is widely accepted that diabetic patients suffer from neuronal present as severe unilateral or bilateral lower extremity pain with
ischemia and infarction, most commonly in the peripheral nervous weakness. Gower’s sign may be exhibited on standing from
system. Observations suggest that endoneural capillaries are partic- the sitting position, in which patients are unable to stand without
ularly prone to ischemic injury in these patients.12 Comorbid con- placing their hands on their knees for support. Most patients will
ditions, such as hypertension, hyperlipidemia, and peripheral develop distal, bilateral symptoms over a period of months.
vascular disease, further decrease endoneural blood flow and accen- Initially, pain is most notable, but eventually, weakness predomi-
tuate microvascular compromise, suggesting an interplay between nates with muscle atrophy, leaving some patients wheelchair-
multiple mechanisms that culminates in hyperglycemia-induced bound.17 The patients may complain of concomitant autonomic
neurovascular damage. The resulting sensory afferent fiber dysfunc- symptoms, such as lightheadedness on standing, palpitations,
tion can cause allodynia, a painful sensation to a nonpainful stim- erectile dysfunction, urinary retention, nausea, vomiting, constipa-
ulus. Herein are listed some of the best-supported molecular tion, or diarrhea. With symptoms resembling cachexia and possible
theories implicated in diabetic microvascular pathology based on compressive neuropathy, it is important to exclude malignant
experimental and clinical studies: (1) activation of the polyol path- disease.
way, oxidative stress, and nitric oxide deficiency; (2) formation of As noted previously, distal symmetrical polyneuropathy is the
advanced glycosylation end-products; (3) induction of the hexos- most common form of neuropathy seen in diabetic patients. Its
amine pathway; (4) activation of protein kinase C (PKC); and (5) presentation opposes that of amyotrophy in that it has a distal to
alterations in neurotrophic factors. A detailed discussion of these proximal spread, affecting the longest nerve fibers first. Patients
mechanisms is beyond the scope of this chapter. complain of numbness and tingling in the distal lower extremities
that migrate proximally in a symmetrical fashion over months to
years. Numbness in the plantar surfaces of the feet and loss of
SIGNS AND SYMPTOMS proprioception in the joints manifest as escalating difficulty with
balance. When symptoms climb from the toes to the knees,
Focal neuropathies can be grouped into cranial, peripheral, or patients begin to feel concomitant numbness and tingling in the
radicular neuropathies. Cranial nerve palsies are presumably fingertips. Patients develop symptoms in what is known as the
glove-and-stocking distribution. Pain is described as ‘‘spontaneous Pharmacologic

electrical shooting,’’ ‘‘stabbing,’’ and ‘‘hot or cold burning’’ sen-
sations. In general, symptoms are worse at night. Painful small Oral hypoglycemic agents and insulin are the mainstay of therapy in
fiber neuropathy is a variant of peripheral neuropathy in which treating diabetes and its complications.21 Because no other medica-
primarily small myelinated fibers are affected. In this case, the tions will slow the natural progression of this disease, the current
patient may begin to experience pain and hyperesthesias with goal of pharmacotherapy in PDPN is symptomatic control. Until
only impaired glucose tolerance even prior to the diagnosis of recently, the U.S. Food and Drug Administration (FDA) had not
diabetes. Neuropathy affecting predominantly the large nerve approved any drug therapies specifically for the treatment of PDPN.
fibers results in motor and proprioceptive dysfunction. Absence Instead, treatment was based on the mechanism-oriented applica-
of sensory deficits differentiates acute self-limited painful neurop- tion of drugs already developed for other indications. Pain signals
athy from persistent painful neuropathy. Physical examination of transmitted to the central nervous system from peripheral stimuli
the lower extremities in patients with chronic peripheral neurop- are modulated by neurotransmitters at the level of both the periph-
athy can reveal hair loss, shiny skin, and muscle atrophy. eral and the central nervous systems. Many of the current therapies
Charcot’s joints, a joint neuropathy, is a later complication of for neuropathic pain are aimed at regulating the action of neuro-
advanced disease, often accompanied by significant pain and lim- transmitters such as serotonin and norepinephrine at receptors and
ited mobility. ion channels. Substance P is the major neurotransmitter at small
unmyelinated C fibers. By depleting substance P, therapeutic agents
can decrease pain. Similarly, other agents can prevent the action of
DIAGNOSIS glutamate, the primary neurotransmitter of Ad-fibers, by blocking
its effects on sodium channels.
Evaluation in the pain clinic includes a detailed diabetic history
and a comprehensive physical examination. This takes into
Antidepressants
account any family history of diabetes and neuropathy. Initially,
the patient should be asked about the duration and management Antidepressants, such as tricyclic antidepressants (e.g., amitripty-
of his or her disease. A list of medications, homeopathic remedies, line, nortriptyline, desipramine), are often the first line of therapy
and pertinent laboratory studies such as the glycosylated hemo- for neuropathic pain. These medications could have the additional
globin level should be reviewed. Pain scores can help to evaluate benefit of simultaneously treating depression, which can coexist in
current level of discomfort and to follow future treatment out- chronic pain patients. However, they have relatively frequent,
comes. In addition, the quality, intensity, duration, and location poorly tolerated adverse effects, including cardiotoxicity, confusion,
of the pain should be evaluated. Orthostatic blood pressure mea- urinary retention, orthostatic hypotension, nightmares, weight gain,
surements can reveal autonomic involvement. Cardiovascular drowsiness, dry mouth, and constipation (Table 34–1). Care should
signs may uncover arrhythmias, diminished pulses, and peripheral be taken in prescribing these agents to elderly patients. Newer anti-
edema. Inspection of the skin can show trophic changes such as depressants (e.g., venlafaxine, duloxetine) are now being used as
calluses or signs of atrophy and hair loss. These should be docu- well. The lack of anticholinergic, a-adrenergic blocking, and cardiac
mented to note the status and evolution of the disease state. The conduction effects make the newer medications more attractive
sensorimotor examination includes testing the cranial nerves, choices for elderly patients. Still, although these have an improved
assessing range of motion, and identifying any sensory and side effect profile, their efficacy has not been shown to equal that of
motor deficits. Small nerve fiber involvement will result in the older agents.22,23
changes in temperature, light-touch, and pain sensation. These
patients may exhibit allodynia, paresthesias, dysesthesias, cramp-
Antiepileptic Drugs
ing, and antalgic gait. Large fiber neuropathy includes difficulty
with position and vibration sense, strength, and two-point dis- Antiepileptic drugs (AEDs) have been used for the treatment of
crimination. In this case, muscle weakness, atrophy, and ataxia neuropathic pain for many years.24 Both first-generation AEDs
may be evident. In the end, a careful examination along with a (e.g., carbamazepine, phenytoin) and second-generation AEDs
thorough history will allow the pain specialist to classify the (e.g., gabapentin, pregabalin) have been found to be effective for
patient’s signs and symptoms into one or a combination of the this purpose.25,26 Thus, their use has been extrapolated to the treat-
previously mentioned categories of PDPN. Before a final diagnosis ment of PDPN. The second-generation agents are better tolerated
is made, other conditions that can lead to neuropathic symptoms with fewer side effects. Some of the mechanisms of action of AEDs
such as malignant or infectious diseases, vitamin B12 deficiency, include sodium channel blockade, potentiation of g-aminobutyric
alcoholism, toxic exposures, medications, and autoimmune dis- acid activity, calcium channel blockade, and antagonism of gluta-
ease, to name a few, must be excluded. mate. Evidence suggests that gabapentin, pregabalin, and levetirac-
etam act on voltage-gated calcium channels to treat neuropathic
pain. With a host of different mechanisms, failure of therapy with
TREATMENT one AED does not preclude a trial with another drug of the same
class. In addition, AEDs can be used in conjunction with other
Diabetic patients should be screened regularly and followed by their medications to complement their actions and achieve better results
primary care physicians with respect to glycemic control and the than with anticonvulsants alone. For example, combination therapy
development of associated comorbidities. Maintenance of normo- between AEDs and antidepressants may be efficacious for those
glycemia is the single most important factor in the slowing of dis- patients who fail monotherapy.27
ease progression and in the prevention of diabetic complications
like PDPN.18 Achieving ideal body weight and adequate lipid levels
Local Anesthetics
will also forestall the development of PDPN. Once PDPN has been
diagnosed, psychological intervention may be warranted.19 Chronic Local anesthetics such as transdermal lidocaine serve as topical
pain has a well-described association with depressed mood and analgesics that provide temporary, localized pain relief with
sleep disturbances. Because affective factors may enhance pain, no reported side effects. These agents block sodium channels
these must be addressed alongside pain management.20 Treatment that propagate action potentials in sensory neurons, thereby
options that can be offered by the pain specialist to alleviate painful decreasing the transmission of pain from the periphery to the cen-
symptoms in patients with PDPN are discussed later. tral nervous system. Lidocaine patches can be effective adjuvants to
Table 34^1. Some of the Oral Agents Commonly Used in theTreatment of Painful Diabetic Peripheral
Neuropathy
Category Drug Mechanism Doses (mg/day)* Concerns

Antidepressants Amitriptyline TCA; SNRI 10–100 Sedation, dysrhythmias, anticholinergic action,
orthostatic hypotension
Nortriptyline TCA; SNRI 10–100 Mild sedation, anticholinergic activity
Desipramine TCA; SNRI 10–100 Mild sedation, mild anticholinergic action, orthostatic
hypotension
Duloxetine SSRI 30–60 Sedation, nausea, dizziness, insomnia, limited
anticholinergic action
Anticonvulsants Carbamazepine Na channel block 100–1200 Dizziness, diplopia, nausea, leukopenia
Inhibits substance P
Oxcarbazepine Na channel block 75–600 Reduced side effects of carbamazepine, ataxia, tremor,
dyspepsia, leukopenia, thrombocytopenia,
hyponatremia
Lamotrigine Na channel block 25–400 Dizziness, ataxia, sedation, headache, diplopia, nausea,
Inhibits glutamate confusion, aplastic anemia, toxic epidermal necrolysis
Gabapentin Binds Ca channel 100–3600 Drowsiness, dizziness, fatigue, nausea, sedation, weight
Unclear mechanism gain, leukopenia
Pregabalin Binds Ca channel 50–300 Drowsiness, dizziness, fatigue, nausea, sedation, weight
Unclear mechanism gain, edema
*Approximate total doses per day for a 70-kg patient (doses can vary considerably and should be adjusted individually).
SNRI, selective serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
Anticholinergic, dry mouth, blurred vision, sedation, urinary retention, constipation.
a multimodal treatment plan.28–30 Lidocane infusions have also its inhibition of serotonin and norepinephrine reuptake, and its lack
been shown to provide clinical analgesia in neuropathic pain of active metabolites leading to fewer side effects than other
states.31 Mexiletine is an orally active local anesthetic that can be opioids.36
used as an alternative mode of therapy for those patients who do
not obtain relief from or who can not tolerate first-line agents.32
Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) have a limited role
Capsaicin
in the treatment of neuropathic pain. Long-term use can impair
Capsaicin is a chemical derived from the Solanaceae family of renal function and lead to gastrointestinal bleeding. Therefore, these
plants, which includes the chili pepper. It is applied topically in agents are not recommended for routine use as monotherapy and
the form of a cream. The analgesic effects of capsaicin cream should be considered only for short-term pain relief.28 Selective
occur by depleting substance P in peripheral sensory neurons. cyclooxygenase-2 (COX-2) inhibitors may be preferable because
Substance P is a chemomediator involved in the transmission of they appear to have fewer side effects.
pain signals to the central nervous system.33 This cream has not
been found to have negative side effects, but its use is not recom-
Ketamine
mended on broken or irritated skin. Currently, injectable mixtures
of capsaicin with local anesthetics are being developed. Ketamine is an NMDA antagonist. It is considered a third-line
agent. Although the analgesic properties of ketamine have long
been known, no rigorous studies support its use in the management
Opioids
of neuropathic pain. A logical application may be in patients suf-
Opioids are considered more effective in the treatment of nocicep- fering from severe acute refractory neuropathic pain and hyperal-
tive than neuropathic pain. In addition, they have a significant side gesia after chronic opioid therapy, in which NMDA receptors
effect profile that includes respiratory depression, itching, constipa- activation has occurred. Ketamine infusions have been used suc-
tion, nausea, and vomiting, and they have the potential for addic- cessfully in combination with lidocaine infusions.37 Side effects
tion and abuse. However, they can serve as adjuncts/analgesic include hallucinations and memory impairment. Alternatively, dex-
agents in the treatment of refractory PDPN (Table 34–2). Opioid tromethorphan could be used instead, though it seems to have
analgesics may enhance the pain relief provided by other medica- fewer analgesic along effects with its decreased side effects.
tions. For example, systemic and topical opioids have shown syn-
ergism with local anesthetics and other adjuvant neuropathic pain
Corticosteroids
medications.34 Tramadol and dextromethorphan are weak opioids
that have also been employed in the treatment of neuropathic The anti-inflammatory property of corticosteroids such as predni-
pain.35 Methadone could be another effective option owing to its sone and dexamethasone makes these drugs appealing choices to
actions as an N-methyl-D-aspartate (NMDA) receptor antagonist, ameliorate the neurogenic inflammation aspect of PDPN. However,
Table 34^2. Commonly Used Adjuvants and Analgesics toTherapy
Category Drug Mechanism Doses Concerns

Local anesthetics Intravenous lidocaine Na channel block 1–5 mg/kg over 20–60’ Drowsiness, fatigue, nausea, dizziness
Lidocaine patch Na channel block 5% to affected area for Not to exceed 4 patches daily
12 hr
Oral mexiletine Na channel block 150–900 mg/day in divided Drowsiness, fatigue, nausea, dizziness,
Decreases substance P doses transient tachycardia
Opioids Tramadol Opioid agonist 50–400 mg/day in divided Nausea, sedation, constipation,
SNRI doses headache, dry mouth, urinary
retention, seizures, tremor
Numerous short- and Opioid agonists Variable doses Sedation, dizziness, nausea, dry
long-acting opioids mouth, constipation, respiratory
depression, dependence
NSAIDs Various drugs COX inhibition Variable doses Renal failure, gastrointestinal bleeding
Others Clonidine a2-Adrenergic agonist 0.1 mg/7days patch Sedation, hypotension
Capsaicin cream Depletes substance P 0.025–0.075% tid–qid daily Burning, irritation, rash, coughing
COX, cyclooxygenase; NSAIDs, nonsteroidal anti-inflammatory drugs; SNRI, selective serotonin-norepinephrine reuptake inhibitor.
Neuroimmunomodulatory Agents
the risk of adverse effects, namely edema, dyspepsia, fungal infec-
tion, and gastrointestinal bleeding, increases with drug dose and Emerging evidence suggests a role for neuroimmunomodulatory
duration of therapy. Thus, they are more likely to be reserved for agents in the treatment of PDPN. Proinflammatory interleukins,
short-term use during acute painful episodes associated with func- tumor necrosis factor-a (TNF-a), and the transcription factor nuclear
tional impairment or for direct injection with or without local factor kB (NF-kB) have all been implicated in the development of
anesthetics to the area surrounding the affected nerve.28 neurogenic inflammatory pain. Neutralizing antibodies to inflamma-
tory cytokine receptors and inhibitors of transcription factors are
examples of viable treatment options that have yet to be developed.
Clonidine
a2-Adrenoceptors located in the central nervous system and the
dorsal root ganglia are involved in modulating pain signals. Interventional
Clonidine, an a2-adrenergic agonist, is a potent analgesic known
to potentiate the effects of opioids.28 It has been administered Whereas pharmacotherapy is the major mode of management of
orally, intrathecally as a topical cream, and by local injection to PDPN, one trial of electrical spinal cord stimulation showed prom-
treat neuropathic pain. Accumulating evidence supports the use ising results for a patient who did not respond to conventional treat-
of a2-adrenergic agonists in intractable neuropathic pain states, in ment.41 Still further studies need to be performed to clarify its
which alterations in a2-adrenoceptors makes these agents even efficacy. Numerous peripheral nerve blocks and sympathectomies
more effective.38 Side effects limiting their use include sedation commonly done for various types of neuropathic pain syndromes
and hypotension. do not seem to be beneficial for PDPN. In specific cases involving
chronic nerve compression associated with PDPN, surgical decom-
pression of peripheral nerves can be therapeutic.42
Cannabinoids
Cannabinoids are chemicals derived from the cannabis plant, com-
monly known as marijuana. The U.S. Marijuana Tax Act of 1937 Alternative/ComplementaryTherapies
made cannabis prescriptions illegal in the United States. Its use for
medical purposes remains controversial owing to its widespread use Alternative therapies include acupuncture, which is supported only
as a recreational drug. Although it has more commonly been used by open-labeled studies.43 Others have attempted to reduce symp-
as an antiemetic, cannabis also has both antiallodynic and antihy- toms via various physical treatments including frequency-modu-
peralgesic effects.39,40 Tetrahydrocannabinol (THC) is the psycho- lated electromagnetic neural stimulation, high-frequency external
active substance that produces the ‘‘high’’ associated with smoking muscle stimulation, low-intensity laser therapy, monochromatic
marijuana and can also lead to central nervous system depression. A infrared treatment, and static magnetic field therapy. The efficacy
synthetic version of THC is used to make dronabinol, an oral form of these modalities has not yet been proven.
of cannabis intended for medical use.
Baclofen CONCLUSION
Baclofen is a g-aminobutyric acid (GABA) analogue that acts as an PDPN is a growing problem without a definitive solution. However,
agonist at central GABAB receptors in much the same way as the an array of choices exists for the symptomatic management of
inhibitory neurotransmitter, GABA. Although baclofen has been this common complication of diabetes. The informed physician is
used primarily as a spasmolytic, more recently, it has been combined in a better position to help patients improve their quality of life
intrathecally with opioids to treat intractable neuropathic pain with with this disease. Many times, a combination of medications will
spasticity. Common side effects include weakness, drowsiness, confu- be necessary to achieve adequate pain control. Whereas no single
sion, and hypotension. Abrupt discontinuation can result in seizures. treatment plan will provide effective pain relief for all diabetic
patients, a directed approach that takes into account the specific treatment of painful neuropathy in patients with diabetes mellitus: a
patient’s symptoms, limitations, comorbidities, and lifestyle goals is randomized controlled trial. JAMA 1998;280:1831–1836.
likely to be most successful. In the majority of cases, a multimodal 21. Diabetes Control and Complications Trial Research Group. The effect
approach including medical therapy with glucose control, psycho- of intensive diabetes therapy on the development and progression of
logical support, and pain management is required. neuropathy. Ann Intern Med 1995;122:561–568.
22. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane
Database Syst Rev 2005;(3):CD005454.
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256 Chapter 35 TRIGEMINAL NEUR ALGIA
Chapter 35 area—thenerve root entry zone—defines the transition from

peripheral to central myelin. The result of chronic irritation of
TRIGEMINAL NEURALGIA this vulnerable area is circumscribed demyelination, leaving the
axon bare and unprotected.
Andrew Linn and Zahid H. Bajwa The mechanism of pain in TGN is controversial, and there is
evidence for both peripheral and central mechanisms.6,7 One theory
is that the exposed axons allow cross-talk between neural pathways
of touch and pain to occur, generating ectopic nerve impulses.7
Pain pathways in the trigeminal nucleus in the midbrain are likely
to become disinhibited from the alterations in afferent input that
accompany TGN. The refractory period between paroxysms and the
INTRODUCTION repetition of painful sensation after a single stimulus also suggest a
component of central sensitization. Medications used to treat TGN
Trigeminal neuralgia (TGN) is characterized by a severe, sudden, facilitate inhibition of the trigeminal nucleus and inhibit excitatory
and brief stabbing episode of pain that is unilateral with distribu- neurotransmission.
tion in one or more of the branches of the fifth cranial nerve. The Arterial aneurysms, mass lesions, multiple sclerosis, and chronic
pain is greatest at onset and often severe enough to cause involun- meningitis are less common causes of TGN, and these are more
tary facial spasm, which is the basis for the early term for TGN, tic frequently seen in those under the age of 40.
douloureux. The paroxysms usually last less than 5 seconds, but can A condition of pretrigeminal neuralgia, a dull ache in the jaw
occur for up to 2 minutes. In most patients, there is a refractory preceding the development of TGN, occurs in some patients. This
period in which no further pain response can be elicited; rarely, the condition has often been misdiagnosed as pain originating from the
response to stimulus is not refractory; and the pain response can be teeth, and many dental procedures have been performed unneces-
repetitive. Attacks of TGN can last weeks to months and, if left sarily as a result. Pretrigeminal neuralgia can be difficult to diagnose
untreated, will usually have a spontaneous remission of variable until paroxysms begin, which can be weeks to years after the initial
length. facial pain. Atypical TGN occurs when a patient has unilateral dull
Often found within the involved areas are trigger points that ache in the jaw (i.e., symptoms of pretrigeminal neuralgia) with the
respond to tactile stimulation—frequently simply lightly touching paroxysms and other clinical indicators of TGN.
the skin will activate paroxysms. Trigger points are most commonly The course of TGN is quite variable. The incidence of TGN over
found near the midline near the nose and mouth. Other common a course of 39 years was reviewed in one study, finding 29% of
triggers include chewing, talking, yawning, smiling, and brushing patients had only one episode of pain, whereas 28% had four or
teeth; patients will often protect these areas to avoid setting off an more episodes.1 Each episode of TGN lasted anywhere from 1 day
attack. It is not uncommon to have a dramatic weight loss with to 4 years, with an average of 49 days. Two thirds of patients in the
TGN because patients try to avoid a paroxysm caused by chewing or study had a second episode within 5 years of the first.
by drinking hot or cold liquids. The diagnosis of TGN is clinical, based on the symptoms listed
The fifth cranial nerve has three divisions that supply distinct previously: unilateral, severe, sharp, or lacinating pain, in distri-
areas of sensory innervation of the face: the ophthalmic (V1), max- butions of the trigeminal nerve, with possible demonstration
illary (V2), and mandibular (V3) branches. V3 also contains motor of trigger zones, which are most often found near the midline
nerves that supply muscles of mastication (Fig. 35–1). The divisions (Box 35–1). Because TGN, especially pretrigeminal neuralgia,
V1–V3 pass the bony structures of the face via the superior orbital can be difficult to distinguish from tooth pain, the patient
fissure, foramen rotundum, and foramen ovale, respectively. They should be carefully examined for ipsilateral dental pathology.
converge on the gasserian ganglion (also called the semilunar or Sensory loss in the trigeminal nerve distribution is not typical
trigeminal ganglion), which contains the cell bodies of the afferent of TGN, nor is motor loss. If these are found, the patient
nerves, analogous to the dorsal root ganglia of the spinal nerves should have a full diagnostic work-up for multiple sclerosis or
(Fig. 35–2). The ganglion is located between the layers of the mass lesions causing the symptoms.
dura mater in a depression on the floor of the middle cranial More common conditions can mimic TGN, and their possibility
fossa called Meckle’s cave. The sensory and motor roots then should be excluded during the evaluation of facial pain.
enter and exit the brainstem at the midlateral surface of the pons.
TGN in Western countries is estimated at 4 to 9 cases per n Temporomandibular joint (TMJ) pain is characterized by
100,000 persons. In the United States, 15,000 new cases are diag- dull pain over the TMJ that radiates to the jaw, temporal
nosed annually.1-3 The incidence of TGN increases with patient age; area, and eye. TMJ pain is made worse by chewing and
it is rarely seen in those under the age of 40 and is one of the most often has an associated click when opening the mouth.
common neuralgias in the elderly. It is seen more often in females n Postherpetic neuralgia can have a trigeminal distribution, but
than in males by a ratio of approximately 3:2, perhaps owing to the the pain is constant and is preceded by a history of shingles.
greater life expectancy of women.4 Tactile allodynia is usually present, and there is often a sen-
sory deficit.
n Cluster migraine headaches do not involve trigger points,
although the pain can be paroxysmal and is usually accom-
ETIOLOGY
panied by rhinorrhea and tearing.
TGN is caused by focal areas of demyelination of the cranial nerve. n Giant cell arteritis causes a constant pain in the forehead,
Eighty percent to 90% of cases are associated with anatomically neck, and temple, sometimes with jaw claudication.
aberrant vasculature, commonly the superior cerebellar artery, con- Transient loss of vision on the affected side is an occasional
tacting and compressing the nerve as it exits the pons.5 This finding in patients with giant cell arteritis.
Figure 35^1. Lateral view of the major branches of the trigeminal nerve. (From Gray H. Anatomy ofthe Human Body. Philadelphia: Lea & Febiger,
1918; Bartleby.com, 2000, p 886.)
n Occipital neuralgia and glossopharyngeal neuralgia can mimic who are poor responders to medical therapybecauses these groups
TGN. They cause lancinating pain that follows the areas of are more likely to have a mass lesion or multiple sclerosis as caus-
afferent input. Glossopharyngeal neuralgia causes pain in the ative agents of TGN.
posterior pharynx and ear and is often triggered by yawning,
coughing, or swallowing hot or cold liquids. Occipital neural-
gia is located in the posterior aspect of the head.
MEDICATIONS
The available evidence we have in the medical management of TGN
suggests that carbamazepine (Tegretol) should be the first-line agent
IMAGING used in the treatment of TGN (Table 35–1). Carbamazepine
suppresses spontaneous neuronal discharges by slowing the recovery
Magnetic resonance imaging (MRI) and magnetic resonance angi- of sodium ion channels, thereby minimizing the excitatory afferent
ography (MRA) can identify areas of demyelination, vascular ana- impulses of TGN. It is initially effective (50% experienced greater
tomic variants that are contacting the trigeminal nerve, mass pain relief over placebo) in over 70% of patients, with onset of pain
lesions, and multiple sclerosis. In a study using surgical findings relief most often in less than 48 hours.11-14 Many authors would
as the standard, the sensitivity of MRI/MRA at identifying patients suggest that initial treatment failure with carbamazepine should
with TGN was 90% and the sensitivity was 50%.8 prompt the reconsideration of the diagnosis of TGN.15,16 Despite
The use of MRI/MRA as part of the initial work-up is contro- excellent short-term response to carbamazepine, long-term pain
versial. Studies have found that it is not possible to differentiate relief is often not maintained; it is unknown whether this is due to
patients who have a mass lesion based on clinical findings alone.8,9 tolerance or to disease progression. There is a high rate of adverse
A retrospective review of 42 patients with TGN found 6 patients effects associated with carbamazepine; thus, the initial dosing should
had a structural lesion that was identified on MRI. The mean age of be low (100 mg twice daily) and titrated upward carefully.
this subgroup was 53; all had typical pain history and symptoms, Oxcarbazepine (Trileptal) is a derivative of carbamazapine.
with 3 having a complete response, 2 with a partial response, and With shared therapeutic properties and fewer and less severe side
1 patient with no response to medical therapy. These variables were effects than its parent drug, oxcarbazepine is often substituted in
no different from those in the patients without structural abnorm- patients who have effective pain relief but poor tolerance of carba-
alities on MRI, leading the authors to conclude that all patients with mazepine. Oxcarbazepine is effective in patients refractory to
TGN should undergo imaging.9 carbamazepine.
A separate study identified clinical features of TGN that indi- Similar to carbamazepine, phenytoin (Dilantin) slows the recov-
cated the presence of a structural lesion.10 Patients under the age of ery of sodium ion channels postactivation, decreasing the excitabil-
29 had a 100% incidence of mass or multiple sclerosis causing the ity of the trigeminal complex. Phenytoin is commonly given if
symptoms, whereas those aged 29 to 39 had a 45% incidence. Those patients fail medical therapy with carbamazepine or are unable to
aged 40 to 60 and those over 60 had a mass or multiple sclerosis tolerate its side effects. In addition to daily maintenance dosing,
20% and 18% of the time, respectively. Patients who had pain in phenytoin can be given intravenously (250 mg over 5 min) to con-
more than one branch of the trigeminal nerve were found to have a trol acute pain exacerbations of TGN.
mass causing the symptoms. Gabapentin (Neurontin) is another antiepileptic used in the
There is no clear consensus on when to utilize MRI/MRA to help treatment of TGN. Gabapentin’s mechanism of action is unknown.
differentiate possible etiologies of TGN. However, it should prob- It is structurally similar to the neurotransmitter g-aminobutyric
ably be used in those younger than 40, in patients with sensory or acid (GABA) but does not interact with GABA receptors. It appears
motor involvement, in those with bilateral symptoms, and in those that gabapentin exerts an action on calcium conductance via
Semilunar Maxillary n.
Sensory root ganglion
Motor root Lacrimal n.
5th
1
Palpebral n.
Zygomatic
2 n.
Facial n. Posterior
3
superior
Pt alveolar n.
Chorda ex eryg
te o
tympani n. rn ide
us u
m s
.
Mandibular n.
Auriculotemporal
nerve Nasal n.
Pte Labial n.
Lingual n. ry Buccinator m.
inte goideu
rnu
Buccal n. sm s Anterior
. superior
Inferior alveolar n.
alveolar n.
Dorsum
Mylo-hyoid n. of tongue
Hyoglossus
Mental n.
Submaxillary
gland Mylo-hyoid m.
Digastric m.
Figure 35^2. Innervation distribution of the three major branches - ophthalmic, maxillary, and mandibular of the trigeminal
nerve. (From Hansen JT, Lambert DR. Netter’s Clinical Anatomy. Philadelphia: Saunders, 2005, p 560.)
its interaction with a binding protein associated with a subunit Carbamazepine or oxcarbazepine has been recommended in the
(a2d-subtype) of the presynaptic calcium channel (probably European Federation of Neurological Societies (EFNS) guidelines as
N-type) with subsequent reduced release of presynaptic transmit- first-line agents for the treatment of TGN.21 Baclofen or lamotrigine
ters.17 It has shown initial promise in the treatment of the pain of have been proposed as add-on or alternative agents for use in
TGN, with effectiveness in greater than 80% of patients when used patients unable to tolerate and/or refractory to carbamazepine or
as a first-line agent, and in over 50% of patients who failed medical
treatment with carbamazepine.18
Lamotrigine (Lamictal) indirectly causes decreased release of the Box 35^1 CURRENT DIAGNOSIS
excitatory neurotransmitter glutamate by blocking voltage-gated
sodium channels. It has been shown to be effective when added A clinical diagnosis of trigeminal neuralgia can be made if the criteria are
to the medical therapy of patients receiving and refractory to car- met: paroxysmal attacks of facial pain that last a few seconds to less
than 2 minutes. The pain must have at least four of the following
bamazapine or oxcarbazepine.19 Initial results as a monotherapy
characteristics:
have shown approximately 70% excellent response rate. The inci- Distribution along one or more divisions of the trigeminal nerve.
dence of side effects associated with lamotrigine is high. Sudden, intense, sharp, superficial, stabbing, or burning in quality.
Baclofen (Lioresal) is a GABAB-agonist; which is available as Severe intensity.
a racemate in the United States, depresses excitatory neural activ- Precipitation from trigger areas or by certain daily activities such
ity in the trigeminal nucleus. It has shown some success as as eating, talking, washing the face, or cleaning the teeth.
monotherapy, but is generally used in combination with carba- The patient is entirely asymptomatic between paroxysms.
mazepine or oxcarbazepine in the treatment of patients with TGN No neurologic deficit.
pain. L-Baclofen (not available in the United States) may be more Attacks are stereotyped in the individual patient.
Exclusion of other causes of facial pain by history, physical examination
effective than five times as much racemic baclofen and better
findings, and special investigation when necessary.
tolerated.20
Table 35^1. Current Therapy
Drug Initial Dose Maintenance Dose Adverse Effects

Carbamazepine 200 mg/day 400–1200 mg/day Sedation, dizziness, ataxia, cognitive impairment,
headache, gastrointestinal symptoms, leucopenia, rash
(including Stevens-Johnson syndrome, toxic epidermal
necrolysis)
Oxcarbazepine 300 mg/day 600–1800 mg/day Sedation, dizziness, cognitive impairment, rash
Phenytoin 300 mg/day 300–400 mg/day Sedation, ataxia, diplopia, slurred speech, rash (including
Stevens-Johnson syndrome, toxic epidermal necrolysis)
Gabapentin 300 mg/day 900–3600 mg/day Dizziness, somnolence, pheripheral edema, dry mouth,
Creatinine clearance 15–30 ml/min 300 mg/day myalgias, ataxia tremor, nystagmus, fatigue, alterations
Creatinine clearance < 15 ml/min 300 mg every other day in behavior and/or mood, rash, and rarely, Stevens-
Johnson syndrome
Lamotrigine 25–50 mg/day 200–400 mg/day Severe rash (including Stevens-Johnson syndrome, toxic
epidermal necrolysis), sedation, dizziness, ataxia
Baclofen 10 mg/day 30–80 mg/day Sedation, ataxia, fatigue, gastrointestinal symptoms,
muscle weakness
oxcarbazepine (especially if these patients cannot undergo or refuse Surgery

surgery).21
Kanai and colleagues22 found that intranasal lidocaine 8% admi- Microvascular decompression (MVD) involves the removal of aber-
nistered by a metered-dose spray produced prompt but transient rant vasculature away from the trigeminal nerve. It uses a retro-
analgesia without serious side effects in patients with second-divi- mastoid craniectomy, which exposes the trigeminal nerve from its
sion TGN. entry point at the pons to its exit at Meckle’s cave (Fig. 35–3).
Preclinical research suggests that synthetic cannabinoids atten- A large study of over a thousand patients, following 20 years of
uate allodynia and hyperalgesia in rat model of trigeminal neuro- MVD surgery, found immediate postoperative complete relief of
pathic pain produced by chronic constrictive injury of the pain after initial MVD in about 82% of patients, partial pain
infraorbital branch of the trigeminal nerve.23 relief in 16%, with only 2% demonstrating no pain relief.24
Approximately 30% of the patients had recurrences of TGN pain
during the study period. A total of 132 patients (roughly 11%) had
INTERVENTIONALTHERAPIES second operations for recurrent or refractory TGN pain. At 10 years
out, in patients who had either one or two operations (MVD),
Interventional techniques for the treatment of TGN are usually approximately 70% of patients had excellent results and 4% had
considered only after trials of medications have failed or have lost partial relief.24 Risk factors for the recurrence of symptoms include
their efficacy, because of the high response rate to medical manage- female gender, preoperative symptoms lasting longer than 8 years,
ment. Surgical decompression of vascular malformations appears to and venous compression of the trigeminal root entry zone.
provide the greatest long-term pain relief, but this requires a cra- Morbidity and mortality associated with the operation are low
niectomy. Other less invasive interventions exist that have been and have become even lower after the introduction of routine use
found to be reasonably safe and efficacious. of brainstem evoked potentials in the 1980s.
trigeminal nerve
aberrant loop of superior

cerebellar artery
Figure 35^3. Microvascular decompression of an aberrant artery contacting the trigeminal nerve at the nerve root entry.
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851–856. 32. Maesawa S, Salame C, Flickinger JC, et al. Clinical outcomes after
28. Saini SS. Retrogasserian anhydrous glycerol injection therapy in stereotactic radiosurgery for idiopathic trigeminal neuralgia. J
trigeminal neuralgia: Observations in 552 patients. J Neurol Neurosurg 2001;94:14–20.
Neurosurg Psychiatry 1987;50:1536–1538. 33. Pollock BE, Phuong LK, Gorman DA, et al. Stereotactic
29. Constantoyannis C, Kagadis G, Chroni E. Percutaneous balloon radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg 2002;
compression for trigeminal neuralgias and autonomic cephalalgia. 97:347–353.
Headache 2008;48:130–134. 34. Taub E, Munz M, Tasker RR. Chronic electrical stimulation of the
30. Skirving DJ, Dan NG. A 20-year review of percutaneous balloon gasserian ganglion for the relief of pain in a series of 34 patients.
compression of the trigeminal ganglion. J Neurosurg 2001;94:330–332. J Neurosurg 1997;86:197–202.
Chapter 36 disproportionately represented.1 Both the severity and the dura-

tion of PHN increase with age. A study examining the probability
POSTHERPETIC NEURALGIA of developing PHN after a single episode of HZ reveals that
whereas 2% of those younger than 60 years have pain 3 months
Paul J. Christo and Brian D. Cauley after acute HZ infection, the odds ratio of continued pain at 12
months increases by 2.33 per 10 years of additional age.
Approximately 50% of patients over the age of 70 with PHN
have pain lasting over 1 year after resolution of the acute HZ
rash. There does not appear to be a gender predilection.
PATHOPHYSIOLOGY
INTRODUCTION
PHN is caused by the varicella-zoster virus (VZV), a double-
Postherpetic neuralgia (PHN) is one of the most common types of stranded DNA virus within the herpes family. Viral infection with
neuropathic pain encountered by practitioners of pain medicine. VZV causes two illnesses: the initial infection, known as chickenpox,
This syndrome is characterized by prolonged pain after an episode and a reactivation illness known as herpes zoster, or shingles.
of herpes zoster (HZ), classically known as shingles. After the acute During the initial infection with VZV, the virus gains access to
rash of HZ has resolved, pain can often persist at the site of the and establishes latency within the dorsal root ganglion, the mechan-
healed rash. This pain, termed postherpetic neuralgia, is one the isms of which remain unclear. Owing to cell-mediated immunity
most debilitating features of HZ infection and can persist for acquired during the initial infection with VZV, the virus remains in
months to years after the initial HZ infection. It is well recognized a latent form. Reactivation is associated with declines in cell-
that the incidence of PHN after acute HZ increases with age, occur- mediated immunity that may result from natural aging, acquired
ring in as many as 50% of the population older than 60 years. With immunodeficiency syndrome (AIDS), organ transplantation, or
the population of individuals 65 and older in industrialized coun- various other causes of immunocompromised states. During reac-
tries increasing rapidly, PHN can be expected to increase in both tivation, the manifestations of HZ occur when the virus replicates in
incidence and prevalence. The associated public health costs, as well ganglionic nerve cells and migrates along peripheral afferent sensory
as demands placed upon pain practitioners for effective therapies, pathways, causing inflammation and partial denervation of the skin
can be expected to be considerable. in a dermatomal distribution. Inflammatory changes occur in both
the peripheral nerves and the dorsal root ganglia, often lasting
months and resulting in demyelination, axonal loss, necrosis, and
TAXONOMY fibrosis of affected areas. Postmortem studies in patients with PHN
pain have found dorsal horn atrophy, demyelination with fibrosis,
Given that PHN occurs after an outbreak of HZ, there has been and cell loss.2 Current evidence suggests that the combination of
considerable argument over the precise temporal relationship demyelinated afferent sensory neurons and dorsal horn neuronal
between PHN and the preceding acute HZ activation. Definitions plasticity may result in loss of inhibition and increased activity
of PHN vary in terms of both onset and duration of pain, ranging within small fiber afferents, possibly leading to the pain of PHN.3,4
from any pain immediately after the resolution of the HZ rash to
pain lasting for 6 months or longer after the rash has healed.
Currently, a frequently used clinical case definition is persistent of CLINICAL FEATURES
pain for more than 3 months after resolution of the rash.
Clinical features of PHN derive from the associated rash and pain of
acute HZ (Fig. 36–1 and Box 36–1). HZ initially presents with
EPIDEMIOLOGY activation, infection, and spread within the affected sensory gan-
glion and peripheral afferent nerve. During this period, concurrent
Variable case definitions for PHN have complicated the calcula- inflammation, demyelination, and necrosis may present as a pro-
tion of PHN incidence and prevalence in the population. It drome of pain or discomfort in the corresponding dermatome. This
is estimated that more than 1 million people in the United pain can often confuse patients and physicians, masquerading as
States currently suffer from PHN, with the elderly population myocardial infarction, a herniated vertebral disck, or a variety of
27. North RB, Kidd DH, Piantadosi S, Carson BS. Percutaneous 31. Kondziolka D, Lunsford LD, Flickinger JC, et al. Stereotactic
retrogasserian glycerol rhizotomy: Predictors of success and radiosurgery for trigeminal neuralgia: A multiinstitutional study using
failure in treatment of trigeminal neuralgia. J Neurosurg 1990;72: the gamma unit. J Neurosurg 1996;84:940-994.
851–856. 32. Maesawa S, Salame C, Flickinger JC, et al. Clinical outcomes after
28. Saini SS. Retrogasserian anhydrous glycerol injection therapy in stereotactic radiosurgery for idiopathic trigeminal neuralgia. J
trigeminal neuralgia: Observations in 552 patients. J Neurol Neurosurg 2001;94:14–20.
Neurosurg Psychiatry 1987;50:1536–1538. 33. Pollock BE, Phuong LK, Gorman DA, et al. Stereotactic
29. Constantoyannis C, Kagadis G, Chroni E. Percutaneous balloon radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg 2002;
compression for trigeminal neuralgias and autonomic cephalalgia. 97:347–353.
Headache 2008;48:130–134. 34. Taub E, Munz M, Tasker RR. Chronic electrical stimulation of the
30. Skirving DJ, Dan NG. A 20-year review of percutaneous balloon gasserian ganglion for the relief of pain in a series of 34 patients.
compression of the trigeminal ganglion. J Neurosurg 2001;94:330–332. J Neurosurg 1997;86:197–202.
Chapter 36 disproportionately represented.1 Both the severity and the dura-

tion of PHN increase with age. A study examining the probability
POSTHERPETIC NEURALGIA of developing PHN after a single episode of HZ reveals that
whereas 2% of those younger than 60 years have pain 3 months
Paul J. Christo and Brian D. Cauley after acute HZ infection, the odds ratio of continued pain at 12
months increases by 2.33 per 10 years of additional age.
Approximately 50% of patients over the age of 70 with PHN
have pain lasting over 1 year after resolution of the acute HZ
rash. There does not appear to be a gender predilection.
PATHOPHYSIOLOGY
INTRODUCTION
PHN is caused by the varicella-zoster virus (VZV), a double-
Postherpetic neuralgia (PHN) is one of the most common types of stranded DNA virus within the herpes family. Viral infection with
neuropathic pain encountered by practitioners of pain medicine. VZV causes two illnesses: the initial infection, known as chickenpox,
This syndrome is characterized by prolonged pain after an episode and a reactivation illness known as herpes zoster, or shingles.
of herpes zoster (HZ), classically known as shingles. After the acute During the initial infection with VZV, the virus gains access to
rash of HZ has resolved, pain can often persist at the site of the and establishes latency within the dorsal root ganglion, the mechan-
healed rash. This pain, termed postherpetic neuralgia, is one the isms of which remain unclear. Owing to cell-mediated immunity
most debilitating features of HZ infection and can persist for acquired during the initial infection with VZV, the virus remains in
months to years after the initial HZ infection. It is well recognized a latent form. Reactivation is associated with declines in cell-
that the incidence of PHN after acute HZ increases with age, occur- mediated immunity that may result from natural aging, acquired
ring in as many as 50% of the population older than 60 years. With immunodeficiency syndrome (AIDS), organ transplantation, or
the population of individuals 65 and older in industrialized coun- various other causes of immunocompromised states. During reac-
tries increasing rapidly, PHN can be expected to increase in both tivation, the manifestations of HZ occur when the virus replicates in
incidence and prevalence. The associated public health costs, as well ganglionic nerve cells and migrates along peripheral afferent sensory
as demands placed upon pain practitioners for effective therapies, pathways, causing inflammation and partial denervation of the skin
can be expected to be considerable. in a dermatomal distribution. Inflammatory changes occur in both
the peripheral nerves and the dorsal root ganglia, often lasting
months and resulting in demyelination, axonal loss, necrosis, and
TAXONOMY fibrosis of affected areas. Postmortem studies in patients with PHN
pain have found dorsal horn atrophy, demyelination with fibrosis,
Given that PHN occurs after an outbreak of HZ, there has been and cell loss.2 Current evidence suggests that the combination of
considerable argument over the precise temporal relationship demyelinated afferent sensory neurons and dorsal horn neuronal
between PHN and the preceding acute HZ activation. Definitions plasticity may result in loss of inhibition and increased activity
of PHN vary in terms of both onset and duration of pain, ranging within small fiber afferents, possibly leading to the pain of PHN.3,4
from any pain immediately after the resolution of the HZ rash to
pain lasting for 6 months or longer after the rash has healed.
Currently, a frequently used clinical case definition is persistent of CLINICAL FEATURES
pain for more than 3 months after resolution of the rash.
Clinical features of PHN derive from the associated rash and pain of
acute HZ (Fig. 36–1 and Box 36–1). HZ initially presents with
EPIDEMIOLOGY activation, infection, and spread within the affected sensory gan-
glion and peripheral afferent nerve. During this period, concurrent
Variable case definitions for PHN have complicated the calcula- inflammation, demyelination, and necrosis may present as a pro-
tion of PHN incidence and prevalence in the population. It drome of pain or discomfort in the corresponding dermatome. This
is estimated that more than 1 million people in the United pain can often confuse patients and physicians, masquerading as
States currently suffer from PHN, with the elderly population myocardial infarction, a herniated vertebral disck, or a variety of
262 Chapter 36 POSTHERPETIC NEUR ALGIA
Figure 36^2. Typical hypopigmented scar of postherpetic neuralgia

in the V1 distribution.This patient demonstrated mechanical allodynia
and hyperalgesia to pinprick in the affected region extending from her
left eyebrow to her scalp.
EVALUATION
Diagnosis of HZ and PHN relies upon a sound history and physical
Figure 36^1. A patient displays the thoracic dermatomal rash of examination, often combined with laboratory diagnostic testing.
herpes zoster (shingles). In a patient with a recent history of dermatomal HZ rash, persistent
pain after rash resolution can establish the diagnosis of PHN
relatively easily. Examination of the skin may reveal a loss of sen-
gastrointestinal and gynecologic disorders. An important clue to sation to touch, temperature, and pinprick in the affected derma-
HZ infection during this period is cutaneous hypersensitivity in tome, often with extension of sensitivity and pain to areas
the affected dermatome. surrounding the rash site. HZ may present without rash, however,
Once the virus infects the skin, the characteristic rash appears in and particularly in the elderly (‘‘zoster sine herpete’’). Those
a classic, red maculopapular eruption that progresses to vesicles in a patients whose HZ infection is characterized by cranial neuritis
unilateral dermatomal distribution and, most frequently, involves or meningoencephalitis may also present diagnostic challenges for
the T1–L2 and V1 dermatomes. The rash is associated with a painful the physician evaluating a patient with suspected PHN.
acute neuritis, described as ‘‘burning,’’ ‘‘aching,’’ ‘‘tingling,’’ In patients who do present with the characteristic zoster rash,
‘‘itching,’’ or ‘‘stabbing’’ pain, with severity ranging from mild to the differential diagnosis is primarily between HZ and zosteriform
severe. The vesicles crust over in 7 to 10 days and the rash heals, herpes simplex. HZ patients are typically older, whereas herpes
sometimes with residual scarring or pigmentation of the affected simplex patients often experience recurrent episodes and usually
area (Fig. 36–2). do not experience chronic pain.
Continued pain after resolution of the HZ rash classically char- Although a clinical diagnosis is often sufficient in those patients
acterizes PHN, but pain can also occur after an asymptomatic presenting with the classic HZ rash, for cases involving atypical
period following the acute HZ infection. Patients with PHN can presentations and possible herpes simplex infection, laboratory test-
exhibit a variety of pain and sensory patterns, including constant ing can be useful. Both immunofluorescence VZV antigen detection
pain (burning or throbbing), intermittent pain (shooting or stab- and VZV detection by viral polymerase chain reaction (PCR) are
bing), and allodynia (pain due to a nonpainful stimulus). Areas of excellent tests with high specificity and sensitivity (90%–100%).
hypesthesia and hyperesthesia can also be present in the affected Serologic testing of acute and convalescent VZV immunoglobulin
area, sometimes in combination. The development of psychosocial G (IgG) titers can also be used in establishing a diagnosis of HZ.
symptoms related to the ongoing pain may include depression,
sleep disorders, chronic fatigue, and anxiety.
MANAGEMENT
Formation of evidence-based guidelines for management of PHN
has been complicated by poor study design, including lack of
Box 36^1 CURRENT DIAGNOSIS long-term follow-up of study participants, heterogeneous popula-
tions, varying PHN case definition among studies, and small sam-
Postherpetic neuralgia (PHN) is a typical form of neuropathic pain, ple sizes. In addition, the natural history of PHN is characterized
with increased incidence among the older adult population.
PHN refers to prolonged pain associated with herpes zoster and
by spontaneous resolution over time; pain reduction may, there-
reflects a reactivation of the original infection with varicella-zoster fore, mistakenly be attributed to treatment. However, growing
virus (chickenpox). collections of rigorous, prospective, randomized, controlled trials
Diagnosis of PHN is based primarily on clinical features. show a variety of therapeutic modalities effective in the treatment of
PHN case definitions vary but are often defined as pain persisting for PHN1,5-10 (Box 36–2).
greater than 3 mo after resolution of a herpes zoster rash. The management of PHN relies primarily upon pharmacother-
Patients with PHN can exhibit a variety of pain and sensory patterns, apy for alleviation of pain symptoms. Even with appropriate man-
including constant pain (burning or throbbing), intermittent pain agement, individual responses to PHN treatments are difficult to
(shooting or stabbing), and allodynia (pain caused by a nonpainful sti- predict. With current therapies, up to 40% to 50% of patients
mulus). Areas of hypesthesia and hyperesthesia can also be present in
the affected area, sometimes in combination.
with PHN lack satisfactory relief from pain. However, there are
several classes of effective medications with favorable side effect
pain relief, dosage can be increased in 10-mg increments until

Box 36^2 CURRENT THERAPIES either adequate pain relief, intolerable side effects, or a maximum
dose of 150 mg by mouth occurs. A more aggressive dosing sched-
Current management of postherpetic neuralgia (PHN) relies primarily ule can be employed in healthy and younger patients (<65 yr) and
on pharmacologic management of clinical symptoms.
Classes of medication effective for PHN include tricyclic antidepres- includes beginning at 25 mg by mouth at night, then increasing
sants, opioids (both long- and short-acting), anticonvulsants (gaba- in 25-mg increments every week until a target dose of 150 mg at
pentin, pregabalin), tramadol, and formulations of topical lidocaine night is reached. Once therapy with TCAs is initiated, at least 4 to
and capsaicin. 8 weeks of treatment is recommended, ideally extended to 3 to
More invasive therapies, such as intrathecal steroids and spinal cord 6 months for adequate pain relief.
stimulation, have been shown in limited studies to be effective in
some patients.
In general, the practitioner treating PHN should begin with pharmaco-
logic management of PHN, progressing to more invasive therapies Anticonvulsants (Gabapentin and Pregabalin)
only if pain symptoms remain refractory to more conservative
management. Gabapentin and pregabalin both act centrally at the a2d-subunit of
Even with appropriate management, individual responses to PHN cortical membrane voltage-gated calcium channels and serve to
treatments are difficult to predict. Even with current therapies, up to reduce neurotransmitter release. Although exact mechanisms of
40%^50% of patients with PHN lack satisfactory relief from pain. action are unknown, recent trials have shown that both are effective
for reducing pain associated with PHN.1,6
Gabapentin, originally developed as adjunctive therapy for
refractory epilepsy, has been rigorously evaluated in two recent
profiles that should be considered as first-line agents for the treat- large, multicenter, placebo-controlled, randomized trials. In both
ment of PHN (Table 36–1). These include tricyclic antidepressants studies, patients on gabapentin, most with dosages from 2400 mg
(TCAs), gabapentin (Neurontin), tramadol (Ultram), pregabalin to 3600 mg daily, were found to have a statistically significant
(Lyrica), opioids, capsaicin (Zostrix), and topical lidocaine (lido- reduction in Likert pain score compared with placebo. In one
derm patch). Various other drug classes and more invasive thera- trial, the average decrease in Likert pain scale score was 2.1 on
pies have been used for treatment of PHN, but these lack strong gabapentin versus 0.5 on placebo. Of those patients on gabapentin,
evidence for first-line treatment. In general, alternative medications the NNT (number of patients needed to treat for one patient to
or invasive therapies are reserved for those patients lacking response show improvement) was 2.2 for any pain improvement and 2.8 for
to first-line agents. moderate pain improvement. In a second double-blind, rando-
mized, controlled trial, a 50% or greater decrease in pain as mea-
sured by Likert pain scale occurred in 33% of those on gabapentin
TCAs versus 14% on placebo.
Adverse effects of gabapentin include dizziness, somnolence, and
A significant body of evidence supports the use of TCAs for ataxia. It may lead to cognitive impairment as well as gait or balance
the treatment of PHN as well as other forms of neuropathic pain. problems in the elderly. Because gabapentin is excreted renally,
This class of medications operates by inhibiting the reuptake of dosage adjustment is required in patients with renal insufficiency.
norepinephrine and serotonin at presynaptic nerve terminals and In large trials, intolerable adverse effects leading to study withdrawal
by enhancing function of the descending antinociceptive pain path- ranged from 4% to 5% with gabapentin compared with 1.7% with
ways. The TCAs also possess both anxiolytic and sedative properties placebo.
that are often useful in the treatment of sleeplessness and anxiety, Generally, gabapentin has an excellent safety profile and is well
comorbidities frequently found among sufferers of PHN. tolerated, with side effects frequently resolving within 2 weeks of
In the clinical management of PHN, both tertiary amines (ami- initiating treatment. Similar to the TCAs, therapy should be
triptyline, doxepin) and secondary amines (nortriptyline, desipra- initiated at low dosages and with slow titration to prevent adverse
mine) are incorporated. Amitriptyline (Elavil) and nortriptyline effects. A typical dosing regimen would begin with 100 mg three
(Pamelor) are the most frequently used. Both medications are times daily, with 100- to 300-mg dosage increases approximately
associated with significant decreases in visual analog pain scores every 5 to 7 days. Target dosages that have been found beneficial are
of about 50% among randomized, controlled trials of PHN. 900 to 1200 mg daily, with titration as tolerated up to 3600 mg daily
Whereas the magnitude of benefit appears similar for both amitrip- in three divided doses. An appropriate gabapentin trial includes a
tyline and nortriptyline, nortriptyline may be preferred owing to its 3- to 8-week titration period to allow for development of tolerance
more favorable side effect profile. to adverse effects with 1 to 2 additional weeks at the maximum
Adverse effects of TCAs include nausea, blurred vision, weight tolerated dose. The U.S. Food and Drug Administration (FDA)
gain, confusion, and dizziness. Tertiary amine TCAs appear to have has approved gabapentin for use in treating PHN.
a more severe side effect profile than secondary amines. Both ter- Pregabalin, an a2g-ligand at cortical voltage-gated calcium
tiary and secondary amines possess anticholinergic properties and channels has been shown to be effective in reducing pain associated
should be used cautiously in the elderly. Patients often complain of with PHN. Recently approved for treatment of PHN and diabetic
fatigue and dry mouth, with constipation, gait imbalance, falls, uri- neuropathy by the FDA, preabalin has a mechanism of action and
nary retention, and palpitation are also reported. TCAs are also side effect profile (dizziness, somnolence, ataxia) similar to those of
associated with dysrhythmias; therefore, patients with preexisting gabapentin. In a multicenter trial, pregabalin at dosages of 600 mg
conduction abnormalities should receive an electrocardiogram daily was associated with half of subjects having a 50% or greater
before initiating therapy. Relative contraindications to the use of reduction in pain compared with 20% on placebo, with a NNT of
TCAs include recent myocardial infarction, epilepsy, narrow-angle 3.3. Of note, a greater percentage of patients in this trial discon-
glaucoma, heart block, urinary retention, and concomitant use of tinued therapy owing to adverse events (32%) than patients in trials
monoamine-oxidase inhibitors. of gabapentin. Consequently, clinicians should be cautious with
Adverse effects of TCAs are often dose related and can be miti- initial dosage and titration schedules when beginning pregabalin
gated by beginning with low doses and titrating slowly. A conser- treatment.
vative dosing regimen would begin with 10 mg by mouth at night, Dosing of pregabalin should begin at 75 mg twice daily. If the
gradually increasing by 10 mg per week to an initial target dose of patient tolerates the initial dosage, titration to 150 mg twice
50 mg at night. If the patient is still experiencing inadequate daily within 1 week is appropriate. If pain relief is not achieved at
Table 36^1. Useful Medications for Postherpetic Neuralgia
Medication Initial Dosage Titration Schedule Adverse Effects

Amitriptyline, 10 mg every evening (older Increase by 10 mg or 25 mg every 7 Sedation, xerostomia, confusion,
nortriptyline adults) or 25 mg every days to 100 mg, then to maximum dysrhythmias, weight gain, dizziness
evening of 150 mg nightly if needed
Antiepileptics
Gabapentin 100 mg 3 times daily 100–300 mg increased every 5 days to Somnolence, dizziness, fatigue, ataxia
total dose of 1800–3600 mg daily
Pregabalin 75 mg twice daily Increase to 150 mg twice daily within Somnolence, dizziness
1 wk
Opioids
Oxycodone sustained 10 mg every 12 hr Titrate as needed for pain, balancing Nausea, constipation, sedation,
release analgesia and adverse effects cognitive dysfunction, hormonal
changes
Transdermal fentanyl 12 mcg/hr (older adults) or Titrate as needed for pain, balancing Nausea, constipation, sedation,
25 mcg/hr, changed every analgesia and adverse effects cognitive dysfunction, skin
3 days irritation, hormonal changes
Morphine (sustained- 15 mg every 12 hr Titrate as needed for pain, balancing Nausea, constipation, sedation,
release) analgesia and adverse effects cognitive dysfunction, hormonal
changes
Methadone 2.5 mg (older adults) or Titrate as needed for pain, balancing Nausea, constipation, sedation,
5 mg three times daily analgesia and adverse effects cognitive dysfunction, hormonal
changes
Extended-release 5 mg every 12 hr Titrate as needed for pain, balancing Nausea, constipation, sedation,
oxymorphone analgesia and adverse effects cognitive dysfunction, hormonal
changes
Transdermal 35 mcg/hr, changed every Titrate as needed for pain, balancing Nausea, constipation, sedation,
buprenorphine 3 days analgesia and adverse effects cognitive dysfunction, skin
(currently unavailable irritation, hormonal changes
in the United States)
Other Classes of Medications
Tramadol (immediate- 50 mg daily Increase by 50 mg every 3–4 days to Nausea, emesis, dizziness, vertigo,
release) total dose of 100–400 mg daily, in somnolence, headache, constipation
divided doses
Transdermal 5% One to three patches worn None Local skin irritation
lidocaine for 12-hr intervals
5% Lidocaine gel Apply to affected area None Local skin irritation
EMLA Apply to affected area None Local skin irritation
Capsaicin 0.025%–0.075% cream or None Localized burning sensation
lotion applied to affected area
this dose, practitioners may titrate to 300 mg twice daily, assuming investigating combination therapy with opioids and gabapentin
a favorable side effect profile. Several well-designed studies have also proved effective.11
document pain relief within 1 week of initiation of pregabalin. In a recent placebo-controlled, double blind, two-way cross-over
Clinically, a 2-week trial period is suggested to assess for favorable study using sustained- release oxycodone (Oxycontin) for treatment
response. of PHN, a 50% decrease in the visual analog score was reported for
22 of the 38 patients who completed the study. The rate of discon-
tinuation owing to treatment failure was similar in both arms
Opioids (24%), with only 1 patient stopping treatment with controlled-
release oxycodone owing to adverse effects.
Opioids have been used widely in the treatment of both acute and In the study described previously, opioid therapy was also com-
chronic pain, and recent studies support their use for the treatment pared with TCAs and placebo. For instance, using controlled-release
of PHN. Generally, studies using opioids with follow-up intervals of morphine sulfate (MS Contin) titrated to a maximum dosage of 240
intermediate length have found benefit in PHN and a direct rela- mg daily, opioid analgesics provided statistically significant
tionship between dosage and pain reduction. Complications include improvement in both pain and sleep disturbances. In fact, both
a greater degree of adverse effects with higher dosages. In addition opioids and TCAs produced greater pain relief (38% and 32%,
to trials examining opioid therapy alone for PHN, new studies respectively) than placebo (11%). Despite greater adverse effects
and more dropouts associated with opioid therapy, comparison of or propoxyphene combined with acetaminophen, aspirin, or ibu-
controlled-release morphine and nortriptyline showed greater profen (Tylox/Percocet/Roxicet/Percodan/Cobunox; Lorcet/Lortab/
reductions in PHN pain with morphine.12 Moreover, subjects Vicoprofen; Darvocet/Darvon, respectively).
who completed all treatment arms preferred opioids to TCAs and Patients should be monitored for 1 to 2 weeks after initiating
placebo. therapy with short-acting opioids to determine total daily dosages
Buprenorphine (Buprenex) is a partial m opioid receptor agonist, required for adequate pain control and to monitor for adverse side
k antagonist, and d antagonist, and initial studies suggest that it effects. Further, clinicians must calculate the total daily dose of
may hold value for the treatment of PHN.13 Recent case studies in acetaminophen contained in combination with short-acting
patients with neuropathic pain reported pain relief with minimal opioids. Doses should not exceed 4 g/day in order to avoid hepatic
side effects in patients treated with transdermal buprenorphine in damage.
doses of either 35 mcg/hr or 79 mcg/hr. An open-label, long-term After 1 to 2 weeks, total daily dosages of short-acting opioids can
follow-up study (>5.7 yr) in 239 cancer and noncancer patients be converted to long-acting formulations such as sustained-release
who had participated in a previous double-blind, placebo- morphine, sustained-release oxycodone, methadone hydrochloride,
controlled transdermal buprenorphine study found that 47.3% transdermal buprenorphine (not available in the United States),
experienced satisfactory pain relief, 38.9% reported good pain extended-release oxymorphone (Opana ER), or transdermal fenta-
relief, and 3.8% described complete pain relief from buprenorphine nyl (Duragesic). Depending on the clinical situation, access to
treatment (35 mcg/hr changed every 3 days). Treatment was well short-acting opioids for breakthrough pain may be indicated.
tolerated by patients, and minimal side effects were reported. Future After conversion to long-acting opioids, an additional 1- to
randomized, controlled studies with buprenorphine in patients with 2-week period of dosage adjustment may be required for optimiza-
PHN are needed to further determine its therapeutic role in PHN tion. An adequate trial of opioid analgesics may require 4 to 6 weeks
management. of therapy at a stable dosage. With appropriate titration and careful
Combination therapy of opioids with gabapentin has been monitoring for adverse effects and functional improvement,
investigated in a single randomized, double-blind, active- dosages can be escalated. The benefit of morphine sulfate equian-
placebo-controlled cross-over study comparing combination treat- algesic dosages exceeding 180 mg daily in the treatment of neuro-
ment with sustained-release morphine/gabapentin and each medi- pathic pain have not been investigated with rigorous studies.
cation used independently. Patients with PHN and painful diabetic
neuropathy were studied. Combination treatment resulted in
greater pain relief in both PHN and painful diabetic neuropathy Tramadol
relative to either agent alone or placebo. Benefits of combination
therapy extended beyond simple pain reduction to include Tramadol (Ultram), a centrally acting, weak m-opioid receptor ag-
improvements in daily activities, mood, and health-associated qual- onist and reuptake inhibitor of serotonin and norepinephrine, has
ity of life. Combination therapy was associated with higher inci- been shown effective in reducing PHN in a multicenter randomized,
dence of adverse-effects, however. Researchers reported a greater controlled clinical trial. In this trial, a greater than 50% reduction in
frequency of constipation, sedation, and dry mouth in the combi- pain was achieved in 78% of those patients on immediate-release
nation group compared with groups receiving either gabapentin or tramadol compared with 56% on placebo. Additional studies have
morphine alone. Importantly, this study is unique in examining suggested that tramadol is effective in reducing PHN pain, partic-
combination therapies for the treatment of PHN. Combination ularly in patients experiencing intolerable adverse effects with more
therapy is relatively understudied and merits further investigation potent opioid agonists.
as a treatment modality for PHN. Adverse side effects associated with tramadol include dizziness,
Common side effects of opioid analgesics include constipation, constipation, headache, nausea, somnolence, and orthostatic hypo-
sedation, nausea, and sometimes, hypogonadism. In older adults, tension. These effects are more frequently seen with rapid titration
cognitive impairment and difficulty with ambulation may occur. schedules and concomitant use of other medications with similar
Tolerance frequently develops to these adverse effects, although side effect profiles. Tramadol has been shown to increase seizure
constipation often persists throughout the course of treatment risk in patients with a history of seizures or in those patients on
and demands laxative therapy. Caution is suggested in those other medications that lower the seizure threshold. Owing to tra-
patients with a history of substance abuse or suicidal ideation madol’s inhibition of serotonin reuptake, serotonin syndrome (i.e.,
because opioid overdose can result in accidental or intentional cognitive changes, neurologic changes, and autonomic instability)
death and previous history of a substance use disorder elevates may occur if tramadol is used with other serotonergic medications,
the risk of addiction with psychoactive substances. Tolerance to specifically selective serotonin reuptake inhibitors (SSRIs) and
opioids is also frequently seen as a reduction in analgesia over monoamine oxidase inhibitors (MAOIs). Dosage adjustment is
time or even as hyperalgesia (opioid-induced pain sensitivity that required in patients with renal and/or hepatic disease.
leads to a worsening pain state). Despite the development of phar- Suggested starting dosage is 50 mg daily, titrating by 50-mg
macologic tolerance, stable dosages can often be achieved in increments every 3 to 4 days. The maximum dosage of tramadol
patients responsive to opioid therapy. Finally, patients on opioid is 100 mg four times daily, with reduced dosages of 300 mg daily in
analgesics develop physical dependence and should be advised not divided doses in elderly patients. A 4-week trial period is recom-
to abruptly discontinue medication or decrease dosage. Dose mended when starting tramadol treatment.
adjustments should be determined by a treating clinician in concert
with the patient.
There is considerable disagreement over recommended dosing Topical Lidocaine
regimens for opioids in the treatment of PHN. As with other classes
of medications, initiating low-dose therapy with slow titration to Lidocaine in the form of a gel, an eutectic mixture of local anes-
analgesic effects is desirable. This strategy minimizes the potential thetics (EMLA = lidocaine 2.5% and prilocaine 2.5%), and lidocaine-
for adverse medication effects and maximizes the potential for impregnated patches appear effective in the treatment of PHN.
meaningful pain relief and improved function. A recommended The lidocaine patch (Lidoderm), consisting of a 10 x 14-cm
course may begin with short-acting opioids at dosage levels that nonwoven, polyethylene backing and medication-containing
are equianalgesic to 5 to 15 mg of orally administered morphine adhesive of 5% lidocaine (700 mg/patch), has been approved
sulfate every 4 hours as needed. Examples of immediate-release by the FDA for treatment of PHN. Compared with systemic
opioid formulations include oxycodone, hydrocodone bitartrate, analgesics, topical therapies offer the ability to reduce the pain
of PHN with little to no systemic side effects. The lidocaine patch Interventional Therapies
can be cut to the desired dimensions based upon cutaneous pain
patterns and produces an analgesic effect without associated local Neuraxial Steroids
anesthesia. Drug absorption is directly related to the area of con-
tact between the skin and the patch as well as the duration of In general, invasive therapies for PHN are reserved for those
patch application. Assuming normal hepatic function, blood patients with pain refractory to more conservative, pharmacother-
levels of lidocaine are minimal when following a 12-hours on/ apy-based treatment strategies. At present, interventional therapies
12-hours off lidocaine patch application schedule. are supported by limited data for efficacy in the treatment of PHN.
Three randomized, controlled trials have shown the 5% lido- Intrathecal steroid administration for PHN has been evaluated
caine patch to effective for reducing pain and allodynia associated in a randomized, double-blind, controlled trial.17 In this study,
with PHN.14,15 In one study, a statistically significant decrease in patients with refractory PHN failing conventional therapy were
visual analog score was seen in patients receiving 5% lidocaine randomized to (1) no lumbar puncture; (2) 3 ml of 3% intrathecal
patch application, with the benefit persisting for longer than lidocaine; or (3) 60 mg of preservative-free methylprednisolone in
4 hours after removal. This suggests that the pain benefit 3 ml of 3% lidocaine. Results indicated that 90% of patient receiv-
associated with the lidocaine patch extends beyond the initial anal- ing intrathecal methylprednisolone reported good to excellent
gesia associated with patch application. Additional benefit appears pain relief coupled with a reduction in their usage of nonsteroidal
to derive from the protective effect of the patch on allodynic skin, anti-inflammatory medications. Analgesia in these patients per-
which prevents mechanical irritation and exacerbation of pain sisted through 2 years of follow-up with no observed complications
symptoms. Accordingly, the lidocaine patch appears most effective related to treatment.
in PHN patients who display allodynia without cutaneous sensory Epidural steroid use in PHN patients has also been studied in a
loss. Complete pain relief using only the lidocaine patch is rare, but randomized, controlled, single-blinded study comparing intrathecal
partial relief has been seen in up to 91% of patients in one rando- methylprednisolone injection with epidural methylprednisolone
mized, controlled trial of the 5% lidocaine patch. injection administered weekly for 4 weeks. No benefit was observed
Adverse effects from the lidocaine patch are rare. Patients who in the epidural injection group, but significant relief was seen in the
discontinue therapy usually report ineffective cutaneous pain reduc- intrathecal injection group at both 1 and 24 weeks after study
tion or local skin irritation. completion.
Current treatment recommendations (and FDA approval) sug- Whereas intrathecal methylprednisolone injection was associat-
gest a 12-hours on/12-hours off application schedule of no more ed with no adverse events in the randomized, controlled trial
than three 5% lidocaine patches.16 If EMLA is applied, patients described previously, other studies of intrathecal steroid injection
should spread the cream over the affected area once a day and for pain states have documented risks including chemical meningi-
cover it with an occlusive dressing. A 2-week trial period is sug- tis, chronic arachnoiditis, and transverse myelitis.18 Complications
gested to assess for benefit before abandoning therapy. such as aseptic and bacterial meningitis, cauda equina syndrome,
and cerebral vein thrombosis have also been published in associa-
tion with intrathecal steroid injection.
OtherTopical Agents (Capsaicin and Topical Based on limited data involving small patient numbers, intra-
Aspirin Ointment/Cream) thecal methylprednisolone appears effective for PHN. Based on the
invasiveness of this therapy, along with associated risks of neuraxial
Capsaicin (Zostrix) is an alkaloid extract derived from hot chili steroid injection and the difficulty in obtaining preservative-free
peppers that is available as both a cream and a lotion in strengths methylprednisolone in the United States, clinicians should consider
of 0.025% and 0.075%. The mechanism of action in humans intrathecal steroid injection only in patients with PHN refractory to
appears to be through degeneration of intracutaneous nerve more conservative medical therapies.
fibers, thereby providing pain relief through neurodegenerative
changes. Many believe that capsaicin depletes neuronal stores of
Spinal Cord Stimulation
neurotransmitters like substance P and other neuropeptides.
Ultimately, local nociceptive function is inactivated and pain The application of spinal cord stimulation (SCS) in PHN stems
relief ensues. from the search for more effective treatments for this painful disease
Two randomized trials have shown capsaicin to be modestly and from a desire to avoid the disadvantages of systemic pharma-
effective in treating PHN.10 In a 6-week randomized, double cotherapy. SCS of the dorsal columns may activate spinal and
blind, placebo-controlled trial of 0.075% capsaicin, a modest reduc- supraspinal inhibitory pain processes and reestablish a balance
tion in visual analog score (23% decrease from baseline after 4 between excitatory and inhibitory pathways in dorsal horn cells.
wk) was observed in 65% of patients receiving capsaicin treatment. Overall, the literature reveals mixed results in treating PHN with
The primary side effect of capsaicin in this study was a burning spinal cord stimulation. For instance, Kumar and coworkers,19 in a
sensation, reported in 60% of patients on capsaicin versus 30% on prospective case series, showed that three eighths (38%) of PHN
placebo. Of those patients on capsaicin after 2 years, 77 of 83 patients reported pain relief after implantation, and only one fourth
patients maintained pain relief with capsaicin. (25%) described pain relief at an average follow up of 7.3 years.
Topical aspirin ointment has been examined in randomized, However, Harke and associates,20 in a prospective case series,
double-blinded studies in combination with 5% lidocaine gel, and demonstrated that 23 of 28 patients (82%) with PHN reported
a decrease of 73% in the visual analog scale has been reported in long-term pain relief at more than 2 years. Further, patients expe-
patients treated with these agents. Significant methodological pro- rienced significant improvements in activities of daily living noted
blems with the trial, including comparison of two active agents to by the pain disability index. More than 50% of these PHN patients
the baseline pain condition, limit the evaluation of aspirin as an no longer required pain medications during SCS treatment. Meglio
effective treatment for PHN. and colleagues,21 in a retrospective case series, found that 6 of
Based on initial data, neither capsaicin nor topical aspirin for- 10 patients with chronic PHN reported 53% pain relief with SCS
mulations are currently recommended as first-line agents for treat- over a 46-month follow-up period.
ment of PHN. However, given that topical agents are less likely In sum, despite the results of lower-quality evidence to support
associated with systemic side effects, they may serve as useful the use of SCS in PHN, SCS may be of value in treating unbearable
adjuncts for pain relief. PHN pain unresponsive to pharmacologic treatments.
OtherTherapies early treatment of acute herpes zoster will reduce the incidence of
PHN in the general population.
Numerous other therapies have been attempted to reduce pain
associated with PHN including sympathetic blockade, skin excision,
dorsal root entry lesions, cordotomy, thalamotomy, SCS, and deep
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in postherpetic neuralgia: a quantitative systematic review. PLoS Med
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established through rigorous research trials. A diagram of suggested neuralgia: a randomized, double blind, placebo-controlled trial. Pain
treatment strategies is shown in Box 36–2. First-line agents for PHN 2003;103:323–331.
may include TCAs, the 5% lidocaine patch, pregabalin, and gaba- 9. Meier T, Wagner G, Faust M, et al. Efficacy of lidocaine patch 5% in
pentin. Lidocaine patches have been found effective for treatment of the treatment of total peripheral neuropathic pain syndromes: a
PHN, particularly in patients with a marked allodynic component randomized, double blind, placebo-controlled study. Pain
2003;106:151–158.
to their pain. The favorable side effect profile combined with lack of
10. Bernstein JE, Korman NJ, Bickers DR, et al. Topical capsaicin
systemic toxicity suggests the lidocaine patch to be safe and effective treatment of chronic postherpetic neuralgia. J Am Acad Dermatol
for a variety of PHN patients. 1989;21:265–270.
In conjunction with the 5% lidocaine patch, amitriptyline and 11. Gilron I, Baily J, et al. Morphine, gabapentin, or their combination
nortriptyline along with gabapentin and pregabalin have been for neuropathic pain. N Engl J Med 2005;352:1324–1334.
found effective in a variety of randomized, controlled trials for 12. Raja SN, Haythornthwaite JA, et al. Opioids versus antidepressants in
PHN. Given the more favorable side effect profile of nortriptyline, postherpetic neuralgia: a randomized, placebo-controlled trial.
clinicians should consider its use over amitriptyline, particularly in Neurology 2002;59:1015–1021.
older adults. Gabapentin or pregabalin may also be incorporated 13. Lee K, Akil H, Woods JH, et al. Differential bending properties of
oripavines at cloned mu and delta opioid receptors. Eur J Pharmacol
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In patients who fail to respond to these agents, initiating a short- herpetic neuralgia. Pain 1996;65:39–44.
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weeks is supported by current evidence as effective therapy. Opioids treats all neuropathic pain qualities: results of a randomized, double
may be considered after other agents have failed to provide reason- blind, vehicle-controlled, 3-week efficacy study with use of
able analgesia. Clinicians should monitor patients for adverse Neuropathic Pain Scale. Clin J Pain 2002;18:297–301.
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these therapies should be reserved for patients refractory to more 19. Kumar K, Toth C, et al. Spinal cord stimulation for chronic pain in
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Unfortunately, data on therapy for PHN show that as many as 20. Harke H, Gretenkort P, et al. Spinal cord stimulation in
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268 Chapter 37 POST AMPUTATION PAIN DISORDERS
Chapter 37
phantom teeth), and similar phenomena can occur after spinal
POST AMPUTATION PAIN cord injury (e.g., phantom body). Roughly 30% of patients after
amputation with phantom limb sensations undergo a phenomenon
known as telescoping10 (although this is a poor term because what
DISORDERS happens is actually a shrinking of the sensation and retraction of the
phantom toward the residual limb).
Howard S. Smith, Andrew Dubin, and Amar Parikh
EPIDEMIOLOGY
In 1983, Sherman and coworkers20 published a survey of 590 war
veteran amputees in which 85% reported phantom pain. A study
with 2694 amputees showed that 51% experienced PLP severe
INTRODUCTION enough to hinder lifestyle on more than 6 days per month, 21%
reported daily pain over a 10- to 14-hour period, and 27% for more
Ambrose Paré,1,2 a French military surgeon, provided the first med- than 15 hours per day.21 The incidence of PLP increases with more
ical description of postamputation phenomena. He noticed, as early proximal amputation. Reports of PLP after hemipelvectomy ranged
as 1551, that amputees may complain of severe pain in the missing from 68% to 88% and after hip disarticulation from 40% to
limb a long time after amputation. Civil War surgeon Silas Weir 88%.19,22 After lower extremity amputation, variations of PLP
Mitchell3 in 1872 popularized the concept of phantom limb pain exist, being as high as 72%13 and as low as 51% after upper limb
(PLP) and coined the term phantom limb with publication of a amputation.4 PLP has been reported to occur as early as 1 week and
long-term study on the fate of Civil War amputees. as late as 40 years after amputation.23,24 Phantom pain may dimin-
Limb amputation is frequently followed by the sensation that the ish with time and eventually fade away. However, some prospective
deafferented body part is still present. The feeling that the missing studies indicated that even 2 years after amputation, the incidence
limb may still be present is termed phantom limb awareness, and the was not greatly diminished from that at onset.17,25 It was reported
specific sensory and kinesthetic sensations that may be noted are that almost 60% of patients continue to have PLP25,26 after 1 year
referred to as phantom limb sensations. These nonpainful phantom (after this point, successful treatment appears more difficult).
sensations may include a specific position, shape, or movement of The most common incidence of PLP in the 1990s and beyond
the phantom, feelings of warmth or cold, itching, tingling, or elec- appears to be in the range of 50% to 59% of amputee patients.
tric sensations, and other paraesthesias.4 Sixty-four percent of the Netherlands sample reported experiencing
Phantom limb sensation occurs in 85% to 98% of amputees and at least a ‘‘moderate’’ amount of suffering from their pain, with
tends to be seen in the first 3 weeks after amputation,5 whereas in a 40% of the sample of 124 amputees reporting that they ‘‘always’’
small proportion of the patients (approximately 8%), phantom experienced PLP and another 20% reporting PLP a ‘‘few times a
limb sensation may not occur until 1 to 12 months after amputa- day.’’4,27,28
tion.6 Most phantom sensations generally resolve after 2 to 3 years
without treatment, except in the cases in which phantom pain
develops. Phantom limb sensation is strongest in amputations ETIOLOGY
above the elbow and weakest in amputations below the knee7 and
is more frequent in the dominant limb of double amputees.8 The development of PLP can best be described as multifactorial. It
Occasionally, the limb is felt to be bent or twisted into an unnat- is becoming appreciated that preamputation pain is a risk factor for
ural position that tends to elicit discomfort. Pain in a body part that the development of significant PLP.26,29–31 Phantom pain may
is no longer present (phantom pain) occurs in 50% to 80% of all mimic preamputation pain.32,33 Preamputation pain does not
amputees.9 Pain may be related to certain positions or movements need to occur within a specific time frame before amputation in
of the phantom and may be elicited or exacerbated by a range of order to facilitate the development of PLP because it has been
physical factors (e.g., changes in weather or pressure on the residual shown that trauma or injury even years before the amputation
limb) and psychological factors (e.g., emotional stress). It seems to can be reexperienced as PLP. Furthermore, preexisting nerve dys-
be more intense in the distal portions of the phantom and can have function (e.g., chemotherapy-induced neuropathy, invasive meta-
several different qualities, such as stabbing, throbbing, burning, or static cancer) could conceivably be a risk factor for the development
cramping.10 Residual limb pain—previously referred to in the liter- of PLP after limb amputation.
ature as stump pain—refers to a regional pain restricted to the distal Phantom pain may be modulated by multiple factors, both
residual part. Unlike phantom pain, it occurs in the area of the body internal and external. Exacerbations of pain may be produced by
that actually exists. Patients may also experience feelings of tingling, trivial, physical, or emotion stimuli. Anxiety, depression, urination,
itching, cramping, or involuntary movements in the residuum. cough, defecation, sexual activity, cold environment, or changes in
Residual limb pain is reported in up to 50% of amputees.11–17 the weather may worsen PLP.18–20,22,25,34–36 It also has been
Reports showed that 50% to 88% of the patients with phantom reported that general, spinal, or regional anesthesia in amputees
pain also reported residual limb pain.18,19 may cause appearance of phantom pain in otherwise pain-free sub-
Some patients experience the pain with such intensity that they jects.37–42 If symptoms of PLP increase in severity or they start after
report an inability to work, sleep, or perform daily activities. long periods of time after amputation, a differential diagnosis must
Phantom pains have also been reported as a consequence of the be entertained.
loss of any body part (e.g., phantom breast, phantom rectum, phan- Multiple causes that may increase or exacerbate PLP (other than
tom penis, phantom testicles, phantom eye, phantom tongue, the changes in the weather, autonomic stimulation, and the like)
include radicular pain, angina, postherpetic neuralgia, vascular proposed to contribute this spontaneous activity.10 However, PLP
insufficiency, infection, and metastatic cancer. is present in many patients immediately after amputation before a
neuroma could have formed.10 Moreover, local anesthesia of the
stump does not eliminate PLP in all cases.48
MECHANISMS OF PHANTOM PAIN Kuiken and associates49,50 reported on the development of a
neural-machine interface called targeted reinnervation (TR) that
Experimental and clinical studies continue to provide increasing provides enhanced motor control and the potential for meaningful
knowledge on the mechanisms underlying phantom pain. sensation feedback for artificial arms. TR was employed to transfer
Currently, the pathophysiology remains uncertain; however, it is remaining arm nerves to residual chest muscles after an amputa-
believed that the generation of phantom pain is due to both periph- tion.51 This technique allows some sensory nerves from the ampu-
eral and central factors.10 tated limb to reinnervate overlying chest skin.51 When this
reinnervated skin is touched, the amputees perceive that they are
being touched on their missing limb.51 Kuiken and colleagues51
Peripheral Factors found that touch thresholds of the reinnervated chest skin fall
within near-normal ranges, indicating the regeneration of large
Physical trauma/insult to nerves during amputation may lead to the fiber afferents. The perceptual identities of the limb and chest
clustering of nerve endings in the residuum resulting in the devel- were maintained separately, even though they shared a common
opment of neuromas (of which it has been estimated about 20% skin surface. A cutaneous expression of proprioception also
serve clinically significant pain generators) for postamputation pain occurred in one reinnervated individual.51 Experiments with peltier
(PAP) pain. temperature probes and surface electrical stimulation of the rein-
nervated skin along with the painful sensations referred to missing
limb indicate the regeneration of small–diameter temperature and
PAP Pathophysiology pain afferents from the transferred peripheral nerves.51
Sites of ectopic discharge after amputation may occur in the
Peripheral PAP Pathophysiology residual limb but also in the dorsal root ganglion (DRG).
Spontaneous as well as triggered neuronal activity (e.g., emotional
Nikolajsen and Jensen43 described several clinical observations distress leading to increased cathecholamines) may occur from neu-
(Box 37–1) that suggest that mechanisms in the periphery, either romas as well as at the level of the DRG.52 Ectopia in the DRG can
in the residuum or in the central parts of sectioned primary affer- amplify discharges coming from the residual limb or can lead to
ents, may be involved in the perception of PLP. Peripherally, spon- cross-excitation and promote the depolarization of neighboring
taneous and abnormal evoked activities after mechanical or neurons.45 In human beings, an anesthetic block of a neuroma
neurochemical stimulation are observed in nerve end neuro- eliminated nerve activity related to the stimulation of the stump
mas.44,45 This increased activity is assumed to be the result of a but not spontaneous activity, which may be originating in the
novel expression or up-regulation of sodium channels.29,46 DRG.53
Ectopic discharge from a stump neuroma has been postulated as
one important peripheral mechanism of phantom pain.44 When
Spinal PAP Pathophysiology
peripheral nerves are cut or injured during amputation, regenerative
sprouting of the injured axon occurs. In this process, a neuro- Nikolajsen and Jensen43 reported that the pharmacology of spinal
ma (e.g., enlarged and disorganized endings of C-fibers and sensitization involves increased activity in the N-methyl-D-aspartate
demyelinated A-fibers that show an increased rate of spontaneous (NMDA) receptor complex,54 and many aspects of the central sen-
activity10) in the residual limb is generally formed, which in certain sitization can be reduced by NMDA receptor antagonists. This was
circumstances may be a ‘‘pain generator’’ of PAP. Mechanical supported in human amputees in whom the evoked stump or phan-
(e.g., pressure; Tinel’s sign) and chemical (e.g., norepinephrine) tom pain produced by repetitive stimulation of the stump by non-
stimulation may further increase the rate of discharge, which noxious pinprick was reduced by the NMDA receptor antagonist
seems to be mainly related to spontaneous ectopia (neuronal dis- ketamine.55
charge that is generated along the axon or in the soma) as a conse- Waxman and Hains52 proposed that abnormal expression of
quence of nerve injury and seem to be a result of the up-regulation Nav 1.3 sodium channels in the second- and third-order neurons
or novel expression of sodium channels.29,47 Nonfunctional connec- along nociceptive pathways after spinal cord injury may make these
tions between neighboring axons (ephapses) have also been neurons hyperexcitable.52 These neurons may then function as pain
amplifiers/generators and conceivably contribute to phantom phe-
nomena (Fig. 37–1).
Chaotic afferent firing may lead to altered centrally projecting
Box 37^1 CLINICAL OBSERVATIONS OF PHANTOM LIMB neurons in the dorsal horn, increased spinal cord metabolic activity,
PAIN and expanded receptive fields.10 Centrally projecting neurons may
then induce an alteration in the organization of the spinal neurons
Phantom limb sensations can be modulated by various stump and the cerebral cortex. It is hypothesized that this ‘‘reorganizaton’’
manipulations. leads to the generation of persistent or recurring PLP. Thus, it is
Phantom limb sensations are temporarily abolished after local stump likely that events that originate within the periphery may lead to a
anesthesia. cascade of changes that then alter central nervous system neurons as
Stump revisions and removal of tender neuromas often reduce pain, at well.10
least transiently.
Phantom pain is significantly more frequent in those amputees with
long-term stump pain than in those without persistent pain. Supraspinal PAP Pathophysiology
Although obvious stump pathology is rare, altered cutaneous sensibil-
ity in the stump is a common if not universal feature. A significant phenomenon that may contribute to phantom pain is
Changes in stump blood flow alter the phantom limb perception. cortical reorganization of the somatosensory cortex. Melzack56
observed that a substantial number of children who are born with-
Adapted from Nikolajsen L, Jensen TS. Postamputation pain. In Melzack R, Wall PD (eds):
Handbook of Pain Management. Edinburgh: Churchill Livingstone, 2003; pp 247^257.
out a limb feel a phantom of the missing part and suggested the
existence of a neural network, or ‘‘neuromatrix’’ that subserves
Thalamic
amplifier/
S1 generator
VPL
T9 SCI
Spinal
amplifier
DRG L4
A B Na⫹
Figure 37^1. Pain amplifiers and generators. A, The pain pathway. Heat and pain stimuli are transmitted by first-order neurons of dorsal
root ganglia (DRG) into the spinal dorsal horn. Axons of second-order neurons ascend to the ventroposterior lateral thalamus (VPL), and third-
order neurons transmit information from here to the primary sensory cortex (S1). B, Abnormal expression of Nav 1.3 within both dorsal horn and
thalamic neurons after spinal cord injury (SCI) suggests multitiered dysregulation of NaCl channels. In this model, pain-processing neurons at
different levels of the pain pathway pathologically amplify and generate nociceptive information after SCI. Second-order neurons within the dorsal
horn increase the gain with which they respond to innocuous and noxious inputs after SCI.The exaggerated responses of these dorsal horn
neurons in response to peripheral stimulation poise them to amplify both normal and inappropriate pathologic nociceptive signals.The thalamus
acts as another pain amplifier by responding with increased vigor to nociceptive information relayed from the dorsal horn, and thalamic circuitry
can also act as an autonomous pain signal generator after SCI.The changes in excitability of neurons along this pathway after SCI can give rise to
chronic pain, such as mechanical allodynia and thermal hyperalgesia. (A and B, FromWaxman SG, Hains BC. Fire and phantoms after spinal cord injury:
Na+ channels and central pain.Trends Neurosci 2006;29:207^215.)
body sensation and has a genetically determined substrate that is anterior cingulate cortex (ACC) pyramidal neurons quickly depo-
modified by sensory experience. Lotze and colleagues57 revealed larized from apporximately –70 mV to approximately –15 mV and
that functional magnetic resonance imaging (fMRI) data from then slowly repolarized over about 40 minutes. The depolarization
amputees with pain and from healthy volunteers during a lip- is activity-dependent because peripheral application of lidocaine
pursing task were similar. In amputees with PLP, however, the cor- significantly reduced it.61 Furthermore, the depolarization was
tical representation of the mouth extends into the region of the significantly reduced by an NMDA receptor antagonist, MK-801.
hand and arm. Giummarra and coworkers58 proposed that phan- Wu and associates61 suggested that these results provide direct in
tom pain may reflect a maladaptive failure of the neuromatrix to vivo electrophysiologic evidence that ACC pyramidal cells undergo
maintain global bodily constructs. Cortical map reorganization may rapid and prolonged depolarization after digit amputation and the
be facilitated via selective loss of C-fibers, which occurs after ampu- amputation-induced depolarization in ACC neurons might be
tations. C-fibers appear to have an important role in the mainte- associated with the synaptic mechanisms for phantom pain.61
nance of cortical maps.
Animal work on stimulation-induced plasticity suggested that
extensive behaviorally relevant (but not passive) stimulation of a Psychological Factors
body part leads to an expansion of its representation zone.59
Intensive use of a myoelectric prosthesis is positively correlated Empirical studies on psychological characteristics of patients who
with reduced cortical reorganization and analgesic effects.57 These have PLP and on those of controls showed that these patients tend
effects could not be achieved with standard medical treatment and to have normal psychological profiles62; however, PAP may be trig-
general psychological counseling because it is believedt that in order gered and exacerbated by psychological factors. Longitudinal diary
to achieve analgesia, input into the amputation zone of the cortex is studies showed that there was a significant relation between stress
needed in order to ‘‘undo’’ the reorganizational changes induced by and the onset and exacerbation of episodes of PLP, probably
amputation. Similar beneficial effects on phantom pain and cortical mediated by activity in the sympathetic nervous system and
activation were reported for imagined movement of the phantom increases in muscle tension.63 Patients who received less support
and may also occur to some degree with mirror treatment (in which before the amputation tended to report more PLP.12
a mirror is used to trick the brain into perceiving movement of the Richardson and colleagues64 conducted a prospective study of
phantom when the intact limb is moved).60 59 patients listed for amputation of a lower limb owing to periph-
Wu and associates61 reported that shortly after digit amputation eral vascular disease. Each was interviewed before amputation, and
of the hind paw, the membrane potential of intracellularly recorded the survivors were reinterviewed 6 months afterward.64 Pain and
coping style were the primary outcome measures. The use of high study in which 0.5% bupivicaine at 1 ml/hr was injected adjacent to
levels of passive coping strategies (P = .001), especially catastrophiz- rather than inside of the nerve sheaths. Overall, 11 of 14 patients
ing (P = .02) before amputation, were found to be associated with who completed a questionnaire reported a decrease in pain between
PLP development.64 Pain was only weakly associated with the pres- the 3- and 6-month evaluations. Despite this, there was no signif-
ence of PLP 6 months after amputation.64 The ability to move the icant difference in the incidence of PLP. They concluded that peri-
phantom (P = .01) and stump pain (P = .01) were postamputation neural infusion of bupivicaine is a safe and effective technique to
factors associated with PLP.64 relieve postoperative pain but does not prevent residual PLP in
those amputees with ischemic peripheral vascular disease.70
Madabhushi and coworkers72 reported on a patient with a his-
PREVENTIONOF PAP tory of PLP from a below-knee amputation who then came for an
above-knee amputation in the same extremity. Before transection,
No known strategies can completely prevent PAP conditions. the sciatic nerve was infiltrated with 0.25% bupivacaine 5 ml and
Epidural administration of opioids, which is often effective in the clonidine 50 mcg. After the nerve was severed, a 20-gauge epidural
treatment of postoperative pain, has been advocated to administer catheter was inserted into the nerve sheath and externalized laterally
preoperatively in efforts to prevent future pain. Nikolajsen and through a separate skin incision. Before closure, 0.25% bupivacaine
associates65 conducted a trial on the use of epidural bupivicaine 10 ml and clonidine 50 mcg was injected, and then 0.1% bupiva-
and morphine on the prevention of stump and phantom pain in caine and clonidine 2 mcg/ml was infused perineurally for the first
lower limb amputees.65 Patients were given either epidural mor- 96 hours postoperatively. The mean postoperative pain score (from
phine 5 mg and bupivicaine 75 mg in 60 ml of normal saline or a 0–10) for 96 hours was 1.2 ± 0.7.72 The patient required a total of
control 18 hours before and during the operation. One week later, 10 mg of oxycodone postoperatively. Over a 1-year follow-up
the differences in the development of phantom pain were not sta- period, the patient never reported stump or phantom pain.72
tistically significant. These patient groups reported no difference Rasmussen and Kehlet73 suggested that future studies should
when followed for 3 months, 6 months, and 1 year. Despite this, help define nerve-handling techniques at the time of amputation
results did show that the intensity of postoperative stump pain was that should then be disseminated and used consistently. Perhaps
reduced.65 surgical techniques used to treat PLP as described by Prantl and
Gehling and Tryba66 showed that pre-, intra-, and postoperative associates74 may be beneficial if performed at the time of amputa-
epidural anesthesia was associated with a significant reduction of tion. Prantl and associates74 split the sciatic nerve about 3 cm prox-
PLP 12 months after amputation. They concluded that periopera- imal to the popliteal fossa and reconnected the two parts in a sling
tive epidural anesthesia has been shown to be an effective prophy- fashion, using an epiperineural technique under microscopic vision,
laxis of PLP. Perioperative epidural anesthesia does not completely which was then covered with a fibrin patch and anesthetics.
abolish PLP but may increase the number of patients with a mild
form of phantom pain.
Although there is a positive correlation between the intensity PAP EVALUATION
of preamputation pain and the incidence of PLP 3 months after
amputation,17 perioperative epidural analgesia did not prevent the In terms of patient evaluation, documentation of a complete and
development of PLP in a randomized, controlled trial.65 The peri- thorough history and physical examination is extremely important.
operative infusion of the NMDA antagonist ketamine did not affect However, attempts to gain insights into optimal treatment regimens
acute postoperative pain or the incidence of PLP at 6 months.67 No on the basis of sensory function have been disappointing.
scientifically validated prevention modality exists for PLP, including Hunter and colleagues75 carefully evaluated 12 subjects who had
perioperative gabapentin and epidural ketamine. undergone traumatic unilateral upper extremity amputation within
The use of epidural clonidine (150 mcg) injections has also been the past 6 months. Despite a common injury, the sensory abnorm-
suggested; however, adverse side effects including hypotension, uri- alities varied within these subjects. In addition, psychophysical
nary retention, and bowel incontinence may occur. Jahangiri and threshold measures of sensory function (e.g., tactile detection
colleagues68 conducted a study combining the epidural clonidine thresholds, two-point discrimination thresholds, thermal thresh-
150 mcg, bupivicaine 75 mg, and diamorphine 5 mg in 60 ml of olds) did not reflect, in any simple way, subjective phantom
normal saline.68 Although the trial was very small, there was a sig- phenomena.75 Furthermore, altered tactile acuity reflects S1 reorga-
nificant reduction in postoperative phantom pain at 1 week as well nization.76,77 They found no evidence that a simple, direct relation-
as 6 and 12 months; although there was no significant change in the ship exists between somasensory remapping and dual percepts.75
incidence of stump pain.68 Future research is still required involving Therefore, classification of phantom phenomena based on peri-
well-designed studies with larger patient populations. pheral sensory function may be a misleading step in the search
Wilson and coworkers69 recruited 53 patients undergoing lower for specific mechanisms underlying postamputation sensory
limb amputation who received a combined intrathecal/epidural phenomena.75
anesthetic for surgery followed by a randomized epidural infusion Despite a common injury and a similar timeframe after injury,
(Group K received racemic ketamine and bupivacaine; Group S the sensory abnormalities differed between subjects. In the search
received saline and bupivacaine). Neither general anesthesia nor for the mechanisms underlying phantom sensation and phantom
opioids were used during the perioperative period. Pain character- pain, classification of phantom phenomena by the perceived sen-
istics were assessed for 12 months. The primary end-point was inci- sory qualities may be misleading. Subjective thermal phenomena
dence and severity of PAP.69 Persistent pain at 1 year was much did not consistently reflect actual limb temperature, and one
less in both groups than in comparable studies, with no significant could not be inferred from the other. Measures of static to punc-
difference between groups (Group K = 21% [3/14] and 50% tuate sensory tactile thresholds and thermal thresholds involving a
[7/14]; and Group S = 33% [5/15] and 40% [6/15] for stump comparison of the stump and the contralateral limb provided no
and phantom pain, respectively). Postoperative analgesia was sig- evidence of a generalized sensitization, all of which have some
nificantly better in Group K, with reduced stump sensitivity.69 degree of ongoing pain. Areas of heightened tactile spatial acuity
Malawer and associates70 injected 0.25% bupivicaine at 10 ml/hr were always distributed in a pattern best explained by localized
into peripheral nerve sheaths via catheters at the time of surgery peripheral sprouting at the scar. Thus, in the short term (<6 mo)
after the amputation. The procedure was found to take no more after traumatic amputation, phantom limb sensations and PLP were
than 10 minutes and led to an 80% decrease in narcotic require- not related in any simple way to peripheral or segmented sensory
ments postoperatively. Pinzur and colleagues71 conducted a similar function as measured by static tactile and temperature thresholds.75
A common cause of residual limb pain is improper prosthetic have been tried. Although tricyclic antidepressants and sodium
fitting. Residual limb pain can occur if the prosthetic socket is too channel blockers are the treatments of choice for neuropathic
tight or too loose or if the rims or trim lines of the prosthesis are pain,80 with the exception of Wilder-Smith and associates,81 there
inappropriate. Abnormal suspensions can alter the pressure in cer- have been no specific controlled studies of these agents for PLP.
tain areas and can induce soft tissue pain. Careful prosthetic eva- Controlled studies have been performed for gabapentin,82 opioids,83
luation, meticulous prosthetic fitting, and extensive prosthetic and ketamine55 and have been reported to have the potential to
training must all be coordinated to minimize these problems. effectively reduce PLP. However, Nikolasjen and colleagues84 con-
Abnormal tissues such as bony exostoses, heterotrophic ossifica- cluded that gabapentin does not reduce the incidence or intensity of
tion, adherent scars, or sepsis may facilitate residual limb pain as PAP. Also, lidocaine decreased PLP of patients with neuromas in
well. Ischemia can also be a major contributor to distal residual the residuum in two small controlled studies.85,86
limb pain. Thorough evaluation and assessment of an individual Antidepressants are commonly used for many painful conditions
patient’s physical condition and regulation of local blood flow are but especially for neuropathic pain. Although, antidepressants are
essential components in the evaluation of the patient with residual utilized for the treatment of PAP conditions, they have not been
limb pain. well studied for PAP. Wilder-Smith and associates81 studied 94
treatment-naı̈ve post-traumatic limb amputees with phantom
pain (mean visual analog scale [VAS] score of 40 mm) who were
PAP MANAGEMENT randomly assigned to receive individually titrated doses of trama-
dol, placebo (double-blind comparison), or amitriptyline (open
Similar to the goals of preventive techniques, treatments for phan- comparison) for 1 month. Wilder-Smith and associates81 concluded
tom pain are directed at addressing the central and peripheral that in treatment-naı̈ve patients, both amitriptyline and tramadol
factors presumed to be contributing to pain. Overall, however, provided excellent and stable PLP and stump pain control with no
PAP treatment is also not terribly effective at present. Medical, major adverse events. Alternatively, Robinson and coworkers87
psychological, interventional, and surgical interventions have been studied 39 persons with amputation-related pain lasting more
used for PAP as potential therapeutic options with limited success than 6 months in a 6-week randomized, controlled trial of amitrip-
(Table 37–1). A survey of 2694 amputees with phantom pain tyline (titrated up to 125 mg/day) or an active placebo (benztropine
showed that treatment was successful in only 1% of cases.21 Most mesylate). No significant differences were found between the treat-
of the studies conducted thus far have used small sample sizes, have ment groups in outcome variables when controlled for initial pain
lacked adequate power and rigor, and do not have long-term scores; thus, this did not support the use of amitriptyline in the
follow-up data. treatment of PAP.87
The treatment of PLP in amputees of malignant origin may Kuiken and associates88 studied four individuals with PLP for at
be more successful. Mishra and coworkers79 reported that patients least 3 months after amputation. All subjects received oral mirtaz-
complaining of phantom sensation, phantom pain, and stump pain apine between 7.5 and 30 mg/day.88 An 11-point numerical rat-
decreased from 69%, 60%, and 31%, respectively, at 1 month to ing scale (NRS-11; 0–10) measured pain intensity and relief
32%, 32%, and 5% at the end of 2 years with the addition of opioids during monitored outpatient follow-up visits. Mirtazapine use
per the World Health Organization (WHO) three-step analgesic improved the PLP experienced by these subjects by at least 50%
ladder (perhaps this study was more successful because of the use measured by NRS-11.88 Subjects with PLP-related sleeping difficul-
of WHO step 3 opioids for severe PAP).79 ties reported the greatest pain relief concomitant with improved
sleep quality.88
Mirtazapine is more specific than many tricyclic antidepres-
Pharmacologic Interventions sants to serotonin/norepinephrien (5-HT/NE) modulation and
therefore may block PLP primarily through centrally medi-
Pharmacologic therapy is perhaps the most commonly used method ated mechanisms.88 Mirtazapine has a unique dual mechanism of
for treatment of phantom pain. Many pharmacologic interventions action that enhances both noradrenergic transmission by blocking
Table 37^1. Treatments for Phantom Pain
Medical Nonmedical Surgical

Antidepressants TENS Neurectomy
Anticonvulsants Acupuncture Stump revision
Lidocaine/mexiletine Biofeedback Rhizotomy
Opioids/tramadol Intrathecal drug delivery systems (e.g., ziconotide) Cordotomy
NMDA receptor antagonists Stump massage/electromagnetically shielding stump liner Tractotomy
Mirtazapine Stump ultrasound DREZ lesion
Intravenous salmon calcitonin Electroconvulsive therapy Tractotomy
Clonazapam Nerve blocks/perineural infusions Lobectomy
Baclofen Psychological therapy/cognitive-behavioral therapy Sympathectomy
Clonidine/tizanidine Immersive virtual reality treatment/mirror feedback Spinal cord stimulation/peripheral
therapy nerve/stump stimulation
Topical capsaicin/clonidine Botulinum toxin injections into the residuum Deep brain stimulation/motor cortex
stimulation (after fMRI)
DREZ, dorsal root entry zone; fMRI, functional magnetic resonance imaging; NMDA, N-methyl-D-aspartate; TENS, transelectrical nerve stimulation.
Derived from Nikolajsen L, Jensen TS. Phantom limb pain. Br J Anaesth 2001;87:107–116.
presynaptic inhibition of NE release (a2-antagonist) and specific conducted to test the efficacy of topiramate in managing various
serotonergic activity (5-HT1 agonist, 5-HT2 and 5-HT3 antago- neuropathic pain conditions associated with rehabilitation.98 This
nists).89 This results in a net increase of NE and 5-HT in the case series analyzed by time-series methodology described the use of
synaptic cleft, which theoretically blocks pain, not only at the topiramate in treating PLP.98 Three of four subjects showed a sig-
dorsal horn but also likely throughout the neuraxis.88 The drug nificant decrease in pain at some dose level.98 However, consistent
also has antihistaminic effects, which, along with 5-HT1–agonist decreases in pain were not seen until the 800-mg dose level in two of
effects, enhance the quality and quantity of sleep.88 the three responders, indicating a potential dose-related response.98
Zhu and colleagues90 administered oral mirtazapine (10, 20, and The three subjects who responded had experienced more than 2
30 mg/kg, respectively) to rats daily for 14 days, beginning from the years of refractory PLP that was significantly reduced after treat-
5th day after nerve transaction.90 Mechanical and thermal hyperal- ment with topiramate.98
gesia was measured using Von-Frey filament and Hargreaves tests Opioid analgesics are broad-spectrum analgesics that may be
before and after the surgery.90 Rats were then sacrificed on days 3, 7, used either alone or in combination with other drugs for the treat-
14, and 21 postadministration.90 The inflammatory cytokine pro- ment of phantom pain; however, higher than usual doses may be
duction (e.g., tumor necrosis factor-a [TNF-a], interleukin-1b [IL- needed for the successful treatment of phantom pain. Mishra and
1b], IL-10, and nuclear factor kB [NF-kB] activity) in brain was colleagues99 reported a case of intractable PLP whose pain did not
quantified using enzyme-linked immunosorbent assay (ELISA) and respond to the usual treatment, and only a high dose of morphine
electrophoretic mobility shift assay (EMSA). Zhu and colleagues90 made the patient totally pain-free.
found that mirtazapine (20 and 30 mg/kg) markedly attenuated The use of tramadol has been especially intriguing because of its
mechanical and thermal hyperalgesia produced by nerve transec- dual mechanism of monoamine reuptake inhibition and opioid
tion, most significantly on the 14th day. The elevated TNF-a, IL-1b, agonism. In a recent study, 94 treatment-naı̈ve post-traumatic
and NF-kB in brain were accordingly reduced, while the expression limb amputees with phantom pain were randomly assigned
of increased IL-10 was enhanced after repeated mirtazapine admin- to receive individually titrated doses of tramadol (mean dose
istration.90 Zhu and colleagues90 concluded that mirtazapine sup- 448 mg) or placebo (double-blind comparison) for 1 month. It
pressed neuropathic pain partially through inhibiting cerebral was found that tramadol provided excellent and stable PLP and
proinflammatory cytokines production and NF-kB activation in residual limb pain control with no major adverse events.81 A
the central nervous system. review found a 50% to 90% reduction in pain at 12 to 26 months
Carbamazepine, an anticonvulsant (and heterocyclic), has also with methadone 10 to 20 mg per day.100
been well documented for use in neuropathic pain syndromes and Huse and coworkers83 studied the efficacy of oral long-acting
serves as a potent sodium channel blocker. Historically, it had also morphine sulfate (MS) against placebo in a double-blind, cross-
been the most commonly prescribed anticonvulsant for pain. over design in 12 patients with PLP after unilateral leg or arm
Despite this, the results of its efficacy on PLP have been mixed. amputation.83 Two counterbalanced treatment phases of 4 weeks
Patterson91 and Elliott and coworkers92 reported cases of phantom each were initiated with an intravenous test infusion of MS or
pain that were alleviated with the use of oral carbamazepine.91,92 placebo. The titration phase was 2 weeks. The dose of MS was
However, only brief, shocklike pain was assessed.91 No studies titrated to at least 70 mg/day and at the highest 300 mg/day.83
showed its effectiveness in treating any of the other qualities of Pain intensity was assessed hourly on VASs during a 4-week treat-
pain that may exist. ment-free phase, during both treatment phases, and at two follow-
Gabapentin became the most common anticonvulsant pre- ups (at 6 and 12 mo).83 Reorganization of somatosensory cortex,
scribed for phantom pain relatively shortly after its analgesic qua- electrical perception, and pain thresholds as well as selective atten-
lities came to light. It has achieved a high level of popularity tion were measured before and after treatment.83 A significant
primarily owing to its favorable side effect profile and no require- pain reduction was found during MS but not during placebo. A
ments to constantly monitor patient blood levels, as is the case with clinically relevant response to MS (pain reduction > 50%) was
many other anticonvulsants. The effectiveness of gabapentin in evident in 42% and a partial response (pain reduction 25%–50%)
postamputation PLP was studied in a randomized, double-blind, in 8% of the patients.83 Neuromagnetic imaging of 3 patients
placebo-controlled, cross-over study by Bone and associates.82 They showed initial evidence for reduced cortical reorganization with
evaluated analgesic efficacy of gabapentin in PLP in patients attend- MS treatment concurrent with the reduction in pain intensity.83
ing a multidisciplinary pain clinic. Each treatment was for 6 weeks Huse and coworkers83 concluded that opioids show efficacy in
separated by a 1-week washout. The daily dose of gabapentin the treatment of PLP and may potentially also influence cortical
was titrated in increments of 300 to 2400 mg or the maxi- reorganization.
mum tolerated dose. Nineteen eligible patients were randomized, Intravenous lidocaine and morphine have also been evaluated
of whom 14 completed both arms of the study. Both placebo and for their therapeutic use in PAP. Wu and associates101 conducted a
gabapentin treatments resulted in reduced VAS scores compared randomized, double-blind trial to compare the analgesic effects of
with baseline. However, the pain intensity difference was signifi- intravenous morphine and lidocaine on postamputation stump and
cantly greater than placebo for gabapentin therapy at the end phantom pains. A bolus of morphine, lidocaine, and an active pla-
of the treatment. These authors concluded that after 6 weeks, gab- cebo (diphenhydramine) were used over a span of 3 consecutive
apentin monotherapy was better than placebo in relieving postam- days. The results showed that 31 of 32 subjects enrolled completed
putation PLP. the study. Eleven subjects had both stump and phantom pains,
Nikolajsen and colleagues84 examined whether postoperative 11 and 9 subjects had stump and phantom pain alone, respectively.
treatment with gabapentin could reduce postamputation residual Compared with placebo, morphine reduced both residual limb and
limb and phantom pain and concluded that gabapentin admin- phantom pains significantly. In contrast, lidocaine decreased resid-
istered in the first 30 postoperative days after amputation ual limb pain but not phantom pain. The authors concluded that
does not reduce the incidence or intensity of PAP.84 Pregabalin the mechanisms of residual limb pain and phantom pain are
may exhibit analgesic effects on PAP states but has not yet been different.101
evaluated. NMDA receptor blockers have been another option of drug
Topiramate is an antiepileptic drug that has been reported therapy for phantom pain patients. As mentioned, it has been
to relieve neuropathic pain.93–95 Topiramate is a g-aminobutyric demonstrated that phantom pain is associated with persisting
acid (GABA) agonist, sodium channel blocker, and kainate changes in the somatosensory cortex and motor cortex. The
antagonist.96–98 Four PLP subjects were treated during a pros- neural mechanisms by which this occurs are not yet understood.
pective, double-blind, randomized, placebo-controlled, pilot study For the establishment of the new cortical maps, it has been
proposed that synaptic changes must occur. Among the receptor Interventional Therapy
types involved in synaptic ‘‘plasticity,’’ the NMDA receptor seems
to be a key structure. The significance of NMDA receptors for cen- A wide variety of types of neural blockade have been utilized in
tral nervous system changes initiated clinical studies using NMDA the treatment of PLP. Trigger point injections, sympathetic
receptor antagonists (e.g., ketamine, amantidine, memantine) to blocks, stump injections, peripheral nerve blocks, and epidural
block the receptor and thereby protect the neuron from sensitiza- and subarachnoid blocks have been used.21 Despite this, studies
tion. However, a study by Wiech and colleagues102 did not demon- have shown that only 14% of patients report a significant tem-
strate a therapeutic effect of the NMDA receptor antagonist porary change and 5% report a prolonged change with these
memantine in a dosage of 30 mg/day over a 4-week period on blocks.21
chronic phantom pain or on pain in the residual limb. It was The use of neural blockade in the treatment of PLP is largely
suggested that one reason for the failure may be the development based on anecdotal reports in the literature.108–110 Blankenbaker108
of implicit somatosensory ‘‘pain memories,’’ or long-term changes reported that sympathetic blocks are successful if amputees are
in the central nervous system resulting from persistent painful treated soon after the onset of PLP. However, Halbert and cow-
input. These memories may not be able to be targeted by current orkers,111 in a systematic review to evaluate evidence for the optimal
analgesics. Combination therapy (e.g., amantidine and clonidine, management of acute and chronic phantom pain, were unable to
morphine and dextromethorphan, with or without intravenous or find any trials that met criteria for inclusion.
epidural lidocaine, may be a potential therapeutic option) but has Botulinum toxin A injections in PLP patients have also been
not been studied. utilized for analgesia. It is conceivable that muscle tension (perhaps
Stannard and Porter103 described three cases in which PLP was resulting from cortical reorganization) may contribute to phantom
successfully treated with ketamine hydrochloride. Nikolajsen and pain as a trigger of spinal reflexes, and botulinum toxin by muscle
coworkers104 administered ketmaine intravenously to a patient relaxation in the stump or via inhibition of the release of various
with established stump pain in a double-blind, saline-controlled neurotransmitters may lead to analgesia. In a small pilot trial,
fashion. After infusion stump pain was alleviated for 31 hours, researchers injected 100 IU of botulinum toxin A in four muscle
ketamine reduced the allodynic area and wind-up–like pain and trigger points of an amputation stump. These trigger points were
increased pressure-pain thresholds.104 Treatment was started painful to compression before injection, and all patients reported
with ketamine 50 mg four times a day dissolved in juice.104 No referred sensations in the phantom foot from at least one of the
side effects or development of tolerance was observed during a points. It was found that the use of botulinum toxin A reduced
3-month treatment period.104 phantom pain about 60% to 80%.112
Nikolajsen and associates55 administered ketamine (bolus at 0.1 Kern and associates113 administered a total dose of 2500 IU of
mg/kg/5 min followed by an infusion of 7 mcg/kg/min) intrave- botulinum toxin type B (Neurobloc, Elan Pharma, Munich,
nously to 11 patients with established stump pain and PLP in a Germany) to the residuum of two arm amputations, and a total
double-blind, saline-controlled study. All 11 patients responded dose of 5000 IU into the residuum of lower leg amputations. Two
with a decrease in the rating of stump pain and PLP assessed by patients reported that the injection was very painful. All patients
VAS and McGill Pain Questionnaire (MPQ). Ketamine increased experienced a reduction in stump pain that lasted for many
pressure-pain thresholds significantly. Wind-up–like pain (pain weeks.113 Other reports included a reduction in the frequency of
evoked by repeatedly tapping the dysaethetic skin area) was reduced pain attacks, cessation of ‘‘balloon feelings,’’ improvement in stump
significantly by ketamine. In contrast, no effect was seen on pain allodynia, and decreased occurrence of involuntary stump move-
evoked by repeated thermal stimuli. Side effects were observed in ments. In addition, quality of sleep at night significantly improved
9 patients. in one patient.113
Although calcitonin may have analgesic effects for PAP post- Multiple other cases have been reported of botulinum toxin
operatively,105 it does not appear to be effective for chronic PAP injections into the stump for PLP.114 A total of 300 to 500 U of
conditions.106 Eichenberger and colleagues106 conducted a rando- botulinum toxin A injected into the stump under electromyo-
mized, double-blind, cross-over study in which 20 patients graphic guidance (distributed over roughly 4 to 12 muscle points
received four intravenous infusions of a. 200 International Units that exhibited strong [maximal] fasciculation) provided significant
(IU) calcitonin; b. ketamine 0.4 mg/kg (only 10 patients); c. 200 analgesia (with reduced pain intensity and frequency) lasting about
IU of calcitonin combined with ketamine 0.4 mg/kg; and d. pla- 8 to 11 weeks before waning. At least 1 patient continues to receive
cebo (0.9% saline). The intensity of phantom pain (VAS) was these injections at 3-month intervals with reproducible significant
recorded before, during, at the end, and at 48 hours after each analgesia over a 7-year period.114
infusion.106 Pain thresholds after electrical, thermal, and pressure Furthermore, Kern and colleagues114 suggested that by dimin-
stimulation were recorded before and during each infusion.106 ishing muscle tone, pain, and hyperhidroses, botulinum toxin may
Ketamine, but not calcitonin, reduced PLP.106 The combina- facilitate prosthesis use. Four postamputation patients (one with
tion was not superior to ketamine alone. There was no difference phantom pain, three with stump pain) were each treated with 100
in basal pain thresholds between the amputated and the contra- IU of botulinum toxin A, divided between several trigger points in
lateral side except for pressure pain.106 Pain thresholds were unaf- the distal stump musculature. In one female patient (along with a
fected by calcitonin.106 The analgesic effect of the combination of pronounced reduction in phantom pain), hyperhidrosis of the
calcitonin and ketamine was associated with a significant increase stump ceased completely, probably after diffusion of the drug
in electrical thresholds, but with no change in pressure and heat into the dermal sweat glands, leading to longer and safer use of
thresholds.106 Ketamine, but not calcitonin, affects central sensiti- the prosthesis. Intentional intradermal injection for this issue,
zation processes that may be involved in the pathophysiology therefore, could be valuable. Another patient was able to use her
of PLP.106 prosthesis for the whole day again after botulinum toxin A treat-
Topical capsaicin was also utilized for the treatment of PLP. ment for substantial stump pain, compared with only 4 hours a day
In a study performed in a double-blind fashion with 24 before treatment. In two male patients, stump pain while wearing
patients, the authors concluded that capsaicin may be used as the prosthesis subsided to a considerable extent; one of the two
an alternative treatment for PLP.107 Future developments may reported an improvement in steadiness of gait. We suggest that
produce higher-strength capsaicin products, more potent capsai- stump treatment with botulinum toxin in rehabilitative medicine
cin analogues, and intravenous capsaicin formulations. Topical should be investigated in more detail.
clonidine patches have been utilized on the residuum but not Dahl and Cohen115 treated six soldiers with residual limb pain
studied. and PLP with a series of perineural etanercept injections. Five of the
six patients reported significant improvements in residual limb pain of seizures). MCS started in 1990 and 28 studies involving 271
at rest and with activity, PLP, functional capacity, and psychological patients have been reported thus far.124
well-being 3 months after injections.115 The one soldier who failed Sol and associates125 used chronic MCS (CMCS) in three
therapy was the only patient who presented with pain of longer than patients with intractable PLP after upper limb amputation. fMRI
1 year in duration. At the reduced doses administered, no adverse correlated to anatomic magnetic resonance imaging (MRI) permit-
effects were observed. These results seem to warrant further large ted frameless image guidance for electrode placement. Pain control
well-designed studies.115 was obtained for all the patients initially, and the relief was stable in
Acupuncture has shown some promise to provide relief from two of the three patients at 2-year follow-up. fMRI data may be
phantom pain as well. Multiple cases have been presented in which useful in assisting the neurosurgeon in electrode placement for this
amputees with chronic or acute phantom pain were treated with indication.125
Western medical acupuncture in the asymptomatic limb.116 Saitoh and Yoshimine124 suggested that in the future, repetitive
Although larger cohorts are needed for a full assessment, there transcranial magnetic stimulation of the primary motor cortex
have been reports of significant relief from PLP and phantom (M1) may take over from electrical stimulation as a treatment for
limb sensation. deafferentation pain. Koppelstaetter and colleagues126 use fMRI
Kern and coworkers117 wanted to find out whether an ‘‘electro- before MCS. fMRI may reveal evidence of cortical reorganization,
magnetic-sponge–like’’ shielding stump stocking interwoven with and thus, fMRI may contribute to the indication for MCS for PLP
metal (mediproÕ Liner RELAX [medi Bayreuth, Bayreuth, and additionally may help in electrode positioning.
Germany]) could have a positive effect on phantom pain. A
double-blind, randomized, cross-over trial in a total of 30 leg ampu-
tees compared the experimental (= verum) silicon liner (VL) fitted Surgical Interventions
to the amputation stump with a dummy (= placebo) liner (PL).117
Each liner was worn for 2 weeks after a 2-week baseline period. On a PLP has generally been difficult to treat with surgical interventions.
0 to 10 NRS, the median pain intensity before treatment was 4, and Part of the difficulty in addressing PLP/stump pain surgically lies in
the median of maximum pain was 6. VL versus PL reduced pain the postsurgical restriction or growth retardation of stump neuro-
significantly more often (P = .008), the odds ratio was 5.95.117 The mas. Residual limb neuromas develop at the site of the severed end
degree of pain reduction was likewise highly significant (< .001). of peripheral nerves. Surgical management may involve implanting
Wilcoxon’s matched-pairs signed-rank test for the medians of the end of severed nerves into a nearby or adjacent large muscle
daily maximum pain showed a significant reduction for both PL belly, which may alleviate stump pain somewhat, although it does
(P < .001) and VL (P < .001) compared with baseline, with VL not permanently cure patients.74
being highly superior again (P < .001) versus PL.117 Sehirlioglu and coworkers127 retrospectively studied 75 patients
Anecdotes of electroconvulsive therapy for PAP conditions exist. who were treated for painful neuroma after lower limb amputation
One case report noted two patients with severe PLP refractory to following landmine explosions between the years 2000 and 2006.
multiple therapies, and without a concurrent psychiatric disor- The average time period from the use of the prosthesis to the start
der,118 enjoying substantial pain relief of phantom pain on long- of symptoms suggesting neuroma was 9.6 months. The average time
term follow-up at 3.5 years. period from start of pain symptoms to neuroma surgery was 7.8
months. All clinically proven neuromas were surgically resected.127
In the mean follow-up of 2.8 years, all patients were satisfied with
Neuromodulation the end results and all were free of any pain symptoms.127 Painful
stump with clinical diagnostic findings of neuroma described pre-
Transcutaneous electrical nerve stimulation (TENS) has been used viously may be regarded as neuroma without requiring any further
with some success in the treatment of phantom pain. Katz and imaging modalities and is an indication for surgery if conservative
Melzack119 reported that 10 minutes after receiving low-frequency measures fail.127
(4-Hz) high-intensity (10–30 V) auricular TENS, phantom pain Aggressive surgical techniques, such as anterolateral cordotomy
patients demonstrated a modest, yet statistically significant, and DREZ lesions, have been attempted in PLP but do not have
decrease in pain as measured by the MPQ. However, ratings of large multicenter studies supporting their use at all and have sig-
mood, sleepiness, and anxiety remained virtually unchanged nificant morbidity and some mortality.
across test occasions and sessions, indicating that the decrease in
pain was not mediated by emotional factors. Investigators have
reported good to excellent results in roughly 25% of patients treated Psychological Interventions
with TENS.119,120
Spinal cord stimulation (SCS) has also been used for PLP. Many psychological modalities have been attempted to manage
Krainick and associates121 reported that 52% of patients with SCS those with PLP, including: cognitive-behavioral therapy, biofeed-
had a 50% or more decrease in pain but with long-term follow-up back, and muscular training.128
this fell to 39% after 5 years. Intracranial neurostimulation has also Relaxation training has also been shown to provide significant
been done successfully. Thalamic stimulation may be able to block benefit in many patients. One report noted that 12 of 14 patients
the spontaneous neuronal activity that is believed to occur during with chronic PLP improved with muscular relaxation training.128
reorganization in the central nervous system. Hypnotic imagery has been used alone and with relaxation training;
Bittar and colleagues122 concluded that deep brain stimulation however, further studies need to be done before any conclusions
has been utilized successfully for the treatment of PLP with a resul- regarding this therapy can be made.129
tant decreased pain, decreased opiate intake, and improved quality Biofeedback treatments resulting in vasodilation or decreased
of life. Bittar and coworkers123 published a meta-analysis support- muscle tension in the residual limb may help to reduce PLP and
ing this pain improvement as well, especially in the burning com- seem promising in patients in whom peripheral factors contribute
ponent—perhaps via a reorganization in the central nervous system. to the pain.130 Findings from neuroelectrical and neuromagnetic
Motor cortex stimulation (MCS) may serve as an adjunct in mana- source imaging suggest that changes in cortical reorganization
ging PLP for those who have failed other therapies. The magnitude might influence PLP. The use of a myoelectrical prosthesis might
and duration of MCS are highly variable, but if pain control is lost, be one way to influence PLP. Intensive use of a myoelectrical pros-
intensive reprogramming may recapture the benefit (however, thesis was positively associated with both less PLP and less cortical
intensive reprogramming may also significantly increase the risk reorganization.131 When cortical reorganization was controlled for,
the relation between prosthesis use and decreased PLP was no behavioral medicine, and nursing. It is also imperative to have
longer significant. Thus, cortical reorganization seems to mediate educational sessions with patients (and their families) prior to
this association. Another approach in patients for whom prosthesis amputation of a limb, in addition to continued postamputation
use is not practicable is the use of behaviorally relevant stimulation. educational support. Rehabilitation should begin before the opera-
A 2-week training course that consisted of discrimination training tion and should continue well after the time of surgery. Much
of electrical stimuli to the stump for 2 hours per day led to signif- research is needed in both the evaluation and the management of
icant improvements in PLP and a significant reversal of cortical phantom pains, in efforts to achieve improved analgesia and quality
reorganization.10 A control group of patients who received standard of life.
medical treatment and general psychological counseling during this
period did not show these changes in cortical reorganization or
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morphine on post amputation pain: a randomized double-blind, with muscular relaxation training to disrupt the pain-anxiety-tension
active placebo-controlled, crossover trial. Anesthesiology 2002; cycle. Pain 1979;6:47–55.
96:841–848. 129. Oakley DA, Whitman LG, Halligan PW. Hypnotic imagery as a
102. Wiech K, Kiefer RT, Töpfner S, et al. A placebo-controlled treatment for phantom limb pain: two case reports and a review.
randomized crossover trial of the N-methyl-D-aspartic acid receptor Clin Rehabil 2002;16:368–377.
130. Sherman RA. Stump and phantom limb pain. Neurol Clin 134. Harden RN, Houle TT, Green S, et al. Biofeedback in the treatment
1989;7:249–264. of phantom limb pain: a time-series analysis. Applied Psychophysiol
131. Lotze M, Flor H, Grodd W, et al. Phantom movements and pain: an Biofeedback 2005;30:83–93.
fMRI study in upper limb amputees. Brain 2001;124:2268–2277. 135. Murray CD, Pettifer S, Howard T, et al. The treatment of phantom
132. Huse E, Preissl H, Larbig W, Birbaumer N. Phantom limb pain. limb pain using immersive virtual reality: three case studies. Disabil
Lancet 2001;358:1015. Rebabil 2007;29:1465–1469.
133. Ramachandran VS, Rogers-Ramachandran D. Synaesthesia in 136. Schneider J, Hoffman A, Rost C, Shapiro F. EMDR in the treatment
phantom limbs induced with mirrors. Proc R Soc Lond B Biol Sci of chronic phantom limb pain. Pain Med 2008;9:76–82.
1996;263:377–386.
Chapter 38 musculoskeletal pain approximately 60%, and visceral pain 5% to

10%.4,5 Shoulder pain is the most common type of nociceptive
SPINAL CORD INJURY pain, affecting 40% to 50% of SCI subjects.6 Neuropathic pain is
often long lasting with a low tendency to spontaneous recovery.
Nanna Brix Finnerup Onset may occur immediately after the injury or delayed up to
several months. Any delayed onset of neuropathic pain should
prompt an examination for other causes, for example, syringomy-
elia if the pain is segmental and extending above the original neu-
rological level.
INTRODUCTION PATHOPHYSIOLOGY
Chronic pain has substantial effects on the quality of life of patients Extreme joint postures and overhead activities, high mechanical
with spinal cord injuries (SCIs). Several types of pain may severely stresses, and repetitive movements during wheelchair propulsion
affect rehabilitation, daily activities, social relations, sleep, and cause excessive burden on the upper extremities. In patients with
mood and require a multidisciplinary approach to treatment. shoulder pain, impingement syndrome is common and, in part,
secondary to muscle instability. Vertebral column pain due to sco-
liosis, mechanical instability, osteoporosis, and secondary changes
TAXONOMY after fractures, dislocations, and fixation may also occur
Little is known of the pathology of visceral pain. In some
Both nociceptive and neuropathic pain are common in SCI. The patients, a relation to bowel, bladder, or kidney problems can be
Spinal Cord Injury Pain Task Force of the International Association documented, but it is likely that visceral pain may occur in the
of the Study of Pain (IASP) has developed a classification for SCI absence of any abdominal organ dysfunction. Whether visceral
pain (Table 38–1).1 pain is a type of neuropathic pain is a subject of debate. Visceral
The most common types of musculoskeletal pain related to SCI pain has a late onset, often years after the injury.
are secondary overuse syndromes and pain related to muscle spasms A central nervous system lesion causes functional changes in the
and spasticity. Shoulder pain and pain in the elbow, wrist, hand, transmission of pain. Central neurons in the pain pathway obtain
and back are frequently reported. Osteoporosis may develop early decreased thresholds and heightened responsiveness to synaptic
after an SCI, and even a low burden on, for example, the feet during inputs, increased receptive fields, and ongoing neuronal activity.
rehabilitation may cause fracture. A special type of pain in the This gain in the pain system may be present in dorsal horn neurons
SCI population is hypertensive headache due to autonomic dysre- as well as supraspinal areas (e.g., the thalamus and cortical areas).
flexia, and this type of pain requires immediate attention to the Loss of intraspinal inhibitory neurons and a disturbed balance in
underlying pathology, which in many cases is bladder or bowel modulating systems originating in the brainstem may cause an
dysfunction. Visceral pain is pain located in the abdominal region. imbalance between facilitatory and inhibitory effects upon dorsal
Neuropathic pain is defined as ‘‘pain initiated or caused by a horn neurons, further increasing the gain in the system. These cen-
primary lesion or dysfunction in the nervous system.’’2 An SCI tral changes may result in hyperalgesia (increased response to a
may cause neuropathic pain that is located at and/or below the painful stimulus), allodynia (the elicitation of pain in the affected
injury level. At-level neuropathic pain refers to neuropathic pain area by nonnoxious stimulation with light touch or innocuous cold
located within the dermatome of the neurological level and three or warmth), and spontaneous pain and dysesthesia (unpleasant
dermatomes below this level, whereas below-level neuropathic pain abnormal sensations, e.g., tingling, pricking, and burning).
refers to pain that is present in the region more than three derma-
tomes below the neurological level of injury. Compressive mono-
neuropathies (particularly carpal tunnel syndrome) due to overuse CLINICAL FEATURES
of the wrists may cause neuropathic pain above level.
Musculoskeletal pain is present in areas with preserved sensation, is
often related to movement or certain positions, and may be
EPIDEMIOLOGY described in terms such as ‘‘aching’’ or ‘‘dull’’ (Table 38–2). It is
important to remember that there is substantial overlap in the use
The average reported frequency of chronic pain in SCI is 65%, of verbal descriptors across pain types and the diagnosis of noci-
with around one third of those patients affected reporting severe ceptive versus neuropathic pain cannot rely on single pain descrip-
pain.3 Neuropathic pain affects 40% to 50% of SCI patients, tors. Visceral pain usually presents as constant or intermittent, dull
130. Sherman RA. Stump and phantom limb pain. Neurol Clin 134. Harden RN, Houle TT, Green S, et al. Biofeedback in the treatment
1989;7:249–264. of phantom limb pain: a time-series analysis. Applied Psychophysiol
131. Lotze M, Flor H, Grodd W, et al. Phantom movements and pain: an Biofeedback 2005;30:83–93.
fMRI study in upper limb amputees. Brain 2001;124:2268–2277. 135. Murray CD, Pettifer S, Howard T, et al. The treatment of phantom
132. Huse E, Preissl H, Larbig W, Birbaumer N. Phantom limb pain. limb pain using immersive virtual reality: three case studies. Disabil
Lancet 2001;358:1015. Rebabil 2007;29:1465–1469.
133. Ramachandran VS, Rogers-Ramachandran D. Synaesthesia in 136. Schneider J, Hoffman A, Rost C, Shapiro F. EMDR in the treatment
phantom limbs induced with mirrors. Proc R Soc Lond B Biol Sci of chronic phantom limb pain. Pain Med 2008;9:76–82.
1996;263:377–386.
Chapter 38 musculoskeletal pain approximately 60%, and visceral pain 5% to

10%.4,5 Shoulder pain is the most common type of nociceptive
SPINAL CORD INJURY pain, affecting 40% to 50% of SCI subjects.6 Neuropathic pain is
often long lasting with a low tendency to spontaneous recovery.
Nanna Brix Finnerup Onset may occur immediately after the injury or delayed up to
several months. Any delayed onset of neuropathic pain should
prompt an examination for other causes, for example, syringomy-
elia if the pain is segmental and extending above the original neu-
rological level.
INTRODUCTION PATHOPHYSIOLOGY
Chronic pain has substantial effects on the quality of life of patients Extreme joint postures and overhead activities, high mechanical
with spinal cord injuries (SCIs). Several types of pain may severely stresses, and repetitive movements during wheelchair propulsion
affect rehabilitation, daily activities, social relations, sleep, and cause excessive burden on the upper extremities. In patients with
mood and require a multidisciplinary approach to treatment. shoulder pain, impingement syndrome is common and, in part,
secondary to muscle instability. Vertebral column pain due to sco-
liosis, mechanical instability, osteoporosis, and secondary changes
TAXONOMY after fractures, dislocations, and fixation may also occur
Little is known of the pathology of visceral pain. In some
Both nociceptive and neuropathic pain are common in SCI. The patients, a relation to bowel, bladder, or kidney problems can be
Spinal Cord Injury Pain Task Force of the International Association documented, but it is likely that visceral pain may occur in the
of the Study of Pain (IASP) has developed a classification for SCI absence of any abdominal organ dysfunction. Whether visceral
pain (Table 38–1).1 pain is a type of neuropathic pain is a subject of debate. Visceral
The most common types of musculoskeletal pain related to SCI pain has a late onset, often years after the injury.
are secondary overuse syndromes and pain related to muscle spasms A central nervous system lesion causes functional changes in the
and spasticity. Shoulder pain and pain in the elbow, wrist, hand, transmission of pain. Central neurons in the pain pathway obtain
and back are frequently reported. Osteoporosis may develop early decreased thresholds and heightened responsiveness to synaptic
after an SCI, and even a low burden on, for example, the feet during inputs, increased receptive fields, and ongoing neuronal activity.
rehabilitation may cause fracture. A special type of pain in the This gain in the pain system may be present in dorsal horn neurons
SCI population is hypertensive headache due to autonomic dysre- as well as supraspinal areas (e.g., the thalamus and cortical areas).
flexia, and this type of pain requires immediate attention to the Loss of intraspinal inhibitory neurons and a disturbed balance in
underlying pathology, which in many cases is bladder or bowel modulating systems originating in the brainstem may cause an
dysfunction. Visceral pain is pain located in the abdominal region. imbalance between facilitatory and inhibitory effects upon dorsal
Neuropathic pain is defined as ‘‘pain initiated or caused by a horn neurons, further increasing the gain in the system. These cen-
primary lesion or dysfunction in the nervous system.’’2 An SCI tral changes may result in hyperalgesia (increased response to a
may cause neuropathic pain that is located at and/or below the painful stimulus), allodynia (the elicitation of pain in the affected
injury level. At-level neuropathic pain refers to neuropathic pain area by nonnoxious stimulation with light touch or innocuous cold
located within the dermatome of the neurological level and three or warmth), and spontaneous pain and dysesthesia (unpleasant
dermatomes below this level, whereas below-level neuropathic pain abnormal sensations, e.g., tingling, pricking, and burning).
refers to pain that is present in the region more than three derma-
tomes below the neurological level of injury. Compressive mono-
neuropathies (particularly carpal tunnel syndrome) due to overuse CLINICAL FEATURES
of the wrists may cause neuropathic pain above level.
Musculoskeletal pain is present in areas with preserved sensation, is
often related to movement or certain positions, and may be
EPIDEMIOLOGY described in terms such as ‘‘aching’’ or ‘‘dull’’ (Table 38–2). It is
important to remember that there is substantial overlap in the use
The average reported frequency of chronic pain in SCI is 65%, of verbal descriptors across pain types and the diagnosis of noci-
with around one third of those patients affected reporting severe ceptive versus neuropathic pain cannot rely on single pain descrip-
pain.3 Neuropathic pain affects 40% to 50% of SCI patients, tors. Visceral pain usually presents as constant or intermittent, dull
280 Chapter 38 SPINAL CORD INJURY
Table 38^1. International Association for the Study of Pain Classification of Pain Related to Spinal Cord Injury
Broad Type (Tier 1) Broad System (Tier 2) Specific Structures/Pathology (Tier 3)

Nociceptive Musculoskeletal Bone, joint, muscle trauma or inflammation
Mechanical instability
Muscle spasm
Secondary overuse syndromes
Visceral Renal calculus, bowel, sphincter dysfunction, and the like
Dysreflexic headache
Neuropathic Above level Compressive mononeuropathies
Complex regional pain syndromes
At level Nerve root compression (including cauda equina)
Syringomyelia
Spinal cord trauma/ischemia (e.g., transitional zone)
Dual-level cord and root trauma (double-lesion syndrome)
Below level Spinal cord trauma/ischemia
From Siddall PJ, Yezierski RP, Loeser JD. Pain following spinal cord injury: clinical features, prevalence, and taxonomy. IASP Newsl 2000;3. Also published
by Siddal PJ, Loeser JD. Spinal Cord 2001;39:63-73.
or cramping, uncomfortable and painful abdominal sensations, MANAGEMENT

which may be associated with nausea and autonomic reactions; it
is often difficult to distinguish it from neuropathic pain. After a diagnosis is established, the underlying condition should be
Neuropathic pain is seen in an area with sensory deficits, especially treated whenever possible, but in many cases, we can provide only
to temperature, and may be accompanied by paresthesias symptomatic relief from pain and related disability (Table 38–3).
(e.g., numbness), dysesthesias, allodynia, and hyperalgesia. It is A broad approach to the treatment of chronic SCI pain is essential
often described as ‘‘burning,’’ ‘‘pricking,’’ or ‘‘shooting’’ and is and should include an explanation of the underlying cause of pain
often continuous, but it may be intermittent or paroxysmal. and an evaluation and treatment of any associated depression, sleep
Spontaneous pain is often the most disabling type of pain, but disturbance, or other psychosocial problems.
some patients have severe allodynia, causing even light touching
from cloth to be intolerable. Allodynia may, in a few cases, be
present without spontaneous pain. Concurrent infections or other Musculoskeletal Pain
illnesses and cold weather may aggravate neuropathic pain.
Depending on the underlying cause, management should be
directed at treating inflammation, weakness, instability, stiffness,
EVALUATION posture, and obesity. Prevention and early treatment of overuse
or poor posture are important, and wheelchair and home/work
The pain history should try to classify the pain type, the impact, and modifications may be needed. A physical therapist may help cor-
the multidimensional aspects of pain and include a description of recting poor posture and offer well-balanced exercise programs with
the pain intensity and quality, distribution, temporal aspects strengthening and stretching exercises.
including onset, associated symptoms, provoking and relieving When the underlying mechanism causing the pain cannot be
factors, and response to current and previous treatments. A careful treated, and during the healing process, symptomatic treatment of
clinical and neurological examination is essential and should pain and related disability should be offered. Reports on the use
include a motor and sensory examination, evaluating range of of transcutaneous electrical nerve stimulation (TENS) and acu-
motion; muscle strength; muscle tone; spasms; decreased or puncture in SCI patients are limited, but these may be used as
increased responses to touch, vibration, pinprick, cold, and for musculoskeletal pain in patients without SCIs. Simple analgesics
warmth; as well as a mapping of the distribution of the sensory such as paracetamol should be the first drug choice. Second
dysfunction. Additional diagnostic tests such as ultrasound, x-ray, choices include weak opioids such as codeine and tramadol and,
computed tomography (CT), magnetic resonance (MR), or neuro- for a temporary period, nonsteroidal anti-inflammatory drugs
physiologic testing may be indicated to identify factors such as (NSAIDs). It should be considered that tetraplegics might not
fracture, root compression, and abdominal pathology. detect upper gastrointestinal ulceration.
Table 38^2. Current Diagnosis
Nociceptive Pain Neuropathic Pain

Relation to movement Often provoked or increased by movement None or less consistent relationship to movement
Descriptors May be dull or aching May be burning, pricking, shooting
Sensation in pain area Always preserved Always abnormal sensation
Often normal Often decreased thermal sensation
Evoked pain Often musculoskeletal tenderness Maybe touch or cold allodynia or pinprick hyperalgesia
Table 38^3. Current Therapy
First-lineTherapy Second-lineTherapy
Musculoskeletal pain Physiotherapy Paracetamol-codeine, tramadol
Paracetamol NSAIDs (for a short period)
Opioids
Muscle spasm pain Baclofen Intrathecal baclofen
Tizanidine
Neuropathic pain Gabapentin/pregabalin TCAs/SNRIs
Tramadol/opioids
Cannabinoids
Lamotrigine (incomplete SCI)
NSAIDs, nonsteroidal anti-inflammatory drugs; SCI, spinal cord injury; SNRIs, selective serotonin-norepinephrine reuptake inhibitors; TCAs, tricyclic
antidepressants.
Pain due to muscle spasms and spasticity is best relieved by Gabapentin is initiated with 300 mg daily, which is slowly
spasmolytics. A sudden increase in spasticity and spasms may be increased to a final daily dose between 1800 and 3600 mg, adminis-
due to an underlying pathology that needs to be identified. tered three times daily. Pregabalin may be initiated with 75 or
150 mg daily and increased up to 600 mg in two divided doses.
Both gabapentin and pregabalin undergo renal excretion, and renal
Visceral Pain impairment requires dosage adjustment. Except for the difference in
dosing frequency, there is little evidence for choosing one of these
When no underlying pathology (e.g., urinary tract infection or drugs over the other. Also, it is unknown to what extent patients
constipation) can be identified, treating visceral pain is difficult. failing to respond to one of these drugs will benefit from the other,
Treatments used to manage neuropathic pain may be tried, but but some patients seems to do so, and it may be worth trying.
there is little or no information on the effect of such treatment
for visceral pain.
Recently, a randomized controlled trial found effect of the tricyclic
Neuropathic Pain antidepressant (TCA) amitriptyline in SCI pain and they are the
most effective drugs in many neuropathic pain conditions, includ-
The underlying cause of neuropathic pain can seldom be found and ing the other central pain conditions: central poststroke pain and
managed except for surgical treatment of syringomyelia and surgical central pain in multiple sclerosis.8 TCAs inhibit the presynaptic
decompression of nerve roots. The symptomatic treatment of neu- reuptake of noradrenaline and serotonin, antagonize N-methyl-D-
ropathic pain is difficult, and pharmacologic treatment is often, at aspartate (NMDA) receptors, and block sodium channels.
best, able to only partially reduce pain. Neuronal hyperexcitability Antidepressants have a pain-relieving effect independent of their
and loss of central inhibition of pain pathways are major mechan- antidepressant effect.
isms behind SCI neuropathic pain, and therefore, anticonvulsants Anticholinergic side effects are common (e.g., dry mouth, con-
and antidepressants are the main drug classes used to treat this pain stipation, urinary retention, sweating, and blurred vision). SCI
(Table 38–4). Only very few randomized trials exist in SCI-related patients with urinary incontinence may benefit from these effects,
neuropathic pain.7 At present, there is little evidence for patients whereas patients with constipation or urinary retention will be
with specific injury-related characteristics or specific pain symp- more reluctant to try these drugs. Especially in the elderly and in
toms to be treated with specific drugs, and the treatment is often patients treated with concomitant centrally acting drugs, somno-
a trial-and-error process. Also, the best timing of treatment is lence and gait disturbances are concerns. Especially patients with a
unknown, and no clinical studies have examined the effect of preexisting gait disturbance should be informed about this.
early or preemptive treatment. Orthostatic hypotension is another possible side effect, and there-
fore, careful monitoring for deterioration of preexisting orthostatic
hypotension is recommended. It has been suggested that TCAs
Gabapentin/Pregabalin
may increase spasticity.9 TCAs are contraindicated in patients
Gabapentin and pregabalin, which bind to the a2d-subunit of with epilepsy. Cardiotoxicity and increased risk of sudden cardiac
voltage-gated calcium channels, are first-line drugs for SCI neuro- death in patients treated with more than 100 mg daily are other
pathic pain. The pain relief is rapid, within the 1st or 2nd week, and major concerns. Electrocardiography should always be obtained
accompanied by improvements in sleep and quality of life measures. prior to treatment, and TCAs are contraindicated in patients with
The average pain reduction provided by these drugs is about 20% heart failure and cardiac conduction blocks.
to%, but they are far from effective in all patients, and so far, no Amitriptyline and imipramine are the drugs most studied.7
clinical symptom or sign is known to be predictive of efficacy. Imipramine is less sedating than amitriptyline, but it is also
Gabapentin and pregabalin have no drug interactions and are suggested that the secondary amines (desipramine and nortripty-
generally well tolerated. Somnolence and dizziness are the most line) may be better tolerated than tertiary amines (imipramine,
common side effects and seem sometimes to be particularly both- amitriptyline, and clomipramine).10 Effective doses vary consider-
ersome in SCI patients, who may have decreased mobility and ably among patients owing to a large pharmacokinetic variability in
balance problems and are often treated with spasmolytics with the metabolic pathways. The initial dose should be low, 10 to 25 mg
sedative side effects. Peripheral edema, weight gain, nausea, vertigo, daily, and slowly increased to 50 to 150 mg daily in two divided
asthenia, dry mouth, and ataxia may occur. Side effects may resolve doses. Monitoring of serum drug concentrations may be helpful in
or diminish some days after dose escalation (Table 38–5). guiding treatment.
282 Chapter 38 SPINAL CORD INJURY
Table 38^4. Drug Dosage Schedules for Drugs Used toTreat Spinal Cord Injury Neuropathic Pain
Drug Starting Daily Dose and Dose Escalation Final Daily Dosage (mg) Dosage Frequency
Anticonvulsants
Gabapentin 300 mg 1800–3600 tid
300 mg every 1–7 day
Pregabalin 75–150 mg 300-600 bid
75–150 mg every 3–7 day
Lamotrigine 25 mg 200–400 bid
25 mg (later 50–100 mg)
every other wk
Antidepressants
Imipramine/amitriptyline 25 mg daily (10 mg in the elderly) 50–150 bid
25 mg every 3–7 day
Duloxetine 30 mg 60 od
Venlafaxine 37.5 mg 150–225 bid
75 mg weekly
Cannabinoids
Dronabinol 2.5 mg 5–10 bid
2.5 mg every 2 day
Table 38^5. Common or Serious Side Effects of Drugs Used for Spinal Cord Injury Nociceptive and
Neuropathic Pain
Drug/Drug Class Side Effects

Paracetamol Seldom gastrointestinal side effects, caution with concomitant liver and renal insufficiency
Codeine Constipation
Tramadol Nausea, constipation, dizziness, somnolence, sweating
Increased risk of seizures in patients with decreased seizure threshold
NSAIDs Dyspepsia, abdominal pain (may not be present in high spinal cord injury or present as increased
spasms or sweating), headache, allergic reaction, renal dysfunction especially in patients with
preexisting renal disease
Gabapentin/pregabalin Somnolence, dizziness, peripheral edema, weight gain
Renal impairment requires dosage adjustment
TCAs Dry mouth, constipation, urinary retention, sweating, blurred vision, orthostatic hypotension,
somnolence, cardiotoxicity
Contraindicated in patients with heart failure and cardiac conduction blocks (electrocardiograph
needed) Contraindicated in patients with epilepsy
SNRIs Nausea, somnolence, dizziness, constipation, anorexia, sweating
Venlafaxine: increase in blood pressure
Lamotrigine Dizziness, ataxia, diplopia, somnolence, nausea, allergic exanthema and Stevens-Johnson–like
syndrome
Very slow dose escalation recommended
Cannabinoids Dizziness, somnolence, impaired psychomotor function, dry mouth, dysphoria
Opioids Sedation, constipation, nausea, urinary retention, dizziness, dysphoria, nightmares
NSAIDs, nonsteroidal anti-inflammatory drugs; SNRIs, selective serotonin-norepinephrine reuptake inhibitors; TCAs, tricyclic antidepressants.
central pain, and with further development, such treatment may

Selective Serotonin Reuptake Inhibitors
be available in the future.
Duloxetine and venlafaxine are new alternatives to the TCAs and act
also by inhibiting the presynaptic reuptake of noradrenaline and
serotonin. Their effect has not been evaluated in SCI pain, but Psychological Management
they have a well-established efficacy in peripheral neuropathic
pain with an effect size lower than TCAs but comparable with Chronic pain may have consequences for daily activities, sleep,
those of gabapentin and pregabalin. cognition, and emotional, behavioral, and social relations.
Duloxetine and venlafaxine are generally well tolerated. The Concomitant anxiety, depression, and psychological distress
most common side effect is nausea, but somnolence, dizziness, should be evaluated and treated. Cognitive-behavioral therapy
constipation, and sexual dysfunction may also be seen. Duloxetine includes different cognitive and behavioral techniques that may
does not seem to be associated with clinically significant cardiovas- be helpful when treating SCI patients with chronic resistant pain11:
cular changes, but venlafaxine may cause elevated blood pressure.
n Cognitive reconstructuring and coping strategies. Negative,
Duloxetine is easy to administer; the starting dose is 30 mg, and the
catastrophizing pain-related thoughts and behaviors are
dose can be increased to 60 mg once daily. Venlafaxine is adminis-
assessed and the patient is helped to become aware of these.
tered twice daily in doses up to 150 to 225 mg daily.
The therapy aims to help the patient develop the ability to
challenge her or his emotional response to pain and enhance
Other Drugs, Drug Combinations, and Nonpharmacologic her or his perception of pain control.
Treatment n Problem solving. Problems associated with pain are identified
and the patient tries alternative solutions to solve the problems.
Cannabinoids relieve central pain in multiple sclerosis and also
n Relaxation training. The patient is trained in relaxation and
seem to have an effect on spasms and spasticity, although the results
taught controlled diaphragmatic breathing. Different relax-
on these symptoms are less consistent. Various preparations of
ation techniques may be used, such as active efforts like walk-
cannabinoids exist and may be administered in, for example,
ing or engaging in pleasurable activities or passive methods
capsule form or oromucosal spray. Especially during drug titration,
such as controlling muscle tension.
dizziness, drowsiness, impaired psychomotor function, and dry
n Attention-diversion techniques. The patient is taught to focus
mouth are common side effects but may resolve with continued
and get control over his or her attention and taught various
treatment. Psychoactive effects like dysphoria may also be present,
distraction techniques.
and dependency and addiction as well as legal and regulatory issues
n Assertiveness training. Training aimed at reestablishing the
may be concerns for long-term treatment.
patient’s role in her or his family and social contacts.
The newer anticonvulsant lamotrigine, which is a sodium channel
blocker, is not well studied in neuropathic pain, but is suggested to
have some effect in incomplete SCI and has been shown to relieve
central poststroke pain. Lamotrigine treatment should be initiated OUTCOMES
very slowly, and it may take up to 8 weeks to reach the final dose of
200 to 400 mg daily. The reason for slow-dose escalation is the risk of SCI patients may experience both nociceptive and neuropathic
allergic exanthema and Stevens-Johnson syndrome during lamotri- types of pain that are inadequately relieved and persistent. SCI
gine treatment. Exanthema during lamotrigine treatment requires neuropathic pain is quite refractory to treatment, and available
discontinuation of lamotrigine treatment. Other side effects include treatments, if effective, often provide only a 20% to 30% pain
dizziness, sedation, and ataxia. reduction. This may, however, be a clinically important pain relief
Opioids such as morphine, oxycodone, and methadone as well reducing the pain to a more tolerable level, but realistic expectations
as tramadol also relieve neuropathic pain in some patients, but for the outcome of a given treatment are important. The majority of
these have not been studied in SCI pain. The common side patients have tried various treatments; some may not get any pain
effects—sedation, constipation, nausea, urinary retention, and relief from available treatments, and cognitive-behavioral therapy
dizziness—may limit their use in SCI patients and should be tried may be useful to help patients live with their pain.
only when first-line drugs and other second-line drugs have been
tried. They may, however, be indicated in patients with intermittent
pain in whom long-term treatment is not indicated (e.g., tramadol CONCLUSIONS
50 mg for attacks of neuropathic pain). For long-term therapy,
tramadol can be increased up to 400 mg daily in four divided doses. A broad approach to the treatment of chronic pain in SCI patients
Case reports suggest efficacy of topical lidocaine patches for at- is essential. SCI patients are likely to have several concurrent
level pain, but this treatment has not been tested in controlled trials. medical problems and impairments, such as bowel and bladder
If one drug provides partial pain relief, a combination with dysfunction, spasticity, and depression, and may be treated with
another drug can be tried. The final dose tolerated may be lower multiple drugs with unwanted side effects. Furthermore, they may
than with either drug alone, and patients should be evaluated not recognize certain side effects. A diagnosis of the underlying
for additive adverse effects, especially in those already treated mechanisms is the first important step and requires a thorough
with many drugs (e.g., for spasticity). Possible drug combinations assessment, but often, two or more pain problems coexist and diag-
include gabapentin or pregabalin together with an antidepressant nosing the underlying cause is not always easy.
or an opioid, or an antidepressant together with an opioid. It is
advisable not to combine an antidepressant with tramadol because
both these drug classes increase the levels of serotonin. Key Points
Spinal drug administration can be considered in refractory pain.
Intrathecal morphine alone or in combination with clonidine Owing to the limited number of randomized studies in SCI pain,
may be tried, but the long-term effects of such treatments are the proposed treatment algorithm (see Table 38–3) is based partly
unknown. Acupuncture, TENS, and spinal cord stimulation are on the evidence in other nociceptive and central and peripheral
other alternatives, especially in patients with at-level pain or incom- neuropathic pain conditions. For overuse syndromes, prevention
plete lesions, but no well-controlled studies exist. Recent studies and physiotherapy are important. As for other musculoskeletal
suggest the efficacy of transcranial motor cortex stimulation for pain syndromes, paracetamol is the first drug choice. Tramadol
284 Chapter 39 COMPLEX REGIONAL PAIN SYNDROME: TREAT MENT APPROACHES
and codeine are second choices, whereas NSAIDs for 1 to 2 weeks pain in persons with spinal cord injury. Arch Phys Med Rehabil
and strong opioids are third choices. Muscle spasms and pain 2007;88:1547–1560.
related to spasticity are best treated with spasmolytics. For neuro- 9. Cardenas DD, Warms CA, Turner JA, et al. Efficacy of amitriptyline
pathic pain, gabapentin and pregabalin are the first drug choices, for relief of pain in spinal cord injury: results of a randomized
controlled trial. Pain 2002;96:365–373.
followed by antidepressants and drug combinations, and finally, by
10. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic
tramadol, opioids, cannabinoids, and lamotrigine. management of neuropathic pain: Evidence-based recommendations.
Pain 2007;132:237–251.
REFERENCES 11. Turk DC, Flor H. The cognitive-behavioral approach to pain
management. In McMahon SB, Koltzenburg M (eds): Wall &
1. Siddall PJ, Yezierski RP, Loeser JD. Pain following spinal cord injury: Melzack’s Textbook of Pain. London: Elsevier, Churchill Livingstone,
clinical features, prevalence, and taxonomy. IASP Newsl 2000;3. 2006; pp 339–348.
Also published by Siddal PJ, Loeser JD. Spinal Cord 2001;39:63-73.
2. Merskey H, Bogduk N: Classification of Chronic Pain: Descriptions of
Chronic Pain Syndromes and Definitions of Pain Terms, Seattle: IASP SUGGESTED READINGS
Press, 1994.
3. Siddall PJ, Loeser JD. Pain following spinal cord injury. Spinal Cord Finnerup NB, Jensen TS. Spinal cord injury pain—mechanisms and
2001;39:63–73. treatment. Eur J Neurol 2004;11:73–82.
4. Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ. A longitudinal Hastings J, Goldstein B. Paraplegia and the shoulder. Phys Med Rehabil
study of the prevalence and characteristics of pain in the first 5 years Clin N Am 2004;15:699–718.
following spinal cord injury. Pain 2003;103:249–257. Hulsebosch CE. From discovery to clinical trials: treatment strategies for
5. Budh CN, Lund I, Ertzgaard P, et al. Pain in a Swedish spinal cord central neuropathic pain after spinal cord injury. Curr Pharm Des
injury population. Clin Rehabil 2003;17:685–690. 2005;11:1411–1420.
6. Goldstein B. Musculoskeletal conditions after spinal cord injury. Siddall PJ, Middleton JW. A proposed algorithm for the management of
Phys Med Rehabil Clin N Am 2000;11:91–108. pain following spinal cord injury. Spinal Cord 2006;44:67–77.
7. Finnerup NB, Otto M, McQuay HJ, et al. Algorithm for neuropathic Vierck CJ, Siddall P, Yezierski RP. Pain following spinal cord injury:
pain treatment: an evidence based proposal. Pain 2005;118:289–305. animal studies and mechanistic studies. Pain 2000;89:1–5.
8. Rintala DH, Holmes SA, Courtade D, et al. Comparison of the Widerstrom-Noga E, Biering-Sorensen F, Bryce T, et al. The international
effectiveness of amitriptyline and gabapentin on chronic neuropathic spinal cord injury pain basic data set. Spinal Cord 2008.
Chapter 39 and painful conditions in patients who were previously highly func-
tional. The manifestations of this pathophysiologic process have
COMPLEX REGIONAL PAIN been described in many ways, but the name was ultimately changed
to complex regional pain syndrome (CRPS) at a consensus workshop
in 1995.
SYNDROME: TREATMENT
APPROACHES TAXONOMY
Paul J. Christo and Chauncey T. Jones CRPS was probably first described by Dr. Silas Mitchell as severe
burning pain after gunshot wounds sustained by soldiers during
the American Civil War. Many other names—such as reflex sym-
pathetic dystrophy (RSD), causalgia, algodystrophy mineures,
mimocausalgia, sympathalgia, and post-traumatic spreading syn-
drome—have been attached to this syndrome. The name commonly
used for this syndrome, reflex sympathetic dystrophy, is actually a
INTRODUCTION misnomer in that it implies a reflex mechanism associated with a
hyperactive sympathetic nervous system. However, animal models
The physiologic response to an injury includes pain and inflamma- have suggested that altered neuromodulation, nerve hyperexcitabil-
tion that is typically proportional to the severity of tissue damage. ity, and central sensitization may all contribute to this complicated
Tissue injury activates peripheral pain fibers, ag- and C-fibers. disease process known as CRPS. In order to incorporate new
Acute-phase reactants such as cytokines and free radicals cause research findings and create uniform terminology and diagnostic
local swelling (tumor), redness (rubor), pain (dolor), and increase criteria, the International Association for the Study of Pain (IASP)
in temperature (calor). This normal physiologic process serves as a proposed taxonomy that grouped the disorders under the term
protective mechanism to prevent ongoing insult to an injured area ‘‘complex regional pain syndromes.’’ The term CRPS is broad
of the body. As the affected area heals, pain and swelling improve and nonspecific and incorporates the array of signs and symptoms
and full function is restored. that this syndrome exhibits in patients. Two subtypes exist: CRPS I
However, inappropriate or abnormal activation of this pain (RSD) and CRPS II (causalgia). CRPS I refers to a post-traumatic
pathway can produce a disease state that can lead to debilitating syndrome causing spontaneous pain not limited to the distribution
and codeine are second choices, whereas NSAIDs for 1 to 2 weeks pain in persons with spinal cord injury. Arch Phys Med Rehabil
and strong opioids are third choices. Muscle spasms and pain 2007;88:1547–1560.
related to spasticity are best treated with spasmolytics. For neuro- 9. Cardenas DD, Warms CA, Turner JA, et al. Efficacy of amitriptyline
pathic pain, gabapentin and pregabalin are the first drug choices, for relief of pain in spinal cord injury: results of a randomized
followed by antidepressants and drug combinations, and finally, by
10. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic
tramadol, opioids, cannabinoids, and lamotrigine. management of neuropathic pain: Evidence-based recommendations.
Pain 2007;132:237–251.
REFERENCES 11. Turk DC, Flor H. The cognitive-behavioral approach to pain
management. In McMahon SB, Koltzenburg M (eds): Wall &
1. Siddall PJ, Yezierski RP, Loeser JD. Pain following spinal cord injury: Melzack’s Textbook of Pain. London: Elsevier, Churchill Livingstone,
clinical features, prevalence, and taxonomy. IASP Newsl 2000;3. 2006; pp 339–348.
Also published by Siddal PJ, Loeser JD. Spinal Cord 2001;39:63-73.
2. Merskey H, Bogduk N: Classification of Chronic Pain: Descriptions of
Chronic Pain Syndromes and Definitions of Pain Terms, Seattle: IASP SUGGESTED READINGS
Press, 1994.
3. Siddall PJ, Loeser JD. Pain following spinal cord injury. Spinal Cord Finnerup NB, Jensen TS. Spinal cord injury pain—mechanisms and
2001;39:63–73. treatment. Eur J Neurol 2004;11:73–82.
4. Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ. A longitudinal Hastings J, Goldstein B. Paraplegia and the shoulder. Phys Med Rehabil
study of the prevalence and characteristics of pain in the first 5 years Clin N Am 2004;15:699–718.
following spinal cord injury. Pain 2003;103:249–257. Hulsebosch CE. From discovery to clinical trials: treatment strategies for
5. Budh CN, Lund I, Ertzgaard P, et al. Pain in a Swedish spinal cord central neuropathic pain after spinal cord injury. Curr Pharm Des
injury population. Clin Rehabil 2003;17:685–690. 2005;11:1411–1420.
6. Goldstein B. Musculoskeletal conditions after spinal cord injury. Siddall PJ, Middleton JW. A proposed algorithm for the management of
Phys Med Rehabil Clin N Am 2000;11:91–108. pain following spinal cord injury. Spinal Cord 2006;44:67–77.
7. Finnerup NB, Otto M, McQuay HJ, et al. Algorithm for neuropathic Vierck CJ, Siddall P, Yezierski RP. Pain following spinal cord injury:
pain treatment: an evidence based proposal. Pain 2005;118:289–305. animal studies and mechanistic studies. Pain 2000;89:1–5.
8. Rintala DH, Holmes SA, Courtade D, et al. Comparison of the Widerstrom-Noga E, Biering-Sorensen F, Bryce T, et al. The international
effectiveness of amitriptyline and gabapentin on chronic neuropathic spinal cord injury pain basic data set. Spinal Cord 2008.
Chapter 39 and painful conditions in patients who were previously highly func-
tional. The manifestations of this pathophysiologic process have
COMPLEX REGIONAL PAIN been described in many ways, but the name was ultimately changed
to complex regional pain syndrome (CRPS) at a consensus workshop
in 1995.
SYNDROME: TREATMENT
APPROACHES TAXONOMY
Paul J. Christo and Chauncey T. Jones CRPS was probably first described by Dr. Silas Mitchell as severe
burning pain after gunshot wounds sustained by soldiers during
the American Civil War. Many other names—such as reflex sym-
pathetic dystrophy (RSD), causalgia, algodystrophy mineures,
mimocausalgia, sympathalgia, and post-traumatic spreading syn-
drome—have been attached to this syndrome. The name commonly
used for this syndrome, reflex sympathetic dystrophy, is actually a
INTRODUCTION misnomer in that it implies a reflex mechanism associated with a
hyperactive sympathetic nervous system. However, animal models
The physiologic response to an injury includes pain and inflamma- have suggested that altered neuromodulation, nerve hyperexcitabil-
tion that is typically proportional to the severity of tissue damage. ity, and central sensitization may all contribute to this complicated
Tissue injury activates peripheral pain fibers, ag- and C-fibers. disease process known as CRPS. In order to incorporate new
Acute-phase reactants such as cytokines and free radicals cause research findings and create uniform terminology and diagnostic
local swelling (tumor), redness (rubor), pain (dolor), and increase criteria, the International Association for the Study of Pain (IASP)
in temperature (calor). This normal physiologic process serves as a proposed taxonomy that grouped the disorders under the term
protective mechanism to prevent ongoing insult to an injured area ‘‘complex regional pain syndromes.’’ The term CRPS is broad
of the body. As the affected area heals, pain and swelling improve and nonspecific and incorporates the array of signs and symptoms
and full function is restored. that this syndrome exhibits in patients. Two subtypes exist: CRPS I
However, inappropriate or abnormal activation of this pain (RSD) and CRPS II (causalgia). CRPS I refers to a post-traumatic
pathway can produce a disease state that can lead to debilitating syndrome causing spontaneous pain not limited to the distribution
of a single nerve and disproportionate to the inciting event. CRPS II

represents a pain syndrome occurring after evidence of a specific
nerve injury and not necessarily limited to the territory of the
injured nerve.
EPIDEMIOLOGY
CRPS occurs more frequently in young adults and more often in
women than in men. The disease may be triggered by any number
of insults including major or minor trauma, surgery, inflammation,
stroke, nerve injury, myocardial infarction, certain neoplasms, and
immobilization. No correlation exists between severity of injury and
subsequent severity of CRPS. Psychological stressors and poor
coping skills can influence the natural history and severity of CRPS.
PATHOPHYSIOLOGY
Like many neuropathic syndromes, the pathophysiologic mechan-
isms of CRPS are ill defined. Animal studies have demonstrated that
acute-phase inflammatory reactants and free radicals can cause
signs and symptoms similar to those of CRPS in the acute setting.
Further, animal models have shown sprouting of sympathetic nerve
fibers around sensory neurons in the dorsal root ganglia (DRG)
after peripheral nerve injury. In fact, abnormal nerve sprouting
and C-fiber (pain fiber) excitation by the sympathetic nervous
system may explain abnormal discharges seen in peripheral nerves
after nerve damage. Human studies, however, have implicated the Figure 39^1. Complex regional pain syndrome (CRPS) I of the
sympathetic nervous system less directly. For instance, there is vari- left ankle. (Symptoms and signs include edema, skin discoloration,
able response to sympathetic blockade with high rates of relapse dryness, shiny skin, dystonia, atrophy, and contracture.)
among patients receiving these injections. Researchers have
hypothesized that changes in the dorsal horn of the spinal cord
may lead to the hyperexcitable state of CRPS. Central sensitization of patients with CPRS, type I describes three patterns of spread
and continual activation of N-methyl-D-aspartate (NMDA) recep- from the initial area of presentation: contiguous spread noted in
tors in the central nervous system may maintain this state of neural all patients and characterized by an enlargement of the affected
hyperarousability after nerve injury. area; independent spread noted in 70% of patients and described
as the appearance of symptoms in a distant and non-continguous
location; and mirror-image spread noted in 15% of patients and
CLINICAL FEATURES highlighted by symptoms on the opposite side of the affected
region that mimicked the site of initial presentation.6
Patients with CRPS exhibit a diversity of symptoms. Manifestations
of CRPS reflect pathologic changes in the autonomic, sensory, and
motor systems (Fig. 39–1). Patients often report ‘‘stinging’’ and
‘‘burning’’ pain, although they may describe ‘‘aching,’’ ‘‘shooting,’’
Box 39^1 CURRENT DIAGNOSIS*
‘‘squeezing,’’ and ‘‘throbbing’’ sensations. Many patients describe 1. A neuropathic pain syndrome that displays sudomotor and vasomo-
hyperesthesia (increased sensitivity to stimulation) to common tor disturbances.
mechanical stimuli such as clothing touching an affected region 2. Previous descriptors include RSD and causalgia.
or even cool breezes blowing on an extremity. Alterations in envi- 3. Severity and duration are highly variable and stages of the disease
ronmental temperature may also provoke or exacerbate the pain. may not be evident.
The IASP differentiates only between two general subtypes of 4. Two subtypes exist: CRPS I (RSD) and CRPS II (causalgia).
CRPS: type I and type II.1-4 Type I refers to a syndrome that 5. CRPS I: Post-traumatic syndrome causing spontaneous pain not lim-
lacks a specific nerve lesion (see Fig. 39–1), whereas type II reflects ited to the distribution of a single nerve and disproportionate to
the inciting event.
clear evidence of nerve injury. The somatosensory symptoms of 6. CRPS II: Pain syndrome occurring after evidence of a specific nerve
CRPS II extend beyond the course of the affected peripheral injury and not necessarily limited to the territory of the injured
nerve and thus distinguish it from isolated peripheral mononeuro- nerve.
pathies. Both types can manifest the same symptoms and signs, and 7. Regional, spontaneous pain, allodynia, or hyperalgesia not limited to
clinicians may use both the IASP diagnostic criteria and the pro- the territory of a single peripheral nerve and disproportionate to a
posed modified research diagnostic criteria to aid in formulating a known inciting event.
diagnosis (Boxes 39–1 and 39–2). The literature notes a series of 8. Evidence of edema, changes in skin blood flow, or abnormal sudomo-
sequential stages of untreated CRPS beginning with stage I (early, tor activity in the painful region.
acute, and marked by sensory/vasomotor, sudomotor disturbances), 9. Presence of a noxious event or cause or immobilization (may be
absent in 5%^10% of patients).
stage II (increased pain, vasomotor disturbance, and substantial 10. No other condition can otherwise account for the degree of pain and
motor/trophic changes), and stage III (diminished pain, signifi- dysfunction.
cantly increased motor/trophic changes, and continued vasomotor
changes).5 In practice, the distinction between these stages may not *Nos. 7^10 represent the IAPS Diagnostic Criteria for CRPS.
CRPS, complex regional pain syndrome; IASP, International Association for the Study of Pain;
be appreciated, and the importance of making such distinctions for RSD, reflex sympathetic dystrophy.
treatment purposes has yet to be discovered. A retrospective analysis
Criteria for CRPS attempt to standardize the diagnosis and aid in

Box 39^2 PROPOSED MODIFIED RESEARCH DIAGNOSTIC more homogenous research investigations (see Box 39–2).
CRITERIA FOR CRPS Current IASP diagnostic criteria for CRPS include (1) the pres-
ence of an initiating noxious event or a cause of immobilization, (2)
Diagnostic criteria for CRPS in scientific settings (clinical trials): continuing pain, allodynia, or hyperalgesia in which the pain is dis-
1. Continuing pain that is out of proportion to the inciting event. proportionate to any known inciting event, (3) evidence at some time
2. Patient reports at least one symptom in each of the four categories: of edema, changes in skin blood flow, or abnormal sudomotor activ-
a. Sensory: Reports of hyperesthesia, allodynia, or hyperalgesia.
b. Vasomotor: Reports of temperature asymmetry or skin color ity in the region of pain (can be a sign or symptom), and (4) this
changes. diagnosis is excluded by the existence of other conditions that would
c. Sudomotor: Reports of hyperhidrosis, dryness, edema, or shiny otherwise account for the degree of pain and dysfunction. Although
skin. the current diagnostic criteria (see Box 39–1) do not require that a
d. Motor: Reports of spasm, tremor, weakness, decreased range of patient display or a clinician observe a specific number of symptoms
motion, atrophy, dystonia, contractures, or dystrophic changes or signs before diagnosing CRPS, the Proposed Modified Diagnostic
to hair, nails, or skin. Criteria (see Box 39–2) do make that distinction. For instance,
3. Displays at least one sign in two or more of the following four patients should report pain that is disproportionate to any inciting
categories:
event, describe at least one symptom in each of the four categories
a. Sensory: Evidence of hyperesthesia, allodynia, or hyperalgesia.
b. Vasomotor: Evidence of temperature asymmetry or skin color
(sensory, vasomotor, sudomotor/edema, and motor/trophic), and
changes. display at least one sign in two or more of the following categories:
c. Sudomotor: Evidence of dryness, sweating, edema, or shiny skin. sensory, vasomotor, sudomotor/edema, and motor/trophic.
d. Motor: Evidence of spasm, tremor, weakness, decreased range of Laboratory testing may clarify the existence of SMP and auto-
motion, atrophy, dystonia, contractures, or dystrophic changes nomic disturbance or may exclude conditions that resemble CRPS.
to hair, nails, or skin. That is, vascular studies can help exclude deep vein thrombosis
CRPS, complex regional pain syndrome; IASP, International Association for the Study of Pain. (DVT); electromyography testing/nerve conduction testing (EMG/
NCT) can help exclude peripheral neuropathy; magnetic resonance
imaging (MRI) and radiographs can help exclude soft tissue or disk
disease, central canal stenosis, neuroforaminal stenosis, or bone
Patients typically report pain caused from stimuli that ordinarily disease; and blood testing can help exclude infection, cellulitis, or
do not provoke pain (allodynia) and/or describe exaggerated rheumatologic disease.
responses to stimuli that are normally painful (hyperalgesia). Other tests may reinforce the diagnosis of CRPS by detecting
Certain patients may even protect the affected part from mechanical abnormalities in sympathetic activity or disturbances in blood flow
or thermal stimulation by wearing a glove or a boot or assuming in affected regions. Outcome studies fail to support the diagnostic
defensive postures. Other common CRPS symptoms include vaso- or therapeutic value of any of the following tests:
motor disturbances such as temperature asymmetry and/or skin
Thermography: An infrared thermometer measures thermal differ-
color changes. For instance, patients may complain that a limb
ences in the skin of two extremities.
feels warm and appears red or feels cool and looks dusky or bluish.
Quantitiative Sensory Tests: These assess differences required to
Further, patients may report sudomotor changes in the form of
produce light touch, vibration, heat, cold, and thermal pain
asymmetry of hyperhidrosis (sweating), dryness, edema, or skin
thresholds.
in the affected region. Motor dysfunction may manifest as spasm,
Radiographs: X-rays image areas of CRPS that may display a range
tremor, dystonia, weakness, atrophy, or contracture in the
of patchy osteopenia as soon as 2 weeks after onset to general-
affected extremity. Patients often refer to symptoms of myofascial
ized osteopenia and cortical erosions.
pain in the proximal joint as well. Trophic disturbances may
Three-phase bone scan: Bone scan demonstrates increased uptake
present as changes in skin, nails, or hair pattern.
into joints of the affected limb during the third phase (bony
Selective sympathetic blockage to the affected limb may be per-
uptake of 99mTc-labeled phosphates). This is frequently ordered
formed for both diagnostic and therapeutic purposes. If the block
and its utility is questionable.
reduces pain, the patient is regarded as having a sympatheti-
Sudomotor Testing: Sudomotor testing compares resting and pro-
cally mediated pain (SMP) component associated with the CRPS.
voked sweat output in the painful limb compared with the unaf-
However, no pain relief probably suggests sympathetically independent
fected limb.
pain. Results of the sympathetic blockade should be viewed with cau-
Sympathetic blocks (stellate ganglion (SG) or lumbar sympa-
tion, given the potential for false-positive and false-negative outcomes.
thetic) or pharmacologic sympathetic block via phentolamine
CRPS, like many chronic pain conditions, may be viewed as a
(generic) intravenous infusion: These aid in assessing an SMP
biopsychosocial disturbance. Patients frequently experience depres-
component and in facilitating pain relief for functional restora-
sion, anxiety, fear, progressive disuse of the affected part, and social
tion (physical therapy [PT], occupational therapy [OT]).
withdrawal. No well-controlled studies have linked these symptoms
to a cause of CRPS or a result of the syndrome; however, clinicians
should recognize the psychological/behavioral factors associated
with CRPS-related pain and disability. MANAGEMENT
Treatment of CRPS should consist of an early, aggressive, multimo-
EVALUATION dal approach. Goals of therapy should be threefold: pain relief,
functional restoration, and psychological stabilization (Box 39–3).
The hallmark of CRPS diagnosis remains a thorough clinical evalua- Pain control is important in order to facilitate active participation
tion of symptoms and signs. The literature suggests that some quan- in physical rehabilitation. Clinicians should consider several mod-
titative testing may aid in confirmation, however. The IASP criteria alities for the treatment of CRPS such as pharmacotherapeutic
for diagnosis (see Box 39–1) are broad and quite sensitive and can lead agents; nerve blocks; occupational, physical, vocational, and recre-
to overdiagnosis. Consequently, a separate set of criteria have been ational therapy; psychological/behavioral therapy; and neuromod-
proposed to the IASP that retain much of the diagnostic sensitivity of ulation (Fig. 39–2). Patients and clinicians alike should understand
the current criteria while almost doubling the specificity (reducing that a multidisciplinary approach reflects the best method of
false positives). In effect, the Proposed Modified Research Diagnostic improving symptoms and function and enhancing quality of life.
at presynaptic nerve terminals and facilitate the descending antino-

Box 39^3 CURRENT THERAPY ciceptive (pain-relieving) pathway in the central nervous system.
They may confer further benefit to CRPS patients through their
Therapy is achieved via a multimodal approach. The overarching goal is sedative effects (antihistaminergic) and anxiolytic actions. Both
functional restoration.
1. Pharmacologic: TCAs, anticonvulsants, opioids, bisphosphonates, the tertiary amines (amitriptyline, doxepin) and the secondary
steroids, topical therapy. amines (nortriptyline, desipramine) are used clinically. Adverse
2. Functional restoration: Physical therapy, occupational therapy, rec- effects are more common with tertiary amines; therefore, the sec-
reational therapy, vocational therapy. ondary amines should be strongly considered for initial treatment.
3. Interventional procedures: Sympathetic nerve blockade (stellate A reasonable dosing regimen consists of 25 mg by mouth before
ganglion/lumbar), spinal cord stimulation, peripheral nerve stimula- bedtime, gradually increasing by 25 mg every week until reaching a
tion, intraspinal infusion therapies. target dose of 100 mg by mouth at bedtime. If patients experience
4. Psychosocial elements: Assessment and treatment of psychiatric insufficient pain relief and do not develop intolerable adverse
diagnoses (axis I), assess patient and family response to CRPS, assess effects, the dose can be escalated in 25-mg increments until a max-
significant ongoing life stressors, relaxation/biofeedback training,
coping skills, cognitive-behavioral interventions.
imum dose of 150 mg at bedtime is reached.
Adverse effects may include conduction abnormalities (sodium
CRPS, complex regional pain syndrome; TCAs, tricyclic antidepressants. channel antagonism), anticholinergic side effects (fatigue, xerosto-
mia, constipation, imbalance, urinary retention, and palpitations),
orthostatic hypotension (a1-adrenergic antagonism), weight gain
(antihistaminergic effect), and sedation (antihistaminergic effect).
In the absence of any uniformly efficacious medical or surgical Often, adverse effects are dose-related and less pronounced when
treatment, a multimodal strategy represents a ‘‘best practice’’ for low doses are increased gradually. Relevant contraindications to
the successful management of CRPS. TCAs include recent heart attack, epilepsy, narrow-angle glaucoma,
heart block, urinary retention, and use of monoamine oxidase inhi-
bitors. Prescribe cautiously in patients with congenital QT syn-
Pharmacotherapy drome, cardiovascular disease, or hypokalemia. Clinicians should
consider tapering TCAs over 1 to 2 weeks to avoid the discontinua-
Several classes of medications are used to treat CRPS patients tion syndrome (malaise, chills, myalgias, nasal discharge). More
despite the paucity of randomized, controlled studies to support conservative doses should be used in older persons such as 10 mg
their efficacy in this disease. Some medications (gabapentin, pre- by mouth before bedtime then escalating in increments of 10 mg
gabalin, tricyclic antidepressants [TCAs], opioids, transdermal weekly to a maximum dose of 150 mg at bedtime. Note that over-
lidocaine) have been adequately studied in patients with painful dose of TCAs can be lethal; therefore, avoid using these medications
diabetic neuropathy and/or postherpetic neuralgia, and the results in patients who are actively suicidal.
extrapolated to the treatment of CRPS (Table 39–1). Selective serotonin reuptake inhibitors (SSRIs) are less effective
in treating neuropathic pain, although venlafaxine (Effexor), dulox-
etine (Cymbalta), and other antidepressants that block both sero-
TCAs
tonin and norepinephrine reuptake (SNRIs) may be more effective.
TCAs have been used for many years in the treatment of neuro-
pathic pain. Randomized, controlled trials have documented their
Anticonvulsants
analgesic properties aside from their antidepressant effects. These
medications can ease pain, alleviate depression, and promote sleep Anticonvulsants are effective in treating neuropathic pain associated
(often disrupted because of pain and limb immobility) in patients with trigeminal neuralgia, postherpetic neuralgia, and diabetic
with CRPS. TCAs inhibit reuptake of serotonin and norepinephrine neuropathy. Only case series suggest that gabapentin (Neurontin)
may be effective in treating CRPS.7 Most anticonvulsants have been
used in individual patients, but none have been properly studied to
Pharmacological determine their efficacy in CRPS. Commonly used medications
therapies include gabapentin, pregabalin (Lyrica), phenytoin (Dilantin), and
carbamazepine (Tegretol). Other agents incorporated into CRPS
treatment may include lamotrigine (Lamictal), oxcarbazepine
(Trileptal), topiramate (Topamax), and tiagabine (Gabitril).
A rational dosing structure for gabapentin may be 300 mg three
times daily with 100- to 300-mg increments every 5 days or so until a
maximum dose of 3600 mg/day is obtained if patients fail to achieve
adequate relief at lower doses. Dose adjustment is necessary for
Cognitive- patients with renal insufficiency. Frequently reported adverse effects
Functional are somnolence and dizziness, and sometimes, ataxia and fatigue.
behavioral
restoration These effects often resolve within 2 weeks of initiation of treatment.
therapy
Typical pregabalin dosing begins at 75 mg twice daily and
increasing to 150 mg twice daily within 1 week if patients are
tolerating the medication. Adverse events (dizziness, somnolence)
are similar to those of gabapentin.
Less often used, phenytoin and carbamazepine may follow similar
dosing schedules for treating trigeminal neuralgia and diabetic neu-
ropathy. Serum levels of both should be assessed for toxicity.
Theoretically, carbamazepine (sodium channel blocking capacity)
Interventional may be effective for CRPS II because injury to the peripheral nerve
procedures changes the expression and distribution of sodium channels on axons.
Figure 39^2. Functional restoration of CRPS is achieved by a Dosing of other anticonvulsants for CRPS is speculative, given
multimodal approach. the dearth of evidence for their utility in neuropathic pain.
Table 39^1. Proposed Pharmacotherapeutic Agents for theTreatment of Complex Regional Pain Syndrome
Drug Dose Comments

Antidepressants (Oral):
TCAs
Nortryptyline (Pamelor) 10–25 mg qhs initial dose and titrate Caution in elderly, pts. with suicidal ideation, and pts. with
Desiprimine (Norpramin) up to max of 150 mg qhs over recent cardiac events.
Amitryptyline (Elavil) several wks. Consider tapering over 1–2 wk to avoid malaise, chills,
Doxepin (Sinequan) myalgias, nasal D/C.
Venlafaxine (Effexor) 37.5 mg bid initially. Similar to TCA precautions.
Maximum dose 225 mg.
Titrate up over several wks.
Anticonvulsants (Oral)
Gabapentin (Neurontin) 300 mg day 1, bid day 2, tid day 3. D/C taper over 7 days.
Max 3600 mg/day.
Titrated up over several wks.
Pregabalin (Lyrica) 75 mg bid for 1 wk, then 150 mg bid D/C taper over 7 days.
Phenytoin (Dilantin) 150 mg bid Must follow serum levels.
Carbamazepine (Tegretol) 100 mg bid initially. Must follow serum levels. Useful especially for CRPS II.
Titrate over several days.
Maximum 600 mg/day
Opioids
Initial dosages:
Methadone (Methadose) 5 mg tid Increase while balancing analgesia and adverse effects.
Fentanyl patch (Duragesic) 12.0 mcg/hr
Morphine (MS Contin) 15 mg q 12 hr. Do not crush or chew.
Oxycodone (OxyContin) 10 mg q 12 hr. Do not crush or chew.
Tramadol (Ultram) 50–100 mg q 4–6 hr. Can cause N/V, dizziness, HA, somnolence, constipation.
Oxymorphone (Opana ER) Titrate to 400 mg/day maximum
5 mg q 12 hr.
Bisphosphonates
Intranasal calcitonin 100 IU/spray tid x 3 wk. Common adverse effects: Flushing, N/V, backache, rhinitis.
(Miacalcin Nasal) Rare: MI, anemia, anaphylaxis, CVA, bronchospasm.
Intravenous clodronate 300 mg daily for 10 days.
Intravenous alendronate 7.5 mg daily for 3 days.
Steroids
Prednisone 30 mg/day; max 12 wk. Taper slowly.
Topical Agents
Lidocaine patch (Lidoderm) 5%; apply 12 hr/day Usage longer than 12 hr/day may lead to tolerance; skin
irritation.
Capsaicin (Zostrix) 0.025% apply tid Induces cutaneous burning.
50% DMSO (Rimso-50) Apply daily for 8 wk.
CRPS, complex regional pain syndrome; D/C, discontinuation; DMSO, dimethyl sulfoxide; HA, headache; TCA, tricyclic antidepressants.
Clinicians may consider tapering anticonvulsants over 7 days to

Topical Agents
avoid the unlikely potential of withdrawal seizures in CRPS patients.
Topical agents for CRPS may be useful. For instance, lidocaine
(Lidoderm) patches 5%, applied for 12 hours per day can help
Corticosteroids
treat focal, allodynic areas of pain.8 Capsaicin (Zostrix) cream
Corticosteroids have been reported in studies to be effective treat- 0.025% applied two or three times a day produces analgesia in
ment for CRPS. They may suppress ectopic neural discharges and CRPS through release and reuptake inhibition of substance
reduce the inflammatory component of CRPS. Chronic steroid use P. Unfortunately, most patients cannot tolerate the cutaneous burn-
is not recommended owing to an unfavorable risk-to-benefit ing sensation associated with capsaicin application. Some studies
profile. However, some evidence indicates that prednisone 30 mg suggest that topical 50% dimethyl sulfoxide (DMSO [Rimso-50])
per day for 12 weeks may be helpful. may be beneficial as well.
include clonidine (oral and transdermal), reserpine (Resa), phenox-

Opioids
ybenzamine (Dibenzyline), and prazosin (Minipress). Phentolamine
Opioids are gaining favor for the treatment of chronic neuropathic (Regitine) infusion tests are sometimes used as an adjunctive tool
pain through prospective and some randomized, controlled stu- in determining the presence of adrenergic mechanisms associated
dies.9-12 Because opioids can produce significant adverse effects as with CRPS.
well as tolerance, physical dependence, and addiction, they are often
reserved for CRPS-related pain that responds inadequately to other
Other Medications
medical or procedural therapies. When opioids are incorporated,
patients should develop specific goals of treatment such as more Other medications have been tried in the treatment of CRPS, but no
active participation in functional restoration and/or engagement in randomized, controlled trials can confirm their efficacy. These agents
social activities. Long-acting or sustained-release opioids provide include calcium channel blockers, thalidomide (Thalomid), benzo-
continuous medication with fewer fluctuations in serum levels, diazapines, ketamine (Ketalar), clonidine (Catapres), and muscle
better compliance with dosing regimen, and consequently, better relaxants. Intrathecal baclofen (Lioresal) may aid in alleviating
pain control. Reasonable starting doses of typical opioids include dystonia or exaggerated flexor reflexes in select patients with CRPS.
methadone (Methadose) 5 mg by mouth three times daily, sus-
tained-release morphine (MS Contin) 15 mg by mouth every 12
hours, sustained-release oxycodone (Oxycontin) 10 mg by mouth Procedures
every 12 hours, extended-release oxymorphone (Opana ER) 5 mg
by mouth every 12 hours, or trandermal fentanyl (Duragesic) Sympathetic Nerve Blocks
12 mcg/hour every 3 days. Because NMDA receptor antagonists
may more effectively treat neuropathic pain and methadone dis- Sympathetic blockade with local anesthetics have been performed
plays NMDA receptor blocking capacity, clinicians may consider for both diagnostic and therapeutic purposes in the management
methadone as an initial opioid for CRPS. The goal of opioid therapy of CRPS. Despite widespread use, there is weak evidence for
consists of achieving a balance between analgesia and intolerable sympathetic blockade as a beneficial therapy, and no guidelines
adverse effects; therefore, no maximal dose can be recommended. for selecting patients or drugs for sympathetic blocks (SG or
The dose should be customized for each patient. lumbar sympathetic) currently exist. A subset of CRPS patients
Bear in mind that opioids are often associated with adverse may display SMP, and those patients are more likely to derive
effects such as nausea, constipation, sedation, hormonal changes, pain relief from sympathetic blocks. Furthermore, anecdotal reports
immunologic alterations, hyperalgesia, and impaired cognitive coupled with the literature suggest that patients with mechanical
function. Tolerance to the constipative effects of opioids rarely allodynia and burning pain along with temperature and color
develops; hence, concurrent laxative therapy is critical. changes may represent good candidates for sympathetic blockade.
Comprehensive and ongoing assessment of opioid responsiveness, A positive response (pain relief) may not be diagnostic of the
adverse effects, and aberrant behavior (diversion, self-escalation) SMP subset of CRPS patients, given the risk of false-positive and
should be integral to treatment. false-negative outcomes associated with these procedures. For
Tramadol (Ultram), a synthetic derivative of codeine acts as a instance, improper needle placement may result in no block or in
weak m-receptor agonist, inhibits reuptake of serotonin and norepi- pain relief from partial or total sensory/motor block (somatic nerve
nephrine (similar to TCAs), and facilitates neuronal serotonin block). Consequently, some clinicians use pharmacologic sympa-
release. Randomized, controlled trials demonstrate tramadol’s thetic block with phentolamine to help confirm the involvement
effectiveness for peripheral neuropathy,13,14 and may be useful for of a sympathetically maintained component in CRPS patients.
patients with CRPS. The usual dosing consists of 50 to 100 mg by Patients who report pain reduction, increased range of motion,
mouth every 4 to 6 hours and gradually escalating by 50-mg incre- and greater participation in functional restorative techniques (PT,
ments every 3 to 4 days to diminish the onset of adverse events. The OT) may benefit from an extended series of repeat blocks. PT
maximum dose is 400 mg/day. An extended-release formulation is should be coordinated after the blocks to maximize the analgesic
available. Common adverse effects may include nausea, vomiting, benefit of the procedure.
dizziness, vertigo, constipation, somnolence, and headache. CRPS of the upper extremity can be treated with cervicothoracic
Clinicians should be mindful of the potential for increased risk of (SG) blocks, and that of the lower extremity can be treated by
seizures or serotonin syndrome in patients concurrently using tra- lumbar sympathetic blocks. Both blocks of the sympathetic chain
madol with SSRIs, selective monoamine oxidase inhibitors, or should preserve sensory and motor function, thereby allowing
TCAs. full engagement in PT and rehabilitation strategies. Sympathetic
blockade is assessed by thermography, observing a rise in skin
temperature to core body temperature in the blocked extremity.
Bisphophonates
In the upper extremity and head, clinicians will further note
Bisphosphonates may represent the most thoroughly studied evidence of Horner’s syndrome (ptosis, myosis, enophthalmos,
therapy for CRPS to date. They act as powerful inhibitors of bone conjunctival injection, nasal congestion, and facial anhidrosis) as
resorption and may help interfere with local production of well as engorgement of veins of the back of the hand and forearm.
cytokines. In effect, their use may help combat the development In the lower extremity, practitioners will typically notice warmth
of patchy osteoporosis associated with CRPS. Placebo-controlled along with a temperature rise. Informed consent must be obtained
studies have documented the benefit of three bisphophonate prior to all procedures. Prudent clinicians initial the operative side
compounds: intranasal calcitonin (Miacalcin), intravenous clodro- prior to performing the injection. All injections should be preceded
nate, and intravenous alendronate. The doses of each are listed in by proper sterile technique.
Table 39–1 and reflect the doses used in the respective studies.
In practice, few clinicians have adopted these agents for the Cervicothoracic (SG) Block
treatment of CRPS.
Anatomy
Sympatholytic Agents
Preganglionic axons to the head and neck join the sympathetic
Sympatholytic agents are often used as a treatment for CRPS, chain and synapse at the SG (fusion of the inferior cervical
despite the lack of randomized, controlled trials. These medications and first thoracic ganglion), middle cervical ganglion, or superior
2
Superior
cervical
3
ganglion
4 Longus colli
muscle
Vertebral 5
artery Middle
cervical
6
ganglion
Intermediate
7 cervical
ganglion
Stellate
ganglion
Esophagus
Trachea
Sternothyroid
Subclavian Sternohyoid
artery Sternocleidomastoid
Figure 39^4. Cervicothoracic (stellate ganglion) block in
Common carotid
artery
anteroposterior (AP) view at C7. Cervicothoracic (stellate
ganglion) block under fluoroscopy. Needle is positioned at the left C7
Figure 39^3. Anatomy of the stellate ganglion. (From Loeser JD
transverse process.
[ed]: Bonica’s Management of Pain. Philadelphia: Lippincott Williams &
Wilkins, 2001, with permission.)
at the junction of the vertebral body and transverse process. Avoid
cervical ganglion (Fig. 39–3). Postganglionic fibers either follow the puncture of the carotid sheath by retracting it laterally with the
carotid arteries to the head or merge with the gray communicating sternocleidomastoid muscle. Once the periosteum is encountered,
rami to join the cervical plexus or upper cervical nerves the needle is withdrawn about 2 mm. Intermittent fluoroscopic
that innervate the neck and upper extremity. Therefore, to guidance can be used to verify appropriate needle trajectory and
successfully block the sympathetic innervation to the head and to confirm correct needle placement in relation to the C6 or C7
neck, one needs to block the SG. This ganglion receives all pregan- transverse process (Fig. 39–4). The needle tip should align medial to
glionic nerves that are traveling to more superior ganglia. The SG the vertebral artery, superior to the subclavain artery, and anterior
supplies sympathetic innervation to the upper extremities through to the epidural space in this position. Note that the vertebral artery
C7–T1. Some contributions derive from T2 and T3, which do not is more exposed and less protected by the transverse process at the
pass through the SG; these are termed Kuntz’s nerves. They join the level of C7. Before injection, careful aspiration is performed to rule
brachial plexus and innervate distal structures of the upper extrem- out the presence of blood or cerebrospinal fluid. If aspiration
ity. If the SG block fails to track sufficiently inferior, Kuntz’s nerves is negative, 1 ml of contrast is injected to verify proper spread
can cause persistent pain in an upper limb. along the cervicothoracic ganglia and to exclude intravascular or
The SG lies in the anterior neck and in front of the first rib. It intrathecal injection (Fig. 39–5). Next, a 1-ml test dose of local
extends to the interspace between C7 and T1, is bounded medially by anesthetic should be injected to exclude signs of central nervous
the longus colli muscle, laterally by the scalene muscles, anteriorly by system toxicity (intravascular injection) or spinal anesthesia
the subclavian artery, posteriorly by the transverse process, and infer- (intrathecal or epidural injection). Finally, a total of 10 mL of
iorly by the posterior aspect of the pleura. The SG is positioned local anesthetic is injected with intermittent aspiration after each
posterior to the vertebral artery, but the vertebral artery lies behind 3 to 4 ml of solution. This volume of local anesthetic should block
the transverse process of C6 (Chassaignac’s tubercle). Classic teach- the sympathetic innervation to the upper extremity even if Kuntz’s
ing of the SG block requires needle positioning at the level of C6, nerves are present.
which safely places the needle anterior to the artery. However, needle
positioning at the level of the C7 vertebral body is also performed.
Complications
Complications include infection; tracheal or esophageal puncture;
Technique
thoracic duct trauma (left side); hematoma; pneumothorax; intra-
Patients are positioned supine with the neck in slight extension. vascular, subarachnoid, or epidural injection; brachial plexus block;
An intravenous catheter should be strongly considered as a conduit recurrent laryngeal nerve paresis with hoarseness; phrenic nerve
for resuscitative medications or for sedation. Immediate access to block with temporary diaphragmatic paralysis; cardiovascular
resuscitative drugs, suction, oxygen, defibrillator, and an endotra- instability; seizure; coma; or death. A small volume of local anes-
cheal tube should be available. The level is identified under antero- thetic (< 1 ml) injected intravascularly, especially into the vertebral
posterior (AP) fluoroscopy or by palpation of the C6 transverse artery, can induce unconsciousness, respiratory paralysis, seizures,
process (Chassaignac’s tubercle). Anatomic landmarks include the and severe hypotension. If less than 2 ml of solution is injected
trachea, sternocleidomastoid muscle, cricoid cartilage, and trans- intravascularly, these sequelae are typically short lived. There is
verse process of C6. The SG lies just anterior to the transverse a higher risk of pneumothorax if the C7 transverse process is
process of C7. A 22- to 27-gauge, 3.5-inch beveled needle is typically used as a landmark and the needle is inserted too caudally. The
advanced slightly inferiorly to contact the periosteum of C6 or C7 needle can puncture the dome of the lung (located around the C7–
Intermesenteric
Sympathetic aortic plexus
trunks Right lumbar plexus
Genitofemoral n.
Psoas m.
Ao. IVC
Colon
Disc
L3-4
Quadratus
lumborum m. Paraspinous muscles
Figure 39^6. Transverse image of lumbar sympathetic
ganglia. (From Brown DL [ed]: Atlas of Regional Anesthesia, 2nd ed.
Philadelphia:WB Saunders,1999, with permission.)
vertebra (L2 or L3, typically) to the point at which the tip of the
transverse process can be viewed just lateral to the vertebral body
Figure 39^5. AP fluoroscopic view of needle positioned at C7 and (Fig. 39–7). Local anesthetic can be used to anesthetize the skin and
proper spread of contrast along the stellate ganglion and subcutaneous tissue at the anticipated needle entry point. A 22- to
cervicothoracic region. 25-gauge, 5- to 7-inch spinal needle is then inserted in oblique view
to the anterolateral aspect of the vertebral body, verified with both
T1 interspace), especially in thin, tall patients because the dome of AP and lateral fluoroscopic imaging (see Figs. 39–7 to 39–9). The
the lung is positioned more cephalad. needle may pass lateral or caudad to the lumbar transverse process.
If the needle tip contacts the vertebral body too posteriorly, it may
be slightly withdrawn and advanced more anteriorly. If the
Absolute contraindications
approach is too lateral, the needle may pierce the kidney, and an
Absolute contraindications include patient refusal, coagulopathy, overly medial approach may access the epidural or intrathecal
pneumothorax, or pneumonectomy on the contralateral side space. Contrast injection (2–3 ml) should confirm proper spread
(risk of additional pneumothorax), recent myocardial infarction anterior to the vertebral body (on lateral imaging) and lateral to
(SG blockade interrupts the cardiac accelerator nerves), overlying midline of the vertebral body (on AP imaging) (Figs. 39–10 and
skin infection, and systemic infection. 39–11). Further, both contrast injection and needle aspiration
should be performed prior to local anesthetic injection to ensure
the absence of intravascular communication (aorta on the left side
Relative contraindications
and inferior vena cava on the right side). Approximately 15 ml of
Relative contraindications include previous cervical surgery in the
region, pregnancy if incorporating fluoroscopy, glaucoma (repeated
SG blocks may exacerbate glaucoma), and marked atrioventricular
heart block (SG block interrupts upper thoracic sympathetic ganglia
which may produce bradycardia).
Lumbar Sympathetic Block
Anatomy
Preganglionic sympathetic fibers arise from the dorsolateral aspect
of the spinal cord (typically T11, T12, L1, and L2) and then synapse
with the lumbar sympathetic ganglia located on the anterolateral
aspect of the L2–4 vertebral bodies. The lumbar sympathetic ganglia
lie anterior to the psoas muscle (Fig. 39–6). Most postganglionic
sympathetic fibers follow spinal nerves of the lumbar and lumbo-
sacral plexuses to join all major nerves and corresponding vessels of
the lower extremities. Because the majority of fibers pass through
the L2 and L3 sympathetic ganglia, blockade of these two structures
produces nearly complete denervation of the lower extremity.
Technique
The patient is positioned prone with one or two pillows placed
across the anterior iliac crest to permit flexion of the lumbar
spine and to open the transverse process interspaces. The clinician Figure 39^7. Lumbar sympathetic block. Needle position at L3
obtains an oblique fluoroscopic image of the targeted lumbar in oblique view.
Figure 39^10. Lumbar sympathetic block. Contrast spread on

Figure 39^8. Lumbar sympathetic block. Needle positioned at AP fluoroscopic imaging.
L3 vertebral body and viewed under lateral fluoroscopic guidance.
local anesthetic is then injected with intermittent aspiration to pro-

Contraindications
vide proper cephalad and caudad spread of solution along the sym-
pathetic chain. Comtradictions include patient refusal, overlying skin infection,
systemic infection, pregnancy (radiation exposure from fluoro-
scopy), and coagulopathy.
Complications
Chemical (phenol or alcohol), surgical, and radiofrequency sym-
Complications include infection, hematoma, intravascular injec- patholytic procedures of the SG and lumbar sympathetic chain have
tion, epidural or intrathecal injection, lumbar plexus block (causing been performed to more permanently interrupt the pain associated
quadriceps paresis), nerve root injury, disk trauma, renal injury with the sympathetic nervous system. To date, only poor-quality
(hematuria), hypotension, paraplegia, ureteral injury, and visceral evidence supports the use of these neurolytic interventions.
perforation. Given the occurrence of bothersome side effects, clinicians should
Figure 39^9. Lumbar sympathetic block. Needle verification of Figure 39^11. Lumbar sympathetic block. Contrast spread on
proper position under AP fluoroscopy. lateral fluoroscopic imaging.
seriously consider the value of performing neurolysis until higher- The three SCS manufacturers (Advanced Neuromoduation Systems,
quality evidence defines their effectiveness. Medtronic, and Boston Scientific) offer rechargeable implanted bat-
teries and sophisticated systems that permit multiple programming
options to maximize coverage and subsequent pain relief.
Neuromodulation
Complications. Complications include spinal cord injury or
Spinal cord stimulation nerve injury, cerebrospinal leak, infection, bleeding, lead migra-
The mechanism of action of dorsal column stimulation remains tion/malposition, lead fracture, epidural hematoma, epidural
vague, although the goal remains clear: relieve pain by applying abscess, and generator (battery) failure.
electrical stimulation to a degree that paresthesias cover the painful
region without discomfort or motor dysfunction. Current theory Contraindications. Contraindications include patient refusal,
suggests that large fiber stimulation may ‘‘close the gate’’ to painful sepsis, coagulopathy, pregnancy, untreated psychiatric comorbid-
input from small, unmyelinated ad-, C-fibers. Further, spinal cord ities (anxiety, depression), substance use disorder, inability to coop-
stimulation (SCS) may inhibit sympathetic outflow by stimulating erate, secondary gain, demand cardiac pacemaker (need to change
a- and b-fibers in the dorsal column of the spinal cord. The entire to a fixed rate), and specific needs for MRIs (SCS equipment is
process of SCS may trigger the descending modulatory pain system incompatible with MRI).
and promote changes in spinal or supraspinal g-aminobutyric acid
(GABA)–mediated neurochemistry.
Peripheral nerve stimulation
The use of SCS for CRPS is controversial, though growing in its
application. In select patients who require facilitation of their treat- Peripheral nerve stimulation may be effective for CRPS II, in which
ment goals or who are achieving limited benefit with conservative patients have a well-defined nerve injury. Current literature is scant
therapies, SCS may improve health-related quality of life. For on the benefit of peripheral nerve stimulation in CRPS, however.
instance, one randomized, controlled trial showed a significant
decrease in pain intensity with SCS in CRPS patients, but no
Deep brain stimulation
improvement in functional status.15,16 Other, more recent studies
support SCS therapy in carefully screened patients who respond There are minimal data to support the use of deep brain stimulation
favorably to a SCS trial. for CRPS. This should be considered in refractory cases when the
potential for enhanced quality of life or functional restoration is
Technique. Psychiatric comorbidities, substance use disorders, likely.17
and issues of secondary gain should be assessed prior to implemen-
tation, usually by a licensed psychologist. Test stimulation with
Intrathecal infusion devices
temporary lead placement is performed under fluoroscopic guid-
ance followed by a 3 to 7 day trial period on an outpatient basis. Most data citing the benefit of intrathecal infusion therapies consist
Clinicians should offer a permanent implant to patients who report of case reports. Little evidence supports the use of intrathecal med-
approximately a 50% reduction in pain and demonstrate stable ications for the treatment of CRPS; however, case reports suggest
medical regimens. SCS trials are performed on an outpatient that morphine may ease intractable pain and one RCT demon-
basis, and implantations require either outpatient or short inpatient strates the effectiveness of baclofen in reducing dystonic postures.18
stays. Patients are typically placed prone and lightly sedated in order The role of clonidine, ziconotide (Prialt), and other opioids for
to communicate the sensation of paresthesias in the appropriate CRPS has yet to be discovered.
anatomic region. Coverage of lower extremity pain requires lead
placement in the lower thoracic region, whereas capturing pain in
the upper extremities demands lead placement in the lower cervical Psychological/Behavioral Approaches
region. Dual leads may best cover bilateral symptoms (Fig. 39–12).
Pain-related psychological distress resulting from CRPS may exac-
erbate pain intensity and promote disuse of the affected extremity.
Although confirmative studies are lacking, experts have proposed
that psychological treatments for CRPS focus on interrupting
learned disuse and stress/distress and offering coping skills that
will facilitate function and quality of life. Several case series suggest
that specific techniques such as guided imagery, thermal biofeed-
back, hypnosis, progressive muscle relaxation, and autogenic
training may diminish the pain of CRPS. Other studies highlight
the benefit of integrating psychological approaches with multidisci-
plinary treatment (medications, physical restoration, procedural
interventions) in a broad effort to help patients manage CRPS.
Specifically, cognitive-behavioral therapy may help patients
identify and develop constructive pain coping mechanisms that
will make their condition more tolerable and minimize the dramatic
impact on their daily life. Psychological assistance with kinesopho-
bia, or the fear of pain from movement of an affected limb, can aid
in improving physical rehabilitation. Clinicians should request
psychological evaluation in four areas: (1) Axis I psychiatric disor-
ders (anxiety disorder, depression, panic disorder, post-traumatic
stress disorder), (2) a patient’s cognitive, behavioral, and emotional
response to CRPS, (3) a patient’s ongoing life stressors, and (4)
response of significant others to the patient’s CRPS. Similar to
Figure 39^12. Spinal cord stimulator implantation. Two leads other chronic pain conditions, CRPS is considered a biopsychoso-
located in the dorsal epidural space are viewed under fluoroscopy. cial disorder. Accordingly, the most successful treatments will target
the biologic, psychological, and social elements of this syndrome. Similarly, there is no single therapy or combination of therapies
All psychological hindrances to physical rehabilitation should that is universally effective for all CRPS patients. Currently, treat-
be addressed and treated in the context of a comprehensive multi- ment of CRPS focuses on an early, aggressive multimodal
disciplinary treatment program. approach that targets pain reduction and functional rehabilitation.
Interventions aimed toward the attainment of these goals include
specific pain-relieving medications, sympathetic nerve blockade,
Functional Restoration neuromodulation, functional restorative approaches (PT, OT, rec-
reational therapy, vocational counseling), and psychological/beha-
OT, PT, recreational, and later, vocational rehabilitation therapy vioral treatments.
should be considered soon after diagnosis. In many instances,
CRPS patients will require concomitant pain-specific medications,
psychological intervention, and perhaps specific injections before, REFERENCES
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that occur in every patient that is pathognomonic for CRPS.
Chapter 40 endings, these Ab-fiber endings were rarely seen compared with
control skin. Additional losses of calcitonin gene–related peptide
COMPLEX REGIONAL PAIN (CGRP)–positive innervation were noted among dermal papilla
and within the epidermis (see Fig. 40–1E and F) of the skin of
SYNDROME PATHOPHYSIOLOGY CRPS I patients. In fact, although deep nerves in CRPS skin con-
tained numerous CGRP-positive axons, compared to control skin,
hardly any CGRP was detected among the epidermal and upper
Howard S. Smith, Phillip J. Albrecht, and Frank L. Rice dermal innervation.
Alterations in the composition of dermal nerves were also
observed. As shown in Figure 40–2A, dermal nerves normally contain
a contingent of large- (ab-) and smaller- (ad-) caliber fibers that
appear with a neurofilament (NF) label that is clean and separate
and always myelin basic protein (MBP)–positive. The spaces between
the NF fibers are presumably the location of small-caliber C-fibers,
INTRODUCTION which do not express NF but which do express growth-associated
protein–43 (GAP43). In contrast, the CRPS dermal nerves appeared
Reflex sympathetic dystrophy (RSD) and causalgia are disorders of with NF expression among these smaller-caliber fibers and without
the nervous system first described around the time of the American MBP (see Fig. 40–2B). In normal skin, GAP43 and NF do not appear
Civil War. Both conditions are characterized by excessive pain to colocalize among dermal nerves, and GAP43 is found among
associated with sympathetic and sensory alterations in an affected most, if not all, FNE. In the skin of CRPS I patients, the GAP43-
limb; the diagnostic difference being the presence of a defined nerve positive fibers remained NF negative, implying that the small-caliber,
injury (causalgia) or the absence of a defined nerve lesion (RSD). potentially pathologic, NF fibers detected were remaining GAP43
In the 100+ years since these initial descriptions and the clinical negative (see Fig. 40–2C and D). Large-caliber, ab-fiber innervation
recognition of the different manifestations of these disorders, they to hair follicles was also disrupted in CRPS I skin. Although the
were renamed to better reflect the consistent pathology, pain. CPRS skin still retained some normal looking Meissner’s corpuscles
Complex regional pain syndrome type I (CRPS I) has replaced and Merkel endings, these Ab-fiber endings were rarely seen com-
the RSD diagnosis, and type II (CRPS II) has replaced causalgia.1 pared with control skin. Normal innervation involves the precise
In many cases of CRPS I, sympathetic hyperactivity can be cau- organization of terminals around the follicle in a piloneural
sative, and hence, sympathectomy becomes palliative; yet in many complex (PNC; see Fig. 40–2E). In the CRPS skin, the ab-fiber orga-
others, this procedure is ineffective. CRPS I which is unresponsive nization was disrupted, and additional small-caliber, GAP43-positive
to pharmacologic sympathetic block and which does not have iden- fibers appeared in PNC territories not normally innervated (see Fig.
tifiable nerve pathologies using traditional nerve evaluations, is also 40–2E and F). Additional evidence of a loss of sensory peptidergic
difficult to manage with pain medications. These factors have, fibers was found among the sweat glands, where the CRPS I skin had
therefore, raised questions regarding the true neuropathic nature a loss of CGRP-positive fibers (see Fig. 40–2G and H).
of the syndrome and muddied the waters of clinical diagnosis and Vascular innervation and structural alterations were also
care. Most patients diagnosed and suffering with chronic pain observed in the CRPS I tissue (Fig. 40–3). Superficial arterioles
conditions experience exacerbating psychological phenomena among normal skin receive solely CGRP-positive innervation (see
(e.g., fear, depression, anxiety); in the cases of CRPS I, additional Fig. 40–3A), whereas deeper arteriovenous shunts (avs) contain
psychological factors around suspicion of malingering can be ample CGRP-positive and neuropeptide Y (NPY)–positive separate
observed, both on the side of the patient and/or on the side of the innervation (see Fig. 40–3B). A loss of CGRP-positive vascular
treating physician.1 Recently, two separate investigations demon- innervation is detected among the superficial arterioles and the
strated small fiber neuropathy in CRPS I–diagnosed patients.2,3 deeper avs in the CRPS I skin (see Fig. 40–3A–D). As well, aberrant
We have performed immunofluorescent evaluations of the skin expression or sprouting of NPY-positive fibers onto the superficial
of two patients with longstanding CRPS I diagnosis and attempts at arterioles was detected in the CRPS I skin (see Fig. 40–3B). A loss of
treatments who required limb amputation.2 We observed a loss of vascular structural integrity was observed among the upper dermal
thin-caliber, C-fiber epidermal endings, as has been shown by vessels in the CRPS I skin compared with normal (see Fig. 40–3E
others, but also found dramatic alterations of large caliber fibers and F), and vessels that had lost innervation contained extremely
innervating hair follicles and a loss of innervation to superficial hypertrophied walls (see Fig. 40–3G and H).
peripheral vasculature accompanied by severe vessel wall pathology. Alterations of the CRPS I tissue were also found involving the
In addition, increased expression of specific voltage-gated sodium terminal structure for many small-caliber C-fibers, the epidermis.4
channel (NaV) subunits was detected in epidermal keratinocytes. In addition to alterations of the peripheral nervous system and
Altogether, these alterations indicate a complex of losses in neural innervation, we noted changes in the chemistry of the epidermal
fiber innervation and accompanied tissue reorganization as well as keratinocytes in the CRPS I skin (Fig. 40–4). For example, the
changes in the terminal cells associated with some of these fibers. expression of specific NaV subunits in keratinocytes (a novel find-
As depicted in Figure 40–1, there are dramatic loss of fine nerve ing in itself) was increased for NaV1.1, NaV1.2, NaV1.6, NaV1.7,
endings (FNE; see Fig. 40–1A–D), in the epidermis and small and NaV1.8 among the CRPS I skin (see Fig. 40–4A–C). Zhou et al.4
nerves, and axons in the upper dermis among the skin of CRPS I proposed that pathological increases in keratinocyte sodium chan-
patients compared with control skin. Additional losses of large- nel expression in CRPS, may contribute to pain by increasing epi-
caliber ab-fiber innervation were noted along with a loss of dermal ATP release, resulting in excessive activation of P2X
Meissner’s corpuscles and Merkel cell innervation (see Fig. 40–1C receptors on primary sensory neurons.
and D) among the CRPS I skin. Although the CRPS skin still The epidermis is composed of approximately 85% to 90%
retained some normal looking Meissner’s corpuscles and Merkel keratinocytes, 10% Langerhans cells, and less than 5% Merkel
296 Chapter 40 COMPLEX REGIONAL PAIN SYNDROME PATHOPHYSIOLOGY
Control forearm CRPS forearm

PGP PGP
ep
ep
A d B d
Control palmar CRPS palmar

PGP PGP
dp ep
ep
dp
C d D d

CGRP CGRP
dp ep ep
dp
d d
E F
Figure 40^1. Neuro-, vasculo, and dermatopathologies in complex regional pain syndrome (CRPS) I. A^D, Protein gene product
(PGP) in the forearm of a control (A) and a complex regional pain syndrome (CRPS) patient (B) and the palmar surfaces of a control (C) and a
CRPS patient (D). Clear losses are seen in the peripheral nerve fiber distribution of small-caliber C-fiber endings, most frequently detected as
epidermal free nerve endings (FNE; open arrowheads) in the CRPS I skin. C and D, Additional losses of large-caliber ab-fiber innervation are seen
along with a loss of Meissner’s corpuscles (curved arrow) and Merkel cell innervation (circle). E and F, The palmar surfaces of a control (E) and a
CRPS I patient (F) are shown. Additional losses of calcitonin gene ^ related peptide (CGRP)^ positive innervation are seen among the dermal
papilla and within the epidermis (white arrowheads) from the CRPS I skin. d, dermis; dp, dermal papilla; ep, epidermis. (A^F, From Albrecht PJ, Hines
S, Eisenberg E, et al. Pathologic alterations ofcutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome.
Pain 2006;120:244^266.)
cells and has well-documented essential homeostatic functions

related to keratinization, wound healing, and immunologic surveil- POTENTIAL PERIPHERAL MECHANISMS
lance. More recently, the role of this dynamic structure in sensory THAT MAYCONTRIBUTE TO CRPS
stimulus processing and integrating is becoming uncovered.
Because recent evidence is pointing toward a direct role of the epi- Paul Sudeck initially proposed an exaggerated inflammatory reac-
dermis as a sensory transducing and integrating structure in com- tion underlying CRPS, and Taha and Blaise5 further addressed this.
munication with the FNE of the sensory system, the alterations of Altered expression/responsiveness/signaling of a-adrenoceptors as
peripheral nerves that terminate in the epidermis, and in the expres- well as inflammatory mediators (e.g., cytokines), reactive oxygen
sion of neural signaling components in the keratinocyte fields where species, and neutrophic factor (e.g., nerve growth factor [NGF])
these fibers terminate, may be indicative of neuro- and dermato- may all potentially contribute to the peripheral mechanisms that
pathologies, which together with the observed vasculopathologies, could play a role in CRPS.
form another logical basis for the chronic pain associated with Neurogenic inflammation may be involved in the pathogenesis
this syndrome. Furthermore, the uncovering of skin mechanisms of edema, vasodilatation, and sweating in CRPS. The use of nuclear
involved in chronic pain should reveal numerous new targets for scintigraphy with radiolabeled immunoglobulins in acute CRPS has
potential pharmacologic, or other, analgesic interventions. demonstrated extensive plasma extravasation probably from signif-
The pathophysiology of CRPS and the resulting neuro-, vasculo-, icantly increased vascular permeability from acute CRPS inflamma-
and dermatopathologic alterations that may be seen remains uncer- tory processes.
tain and is almost certainly multifactorial. Both peripheral and In 12 patients and in 12 healthy volunteers, dermal microdialysis
central processes are likely involved in CRPS pathophysiology. in combination with electrical C-fiber stimulation was employed to

MBP/NF MBP/NF
A B
GAP43/NF GAP43/NF
C D
GAP43/NF GAP43/NF
Follicle Follicle
E F
CGRP CGRP
G H
Figure 40^2. Neuro-, vasculo, and dermatopathologies in CRPS I. A, In the forearm of a control, dermal nerves normally contain a
contingent of large- (Ab-) (curved arrows) and smaller- (Ad-) (straight arrows) caliber fibers that appear with a neurofilament (NF) label that is clean
and separate and always myelin basic protein (MBP)^ positive.The spaces between the NF fibers are presumably the location of small-caliber
C-fibers (arrowheads), which do not express NF, but which do express growth-associated protein 43 (GAP43). B, In the forearm of a CRPS I
patient, the dermal nerves appear with NF expression among the smaller-caliber fibers and without MBP. C, In the control forearm, GAP43 and
NF do not appear to colocalize among dermal nerves, and GAP43 is found among most, but not all, FNE. D, In the CRPS I skin, the GAP-positive
fibers remain negative, implying that the small-caliber, potentially pathologic, NF fibers detected remained GAP43 negative. E and F, Large-caliber
ab-fiber innervation to hair follicles is also disrupted in CRPS skin (F). Normal innervation (E) involves the precise organization of terminals
around the follicle in a piloneural complex (PNC; broken line rectangles). In CRPS skin (F), the piloneural complexes were in disarray with
irregularly oriented lanceolate endings (straight arrows), presumably from Ab fibers (curved arrows), and dense concentrations of disorganized small
fiber terminations. Dense plexuses of small caliber terminations were also in aberrent locations below (solid line rectangle) and above the PNCs.
Consistent with the content of CRPS nerves, the aberrent plexuses of small caliber innervation included GAP43-positive/NF-negative
(black arrowheads) and GAP43-negative/NF-positive fibers (white arrowheads). G, In the control forearm, the sweat glands display normal sensory
peptidergic fibers. H, Additional evidence of a loss of sensory peptidergic fibers is found among the sweat glands, where the CRPS I skin has a
loss of CGRP-positive fibers. (A^H, From Albrecht PJ, Hines S, Eisenberg E, et al. Pathologic alterations ofcutaneous innervation and vasculature in
affected limbs from patients with complex regional pain syndrome. Pain 2006;120:244^266.)
induce neuropeptide release.6 Dialysate protein concentration and competitive binding assay, it can be shown that at least some of
axon reflex vasodilation were measured. Neither in patients nor in the CRPS sera bind to the same neuronal epitope.
controls did electrical stimulation lead to protein extravasation, Kingery and associates12 demonstrated that the usual rat hind-
whereas axon reflex vasodilation was significantly enhanced even paw increased protein extravasation after sciatic nerve transaction
on the patients’ unaffected limbs (P < .05).6 These results support was inhibited by the long-acting substance P receptor (NK[1])
the hypothesis that facilitated neurogenic inflammation is a predis- antagonist LY303870. Systemic administration of LY303870 also
posing factor for CRPS.6 It appears that neurogenic inflammation reversed hindpaw edema and cutaneous warmth.12 Intrathecal,
with release of CGRP7 and substance P8–10 may contribute to CRPS but not systemic, administration of LY303870 reversed soft tissue
pathophysiology. and articular mechanical hyperalgesia in the hindpaw.12
Blaes and coworkers11 advanced an autoimmune etiology of Collectively, these data further support the hypothesis that the sci-
CRPS because autoantibodies against nervous system structures atic nerve transection model closely resembles CRPS and that sub-
have been described in CRPS patients. These autoantibodies bind stance P contributes to the spontaneous extravasation, edema,
to the surface of peripheral autonomic neurons.11 Using a warmth, and mechanical hyperalgesia observed in this model.12

NPY/CGRP ep NPY/CGRP
ep
dp dp
a a
A B
NPY/CGRP NPY/CGRP
avs avs
C D
Control digit CRPS digit
ep ep
dp dp dp
dp
d d
E F
PECAM/PGP/Hoechst PECAM/PGP/Hoechst
Control digit CRPS digit
PGP/autofluorescence PGP/autofluorescence
G H
Figure 40^3. Neuro-, vasculo, and dermatopathologies in CRPS I. A and B, CRPS affected palmer skin had normal NPY^ positive
innervation to arteriovenous shunts, but had lost the normal expression of CGRP innervation in the dp (closed arrowheads) and CGRP^ positive
fibers in the dermis (open arrowhead). Additionally, superficial arteries (a) had lost the normal expression of CGRP, but contained an abnormal
expression of NPYon innervation (B, arrow). C and D, CRPS palmar skin lacked normal CGRP^ positive innervation to vascular components and
had aberrent NPY^ positive innervation onto superficial arterioles compared with control. Control palmer skin contained numerous
arteriovenous shunts in the deep to mid-dermis that were innervated by a mix of NPY^ positive (arrows) and CGRP^ positive (arrowheads) fibers.
E and F, Regions of CRPS skin had a dramatic loss of vascular integrity and increased perivascular cellular dispersion compared with control. Note
that all of the dermal papillae in the control skin contained capillaries. In contrast, CRPS digit skin had a dramatic loss of uniform PECAM staining
in superficial capillaries and precapillary arterioles, indicative of a loss of superficial capillary integrity. G and H, Regions of CRPS skin had
denervated arteries that had become hypertrophied and multi-laminated compared with control or innervated arteries. Arteries from control
digit skin contained PGP^ positive innervation (arrows) around the entire perimeter of the vessel and also had only a single inner band of
autofluorescent elastin adjacent to the vessel lumen. In contrast, CRPS affected skin showed dramatic arterial abnormalities characterized by an
overall loss of PGP^ positive innervation coupled with hypertrophic, multi-laminated vascular walls. avs, arteriovenous shunts; d, dermis; dp,
dermal papilla; e, epidermis. (A^H, From Albrecht PJ, Hines S, Eisenberg E, et al. Pathologic alterations ofcutaneous innervation and vasculature in
affected limbs from patients with complex regional pain syndrome. Pain 2006;120:244^266.)
Xanthos and Coderre13 evaluated agents that relieve mechanical 12 weeks of high-dose glucocorticoid treatment alleviated symp-
allodynia in an animal model of CRPS I (chronic postischemia toms in CRPS and that the therapeutic effects persisted after the
pain [CPIP]) produced by 3 hours of hindpaw ischemia-reperfusion treatment.14,15 These trials employed clinician-assessed composite
injury. Systemic guanethidine, phentolamine, clonidine, and prazo- outcome scales that incorporated hyperalgesia, edema, and range of
sin are effective in reducing mechanical allodynia, particularly at motion on an ordinal scale. Kozin and associates16 performed a
2 days after reperfusion, and less so at 7 days after reperfusion.13 small, uncontrolled study that also reported a gradual reduction
A nitric oxide (NO) donor vasodilator, SIN-1, also reduces mechan- in CRPS digit circumference during high-dose glucocorticoid treat-
ical allodynia more effectively at 2 days after reperfusion, but not at ment that persisted after the completion of the treatment. Guo
7 days after reperfusion.13 These results suggest that the pain of and colleagues17 observed that a 4-week methylprednisolone
CPIP, and possibly also CRPS I, is relieved by reducing sympathet- infusion reversed hindpaw edema in rat tibia fracture CRPS
ically mediated vasoconstriction or enhancing vasodilatation.13 model and lasted for at least 2 weeks after discontinuation of the
Glucocorticoids may have beneficial therapeutic effects on glucocorticoid.
‘‘immunologic mechanisms’’ that may be at play on the develop- Kingery and coworkers18 tested the effects of continuously
ment of CRPS. Two small, controlled trials reported that 4 to infused methylprednisolone in sciatic nerve–transected rats.
Nav 1.1 Nav 1.2 Nav 1.5 Nav 1.6 Nav 1.7 Nav 1.8 Nav 1.9
SC
SG
SS
SB
Normal #1
hypothenar (no pain)
A
SC
SG *
SS
SB
CRPS #1
hypothenar
(severe pain)
B
*
SC
SG
SS
CRPS #2
lateral foot SB
(severe pain)
C
Figure 40^4. Neuro-, vasculo, and dermatopathologies in CRPS I. A^C,The expression of specific voltage-gated sodium channel (NaV )
subunits is increased for NaV1.1, NaV1.2, NaV1.6, NaV1.7, and NaV1.8 among the CRPS I skin. A, Normal hypothenar eminence.B, Hypothenar eminence
from a CRPS patient with severe hand pain.C, Lateral foot from another CRPS patient with severe foot pain.Dashed lines indicate the basement
membrane, dotted lines indicate the border of the SG and SC. *, increased immunolabeling in the dead keratinocytes of the SC; SB, stratum basalis;
SC, stratum coreneum; SG, stratum granulosum; SL, stratum lucidum; SS, stratum spinosum. (A^C,From Zhou P, BarrTP, Hou Q, et al.Voltage-gated
sodium channelexpressioninratand human epidermalkeratinocytes: evidence forarolein pain.Pain 2008 [in press].)
Continuous infusion of methylprednisolone (3 mg/kg per day for enhanced spinal cord Fos expression, osteopenia, and enhanced
21 days), started after the development of neuropathic hyperalgesia, cytokine content of hindpaw skin on the side of the fracture.19
reversed both heat and mechanical hyperalgesia over 2 weeks, and Anti-NGF treatment reduced nociceptive sensitization, bone loss,
this effect persisted for at least 1 week after discontinuing methyl- neuropeptide levels in sciatic nerve, and Fos expression.19
prednisolone.18 In addition, continuous methylprednisolone infu- Sabsovich and colleagues,20 utilizing the same rat tibia fracture
sion partially reversed nerve injury–evoked Fos expression in the model of CRPS I, revealed that tibia fracture chronically up-
dorsal horns, suggesting that glucocorticoids can inhibit the spinal regulated tumor necrosis factor (TNF) expression and protein
neuron hyperactivity induced by chronic sciatic nerve transection.18 levels in the hindpaw skin and sciatic nerve and bone. The rates
Sabsovich and associates19 hypothesized that NGF may play a developed hindpaw mechanical allodynia and unweighting that
role in contributing to the clinical picture in CRPS I. Utilizing tibia were reversed by soluble TNF receptor type 1 (sTNF-R1) treatment.
fracture model of CRPS I, Sabsovich and associates19 injected rats sTNF-R1 also inhibited the increase in spinal Fos after fracture.20
with anti-NGF antibodies or vehicle at days 17 and 24 postfracture. Wei and colleagues demonstrated that pentoxifylline attenuated
They found that tibia fracture upregulated NGF expression in hind- nociceptive sensitization and cytokine expression as well as some of
paw skin and tibia bone along with sciatic nerve neuropeptide con- the vascular sequelae of fracture (e.g., CRPS–like changes) in the
tent.19 In addition, they demonstrated nociceptive sensitization, same tibia fracture rat model of complex regional pain syndrome.21a
Levels of interleukin-6 (IL-6) and TNF-a in blister fluid of the proinflammatory cytokines IL-6 and IL-1b were elevated, although
affected extremities of CRPS patients were significantly higher than the IL-1b measures were near the level of detection for the assay.32
in the uninvolved extremity, and these higher levels correlated Shinkel and coworkers33 studied venous blood samples drawn
significantly with disease activity impairment.21 Huygen and cow- from unaffected and affected arms in 25 patients with acute CRPS
orkers21 reported successful treatment of CRPS I with anti–TNF-a. and compared them with 30 healthy volunteers. No differences were
Reactive oxygen species may also contribute to CRPS patho- noted for white blood cell count or for levels of C-reactive protein,
physiology. Free radical scavengers, N-acetyl-L-cysteine and 4- IL-6, NPY, or CGRP. Significant elevations were noted for IL-
hydroxy-2,2,6,6-tetramethylpiperidine, reduce signs of hyperalgesia 8–soluble TNF receptors I and II, and substance P in CRPS patients
and allodynia in animal models of CRPS.22 Clinically, topical treat- versus normal subjects, but no difference was found between the
ment with 50% dimethyl sulfoxide cream can be effective in unaffected and the CRPS-affected arms within the patient group.
decreasing the hypoxia-related production of free oxygen radicals.23 The localized inflammation of a CRPS-affected limb could
Coderre and associates24 found that reactive oxygen species may involve a wide range of immunocompetent cells including activated
contribute to CRPS Pathophysiology, utilizing an ischemia-reperfu- T lymphocytes, monocytes, and macrophages as well as skin resi-
sion animal model of CRPS (CPIP); however, this model may not dent cells such as keratinocytes, fibroblasts, endothelial cells, and
represent an ideal animal model correlate of human CRPS.25 mast cells.21,34,35
In a double-blind, prospective, multicenter trial, 416 patients Thalidomide may inhibit the production of a wide range of
with 427 wrist fractures were randomly allocated to treatment proinflammatory mediators (e.g., TNF-a, IL-1b, IL-6, and IL-8)
with placebo or treatment with 200, 500, or 1500 mg of vitamin and also increase levels of IL-10, IL-2, and interferon (IFN)-g.36
C daily for 50 days. The effects of gender, age, fracture type, and Thalidomide inhibits the activation of nuclear factor kappa B
cast-related complaints on the occurrence of CRPS were analyzed.26 (NF-kB) in response to certain stimuli, such as TNF-a and hydro-
Three hundred seventeen patients with 328 fractures were rando- gen peroxide, but not in response to other stimuli including
mized to receive vitamin C, and 99 patients with 99 fractures were ceramide, lipopolysaccharide, or phorbol ester,37,38 likely via sup-
randomized to receive a placebo. The prevalence of CRPS was 2.4% pression of IkB kinase activity.39 Thalidomide may also inhibit the
(8 of 328) in the vitamin C group and 10.1% (10 of 99) in the production of TNF-a from human microglial cells.40
placebo group (P = .002); all of the affected patients were elderly Rajkumar and associates41 reported on a 43-year-old woman
women. Analysis of the different doses of vitamin C showed that the with a 3-year history of severe CRPS treated with thalidomide for
prevalence of CRPS was 4.2% (4 of 96) in the 200-mg group (rela- newly diagnosed multiple myeloma. Her CRPS resulted from a
tive risk [RR], 0.41; 95% confidence interval [CI], 0.13–1.27), 1.8% traumatic injury to her left hand. At the time of the multiple
(2 of 114) in the 500-mg group (RR, 0.17; 95% CI, 0.04–0.77), and myeloma diagnosis, the patient was nonambulatory and was con-
1.7% (2 of 118) in the 1500-mg group (RR, 0.17; 95% CI, 0.04– fined to a bed or wheelchair owing to left leg pain, swelling, and
0.75). Early cast-related complaints predicted the development of ulceration. She complained of severe attacks of pain and, on phys-
CRPS (RR, 5.35; 95% CI, 2.13–13.42).26 Zollinger and colleagues26 ical examination, had atrophy of the muscles of the left hand with
concluded that vitamin C reduces the prevalence of CRPS contractures of the digits and swelling involving the upper and
after wrist fractures. A daily dose of 500 mg for 50 days is lower extremities on the left side. The patient was enrolled in a
recommended.26 multiple myeloma clinical trial of single-agent thalidomide at 200
An inflammatory theory for CRPS phenomena is supported by mg/day, increased to 400 mg/day after 2 weeks. After 1 month of
(1) an increased extravasation of indium-labeled immunoglobulin thalidomide therapy, the patient had a marked improvement, with
as a sign of increased capillary permeability for macromolecules,27 near-resolution of CRPS symptoms. Her leg ulcerations and edema
(2) a therapeutic response to various oxygen radical scavengers,28 healed completely, allowing her to walk normally. In subsequent
(3) skin biopsies in CRPS patients revealing striking increases in months, she regained function in her left hand as well.41
the number of Langerhans cells (which can release immune cell Prager and colleagues42 reported positive results (e.g., a 2-point
chemoattractants and proinflammatory cytokines), (4) higher or greater drop in numerical rating scale-11 [NRS-11]) in seven of
levels of IL-6 and TNF-a in blister fluid of artificially produced nine CRPS I patients (78%) treated with thalidomide, 50 to 300 mg
skin blisters in the involved extremity in comparison with the unin- once daily, for 1 to 3 months. Therapy was initiated at 50 mg
volved extremity,21 and (5) a successful therapeutic intervention in by mouth at bedtime and titrated by 50 mg per month according
a pilot study with anti-TNF.29 In a limited study of two patients, to patient tolerability and response.42 The average NRS-11 decrease
these investigators were able to show that infliximab (a TNF-a was nearly 4 points (baseline prethalidomide baseline average = 7;
inhibitor) not only reduced cytokine levels but also reduced pain thalidomide treatment average = 3.3) with no patients in the study
and improved joint mobility.29 experiencing new or exacerbated pain symptoms.42 Of the respon-
The patchy osteoporosis that may be seen in advanced CRPS ders, two patients noted a significant reduction in concomitant pain
may be at least partly due to a regional inflammatory process in medication use, and one patient who was bedridden became able to
deep somatic tissues. IL-1 and IL-6 may lead to proliferation and perform normal activities of daily living.42
activation of osteoclasts and suppress the activity of osteoblasts. Schwartzman and associates44 performed an open-label CRPS
Furthermore, TNF and IL-1 may directly inhibit hair growth. study in which 42 patients were treated for a total of 3 months at
Keratinocyte-derived TNF and IL-6 may result in retarded hair three institutions, receiving thalidomide at doses of 200 to 400 mg
growth, signs of fibrosis, and in turn, immune infiltration of the per day. Thirteen of the patients experienced at least moderate
dermis, clinical features that may be appreciated in CRPS. relief, with 7 of these reporting ‘‘dramatic’’ responses, including a
However, any supposed relation between CRPS and local levels reduction of concurrent analgesic medications. Treatment
of proinflammatory cytokines may be complex and perhaps responses, which appeared within 4 to 6 weeks of starting thalido-
(at least in the intermediate stage) somewhat obtuse, because mide, included improvements in deep joint pain, allodynia, and
the blister fluid levels of IL-6 and TNF-a in the affected extrem- inflammatory skin changes without significant changes in quanti-
ity may remain elevated despite improvement in CRPS signs and tative sensory detection thresholds. Bengston and colleagues45
symptoms.30 reported positive results in a 6-month phase II study that used
Manning31 wrote a coherent chapter of potential immunologic thalidomide, 100 to 400 mg per day, in the treatment of CRPS.
aspects of CRPS and approaches to CRPS treatment via immuno- Of the 12 patients enrolled, 6 reported significant reductions in
modulation from which specific points are presented. Increased their levels of pain. Adverse events included rash, somnolence,
cytokine levels were reported in the cerebrospinal fluid (CSF) of and constipation, which were mostly mild and transient and were
patients with CRPS compared with controls. CSF levels of often managed by thalidomide dose reduction.
Lenalidomide is minimally, if at all, able to penetrate the 5 hours, redness and pain ‘‘like broken glass running through my
blood-brain barrier. It is approximately 1000 times as potent as veins’’ developed in his hands and feet. His pain worsened when he
thalidomide in stimulating the proliferation of T-cells after primary showered with warm water and improved with cold water immer-
induction by T-cell receptor (TCR) activation and 100 to 200 times sion. His medical history revealed only childhood pneumonia and
as potent as thalidomide in augmenting the production of IL-2 and treatment for anxiety and depression. He was a high-level lacrosse
IFN-g after TCR activation of peripheral blood mononuclear cells.36 competitor who occasionally used alcohol, but no tobacco or illicit
Rats treated with lenalidomide at a dose of 50 mg/kg intraper- drugs. He had no family history of neurologic disorder.56
itoneally prior to carrageenan injection into the footpad experi- Examination revealed hypertension and red swollen feet, which he
enced a significant (P < .05) reduction in paw edema of 36%, a had submerged in cold water. A neurologist’s examination was
reduction in mechanical hyperalgesia of 50%, and a reduction in reported as entirely normal. Extensive work-up—including
thermal hyperalgesia of 44%. This suppression of edema and normal erythrocyte sedimentation rate, CSF evaluation, and imag-
hyperalgesia by lenalidomide is consistent with the ability to inhibit ing studies of ankle and brain—was essentially negative.56 Multiple
the proinflammatory mediators TNF-a, IL-1b, and IL-6 and medications (including ibuprofen, aspirin, naproxen, ketorolac,
cyclooxugenase-2 (COX-2)–derived prostaglandin E2. amitriptyline, venlafaxine, buproprion, duloxetine, gabapentin,
Schwartzman and associates conducted a six-center, open-label pregabalin, phenytoin, valproic acid, lamotrigine, acetaminophen,
study in men and women with chronic, unilateral type I CRPS, cyclobenzaprine, mexiletine, mannitol infusion, clonidine patches
lasting at least 1 year, diagnosed according to the criteria published to dorsum of hands, intravenous ketamine as well as topical
by the International Association for the Study of Pain (IASP),46,47 treatments with aquaphor, lidocaine ointment, capsaicin, lidocaine
and treated with lenalidomide at an oral dose of 10 mg/day for patch 5%) did not provide effective analgesia. Punch skin biopsies
12 weeks. from his distal leg showed erythrocyte extravasation, mast cells,
Pain was assessed on an NRS of pain intensity (NRS-PI), on the fluid in the dermis, and no amyloid birefringence. Protein gene
Short-Form McGill Pain Questionnaire (SF-MPQ),48 and on the product 9.5 (PGP9.5) immunolabeling of axons was nearly
pain-rating scales of the Brief Pain Inventory (BPI).49 Mechanical absent, indicating severe distal sensory axonopathy. Skin biopsies
allodynia was determined by stroking the most painfully sensitive from other patients that were processed simultaneously labeled
area of the skin three times over 5 seconds at a rate of 5 cm/sec with normally. Small fiber predominant axonopathy was diagnosed
a foam brush. The pain rating was rescored on NRS-11. and attributed to autoimmune causes.56 This case of acute onset
Forty subjects with chronic CRPS I for an average of 6 years, erythromelalgia presumably owing to autoimmune small fiber axo-
were at least partially refractory to conventional therapy and had nopathy was later cured with high-dose corticosteroids, 4 days of
high pain scores (7.1 ± 1.3), enrolled in the baseline phase, and 31 lidocaine infusion, and a prednisone taper.56
completed the core treatment after 52 weeks, and 15 subjects have Inherited erythromelalgia has been proposed to be a sodium
completed over 104 weeks of therapy.31 Lenalidomide provided sig- channelopathy. Inherited erythomelalgia/erythermalgia (IEM) is a
nificant reduction in pain intensity as assessed by NRS-PI (34% neuropathy characterized by pain and redness of the extremities
achieved greater than a 2-point reduction; mean decrease = 1.2 that is triggered by warmth. IEM has been associated with missense
[± 2.1 standard deviation {SD}], P < .001), SF-MPQ (total score mutation of the NaV1.7, which is preferentially expressed in most
P < .01, sensory score P < .01), and BPI pain scores (P < .05). nociceptive dorsal root ganglia (DRGs) and sympathetic ganglion
Mechanical allodynia assessed by NRS decreased by 1.3 (± 2.5 SD) neurons. Several mutations occur in cytoplasmic linkers of NaV1.7,
units from a baseline of 6.1 units (± 3.3 SD, P < .005). Any with only two mutations in segment 4 (S4)57 and S6 of domain I as
improvements experienced by subjects were sustained with signifi- well as potentially with an alanine 863 substitution by praline
cant effects for at least 1 year. Adverse events were mild and time- (A863P) in S5 of domain II of NaV1,7.58 These mutant channels
limited. Rash, pruritus, dizziness, headache, nausea, increased may lead to hyperexcitability in DRG neurons, which may contrib-
sweating, and decreased thyroid-stimulating hormone were the ute to IEM pathophysiology.
most common. Seven serious adverse events (3 thromboembolic IEM may share certain similarities with CRPS I and CRPS II
events, 3 cytopenias, and 1 case of rectal bleeding) were suspected (although, typically, CRPS is exacerbated more often with exposure
to be related to lenalidomide, and 10 adverse events were consid- to cold temperatures and erythromelalgia is classically exacerbated
ered to be unrelated.31 with warm temperatures), and thus, conceivably certain CRPS
Huygen and coworkers50 examined tryptase levels in artificially cases may also be mediated in part by an increase in the density
produced blisters in affected and unaffected extremities in 20 people or excitability of voltage-sensitive sodium channels in injured axons
with CRPS I confined to one extremity. Tryptase is a specific pro- and the DRG of injured axons. Wallace and associates59 conducted
teolytic enzyme synthesized and released by mast cells (as well as a randomized, double-blind, placebo-controlled design study in
produced constitutively where it is stored at levels about 10–35 pg/ 16 subjects suffering from CRPS I or II with prominent allodynia.
cell) and is considered a good marker of mast cell presence. They Each subject received an intravenous infusion of lidocaine
found blister fluid levels of tryptase in the involved extremity were (a sodium channel blocker) and diphenhydramine separated by
37 ng/ml (20.5–62.3) versus 12.5 ng/ml (a relatively normal 1 week.59 A computer-controlled infusion pump targeted stairstep
level; 6.7–23.5) in the uninvolved opposite extremity.50 There increases in plasma levels of lidocaine of 1, 2, and 3 mcg/ml. At
was a significant correlation between pain intensity and tryptase baseline and at each plasma level, spontaneous and evoked pain
levels in the involved extremity (Spearman’s test, P < .05).50 scores and neurosensory testing within the painful area were mea-
Huygen and coworkers50 concluded that mast cells are involved sured.59 The neurosensory testing consisted of thermal thresholds,
in CRPS I. tactile thresholds and the area of allodynia to punctate, and stroking
Mast cells may also contribute to other various painful condi- and thermal stimuli.59 Intravenous lidocaine and diphenhydramine
tions (e.g., interstitial cystitis, irritable bowel syndrome, endome- had no significant effect on the cool, warm, or cold pain thresholds.
triosis),51–54 and inhibitors of janus kinase 3 (JAK3), which is However, lidocaine caused a significant elevation of the hot pain
required for the full expression of high-affinity immunoglobulin thresholds in the painful area. Intravenous lidocaine caused a sig-
E (IgE) receptor–mediated mast cell inflammatory sequelae, may nificantly decreased response to stroking and cool stimuli in the
potentially be a future therapeutic option worth evaluating for mast allodynic area.59 There was also a significant decrease in pain
cell–mediated nociception.55 scores to cool stimuli at all plasma levels and spontaneous pain at
Another instance in which mast cells may have had significant the highest plasma level.59
involvement is that of an otherwise healthy 20-year-old man who Tan and colleagues60 hypothesized that CRPS I is an exaggerated
was vacationing in Bermuda when he sprained his ankle.56 Within inflammatory response and that the increased capillary permeability
can be due to endothelial damage caused by oxygen radical species blockade of a1- and a2-adrenergic receptors. They further hypothe-
directly or mediated by polymorphonuclear leukocytes. sized that this blockade could reduce stimulation of an increased
Tan and colleagues60 performed radiolabeled autologous leuko- population of adrenergic receptors in hyperalgesic skin, blunt the
cyte imaging of both hands in patients with CRPS I of one upper stimulation by norepinephrine (NE) of a2-adrenergic receptors on
extremity after a fracture or operation of the hand and compared macrophages, and ultimately reduce the release of proinflammatory
that with the unaffected contralateral hand. Leukocytes were iso- cytokines from cellular elements.75
lated and labeled with 200 MBq 99mTc-hexamethylpropyleneamine In an animal model of CRPS I induced by hindpaw ischemia-
oxime (99mTc-HMPAO), as described by Peters and coworkers,61 reperfusion injury, intradermal injections of NE to the affected
and reinjected in the cubital vein. HMPAO is an efficient leukocyte hindpaw induced dose-dependent nociceptive behaviors in CPIP
label that labels granulocytes with more stability than mononuclear rats, but not sham animals.76 These behaviors were blocked by
leukocytes.62,63 At 4 hours postinjection, there was clear, asymmet- a1- and a2-adrenergic receptor antagonists or an NO donor.76
rical leukocyte accumulation in the affected extremity with a mean Using laser Doppler flowmetry, we detected vasoconstrictor hyper-
ratio of 1.49 ± 0.19. In control patients, no asymmetry was observed sensitivity in the ipsilateral CPIP hindpaw compared with responses
between hands (mean ratio 1.09 ± 0.06), indicating the absence of in sham animals or the contralateral hindpaw.76 The vasoconstric-
specific leukocyte accumulation. There was a statistically significant tor hypersensitivity was also attenuated by adrenergic antagonists.
difference between CRPS I and control subjects 4 hours postinjec- Intradermal injection of [Arg8] vasopressin (AVP) or the endothe-
tion (P = .01).60 Tan and colleagues60 found evidence of increased lial NO synthase (eNOS) inhibitor, L-NIO, to the affected paw also
leukocyte accumulation in acute CRPS I after a trauma or operation induced nociceptive behaviors in CPIP rats, but not sham rats.76
of the hand, which seemed to decrease with the interval between Furthermore, it appears that these effects may be least partially due
trauma and imaging and was essentially gone by 9 weeks post- to a supersensitivity of a-adrenergic receptors.
trauma. Two groups reported aberrant migration and sprouting of non-
Eisenberg and associates64 showed that there were no significant perivascular sympathetic fibers in rat skin from the hindpaw77 and
differences in endothelin-1 (ET-1) plasma levels between three lower lip78,79 into the upper dermis after chronic nerve injury to the
groups of patients (one group with severe CRPS, one group with sciatic and mental nerve (a purely sensory branch of the trigeminal
non-CRPS chronic painful conditions, and one group of healthy nerve), respectively.
volunteers). However, it is conceivable that there exists altered Newly sprouted aberrant sympathetic fibers were observed to
ET activity locally in the affected region. Klass and colleagues65 wrap around sensory fibers, forming novel associations that poten-
demonstrated that chronic constriction injury of the sciatic nerve tially provide a histologic substrate for chemically mediated cou-
in rats is associated with up-regulation in the expression of immu- pling between sympathetic nerve terminals and sensory receptors.77
noreactive ET-1 and its receptors specifically at the site of injury. The time-course of the cutaneous changes reported in these studies
It is conceivable that there are significant changes in ET receptors in was observed to be consistent with changes in pain-related
CRPS skin2 that potentially could contribute to pain/hyperalgesia.66 behaviors.79
Groeneweg and coworkers67 demonstrated increased ET-1 and Previously unpublished data from the Phillips laboratory
diminished NO levels (which varied inversely with each other) in demonstrate a close physical association between sympathetic neu-
blister fluids of patients with CRPS I.67 It appears that cross-talk rons and sensory neurons in the upper dermis of normal rat and
exists between NO and the ET-1 system, with NO functioning as a human skin.72 Double-labeled immunohistochemistry was used to
regulatory mechanism against ET-1–induced vasoconstriction. visualize sensory and sympathetic nerve fibers in skin sections.
Namer and associates68 utilized microneurography to record Sensory nerves were stained using antibodies to CGRP, whereas
action potentials from afferent C-fibers in cutaneous fascicles of sympathetic noradrenergic fibers were stained using antibodies to
the peroneal nerve in healthy volunteers and found the following: tyrosine hydroxylase (TH), the rate-limiting enzyme in the nor-
(1) in humans, ET-1 activates mechanosensitive, but not mechan- adrenaline biosynthetic pathway. In normal skin taken from hind-
oinsensitive, nociceptors, (2) histamine released from mast cells is paw plantar pads of Wistar male rats as well as the dorsal surface of
not responsible for all effects of ET-1 on C-nociceptors, and (3), the hand, sympathetic and nociceptive fibers were seen throughout
ET-1 could have a differential role in pain compared with other the dermis. The fibers were observed in close proximity to each
chemical algogens which activate additionally or even predomi- other in nerve bundles and near blood vessels and were seen to
nantly mechanoinsensitive fibers. intertwine in complex patterns in many locations.
Norepinephrine has been shown to influence nociception in Under the altered conditions, a-adrenoceptors associated with
normal human subjects after skin sensitization. In human skin sen- afferent nociceptive fibers may become increasingly sensitized or
sitized by topical capsaicin, thermal hyperalgesia was exacerbated by even fire spontaneously.80 Following nerve lesion, inflammatory
transcutaneous iontophoresis of noradrenaline and also tyramine cells accumulate at the site of injury and subsequently at prox-
(which augments the release of neural norepinephrine).69,70 The imal and distal sites. In the lingual nerve of humans, macrophage
induced thermal hyperalgesia was shown to be independent of accumulation has been shown to persist for up to 47 weeks.81 In
reduced regional blood flow resulting from vasoconstriction70,71 the sciatic nerve of rats, macrophages accumulate within the
and was, therefore, attributed to the pharmacologic action of epineurium and endoneurium by 3 days postinjury and persist
noradrenaline on neurons.72 for at least 8 weeks.82 In neuromas produced in rats by sciatic
The introduction of a physiologically relevant dose of noradren- ligation, infiltrating macrophages also shared a close relationship
aline via intradermal injection has been shown to both evoke and with axons in that they were often situated between openings in
increase spontaneous pain and dynamic hyperalgesia in affected the basal laminae and cytoplasm of Schwann cells.83 These close
skin, but not in unaffected contralateral skin in sympathetically relationships may result in the exposure of nociceptive axons to
mediated pain (SMP) patients or in control subjects.73 sensitizing molecules secreted from macrophages. Activated
There is strong evidence to suggest that the nociceptive actions macrophages may release eicosanoids, NGF (which may induce
of norepinephrine are mediated by a1-adrenoceptors in SMP. mast cell degranulation and the release of prostaglandins, brady-
Autoradiographic studies show that, compared with normal skin, kinin, histamine and serotonin), and IL-1 (which may promote
the hyperalgesic skin of CRPS patients expresses a1-adrenoceptors nonneuronal cells to generate NGF). Also, substance P can
in greater numbers in the epidermis and upper dermis.74 induce oxidative bursts in macrophages, increase phagocytic
Inchiosa and Kizelshteyn75 reported an apparent clinical benefit activity, and stimulate the release of oxygen radicals, cytokines,
of norepinephrine in three of four CRPS patients after oral admin- and NO.81 Furthermore, it is conceivable that certain cases of
istration probably owing to the noncompetitive (irreversible) CRPS may be due to a mitochondriopathy.84 If this is the
case, then perhaps therapies that may have protective or rescue Siegel and associates94 prospectively investigated whether distal
effects on C-fiber mitochondria, such as acetyl-L-carnitine nerve injuries (DNIs) are sufficient to cause CRPS-like abnormal-
(ALCAR), may have some utility for treatment because it ities in animals. Left tibial nerves of male Sprague-Dawley rats were
seemed to help with paclitaxel-evoked pain syndrome and mito- transfixed once by 30-, 22-, or 18-gauge needles. At day 7 post-
chondrial insult.85 operatively, thresholds for ipsilateral-hindpaw withdrawal from
Semmes-Weinstein monofilaments were reduced by 51% or greater
in 0% of sham-operated controls; 67% of rats that received 18-
POTENTIAL SPINAL MECHANISMS gauge DNIs, 88% that received 22-gauge DNIs, and 89% that
THAT MAYCONTRIBUTE TO CRPS received 30-gauge DNIs.94 Fifty-seven percent of all DNI rats had
contralateral hindpaw mirror changes.94 Hyperalgesic responses to
Schoffnegger and colleagues86 studied whether excitation evoked in cold and pinprick applied to the plantar hindpaw were less common
deep dorsal horn neurons either via stimulation of primary afferent and were ipsilesional only, as was neurogenic hindpaw edema.
ab-fibers, by direct electrical stimulation, or via glutamate micro- Ipsilesional-only, tonic, dystonic-like hindpaw postures were
injection leads to activation of neurons in the superficial dorsal evident in 42% of 18-gauge DNIs, 6% of 22-gauge DNIs, and no
horn using Ca2+-imaging in transversal spinal cord slices of neuro- 30-gauge DNIs or sham-operated control rats.94 The prevalence of
pathic and control animals to monitor spread of excitation from postural abnormalities correlated with needle diameter (P = .001).94
the deep to the superficial spinal dorsal horn. In neuropathic but Counting PGP9.5-immunolabeled axons in skin biopsies from rats’
not control animals, a spread of excitation occurred from the deep ipsilesional hindpaws demonstrated mean reductions of 0% after
to the superficial dorsal horn.86 The spread of excitation was synap- 30-gauge needlestick, 15% after 22-gauge needlestick, and 26% after
tically mediated because it was blocked by the alpha-amino- 18-gauge needlestick, which closely reproduce the 29% mean epi-
3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor dermal neurite losses of CRPS I patients.94 Siegel and associates94
antagonist CNQX. In contrast, block of N-methyl-D-aspartate concluded that needlestick DNI models several clinical and patho-
(NMDA) receptors was ineffective. In control animals, the violation logic features of human CRPS and provides direct prospective
of modality borders could be reproduced by bath application of evidence that even minor DNIs can cause CRPS-like abnormalities
g-aminobutyric acidA (GABAA) and glycine receptor antagonists.86 in rats.
Neuropathic animals were also more prone to synchronous network
activity than control animals. Thus, after peripheral nerve injury,
excitation generated in dorsal horn areas that process nonnocicep- THE NMDA RECEPTOR COMPLEX
tive information can invade superficial dorsal horn areas that IN CRPS
normally receive nociceptive input. This may be a spinal mecha-
nism of touch-evoked pain.86 The NMDA receptor complex appears to play a role in CRPS. Kiefer
There has been an increasing appreciation that glia may be and colleagues95 performed an open-label phase II study in which 20
involved in contributing to various persistent painful states87–90; patients who had severe CRPS and failed available standard therapies
specifically in painful states that may involve ‘‘mirror-image’’ received ketamine in anesthetic dosage over 5 days. Outcome criteria
pain (e.g., CRPS I), a role for glia is conceivable.91,92 were pain relief, effect on movement disorder, quality of life, and
A role for glia involvement in CRPS pathophysiology is a disability to work at baseline and at discharge (days 10–16), one
tinct possibility. Alexander and coworkers92 compared CSF levels monthly and at 3 and 6 months after treatment. Pain assessment
of pro- and anti-inflammatory cytokines, chemokines, and several was rated by an NRS-11 and the degree of pain relief was
biochemical factors (glial fibrillary acidic protein [GFAP], the NO calculated as percent pain relief = (NRSbaseline – NRSfollow-up/
metabolites [nitrate plus nitrate], the excitatory amino acid neu- NRSbaseline x 100). (All patients needed a baseline pain score of 7
rotransmitter glutamate, calcium, total protein, and glucose) in for inclusion].
patients afflicted with CRPS to levels found in patients suffering Assessment of active range of motion was based on norms
with other nonpainful or painful conditions. The most common described by Kendall and coworkers.96 Arm movement was quanti-
pattern was found in 50% (11 out of 22) of the CRPS patients and fied by utilizing a combination of the performance of specific motor
consisted of elevated IL-6, low levels of IL-4 or IL-10, increased tasks (placing a book in a shelf above shoulder level, ability to comb
GFAP or monocyte chemoattractant protein (MCP)-1 and one’s hair, putting on a sweater, tying an apron) in addition to the
increases in at least two of the following markers: NO metabolites, results of the range of motion evaluation. Hand movement assess-
calcium, or glutamate.92 Thus, it is conceivable that glial inhibitors ment combined grip function (gripping and holding a cup) and
may be future potential therapeutic agents for the treatment pinch grip ability (gripping, holding, and using a key or pencil,
of CRPS. and writing). Based on the observed range of movement combined
Animal models appear to support the potential development of with performance in the described functional tasks, the movement
mirror-image pain, despite the fact that there are no known distinct disorder was quantified utilizing a 4-point rating scale: 0, normal
neuroanatomic connections between neurons that innervate movement; 1, moderate disability (moderately reduced active range
homologous right and left body parts.93 Oaklander and coworkers3 of motion, muscular strength, initiation, and completion of motor
studied 18 adults with IASP-defined CRPS I affecting their arms and tasks); 2, severe disability (severely restricted active range of motion,
legs to address whether CRPS was associated with minimal distal weakness, poor initiation, and completion of motor tasks); and 3,
nerve injuries (MDNI). Skin biopsies were taken at three sites on total disability (only residual movement, severe weakness, and
subjects’ CRPS-affected and matching contralateral limb, the CRPS- inability to perform motor tasks).95
affected site, and nearby unaffected ipsilateral and matching The assessment of motor function of the lower extremity was
contralateral control sites. Quantitative mechanical and thermal based on the ability to walk and was scored on a 4-point rating
sensory testing (QST) was performed followed by quantitation of scale: 0, normal movement (unimpaired walking); 1, moderate dis-
epidermal neurite densities within PGP9.5-immunolabeled skin ability (inability to walk 500 m); 2, severe disability (inability to
biopsies. QST revealed mechanical allodynia (P < .03) and heat- walk 200 m); and 3, total disability (ability to walk < 50 m or
pain hyperalgesia (P < .04) at the CRPS-affected site. Axonal inability to walk).
densities were highly correlated between subjects’ ipsilateral and Patients were asked to rate their performance of typical activities
contralateral control sites (r = 0.97), but were diminished at the of daily living. The representative tasks of everyday life were based
CRPS-affected sites of 17 of 18 subjects, on average by 29% on selected key items contained in valid questionnaires, such as the
(P < .001).3 West Haven-Yale Multidimensional Pain Inventory (WHYMPI)97
and the Stanford Health Assessment Questionnaire (HAQ).98 At 1, 3, and 6 months, a significant (P < .001) reduction of the sum
Patients were instructed to rate their ability to independently per- score was noted for the movement impairment in the arms (1.4 ±
form the following tasks: self-care (preparing meals and eating [cut- 0.83, 0.5 ± 0.8, and 0.4 ± 0.8) and hands (1.6 ± 0.8, 0.5 ± 0.9, and
ting food], drinking, dressing, washing, drying, and combing) and 0.5 ± 0.8), respectively.95 Statistical analyses of scores for decreased
household activities (house cleaning, grocery shopping, washing movement in the lower extremities were based on the direct scores
dishes, and gardening). The degree of impairment was rated using of the aforementioned 4-point–based NRS. Of the entire group,
a 4-point numerical scale: 0, no impairment (all tasks can be per- only those with a movement disorder in the lower extremity were
formed independently), 1, moderate impairment (tasks can be included for statistical analyses. At baseline, patients with move-
accomplished but with difficulty), 2, severe impairment (< 50% ment disorder of the lower extremity (N = 15) had a score of
of activities can be performed independently); and 3, total impair- 2.3 ± 0.7 (mean ± SD). After treatment, their impairment was
ment (majority of tasks cannot be performed; dependent on the significantly reduced at 1, 3, and 6 months (1.3 ± 0.9, 0.6 ± 0.7,
help of others).95 and 0.6 ± 0.6, N = 15, P < .001).95
Patients were asked to evaluate their ability to function socially At baseline, the ability to independently accomplish activities of
and rated their overall impairment. Representative activities were daily living was rated as severely impaired by 7, and as totally
chosen from the aforementioned validated questionnaires impaired by 13 patients, with a mean score of 2.35 ± 0.4 (mean ±
(WHYMPI, HAQ). Patients rated their ability to perform recre- SD) for the entire group. At 3 months, the impairment was rated as
ational activities (pursuing hobbies, playing sports, taking trips, severe by 1, as moderate by 12, and as not impaired by 7 patients,
seeing friends/relatives, reading, going out), cultural activities with a mean score of 0.7 ± 0.6, and a significant difference compared
(attending concerts, movies, theater). The degree of impairment with baseline (P < .001). At 6 months, there was a significant differ-
was rated using a 4-point numerical rating scale: 0, no impairment; ence in the ability to perform activities of daily living compared with
1, moderate impairment (all activities can be performed, but with baseline. One patient rated total impairment, 3 severe impairment, 6
difficulty); 2, severe impairment (< 50% of activities can be per- moderate impairment, and 10 patients no impairment for a mean
formed independently); and 3, total impairment (majority of activ- score of 0.7 ± 0.9 (P < .001).95
ities cannot be performed and the patient is dependent on the help The impairment in social integration prior to treatment was
of others). The ability to work was rated on a 4-point scale: 0, no rated as complete by 11 patients and severe by 9. Their mean
impairment; 1, moderate impairment (able to work more than 4 hr/ impairment score was 2.5 ± 0.5. At 3 months, their impairment
day but less than 8 hr/day); 2, severe disability (able to work up to 4 was rated as severe by 1, as moderate by 10, and 9 were unimpaired.
hr/day); and 3, total impairment (able to work only 2 hr/day or Their mean score of 0.6 ± 0.6 was significantly improved compared
totally unable to work).95 with their pretreatment baseline (P < .001). At 6 months, there was
Pain intensities were analyzed for the entire group as well as for significant improvement in the group, with 1 patient rating total
the subgroup of patients with recurring initiating or maintaining impairment, 2 severe impairment, 6 moderate impairment, and
pain (nociceptive or neuropathic, but without associated CRPS 11 patients no impairment (mean score of 0.6 ± 0.8, P < .001).95
signs or symptoms) and the subgroup with relapsing CRPS (neuro- The impairment in the ability to work prior to treatment was
pathic pain and associated CRPS signs and symptoms).95 At base- rated as complete by 11, severe by 5, and as moderate by 4 patients
line, pain intensity of the entire group (N = 20) and of the (mean impairment score of 2.3 ± 0.8). At 3 months, the impairment
subgroups with later recurring pain and relapsing CRPS were in ability to work was rated as complete and severe by 1 patient in
NRS 8.9 ± 0.3, 8.8 ± 0.2, and 9.2 ± 0.2 (mean ± SD), respectively, each category, as moderate by 8, and as not impaired by 10 patients
and no statistically significant differences between the groups were (mean score of 0.6 ± 0.8), which was significantly improved
detected.95 After ketamine treatment, a significant reduction of pain compared with their baseline (P < .001). At 6 months, there was
intensity was observed at 1 week and 1 month for the entire group significant improvement in the ability to work because only
(NRS 0.5 ± 0.8 and 0.6 ± 1.0), and the subgroup with recurring pain 2 patients in the cohort were unable to work, 4 had moderate
(1.4 ± 0.7, and 1.7 ± 1.1, n = 7) (P < .001). At 3 months, pain impairment, and 14 patients had no impairment (mean score of
intensity was significantly (P < .001) reduced compared with base- 0.5 ± 0.9, P < .001).95
line in the entire group (NRS 0.9 ± 1.6) and the subgroup with
recurring pain (2.0 ± 0.9, n = 4). Three patients had a CRPS relapse,
but had significantly reduced pain compared with baseline (NRS POTENTIAL SUPRASPINAL
3.8 ± 1.4, P < .004). Pain intensity at 6 months was significantly MECHANISMS THAT MAYCONTRIBUTE
reduced for the entire group of patients (2.0 ± 2.4, P < .001), the TO CRPS
subgroups with recurring pain (3.6 ± 2.0, P < .001, n = 6), and
those with a CRPS relapse (4.6 ± 1.1, P < .002, n = 4).95 Endo and associates99 demonstrated that cerebral activations in
The calculated percentage of pain relief was significant after keta- contralateral primary somatosensory cortex (SI) are markedly cor-
mine treatment at 1 week (mean ± SD, 94.5% ± 8.9) and at 1, 3, and 6 related with different behavioral characteristics of these animals.
months (93.5% ± 11.1, 89.4% ± 17.0, 79.3% ± 25.3) in the entire Identical electrical stimulation, applied on trunks of spinally injured
group of patients (P < .001). Analyses for the subgroup with recur- hypersensitive and nonhypersensitive rats, evoked significantly
ring pain showed significant pain relief at 1 week (84.4% ± 8.22, higher responses in SI of the former than the latter.99
n = 7, P < .001) and 1, 3, and 6 months (81.4% ± 11.5, 77.8% ± Shiraishi and colleagues100 studied the brains of patients with
10.1, and 64.32% ± 23.8, n = 7, 4, and 6, respectively; P < .001 in CRPS utilizing 18F-fluorodeoxyglucose positron emission tomogra-
all).95 Pain relief in the subgroup of CRPS patients with relapse was phy. These authors100 showed that glucose metabolism was bilater-
maintained at 3 and 6 months (59% ± 14.7, n = 3, P < .004, and ally increased in the secondary SI, mid–anterior cingulate cortex
50.21% ± 10.6, n = 4, P < .002).95 (ACC) or posterior cingulate cortex (PCC) (or both), parietal
For statistical analyses, the separately assessed scores of the cortex, posterior parietal cortex (PPC), and cerebellum as well as
impairment of movement in the arm and hand of each side of in the right posterior insula and right thalamus in CRPS patients. In
the body was added to a total score for hands and arms. Thus, contrast, glucose metabolism was reduced contralaterally in the
the minimal sum score was 0 (normal bilateral movement) and dorsal prefrontal cortex and primary motor cortex.100 Glucose
maximal 6 (total bilateral impairment). All patients (N = 20) metabolism was bilaterally elevated in the mid-ACC/PCC and the
showed impaired movement in the upper extremities.95 At baseline, PPC, which correlated with pain duration.100
a sum score of 3.2 ± 1.2 (mean ± SD) for movement in the arms, Six normal control subjects having one 99mTc-HMPAO scan
and 3.7 ± 1.2 for movement in the hands was documented (N = 20). each and the patient with CRPS having three 99mTc-HMPAO
scans (once before treatment and twice at 4 months and 6 months calculating the locations, orientations, and strengths of the equiva-
after treatment, respectively).101 The patient with CRPS showed lent current dipoles (ECDs) best describing local source currents at
lower regional cerebral blood flow (rCBF) than normal controls the peak of the responses.107 The source areas were superimposed
in the left thalamus and higher rCBF than normal controls in the on the subject’s individual magnetic resonance imaging (MRI)
right parietal lobe and left frontal lobe. After subsequent treatment scans to detect the generator area with respect to anatomic
with pain relief, the subtraction images showed increased rCBF in structures.107
the left thalamus and decreased rCBF in the right parietal and left Figure 40–5 shows locations of the representation areas of the
frontal lobes.101 thumbs and little fingers at the SI cortex in one CRPS patient.107
Fukui and coworkers102 conducted a course of eight electrocon- The distance between thumb and little finger representations is
vulsive therapy (ECT) sessions over a month on four patients with shorter in the affected (left) hemisphere compared with the healthy
CRPS I who had failed to respond to standard pain treatments side, indicating plastic changes of the cortical finger representa-
for their persistent pain. To investigate the potential role of rCBF tions.107 Such statistically significant shifts in finger representations
in ECT analgesic effect, we measured significant changes in the were observed in all patients.
rCBF in the thalamus before and after a course of bilateral ECT Several other studies using MEG, electroencephalography
using 99mTc-ethyl cysteinate dimer (ECD) single-photon emission (EEG), and functional MRI (fMRI) have supported these find-
computed tomography (SPECT).103 Furthermore, to examine ings.108,109 Pleger and associates109 demonstrated that pain intensity
whether the changes in rCBF in the thalamus were related to the over the last month was correlated with the extent of the hand
analgesic efficacy of ECT, they compared these values between representation at the SI cortex. The results indicated that individual
responders and nonresponders.102 Two of four (50.0%) patients expansion of hand representation contralateral to the CRPS-affected
responded to ECT treatment (response defined as a reduction of limb was significantly correlated with mean pain intensity. Thus,
at least 60% on the visual analog scale [VAS]). In two CRPS low pain levels were linked to small representational side-to-side
patients, ECT dramatically relieved severe chronic pain and vascular differences, whereas subjects with a distinctive hemispherical asym-
abnormalities. After ECT, they rated their average pain severity as metry reported the highest pain levels.109
0 to 1 on a VAS. These patients obtained a very satisfactory pain- It appears that the plastic changes may be, at least to some
relieving effect from ECT. After ECT treatment, the patients still extent, reversible, suggesting that rehabilitation should be targeted
experienced minimal pain, but reported it as tolerable. On follow- to ‘‘turn back the clock’’ for regaining the orderly baseline (pre-
up 6 months after the end of ECT treatment, the reductions of CRPS) somatotopic arrangement at the SI cortex.107 Maihofner and
the pain were persisting. The remaining two CRPS patients failed colleagues110 followed CRPS I patients over a year or more with
to respond to ECT treatment.102 MEG imaging to explore changes in the cortical representation of
In responders before ECT, the mean contralateral and ipsilateral digits (D) 1 and 5 in relation to the lower lip on the unaffected and
thalamus-to-cerebellum ratios were 74.8% and 81.9%, respectively. affected side. The results suggested that cortical reorganization
After ECT, SPECT showed that the mean contralateral and reversed coincident with clinical improvement and that reduction
ipsilateral thalamus-to-cerebellum ratios increased to 85.7% and of CRPS pain correlated with recovery to order baseline cortical
86.0%, respectively, when the pain subsided. The mean thalamus- organization from cortical reorganization.110 Maihofner and collea-
to-cerebellum ratio in the contralateral thalamus increased 11.5% gues110 concluded that changes of the somatotopic map within the
compared with the ratio before ECT in responders.102 In nonre- S1 cortex may depend on CRPS pain and its recovery.110 fMRI
sponders before ECT, the mean contralateral and ipsilateral thala-
mus-to-cerebellum ratios were 77.2% and 88.1%, respectively. After
ECT, SPECT showed that mean contralateral and ipsilateral thala-
mus-to-cerebellum ratios changed to 78.5% and 89.9%. The mean
thalamus-to-cerebellum ratio in the contralateral thalamus
increased only 1.6% compared with the ratio before ECT in
nonresponders.102
Eisenberg and associates104 studied 12 patients with CRPS I,
confined to the distal part of a limb (6 in an upper limb and 6 in
a lower limb). The quantitative thermal, mechanical, and wind-
up–like pain testing was performed at the most painful site in the
affected limb and in the ipsilateral limb along with transcranial D1
magnetic stimulation (TMS).104 Their results suggest that in D1
patients with well-localized CRPS, there is evidence for sensory
and motor central nervous system hyperexcitability, although it
seems to involve only corresponding regions within the central D5 D5
nervous system rather than the entire hemisphere.104
Flor and colleagues105 showed that changes in afferent input
may lead to cortical reorganization of sensory representations
(e.g., amputation of upper limbs may result in diminished hand
representation area and expansion of the face representation area to
the former hand area in the primary somatosensory [S1] cortex).
Furthermore, the extent of the reorganization correlates positively
with the reported intensity of phantom limb pain (i.e., the more
intense the pain, the larger plastic changes observed at the
cortex).105 Juottonen and coworkers106 studied locations of finger
representations in CRPS I patients with chronic unilateral persistent Left Right
pain. Tactile stimuli were delivered to the first and fifth fingertips of
the healthy and painful hands, and the evoked responses were Figure 40^5. Locations of the thumb (D1) and little finger (D5)
recorded with whole scalp magnetoencephalography (MEG).107 representations of the healthy (circles) and painful (squares) hands of
The evoked responses peaked at about 65 msec after the stimulation one patient superimposed on a three-dimensional surface
onset, and the sources of the measured responses were identified by reconstruction of her magnetic resonance imaging (MRI) studies.
studies with CRPS patients showed that behavioral treatment over 1 affected hand in patients showed reduced activation ipsilaterally in
to 6 months, consisting of graded sensorimotor retuning, led to a the premotor and adjacent prefrontal cortices and in a cluster com-
persistent decrease in pain intensity, which was accompanied by a prising the frontal operculum, the anterior part of the insular
restoration of the impaired tactile discrimination and regaining of cortex, and the superior temporal gyrus.123 Contralaterally, reduced
cortical map size in contralateral SI and SII.111 This suggests that the activation was seen in the inferior parietal and adjacent primary
reversal of tactile impairment and cortical reorganization in CRPS is sensory cortex. There were no differences between patients and
associated with a decrease in pain.111 controls when they executed movements nor when they imagined
Thus, it may be conceivable that rehabilitation programs may be moving their unaffected hand.123 The altered cerebral activation
able to be tailored to a specific patient in efforts to help regain pattern in patients with CRPS I–linked dystonia most likely reflects
normal somatotropic arrangement of the SI cortex with commit- an interface between pain-associated circuitry and higher-order
ment reduction of pain. Forss and coworkers107 found that for motor control, which points at a specific mechanistic pathophysi-
chronic CRPS patients who had suffered from CRPS symptoms ology of this type of dystonia.123 Gietling and associates123 con-
for more than 5 years, rehabilitation did not induce reorganization cluded that patients with CRPS I and dystonia displayed areas
at the cortical level and the pain levels were not decreased. with decreased activation during imagining tasks that are involved
Therefore, the optimal rehabilitation program type, duration, and in planning of movement, multimodal sensorimotor integration,
timing to achieve the best outcome for CRPS patients—inducing autonomic function, and pain. Pain may profoundly alter the cere-
cortical reorganization, and diminishing pain—remain uncertain. bral organization of movement by functional interaction between
There may also be significant alterations in the normal motor these regions.123
cortex function in CRPS. The human cortical m rhythm, prominent
in the rolandic areas in both EEG and MEG recordings, consists of
dominant approximately 10- and approximately 20-Hz frequency SUMMARY
bands.112 The cortical m rhythm reacts to tactile and motor stimuli;
for example, electric median nerve stimuli result in an initial It would appear that a number of heterogeneous factors may con-
decrease of the m rhythm level, followed by strong rebound tribute to the clinical picture of CRPS. Changes in the periphery,
within 1000 msec after stimuli. The rebound is suppressed during spinal cord, and supraspinal levels may all be at play, affecting both
finger movements,113 motor imagery,114 and even by viewing sensory and motor systems. Pharmacologic, physical, behavioral,
another person to make movements.115 Previous MEG and TMS and neuromodulatory therapeutic strategies aimed at reducing
studies have suggested that increase of the 20-Hz rhythm nociceptive afferent input to higher central nervous system centers,
(‘‘rebound’’) reflects inhibition of the motor cortex,116,117 whereas reversing central sensitization, increasing thalamic synaptic activity,
decrease of the 20-Hz rhythm indicates excitation or disinhibition and reversing cortical reorganization may contribute to analgesia in
of the motor cortex. various patients with CRPS.
In efforts to study interaction between the motor and the pain
systems in chronic pain patients, Juottonen and coworkers106
recorded reactivity of the 20-Hz rhythm in six chronic CRPS I ACKNOWLEDGMENTS
patients during tactile stimulation of the painful hand. Reactivity
of the motor cortex was significantly altered in all CRPS patients; The authors wish to thank Marilyn Dockum, for assistance with all
the rebound of the m rhythm was shortened or lacking, suggesting aspects of tissue processing, and all of our collaborators.
decreased inhibition of the motor cortex.106 TMS has also revealed
signs of disinhibition or hyperexcitability of the motor cortex in
CRPS patients.118 Prolonged disinhibition of the motor cortex may
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Chapter 41 Even the identification and measurement of the pain, the prin-
ciple symptom of CRPS, is problematic. The defining characteristic
INTERDISCIPLINARY (and critical diagnostic criterion) is ‘‘continuing pain that is dis-
proportionate to any inciting event’’4—pain deemed dispropor-
MANAGEMENT FOR COMPLEX tionate, that is, in intensity and duration according to the
(subjective) opinion of the diagnosing physician (see ‘‘Principles
REGIONAL PAIN SYNDROME of Functional Restoration,’’ below). This necessary yet flawed
assessment of pain is compounded by the patient’s outlook; for
although pain is clearly a central component of a CRPS patient’s
R. Norman Harden condition, its report is always a personal, private, and entirely
subjective experience. Any number of factors can affect pain
report, including culture, memory of past pain experiences, the
meaning and context of the pain, personality type, affective state,
and many other functional variables.5,6 Furthermore, pain report is
behavioral: filling out a visual analog scale is a behavior, and any
such behavior can be affected by a range of psychosocial/operant
INTRODUCTION features. Unfortunately, only the subjective experience of pain is
quantifiable. Limited by this subjectivity of both physician and
Complex regional pain syndrome (CRPS) is sometimes a very patient, the most pragmatic assessment of pain must be based
difficult condition to treat successfully. Not only is the syndrome on the patient’s complete context: biologic, psychological, and
biomedically multifaceted, comprising both central and peripheral sociologic. Obviously, the only treatment methodology that can
pathophysiology, but it also frequently contains psychosocial treat all these aspects effectively is, again, the interdisciplinary
components that are pivotal diagnostic features (and thus, approach.
treatment targets). The array of possible patient presentations and It is critical to identify and aggressively treat all spheres of the
the fact that the presentation often changes over time also compli- pain experience. Obsessing with only the biomedical sphere often
cate successful identification and treatment.1 To further add to the dooms the clinician and patient to failure, especially in chronic
clinical challenges of managing CRPS, the epidemiology and natural CRPS. The other equally important feature for accurate diagnosis
history of CRPS are only superficially known; evidence concerning and a responsive treatment target in CRPS are psychological factors/
CRPS treatment has developed slowly, owing in large part to the comorbidity (see ‘‘Recreational Therapy,’’ below). The psychologi-
vagaries of diagnosis (see ‘‘Principles of Functional Restoration,’’ cal spheres of the pain experience can now be identified through the
below); and research data—when they are available—are challen- many psychometric, quantified measures that have been created and
ging to interpret.2 Given these obstacles to diagnosis, treatment, and that have demonstrated efficacy in psychological assessment.6–8
research, how is a specialist to embark on a path toward the suc- Psychological features are sometimes critically important diagnostic
cessful treatment of such a complicated and partially understood components to identify and aggressively treat; psychometric scores
condition? The only treatment methodology that can possibly suc- are also often employed as secondary outcomes in research. CRPS is
cessfully span these gaps in medical science is a systematic and not a psychological disorder, however, and it is therefore illogical to
orderly interdisciplinary approach.3 designate psychometric outcomes as primary benchmarks of
108. Maihofner C, Handwerker HO, Neundorfer B, Birkelin E. Patterns 116. Salmelin R, Hari R. Spatiotemporal characteristics of sensorimotor
of cortical reorganization in complex regional pain syndrome. MEG rhythms related to thumb movement. Neuroscience
Neurology 2003;23:1707–1715. 1994;60:537–550.
109. Pleger B, Tegenthoff M, Janssen E, et al. Mean sustained pain levels 117. Chen R, Corwell B, Hallett M. Modulation of motor cortex excitability
are linked to hemispherical side-to-side differences of primary by median nerve and digit stimulation. Exp Brain Res 1999;129:77–86.
somatosensory cortex in the complex regional pain syndrome I. Exp 118. Schwenkreis P, Janssen F, Rommel O, et al. Bilateral motor cortex
Brain Res 2004;155:115–119. disinhibition in complex regional pain syndrome (CRPS) type 1 of
110. Maihofner C, Handwerker HO, Neundorfer B, Birklein E. Cortical the hand. Neurology 2003;61:515–519.
reorganization during recovery from complex regional pain 119. Pleger B, Ragert P, Schwenkreis P, et al. Patterns of cortical
syndrome. Neurology 2004;24:693–701. reorganization parallel intact tactile discrimination and pain intensity
111. Pleger B, Tegenthoff M, Ragert P, et al. Sensorimotor retuning in complex regional pain syndrome. Neuroimage 2006;32:503–510.
[corrected] in complex regional pain syndrome parallels pain 120. McCabe CS, Haigh RC, Ring EF, et al. A controlled pilot study of
reduction. Ann Neurol 2005;57:425–429. the utility of mirror visual feedback in the treatment of complex
112. Hari R, Salmelin R. Human cortical oscillations: a neuromagnetic regional pain syndrome (type 1). Rheumatology 2003;42:97–101.
view through the skull. Trends Neurosci 1997;20:44–49. 121. Moseley GL. Graded motor imagery is effective for long-standing
113. Salenius S, Schnitzler A, Salmelin R, et al. Modulation of human complex regional pain syndrome: a randomised controlled trial. Pain
cortical rolandic rhythms during natural sensorimotor tasks. 2004;108:192–198.
Neuroimage 1997;5:221–228. 122. Gay A, Parratte S, Salazard B, et al. Proprioceptive feedback
114. Schnitzler A, Salenius S, Salmelin R, et al. Involvement of primary enhancement induced by vibratory stimulation in complex regional
motor cortex in motor imagery: a neuromagnetic study. Neuroimage pain syndrome type 1: an open comparative pilot study in
1997;6:201–208. 11 patients. Joint Bone Spine 2007;74:461–466.
115. Hari R, Forss N, Avikainen S, et al. Activation of human primary 123. Gieteling EW, van Rijn MA, de Jong BM, et al. Cerebral activation
motor cortex during action observation: a neuromagnetic study. during motor imagery in complex regional pain syndrome type 1
Proc Natl Acad Sci U S A 1998;95:15061–15065. with dystonia. Pain 2008;134:302–309.
Chapter 41 Even the identification and measurement of the pain, the prin-
ciple symptom of CRPS, is problematic. The defining characteristic
INTERDISCIPLINARY (and critical diagnostic criterion) is ‘‘continuing pain that is dis-
proportionate to any inciting event’’4—pain deemed dispropor-
MANAGEMENT FOR COMPLEX tionate, that is, in intensity and duration according to the
(subjective) opinion of the diagnosing physician (see ‘‘Principles
REGIONAL PAIN SYNDROME of Functional Restoration,’’ below). This necessary yet flawed
assessment of pain is compounded by the patient’s outlook; for
although pain is clearly a central component of a CRPS patient’s
R. Norman Harden condition, its report is always a personal, private, and entirely
subjective experience. Any number of factors can affect pain
report, including culture, memory of past pain experiences, the
meaning and context of the pain, personality type, affective state,
and many other functional variables.5,6 Furthermore, pain report is
behavioral: filling out a visual analog scale is a behavior, and any
such behavior can be affected by a range of psychosocial/operant
INTRODUCTION features. Unfortunately, only the subjective experience of pain is
quantifiable. Limited by this subjectivity of both physician and
Complex regional pain syndrome (CRPS) is sometimes a very patient, the most pragmatic assessment of pain must be based
difficult condition to treat successfully. Not only is the syndrome on the patient’s complete context: biologic, psychological, and
biomedically multifaceted, comprising both central and peripheral sociologic. Obviously, the only treatment methodology that can
pathophysiology, but it also frequently contains psychosocial treat all these aspects effectively is, again, the interdisciplinary
components that are pivotal diagnostic features (and thus, approach.
treatment targets). The array of possible patient presentations and It is critical to identify and aggressively treat all spheres of the
the fact that the presentation often changes over time also compli- pain experience. Obsessing with only the biomedical sphere often
cate successful identification and treatment.1 To further add to the dooms the clinician and patient to failure, especially in chronic
clinical challenges of managing CRPS, the epidemiology and natural CRPS. The other equally important feature for accurate diagnosis
history of CRPS are only superficially known; evidence concerning and a responsive treatment target in CRPS are psychological factors/
CRPS treatment has developed slowly, owing in large part to the comorbidity (see ‘‘Recreational Therapy,’’ below). The psychologi-
vagaries of diagnosis (see ‘‘Principles of Functional Restoration,’’ cal spheres of the pain experience can now be identified through the
below); and research data—when they are available—are challen- many psychometric, quantified measures that have been created and
ging to interpret.2 Given these obstacles to diagnosis, treatment, and that have demonstrated efficacy in psychological assessment.6–8
research, how is a specialist to embark on a path toward the suc- Psychological features are sometimes critically important diagnostic
cessful treatment of such a complicated and partially understood components to identify and aggressively treat; psychometric scores
condition? The only treatment methodology that can possibly suc- are also often employed as secondary outcomes in research. CRPS is
cessfully span these gaps in medical science is a systematic and not a psychological disorder, however, and it is therefore illogical to
orderly interdisciplinary approach.3 designate psychometric outcomes as primary benchmarks of
310 Chapter 41 INTERDISCIPLINARY MANAGEMENT FOR COMPLEX REGIONAL PAIN SYNDROME
improvement in treatment. Pain intensity and the psychological components of a functional restoration program yield positive out-
sequelae/comorbidities of pain are recognized, fundamental ele- comes, as well as which modalities should be delivered, when, and
ments in understanding the whole patient, yet the subjective char- for how long, are currently unavailable.11,17
acter of these elements and of their measurement deem them less
suitable for research or for interpreting clinical outcomes. More
objective clinical benchmarks and outcomes should be identified— EVIDENCE
standardson which clinical decisions may be made and success may
be measured. Ideally, treatment of CRPS should rely on an intuitive, The data suggesting the significance of functional restoration and
measurable, and stepwise functional restoration algorithm as the reanimation is modest but credible. It is important to note that in a
pivotal feature of treatment of CRPS.1,9,10 1997 meta-analysis, Kingery2 stated that ‘‘CRPS trials tended to use
Functional restoration has historically and empirically been con- less subjects and were less likely to use placebo controls, double-
sidered a critical and necessary component of interdisciplinary pain blinding, or perform statistical tests for differences in outcome
management programs for CRPS. This contention has been codified measures’’ (than neuropathic pain). Early, uncontrolled work by
by two large international consensus-building conferences.9,11 several investigators focused on preliminary concepts of quantifying
Baron and Wasner12 concluded that physiotherapy is ‘‘of utmost different facets of function and biometrics in ‘‘reflex sympathetic
importance,’’ and Birklein and coworkers13,14 argued that rehabil- dystrophy’’ (RSD, also known as CRPS I).18–22 In a pivotal 1988
itation techniques should always be employed for the ‘‘obvious paper, Davidoff and associates10 conducted a prospective, uncon-
reasons’’ that they outlines in their articles. Furthermore, the trolled study in RSD that determined three key concepts: that objec-
Initiative on Methods, Measurement, and Pain Assessment in tive functional components and biometric data could be quantified
Clinical Trials (IMMPACT) concluded that physical functioning longitudinally, that these components were reactive enough to dis-
is a ‘‘core domain’’ in the assessment of pain treatment efficacy, play change over time (in response to a functional restoration–
second only to pain assessment.15,16 based interdisciplinary program), and that they were associated
Functional restoration emphasizes physical activity (‘‘reani- with improvements in subjective outcomes (e.g., decreased pain),
mation’’), desensitization, and normalization of sympathetic tone (level-three evidence). These initial studies supplied the primary
in the affected limb and involves a steady progression from the most rationale for a reliance on functional measures as the basis for
gentle, least invasive interventions to the ideal of complete rehabil- assessing success in the treatment of RSD/CRPS.
itation in all aspects of the patient’s life (Fig. 41–1). Although the In an open-label sample of musculoskeletal pain, Baker and
benefits of functional restoration may be obvious to experienced associates23 convincingly illustrated the value of quasiquantitative
clinicians, the evidence required to buttress these empirical impres- and psychometric measures in estimating functional outcome
sions remains to be collected. The hard data needed to determine (level-three evidence). Other various uncontrolled studies suggest
which aspects of treatment demonstrate efficacy, which specific that CRPS patients benefited from certain physiotherapeutic mod-
alities, including stress-loading and isometric techniques24 (level-
three evidence). Oerlemans and colleagues17,25 conducted a pro-
spective, controlled study of 135 CRPS patients with pain located
Reactivation
in an upper extremity, and they reported that both physical therapy
Contrast baths
Desensitization (PT) and occupational therapy (OT) proved valuable in managing
Exposure therapy pain, restoring mobility, and reducing impairment (level-two evi-
dence). In their prospective assessment of 145 patients, Birklein and
coworkers13 found that pain was notably less for patients undergo-
ing PT (level-three evidence). In another study of 28 children meet-
Flexibility ing the International Association for the Study of Pain (IASP)
Edema control criteria of CRPS, 92% reduced or eliminated their pain after receiv-
Isometric strengthening
ing exercise therapy26 (level-three evidence).
Correction of postural abnormalities
Diagnosis and treatment of secondary Both functional restoration and reanimation may have beneficial
myofascial pain effects for the CRPS patient. Immobilization is a diagnostic crite-
rion for CRPS that is recognized as a possible cause and/or perpe-
tuating factor in the syndrome (criterion one).4 A prevalence of
motor abnormalities (dyscoordination, dystonia, weakness), and
ROM (gentle) tremor in CRPS is an accepted criterion,27,28 and these have been
Stress loading integrated into the Budapest group’s suggestions for new diagnostic
Isotonic strengthening
criteria (see ‘‘Principles of Functional Restoration,’’ below). In
General aerobic conditioning
Postural normalization and balanced use addition, the role of pathologic involvement of local muscle
spasm, reactive bracing, and disuse in the face of severe pain in
relation to the syndrome should not be misjudged; these aspects
are all logical targets of an interdisciplinary-based functional resto-
Ergonomics ration or ‘‘normalization’’ program.
Movement therapies Normalized movement may also be a key aim in avoiding or
Normalization of use inverting some of the more understated, higher central changes
Vocational/functional rehabilitation linked with the syndrome, usually categorized under the rubric of
Figure 41^1. A sample, stepwise, functional restoration ‘‘altered central processing’’ and recently, ‘‘neglect.’’27 Moseley29
algorithm. From the outset, in appropriate cases, the patient should expanded on this hypothesis and suggested that the elements of
have access to medications and/or psychotherapy and/or injections.If CRPS indicate a central mismatch of afferent input and central
the patient cannot begin, or fails to progress, at any step or in any representation and that graded motor imagery may ‘‘repair this
regard, the clinical team should consider starting (or adding) more or dynamic central mismatch.’’28 In a novel experiment using mirrors,
stronger medications (section 3) and/or more intensive psychotherapies sensory mismatch was demonstrated to produce sensory distur-
(section 4) and/or differentinterventions (section 5). (Extrapolated and bances in normal volunteers30 and has also been employed in a
modified fromthe three clinicalconsensus meetings: Malibu, Minneapolis, controlled pilot study to successfully treat CRPS I.31 These interest-
and Budapest [references 3,9,11].) ing and technical studies provide a theoretical rationale for the
more pedestrian physical and occupational therapeutic methodol- facilitated by pain relief; the use of pharmacologic and/or interven-
ogies of simple functional restoration, graded exposure, and tional procedures to treat specific signs and symptoms; and cogni-
ordered normalization of movement patterns. tive-behavioral psychotherapeutic techniques. As a result of the
In addition to the reversal of immobilization, the subsequent conference, the symposium members produced a white paper
conquest of operant-based movement phobia (‘‘kinesiophobia’’) about the purpose and usefulness of an assortment of functional
presented by so many of our patients may supply another rationale restoration treatment designs; they also recommended formal treat-
for establishing ‘‘functional restoration’’ as a fundamental requirement guidelines.9 These treatment guidelines are considered pivotal,
ment and may provide a primary role for cotreatment of the phys- and the algorithm we present here is a modification of the one
ical and the psychological therapies. The research that Crombez and advocated by the Malibu group (see Fig. 41–1).
coworkers32 conducted on back pain patients supported their state- The Malibu guidelines created some new problems. First,
ment, ‘‘Pain-related fear is more disabling than pain itself,’’ and this although these guidelines recognize several specific interventions
fear appears to be a dynamic clinical factor in CRPS. The fear- to be applied (physical, medical, anesthesiologic, and psychologi-
avoidance paradigm may be very prominent in some CRPS patients, cal), they offer no recommendations regarding optimal sequence or
and an open-label pilot study in back pain conducted by Boersma duration of these various interventions. Second, the guidelines
and associates33 showed that ‘‘lowering’’ fear can reduce the ensuing stress the concept of time contingency, that is, ‘‘the failure to
avoidance of motion and use and thereby lead to improved func- achieve a favorable response with any treatment modality should
tion. Others also successfully exploited this concept for treating low not persist beyond 2 weeks,’’9 which has proved to be far too rigid
back pain34,35 (level-three evidence). A definitive investigation of and unrealistic in this complex clinical scenario. Third, the guide-
this concept in CRPS has not been undertaken, but clinical experi- lines assert that drugs, injections, and psychotherapy should be
ence has indicated that this approach provides a lot of positive reserved and used only in cases in which progress in the functional
reinforcement (at least for the clinicians!) in our clinics. The benefit restoration–based algorithm has not been achieved. They fail to
of a pragmatic integration of graded, supported ‘‘exposure’’ to nor- recognize the frequent necessity of providing medications, blocks,
malized movement into functional restoration programs for CRPS and psychological support from the beginning (and not ‘‘reserve’’
is self-evident, but requires validation. these interventions until after a patient has ‘‘failed to progress’’). In
The traumas usually identified in the etiology of CRPS most fact, in our experience, it is more often than not the case that
likely begin with peripheral nociceptive overstimulation, and this multiple interventions are required to get a patient started in a
‘‘nociceptive barrage’’ can eventually create and sustain the central functional restoration process.
sensitization indicated by the sensory factors of the syndrome. It is
hypothesized that normalization of activity will adjust and normal-
ize the afferent input and its processing; for example, an increased The Minneapolis Conference
functional input on large fiber tracts may modulate or partly
obstruct the activity on small fiber tracts, according to Melzack Because of these and other issues, a second expert panel revisited the
and Wall’s gate theory of pain.36 Blood flow and nutrition to the Malibu guidelines. In August 2001, this second panel reviewed both
area may be improved by local activity in the affected part, and the Malibu guidelines and the pertinent literature up to that time.
processes such as osteopenia (i.e., Sudeck’s atrophy) may also be In response to clinical evidence that suggested that sequencing and
reversed. Research with rats supports this concept, as do compar- timing of the treatment guidelines should be improved (e.g., under
isons made to CRPS patients with casts: patients with prolonged certain circumstances, concurrent rather than linear utilization of
casting of a limb often present with many diagnoses considered part interdisciplinary interventions provided optimum treatment), the
of the CRPS criteria—vasomotor and sudomotor asymmetry, Minneapolis group recommended the use of concurrent
trophic/dystrophic changes including osteopenia, and occasionally, ‘‘pathways,’’ which were still built upon the original domains: reha-
sensory disturbances. Intuitively, normalizing function in such bilitation, pain management, and psychological treatment. In addi-
CRPS patients should reverse changes wrought by casting, and tion, the Minneapolis group liberalized the use of analgesic
this impression has been confirmed in Guo and colleagues’ rat modalities and deemphasized time contingency, yet they also pre-
research.37 served the important focus on the more quantifiable, objective
These studies all support the traditional functional/physiother- functional algorithm.11
apeutic rationale, although there is currently no level-one or -two Both the Malibu and the Minneapolis groups emphasized the
evidence specifically for interdisciplinary treatment for CRPS. It is pivotal importance of functional restoration. Both acknowledged
important to note two meta-analyses that have shown that an inter- that pain was also important, but as a subjective and an operant
disciplinary approach improves symptoms in patients with chronic phenomena that must be secondary as an outcome; yet both groups
pain in general (which included RSD, and both were level-one recognized that pain would logically drive the type, quality, inten-
evidence).38,39 (More details of the available evidence appear in sity, and pace of other interventions used to achieve the primary,
the sections below). functional outcomes. The next sections provide a detailed exami-
nation of each therapy directly involved in functional restoration.
PRINCIPLES OF FUNCTIONAL
RESTORATION OCCUPATIONALTHERAPY
The occupational therapist is the ideal therapeutic leader in the
The Malibu Conference functional restoration process.40 The occupational therapist must
first evaluate the patient’s current functional use of the affected
In order to expedite reanimation and normalization of use and extremity. The therapist objectively gauges active range of motion
movement of the affected extremity, functional restoration should with a goniometer and measures edema (fluid displacement) with a
efficiently supply a range of interventional and noninterventional volumeter (essentially a large graduated beaker into which the
treatment methods. In an effort to explore the creation of a stepwise affected limb is placed, and then water displacement is compared
functional restoration through a physiotherapeutic algorithm, a with the unaffected limb; this process can be followed as an objective
Dahlem-type consensus-building symposium was held in Malibu clinical or research outcome). The occupational therapist must also
in 1987. The core principles of the algorithm generated by this appraise pain/sensation, skin/vasomotor changes, coordination/dex-
group include patient motivation, desensitization, and reactivation terity, and extremity use during activities of daily living (ADLs).
In general, OT of CRPS should aim to normalize sensation, neuromuscular mechanism through stimulation of the propriocep-
promote normal positioning, decrease muscle guarding, minimize tors’’46 and are usually well tolerated during the rehabilitation
edema, and increase functional use of the extremity in order to process.45 In extreme CRPS cases, functional splinting may be
increase independence in all areas—work, leisure, and ADLs.41 required to encourage improved circulation/nutrition to the
OT of CRPS begins with the management of edema, initiation of affected area as well as to promote more normal tissue length/posi-
gentle active movements, and institution of preliminary desensiti- tioning during rehabilitation.
zation modalities. Specialized garments, bandaging, and manual The primary objective of OT for CRPS is to lead the patient
edema mobilization techniques can help manage edema. A small through a program that minimizes pain and edema while maximiz-
randomized, controlled trial of manual lymph drainage plus phys- ing functional use of the affected limb.41 Because the severity and
ical therapy versus PT alone showed no statistical advantage, but a duration of CRPS are quite variable, and can be persistent
‘‘tendency toward greater pain reduction in the group receiving and severe, the therapist must maintain an enthusiastic espousal
lymph drainage.’’42 This trend should be examined with larger of the patient’s progress throughout the rehabilitation process.
numbers. Superficial or subcutaneous desensitization techniques (All occupational therapies mentioned are levels three to four
will aid in normalizing sensation to the affected area43 (such as evidence.)
rubbing the affected area with something soft, like silk, and progres-
sing to rough or textured materials, like burlap). Regular use of
the affected limb during everyday tasks is promoted and strongly PHYSICALTHERAPY
reinforced throughout the rehabilitation process.
A stress-loading program that initiates active movement and PT clearly plays a critical role in functional restoration, and PT
encourages compression of the affected joints should be implemen- activities are designed to complement those of occupational, recrea-
ted as soon as possible.24 Scrubbing and carrying are the sine qua tional, and vocational therapy; according to the experienced Mayo
non of a stress-loading rehabilitation program24,44 (level-three anesthesia group,47 ‘‘Physical therapy is the cornerstone and first-
evidence). At first, stress loading may exacerbate symptoms in the line treatment for CRPS.’’ The physical therapist can help patients
extremity, but after several days, pain and swelling will decrease. increase their range of motion and flexibility and, later, strength
‘‘Scrubbing’’ entails the back-and-forth movement of a weight- through the use of gentle progressive exercise. The physical thera-
bearing affected extremity.24,44 Patients conventionally use a scrub pist tries to improve all functional tasks, such as gait training
brush and assume a quadruped position (for upper extremity (in lower extremity CRPS) and coordinate/collaborate on all OT,
involvement) or an elevated sitting position (for lower extremity recreational, and vocational goals. All PT must be executed within
involvement). Positions can be adapted to encourage optimal com- the bounds of the patient’s tolerance48 and never when the affected
pliance and performance; for instance, upper extremity patients can limb is insensate (such as after a block) or with CRPS II patients
scrub in a standing position, and patients with carpal tunnel syn- who present with pronounced hypoesthesia. Aggressive PT is
drome can scrub with a handled scrub brush.45 The duration of the avoided so it does not trigger the extreme pain, edema, distress,
activity and the amount of weight applied to the affected extremity and fatigue that may in turn exacerbate the inflammation and
are both gradually increased. The Dystrophile is a device designed sympathetic symptoms of CRPS. Use of assistive or range of
to facilitate scrubbing by activating a light when the patient has motion devices, prolonged application of ice, and inactivity may
reached and maintains the preset load. Although it may help the also aggravate CRPS. Physical therapists must teach patients with
patient maintain consistent weight-bearing and compliance, the CRPS that they will experience pain both when they exercise too
device offers no other perceived advantage over a simple scrub much and when they exercise too little. Patients must, therefore, be
brush. At first, stress loading may exacerbate symptoms in the taught to seek the happy medium, and it is the physical therapist’s
extremity, but after several days, pain and swelling will decrease. responsibility to help them find that therapeutic ground and help
‘‘Carrying’’ is the second element in a stress-loading regimen. them to steadily advance toward a more functional and active life-
For upper extremity conditions, patients begin weight-loading by style. In a series of randomized, controlled trials, Oerlemans’
carrying small objects in the hand, progressing to carrying a handled group17,25,49 showed that PT (and to a lesser extent OT) improves
bag, which then can be loaded with increasingly heavy weights; pain scores and ‘‘active mobility’’ versus social work controls in
these weights should be carried at all times during the day while Dutch upper extremity CRPS cohorts.
the patient is standing or walking.24,44 A variety of weight-bearing In children with CRPS, a single-blind, randomized trial of PT
techniques exist for lower extremity patients. Walking is a principal combined with cognitive-behavioral therapy demonstrated signifi-
loading technique, provided that weight-bearing does indeed occur cant improvement on five measures of ‘‘pain and function,’’ with
through the affected leg during gait, particularly when an assistive sustained benefit in ‘‘the majority’’ of subjects.26 In a prospective
device is used. Verbal and physical cueing can help ensure increased review of 103 children with CRPS ‘‘intensive PT’’ (aerobic, hydro-
weight-bearing during gait. Having the patient carry a weighted therapy, and desensitization), supplemented by ‘‘psychological
object on the affected side can also increase weight-bearing. counseling’’ (in 77%), was ‘‘effective in initially treating childhood
Additional methods that can help encourage weight-bearing include CRPS and is associated with low rate of long-term symptoms or
engaging the patient in activities that promote weight shifting/bal- dysfunction.’’43
ance (e.g., a ball toss) or having the patient place the nonaffected The physical therapist should instruct the patient in the avoid-
foot onto a small footstool during stationary tasks. ance of physical stressors (i.e., the stress of extended inactivity and
Once the patient is actively involved in an edema-management bedrest on one extreme, and the stress of excessive exercise at the
and stress-loading program, functional restoration treatment can other). The goal of the PT exercise program is the gradual increase
begin. The decreasing pain and edema will allow the patient to of strength and flexibility, principally through weight-bearing.
better endure and partake in active range of motion, coordina- The therapy program is primarily based on functional goals and
tion/dexterity, and strengthening tasks. One of the first techniques achieved through active or active-assisted means; it should encour-
of functional restoration is the use of proprioceptive neuromuscular age pacing and include rest breaks and relaxation techniques as
facilitation (PNF). PNF patterns are spiral and diagonal combina- well. PT goals can be achieved with the use of devices, including
tions of motion that permit maximum elongation of related muscle foam rubber balls succeeded by spring-grip strengtheners for
groups so that the stretch reflex can be elicited throughout the the upper extremity and Swiss balls, foam rolls, and antigravity
‘‘pattern.’’46 These patterns, akin to normal movement patterns, resistive equipment (such as a Pilates reformer) for the lower
simultaneously facilitate strength and balance as they increase the extremity. These devices help to gradually introduce a variety of
ability to perform ADLs. PNF patterns promote ‘‘response of the weight-bearing/strengthening techniques.
Mat exercises provide strengthening of both the extremity to determine their own leisure lifestyle choices. The increased social
and the postural muscles in a non–weight-bearing approach. contact engendered by these activities will, in turn, heighten the
Particularly valuable mat exercises include movement therapies patients’ chances of remaining active within the community after
such as the Feldenkrais technique. Feldenkrais teaches and treatment.
encourages gentle, active motions within the patient’s available With a bit of advanced planning, recreational therapy can com-
range to increase body awareness and promote appropriate move- plement PT and OT treatment goals. For instance, a recreational
ment patterns. A fundamental aspect of mastering proper move- therapist could reinforce an OT scrubbing protocol by instructing a
ment patterns is the relearning of proprioception. The physical patient to use an affected upper extremity to sand wood in a rec-
therapist can help patients achieve mastery by teaching them neu- reational project. Such planned convergence of goals affords the
romuscular proprioception exercises, advancing them as they gain patient the twofold satisfaction of creating something and simulta-
proficiency. neously accomplishing therapy goals.52 For example, a patient who
Virtually all patients with advanced CRPS will present with is engaged in a desensitization program and who also enjoys gar-
myofascial pain syndrome of the supporting joint. Aggressive treat- dening can be assigned horticulture therapy (i.e., the use of the
ment of this myofascial pain is a critical component of successful hands to work soil).
treatment and is principally the purview of the physical therapist. In addition, recreational therapy can promote mild activity,
Some schools of thought propose that the myofascial pain syn- thereby increasing flexibility and range of motion. The recreational
drome must be treated first, and if successfully treated, the CRPS therapist should plan activities that patients find inherently enjoy-
will often resolve. This would reflect an ‘‘autonomic concomitant in able because patients are more willing to take on fine-motor grasp-
the pain reference zone,’’ with vasoconstriction as a prominent ing and releasing tasks for longer periods of time if they are engaged
feature.50 in an enjoyable activity (e.g., beading a necklace, holding a watering
Aquatic therapy can be quite valuable to CRPS patients because can, playing a card game, or practicing on a keyboard). A recre-
of its hydrostatic principles and its buoyancy effect.43 Hydrostatic ational therapist must be creative because a happily engaged patient
pressure provides a mild compressive force around the extremity will be more inclined to fulfill therapy goals when engaged in
that may help decrease the edema that is widespread in CRPS. fun activities like putting golf balls, playing balloon volleyball, or
Aquatic therapy also provides an outstanding opportunity for shooting pool.
introducing lower extremity weight-bearing, and the buoyancy it In addition to advocating new leisure skills, recreational therapy
provides may be especially useful for early restoration of functional concentrates on reintroducing the patient to stable community
activities such as walking. When conducting aquatic therapy, care involvement. During structured community outings, the CRPS
must be taken to maintain water temperature, because excessively patient can focus on carrying and loading a bag (i.e., loading)
cold or hot water may temporarily exacerbate the CRPS. Water with the affected limb.24,44 This task can be accomplished with a
therapy may allow early participation in progressive PT, because water bottle, shopping bag, or purse. Other tasks can involve
nearly all exercises that are executed on land can be executed in weight-bearing and follow through with gait training on unlevel
the water, where the water adds resistance without adding full surfaces within a realistic community setting. Identified and
stress/weight to the joints. This, of course, is groundwork to full achieved appropriately, successfully completed tasks can increase
weight-bearing, particularly in the lower extremity. patient self-confidence and promote the incorporation of these
Hands-on techniques such as massage and myofascial release can learned skills both at home and within other therapy sessions.
sometimes offer effective relief from the myofascial pain. Massage In summary, recreational therapy effectively combats kinesio-
is often mentioned, but although it has not been formally stud- phobia and promotes increased movement. Recreational therapists
ied (level-four evidence), it may help decrease edema in certain work closely with other disciplines to achieve the therapeutic goals
cases. Electrostimulation modalities have demonstrated some effi- of CRPS patients, and they implement creative tactics that achieve
cacy in our experience, but ultrasound therapy has been less effec- those goals while giving patients more decision-making freedom
tive in our clinic. Contrast baths are another possible, if slightly and more fun. Most significantly, recreational therapy can reintro-
controversial, treatment option for CRPS patients. Through the duce balanced leisure activities into the lives of the patients whose
use of the understood principles of alternating heat and cold, con- conditions may have discouraged such behavior.
trast baths can be beneficial in mild cases to facilitate improved
circulation in the affected extremity by alternating vasodilation with
vasoconstriction. However, the vasomotor changes in advanced VOCATIONAL REHABILITATION
cases of CRPS do not allow for the desired response, and the
immersion in the cold water may exacerbate CRPS symptoms; The vocational rehabilitation (VR) counselor helps prepare the
contrast baths for advanced cases of CRPS are therefore not recom- CRPS patient for a possible return to work, or the ‘‘ultimate’’ func-
mended. (All physical therapies mentioned are levels three to four tional restoration. VR involves restoring a patient to her or his
evidence.) original vocational purpose as expediently and as safely as possible.
Counselors use information from medical, occupational, educa-
tional, financial, and labor market fields to make return-to-work
RECREATIONALTHERAPY assessments. Vocational counseling addresses benefits of work and
accommodations as well as job modifications and the utilization of
Because recreational therapy employs enjoyable activities, the pain-management techniques. The VR specialist can also help each
recreational therapist is frequently the first clinician to succeed in patient to identify with the role of worker and assist in creating a
getting the CRPS patient to initiate increased movement, a primary plan for a return to work.
goal of successful treatment. The incentive of returning to a favorite If possible, the VR counselor should understand all of the
pastime is often the appropriate tool needed to break through the physical demands of the job before addressing return-to-work
kinesiophobia and bracing that often attend CRPS.51 Through the issues. Review of job description and consultation with employer,
use of modifications, adaptive equipment, and creative problem- supervisor, employee health nurse, or other human resource
solving (such as using large-handled gardening equipment for specialist, and work site visit (when appropriate) are steps recom-
gardeners, bowling with the nondominant hand for bowling fans, mended to address specific job duties, especially when determining
and substituting biking for running for athletes), a patient can ability to provide a full-duty release53 or when recommending
find fulfillment in previously lost or new recreational activities. specific restrictions and modifications. The VR specialist also
Recreational therapy reestablishes the patients’ ability and freedom provides job and job site analyses and uses that information to
coordinate job-specific reconditioning or work hardening, work functions and other repetitive motion tasks, tolerating hot and
capacity evaluation, transferable skills analysis, and a functional cold environments, and tolerating any severe vibrational factors.
capacities evaluation.54 The VR counselor must determine whether Any number of these factors may require modification, particularly
or not a client can return to the original job; the counselor in chronic or severe CRPS.
must also consider the alternatives of returning the patient to
either a modified version of the previous job or an alternate job
with the same employer or whether a new job placement referral OTHER THERAPEUTIC INTERVENTIONS
will be needed when return-to-work with the previous employer
is not an option. The VR counselor and occupational therapist Hyperbaric oxygen therapy was assessed in a medium-sized, rando-
should work closely together when assessing return-to-work mized, controlled trial and showed a significant decrease in pain
goals, especially when assessing the possibility of returning to a and edema versus ‘‘normal air.’’ These results should be replicated,
specific job. but cost-benefit considerations will also be important.58 Although
The VR specialist must possess a thorough understanding of acupuncture is mentioned in many treatment reviews, there is only
the prior job description, requirements, and occasionally, the one very small randomized, controlled trial in CRPS that failed
required vocational testing and targeted retraining of the CRPS to show a significant difference in outcomes, but this may be due
patient who intends to return to work. Initially working with the to the small sample size. Korpan and coworkers59 say they are plan-
occupational therapist, the VR specialist assesses a patient’s work ning a ‘‘definitive trial,’’ but this has been pending since 1999. There
activities and provides a simulation of them for the patient in a con- is no research available supporting the use of chiropractic manip-
trolled clinical environment. In the final steps of the VR process, the ulation in CRPS.60
specialist can provide work capacities along with functional capa-
cities and targeted work hardening in order for the patient to
return to gainful employment—the ultimate functional restoration. SUMMARY
Competent VR requires a proficient specialist capable of maintain-
ing a methodical, informed, and experienced approach in order Because the symptoms of CRPS patients encompass all the biopsy-
to grasp and successfully navigate the Byzantine social and medico- chosocial complexities of chronic pain, the best hope of helping our
legal quagmires in which CRPS patients may find themselves. patients is the adoption of a systematic, stable, empathetic,
As with all the interdisciplinary specialists, the VR specialist must and above all, interdisciplinary approach that addresses those symp-
sustain ongoing communication with the others on the team and toms. Drugs, psychotherapy, and interventions should be efficiently
keep the team informed of each patient’s individual vocational deployed for patients who either cannot begin or fail to progress
situation using the interdisciplinary approach outlined here (see
VR specialists regularly encounter hurdles to appropriate return- Occupational Therapy, ‘‘Physical Therapy,’’ and ‘‘Recreational
to-work functions. First, health factors are often presumed to have Therapy,’’ above). Many patients will require medication and
the greatest impact on worker disability, but social scientists have psychotherapy from the beginning to be successful in the pivotal
argued that the most important determinants of work status for functional restoration algorithm (see Fig. 41–1). Treatment guide-
persons with chronic disease are actually age, education, job satis- lines that center on progressive functional restoration delivered
faction, and job status in the labor force.55 Second, other factors by an interdisciplinary team are traditional, have substantial empir-
such as work history, employment in public sector versus private, ical and anecdotal support, and have been assessed and ultimately
current work status, lower social class, level of education, and lack codified by three large, expert, consensus-building conferences.3,9,11
of varied work may also predict work disability for patients with Although high-level evidence supporting the rationale for interdis-
chronic pain.55 Third, long periods of unemployment or reduced ciplinary treatment of CRPS is fairly sparse (as it is for any treat-
employment activity may impact vocational potential. Chronic pain ment of CRPS), much sounder evidence exists for the efficacy of the
sufferers are often patients who have been out of work for long interdisciplinary approach in other pain conditions.38 That func-
periods of time before they are referred to a VR specialist, and tional restoration can and should be the central intervention and
employers are often reluctant to employ persons who have chronic outcome standard in CRPS is a theory that must be tested. Until
pain, have been unemployed for long periods of time, or who have then, the interdisciplinary approach for treatment of patients
workers’ compensation cases.56 In addition, the ability to modify with CRPS remains the most pragmatic, helpful, and cost-effective
the work environment in accordance with limitations has major therapeutic approach available today.
implications in limiting the extent of the disability and/or prevent-
ing injuries.55
Although VR is frequently the final step of rehabilitation ther- ACKNOWLEDGMENT
apy, addressing return-to-work issues early helps to set employment
as a long-term goal.57 Allowing the patient an opportunity to The editor would like to acknowledge and thank the Reflex
participate in a trial work period before providing final release for Sympathetic Dystrophy Association (RSDA) for the use of Dr. R.
work is often an excellent way to observe his or her ability to return Norman Harden’s chapter, which was initially written for RSDA.
to work and perform job duties; it also provides an opportunity to
further assess work behaviors and capacity. Return-to-work can be a
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316 Chapter 42 LUMBAR SPINAL STENOSIS: CURRENT THER APY AND FUTURE DIRECTIONS
57. Dent GL. Return to Work . . . by Design, Stockton, CA: Dennison 59. Korpan MI, Dezu Y, Schneider B, et al. Acupuncture in the treatment
Press, 2001. of posttraumatic pain syndrome. Acta Orthop Belg 1999;65:197–201.
58. Kiralp MZ, Yildiz S, Vural D, et al. Effectiveness of hyperbaric oxygen 60. Muir JM, Vernon H. Complex regional pain syndrome and
therapy in the treatment of complex regional pain syndrome. J Int chiropractic. J Manipul Physiol Ther 2000;23:490–497.
Med Res 2004;32:258–262.
Chapter 42 claudication could be alleviated with resection of the spinal laminae,

such a lower extremity symptom pattern was most often presumed
LUMBAR SPINAL STENOSIS: to be caused by peripheral vascular disease involving the aortoiliac
system.7
CURRENT THERAPY AND The growing burden of this problem in an aging population is
reflected by the fact that approximately 12 million physician office
FUTURE DIRECTIONS* visits in the United States are related to symptoms of lumbar spinal
stenosis.8 Pain, neurogenic intermittent claudication in particular,
is the predominant symptom pattern prompting treatment.4 For
John D. Markman and Jeremy C. Sinkin this chronic pain problem, approximately 125,000 laminectomy
procedures were performed in the United States in 1995.9
Spinal stenosis has been defined as a narrowing of the spinal
canal caused by degeneration of bony and intraspinal soft tissues.10
The confluence of disk degeneration, facet joint capsule hypertro-
phy, infolding of the ligamentum flavum, and osteophyte formation
culminates in a reduction in the volume of the spinal canal in the
INTRODUCTION degenerative form of lumbar spinal stenosis.11 Spinal stenosis
broadly refers to any site of narrowing in the central canal, lateral
Lumbar spinal stenosis is a common cause of low back pain and recess, or intervertebral foramen. In the elderly, these subtypes
the leading indication for lumbar surgery in the United States for frequently coexist.12 The earliest descriptions of lumbar stenosis
persons over 65 years of age.1 Neurogenic intermittent claudication focused on developmental forms such as those found in children
is the hallmark of the clinical syndrome of lumbar spinal stenosis. with dysraphic abnormalities and skeletal dysplasias.13 Such condi-
This distinctive pattern of pain in the back and legs is induced by tions are beyond the scope of this chapter, but it is important to
erect postures, such as when standing or walking. Neurogenic inter- note that older patients with congenitally narrow canals, thickened
mittent claudication is a major cause of impaired mobility and loss laminae, and short pedicles are predisposed to the acquired forms of
of independence.2 stenosis and often seek medical care for neurogenic intermittent
The advent of axial imaging technologies has increased the claudication at an earlier age. This chapter focuses on acquired
sensitivity of diagnostic testing for lumbar spinal stenosis since forms of stenosis. Age-related degeneration of spinal structures
the late 1970s.3 These tools offer precise anatomic characterization associated with the upright posture required for bipedal movement
of spinal structures, but the pathophysiology of neurogenic claudi- is, by far, the most common form of acquired stenosis.
cation is not well understood. Pain medications are widely The progressive collapse of the lumbar disk with normal aging
prescribed for the treatment of neurogenic intermittent claudica- drives segmental narrowing of the lateral recess and central canal.
tion, but no drug has ever been demonstrated to have analgesic Age-related desiccation of the nucleus pulposus and resultant
benefit for this type of pain in a double-blind, placebo-controlled, buckling of the dorsal annulus are most pronounced at the
randomized clinical trial. As a consequence, surgical decompression L3 through L5 spinal levels. Not surprisingly, these are the very
has remained a mainstay of therapy despite lack of consensus about levels at which spinal stenosis is most commonly detected.14 Loss
clinical indications and wide geographic variation in rates of of disk competency increases biomechanical stress on the facet
surgery.4,5 joints. The resultant hypertrophy of these joints due to synovial
There is an even greater evidence gap about the indications for overgrowth and subchondral bone formation encroaches on the
and efficacy of nonsurgical treatments, which likely accounts for lateral aspect of the central canal. Progressive change in the orien-
even wider variation in their use. This chapter aims to characterize tation and shape of these joints endows the canal with the classic
the growing unmet need for the treatment of neurogenic intermit- trefoil form seen in the most severe cases. The loss of disk height
tent claudication in patients with lumbar spinal stenosis and review also decreases tension on the elastic ligamentum flavum that causes
the evidence for current treatment strategies. buckling of the ligament. The movement of one anatomic lumbar
segment in relation to adjacent levels in the context of degenerative
spondylolisthesis is another important cause of stenosis.15
BACKGROUND AND EPIDEMIOLOGY The clinical significance of anatomic narrowing is critically
related to posture in patients with lumbar spinal stenosis.
In his 1954 landmark paper, the Dutch surgeon Henk Verbiest6 Forward flexion increases the cross-sectional area of the neural
linked progressively worsening leg pain and impairment of motor foramen by 12%. Lumbar extension narrows the canal and lateral
function experienced on standing and walking with a narrowed recesses by an additional 15% over a neutral posture.16 Eighty
spinal canal. Until he demonstrated that lower extremity percent of the population have degenerative changes in the spine
evident on imaging studies, but most remain asymptomatic.17,18
The search for a critical threshold of narrowing that separates
*Sections of this chapter have appeared in Geriatric Clinics of North America. mild from moderate to severe symptoms is complicated by multiple
57. Dent GL. Return to Work . . . by Design, Stockton, CA: Dennison 59. Korpan MI, Dezu Y, Schneider B, et al. Acupuncture in the treatment
Press, 2001. of posttraumatic pain syndrome. Acta Orthop Belg 1999;65:197–201.
58. Kiralp MZ, Yildiz S, Vural D, et al. Effectiveness of hyperbaric oxygen 60. Muir JM, Vernon H. Complex regional pain syndrome and
therapy in the treatment of complex regional pain syndrome. J Int chiropractic. J Manipul Physiol Ther 2000;23:490–497.
Med Res 2004;32:258–262.
Chapter 42 claudication could be alleviated with resection of the spinal laminae,

such a lower extremity symptom pattern was most often presumed
LUMBAR SPINAL STENOSIS: to be caused by peripheral vascular disease involving the aortoiliac
system.7
CURRENT THERAPY AND The growing burden of this problem in an aging population is
reflected by the fact that approximately 12 million physician office
FUTURE DIRECTIONS* visits in the United States are related to symptoms of lumbar spinal
stenosis.8 Pain, neurogenic intermittent claudication in particular,
is the predominant symptom pattern prompting treatment.4 For
John D. Markman and Jeremy C. Sinkin this chronic pain problem, approximately 125,000 laminectomy
procedures were performed in the United States in 1995.9
Spinal stenosis has been defined as a narrowing of the spinal
canal caused by degeneration of bony and intraspinal soft tissues.10
The confluence of disk degeneration, facet joint capsule hypertro-
phy, infolding of the ligamentum flavum, and osteophyte formation
culminates in a reduction in the volume of the spinal canal in the
INTRODUCTION degenerative form of lumbar spinal stenosis.11 Spinal stenosis
broadly refers to any site of narrowing in the central canal, lateral
Lumbar spinal stenosis is a common cause of low back pain and recess, or intervertebral foramen. In the elderly, these subtypes
the leading indication for lumbar surgery in the United States for frequently coexist.12 The earliest descriptions of lumbar stenosis
persons over 65 years of age.1 Neurogenic intermittent claudication focused on developmental forms such as those found in children
is the hallmark of the clinical syndrome of lumbar spinal stenosis. with dysraphic abnormalities and skeletal dysplasias.13 Such condi-
This distinctive pattern of pain in the back and legs is induced by tions are beyond the scope of this chapter, but it is important to
erect postures, such as when standing or walking. Neurogenic inter- note that older patients with congenitally narrow canals, thickened
mittent claudication is a major cause of impaired mobility and loss laminae, and short pedicles are predisposed to the acquired forms of
of independence.2 stenosis and often seek medical care for neurogenic intermittent
The advent of axial imaging technologies has increased the claudication at an earlier age. This chapter focuses on acquired
sensitivity of diagnostic testing for lumbar spinal stenosis since forms of stenosis. Age-related degeneration of spinal structures
the late 1970s.3 These tools offer precise anatomic characterization associated with the upright posture required for bipedal movement
of spinal structures, but the pathophysiology of neurogenic claudi- is, by far, the most common form of acquired stenosis.
cation is not well understood. Pain medications are widely The progressive collapse of the lumbar disk with normal aging
prescribed for the treatment of neurogenic intermittent claudica- drives segmental narrowing of the lateral recess and central canal.
tion, but no drug has ever been demonstrated to have analgesic Age-related desiccation of the nucleus pulposus and resultant
benefit for this type of pain in a double-blind, placebo-controlled, buckling of the dorsal annulus are most pronounced at the
randomized clinical trial. As a consequence, surgical decompression L3 through L5 spinal levels. Not surprisingly, these are the very
has remained a mainstay of therapy despite lack of consensus about levels at which spinal stenosis is most commonly detected.14 Loss
clinical indications and wide geographic variation in rates of of disk competency increases biomechanical stress on the facet
surgery.4,5 joints. The resultant hypertrophy of these joints due to synovial
There is an even greater evidence gap about the indications for overgrowth and subchondral bone formation encroaches on the
and efficacy of nonsurgical treatments, which likely accounts for lateral aspect of the central canal. Progressive change in the orien-
even wider variation in their use. This chapter aims to characterize tation and shape of these joints endows the canal with the classic
the growing unmet need for the treatment of neurogenic intermit- trefoil form seen in the most severe cases. The loss of disk height
tent claudication in patients with lumbar spinal stenosis and review also decreases tension on the elastic ligamentum flavum that causes
the evidence for current treatment strategies. buckling of the ligament. The movement of one anatomic lumbar
segment in relation to adjacent levels in the context of degenerative
spondylolisthesis is another important cause of stenosis.15
BACKGROUND AND EPIDEMIOLOGY The clinical significance of anatomic narrowing is critically
related to posture in patients with lumbar spinal stenosis.
In his 1954 landmark paper, the Dutch surgeon Henk Verbiest6 Forward flexion increases the cross-sectional area of the neural
linked progressively worsening leg pain and impairment of motor foramen by 12%. Lumbar extension narrows the canal and lateral
function experienced on standing and walking with a narrowed recesses by an additional 15% over a neutral posture.16 Eighty
spinal canal. Until he demonstrated that lower extremity percent of the population have degenerative changes in the spine
evident on imaging studies, but most remain asymptomatic.17,18
The search for a critical threshold of narrowing that separates
*Sections of this chapter have appeared in Geriatric Clinics of North America. mild from moderate to severe symptoms is complicated by multiple
factors other than posture, such as the number of stenotic levels and of neurogenic intermittent claudication is in need of further study.
effects of recurrent dynamic loading, that appear to influence the Convincing evidence indicates that both the lesions of the nervous
intensity of pain and degree of activity limitation.19 Recognition of system discussed previously and the dysfunction of the cauda
the lack of sensitivity and specificity of static images has engendered equina reviewed in this section are tightly linked to the experience
the development of functional concepts of potential space such as of pain in patients with neurogenic intermittent claudication.
spinal reserve capacity.20 A recent study demonstrated a strong Viewed in this way, neurogenic intermittent claudication represents
association between the minimum cross-sectional area and walking a neuropathic pain syndrome with a distinctive localization and
tolerance in patients undergoing lumbar laminectomy.21 The bor- clinical phenomenology.
derline minimum canal area between moderate and severe symp- Animal models and in vivo studies have correlated neurogenic
toms (e.g., inability to walk 500 m) has consistently been shown intermittent claudication with increases in intraspinal pressure.
in animal models and retrospective series to be in the 70-mm2 Lumbar epidural pressure is elevated (peak values are 82.8 mm
range. Lateral recess and neuroforaminal stenosis giving rise to Hg) when the volume of the canal is reduced, most commonly
unilateral symptom patterns have undergone far less systematic with walking and prolonged standing in an erect posture.30 The
study; an anteroposterior dimension of less than 4 mm in the lateral direct relationship between intraspinal pressure and extensor pos-
recess is a threshold frequently cited as a critical level by experts.22 tures is the best-understood aspect of the syndrome’s pathophysiol-
Characteristic vascular and neuropathologic changes are associ- ogy; it has been quantified with manometry and directly observed
ated with lumbar spinal stenosis and neurogenic intermittent with myeloscopy in symptomatic patients.31 Increased pressure and
claudication. Magnetic resonance imaging (MRI) often reveals venous engorgement, much like the bony changes, are probably not
dilatation of the epidural venous plexus in vivo.23 Cadaveric studies the proximal cause of pain because both of these phenomena are
found constriction of the nerve roots and hypertrophy of the commonly observed in asymptomatic patients with radiographic
pia-arachnoid.24 Watanabe and Parke24 detailed a characteristic evidence of stenosis. However, the predictability with which pres-
reduction in number, collapse, and grossly visible congestion of sure changes normalize with postural adjustment (e.g., flexion) and
veins proximal to the stenotic level. Histologic and scanning alleviate pain symptoms underscores the clinical significance of this
electron microscopy of nerve root sections demonstrate a pro- association.
nounced loss in the count of large caliber fibers, empty axons,
and varying degrees of demyelination. Nonneural changes from
these sections included pia-arachnoid adhesions, interstitial fibrosis, NATURAL HISTORYOF LUMBAR
and thick-walled veins. The clinical significance of the adhesive pia- SPINAL STENOSIS
arachnoiditis is unknown, but many have speculated that imped-
ance of normal cerebrospinal fluid flow figures prominently in the The onset of neurogenic claudication in the setting of lumbar
episodic pain symptoms of neurogenic intermittent claudication. stenosis is insidious and commonly heralded by a long history of
Some lines of evidence from animal models indicated that the central low back pain.32 A recent longitudinal, prospective, con-
demyelination and axonal loss in the type of cauda equina injury trolled cohort study of patients who chose not to undergo decom-
observed in neurogenic intermittent claudication do not cause pressive surgery upheld the claim that lumbar spinal stenosis is not
mechanical allodynia and hyperalgesia.25 Those neurologic exami- associated with progressive neurologic deficit.33 The authors found
nation findings are the clinical hallmarks of classic neuropathic pain that the natural history of lumbar stenosis is characterized by fluc-
syndromes such as postherpetic neuralgia (PHN). The absence of tuation in symptom severity and a tendency toward modest
these findings likely reflects the relative sparing of the dorsal root improvement in patients who do not elect to undergo surgery. In
ganglion in this type of cauda equina injury and dysfunction, but it their landmark study, Johnsson and associates34 compared the
does not make a neuropathic pain mechanism less likely. The course of 19 untreated patients with myelographically defined
painful symptoms of mild to moderate neurogenic intermittent lumbar spinal stenosis for a mean of 4 years. Eighty percent of
claudication appear to be caused by endoneurial edema produced these patients experienced neurogenic intermittent claudication.
by mild levels of ischemia.26 Only the cases of stenosis with severe Severe neurologic deterioration was not found in the untreated
cauda equina compression will reveal a pathoanatomic finding of patients; approximately 60% of these patients were unchanged
wallerian degeneration.27 In general, less is known about the clinical from the standpoint of symptom severity.34
significance of the vascular and neural changes listed previously The prospective, long-term observational studies by Amundsen
because these structures have not—to date—been the targets of and colleagues35 and the Maine Lumbar Spine Study36 offer valu-
therapeutic intervention. The neuroanatomic changes identified able insights about the natural history of this condition. At 4 years,
previously have been linked to the chronic inflammatory conse- the Amundsen and colleagues’ study35 found superior outcomes in
quences of episodic neuroischemia presented in the next section. a greater number of surgically treated patients, but results of
delayed surgery in the patients in the conservative management
group who crossed over were comparable. In Atlas and coworkers’
PATHOPHYSIOLOGYOF NEUROGENIC study36 at 8- to 10-year follow-up, low back pain relief, predomi-
INTERMITTENT CLAUDICATION nant symptom improvement, and current symptoms did not differ
for those initially receiving conservative or surgical treatment. Leg
The underlying pain mechanism of the unique symptom pattern pain relief and function as measured by the modified Roland
known as neurogenic intermittent claudication is a matter of con- disability scale favored those managed surgically at the outset. In
troversy. Narrowing of the spinal canal simply does not equate to summary, the syndrome of lumbar spinal stenosis is marked by
pain. A compelling account of the pathophysiology must at once periodic exacerbations and remittances.36
account for the many patients with stenosis who experience no pain
and the large population whose pain is effectively relieved with
anatomic decompression.18 Increases in pressure applied to the DIAGNOSIS
cauda equina induce both neurophysiologic and local hemodynam-
ic changes. The lines of experimental evidence and in vivo clinical Increased utilization of axial imaging has led to growth in the diag-
observations point to an underlying neurovascular mechanism.28,29 nosis of lumbar spinal stenosis, but these technologies do not
The intricate relationship between recurrent inadequate blood flow, differentiate symptomatic from asymptomatic patients. For this
compromised metabolic status of the nerve roots, modulating reason, it is essential to obtain a thorough history, perform a
inflammatory cell effects on the blood-nerve barrier, and the pain neurologic examination, conduct functional testing, and place
anatomic imaging results in a clinical context (Box 42–1). Advanced in the ability to link pain intensity and function, making it appli-
age, severe lower extremity pain, and absence of pain when seated cable to patients when timing their medication dose for specific
are the historic findings most strongly associated (likelihood ratio activities, such as a walk to their post office box or a trip down a
2) with the diagnosis of lumbar spinal stenosis in a group of grocery aisle. The capacity to assess dose-dependent responses
93 patients from three different specialty clinics.32 Physical exami- to therapy over time is also critical to the task of adapting tread-
nation findings most consistent with the diagnosis were wide-based mill-based methodologies to the evaluation of novel therapeutic
gait, abnormal Romberg’s test result, thigh pain afte 30 seconds of strategies. The incorporation of regular treadmill testing will
lumbar extension, and neuromuscular deficits. The quality of the allow for more precise treatment matching for surgical therapies
pain is classically dull or aching and characterized by patients as and ultimately guide dose titration of emerging therapeutics.
‘‘heaviness’’ or ‘‘weakness.’’ Electromyography mapping of the lumbar paraspinal musculature
Because degenerative changes in multiple spinal structures are has been advocated by some experts as a tool superior to MRI for
ubiquitous in the elderly, the primary role of imaging in this pop- differentiating symptomatic from asymptomatic patients with
ulation with chronic symptoms is in the planning of surgical inter- lumbar spinal stenosis.42
vention. Imaging obtained with the patient in the supine position
may underestimate narrowing that would be apparent in an
upright, weight-bearing position.37 Imaging acute, nonspecific low Differential Diagnosis
back pain has been shown to yield many diagnoses of lumbar spinal
stenosis with little clinical relevance.38 If narrowing of the canal is Although neurogenic intermittent claudication associated with
observed and surgery is considered, computed tomography com- lumbar spinal stenosis is a common condition, other etiologies
bined with myelography (CTM) will provide the most sensitive may create a similar symptom pattern, especially in the elderly, in
picture of posture-dependent anatomic targets. In CTM, myelogra- which patients may have multiple comorbid conditions. Back and
phy is first performed with the patient in the flexed and the leg pain, numbness, and paresthesias are common symptoms asso-
extended standing positions. The myelogram is an invasive tech- ciated with lumbar spinal stenosis. A thorough investigation for
nique that allows visualization of bony and soft tissue encroach- nondegenerative causes of pain must be undertaken to address
ment on the dural sac in the symptomatic posture.39 possibilities such as a tumor, infection, and vascular causes in cir-
Because the degree of narrowing observed in imaging often does cumstances in which risk factors or ‘‘red flags’’ are present. These
not correlate to the severity of symptoms, functional testing should are rare causes of spinal pain, but they may be life threatening.
complement imaging. Treadmill testing has been shown to be a safe, History-taking and physical examination should exclude aortic
easy, and reliable method of assessing a patient’s response to treat- aneurysm, visceral diseases such as pyelonephritis, and systemic
ment.40,41 The unique clinical phenomenology of neurogenic inflammatory conditions including polymyalgia rheumatica. The
claudication lends itself to objective measure because of its direct differential diagnosis includes vascular claudication, which will
impact on the amount of time patients are able to stand and the not be affected by posture and is less likely if peripheral pulses
distance they are able to walk. The value of treadmill testing resides are palpable. Vascular claudication can coexist with neurogenic
intermittent claudication and should be ruled out with flow studies
if clinical suspicion exists. In most cases, the diagnostic challenge
resides in separating the low back and leg pain of lumbar stenosis
Box 42^1 CURRENT DIAGNOSIS from other mechanical causes of pain localizing to soft tissues,
joints, and bony sources. A herniated lumbar disk with correspond-
Thorough HistoryThat Identifies the Unique Symptom Pattern ing level radiculitis and peripheral neuropathy are common con-
of Lumbar Stenosis siderations. A herniated lumbar disk typically has a distinctive
The most common symptom caused by lumbar spinal stenosis is neuro- temporal pattern marked by acute onset of symptoms and other
genic claudication. examination features such as pain elicited with straight leg raise
Neurogenic claudication is a pattern of pain radiating from the low testing. Inflammation associated with facet-mediated pain causes
back to the buttocks and legs. axial predominant symptoms. Because postures such as standing
Neurogenic claudication is typically exacerbated by lumbar extension
and walking require lumbar extension that loads the facet joint,
and improves with lumbar flexion.
Patients with lumbar stenosis are typically without pain when seated; symptoms of this type of mechanical syndrome can overlap with
pain intensity escalates with prolonged standing and walking. lumbar spinal stenosis or mimic the distribution and pattern of
symptom provocation. Osteoporotic compression fractures have a
Physical Examination distinctive pattern of symptom onset (i.e., rapid), commonly pro-
Wide-based gait.
Pain elicited with active, sustained lumbar extension that is alleviated
voke pain in the seated and supine positions, and have a distinctive
with flexion. set of findings on imaging. Neurogenic intermittent claudication
Abnormal Romberg’s test. and osteoporotic compression fractures may coexist when there is
Absence of prominent lower extremity weakness. concurrent stenosis at the symptomatic level owing to associated
changes in canal dimensions. Electrophysiologic techniques such as
Functional Testing
Treadmill testing complements the history, physical examination, and the tibial F-wave can be useful in distinguishing between lumbar
imaging data. spinal stenosis and peripheral neuropathy in cases in which multiple
Treadmill testing couples measures of pain and activity tolerance that neuropathic syndromes are believed to coexist. The key distinguish-
allow for optimal treatment matching in patients evaluated for surgical ing feature of lumbar stenosis is neurogenic intermittent claudica-
decompression. tion. Case reports of pain provoked by extension and exertion that
Imaging remits with rest has been reported in cases of tumors of the conus
Magnetic resonance imaging (MRI) and computed tomography (CT) medullaris and cauda equina, benign cystic lesions, and vascular
offer detailed evidence of reduced cross-sectional area of the central malformations, but these instances are exceptional.
canal and neuron foramina.
CT imaging offers superior characterization of bony changes such as
facet hypertrophy, whereas MRI clarifies the contribution of soft
tissue changes in the disks and ligaments. TREATMENT
Greater than 20% of persons over age 60 may have imaging findings of Treatment approaches for lumbar stenosis target the low back
lumbar spinal stenosis but not symptoms or functional limitations.
and leg pain localizing to the cauda equina with the distinctive
phenomenology of neurogenic intermittent claudication (Box stenosis at the cervical and thoracic levels where the spinal cord
42–2). Increasing activity interference with standing and walking may be compressed. At these spinal levels, surgical decompression
and escalating pain intensity compel patients to seek treatment. frequently spares permanent neurologic deficit and represents
The decision to pursue treatment for a fluctuating symptom pattern definitive treatment.
is highly personalized. Change in societal beliefs about the experi- Studies of nonoperative treatment for lumbar spinal stenosis
ence of pain, expectations for function, and the goal of independent invariably advocate exercise regimens that include strengthening,
living beyond the 7th decade of life appear to be driving increased general stretching, McKenzie’s method of passive end-range
utilization of all treatments for chronic low back pain.43 Increased stretching exercises, and conventional physical therapy. Whereas
reliance on diagnostic imaging by providers is another powerful there is evidence that exercise appears to increase the rate of
driver of surging demand for treatment.44 return to normal activities in patients with persistent low back
The rates of utilization of different treatment methods vary pain, virtually none of these studies focuses on the syndrome of
widely. The preponderance of evidence related to outcomes of lumbar spinal stenosis or the symptom pattern of neurogenic
lumbar spinal stenosis treatment is found in the surgical literature intermittent claudication.49 Exercises that strengthen the abdomi-
focusing on decompressive laminectomy. A relatively robust evi- nal core muscles and promote mobility of the lumbar paraspinal
dence base supports the efficacy of laminectomy, but there is sig- muscles may offer benefit because they can stabilize the lumbar
nificant uncertainty about optimal timing, the advantages of newer spine and minimize lordosis.50 Cardiovascular conditioning can be
techniques and technologies, the durability of functional improve- beneficial by promoting weight loss because heavier patients may
ment, and the benefit of surgery compared with nonsurgical be more likely to develop the degenerative changes leading to ste-
approaches. There is a major gap in the evidence base with respect nosis.51 Multiple studies of conservative or nonoperative treatment
to the controlled evaluation of conservative management.45,46 with a variety of physical therapy approaches have found that a
majority (70%) of patients perceived no worsening of their
symptoms and a smaller number (15%) reported improve-
Nonsurgical Approaches ment.48 In Simotas and associates’ study,48 the surgical groups
tended to report greater reduction in leg pain intensity and
In elderly patients at risk for perioperative complications and in improved activity tolerance, but approximately 30% of conserva-
those with mild to moderate symptom severity, surgery is often not tively managed patients in one cohort study reported no pain or
the preferred treatment.12,47 For these groups of patients and minimal pain at 36 months.
the substantial number of patients with neurogenic claudication There is scant evidence supporting the use of oral analgesics for
that recurs after surgery, conservative treatment may be more the symptom pattern of neurogenic intermittent claudication.
appropriate.35,48 Because the symptom of lumbar spinal stenosis The only positive drug trial specifically targeting this condition is
is provoked by specific activities, the most common intervention a recent, unblended, randomized trial of gabapentin.52 Gabapentin
is activity modification. Many patients control their experience is an amino acid believed to modulate pain intensity through
of pain by simply curtailing the time spent standing or the distances interaction with an auxillary subunit of voltage-dependent Ca2+
walked. The other ubiquitous patient-initiated strategy to control channels.52 In this study, 55 patients were randomized to conser-
pain is forward flexion at the lumbar spine. Patients experiencing vative management with corset and nonsteroidal anti-inflammatory
neurogenic intermittent claudication often unconsciously modify drugs (NSAIDs) or gabapentin (maximum 2400 mg) in addition
their posture to reduce symptoms; others classically report extended to conservative therapy over 4 months. The patients in the gaba-
walking tolerance when adapting to an activity such as leaning on pentin group demonstrated a statistically significant increase in
a shopping cart. The use of a walker or walking stick promotes this walking distance and a decrease in the intensity of low back
postural adjustment; these appliances are likely the most common and leg pain (visual analog scale [VAS]) upon movement. The
solution for neurogenic intermittent claudication. As with other favorable results of this trial should be interpreted with caution
treatment approaches, patient treatment preference is of paramount because of the enhanced placebo effect expected with lack of blind-
importance because even the most advanced cases of lumbar spinal ing. Promising early results for the treatment of Paget’s disease
stenosis are so rarely associated with irreversible neurologic deficit. prompted a trial of calcitonin for neurogenic claudication. Porter
It is critical to remember that such reversibility is not true of and Hibbert53 reported 11 patients with improved walking toler-
ance associated with calcitonin 100 units administered four times
per week for 4 weeks. This polypeptide hormone secreted by the
Box 42^2 CURRENT THERAPY parafollicular cells of the thyroid was believed to possess both anal-
gesic and anti-inflammatory properties in addition to the promo-
The vast majority of symptomatic patients with symptoms associated tion of osteoclastic bone resorption that accounts for efficacy in
with spinal stenosis who do not undergo surgery do not experience Paget’s disease. A large well-designed, double-blind, randomized,
significant change in the first year after initial evaluation. placebo-controlled trial of a nasal spray formulation failed to
There is a lack of high-quality evidence assessing nonoperative show improvement in pain or walking time to first pain.46 Other,
approaches to the treatment of spinal stenosis. nonrandomized studies have reported an improvement in pain
None of the commonly used classes of medication (nonsteroidal anti- scores, but in a second randomized, well-designed study, the benefit
inflammatory drugs [NSAIDs], opioids, or acetaminophen) have been
compared with placebo did not reach statistical significance.54
tested in randomized, controlled trials for this problem.
Anti-inflammatory therapy with NSAIDs and more selective
Nonoperative cyclooxygenase-2 (COX-2) inhibitors has analgesic benefit over
First Tier that of placebo in the minimally detectable range for chronic low
Activity modification and use of assistive devices such as a walker, back pain.55 No trials designed to assess patients with neurogenic
cane, or walking sticks. intermittent claudication were available to be included in this
Second Tier
meta-analysis. Recent evidence of increased cardiovascular risk
Lumbar epidural steroid injection. with long-term use of these medication classes in higher-risk indi-
viduals renders this group of agents a less-appealing option from a
Surgical risk-benefit perspective.56 Evidence supports the use of opioids for
Decompressive laminectomy.
chronic low back pain,48 but their analgesic benefit in neurogenic
Microdecompression.
Interspinous spacers. intermittent claudication remains unknown. In general, opioids
tend to be less effective for movement-evoked pain.
Lumbar epidural steroid injections are commonly used for the improvement in pain and function, only 65% of patients endorsed
treatment of neurogenic intermittent claudication in lumbar spinal general satisfaction with their surgery. The authors hypothesized
stenosis despite controversy about their role.57,58 The rationale for that this finding may be attributed to concurrent depression in
this treatment is reduction of the intraradicular edema and inflam- 5 of the 23 patients in this study.
matory cell infiltration associated with the pain of neurogenic inter- Depression has a relatively high prevalence (36% in one cohort,
mittent claudication.59 There are no prospective, placebo-controlled N = 3801) in patients with lumbar spinal stenosis and has been
studies evaluating the use of epidural steroid injection specifically associated with higher pain intensity, worsened functional status,
for spinal stenosis. This therapy is often considered a second-tier and poorer surgical outcomes.68 The most common cause of failure
conservative approach to managing neurogenic intermittent clau- of surgical decompression is poor selection of patients; however,
dication in patients who wish to avoid surgery. Delport and collea- clear data on which patients are the best candidates for this surgery
gues60 described the outcomes of epidural steroid injection in a are lacking.63,69 Coexisting cardiovascular morbidity and scoliosis
retrospective review of 140 patients. They found that among also predict poorer patient rating of outcome, whereas better base-
patients receiving epidural corticosteroid injections, one third expe- line walking ability, higher self-rated health, higher income, reduced
rienced relief for greater than 2 months and more than 50% of coexisting disease, and pronounced central stenosis predict a more
patients demonstrated an improvement in walking tolerance.60 favorable outcome.70
One recent study was unable to determine the critical spinal canal Surgical indications must be carefully considered, especially in
dimensions, as measured by CT scanning, that would be more elderly patients, who often have many comorbid conditions placing
predictive of a response to interlaminar epidural steroid injection.61 them at risk for perioperative complications and less favorable out-
A second retrospective study showed reduction in pain intensity come in certain circumstances. Patients should be counseled that
that correlated with the number of stenotic levels and the degree the likelihood of benefit from laminectomy may be limited in the
of stenosis except in patients with greater than three levels and MRI case of multilevel stenosis; functional gains may also be reduced in
findings rated as severe.62 the context of a coexisting musculoskeletal disorder. One com-
monly cited liability specific to laminectomy is compromise of
the structure of the lumbar motion segment that in turn may
Surgical Approaches lead to further degeneration, excessive or abnormal motion, or
deformity. Lumbar fusion was believed to have the benefit of
Since its original conception as a disease caused by bony anatomic providing definitive stabilization along with decompression. Since
changes, clinical study of lumbar stenosis has emphasized surgical the introduction of new fusion technologies, the Washington State
treatment. Decompressive laminectomy aims to provide pain relief, registry has seen a 32% greater likelihood of reoperation after the
improve mobility, preserve neural tissue, and prevent worsening of first year postoperatively after an initial fusion versus decompres-
clinical deficits if present. Multiple surgical techniques in wide- sion alone for the indication of lumbar spinal stenosis.71
spread use range from multilevel decompressive laminectomies, Microdecompression is a less-invasive method of decompression
unilateral decompressive hemilaminectomy, and multilevel lami- designed to minimize this iatrogenic insult.72 Patient satisfaction
notomy with a fenestrating technique that preserves the interspi- with microdecompression has been high, but it is a procedure
nous ligaments. The technique typically involves excision of the that requires great technical skill and experience of the surgeon.
ligamentum flavum and partial removal of the laminae; medial Evidence on the relative benefit of this approach compared with
facetectomies and foraminotomies are often performed as well. conventional laminectomy is limited. Because of the risk of early
Surgical treatment is widely considered to be the most effective failure, recurrence of symptoms and complications, a shared deci-
treatment modality in patients with symptomatic lumbar stenosis sion-making model is essential when considering treatment with
and neurogenic intermittent claudication.4 Turner and coworkers’ laminectomy for patients with persistent, moderate to severe neu-
attempted meta-analysis in 1991,4 which included 74 studies of rogenic intermittent claudication.
laminectomy, found good to excellent outcomes at long-term Interspinous process spacers are a new class of implantable
follow-up of 64%. The rates of successful surgical outcomes devices that have recently received U.S. Food and Drug
vary widely.4,63 The authors’ critique of the surgical literature Administration (FDA) approval. This device creates a relative
described heterogeneity with regard to patient population, kyphosis at the level of insertion, reducing extension while allowing
patient selection, and outcome measures. Since that time, several flexion.73 Various designs ranging from static spacers to dynamic
prospective, long-term, observational follow-up studies attempting (i.e., springlike) are surgically inserted between adjacent spinous
to evaluate conservative versus surgical treatment have been com- processes at the culprit level. This type of approach was first intro-
pleted. Surgery has been repeatedly shown to improve short-term duced in the 1950s but fell out of favor because of a tendency for the
outcomes, but long-term outcomes are less favorable than with devices to become displaced over time.74 The first approved device
other approaches.64,65 The Maine Lumbar Spine Study66 found in this class, the X STOP, has an indication for mild to moderate
that for patients with persistent radicular leg pain, radiologic neurogenic intermittent claudication on the basis of a multicenter,
signs of stenosis, nerve root compression, and no previous back prospective, randomized trial with 191 patients.75 Many features of
surgery, outcomes are superior with surgery versus conservative the study design and the use of the neurogenic intermittent claudi-
care. The consensus emerging from this body of research is that cation as an end-point represent important advances in the evalu-
deferring surgical intervention does not preclude a favorable out- ation of treatments for lumbar spinal stenosis. The device was
come at a later date. compared with nonoperative treatment, and the primary end-
A recent cohort study of long-term outcome of laminectomy in point was a questionnaire designed to assess symptom severity
octogenarians (average age at time of surgery, 82.2 yr) with follow- and physical function domains related to neurogenic intermittent
up at 1.5 years resulted in an improvement in back-related func- claudication. At 2 years, there was a significant improvement in
tional status (Oswestry Disability Index) consistent with results in symptoms and function compared with those of epidural steroid
younger age groups, reduction in pain intensity, and use of opioid injection and conservative therapy. One important limitation is the
and NSAID analgesics.67 The authors cited the low complication use of a single epidural steroid injection in most patients as a com-
rate in this small group (i.e., perioperative delirium in 3 patients parator when the half-life of the injected anti-inflammatory medi-
and persistent bladder dysfunction in 1 patient) as evidence of the cation is on the order of weeks. The authors compared the
safety of this procedure in older patients. However, despite the outcomes of the X STOP placement to Katz and associates’ study
of laminectomy63 but highlighted the higher risk of complication 14. Osteoarthritis in lumbar synovial joints. A morphologic study. Acta
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Chapter 43 the limitations and risks of surgery, these patients often tend to have
realistic expectations, resulting in a higher level of satisfactory
FAILED BACK SURGERY outcomes.
SYNDROME ETIOLOGY
Sean Burgest and Thomas C. Simopoulos The causes of FBSS are many. Table 43–1 lists the most common
etiologies. For descriptive purposes, the causes can be grouped into
patient-related factors and factors related to postsurgical changes in
spinal anatomy. This categorization oversimplifies the etiologies of
FBSS. In clinical practice, patients uncommonly present with a
single, isolated pathology. Patients are much more likely to present
with a multifaceted pain complaint that requires a multidisciplinary
INTRODUCTION approach.
Failed back surgery syndrome (FBSS) is commonly defined as the

presence of persistent back pain and functional limitations in a Patient-related Factors
patient who has undergone corrective back surgery. Corrective
back surgery most commonly includes any combination of diskect- Patient-related factors consist of the coexisting psychological, social,
omy, laminectomy, and spinal fusion. and economic aspects of a patient’s life. These areas can dramati-
As a functional diagnosis, the term FBSS is both imprecise cally influence a patient’s perception of pain and degree of func-
and misleading. Usage of the term FBSS is vague, because unlike tional limitations. The importance of this is reflected in the
most other medical diagnosis (e.g., hypertension or diabetes), it aphorism attributed to Sir William Osler: ‘‘It is more important
gives minimal information regarding the etiology of the patient’s to know what type of person has a disease, than it is to know
medical problem. FBSS is equally misleading because it not what type of disease a person has.’’ This can be applied to patients
infrequently suggests that either the patient’s original diagnosis with chronic pain issues: It is more important to know what type of
was wrong or the patient’s corrective back surgery was techni- patient has chronic pain than it is to know what type of chronic
cally inadequate. pain a patient has.
In reality, the term FBSS implies only three facts: (1) The patient Inappropriate patient selection is the most common cause of
had back pain that was refractory to conservative management. (2) FBSS. Many factors may cause a patient to be an inappropriate
Corrective spine surgery was performed in an attempt to alleviate candidate for surgical intervention for back pain. The most
significant pain. (3) After the usual healing time course of back common factors are untreated or suboptimally treated psychiatric
surgery, the patient has persistent back pain and functional limita- illness, issues related to secondary gain, and motivational issues.
tions. Thus, the term FBSS has limited practical utility but has Common psychiatric illnesses in patients with chronic pain include
gained wide acceptance in the medical literature. depression, anxiety, somatization, substance abuse, and personality
disorders. Psychopathology is believed to influence pain complaints
and functional outcomes from spine interventions, including sur-
EPIDEMIOLOGY gery. Appropriate treatment of psychopathology prior to spine
intervention is believed to optimize outcome. However, the corre-
According to data from the National Hospital Discharge Survey, the lation of improved surgical outcome after successful management
rates of corrective lumbar spine surgery in the United States are of the aforementioned psychiatric disorders has not been carefully
diskectomies 250,000 to 300,000 per year; lumbar laminectomies evaluated and established.
200,000 per year; and lumbar spinal fusions 200,000 per year. Issues of secondary gain and motivation in patients with FBSS
Approximately 20% to 40% of these procedures will be unsuccessful typically involve worker’s compensation claims, disability retire-
and will result in persistent back pain and functional disability. It ment, personal injury litigation, and job satisfaction. Any of these
should be noted that the true success rate of corrective back surgery situations can create economic incentives for a patient to prolong
is related to the experience of the surgeon as well as to the location illness or disability. The economic incentives are not insignificant,
of the procedure (e.g., modern, high-volume spine centers vs. low- regardless of a patient’s educational background or social status.
volume institutions). The common denominator is that worker’s compensation, disabil-
As is common to most spine interventions, the actual success ity retirement payments, and personal injury litigation settlements
rate depends on how the outcomes are measured. The definition of are all protected from federal and state income taxes. For this
‘‘success’’ may be different as measured by the surgeon and by the reason, the physician attempting to treat FBSS must be alert to
patient. For example, the surgeon notes marked improvement in these potential ‘‘red flags’’ that may signal a suboptimal response
motor function and posture postsurgery, yet the patient is dissatis- to treatment. Motivational issues that may contribute to FBSS are
fied and complains of persistent pain with usual daily activities. well studied. Patients with a history of poor job satisfaction or
Ample retrospective data suggests that patients who are active par- work-related injury are likely to have a prolonged recovery.
ticipants in their evaluation and treatment decisions benefit more Indeed, patients who have been off work for more than 90 days
than patients who are passive participants. Similar to surgery for as a result of a work-related injury are very unlikely to improve
total knee replacements, surgery for back pain is largely elective for from either medical or surgical interventions. Thus, factors outside
pain relief and improvement in quality of life. When empowered to of the biologic realm can be difficult to evaluate and, at the same
help decide when their chronic pain is severe enough to outweigh time, are major contributors to final outcome.
324 Chapter 43 FAILED BACK SURGERY SYNDROME
Table 43^1. Etiologies of FBSS
Patient-related Factors Surgery-related Factors

Poor patient selection Incorrect procedure (e.g., laminectomy for discogenic pain)
Psychiatric issues Correct procedure with recurrence of original problem or new problem (e.g., recurrence of disk
1. Mood or personality disorders herniation at operative site or another level)
2. Somatoform disorders
Motivational issues Complications related to a correct procedure (e.g., diskitis, hematoma, epidural fibrosis,
1. Undesirable employment pseudomeningocoele)
2. Poor social support
Secondary gain issues Transition syndrome (e.g., accelerated degenerative changes or instability at areas above or
1. Disability fraud below a spinal fusion)
2. Pending litigation Persistent neural injury (e.g., corrective back surgery will not reverse preexisting neural injury)
FBSS, failed back surgery syndrome.
Surgery-related Factors is best suited to institute a comprehensive treatment plan. To this

end, the goal of evaluation (and ultimately, of effective treatment)
Of the factors related to the postsurgical spine, the majority of is not the conversion of FBSS into successful back surgery
patients with FBSS can be given a specific diagnosis that facilitates syndrome. Rather, the goals are to decrease the intensity of symp-
treatment. Slipman and coworkers, in a retrospective case series of toms, prevent further injury, and maximize the quality of life via
197 patients with FBSS, demonstrated that 95% of patients could be optimization of physical function. To realize these objectives, the
given a diagnosis. Surgical and nonsurgical causes contribute evaluation must address five key questions relative to the patient’s
in equal frequencies to FBSS. Table 43–2 lists the most common condition: (1) What is the exact nature of the patient’s pain
structural causes of surgical and nonsurgical FBSS, in order of complaint (e.g., mechanical, neuropathic, or mixed)? (2) Is there
decreasing frequency. Clinically, the patient with FBSS is assessed a coexisting psychological burden (e.g., mood disorder) or mala-
initially in terms of degree of referred leg pain compared with axial daptive coping strategy (e.g., alcoholism)? (3) What is the patient’s
back pain in order to establish a differential diagnosis. Tables 43–3 level of physical functioning before and after surgery (e.g., decon-
and 43–4 list the Initial Presumptive Diagnosis (based on history), ditioned obese patient vs. avid cyclist)? (4) Regarding the patient’s
Initial Diagnostic Tests, Confirmatory Diagnostic Tests, and Initial current level of disability, what are his or her expectations for
and Extended Therapies for FBSS based on location of symptoms in symptoms relief and return of physical activity? (5) Is the patient
the back and leg, respectively. committed to being an active participant in treatment? Once these
question are satisfied and it is determined that the patient is
willing to actively participate in the rehabilitation process, a com-
EVALUATIONOF THE PATIENT prehensive plan of care is developed by the treating physician.
WITH FBSS Lastly, the treating physician communicates the objective treat-
ment goals to the patient and develops a timetable to monitor
Given that FBSS is not a specific diagnosis but a spectrum of illness the patient’s progress.
and disability, it is important to approach these patients in a sys-
tematic manner. Regardless of the patient’s pain complaints, the
evaluation has three components: multidisciplinary assessment, Clinical History
development of a comprehensive plan of care with well-defined
treatment goals, and periodic evaluation of the patient’s response Although patients with FBSS may have a very lengthy and complex
to treatment. medical and surgical history combined with a desire to elaborate on
A thorough multidisciplinary evaluation is needed to elucidate every details of their treatment history, the clinical history should
the multidimensional problem that often accompanies FBSS and be focused on two goals: (1) To rule out any potentially devastating
causes of back pain (e.g., cauda equina syndrome, tumor, infec-
tion) and (2) to characterize the quality of the patient’s pain
complaint (e.g., mechanical, neuropathic, or mixed). Whenever
Table 43^2. Most Common Causes of FBSS possible, it is very valuable to determine how surgery influenced
the initial pain presentation. This alone will help focus the diag-
nosis in either of three categories: (1) The original pain problem
did not adequately respond to surgery. (2) The present pain com-
plaint is a new problem as a result of having surgery. (3) A new or
return of the same pain occurred after initial successful surgery for
an interval of time.
In addition to the patient’s somatic pain complaint, the clinical
history must include psychosocial and physical function informa-
tion. Although this information is typically gathered from the
collateral psychological and physical therapy evaluations, a basic
understanding of these aspects of the patient’s background usually
gives valuable contextual perspective to the clinical history.
From North RB, Campbell JN, James CS, et al. Failed back surgery syn- Box 43–1 lists the common information obtained from the clinical
drome: Five years follow-up in 102 patients undergoing reoperation. history. The clinical history gives the most critical information that
Neurosurgery 1991;28;685–691. guides diagnosis and further management.
Table 43^3. Symptomatic Diagnosis in FBSS Patients Presenting with Back Pain
Presumptive Diagnosis
(Based on Clinical Confirmatory Diagnostic
History) Initial DiagnosticTests Initial Therapy Tests Extended Therapy
Epidural scar/fibrosis History and physical Anti-inflammatories CT/myelography/MRI Epidural lysis of
examination adhesions; epidural
steroid injection
Pseudomeningocele, CT/myelography/MRI Surgical resection/placation CT/myelography/MRI Surgical resection/
arachnoid cyst plication
Diskitis or aseptic History and physical Antibiotics, anti- CT/MRI Surgical débridement
interspace examination + inflammatories
inflammation sedimentation rate,
WBC count
Discogenic pain History and physical Anti-inflammatories, bracing Diskography/CT/MRI
examination
Facet arthropathy History and physical Anti-inflammatories, bracing, Diagnostic facet or Radiofrequency lesioning
examination facet joint injections or medial branch blocks of medial branch
medial branch blocks nerves, spinal fusion
Muscle spasm/myofascial History and physical Trigger point injections/oral Local anesthetic Botulinum toxin;
pain/trigger points examination muscle relaxants injections biofeedback
Spondylosis with MRI/CT Anti-inflammatories, bracing Bracing Spinal fusion
spondylolisthesis
Metastatic neoplasm History and physical Related to primary neoplasm For lytic lesions, CT Same as Initial Therapy
examination and prognosis (surgery or For blastic lesions, bone
(percussion chemotherapy or radiation scan
tenderness) therapy)
Benign neoplasm History and physical Surgical resection MRI/CT Surgical resection
examination
Flabby back syndrome History and physical Therapeutic exercise; oral MRI (to rule out other Patient education
(generalized examination anti-inflammatory + muscle causes) regarding lifestyle
deconditioning) relaxer modification (e.g.,
exercise, nutrition,
tobacco cessation)
Pseudarthrosis or failure Flexion and extension Bracing, anti-inflammatories CT Revision or extension of
of spinal fusion x-ray fusion
CT, computed tomography; MRI, magnetic resonance imaging; WBC, white blood cell.
Adapted from Wilkinson HA. The Failed Back Syndrome: Etiology and Therapy. Philadelphia: Harper & Row, 1983.
Physical Examination n Incomplete return of deep tendon reflexes.

n Less-defined patterns of sensory loss giving rise to unclear
The physical examination for the patient with FBSS can be divided radicular patterns.
into general appearance, musculoskeletal, neurologic, functional, n Incomplete motor recovery despite adequate decompression.
and provocation testing. Whenever possible, it is useful to compare
the current findings with preoperative findings. The examination of the musculoskeletal system includes range of
General appearance begins before the patient is officially intro- motion, careful inspection of the back architecture for symmetry
duced to the treatment team. If possible, observe the patient’s beha- and muscle development, and evaluation of major lower extremity
vior, posture, and grooming prior to the formal introduction. It is joints. The following are common physical examination findings
important to know: Does the patient ambulate with a smooth fluid in FBSS:
gait? Does the patient have a normal cervical and lumbar lordosis?
n Loss of lumbar lordosis and decreased range of motion.
Does the patient patient walk/sit comfortably? Do the patient’s
n Paravertebral muscle atrophy.
shoes show signs of uneven wear or tear? Answers to these questions
n Chronic greater trochanteric bursitis.
give valuable information to the treating physician before a formal
n Extensive myofascial pain of the gluteal musculature.
introduction is made. The physical examination usually confirms
n Tenderness of the sacroiliac joint area and positive provoca-
the history and, uncommonly, changes the differential diagnosis.
tion tests of this joint.
Table 43–5 lists the common maneuvers for musculoskeletal,
n Tenderness and decreased range of motion of the neck and
neurologic, functional, and provocation testing. Evaluation of
upper back.
sensory and motor loss can give insight to potentially involved
spinal nerve roots. The neurologic examination can be altered Functional testing is often used to look for predictive factors for
after surgery by a poor surgical or pain interventional outcome. The most common
Table 43^4. Symptomatic Diagnosis in FBSS Patients Presenting with Leg Pain
Presumptive Diagnosis
(Based on Clinical Confirmatory Diagnostic
History) Initial DiagnosticTests Initial Therapy Tests Extended Therapy
Retained disk or foreign X-ray/CT Anti-inflammatories CT/myelography Surgical exploration and
body (e.g., metallic resection/removal
clips or fibers from
surgical sponges)
Fibrosis of nerve root History and physical PO adjuvant analgesics CT/myelography, Epidural lysis of adhesions
examination (e.g. anticonvulsant or diagnostic nerve root and steroid injections;
antidepressant), anti- block surgical neurolysis
inflammatories
Spinal stenosis (central CT/MRI/myelography Anti-inflammatories, Same as Initial Maintenance epidural
or lateral recess) PO adjuvant analgesics, Diagnostic Tests steroid injections, surgical
epidural steroid injection decompression
Arachnoiditis CT/MRI/myelography Anti-inflammatories, Same as Initial Maintenance epidural
(observe ‘‘clumping’’ PO adjuvant analgesics, Diagnostic Tests steroid injections, surgical
of roots or ‘‘empty sac’’ epidural steroid injection lysis
appearance)
Nerve root cyst CT/MRI/myelography Anti-inflammatories, Same as Initial Surgical resection/placation
PO adjuvant analgesics Diagnostic Tests
Coexisting neuropathy Electromyography, nerve Anti-inflammatories, Same as Initial Same as Initial Therapy
(e.g., diabetic conduction studies PO adjuvant analgesics Diagnostic Tests Limit ongoing damage via
neuropathy, control of original
postchemotherapy pathology (e.g.,
neuropathy) optimization of diabetes
management)
CT, computed tomography; MRI, magnetic resonance imaging.
Adapted from Wilkinson’s The Failed Back Syndrome: Etiology and Therapy. Philadelphia: Harper & Row, 1983.
are Waddell’s signs, as listed later. It is important to keep in mind n Stimulated pain on axial loading.
that although Waddell’s signs do not absolutely exclude a potential n Differential straight leg raise inconsistencies.
pain generator, they do point to the need for careful consideration n Exaggerated pain response to provocation testing.
of psychosocial factors playing a major role in persistent pain n Sudden give-way weakness.
complaints.
n Superficial nonanatomic tenderness.
n Nonneuroanatomic neurologic deficits.
Diagnostic Studies
Often, the patient with FBSS has been subjected to a multitude
Box 43^1 INFORMATION OBTAINED IN THE CLINICAL of diagnostic studies, both noninvasive and invasive. The initial
evaluation should begin with a review of these studies. In the
HISTORY absence of significant changes in the patient’s symptoms or new-
History of Present Illness
onset objective physical examination findings, routine repeat diag-
Mnemonic ‘‘OPQRST’’ nostic studies are unnecessary and often will not identify the cause
1. Onset of complaint of persistent pain. Table 43–6 lists the common diagnostic studies
2. Provoking or palliative factors used in the further evaluation of patients with FBSS.
3. Quality of pain (nociceptive vs. neuropathic) Magnetic resonance imaging (MRI) is believed to be the test
4. Radiation of pain of choice in patients with FBSS. A gadolinium-enhanced MRI is
5. Site and severity of pain helpful when distinguishing between recurrent disk herniation
6. Timing of pain (constant vs. reproducible with activity) and postsurgical scar. The herniated disk is an avascular structure
Psychological Screen and will not enhance with gadolinium, as will scar tissue. It is not
Note: This does not replace the comprehensive psychological evaluation uncommon, however, that posterior disk margins are not easily
(when indicated) distinguished from postoperative tissues changes, especially in the
1. History of mood or personality disorders? Response to treatment? first 6 months after an operation. MRI can be a useful diagnostic
2. History of responses to social stressors: adaptive vs. maladaptive? test for the following entities in particular:
3. History of alcohol abuse or illicit substance use?
n Epidural abscess.
Functional Screen
1. Employment history: Self-employed? How many years at present n Diskitis.
job? Job satisfaction? n Arachnoiditis.
2. Baseline level of physical conditioning: sedentary and obese vs. The important point to bear in mind with any of the diagnostic
triathlete?
modalities presented in Table 43–6 is that there are no consistent
Table 43^5. ProvocationTesting for Patients with FBSS
Motor Sensory DeepTendon Reflex

T12, L1, L2, L3 Iliopsoas muscle (flexes thigh) ‘‘Underwear’’ area of groin (except None/unreliable
genitalia = S2)
L2, L3, L4 Quadraceps muscle (extends knee) Upper two thirds of anteromedial thigh Patella reflex
L4 Tibialis anterior (dorsiflexion of foot) Lower one third of anterolateral thigh + Patella reflex
patella (variable) + great toe
L5 Extensor hallucis longus (extends great toe) Dorsum of foot and anterior tibia None/unreliable
S1 Peroneus longus and brevis Lateral malleolus and fifth digit Achilles reflex
characteristic findings that will pinpoint or predict the pain gen- when to treat, which treatment to employ, and whether the poten-
erators in patients with FBSS. In the absence of lumbar spine insta- tial benefit of the treatment indeed acceptably outweighs the risk of
bility or acute trauma, plain radiographic imaging has very little failure and complication sore taxes the skill, intelligence, and art of
diagnostic information. Computed tomography (CT) has found its the physician—but should not discourage him from rational efforts
main use in detecting subtle pas interarticularis defects and in to help his patients.’’
patients who are not suitable candidates for MRI. Treatment of FBSS begins with recognized the complexity of the
Electromyography studies encompass the evaluation of both problem. This complexity is due to the often-prolonged duration of
peripheral sensory nerves and the motor unit. One of the specific pain and disability, the obligatory psychological response to pro-
limitations is that the test assesses only large, heavily myelinated longed disability, and the associated physical deconditioning.
fibers and not small, unmyelinated C-fibers. Fibrillation potentials Whereas patients with FBSS may present with varied specific pain
develop 3 weeks after a muscle is denervated. An examination after complaints, the ideal treatment plan should address these areas. The
laminectomy may reveal the following findings and limitations: Appendix presents a treatment algorithm for FBSS. Unfortunately,
the literature offers little evidence to substantiate a conservative or
n It does not help in the assessment of axial low back pain.
interventional approach. Most pain management centers offer a
n Fibrillation of the paraspinal muscles are common and persist
combination of physical, psychological, medical, and interventional
for years after lumbar spine surgery.
therapies.
n Fibrillation of the paraspinal muscles may occur without
complaints of radicular pain.
n It does not rule out radiculopathy.
n It may help when imaging studies are inconclusive and a Role of the Pain Psychologist
peripheral neuropathy or a plexopathy is suspected.
An experienced pain psychologist is vital to all aspects of treatment
for patients with FBSS. Such psychologists are not under the incor-
rect impression that the successful treatment of chronic pain will
TREATMENT FOR FBSS reliably make psychopathology disappear. The primary role of the
psychologist is to determine the degree to which psychopathology
The difficulty in treating patients with FBSS is best reflected in the (Box 43–2) and secondary gain issues affect a patient’s pain com-
words of neurosurgeon Harold A. Wilkinson in his classic text The plaints and function. The magnitude of any condition in these two
Failed Back Syndrome: ‘‘Deciding whom to treat or not to treat, categories affects the desire to proceed with future interventions.
Table 43^6. Common Diagnostic Studies to Evaluate FBSS
Diagnostic Study Utility

Plain film x-ray 1.Evaluates spinal stability, fracture, or dislocation
2.Evaluates extent of known spinal hardware prior to interventional techniques
3.Evaluates soft tissue planes and normal/abnormal spinal curvatures
CT 1.Evaluates bony details of spine in axial plan (e.g., fractures, nonunion, osteophytes, calcifications)
2.Evaluates intervertebral disk defects (in patients with contraindications to MRI)
MRI 1.Evaluation of intervertebral disks and other soft tissue pathologies (e.g., nerve root cysts)
2.Evaluates interval changes in anatomy in patients with new-onset objective findings
Myelography 1.Evaluates defects in the spinal canal (spinal stenosis, spinal cord lesions, and dural tears)
2.Demonstrates obstruction to flow of CSF in spinal canal
Skeletal scintigraphy 1.Evaluates for fractures undetectable by x-ray or CT
(bone scan) 2.Evaluates for osteoblastic activity (malignancy) or other pathologic conditions that stimulate skeletal blood
flow (e.g., osteomyelitis, primary bone tumors)
EMG Evaluate the cause of muscle weakness (e.g., neuropathy, denervation, entrapment syndromes)
SSEPs Quantify injury to a specific nerve, spinal cord, or brainstem (e.g., tumors, trauma, demyelinating diseases)
CSF, cerebrospinal fluid; CT, computed tomography; EMG, electromyography; MRI, magnetic resonance imaging; SSEPs, somatosensory evoked
potentials.
challenge exists in the vast majority of patients with FBSS. The

Box 43^2 PSYCHOPATHOLOGY COMMON IN PATIENTS physical therapist is often confronted with a patient who, in addi-
WITH FBSS tion to deconditioning, has structural asymmetries, loss of lumbar
lordosis, paraspinal muscle atrophy, tightening and shortening of
Mood Disorders gluteal and hamstring muscles, as well as persistent pain and fear
1. Depression avoidance behavior. The physical therapist patiently works with
2. Anxiety patients suffering with FBSS to improve range of motion, enhance
3. Dysthymia
strength and endurance, improve ergonometrics, and develop a
Psychological Syndromes daily exercise and stretching routine. At a minimum, successful
1. Post-traumatic stress disorder (PTSD) physical rehabilitation enables the patient with FBSS to participate
2. Somatoform disorders in activities of daily living and independent activities of daily living.
3. Factitious disorders (e.g., Munchausen’s syndrome)
At a maximum, the patient is able to participate in activities very
Self-medication similar to the premorbid level of function. Patients with FBSS must
1. Alcohol abuse/dependence have the motivation to engage in a lifelong program of a physical
2. Illicit substance use/abuse therapy to derive long-term ongoing benefit.
3. Tobacco consumption
4. Excessive caffeine consumption
Medical Management of FBSS

The psychologist determines the appropriateness for the following Medical management of FBSS is divided into the pharmacologic
potential therapies: and the nonpharmacologic approaches, as summarized in Table
43–7 and Box 43–3. Nonpharmacologic approaches, in addition
n Psychotherapy.
to the physical and psychological treatments already discussed, are
n Relaxation techniques.
the encouragement of vocational training. The initial pharmacolog-
n Biofeedback.
ic treatment is rationally approached using symptomatic therapy for
n Mind-body chronic pain programs.
a presumptive diagnosis. For example, chronic use of high doses of
In addition, the psychologist assesses the effectiveness of phar- nonsteroidal anti-inflammatory drugs is common in FBSS for sus-
macologic therapies and may refer the patient to a psychopharma- pected chronic inflammation (e.g., spondylosis). Potential down-
cologist for further treatment. After all appropriate psychological sides include common toxicities such as platelet dysfunction,
and pharmacologic interventions are instituted, the psychologist gastrointestinal erosion, renal dysfunction, and prothrombotic
evaluates the degree of success. Unfortunately, despite comprehen- events (especially cyclooxygenase-2 inhibitors). Dose reduction
sive psychological treatment, a significant number of patients do and short-term or sporadic use may minimize side effects. In clin-
not reach adequate psychological improvement to qualify for pain- ical practice, this is achieved by using multiple modalities, including
modifying interventions. periodic interventional pain procedures. Identification of neuro-
pathic complaints may be treated with combinations of antidepres-
sants and antiepileptic medications. Muscle relaxants are often used
Role of the Physical Therapist chronically to address persistent muscle spasm.
Many patients with FBSS are commonly on chronic opioid ther-
Physical and occupational therapies are important to prevent fur- apy, usually in the form of short-acting agents. Whereas a popula-
ther injury and deconditioning. A formidable rehabilitation tion of patients may derive benefit for years, many do not and
Table 43^7. Common Pharmacologic Agents for FBSS
Class Agent Indications Contraindications Adverse Effects

Anti- NSAIDS/COX-2 Nociceptive somatic pain Abnormal renal function or 1. Renal toxicity
inflammatories inhibitors syndromes (e.g., arthritis) gastrointestinal bleeding 2. Gastrointestinal bleeding
Opioids Use in nonmalignant pain 1. History of substance 1. Constipation: most common
is controversial owing to abuse/use 2. Nausea and vomiting: tolerance
scarcity of long-term data 2. History of aberrant develops to this effect
on outcomes and efficacy behavior (e.g., history of 3. Respiratory depression
illegal behavior)
Adjuvants* 1. Antidepressants Neuropathic pain Specific to each agent Specific to each agent
2. Anticonvulsants syndromes/musculoskeletal
3. GABA agonists pain syndromes/mixed
4. Muscle relaxants pain syndromes
5. Local anesthetics
(topical and oral)
6. NMDA receptor
antagonists
7. a2-Adrenergic
agonists
*Adjuvants (in addition to the approved indications, many adjuvant drugs have widely accepted unapproved uses).
COX-2, cyclooxygenase-2; GABA, g-aminobutyric acid; NMDA, N-methyl-D-aspartic acid; NSAIDs, nonsteroidal anti-inflammatory drugs.
discogenic, facetogenic, sacroiliac, and neuropathic etiologies.

Box 43^3 NONPHARMACOLOGIC MANAGEMENT OF FBSS History, physical examination, and imaging studies in most cases
do not allow for accurate diagnosis of the pain generator(s).
Behavior Modification Accurate injection of the sacroiliac joint or the medial branches
1. Adequate quantity and quality of sleep
2. Nutritional counseling of the facet joints with low volumes of local anesthetic on multiple
3. Daily physical activity visits with assessment of pain relief and range of motion in the
anesthetic phase can give insight as to the pain source. Multiple
Physical and Occupational Therapy sessions of blocking the potential site of pain is necessary to rule out
1. Reverse deconditioning
false-positive results and to determine the contribution of that par-
2. Maximize level of physical function and endurance
3. Prevention of further injury ticular anatomic structure to the axial low back pain complaints.
4. Occupation specific training to maximize function within patient’s Patients may derive adequate long-term relief from injection of
functional limitations medial branches innvervating the facet joints or of the sacroiliac
joint with depo-corticosteroids. Radiofrequecy lesioning may be
Psychological Support
1. Symptom reduction (e.g., cognitive-behavioral therapy,
performed for more extended relief if diagnostic blocks repeatedly
biofeedback) confirm the source of pain.
2. Preservation of social supports (e.g., family counseling, couples Unfortunately, discogenic low back pain is a common cause of
therapy) persistent pain in patients with FBSS. Lumbar laminectomy and
diskectomy do not repair painful disks. In addition, lumbar spine
Vocational Training
1. Acquisition of skill sets conducive to patient’s physical limitations fusion as a treatment for discogenic low back pain is contentious
2. Literacy and educational training, where indicated with modest long-term results. Lumbar disk stimulation (disko-
graphy) remains the only clinical modality that can establish
whether a disk is responsible for a patient’s axial low back pain.
continue on this class of medications. When considering chronic However, the use of provocation lumbar diskography even with the
opioid therapy, functional goals and objectives should be set in aid of pressure-controlled manometric devices in patients with
place before initiating treatment. Unfortunately, this is rarely FBSS is controversial because of the potential for a high rate of
done, and many patients with FBSS continue to take opioid med- false-positive results. Many experts will recommend first ruling
ications with little pain reduction or functional impact. Patients out or treating pain related to the facet and/or sacroiliac joints as
should be aware of the long-term implications of chronic opioid well as performing a careful psychological evaluation before resort-
therapy that have recently been appreciated, including ing to the use of diskography. Once the diagnosis of persistent
discogenic low back pain is established in FBSS, the effective treat-
n Opioid tolerance.
ment options are often limited. Patients with intervertebral body
n Opioid-induced hyperalgesia.
hardware, advanced disk degeneration, or intertransverse process
n Physical and psychological dependence.
fusion are not candidates for intradiskal electrothermal therapies
n Endocrinopathies.
(IDET). The patient must come to the understanding that there
n Immunomodulation.
are no effective treatment solutions for these clinical scenarios. In
Finally, clinicians should monitor for diversion and coexisting addition, the use of IDET even on patients with FBSS who have a
substance abuse. These issues can arise years into chronic opioid relatively preserved disk height and who have a diskography study
therapy as financial loss, depression, and other psychosocial stres- that suggests definitive discogenic low back pain is controversial
sors continue to burden the individual with FBSS. because most studies on this therapy excluded patients with a
prior history of lumbar spine surgery. Not uncommonly, implan-
table programmable drug delivery systems are employed to control
Interventional Management of FBSS the pain in these patients. Although intrathecal drug infusion sys-
tems can improve the quality of life of some patients with FBSS
Table 43–8 provides an overview of the interventional modalities related to the aforementioned etiologies, the therapy requires strong
available for treating patients with FBSS. The common approach to commitment from the patient and the physician to avoid serious
applying interventional modalities is to assess the relative contribu- complications.
tion of radicular pain and axial low back pain to the patient’s overall Lastly, both diagnostic local anesthetic blocks and provocation
chronic pain and dysfunction. Tables 43–3 and 43–4 give an over- diskography results can be negative or indeterminate, so that the
view of the etiologies of axial low back pain and radicular pain with etiology is unknown. In a modest number of patients (Table 43–2),
their respective treatment options. In clinical practice, when the the low back pain may be neuropathic. Such an etiology can
predominant complaint is lumbosacral pain related to radiculopa- respond to spinal cord stimulation or peripheral (‘‘field’’) stimula-
thy, the diagnosis is apparent and treatment can readily be insti- tion. Finally, persistent primary muscle spasm or myofascial pain
tuted. Frequently, patients can be treated with periodic epidural can be palliated with periodic trigger points or botulinum toxin
steroid injections. The duration of relief may be enhanced by an injection.
epidural lysis of adhesions procedure. A minority of patients may be
candidates for percutaneous disk decompression, which is usually
applied to a nonoperated lumbar disk with reasonably well- SUMMARY/CONCLUSIONS
preserved disk height. However, for those patients who fail to
derive adequate relief of neuropathic pain in the lower extremities FBSS is regrettably a common and challenging problem that phy-
from decompressive surgery and injection therapy, spinal cord sicians involved in pain management commonly confront. The
stimulation has become a validated treatment option with a good etiologies for FBSS often represent a variable combination of
clinical success rate. patient-related factors (e.g., psychosocial history) and surgical, non-
The predominant complaint of chronic axial low back pain is, surgical, and rehabilitative causes. A multidisciplinary approach is
unfortunately, very common in patients with FBSS. As listed in believed to be best suited to evaluate and address the multidimen-
Table 43–2, the treating physician must sort through these causes sional problem of FBSS. The etiology(ies) of FBSS can be estab-
and form a differential diagnosis. The clinician in the pain treat- lished in most cases. However, outcomes will continue to vary
ment center is most frequently confronted with multifactorial because the ability to successfully treat all of the multifactorial
causes of low back pain consisting of a varying combination of causes that contribute to FBSS also varies.
Table 43^8. Interventional Modalities for FBSS
Modality Indication Duration of Effect Complications

Trigger point injections Myofascial pain Hours to days 1. Allergic reaction
2. Local anesthetic toxicity
3. Tissue damage (e.g., nerves or
blood vessels, pneumothorax)
Peripheral nerve blocks 1. Diagnostic: to define pain generator Minutes to hours Same as trigger point injections
(e.g., location, central or peripheral)
2. Prognostic: to predict response to a
procedure with a longer duration
(e.g., radiofrequency lesioning)
3. Therapeutic: to reduce pain or break
pain cycle (e.g., greater occipital
nerve blocks for occipital neuralgia)
Epidural steroid injections Inflammatory-mediated pain Days to weeks to Same as trigger point injections
(e.g., spinal stenosis or herniated months + Intrathecal injection, postprocedural
intervertebral disks) headache
Botulinum toxins Painful dystonia and myofascial pain Months 1. Allergic reaction
2. Tissue damage (e.g., nerves, blood
vessels)
Neurolytic block Discretely localized pain pathways Months Depends on modality used:
1. Chemical (phenol, alcohol, 1. Chemical: uncontrolled spread of
glycerol) agent
2. Cold (cryoablation) 2. Cold and heat: deafferentation pain
3. Heat (radiofrequency
lesioning)
Nucleoplasty (includes PDD Pain due to intervertebral disk Insufficient data at 1. Infection of disk requiring surgical
and IDET) pathology (mechanical or chemical) present débridement
2. Recurrence of original disk
pathology (e.g., herniation)
Spinal cord stimulation Neuropathic pain syndromes Indefinite 1. Infection related to foreign body
2. Technical failure of device (e.g.,
lead migration or fraction,
mechanical failure)
Peripheral nerve stimulation Neuropathic pain syndromes Indefinite Same as spinal cord stimulation
Intrathecal drug delivery Cancer-associated pain, painful Indefinite Multiple
spasticity 1. Pharmacologic: lethal overdose or
underdose (e.g., baclofen overdose
or withdrawal)
2. Technical: failure of pump
3. Infection related to foreign body
with possible spread to central
nervous system
IDET, intradiskal electrothermal therapy; PDD, percutaneous disc decompression.
SUGGESTED READINGS
Essential Texts for the Clinician Treating Back Pain and FBSS
Cailliet R. Low Back Disorders: A Medical Enigma. Philadelphia: McQuay H, Carroll D, Jadad AR, et al. Anticonvulsant drugs for
Lippincott Williams & Wilkins, 2003. management of pain: a systematic review. BMJ 1995;311:1047.
Spurling RG. Lesions of the Lumbar Intervertebral Disc. Springfield IL: Richardson BP. Serotonin and nociception. Ann N Y Acad Sci
Charles C. Thomas, 1953. 1990;600:511–519.
Kirkaldy-Willis WH. Managing Low Back Pain, 2nd ed. New York: Willis WD, Westlund KN. Neuroanatomy of the pain system and the
Churchill Livingstone, 1988. pathways that modulate pain. J Clin Neurophysiol 1997;14:2–31.
Wilkinson HA. The Failed Back Syndrome: Etiology and Therapy. Treatment Outcomes in FBSS
Philadelphia: Harper & Row, 1983. North RB, Campbell JN, James CS, et al. Failed back surgery syndrome:
Excellent Overviews of Anticonvulsant and Antidepressant Therapies five years follow-up in 102 patients undergoing reoperation.
for Back Pain Neurosurgery 1991;28:685–691.
Kingery WS. A critical review of controlled clinical trials for peripheral Slipman CW, et al. Etiologies of failed back surgery syndrome. Pain Med
neuropathic pain and complex regional pain syndromes. Pain 1997;73:123. 2002;3:200–214.
APPENDIX II. After the comprehensive assessment, patient education begins

with the goal of explaining the scope of the problem and the com-
TREATMENT ALGORITHM prehensive approach to treatment. Optimal patient education is
achieved when the patient understands the ‘‘4 Ps’’ of symptom
Most comprehensive treatment plans for FBSS can be divided into reduction:
three phases: (1) comprehensive assessment, (2) patient education,
Problem: presumptive etiology of patient’s pain complaint.
and (3) treatment trial.
Plan: the comprehensive plan of care (e.g., medical management,
physical therapy, interventional modalities, cognitive-beha-
vioral therapy).
Prognosis: what constitutes treatment success (patient and treat-
ment team must have congruent quantifiable treatment goals
in order to define treatment success).
Comprehensive Patient Personal decisions*: must explain how patient’s personal lifestyle
assessment education choices affect the response to treatment.
III. The treatment trial is equally diagnostic and therapeutic. If the
initial modality significantly reduces the patient’s symptoms, then
the initial treatment plan could be considered both diagnostic and
therapeutic. However, it is vital that the patient understand that
chronic pain is a chronic disease not unlike hypertension or asthma.
As is the case with management of any chronic disease, compre-
hensive management must address the primary problem and screen
Treatment for end-organ damage.
trial Just as the consultant endocrinologist optimizes blood glucose
and screens for end-organ sequelae of diabetes (e.g., diabetic reti-
I. Given that FBSS is a multifaceted syndrome, the comprehensive nopathy and nephropathy), so too must the consultant pain phy-
assessment (and ultimately, effective treatment) typically involves a sician reduce the patient’s pain symptoms and screen for adverse
multidisciplinary approach. effects of chronic pain. These effects may include depression, phys-
ical deconditioning, secondary gain, and maladaptive coping
strategies.
Medical
evaluation
Comprehensive
assessment
Psychological Functional
evaluation evaluation
*Personal decisions include

Tobacco cessation.
Moderation of alcohol consumption.
Abstinence from illicit drug use.
Maintenance of optimum body weight.
Maintenance of optimum cardiovascular fitness.
Adequate sleep.
332 Chapter 44 POSTSTROKE PAIN
Chapter 44 part of any poststroke pain syndrome evaluation. Careful examina-

tion of the peripheral neuromuscular and skeletal system must be
POSTSTROKE PAIN done before assuming that a patient’s poststroke pain is of uncom-
mon singular central origin.
Andrew Dubin Common causes for hemiparetic shoulder pain are frequently
overlooked. Always consider such mundane diagnoses as glenohu-
meral and acromioclavicular joint arthritis. Evaluate for pain
with passive shoulder abduction, rotator cuff tendinitis, and
arthritic changes at the glenohumeral joint. Focal pain at the acro-
mioclavicular joint with shoulder hyperadduction is classically seen
INTRODUCTION with acromioclavicular joint degenerative joint disease and is a
common cause of pain. Biceps tendinitis can be discovered with
The management of poststroke pain syndromes presents many chal- palpation and stretch or stress of the tendon as it courses through
lenges. Various names ascribed to poststroke pain include Dejerine- the intertubercular groove. In the flaccid acute stroke patient, man-
Roussy syndrome, thalamic pain syndrome, hemiparetic shoulder ually supporting the subluxed humerus in the glenoid may dramat-
pain, complex regional pain syndrome, and shoulder hand syn- ically reduce the shoulder pain that is emanating from a stretched,
drome, just to name a few. flaccid rotator cuff.
Review of this brief and incomplete list of names underscores a
major challenge in poststroke pain. The question of what is the
generator of poststroke pain becomes immediately evident. MANAGEMENT
Clearly, central as well as peripheral mechanisms are at play.
Poststroke pain syndromes would appear to represent an interplay Degenerative joint disease of the glenohumeral joint, impingement
between peripheral nociceptive pain generators, central neuropathic syndromes, subacromial bursitis, and rotator cuff tendinitis may all
generators, in concert with altered central nervous system pain respond to such simple interventions as ice packs for pain control,
signal processing and neuromodulation. acetaminophen or lidocaine patches, and physical therapy. In more
refractory cases, intra-articular injection via a posterior shoulder
approach, utilizing a combination of steroid and local anesthetic,
NOCICEPTIVE VERSUS NEUROPATHIC may give very satisfying results. Care must be used if nonsteroidal
PAIN anti-inflammatory drugs are to be given, because they may worsen
hypertension, congestive heart failure, and renal insufficiency as
Understanding the difference between nociceptive and neuropathic well as cause gastric distress. Biceps tendinitis may respond nicely
pain has implications in the management of poststroke pain. to ice, lidocaine patches, or physical therapy with use of modalities
Nociceptive pain generally refers to pain that is associated with such as ultrasound and gentle range of motion exercises. Injection
tissue damage and is mediated by an intact nervous system. It is can be done, but care must be taken to prevent injection of steroid
not uncommonly described as a ‘‘throbbing, aching’’ pain. The into the tendon to avoid the risk of tendon rupture. Glenohumeral
flaccid shoulder in the acute poststroke patient, with resultant subluxation in the flaccid shoulder is usually managed with a variety
stretch of muscles and capsular structures, would be the classic of slings during ambulation and transfer training and an arm wedge
example for poststroke nociceptive pain. In this scenario, stretch when in a wheelchair.
of muscular, tendinous, and ligamentous structures results in pain Spasticity is a common cause of poststroke pain and can affect
that is transmitted via an intact peripheral nervous system to the a variety of joints. Marked overactivity of musculature in the spas-
brain. Arrival at the poststroke brain now introduces the potential tic phase of a poststroke patient can commonly result in pain.
for alteration in signal processing with the subsequent superimposi- Both central and peripheral mechanisms are at work. The clear
tion of central neuropathic pain. central issue is the stroke that results in the development of
Neuropathic pain is caused by injury to or dysfunction of the limb spasticity. The spastic muscles in turn cause alterations in
peripheral and/or central nervous system. Its pain is typically the normal biomechanics of the limb. This may lead to pain
described as ‘‘shooting,’’ ‘‘electrical,’’ and ‘‘burning’’ in nature. from deforming forces acting across a joint. Pain serves to increase
Review of presumed pain-modulating neurotransmitters further spasticity via nociceptive input into the central nervous system.
expands the interplay between peripheral and central pain mechan- Aggressive treatment is indicated to break the spasticity-pain
isms. Neurogenic inflammation and nociception are believed to cycle. Oral antispasticity medications have a definite role in pain
play a critical role in both acute and chronic pain. The release of and tone modulation, especially if focal injection therapy with
substance P, glutamate, and calcitonin gene–related peptide chemo-denervating agents, such as botulinum toxin A, either is
(CGRP), peripherally as well as centrally, has been implicated in not feasible or is impractical. Baclofen is structurally similar to
pain modulation. Suppression of peripheral release and/or central the inhibitory amino acid g-aminobutyric acid. It suppresses the
release has the potential to dramatically rebalance the transmission release of excitatory neurotransmitters, glutamate, and aspartate.
of pain signals from the periphery to the cerebral cortex via inter- As such, it may help modulate pain that is both peripherally and
mediate processing zones. centrally mediated in addition to controlling pain by decreasing
spasticity. Limitations include the not uncommon side effect of
lethargy. Confusion can be seen in the elderly, and there is the
EVALUATION uncommon risk for hepatotoxicity. Tizanidine, an a-adrenergic
agonist, has well-established utility for treating spasticity.1 By
Given the interplay between central and peripheral pain generators, virtue of its potential influences on descending noradrenergic
a detailed history and physical examination must be performed as pathways, it can also produce pain control. Its utility is limited
by its potential to cause lethargy, orthostasis, and uncommonly A rather common pain syndrome in the poststroke patient is
elevated liver function enzymes. the painful paretic shoulder. It can be treated with EMG-guided
Botulinum toxin offers the potential for pain reduction via its botulinum toxin injections to the subscapularis muscle. If marked
inhibition of the release of substance P, glutamate, and CGRP. It is limitations are noted in glenohumeral abduction and external
also a potent modulator of spasticity via its inhibition of the release rotation, the pectoralis major can also be injected. The sternal
of acetylcholine from the presynaptic terminal of the neuromuscu- component of the pectoralis is a potent internal rotator and adduc-
lar junction. Limitations include the need for multiple injections tor of the glenohumeral joint and, when injected in concert with the
per session and the need to repeat injections every 3 to 4 months. subscapularis, can give a very satisfying result. EMG guidance is
Additional limitations include the need for accurate placement of recommended when injecting the pectoralis to avoid inadvertent
the toxin into appropriate muscles to ensure the optimal response pneumothroax and also when injecting the subscapularis to
with the lowest possible dose of toxin. This is of paramount impor- ensure placement in the muscle and not overlying soft tissue.
tance to decrease the potential for the development of antibodies to The painful spastic flexed elbow can respond well to injections of
the toxin, which can occur with frequent dosing at high doses. botulinum toxin into the biceps, brachialis, and brachioradialis.
The use of electromyography (EMG)–guided motor point blocks The determination of the resting posture of the forearm is critical
with short-acting local anesthetics can be very helpful when trying prior to initiating injection therapy. Elbow flexion with forearm
to resolve the conundrum of peripheral versus central pain genera- supination is primarily the result of biceps brachii overactivity.
tors. If the temporary relaxation of spastic muscles results in The biceps is not only a potent elbow flexor but also functionally
pain reduction, more long-term spasticity control with botulinum and biomechanically the most potent forearm supinator. Primary
toxin injections can be contemplated. If no pain reduction occurs, attention must be paid to the biceps to treat the issue. The deeper
medications with both central and peripheral pain modulation brachialis may also need to be injected to treat the spastic flexed
potential need to be considered. With experience, many regions elbow, but control of persistent supination requires specific control
of the body can be approached with botulinum toxin injection of the biceps. Elbow flexion with a neutral forearm requires that the
therapy to treat spasticity-generated poststroke pain. brachioradialis be specifically targeted. It is the most powerful
Gastrocnemius and soleus complex spasticity can result in a elbow flexor when the forearm is in a neutral position. EMG guid-
painful spastic equinovarus-postured foot. Failure to adequately ance is critical when injecting the brachioradialis to avoid inadver-
manage this can frequently lead to progressive pain, contracture, tent injection of the wrist and finger extensors because their
and loss of mobility. This triad increases the risk of developing compartment lies quite close to the brachioradialis in the proximal
chronic pain and debility. Approach to the gastrocnemius-soleus dorsal forearm. The flexed elbow with pronation requires that all
complex is easily done under EMG guidance. The soleus is located elbow flexors be targeted. In addition, the pronator teres needs to be
deep to the medial and lateral heads of the gastrocnemius. Needle injected in the proximal volar forearm to control pronation. EMG
EMG guidance can be used to find the fascial plane between guidance is critical to avoid inadvertent placement into the flexor
the superficial gastrocnemius and the more deeply located soleus. digitorum superficialis.
Once this fascial plane is located, continued advancement of the A particularly challenging region of the body is the wrist and
botulinum toxin needle to the depth of the soleus is easily accom- hand. Management requires understanding the complex biomecha-
plished. The fascial plane is represented by loss of crisp motor unit nical relationship between the wrist and the finger flexors, their
potentials as one passes through the plane with reappearance of interplay with one another, as well as their interaction with the
new crisp motor units as the soleus is entered. Failure to inject wrist extensors and finger extensors through the tenodesis effect.
the soleus will result in persistence of equinovarus posturing as Failure to appreciate this relationship will result in frustration and
well as pain and deformity. The persistent pain will in turn serve persistence of pain. In all instances, direct needle-stimulation guid-
to ‘‘wind-up’’ the spasticity, resulting in further pain and debility. ance should be utilized prior to injection of any wrist or finger
The hitchhiker’s toe, or persistent Babinski’s sign, can also been flexors or extensor muscles. A particular dilemma that the flexed
seen in the poststroke lower extremity. It is the result of constant wrist presents is one of determining whether the wrist is flexed
spastic overactivity of the extensor hallucis longus (EHL). This from wrist flexor overactivity in isolation or in concert with finger
exposes the great toe to repetitive trauma and can lead to a circular flexor overactivity. The flexed wrist posture may in fact mask some
pain-spasticity-pain cycle. EMG-guided botulinum toxin injections degree of finger flexor spasticity owing to an underlying tenodesis
of the EHL can be easily done under direct needle-stimulation guid- effect. The tenodesis effect merely describes the interrelationship
ance. Direct stimulation of the EHL muscle belly with a Teflon- between the finger flexors and the finger extensors. Namely, with
coated injection needle will ensure accurate localization of the wrist flexion, there is resultant passive stretch of finger extensors,
muscle and placement of botulinum toxin. This will allow the com- facilitating partial opening of the hand; with wrist extension, there
plete relaxation of the EHL, without potentially compromising is resultant passive stretch of the finger flexors, causing partial
function of the tibialis anterior and extensor digitorum longus, hand closure. Clearly, one can appreciate that isolated relaxation
both of which are potent dorsiflexors of the foot. of the wrist flexors without concomitant relaxation of the finger
Anterior knee pain, although not common, can be seen in indi- flexors has the potential to yield a resultant tight-fisted hand
viduals with severe spasticity of the knee flexors after large cortical because the wrist can now potentially achieve a greater degree of
strokes. Persistent knee flexion results in retropatella pain from extension. The use of EMG-guided motor point blocks to the wrist
constant high pressure between the articular surface of the patella flexors, with a short-acting local anesthetic such as lidocaine,
and the femoral intercondylar zone. Management of this syndrome allows for ranging of the fingers and wrist passively to determine
requires injection of primary knee flexors, the medial and lateral whether the flexor digitorum profunda and flexor digitorum
hamstring groups, as well as secondary knee flexors. The gastroc- superficialis are in fact spastic. If, after injection, it becomes appar-
nemius is a secondary knee flexor because it arises from the poste- ent that the flexor digitorum profunda and the flexor digitorum
rior femoral condyle region and crosses the knee joint. The sartorius superficialis are spastic, they can then be injected with botulinum
must also be targeted. With reference to the sartorius, needle EMG toxin along with the wrist flexors for long-term management.
guidance will be critical to avoid inadvertent placement of botuli- Careful placement of botulinum toxin injections should consis-
num toxin into the vastus medialis, which is a potent knee extensor. tently result in a relaxed hand that can be braced in a position
All knee extensors must be left fully intact to prevent issues of of comfort.
instability with standing activities. As such, direct stimulation of Some of the most challenging aspects of poststroke pain are the
the sartorius should always be done prior to botulinum toxin central pain syndromes. These have been classically described in
injection. thalamic level strokes but can also be seen in brainstem level lesions
334 Chapter 44 POSTSTROKE PAIN
and, less commonly, cortical lesions. Its incidence has been reported significant utility in the management of postherpetic neuralgia and
to be between 2% and 5% of stroke patients.2 painful diabetic neuropathy. Particular care must be exercised when
The phenomenon of sensitization plays a significant role in using this class of medication in the elderly. Exacerbations of car-
chronic pain syndromes. Central as well as peripheral mechanisms diac conduction anomalies, glaucoma, urinary retention, memory
drive the sensitization models. The central sensitization model pro- deficits, constipation, confusion, and orthostatic hypotension have
poses that repetitive nociceptive stimulation causes neuroplastic all been seen and reported with the use of TCAs.6
changes in the dorsal horn through the effects of substance P, glu-
tamate, and CGRP.3,4 These changes have also been implicated at
the level of the brain. Complicating the model for chronic central SUMMARY
pain is the peripheral sensitization model. In this paradigm, silent
peripheral afferents become activated after injury via the release of Anecdotal reports and case reports of antidepressants in general and
peripheral nocicpetive mediators.3-5 Activation can occur secondary antiseizure medication as a broad class have noted varying degrees
to progressive spasticity, causing persistent soft tissue irritation and of efficacy. Further research into these classes of medicals is clearly
injury. In response, neuropeptides are released from primary warranted. At the present, management of central poststroke pain
sensory terminals in the injured area. This sensitizes pain receptors remains a challenge that requires cooperation between patient and
that provide a feedback loop that sustains inflammation, pain, clinician, as well as pharmacologic creativity, if it is to be success-
spasticity, and ultimately, allodynia. fully treated.
REFERENCES
PharmacologicTreatment
1. Gelber DA, et al. Open label dose titration safety and efficacy study of
Multiple medications have been used in attempts to treat central tizanidine hydrochloride in the treatment of spasticity associated with
pain syndromes. Few, however, have been rigorously evaluated with chronic stroke. Stroke 2001;32:1841–1846.
double-blind, placebo-controlled trials. Efficacy for tramadol, gaba- 2. Devulder J, et al., Central pain: an overview. Acta Neurol Belg
pentin, tricyclic antidepressants (TCAs), and opiate analgesics has 2002;102:97–103.
been demonstrated. 3. Burstein R. Deconstructing migraine headache into peripheral and
central sensitization. Pain 2001;89:107–110.
Tramadol has shown efficacy in double-blind, placebo-
4. Week MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal
controlled, randomized studies in painful diabetic neuropathy, root ganglia neurons to clostridium botulinum neurotoxins. Toxicon
postherpetic neuralgia, and painful polyneuropathy of nondiabetic 2000;38:245–258.
etiology.6,7 As such, it may have utility in modulating pain of cen- 5. Michealis M, Habler HJ, Jaenig W. Silent afferents: a separate class of
tral nervous system etiology, although it is more commonly used to primary afferents? Clin Exp Pharmacol Physiol 1996;23:99–103.
affect peripheral nervous system neuropathic pain. Doses up to 400 6. Dworkin RH, Ginsburg B, Cohen RI. Pharmacologic treatment of
mg per day may be used. Side effects of dizziness, nausea, constipa- chronic pain in the elderly. Clin Geriatr 2004;12:S1–10.
tion, orthostatic hypotension, lethargy, and confusion in the elderly 7. Harati Y, Gooch C, Swenson M, et al. Double blind randomized trial
clearly limit its utility. There is also an increased risk of seizure of tramadol for the treatment of the pain in diabetic neuropathy.
activity in patients taking tramadol, if they have a history of seizures Neurology 1998;50:1842–1846.
8. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the
or risk factors for seizure or are taking TCAs concomitantly. treatment of postherpetic neuralgia: a randomized controlled trial.
Poststroke patients may have increased risk for seizures secondary JAMA 1998;280:1837–1842.
to possible seizure foci after their stroke, and they may also be on
TCAs.
Gabapentin has demonstrated efficacy in treatment of posther- SUGGESTED READINGS
petic neuralgia, painful diabetic neuropathy, spinal cord injury
Aoki KR, Guyer B. Botulinum toxin type A and other botulinum toxin
pain, Guillain-Barré syndrome, and phantom limb pain.6,8 Doses serotypes: a comparative review of biochemical and pharmacological
up to 3600 mg per day have been used. Side effects of somnolence actions. Eur J Neurol 2001;8(suppl):21–29.
and dizziness can limit its utility. Gait dysfunction can be exacer- Cheshire WP, Abashian SW, Mann DJ, Botulinum toxin in the treatment
bated in the elderly and is of particular concern in the poststroke of myofascial pain syndrome. Pain 1994;59:65–69.
patient because, not uncommonly, their gait is already marginal. Cui M, Aoki KR. Botulinum toxin type a (BTX-a) reduces inflammatory
Tolerance is generally good, and in general, drug interactions are pain in the rat formalin model. Abstract 369. Cephalgia 2000;20:414.
limited. Dosing does need to be adjusted downward for patients Dolly JO. Botulinum Neurotoxin: Mechanism of Action. Neurotoxin
with renal impairment. Institute; 2004; pp 1–13.
Dolly JO, Lawerence G. Mechanistic basis for the therapeutic effectiveness
Oral opiates have been shown to have effectiveness in treating a
of botulinum toxin A on overactive cholinergic nerves. In Barnes PM,
variety of central and peripheral neuropathic pain syndromes. Ward BS (eds): The Clinical Use of Botulinum Toxins, Cambridge:
Common side effects include somnolence, constipation, and Cambridge University Press, 2005.
nausea. In the elderly, issues of cognitive impairment and problems Mense S. Biochemical pathogenesis of myofascial pain. J Musculoskel Pain
with memory can profoundly limit their utility.6 1996;4:145–162.
TCAs have the longest established track record of efficacy in the Wheeler AH, Goolkasian P, Gretz SS. Botulinum toxin A for the
treatment of neuropathic pain syndromes. They have demonstrated treatment of chronic neck pain. Pain 2001;94:255–260.
Chapter 45 As these numbers suggest, the worldwide burden of the disease is

significant. According to the Morbidity and Mortality Weekly Report
PAIN AND PAIN MANAGEMENT (MMWR), published by the U.S. Centers for Disease Control
(CDC) in August 2006, 64% of the world’s HIV population lives
in sub-Saharan Africa.2 In sub-Saharan Africa, transmission is pri-
RELATED TO HIV INFECTION marily through heterosexual contact, and the proportion of infected
females is higher than that of males. In the United States, 44% of
Karan Madan and Srdjan S. Nedeljkovic¤ HIV transmission is among male homosexuals and 17% is among
IVDUs. Despite increased funding and a combined international
effort, only 20% of patients in need of antiretroviral therapy
(ART) worldwide are receiving it. Approximately 55% of patients
in the United States in need of ART received it in 2005.
Developing a vaccine against HIV infection is difficult because of
the variability that exists among the different strains of the virus. The
INTRODUCTION variability among these strains is manifested in their viral envelope.
Because immunization directs antibodies against the viral envelope,
Pain is one of the unfortunate consequences of human immunode- the difference among strains, as well as their propensity to mutate,
ficiency virus (HIV) infection. It is a highly prevalent symptom in presents a considerable challenge to developing an effective vaccine.1
this population but is frequently underdiagnosed and often poorly
treated. Understanding of pain management in the HIV-infected
population requires knowledge of the epidemiology and pathogen- PATHOGENESIS AND
esis of the disease as well as a familiarity with its treatments. PATHOPHYSIOLOGYOF HIV
In addition, because patients are living longer lives with this disease,
it is important to understand the considerations for postoperative The HIV pathogen causes immunodeficiency by continued replica-
pain management in HIV-infected individuals. tion and infection of cells expressing the CD4 antigen, which plays
This chapter reviews an approach to pain management for an important role in cell-mediated immunity. HIV replicates within
patients who have HIV infection. This includes a summary of the the host cells using RNA-dependent DNA polymerase. Viral repli-
various etiologies for pain found with this disease as well as several cation causes cell fusion or cell death. A latent state can be reached
treatment philosophies and paradigms. A special consideration is in which the viral genome can be integrated into the cell genome.
given to understanding the issues in pain management for patients The function of B-lymphocytes and macrophages is also affected by
who have a history of substance abuse and patients in the pediatric the virus, causing humoral and cell-mediated immunodeficiency.
age group. B-lymphocyte dysfunction can cause autoimmune, hypersensi-
tivity, and allergic reactions. Infection with HIV and the ensuing
immunodeficiency and hypersensitivity it causes can affect any
ETIOLOGYAND EPIDEMIOLOGYOF HIV organ system in the body. The time between the introduction of
infection and the development of symptoms can be 10 years.
Acquired immunodeficiency disease (AIDS) was first recognized in Patients can initially develop nonspecific complaints such as persis-
1981 among homosexual young men with Kaposi’s sarcoma and tent fever of unknown origin, night sweats, unexplained weight loss,
Pneumocystis carinii pneumonia. Cases were later reported among anorexia, and nausea. Some tumors and infections are more likely
intravenous drug users (IVDUs) and patients with hemophilia. In with a lower CD 4 count and a higher degree of immunodeficiency,
1984, it was determined that the causative agent for the disease whereas other infections and tumors are unrelated to the CD4
is what is now called the human immunodeficiency virus type 1 counts (Table 45–1).3
(HIV-1). HIV-2 was identified in 1985 in healthy prostitutes from
Senegal. HIV-2 seems to have slower transmission and progression
than HIV-1. However, the manifestations of end-stage disease for
both strains appear to be similar. TREATMENT FOR HIV
HIV is transmitted through sexual contact, parenteral exposure to
contaminated blood and blood products, and perinatally from ART
mother to infant during gestation, delivery, and breast-feeding.
Occupational transmission is known to occur through percutaneous Numerous ARTs have been developed to combat HIV infection
exposure, usually via puncture by a needle or sharp object, or by (Table 45–2). Highly active antiretroviral therapy (HAART) is a
contact of mucous membranes or non-intact skin with infectious regimen composed of multiple anti-HIV drugs prescribed to
fluids. Postexposure prophylaxis with antiretroviral drugs has con- HIV-positive individuals before they develop symptoms of AIDS.
siderably reduced the risk of infection from occupational exposure. The regimen usually includes a combination of one protease
As of December 2007, the total number of people infected with inhibitor, one nucleoside analogue, and either a second nucleoside
HIV was around 33.2 million worldwide, according to the UNAIDS analogue or a nonnucleoside reverse transcriptase inhibitor
(United Nations Programme on HIV/AIDS) epidemiologic survey (NNRTI). Studies have shown that this type of therapy can suppress
(Fig. 45–1). The number of new infections worldwide in 2007 was viral replication and prevent the emergence of drug-resistant muta-
2.5 million, of which there were 46,000 new infections in North tions, suggesting that lifelong suppression is possible.4
America. Worldwide, there were 2.1 million deaths related to HIV/ Drug therapy–related pain syndromes add to the challenge of
AIDS, of which 21,000 were in North America.1 These numbers are treating pain in an HIV/AIDS patient. Some studies have shown
approximate. that starting anti-HIV therapy when CD4 counts are above 200
336 Chapter 45 PAIN AND PAIN MANAGEMENT RELATED TO HIV INFECTION
Figure 45^1. Prevalence of HIV infection. (Reprinted from UNAIDS (2008). Report on the global AIDS epidemic.Joint United Nations Programme
on HIV/AIDS.Geneva, UNAIDS, August 2008, Media Kit.Core slides: Global summary ofthe HIV and AIDS epidemic, 2007. Available at http://
www.unaids.org/en/KnowledgeCentre/HIVData/GlobalReport/2008/2008 -gr-mediakit.asp [accessed August 5, 2008].)
cells/mm3 is associated with less morbidity from the disease.5 and spinal epidural lipomatosis. Neuropsychiatric disturbances—-
However, because a clear clinical benefit to early therapy remains such as suicidal depression, manic behavior, agitation, and aggres-
to be established and owing to the numerous side effects of these sion—can result from the use of efavirenz.
drugs, most guidelines suggest only that patients consider therapy.4 The usual recommended starting therapy for HIV infection is
Patients may have poor tolerance for treatment with antiretroviral two nucleoside reverse transcriptase inhibitors (NRTIs) with a third
drugs owing to their numerous adverse effects.6 However, the risks drug that may be either a protease inhibitor or an NNRTI.8 The use
of stopping therapy are often higher than the risks of continuing of NRTIs may be complicated by the development of lactic acidosis,
therapy, because patients can develop drug-resistant mutations of which can cause symptoms of abdominal pain. Efavirenz is the
the virus. Examples of pain syndromes that can result from side preferred NNRTI, but it may cause central nervous system (CNS)
effects of treatment with these drugs are myalgias and myopathies, side effects and should be used with caution with patients with
pancreatitis, peripheral neuropathies, and myelopathy with spastic- active substance misuse.4 Ritonavir is a protease inhibitor that inhi-
ity (see Table 45–2).4,7 Patients may also develop lipodystrophies bits the cytochrome-P450 (CYP450) CYP3A enzyme, and its use
with other protease inhibitors prolongs both their duration of
effect and their efficacy. In July 2006, the U.S. Food and Drug
Administration (FDA) approved a new once-a-day combination
Table 45^1. Relationship between CD4 Cell Counts drug therapy medication called Atripla. Atripla combines efavirenz
and the Development of Diseases in 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate
HIV-infected Patients 300 mg for the treatment of HIV-1 infection in adults.
Unrelated to CD4 CD4 Counts CD4 Counts

Counts 50^200 cells/ml3 < 50 cells/ml3 Therapies for Malignancies and Opportunistic
Infections
Tuberculosis Toxoplasmosis Histoplasmosis
Herpes simplex Pneumocystosis Disseminated HIV-positive patients with advanced disease, high viral loads, and
Herpes zoster Cryptococcosis Mycobacterium low CD4 counts are vulnerable to many opportunistic infections
Kaposi’s sarcoma Coccydiomycosis avium such as Pneumocystis jiroveci infection, Mycobacterium avium
Hairy cell Cryptosporidiosis Cytomegalovirus complex (MAC) infection, toxoplasmosis, cryptococcal meningitis,
leukoplakia retinitis Cytomegalovirus (CMV) infection, candidiasis, herpes simplex
Vaginal Central nervous infection, and herpes zoster. When possible, infections in HIV-
positive individuals are treated with appropriate antibiotics.
candidiasis system
Prophylactic antibiotics can also be offered for some of these patho-
Pseudomonas lymphoma gens if the patient’s CD4 count falls below a certain level.
pneumonia Patients with HIV infections are also more likely to develop
Haemophilus malignancies. Lymphomas are one common malignancy in this
influenzae population, and their treatment may include surgery, chemother-
pneumonia apy, and/or radiotherapy. Kaposi’s sarcoma is another common
tumor in the HIV-infected patient, and it can manifest itself as
From Carr DB, Goudas LC. Evaluating and managing pain for patients limited or diffuse cutaneous lesions or as visceral disease. Kaposi’s
with HIV/AIDS: an overview. In Nedeljković SS (ed): Pain Management, sarcoma is treated with combination systemic chemotherapy or
Anesthesia, and HIV/AIDS. Boston: Butterworth-Heinemann, 2002; radiotherapy.
pp 119–141.
Table 45^2. Antiretroviral Agents
Category Name Potential Side Effects

Nucleoside reverse Zidovudine, didanosine (ddI), zalcitabine Peripheral neuropathy (didanosine, zalcitabine,
transcriptase inhibitors (ddC), stavudine (d4T), lamivudine (3TC), stavudine, lamivudine)
abacavir, emtricitabine (FTC) Pancreatitis/hepatitis (didanosine, stavudine)
Aphthous ulcers (zalcitabine)
Nucleotide reverse transcriptase Tenofovir Renal dysfunction
inhibitors
Protease inhibitors Saquinavir, tipranavir, indinavir, nelfinavir, Peripheral paresthesias (ritonavir)
lopinavir, amprenavir, fosamprenavir, Gastrointestinal symptoms (fosamprenavir,
atazanavir, darunavir, ritonavir lopinavir, ritonavir)
Renal stones (indinavir)
Diarrhea (nelfinavir, darunavir)
Headache (darunavir)
Osteopenia and higher risk fractures (protease
inhibitor drugs)
Non-nucleoside reverse Nevirapine, delavirdine, efavirenz Neuropsychiatric disturbance (efavirenz)
transcriptase inhibitors
Entry inhibitors Enfuvirtide Local site reactions
Adapted from Deeks SG. Antiretroviral treatment of HIV infected adults. BMJ 2006;332:1489–1493; and Zolopa AR, Katz MH. HIV infection. In Tierney LM,
McPhee SJ, Papdakis MA (eds): Current Medical Diagnoses and Treatment 2007. New York: McGraw-Hill, 2007; pp 1346–1377.
Development of infections and tumors in patients with HIV pain than ambulatory patients.13 Furthermore, many studies
infection exposes these individuals to treatment with additional show that pain is poorly recognized and that patients with HIV
pharmaceutical agents, some of which have a number of adverse disease are undertreated for pain.10 This often results in deterio-
affects including nausea, neutropenia, anemia, hepatitis, drug rash, ration of quality of life for these patients and a worsening of their
Stevens-Johnson syndrome, optic neuritis, peripheral neuritis, car- psychosocial well-being.
diac toxicity, and other disorders. Other drugs can then be admi- HIV/AIDS patients differ from other patients with chronic pain
nistered to ameliorate these disorders. For example, erythropoietin in that they are usually younger and more active. A patient with
can be used for primary or drug-induced anemia in HIV. Human pain related to HIV infection is more likely to experience psycho-
granulocyte colony–stimulating factor (G-CSF) and granulocyte- logical feelings of isolation, frustration, and social withdrawal. Being
macrophage colony–stimulating factor (GM-CSF) have been infected with an incurable disease adds significantly to psychological
shown to increase neutrophil counts, especially in patients receiving distress for the HIV-infected patient. These emotions can lead to
chemotherapy for Kaposi’s sarcoma. hopelessness, pain, despair, and anger.
Pain management for HIV-infected patients can be offered in an
outpatient or, in some cases, an inpatient setting with a multidisci-
APPROACH TO PAIN MANAGEMENT IN plinary approach. The goal of treatment is to improve functional
HIV/AIDS PATIENTS capabilities as well as pain relief. Patients are taught to develop
coping skills and to modify adverse pain behaviors, resulting in
Patients with HIV/AIDS experience pain either directly from the greater independence and insight into the disease process. Pain-
disease process and related tumors and infections or as an adverse management programs should also offer vocational rehabilitation
affect from their antiviral medications and other treatments. Some so that patients can return to the workforce and once again become
patients may also have pre- or coexistent chronic pain states. productive members of society.
Historically, pain in HIV patients has been grossly unrecognized
and undertreated. However, treatment of pain in HIV patients
has improved recently, along with the increased willingness on PAIN SYNDROMES AND THEIR CAUSES
the part of physicians to consider the use of opioids as a component INHIV INFECTION
of management.
Approximately 50% of HIV-infected patients have pain that Pain in patients with HIV/AIDS infection can be caused by the
interferes with the quality of their life, as confirmed by studies by direct effects of the virus, opportunistic infections, and tumors
Hewitt and coworkers,9 Breitbart and associates,10 and and as a side effect of antiviral medications. The nature of the dis-
Nedeljković.11 Often, the incidence of pain increases in patients ease itself and the pain that results from it lead to profound changes
with the progression of disease symptoms and a decrease in CD4 in quality of life, physical functioning, and psychosocial distress.
T-lymphocyte counts. Despite the possibility that pain symptoms The following sections review the major types of pain that can be
can be caused by antiviral medications, patients who were not found in HIV-infected patients.
being treated for HIV infection reported more pain. In an
end-of-life hospice setting, where many patients had highly
advanced HIV disease, 93% reported pain.12 Of these, 88% Visceral Pain
received opioid medications for analgesia and 62% experienced
pain relief from this form of treatment. Overall, studies show that The incidence and prevalence of visceral pain are variable in HIV
hospitalized patients with HIV infection have a higher rate of disease. In a study by Hewitt and coworkers,9 15% of patients had
visceral pain. Newshan14 described abdominal pain in 26% of HIV- abdominal pain. Antiretroviral drugs may also cause enteritis.
infected patients. Pain not related to HIV may be due to bowel intussusception,
The direct effects of HIV infection can cause oropharyngeal and appendicitis, peritonitis, ectopic pregnancy, ileus, and bowel perfo-
esophageal pain owing to herpes simplex, aphthous ulcers, CMV- ration. The diagnosis may be confirmed by CT scanning.
related ulcers, candidiasis, Kaposi’s sarcoma, and histoplasmosis. About one third of HIV patients may have anorectal problems.20
Oropharyngeal and esophageal pain in HIV patients not directly Anorectal disease is more prevalent among homosexual patients
related to the virus can be due to dental abscess, gingivitis, stoma- and is associated with increased risk of anal carcinoma, Kaposi’s
titis, vitamin B deficiency, streptococcal infection, gastric reflux, sarcoma, and lymphoma. Patients usually have ulceration and com-
and esophageal spasm.11 Herpes simplex esophagitis is found in plain of pain in the anorectal area, along with lumps, bleeding,
patients with low CD4 counts.15 Patients with esophagitis experi- discharge, or pruritus. Anal condylomas are the most common
ence chest pain and odynophagia. Further complications may lead pathologic finding, and 10% of these may be associated with neo-
to herpetic pneumonia or visceral dissemination. Esophageal bleed- plasia.21 Painful ulcers are seen with herpes simplex or CMV infec-
ing can occur in up to 25% of such cases. Herpes esophagitis can tion. Barrett and associates22 found that pain was the most common
be introduced iatrogenically through nasogastric insertion of tubes. symptom for HIV patients with perianal disease. Common disor-
In herpes esophagitis, discrete vesicles join to form superficial broad ders causing anorectal pain were condylomas, fistulae, fissures,
ulcers. Up to 70% of patients show rapid clinical response to abscesses, and neoplasms. Patients with anorectal disease related
acyclovir. The incidence of candidal esophagitis in HIV disease to HIV infection have a higher risk of cancer, mainly squamous
varies from 40% to 93%. White exudative plaques and mucosal cell and cloacogenic carcinoma. Even after treatment of the anorec-
hyperemia are seen endoscopically, and biopsy shows mucosal infil- tal disease, patients with HIV are at a higher risk for recurrence of
tration by fungi. CMV infection causes distal esophagitis with large these problems.
deep linear ulcerations, and biopsy results reveal CMV inclusions in Acute surgical abdomen in a patient with HIV disease can be
endothelial cells. Aphthous ulcers can occur early in the course of caused by HIV-related infection, bowel obstruction, perforation,
HIV disease. Patients present with dysphagia, rash, headaches, night and neoplasms of the gastrointestinal tract.23 The most common
sweats, and lymphadenopathy. Tumors, Kaposi’s sarcoma, and gastrointestinal neoplasms in the HIV population are Kaposi’s
other opportunistic infections may also cause aphthous ulcers. sarcoma and non-Hodgkin’s lymphoma. Patients may experience
Biopsy reveals chronic inflammatory infiltrate without fungal severe abdominal pain with misleading localizing signs owing to
organisms. their immunosuppression, debilitation, and concurrent antibiotic
Abdominal pain in HIV disease can be caused by CMV infec- use. CT scanning is the best modality for assessment of AIDS-
tion, lymphoma, and mycobacterium infection. Other causes for related abdominal pain. Abdominal malignancies related to HIV
pain in this population include peptic ulcer disease, hiatus hernia, infection are treated with oncologic therapies along with ART,
and gastritis. Pancreatic pain in HIV may be caused by cryptospor- which improves survival.24 A potentially severe side effect of
idiosis, P. carinii, CMV infection,16 toxoplasmosis, and pancreatic NRTIs, such as stavudine, didanosine, and zalcitabine, is the
invasion by Kaposi’s sarcoma or lymphoma.11 Pancreatic pain may development of lactic acidosis, which can cause abdominal
also be due to causes unrelated to HIV infection, such as alcohol pain, nausea, diarrhea, and abdominal distention.25 In develop-
ingestion, certain drugs, hyperlipidemia, and biliary tract disease. ing nations, opportunistic Mycobacterium tuberculosis infection is
Treatments for HIV, including pentamidine, isoniazid, and didano- the major cause for abdominal pain and surgery in the HIV
sine, may also cause pancreatitis. Drug therapy is the most common population. In a study from Italy, the primary diagnoses
cause for pancreatitis in HIV.17 Pancreatitis is more likely with found in patients with HIV infection who had acute abdomen
multidrug regimens. Overall, about 20% of HIV patients develop were lymphoma, CMV infection, and MAC infections.26 Dull,
pancreatitis.16 Clinically, patients with pancreatitis have symptoms diffuse pain along with diarrhea in HIV-infected patients is usu-
of nausea, vomiting, abdominal pain, and epigastric tenderness. ally caused by infectious enteritis. Acute severe abdominal pain
Laboratory tests reveal elevated lipase and/or amylase levels. can be caused by bowel perforation or peritonitis. Pain accom-
The development of pancreatitis in this population seems to be panied by nausea and abdominal distention may be due to
related to the duration and progression of HIV infection. obstruction.
Biliary tract pain in patients with HIV disease may be caused by
biliary obstruction that occurs with MAC infection, Kaposi’s sar-
coma, cryptosporidiosis, lymphoma, Campylobacter infection and HIV Peripheral Neuropathy
CMV infection.11 Biliary disease most commonly occurs in patients
with low CD4 counts. Pain may also be due to biliary stone disease. Peripheral neuropathy in an HIV-infected person can be due to the
Sclerosing cholangiitis can cause refractory right upper quadrant or disease process itself or to infections or malignancies or can occur as
midepigastric pain in HIV patients.18 Abnormalities include papil- a consequence of drug therapies. The virus itself can cause neurop-
lary stenosis and intrahepatic and/or extrahepatic sclerosis. athy in the form of distal sensory polyneuropathy (DSP), whereas
Cryptosporidia, CMV, and microsporidia are the most common drug therapy can result in antiretroviral drug-induced toxic
causes of sclerosing cholangiitis. Ultrasonography and computed neuropathy (ADTN).27 Up to 30% of patients with HIV/AIDS
tomography (CT) scanning may reveal a dilated biliary tree with develop a neuropathy, most often eliciting symptoms of foot
papillary stenosis. Treatment of biliary pain can be with analgesic pain.28 On autopsy, nearly all patients with AIDS have pathologic
medications, sphincterotomy and biliary stenting, and celiac plexus evidence of DSP. In some cases, DSP may not be caused by HIV
block. infection alone but may be attributed to nutritional deficiencies,
Sclerosing mesenteritis has also been reported in HIV disease.19 CMV infection, advanced age, alcoholism, or any other coexisting
This is a benign mesenteric lesion with fat necrosis, fibrosis, and condition known to cause peripheral neuropathy, such as diabetes
chronic inflammation that presents as recurrent abdominal pain, or vitamin B12 deficiency.27
vomiting, and weight loss. The diagnosis is made by laparoscopy, Drug therapies may also cause peripheral neuropathies. The di-
and the condition is treated with steroids. Tamoxifen may also be deoxynucleoside family of nucleoside-analogue reverse-transcrip-
useful. tase inhibitors such as stavudine (d4T), zalcitabine (ddC), and
Organisms such as Cryptosporidium, MAC, Shigella, didanosine (ddI) can result in ADTN.4 Neuropathy occurs in up
Salmonella, Campylobacter, Clostridium difficile, Entamoeba histo- to 20% of patients and usually occurs after several weeks of treat-
lytica, Cryptococcus, Microsporidia, and Giardia lamblia may ment. Symptoms are more likely as the dose and duration of drug
cause lower abdomen pain. Diarrhea may accompany colicky therapy increase and are worse in patients with other risk factors
for neuropathic pain. The mechanism of nerve injury is believed to

be through mitochondrial toxicity. Box 45^1 PHARMACOLOGIC MODALITIES FOR THE
Histologically, both DSP and ADTN are due to dying-back axo- TREATMENT OF HIV-RELATED
nopathy and distal axonal degeneration.27 There is pathologic NEUROPATHIC PAIN
degeneration of long axons affecting both myelinated and nonmy-
elinated nerve fibers, with reduced numbers of dorsal root ganglion NSAIDs
neurons.29 Toxicity may be induced by the HIV glycoprotein 120, Antidepressants
which also may be a ligand for receptors expressed by dorsal gan- Antiepileptic medications
glion cells.30 The neural pathways for pain are the same as for other Antidysrhythmic agents
peripheral neuropathies. Peripheral ectopic neuronal activity result- Nonopioid analgesics
Opioid analgesics
ing from nerve degeneration causes paresthesias to occur, and Topical anesthetics
secondary central sensitization develops that causes hyperalgesia.27
Disturbances can occur in the balance between the facilitation and NSAIDs, nonsteroidal anti-inflammatory drugs.
the inhibition of nociceptive impulses in the descending and

peripheral pathways, and this cascade of events can cause neuro-
pathic pain that may last for years.
In the early stages of HIV infection, a condition known as mono- to support the efficacy of these interventions. Interventional
neuritis multiplex can result from an autoimmune vascular lesion. pain-management injection techniques, as discussed later, can also
It is marked by a distal, predominantly sensory and axonal neurop- be used for management of HIV-related peripheral neuropathy.
athy that produces sensory symptoms such as burning pain and
reduced sensation. Motor weakness, if any, is usually mild, but it
can occur in advanced cases. Later, as the HIV infection advances, Headache and CNS Lesions in HIV
mononeurtis multiplex can be concurrent with multifocal CMV
and has a progressive and malignant course.11 Headache is the most common pain found among HIV patients,
Pain is the major presenting symptom of HIV-related peripheral with nearly 50% of patients having this complaint.9 Headache can
neuropathy. Patients usually have symptoms of symmetrical, bilat- be caused by opportunistic infections like cryptococcal meningitis,
eral painful paresthesias, dysaesthesias, and/or allodynia of the CMV encephalitis, cerebral toxoplasmosis, and other CNS infec-
lower extremities. As the course of the disease progresses, patients tions. In some patients, mental status changes can accompany the
may complain of similar symptoms in the upper extremities. headache, especially for patients with diffuse disease. Mass lesions
Neuropathic pain often occurs in combination with neurocognitive such as brain abscesses and neoplasia can cause headache. Aseptic
problems including sleep disturbances and depression. meningitis from HIV infection itself can cause chronic headache as
On physical examination, the skin of HIV-infected patients well as cranial nerve palsy. Patients with HIV infection frequently
with neuropathic pain may show trophic changes with hair loss are subject to diagnostic spinal taps and may suffer from post–dural
and thinning in the region with pain. The skin color may puncture headaches. Herpes simplex virus can cause subacute
change to a dusky rubor, and these changes may be accompanied encephalopathy with headache. Sinus infections can also manifest
by pedal edema in the dependent position. There may also be as headache. Tension headaches and migraines can be exacerbated
distal muscle weakness and muscular atrophy as the HIV disease by psychosocial distress, which may be a factor in many patients
advances. Neurologic examination of the affected extremity infected with HIV.
may reveal diminished pain and temperature sensation, whereas Side effects from medications commonly used in HIV patients
proprioception is usually intact. Deep tendon reflexes may be can be a cause for headache. Drugs such as zidovudine, foscarnet,
decreased or absent. Nerve conduction studies and electromyogra- interferon, sulfonamide, amphotericin B, acyclovir, atovaquone,
phy may be used to further confirm and document neurologic fluconazole, and ketoconazole are known to cause headache.
deficits. Although headache is a common symptom in patients with HIV
Peripheral neuropathy related to HIV infection is difficult and infection, it does not predict progression of neurologic disease.
challenging to treat. The prevalence of peripheral neuropathy However, the neurologic manifestations of HIV disease increase
in HIV-infected patients is rising because there are more people with progression of the disease.
living with the disease and using potentially neurotoxic drugs. The etiology of a headache may be difficult to diagnose in an HIV-
The development of drug-induced ADTN poses a particularly infected patient. Radiologic images may help find mass lesions but do
difficult challenge for patients because it is usually not prudent to not give tissue diagnosis, which requires a biopsy. Lumbar puncture
stop medications against the HIV infection. Overall, about 10% of can be used to obtain spinal fluid to help ascertain a diagnosis.
HIV-infected patients stop ART owing to the side effect of intoler- Because cerebrospinal fluid cell counts and total protein levels can
able pain that results from the treatment. Cessation of therapy, be confounded by HIV infection, it is more useful to use organism
however, does not always lead to resolution of pain related to specific tests such as cerebrospinal fluid culture and polymerase
peripheral neuropathy. For some patients, pain symptoms can chain reaction to diagnose CNS infection in these patients.
worsen for months after stopping drug therapy. This period of
worsened pain is called the ‘‘coasting period.’’ In other patients,
when a drug is discontinued, it may take 4 to 6 weeks for resolution Musculoskeletal and Rheumatologic Pain
of the neuropathy.3,7,11,27
There is no FDA-approved pharmacologic therapy specifically Joint pains such as arthritis, arthralgia, or painful articular syn-
for the treatment of neuropathic pain due to HIV infection although drome occur in 31% of patients infected with HIV, as reported
patients are often given trials of drugs typically used to treat by Hewitt and coworkers.9 Muscle pains in the form of myalgia,
general neuropathic pain (Box 45–1). However, pain due to the neu- myositis, and dermatomyositis occur in 27% of HIV-infected
rologic complications of HIV infection often responds poorly to patients. Around 20% of HIV-infected patients complain of bone
traditional drugs used to treat neuropathic pain of other causes. pain and 8% have soft tissue pain. Overall 71% of HIV-infected
Nonpharmacologic cognitive-behavioral therapies such as med- patients complain of some kind of somatic musculoskeletal pain.
itation, relaxation therapy, hypnosis, and biofeedback can be useful Septic complications, including pyomyositis, osteomyelitis, and
measures to help with pain control in patients who have infected joints, are common.31 Surgical drainage, in addition to
HIV-related neuropathic pain. Unfortunately, there are little data antimicrobial therapy, is often necessary.
Arthralgias can be caused by HIV itself, avascular necrosis, skin integrity and to bedding conditions is necessary to prevent
psoriatic arthritis, Reiter’s syndrome, and medications such as rifa- the formation of pressure ulcers.
butin, dideoxycytidine, and pyrazinamide. Joint pain in patients
with reactive arthritis and Reiter’s syndrome can be severe, and
cutaneous manifestations are often more prominent. Nonsteroidal Evaluation and Management of the
anti-inflammatory drugs (NSAIDs) have been the mainstay for Substance-abusing Patient
treatment of painful articular symptoms. Corticosteroids are usually
not helpful in reducing disease manifestations, although steroids It is recognized that there is a high incidence of HIV infection in
and NSAIDs can help patients with mild cases. Drugs such as IVDUs, and this patient population may be more difficult to treat,
tetracycline and sulfasalazine have been known to reduce the especially with implementation of opioid therapy. Several studies
duration of symptoms. Anti–tumor necrosis factor (anti-TNF) concluded that the prevalence of pain in HIV-infected patients is
modifiers such as etanercept and infliximab can be used for the same regardless of whether they use intravenous drugs or
refractory disease, but these drugs can also adversely affect the not.9,32 However, drug abusers with HIV infection are more likely
immune system. Psoriatic arthritis in HIV simultaneously causes to be undertreated for their pain symptoms than other HIV patients
severe pain in the skin and joints and erosive changes and crippling who do not inject drugs.
deformity. When evaluating an HIV-infected patient with a history of drug
Painful myopathies and flulike myalgias can occur in early HIV abuse for the appropriateness of opioid therapy, it is important to
infection. Myopathies can be inflammatory in nature, sometimes set guidelines that must be followed by the patient to receive
occurring early in the course of disease, or a result of toxicity due to this type of therapy. Patients may be asked to sign an ‘‘opioid
ART. Often, they are characterized by proximal muscle weakness as contract’’—an agreement to abide by certain treatment expecta-
well as pain and muscle tenderness. Muscle wasting occurs in later tions, to not use illegal drugs, and to use prescription drugs only
stages of the disease. Polymyositis occurs in all stages of HIV and legally and appropriately. The treatment agreement may set limits
may be caused by HIV itself or by microsporidia infections, illicit so that patients will have only one opioid prescriber, will utilize only
drug use, alcohol use, or medications such as isoniazid (INH), one pharmacy, will not call for early refills or during ‘‘off hours,’’
rifabutin, interferon, zidovudine, and stavudine. Myositis can be and will submit to urine testing and a continued psychological
induced by zidovudine (AZT), and it may occur 3 to 21 months evaluation. Because some patients with substance abuse histories
after the start of treatment. Myalgias and polymyositis caused by who require opioids to manage pain may be tolerant to these
zidovudine can improve by stopping the drug, usually within 1 to drugs, they may require higher starting and maintenance doses.
2 weeks after cessation. Also, patients may have musculoskeletal However, there is no evidence that higher-dose therapy necessarily
pain from other coexisting morbidities such as osteoarthritis improves pain outcomes, and inappropriate dose escalation should
and Lyme disease. Overall, approximately 25% to 50% of patients be avoided. In some cases, patients may benefit from frequent reas-
with HIV-related myopathy require analgesics to treat myalgia- sessment, such as weekly clinic visits, and receive prescriptions for
related pain.11 only a short duration at a time.
For a number of reasons, physicians addressing the issues of
pain in HIV-infected patients may be reluctant to prescribe opioids.
Genitourinary,Cardiopulmonary, Dermatologic, This may be due to bias originating from beliefs about gender, race,
and Other Symptoms substance abuse history, sexual orientation, and socioeconomic
class. Physicians may also have concerns about the effectiveness
Pain in the genitourinary system also occurs commonly in HIV- and adverse side effects of opioids in general, as well as worry
infected patients. Genitourinary pain can be caused by cystitis, about the potential for addiction and drug abuse. This reluctance
herpes simplex, epididymitis, and bartholinitis. Treatment with to treat patients with opioids may be compounded by various
the protease inhibitor indinavir can cause renal stones and pain ethnic, social, and cultural factors that may lead to underreporting
from renal colic. Pelvic pain syndromes in patients with HIV infec- of pain by some groups of patients. To address these issues, it is vital
tion can be due to pelvic inflammatory disease, uterine fibroid to make efforts in communication and education of patients to
tumors, bladder infections, and ovarian cysts. Herpes simplex can improve pain relief.
cause genital ulceration, and a high incidence of cervical neoplasia
has been found in women with HIV infection.
Cardiopulmonary pain is a more common finding in HIV Other Special Issues in HIV Pain
patients with late-stage disease. Over 20% of HIV-infected
patients have cardiopulmonary pain. Some of the causes for A number of other special considerations warrant attention in eval-
cardiopulmonary pain in this population are pneumocystis and uating an HIV-infected patient who has pain. A group of HIV-
bacterial pneumonias, tuberculosis, aspergillosis, Kaposi’s sar- infected individuals deserving special mention is women with this
coma, pneumothorax, and pulmonary embolism. Pericarditis is disease. In addition to gynecologic-based pain syndromes related to
another reason for cardiopulmonary pain, and it may result HIV, women with HIV experience pain more frequently and at a
from toxoplasmosis, CMV infection, MAC infection, lymphoma, higher intensity than men.9,33 Evidence shows that women and
herpes, and cryptococcal infection. Endocarditis can be caused patients of a lower socioeconomic class are more likely to be under-
by Staphylococcus aureus infection. treated for their pain than males and patients in higher social
Dermatologic pain is reported by about 15% of patients with classes. Therefore, it is important to recognize that gender differ-
HIV disease. Herpes zoster, PHN, bacterial abscess, and Kaposi’s ences and gender bias may exist in the management of HIV-infected
sarcoma are some of the causes of skin pain. Varicella-zoster virus individuals.
reactivation is more common in patients with HIV who have more Although there are no objective ‘‘pain markers,’’ HIV-infected
advanced disease and CD4 counts less than 200 cells/mm3. patients will tend to have more pain complaints as their immune
Treatment is with antineuropathic pain medications such as tricyc- system weakens. Therefore, CD4 counts and viral burden should be
lic antidepressants, anticonvulsants, topical lidocaine patches, tra- elicited and documented as part of a comprehensive pain evaluation
madol, and opioids. Patients with end-stage HIV infection may for HIV-infected patients. It should be recognized, however, that
complain of total body pain. This type of pain can be treated the evidence of correlation between CD4 counts and pain is variable.
with NSAIDs and opioids, although psychological, spiritual, and A number of studies concluded that pain syndromes increase
emotional support are of critical importance as well. Attention to with the progression of HIV disease. Immunosuppression from
HIV allows dormant viruses to become active and cause various 2. Phases in which acute, episodic, procedure-related or chronic
infectious pain syndromes. As such, the incidence of pain is reported stable patterns may predominate.
to be higher for inpatient and hospice patients than for ambulatory 3. The presence of comorbidities such as herpes zoster or altered
HIV-infected patients. Conversely, patients with immune-based pharmacokinetics that are caused by concurrent disease or
painful diseases such as rheumatoid arthritis and systemic lupus medications.
erythromatosus may experience decreased pain symptoms because 4. Worsening of suffering because of pain.
they develop reduced CD4 counts and T-cell function with HIV 5. Psychosocial issues including isolation, depression, and others.
disease progression. Similarly, an immune reconstitution inflamma-
tory syndrome can result in patients who have a potent response to For the management of cancer-related pain, consistent evidence
ART, and this syndrome may be accompanied by pain.34 validates the World Health Organization (WHO) ladder as a tool
for pain management.35 Because of the similarities between cancer
and HIV-related pain, the WHO ladder can serve as a good starting
PAIN MANAGEMENT IN PATIENTS point for managing HIV/AIDS-related pain.
WITHHIV INFECTION An adaptation of the WHO ladder36 for cancer pain can be seen
in Figure 45–2. The analgesic ‘‘ladder’’ offers NSAIDs or acetamin-
In many socioeconomically developed countries, the availability of ophen as the first step in pharmacotherapy for pain control,
highly active multidrug regimens has reduced the viral burdens in followed by opioids typically used for relief of mild to moderate
HIV-infected patients to very low levels, thereby allowing infected pain, and then recommends opioids typically used for relief of
individuals to lead nearly normal lives. Such patients may remain moderate to severe pain. Adjuvant medications for pain manage-
free from intolerable pain syndromes related to HIV until the later ment can be used at any stage.
stages of the disease. However, not all patients respond to these However, in spite of their similarities, there are also key differ-
ARTs. Elsewhere, in more impoverished and underdeveloped ences between the cancer pain and the HIV-related pain popula-
regions of the globe, a majority of patients are subject to the full tions. One of the key differences between the two populations is
ravages of HIV, including its painful consequences. Also, even in that the HIV/AIDS population is more likely to be younger, pre-
developed countries, racial minorities, commercial sex workers, and dominantly male, and a member of a minority group. Patients with
substance abusers with HIV infection may have limited access to HIV infection are more likely to have a history of substance abuse,
ART. These patients and almost all patients in the advanced stages trauma, blood transfusions, hemophilia, or sexually transmitted
of their disease bear a significant burden of pain among their other diseases. For cancer patients, there is a possibility of ‘‘cure’’ at the
disease symptoms. Along with the lack of ART options, optimal time of diagnosis of many malignant diseases. However, with HIV
pain evaluation and management may not be available to most of infection, despite increased survival, there is as yet no cure.
the patients in developing and underdeveloped countries and in Immunosuppression is a central feature of HIV/AIDS disease,
some of the marginalized communities, as described previously. whereas in cancer, it can occur as a consequence of the tumor
Equitable distribution of health care resources is a discussion well itself or its treatment. In general, however, the pain in HIV disease
beyond the scope of this chapter. is more often due to a treatable cause than that in cancer.37
The epidemiology of pain in HIV/AIDS shows that it is at least It is the consensus of many experts that a paradigm similar to
as prevalent as it is in cancer. Evaluating pain in HIV-infected the WHO cancer pain ladder may be used to treat patients with
patients can be time-consuming, complex, and costly. Ambulatory pain as a consequence of HIV infection. The first step of the WHO
HIV patients without clinically significant immunocompromise are ladder involves the use of acetaminophen or an NSAID, usually for
unlikely to have life-threatening tumors or opportunistic infections. the treatment of mild painful symptoms. Pertinent for the HIV-
If necessary, some pain problems such as herpes zoster can be
managed without extensive diagnostic investigations. The new
onset of pain in an immunocompromised HIV-infected patient,
however, can herald life-threatening disease and its cause must be Freedom
investigated and treated. A physician’s role in this situation is to cancer p from
make a timely diagnosis and avoid unnecessary and uncomfortable Opioid ain
for m
diagnostic procedures. Prevention of iatrogenic pain should be a to sev oderate
er
copriority. For patients in the terminal stages of HIV infection, as ± Non e pain 3
-op
for those with end-stage cancer, achieving comfort is usually more ± Adju ioid
vant
important than pursuing a specific diagnosis. A discussion of Pain p
end-of-life matters should take place well in advance between the or incr ersisting
practitioner and the patient and his or her family. Opio
easing
id
mod for mild
er to
± No ate pain
n-
± Ad opioid
2
Pharmacologic Management Strategies for juvan
t
HIV-related Pain Pain p
or incr ersisting
Most of the current recommendations for pharmacologic manage- easing
ment of pain in HIV/AIDS disease are based on expert opinion and
anecdotal experience, because the results of randomized, controlled Non
trials or population-based outcomes are not yet available. ± A -opioid
djuv
ant
1
Therefore, these recommendations may reflect the bias of specialists
who primarily treat inpatients in the terminal phase of disease.
No validated protocol exists to treat HIV-related pain. However, Pain
there are many similarities between cancer and HIV patients suf-
fering from chronic pain. These similarities include
1. The potential to enter a phase, after failure of curative therapy, in Figure 45^2. WHO Ladder. (FromWHO.Cancer Pain Relief, 2nd ed.
which palliation becomes a goal. With a Guide to Opioid Availability.Geneva:WHO,1996; pp 36^37.)
infected patient, acetaminophen carries a dose-dependent risk of that may be causing pain should be stopped. Progressive polyradi-
hepatotoxicity and also interacts with zidovudine.38 For all patients, culopathy, another cause for neuropathic pain in HIV-infected
the prolonged use of NSAIDs can lead to gastrointestinal, cardio- patients, presents with pain in the territory of the cauda equina
vascular, and renal side effects. The second step in the WHO ladder initially and then progresses upward, causing limb paralysis and
includes the use of opioids, such as codeine, oxycodone, hydroco- pain. In addition to drug therapy for neuropathic pain, antiviral
done, or dextropropoxyphene, typically used to treat mild to mod- drugs can be added to treatment regimen if CMV infection is sus-
erate pain. Usually, these drugs are given in combination with pected as a cause for this progressive neuropathy. Mononeuropathy
acetaminophen. Patients with more severe pain may need opioids affecting the face, foot, or wrist may occur in some patients. This
such as morphine, hydromorphone, methadone, fentanyl, or oxy- condition may resolve spontaneously within a few months with or
codone, which are typically used to control moderate to severe pain. without immunotherapy. Inflammatory demyelinating polyneuro-
A controlled-release oral or transdermal opioid may give more con- pathies are another source of neuropathic pain in this population,
sistent plasma levels to relieve constant pain. The third step of the and patients usually respond to immunotherapy.3,11
WHO ladder calls for individualized titration with round-the-clock In general, for most causes of neuropathic pain, antidepressants
dosing of analgesic medications typically used to treat moderate to have been consistently shown to help reduce painful symptoms.41
severe pain, along with extra doses for breakthrough pain. Their mechanism of action is presumed to be due to reuptake
Controlled-release formulations of morphine or oxycodone, blockade of noradrenaline and serotonin, which are important
transdermal fentanyl, and oral methadone can be used as round- pain mediators. Antidepressants may also be acting as N-methyl-
the-clock agents. For some patients, the dose and frequency of D-aspartate (NMDA) receptor antagonists and sodium channel
administering analgesic medications may have to be reduced with blockers. Tricyclic antidepressants are more effective analgesics
deterioration of hepatic or renal function. For most patients with a than selective serotonin reuptake inhibitors (SSRIs) and mixed ser-
cancer or HIV diagnosis, the long-term use of meperidine is usually otonin-noradrenaline reuptake inhibitors (SNRIs).41 However, a
inappropriate owing to adverse effects (including anticholinergic study of amitryptiline and mexilitine for painful HIV-related neu-
and epileptogenic side effects) of the accumulated active metabolite ropathy failed to show benefit.42 A recent addition of available
normeperedine. The dosing of opioids should be individualized, drugs in the antidepressant class has been duloxetine, which is a
usually starting at lower doses and then titrating to a balance of combined seritonin and norepinephrine reuptake inhibitor that has
effectiveness and side effects. been FDA-approved for the treatment of neuropathic pain associ-
A number of studies have shown that opioids can be used effec- ated with diabetic peripheral neuropathy.
tively in managing pain related to HIV. Kaplan and associates39 Anticonvulsants are another class of useful medications for the
found that treatment with sustained-release morphine resulted in treatment of neuropathic pain. For trigeminal neuralgia, carbamaz-
pain reduction, good quality of life scores, and an acceptable side epine is considered the first line of treatment.41 Oxcarbazepine, a
effect profile in 44 patients with AIDS-related pain. Doses remained more recently available related drug, has been shown to be useful
stable during the study period. Newshan and Lefkowitz40 reported for treating pain due to diabetic peripheral neuropathy.43
similar results using transdermal fentanyl. Gabapentin is an a2d-subunit voltage-gated calcium channel antag-
The adjuvant-type medications are those that are used for pain onist that has been shown to have analgesic and psychosomatic
or symptom control but that are not in the two major classes of benefit in several non–HIV-related trials.41,44,45 For patients with
analgesics, opioids or NSAIDs. Adjuvant drugs either have analgesic HIV infection, a small study using gabapentin in 19 subjects showed
properties of their own (such as antidepressants and anticonvul- significant relief for painful sensory neuropathy.46 Pregabalin,
sants), are medications that reduce the side effects of opioids which is a gabapentin analogue with higher calcium channel affinity
(laxatives, antiemetics), or are drugs that treat symptoms often and better bioavailability, has been shown to benefit patients with
associated with pain, such as insomnia, depression, and anxiety. pain from diabetic peripheral neuropathy and PHN.41,45 The only
Table 45–3 lists the various adjuvant medications and their indica- anticonvulsant shown thus far in a randomized, placebo-controlled
tions in chronic HIV-related pain management. trial to be effective for HIV-related neuropathic pain is lamotri-
Neuropathic pain occurs with a high frequency in patients with gine.47 This is an anticonvulsant that blocks voltage-sensitive
HIV infection, and it can be difficult to treat. Unfortunately, there sodium channels and inhibits glutamate and aspartate release. It
are few evidence-based proven therapies for HIV-related neuropath- seems to have greater benefit for patients with drug-related neuro-
ic pain, and treatments are based on standard pharmacotherapy pathic pain. A potential advantage of this drug is that is metabolized
generally used for neuropathic pain due to other etiologies. Distal by glucuronic acid conjugation and not the CYP450 system, so it is
symmetrical polyneuropathy occurs in 30% of HIV-infected patients less likely to interact with protease inhibitors.
and drugs such as nucleoside analogues, antibacterial agents, and There is limited evidence to support long-term opioid use for
antineoplastic agents can cause it. If possible, the suspected agent neuropathic pain, and there is no such evidence specific to the HIV-
infected population. In a retrospective review published in 2004,
Watson and colleagues41,48 reported good pain relief with opioid
therapy for 1 year in patients, most of whom had neuropathic pain.
Table 45^3. Adjuvant Medications for HIV-related Tramadol, which is a weak opioid m-agonist and a mixed serotonin-
noradrenaline reuptake inhibitor, can also be used for the treatment
Pain
of neuropathic pain.41,49
Antagonists of the NMDA receptor, of which ketamine is the
Category of Drug Typical Uses and Indications most well-known example, may have analgesic properties against
Anticonvulsants Neuropathic pain neuropathic pain, but their use is limited owing to their psychomi-
Antidepressants Neuropathic pain, depression metic side effect profile. Drugs that act more selectively at the
Benzodiazepines Anxiety NMDA receptor and that function as glutamate and glycine recep-
tor antagonists have shown promise in treating neuropathic pain,
Local anesthetics Neuropathic pain but these are still in development. Certain cannabinoids, like dro-
Corticosteroids Neuropathic pain, end-of-life care nabinol and a mucosal spray containing tetrahydrocannabinol and
Laxatives Constipation cannabidiol, have shown to have some benefit for patients with
Antiemetics Nausea central pain syndromes owing to multiple sclerosis and neuropathic
Neuroleptics Anxiety, insomnia pain.41 A number of other agents have shown promise experimen-
tally in the treatment of neuropathic pain including agents that act
as sodium channel blockers and drugs that activate G-protein– For example, a local anesthetic injection with or without cortico-
coupled receptors implicated in pain. steroid may help relieve pain in a patient who has a well-localized
Topical agents that may be helpful for localized neuropathic somatic or visceral pain of an inflammatory nature. Spinal injection
pain include lidocaine gel and the 5% lidocaine patch, which has therapies may help relieve pain from an inflamed sacroiliac joint or
been shown to provide pain relief in patients with PHN. Capsaicin from discogenic or arthritic pain that may be present in the HIV-
and doxepin cream have been shown to give good relief as topical infected patient. Lidocaine and bupivicaine are the most frequently
agents in neuropathic pain.41,45 A new formulation of both a cap- used local anesthetics. Steroids include methylprednisolone and
saicin patch and an injectable capsaicin has been shown to relieve triamcinolone. Sympathetic nerve blocks, such as celiac plexus
localized pain symptoms. and hypogastric plexus blockade, can help relieve pain from visceral
There has been evidence of benefit from the use of neurotro- causes such as those affecting the pancreas and the pelvic organs.
phins such as recombinant nerve growth factor (NGF) to treat HIV- Extreme care must be taken to avoid intravascular or intraneural
related sensory neuropathy.50 This substance modulates the activity injections of local anesthetics because these can cause catastrophic
of small sensory neurons and can stimulate regeneration of complications.
damaged fibers. In a study of 200 patients with HIV-associated Neurolysis with phenol or alcohol injections can be done under
DSP, significant improvement was seen in average and maximum radiologic guidance in HIV-infected patients with limited life
pain intensity. The beneficial effects on pain relief were dose depen- expectancy who have well-localized somatic or splanchnic pain.
dent, because subjects who received 0.3 mg/kg recombinant human Candidates for neurolytic blockade first undergo a trial injection
NGF fared better than those who received a dose of 0.1 mg/kg. of a local anesthetic to ensure that good pain relief results in the
Although there was pain relief, no improvement was seen in the area of interest. Neurolytic blockade with 5% to 10% phenol can
severity of neuropathy as measured by quantitative sensory testing, then be performed and may eliminate or reduce the need for
neurologic examination, and punch biopsy of nerve fiber density.50 frequently repeating local anesthetic injections. Celiac plexus and
Benefit from NGF therapy has also been demonstrated in the treat- hypogastric plexus neurolysis can be done for splanchnic, pancrea-
ment of drug-induced neuropathies related to ARTs.51 However, tic, or pelvic pain. Neurolysis may also be done for intractable
this agent is not clinically available at the present time. Other neu- intercostal neuralgia, although this may be complicated by the
roregenerative agents that have been studied include neuroimmu- development of deafferentation pain in the area of denervation.
nophilin ligands and prosaposin.52,53 Complications of somatic nerve neurolysis include postinjection
Limited evidence exists for the effectiveness of nonpharmacolo- dysesthesia, risk of motor weakness, disturbance in autonomic
gic therapies for neuropathic pain, including physical therapy tech- function, damage to nontargeted tissues, and sensory overlap caus-
niques, transcutaneous electrical nerve stimulation, acupuncture, ing somatic numbness.57
and cognitive-behavioral therapy. However, the use of such techni- Intrathecal drug delivery has been used with increasing fre-
ques may improve an overall sense of well-being for patients. quency as a modality of pain control. Local anesthetics and opioids
Physical therapy may help prevent functional losses in patients along with various adjuvant medications have been given directly
and is generally recommended as part of a comprehensive pharma- into the neuraxis for analgesia. Morphine is currently the only FDA-
cologic and behavioral pain-management program. approved opioid for intrathecal use via an intrathecal drug delivery
Other than neuropathic pain, certain HIV-related pain syn- device, although the use of other drugs, including hydromorphone,
dromes have their own specific treatments. In patients with late- fentanyl, sufentanil, clonidine, baclofen, and bupivacaine, is com-
stage AIDS and headache symptoms, the use of steroids has been monplace. Ziconitide is an intrathecally administered N-type cal-
found to be beneficial.54 Thalidomide has been used to treat oral cium channel blocker that has been found to have analgesic effects,
aphthous ulcers.55 In addition to systemic treatment with opioids, but its use is limited owing to its side effect profile.
oral pain can also be treated with topical local anesthetic (viscous Neuraxial analgesics can be delivered by means of epidural,
lidocaine) and anti-inflammatory solutions, along with coating intrathecal, or intracisternal infusions. These types of systems
agents (such as sucralfate) and steroids. Drugs to diminish stomach allow delivery of potent analgesics directly to the CNS or at the
acidity (such as proton-pump inhibitors) and to reduce reflux nerve roots. Exponentially smaller doses are required to produce
(metoclopramide) can help with symptoms of painful esophagitis.56 comparable levels of analgesia, thereby reducing the incidence of
For abdominal pain and enteritis, in addition to standard analgesic side effects and potentially improving analgesia. The implantation
treatments, patients may benefit from anticholinergic drugs or anti- of an intrathecal pump for spinal drug delivery is useful for patients
spasmotic and antisecretory drugs such as hyoscine butylbromide. in whom long-term pain treatment is foreseen. It is especially useful
Stool softeners and topical anesthetics may help patients with ano- in patients with opioid-responsive neuropathic pain and chronic
rectal pain problems. visceral pain, such as those with pancreatic and hepatic disease.
Appropriateness for this type of therapy is established by subjecting
a patient to a trial of intraspinal or epidural administration
Interventional Techniques for Management of Pain of opioids. Patients who achieve at least 50% pain relief are con-
in Patients with HIV/AIDS sidered reasonable candidates for implantation. Despite the lower
incidence of side effects than with high-dose opioids given systemi-
Interventional techniques for pain management include the use of cally, patients may experience complications of intrathecal drug
injection therapies and neuromodulation by spinal cord stimulation delivery, including sedation, pruritus, nausea, vomiting, urinary
and spinal delivery of drugs. These techniques may be used for pain retention, myoclonus, and reactivation of herpes simplex virus
management in patients with HIV/AIDS patients under the follow- infection.57 Other long-term complications may include reduced
ing circumstances: testosterone levels, immunosuppression, the development of intra-
thecal catheter tip masses, and osteoporosis from long-term intra-
1. The patient is not obtaining adequate pain relief despite aggres-
thecal opioid exposure. The interventional nature of these
sive pharmacologic and nonpharmacologic therapies.
procedures inherently exposes the patient to other risks such as
2. The patient is having intolerable side effects from systemic anal-
technical complications, post–dural puncture headache, nerve or
gesic medications.
spinal cord injury, and bleeding and infection. For epidural
3. The patient has a specific pain syndrome that is amenable to a
implants, complications include fibrosis at the site of catheter tip
peripheral, regional, sympathetic, or spinal/epidural nerve block-
placement and dural tears.
ade, or to spinal cord stimulation, or to delivery of drugs via
Neuromodulation by means of spinal cord stimulation with
implantable devices such as an intrathecal pump.
electric current applied directly to the spinal cord can be used to
manage intractable pain in select HIV-infected patients. The mech- Neuropsychological symptoms such as dementia, cognitive impair-
anism of analgesia is uncertain, but it is believed to be due to ment, and motor and sensory disturbances frequently coexist,
inhibition of sympathetic efferent activity or at the level of the spi- making it difficult to determine whether the etiology behind these
nothalamic tract. With spinal cord stimulation, small doses of elec- deficits is organic or psychosomatic.59,60
tric current are applied through an epidurally placed electrode. A As a part of the patient’s initial evaluation for pain management,
trial of the procedure using a percutaneous electrode should the following criteria should be included in the overall assessment:
be conducted to establish efficacy before a permanent lead is
1. Pain intensity/level of discomfort.
implanted with a subcutaneous pulse generator. When this modal-
2. Functional capacity and activity measures.
ity is successful, patients experience tingling and numbness in the
3. Mood and personality measures.
painful dermatomes being stimulated that replaces the pain sensa-
4. Substance abuse assessment.
tion with a less-noxious stimulus. Complications include bleeding,
infection, electrode migration, and loss of analgesic efficacy.57 A semistructured interview along with review of chart records will
Certainly, in the immunocompromised patient with a higher risk enable the physician to collect useful data about the patient’s con-
of infection, care should be taken to select only patients who are dition and lifestyle, including a relevant medical history, education
appropriate for these types of implantable interventions. An ongo- level, employment history, history of drug or alcohol abuse, history
ing systemic infection is considered a contraindication for implan- of psychiatric disturbance, and presence or absence of a social sup-
tation of an intrathecal drug delivery or spinal cord stimulation port structure.
system. It is important to educate patients with HIV about their pain, its
Several well-described painful conditions occur in HIV-infected treatments, and reasonable expectations of benefit from the same.
patients that may respond to injection therapies. PHN is more Along with pharmacologic and interventional therapy, patients
common in HIV-infected patients owing to a higher incidence of should be encouraged to maintain a high level of activity and exer-
herpes zoster infection and reactivation in these patients. cise and to consider techniques aimed at decreasing emotional dis-
Infiltration of local anesthetics with corticosteroids directly into tress and increasing self-esteem. Relaxation training with techniques
the affected area can help alleviate pain. The procedure may need such as diaphragmatic breathing, progressive muscle relaxation,
to be repeated a number of times and generally has a low incidence autogenic relaxation, self-hypnosis, and cue-controlled relaxation
of complications. Similarly, epidural injections with methylprednis- may reduce residual muscle tension and help to reduce pain.
olone can relieve pain in some patients who have developed PHN Supportive and cognitive-behavioral therapy are designed to
after an outbreak of shingles. Intercostal nerve blocks can also be help patients control their emotional responses to chronic pain.
performed for symptoms of thoracic PHN. The thoracic sympa- Strategies include identifying maladaptive and negative thoughts,
thetic chain can be blocked at the paravertebral site or with the disputing irrational thinking, constructing and repeating positive
epidural approach for these patients. Some of these patients may self-statements, learning distracting techniques, working to prevent
also be candidates for implantation of drug delivery systems and future catastrophizing, and examining ways to increase social sup-
intrathecal therapy. port.60 These modalities can help patients change their view of
Other indications for neural blockade in the HIV-infected pop- their pain problem from overwhelming to manageable. Therefore,
ulation include spinal pain conditions. Patients with HIV will have patients can take a more active role in their treatment and become
a typical incidence of degenerative disk disease and other arthritic proactive in their pain management, with techniques to help
conditions that affect the spine. In light of preserved general health develop strategies to manage short-term setbacks.
and prolonged life expectancy owing to ART, patients who have Group therapy presents an opportunity for the patients to share
spinal pain may benefit from injections used typically for nonin- and discuss their problems with other individuals who have
fected patients. Regarding specific pain syndromes in the HIV- common concerns and problems. Family therapy educates family
infected patient, sleeve nerve root injections with local anesthetics members about goals of the therapy and gives them an opportunity
and steroids can be performed for isolated monoradiculopathy. to share their concerns. Both modalities can be used alongside indi-
Some patients with refractory neuropathies may be candidates vidual supportive therapy in helping address pain-management
for radiofrequency dorsal root gangliotomy. issues.
Patients with HIV infection have been reported to have symp- As previously noted, physical therapy is an integral part of a
toms of complex regional pain syndrome (CRPS) type I. Local multidisciplinary team approach toward pain management for
anesthetic blocks at the corresponding sympathetic ganglion can patients with chronic pain. Physical therapy supervised by a qual-
provide symptom relief for some patients. Stellate ganglion block- ified therapist will help patients improve their level of physical
ade can be done for relief of pain in the head, neck, and upper function and activity, especially if they have been physically decon-
extremity. Lumbar sympathetic blockade can reduce pain in the ditioned owing to their pain or reluctance to exercise.
lower extremities, and hypogastric plexus blockade may improve
pain in the pelvis. Although the duration of pain relief may outlast
the duration of action of the local anesthetic, most patients have a Postoperative Pain Management for Patients
recurrence of pain and may require a limited number of repeat with HIV
injections. If the local anesthetic blocks are successful but for a
short duration, more prolonged relief may be achieved with sym- In economically developed countries, patients with HIV infection
pathectomy via percutaneous radiofrequency ablation. These are living longer owing to increased availability of pharmacologic
patients may also be candidates for spinal cord stimulation or therapies and generally improved medical care. More patients,
intrathecal drug delivery. therefore, are living long enough to manifest not only the chronic
stigmata of HIV disease but also common unrelated medical con-
ditions. As a result, it is becoming more likely that patients with
Nonpharmacologic Management of Pain in HIV disease, including those with chronic pain, will undergo either
Patients with HIV/AIDS elective or emergent surgeries.
Compared with an age-matched cohort, the HIV-infected pop-
In evaluating and managing pain in patients with HIV/AIDS, it is ulation is actually at a higher risk to develop a medical condition
important to recognize that this disease has major psycho- that may require surgery. Examples of surgical procedures done in
social implications. In this population, there tends to be a high the HIV population include surgery for resistant urinary tract
incidence of substance abuse and psychiatric comorbidities.58 infection, splenectomy for untreatable thrombocytopenia, thoracic
surgery to establish a diagnosis of unexplained lymphadenopathy, responsible for drug metabolism. The hepatic CYP450 enzyme
and bronchoscopy and lung biopsy for pulmonary complications of system is inducible by drugs such as barbiturates, carbamazepine,
HIV. Some HIV-infected patients undergo stereotactic brain phenytoin, and rifampin and by smoking and alcohol ingestion.
biopsies and craniotomies for identification and evaluation of The CYP450 system is inhibited by drugs such as cimetidine,
brain lesions. Anal and gastrointestinal surgery are common erythromycin, ketoconazole, certain calcium channel blockers, and
among HIV patients. Pregnant women with HIV are at a higher neuroleptic drugs such as fluoxetine and haloperidol. The CYP450
risk of needing cesarean section because vertical transmission of enzyme system is responsible for the metabolism of numerous
HIV to the infant has been found to occur through vaginal delivery. drugs including warfarin, digoxin, mexelitine, methadone, and
In its later stages, HIV infection frequently presents with multi- many steroids. Induction or inhibition of the system can decrease
ple-organ system dysfunction including impairments in neurologic, levels of these drugs to subtherapeutic levels or increase their effects
renal, hematologic, and hepatic function. Deranged organ function to toxic levels. For example, ritonavir is a potent inhibitor of the
affects metabolism and excretion of analgesic drugs, alters their CYP450 CYP3A enzyme, and its use can decrease the metabolism
dose-effect profile, and increases the incidence of side effects related of drugs such as benzodiazepines. Stopping or starting CYP450-
to analgesic therapy. Drug interactions may occur between the inducer or -inhibitor drugs can also change serum levels of the
medications used for pain management and those used for HIV affected drug being given. As a result, especially for HIV-infected
disease management. Despite the increase in the number of opera- patients, the careful titration and administration of all drugs is
tive procedures done for HIV-infected patients, no consensus necessary.
guidelines exist for treatment of postoperative pain in these Preemptive analgesia has been shown in some studies to
patients. As with the general population, postoperative analgesia decrease postoperative pain scores and reduce postoperative
can be administered via either systemic pharmacotherapy or regio- opioid requirement. These findings are probably applicable to the
nal analgesic techniques. Opioids are the most common class of HIV-infected population. Preemptive analgesia can be achieved
systemic analgesics used for postoperative pain control, along through various modalities. One of the newer modalities is using
with NSAIDs and muscle relaxants. In some cases, NMDA receptor a bolus of high-dose gabapentin preoperatively. In a study done by
antagonists can be used as adjuvant pain medications. Regional Pandey and coworkers in 2004,61 preemptive dosing with gabapen-
anesthesia techniques include epidural analgesia and various nerve tin was found to reduce postoperative pain scores and perioperative
blocks. Drugs generally administered by means of regional techni- opioid requirements. These findings have been corroborated by
ques include local anesthetics, a2-agonists (such as clonidine), and various studies since, and it has been suggested that using gabapen-
various opioids. tin preemptively may have long-term effects in reducing or prevent-
Intravenous patient-controlled analgesia (PCA) is the most ing the development of chronic pain after surgery. The actual dose
commonly used technique for postoperative pain control, offering and duration of gabapentin therapy required to achieve this effect,
a simple and effective method for postsurgical analgesia. The use of however, is still a matter of discussion. Preemptive analgesia can
intermittent intramuscular opioids is discouraged because it pro- also be achieved by wound infiltration of local anesthetics. Epidural
vides inadequate pain relief owing to inconsistent drug plasma anesthesia and analgesia have been found to reduce postoperative
levels. With intramuscular administration, it is difficult to pinpoint analgesic needs as well.
the dose necessary to achieve plasma drug levels that match the The use of NSAIDs effectively lowers postoperative pain by inhi-
patient’s analgesic therapeutic window. The therapeutic window biting cyclooxygenase, an enzyme that mediates the conversion of
may be narrow such that very small decreases in plasma concentra- arachadonic acid to inflammatory prostaglandins and leukotrienes.
tion of opioids can lead to severe pain in the patient; small increases However, NSAIDs are associated with many drug interactions and a
can result in good analgesia, with further small increases leading to number of well-described complications. Administration of
unwelcome side effects. Besides fear of needles and the logistics NSAIDs can increase the serum drug levels of digoxin, lithium,
involved in giving intermittent intramuscular opioids, interindivi- methotrexate, and phenytoin. Patients taking NSAIDs in the pres-
dual variability in response to these drugs poses a further challenge ence of anticoagulants are at a higher risk of bleeding. Other adverse
in providing adequate pain management. affects of therapy with NSAIDs include gastrointestinal ulceration,
A PCA system allows patients to self-administer small boluses of decreased platelet aggregation, impaired renal function, hyperkale-
opioids, resulting in a consistent and better titration of analgesia. mia, peripheral edema, hepatic dysfunction, bronchospasm, cardio-
PCA systems also allow patients to adapt drug doses to changing vascular complications, CNS alterations, bone marrow suppression,
analgesic requirements as they recover from surgery. Most studies and possibly delayed bone healing. A study by Laguna-Torrest and
have revealed there is improved analgesia with PCA, along with colleagues62 showed that preexisting renal dysfunction may be pres-
decreased or unchanged levels of sedation. Reduced delay in obtain- ent in HIV-infected patients owing to HIV itself, opportunistic
ing pain relief and more rapid delivery of medication also increases infections, and their therapeutic management. For these patients,
patient satisfaction. Institution of PCA requires a patient to have especially for older patients, the use of NSAIDs may be associated
normal cognitive function and adequate intravenous access. Most with further impairment of renal function. The various drug inter-
studies have shown that the implementation of PCA techniques actions and adverse effects of NSAIDs may limit the ability to use
leads to reduced hospital stays, improved pulmonary function, these drugs routinely for HIV-infected patients in the perioperative
and decreased costs overall. period.
Some concern exists with the use of PCA for patients who have a a2-Agonists such as dexmedetomidine and clonidine can be
history of substance abuse and who may have difficulty responsibly useful adjuvants for management of perioperative pain. An increas-
self-titrating pain medications. Although these types of patient ing body of evidence supports the use of dexmedetomidine for
issues should be considered, most practitioners agree that short- preemptive analgesia. The use of these agents may be limited
term use of a PCA device is unlikely to result in a recrudescence owing to side effects such as hypotension, bradycardia, and seda-
of an addictive disorder. Patients who are thought to be at a higher tion. Clonidine has been found effective in relieving intractable pain
risk of substance abuse should be monitored closely while PCA owing to cancer as well as neuropathic pain. Drugs such as cloni-
therapy is being utilized, with clear end-points for discontinuing dine and tizanidine can increase the analgesic efficacy of opioids
therapy and weaning opioids in the postoperative period. When and reduce withdrawal symptoms during opioid-weaning proto-
necessary, specialists in pain medicine and addiction management cols. Clonidine can be used as an analgesic when delivered as an
should be consulted. epidural or intrathecal agent.
HIV infection itself and many of the drugs used to manage it can Epidural analgesia is an acceptable technique of providing post-
alter liver function and affect the CYP450 enzyme system that is operative analgesia for patients with HIV infection. A mixture of an
opioid and a local anesthetic can be given as a continuous infusion diagnostic procedures and treatment interventions. However, pedi-
along with a PCA option. Owing to their synergistic effects, both atric HIV-related pain is more complex and its etiology is multi-
classes of drugs can be given in lower doses if used together than if factorial, because it may be due to the disease itself, secondary
given alone, resulting in improved pain control while minimizing infections and their complications, diagnostic and treatment-related
drug-related side effects. Along with the risks of bleeding, infection, procedures, and other coexistent conditions such as diabetes and
and neurologic injury seen in typical patients, HIV patients with other health problems. Hirschfeld and Moss63 discovered that 59%
severe immunocompromise or systemic infections may have a of children with HIV in their study reported pain that reduced the
higher risk of developing an epidural infection. Peripheral nerve quality of their lives. Chambers and coworkers64 reported that care-
blocks can be used for short-term postoperative analgesia. The anal- givers often underestimate their HIV-infected child’s pain. Similar
gesic effects of regional anesthetic techniques can be prolonged by to findings in the adult literature, pain related to HIV infection in
introducing continuous-infusion catheters at the nerve block sites. children is believed to be underreported and poorly treated.
Because HIV-infected patients can experience bone marrow As with adults, pain in pediatric patients is reported to increase
changes, virus-related thrombocytopenia, and other abnormalities with increased immunosuppression (Table 45–4). In a study by
of the coagulation cascade owing to liver dysfunction, it is impor- Gaughan and associates,65 a decreased incidence of pain from 46%
tant to assess coagulation and the hemostatic system prior to to 29% was found over a 4-year period with increased use of protease
attempting any regional techniques and surgery. inhibitors. Pain was reported to increase with decreased CD4 counts.
Similar to other patients with chronic pain, HIV-infected patients Females were 49% more likely than males to report pain. Children
who need surgery and who are taking opioids preoperatively may below the age of 5 were least likely to report pain, whereas pain was
exhibit tolerance to routine doses of opioids given postoperatively. being reported with a 60% higher frequency by patients who were
The recommendation for managing opioid-tolerant patients perio- age 12 or older. This increase could be attributed to increased ability
peratively is to continue their usual doses of opioids in the postop- and likelihood by this age group to report pain. Low infant birth
erative period and to add supplemental doses of opioids for weight was associated with increased reports of bodily pain, mouth
postoperative analgesia. Therefore, patients should continue to or throat pain, and joint or bone pain. Maternal intravenous drug
receive their long-acting oral or transdermal opioids and also receive abuse and the type of caregiver were not related to the reporting of
supplemental short-acting opioids either through a PCA device or pain. Pain symptoms and the presence of low CD4 counts were
orally for postoperative pain. Because of tolerance, patients may independently associated with decreased survival in the study.
require higher supplemental doses of opioids postoperatively, Infants who are subject to pain early in development may be
while continuing on their usual doses of standard long-acting analge- more prone to pain complaints later in childhood. An animal study
sics. Higher doses of supplemental short-acting opioids should be by Ruda and colleagues66 reported that exposure to noxious stimuli
prescribed for as long as the routine expected course would be during development of the nociceptive pathways in infant rats
for managing that particular type of postoperative pain. Thereafter, resulted in permanent changes of the CNS and these rats were
the higher doses should be tapered off to the patient’s baseline hypersensitive to pain as adults. A similar mechanism is suggested
usual doses of opioids. If the surgery was performed to alleviate as a biologic explanation of these results and hypersensitization to
the source of pain, it can be expected that with recovery, the pain in children with HIV infection. Infants with HIV infection
patient’s requirements for pain medications should be lower than experience pain through multiple blood draws and procedures in
they were preoperatively. These considerations are important in the neonatal period. There is a high incidence of prematurity
recognizing and preventing addictive and drug-seeking behavior in among this population, and this in itself exposes the neonates to
the postoperative period. Care must be taken to continue other more painful procedures. All of these factors may contribute to
nonopioid pain medications and adjuvant drugs, if possible, in oversensitization to pain in these children. In addition, children
the perioperative period. Inadvertently discontinuing antidepres-
sants, anticonvulsants, muscle-relaxants, benzodiazepines, barbitu-
rates, or a2-agonists can lead to withdrawal symptoms.
Patients with HIV infection who have a history of intravenous
drug abuse pose a challenge for perioperative pain management. It
Table 45^4. Painful Diagnoses in Pediatric Patients
is difficult to achieve analgesia in the setting of increased tolerance.
Meanwhile, such patients may continue to exhibit manipulative, Number Reporting Number Reporting
drug-seeking behaviors. The immediate postoperative period is a Diagnosis Diagnosis* Pain (%)
poor time to begin treatments for ‘‘narcotic addiction,’’ although Apthous ulcers 63 25 (40)
the issue should be appropriately addressed. Patients should be Candidiasis 476 171 (36)
given maintenance doses of opioids until a reasonable time has
Cellulitis 72 24 (33)
elapsed postoperatively and then a multidisciplinary substance
abuse program should be initiated with the goal of long-term sta- Colitis 89 31 (35)
bilization and therapy for substance abuse. Impetigo 80 14 (18)
Lymphadenitis 48 8 (17)
Parotitis 76 8 (11)
PAIN IN CHILDREN WITHHIV Peripheral neuropathy 38 20 (53)
An estimated 2.1 million children (age 0–14 yr) are living with HIV Sinusitis 356 106 (30)
infection globally. Improvement and increased availability of ARTs Urinary tract infection 30 12 (40)
in the developed nations has decreased the morbidity and childhood Varicella-zoster virus 136 43 (32)
mortality from HIV considerably. Children in the United States infection
are living with HIV infection as a chronic disease. Patients are
monitored by checking CD4 counts and viral loads, as well as with *Specified painful diagnoses and their relation to pain as reported by
new measures such as health-related quality of life indices that are cohort participants.
used to measure the outcome of treatment plans and their benefits. Reprinted with permission from Gaughan DM, Hughes MD, Seage GR,
The prevalence of pain in children with HIV infection has been et al. The prevalence of pain in pediatric human immunodeficiency virus
found to be comparable with the prevalence of pediatric cancer acquired immunodeficiency syndrome as reported by participants in the
pain. Pediatric cancer pain is reported to be mostly due to Pediatric Late Outcomes Study. Pediatrics 2000; 109:1144–1152.
exposed to opioids in utero may require higher doses as neonates to 9. Hewitt D, McDonald M, Portenoy R, et al. Pain syndromes and
achieve analgesia. etiologies in ambulatory AIDS patients. Pain 1997;70:117–123.
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Chapter 46 patients with sickle cell disease rarely seek treatment for painful
crisis, whereas another third require frequent visits to the physician
SICKLE CELL ANEMIA or the emergency department for the treatment of pain. These
differences may be explained, in part, by the presence of genes
Daniel Brookoff that code for sustained production of hemoglobin F or other traits.
Sickle cell disease affects 1 in 375 African Americans in the
United States and is also present, although less common, in
Americans of Hispanic, Native American, East Indian, Greek,
Italian, and Eastern Asian origin. The disease is especially devastat-
ing in low-income urban populations with large numbers of African
Americans and Hispanics, whose burden of disease is amplified by
INTRODUCTION economic disadvantage. The impact of sickle cell disease extends to
all aspects of the patient’s life, including social interactions, family
Sickle cell disease is the most common hereditary hematologic dis- relations, peer interactions, employment, and spirituality. Patients
order in the United States. In its homozygous state, this disease typically have numerous encounters with health care providers as a
is often characterized by hemolytic anemia, susceptibility to infec- result of the recurrent nature of the painful crises. This leads to a
tions, and painful vaso-occlusive crises leading to ischemic tissue significant financial burden on patients and their families as well as
injury, organ dysfunction, and chronic pain owing to conditions on the health care system. The management of the majority of
such as avascular necrosis. Painful episodes or ‘‘crises’’ can vary patients with sickle cell anemia is primarily palliative—consisting
widely in frequency, intensity, and duration. About a third of of general supportive care and targeted symptomatic management
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Chapter 46 patients with sickle cell disease rarely seek treatment for painful
crisis, whereas another third require frequent visits to the physician
SICKLE CELL ANEMIA or the emergency department for the treatment of pain. These
differences may be explained, in part, by the presence of genes
Daniel Brookoff that code for sustained production of hemoglobin F or other traits.
Sickle cell disease affects 1 in 375 African Americans in the
United States and is also present, although less common, in
Americans of Hispanic, Native American, East Indian, Greek,
Italian, and Eastern Asian origin. The disease is especially devastat-
ing in low-income urban populations with large numbers of African
Americans and Hispanics, whose burden of disease is amplified by
INTRODUCTION economic disadvantage. The impact of sickle cell disease extends to
all aspects of the patient’s life, including social interactions, family
Sickle cell disease is the most common hereditary hematologic dis- relations, peer interactions, employment, and spirituality. Patients
order in the United States. In its homozygous state, this disease typically have numerous encounters with health care providers as a
is often characterized by hemolytic anemia, susceptibility to infec- result of the recurrent nature of the painful crises. This leads to a
tions, and painful vaso-occlusive crises leading to ischemic tissue significant financial burden on patients and their families as well as
injury, organ dysfunction, and chronic pain owing to conditions on the health care system. The management of the majority of
such as avascular necrosis. Painful episodes or ‘‘crises’’ can vary patients with sickle cell anemia is primarily palliative—consisting
widely in frequency, intensity, and duration. About a third of of general supportive care and targeted symptomatic management
of the complications of sickle cell anemia—with the goal of achiev- with sickle cell disease is exposed to low oxygen levels, it can go
ing the best quality of life for the patients and their families. from having the consistency of a drop of water to having the con-
Sickle cell anemia arises from a congenital abnormality of the sistency of petroleum jelly.
hemoglobin molecule, which in many of its sufferers, can lead to This change in RBC viscosity is the essence of sickle cell
a lifetime of severe pain and debility. Its expression can vary disease. Liquid blood becomes a viscous gel that clogs capillaries,
depending on additional genetic factors not directly related to the depriving the cells that depend upon that capillary for oxygen and
configuration of hemoglobin and that is why some patients and other nutrients. Much of the bone pain in sickle cell disease has
families appear to have more severe forms of the illness than been shown to be generated by infarction of the marrow and endo-
others. As recently as the late 1970s, most Americans with sickle steum, which are invested with a rich supply of afferent nerve cells.
cell anemia did not survive through childhood; because of this, This process of tissue infarction is the cause of most of the pain in
many physicians in the United States continue to consider sickle vaso-occlusive crisis, and it is not reversible. As Dr. Samuel
cell anemia to be a pediatric illness. This explains why most of the Charache has written, ‘‘a sickle cell crisis is an event that has already
specialized centers for the care of people with sickle cell disease con- happened.’’
tinue to be found in children’s hospitals. It also explains the paucity Some of the current molecular treatments for sickle cell disease
of specialists who care for adults with this disease and why the med- are based on the finding that cancer patients undergoing chemo-
ical care of adults with sickle cell disease is generally so poor. therapy developed increased levels of fetal hemoglobin (hemo-
Today, we understand that sickle cell disease is not restricted to globin F). This—coupled with the observation that patients with
people who originated in sub-Saharan Africa but that large concen- sickle cell disease who also had the concurrent persistence of
trations of people with sickle cell can be found in a broad belt of hemoglobin F (which is the most common of the hemoglobino-
land that extends from southern India through adjacent areas of pathies) had an improved clinical course—led to the use of cyto-
Arabia, Turkey, Greece, southern Italy, and Sicily. These regions toxic cancer chemotherapy drugs in these patients. The first trials
with high concentrations of sickle cell are also endemic areas for were conducted with 5-azacytidine, which did elevate hemoglobin-
the malarial parasite, Plasmodium falciparum. The ‘‘balanced poly- F levels but turned out to be too toxic. Hydroxyurea eventu-
morphism’’ of being heterozygous for hemoglobin S confers resis- ally became the cytotoxic drug of choice, and it is currently in
tance to infection with malaria, although it also serves to maintain use for sickle cell disease. Studies have shown that hydroxyurea
the disease sickle cell anemia within these populations. can decrease the frequency of painful crises in adults, although
Sickle cell anemia was the first disease to be defined on the the greatest success came when the drug was started early in
basis of molecular characteristics. The specific defect is the substi- childhood.
tution of a valine molecule for the glutamic acid molecule that The genetic basis of sickle cell disease lies in the inheritance of a
normally occupies the sixth position on the b-chain of hemoglo- single point mutation of the gene coding for the b-chain of hemo-
bin. When the resulting molecule—a molecule of hemoglobin globin. To have the disease, a person must inherit two copies of the
S—is deoxygenated, the valine molecule can bind to leucine and mutated gene, one from each parent. The mutation, a single base
phenylalanine molecules on neighboring hemoglobin molecules, change (GAT GTT) in the sixth codon of exon 1 of the b-globin gene,
causing aggregation and the formation of long chains of hemo- results in the replacement of the normal glutamic acid with valine at
globin, called hemoglobin polymers. These hemoglobin polymers position six of the b-globin chain. Inheritance of one normal gene
are poorly soluble within the intracellular matrix of the red and one mutated gene results in sickle cell trait, the heterozygous
blood cell (RBC) and can gel or precipitate, increasing the viscos- carrier state seen in approximately 1 in 10 African Americans and in
ity of the erythrocyte. up to 30% of sub-Saharan Africans. Sickle cell trait is generally
To appreciate how the changes caused by the polymerization of asymptomatic, although it has been linked to hematuria due to pap-
hemoglobin S translate into disease, we have to consider how the illary necrosis caused by sickling in hypertonic areas of the kidney
normal properties of the RBC are essential to its unique function. and to rare cases of sudden death related to exertion.
RBCs are responsible for transporting oxygen to cells in the tissues. Fetuses and young infants with sickle cell disease are usually
To do this efficiently, these cells must contain very high concentra- protected by their high circulating levels of hemoglobin F. Sickle
tions of the oxygen-carrying protein hemoglobin and still be able to cell disease generally becomes clinically manifest after 6 months
flow through narrow capillaries. Hemoglobin is a very special proof age and usually presents as painful vaso-occlusive crisis.
tein, not only because it can transport oxygen but also because it Throughout the lifespan of a patient with sickle cell disease, pain
can stay in solution at very high concentrations. This allows the is the most common reason for presentation to a health care pro-
erythrocyte to have the flow characteristics of water. This fluidity is vider. Sickle cell disease also leads to significant morbidity from
crucial to a cell that is 8 mm in diameter and has to deliver oxygen in recurrent bacterial infections, cerebrovascular events, acute chest
capillaries that average 3 to 4 mm in width. The normal concentra- syndrome, leg ulcers, avascular necrosis, hepatobiliary disease
tion of hemoglobin in an RBC is 36 g/dl, which is astoundingly high (e.g., formation of pigment stones), and complications owing to
compared with other cells that have high concentrations of protein. iron overload (often due to a combination of continuous hemolysis
If we were to substitute a protein similar to hemoglobin but without and repeated transfusions).
its unique solubility characteristics, such as myoglobin, into the The most important medical intervention that has increased the
RBC, the RBC would change from having the fluidity of water to lifespan of people with sickle cell disease has been the management
having the flow characteristics of brick. of bacterial infection through the use of prophylactic penicillin in
One way we can conceptualize the molecular basis of sickle cell childhood, the use of pneumococcal vaccine, and careful monitor-
disease for our patients is to compare normal hemoglobin A to ing. As people with sickle cell disease grow into adulthood, they
Teflon-coated beads that easily roll over each other as the RBC develop severe microvascular disease similar to that seen in dia-
flows in the blood stream. We can then think of hemoglobin S as betics, which can result in renal failure and blindness.
beads in which two bits of the Teflon are removed and replaced
with Velcro. The Velcro is exposed on the bead’s surface only after
the hemoglobin releases its load of oxygen, an event that generally PATHOPHYSIOLOGYOF PAINFUL
occurs in small capillaries. The deoxygenated hemoglobin S mole- CRISES IN SICKLE CELL DISEASE
cule can form a bond to any other hemoglobin molecule. If that
second molecule happens to also be a molecule of deoxygenated The occlusion of microvasculature and the resulting tissue infarc-
hemoglobin S, this can trigger the formation of a chain of hemo- tion do not completely explain the complex pathophysiology of
globin molecules (a hemoglobin polymer). When a RBC of a person sickle cell disease. A larger view of sickle cell disease encompasses
other pathophysiologic processes involving inflammatory mechan-

isms. The damaged tissue releases several inflammatory mediators, Box 46^1 CURRENT DIAGNOSIS
including the interleukins, bradykinin, K+, H+, histamine, substance
P, and calcitonin gene–related peptide, that we are beginning Vasocclusive Crisis
Assess for precipitants particularly bacterial infection.
to understand play a role in many chronic pain states. Timely pain management will limit the crisis.
Interleukin-1, for example, leads to the synthesis of prostaglandins Assess hydration and systemic status, although these are not the
via the up-regulation of the cyclooxygenase gene, which sensitizes usual precipitants.
peripheral nerve endings and facilitates pain transmission.
Cerebral Crisis/Acute Headache
Endogenous inhibitors of the painful stimuli (serotonin, enkepha- Be aware that pediatric patients with sickle cell anemia are at risk for
lin, b-endorphin, and dynorphin) may play a role in explaining, in thrombotic stroke and adults are at increased risk for intracerebral
part, the variation in the frequency and severity of painful crises in bleeds.
patients with sickle cell disease.
Damaged RBCs can also interact with and stimulate vascular Chest Crisis
Characterized by chest pain often accompanied by fever, leucocytosis,
endothelial cells and other tissues, kindling chronic inflammatory and pulmonary infiltrates, often triggered by community-acquired
reactions. Reperfusion injury, resulting in the formation of oxygen pneumonia.
radicals in ischemic tissue, may explain some of the progressive Must consider possibility of pulmonary thrombosis and/or fat
tissue damage in sickle cell disease, such as that which commonly embolism.
occurs in the spleen, kidneys, and lungs. This may account for the May require emergent exchange transfusion.
persistent leukocytosis that is commonly seen in patients with sickle Avascular Necrosis
cell disease. Persistent leukocytosis appears to be a ‘‘generator’’ Oftenpresentsas‘‘acute’’shoulderorhippainwhenitis,infact,chronic.
of disease processes in sickle cell anemia. In a 10-year study of Consider bone scanning in addition to plain radiographs and
children with sickle cell disease, three predictors of adverse out- orthopedics consultation.
comes (e.g., death, stroke, recurrent chest syndrome, frequent Priapism
painful crises) were leukocytosis in the absence of infection, episode Ultimately affects up to 50% of males with homozygous sickle cell
of dactylitis before age 1, and blood hemoglobin levels of less than disease.
7 g/dl. Can occur in boys as young as age 4.
May require drainage of corpora cavernosum and/or exchange
transfusion and emergent urology consultation.
CLINICAL MANIFESTATIONS
The acute painful episode is the hallmark of sickle cell disease. The Phase 3 is called the ‘‘established’’ or ‘‘postinfarctive/inflamma-
painful episode is variable and unpredictable and can be precipi- tory’’ phase and typically lasts for approximately 4 to 5 days. The
tated by a variety of factors. Some common triggers include physical patients report severe, constant pain with muscle tenderness on
stress, trauma, dehydration, and infection. The severity, location, examination. The patient may develop fevers, swelling, joint stiff-
and duration of the pain may vary among patients and in the same ness, and effusions. Hematologic changes include anemia, reticulo-
individual over time. Typically, the pain involves the long bones cytosis, leucocytosis, and an increase in acute-phase reactants
and joints, with pain in the lower back region being the most often (e.g., C-reactive protein, fibrinogen), lactate dehydrogenase
reported site. Pain may occur in other regions of the body, includ- (LDH; indicating tissue damage/bone marrow infarct), creatine
ing the scalp, face, jaw, abdomen, and pelvis. The accepted defini- phosphokinase (CPK; indicating skeletal muscle damage), RDW,
tion of painful crisis is one that requires treatment in a medical and HDW. Phase 4, or the ‘‘resolving/healing/recovery/postcrisis’’
facility with parenteral opioids for 4 or more hours. Severe sickle phase, typically lasts for 1 to 2 days and heralds the end of the vaso-
cell disease is defined as the occurrence of three or more crises per occlusive crisis. This phase is associated with a gradual decrease in
year. Patients with sickle cell disease typically use a variety of terms pain intensity. Laboratory tests can show thrombocytosis, increased
to describe their pain including ‘‘throbbing,’’ ‘‘sharp,’’ ‘‘dull,’’ fibrinogen levels, and a return to baseline hemoglobin levels with
‘‘stabbing,’’ and ‘‘shooting.’’ Objective signs (fever, leukocytosis, decreased sickle cells, percentage of dense red cells, RDW, and
joint effusions, and tenderness) occur in about 50% of patients at HDW. Recent reports appear to support the validity of these
presentation. The absence of objective signs during the sickle cell phases of vaso-occlusive crisis.
crisis, especially during the first few days, may lead to problems
when patients initially seek care from health care providers.
OTHER PAINFUL SYNDROMES
PHASES OF THE VASO-OCCLUSIVE Patients with sickle cell disease may suffer from painful syndromes
CRISIS other than ‘‘typical’’ acute painful vaso-occlusive crisis.
Studies in both children and adults have characterized the vaso-

occlusive crisis as having four phases, with the typical painful Acute Chest Syndrome
episode lasting an average of 10 days (Box 46–1). Phase 1 is the
‘‘prodromal’’ or ‘‘precrisis’’ phase and typically lasts approximately Acute chest syndrome is characterized by acute episodes of fever,
3 days. It is associated with a low-intensity, aching pain. The patient chest pain, leukocytosis, and pulmonary infiltrates. Common
may report numbness and paresthesias. This may be related to a triggers of acute chest syndrome include infection (especially
decrease in RBC deformability and an increase in RBC density as community-acquired pneumonia), pulmonary infarction secondary
more RBCs clog vascular channels. Phase 2 has been termed the to sickling, or bone marrow–fat embolism. This syndrome can
‘‘initial, evolving, infarctive’’ phase. During this phase, the patient sometimes be very difficult to distinguish from pulmonary throm-
experiences a gradual increase from aches to maximum pain with bosis. The possibility of thrombotic or embolic disease must always
associated fear, anxiety, and anorexia. This is often accompanied by be considered in the patient presenting with acute chest syndrome.
a decrease in hemoglobin, an increase in the percentage of dense Acute chest syndrome is the second most common cause of hospi-
RBCs, increased RBC distribution width (RDW), and increased talization for patients with sickle cell disease. It is associated with
hemoglobin concentration distribution width (HDW). significant morbidity and mortality in both children and adults.
Serum levels of secretory phospholipase A2, an enzyme that cleaves age 4. When first described, it was believed to represent a psychi-
fatty acids from triglycerides, may be a biomarker for impending atric ‘‘castration fear complex,’’ although it was soon understood to
chest syndrome. be due to sequestration of sickling cells in the corpora cavernosa.
Most episodes of acute chest syndrome are initially treated as Risk factors include low hemoglobin F levels and high platelet
pneumonia. Because of the possibility of infection with unusual counts. Although most attacks have no obvious precipitant,
organisms, such as Chlamydiae pneumoniae, broad-spectrum anti- priapism can be triggered by sexual intercourse and alcohol inges-
biotics are recommended. Clinical signs such as dyspnea, oxygen tion. Suggested treatments include exchange transfusion, stilbestrol,
saturation, and chest radiographs must be carefully monitored direct aspiration of the corpora using a wide-bore needle, or
because acute deterioration can lead to acute life-threatening emer- intracavernous injection of a dilute solution of phenylephrine.
gencies. In cases in which there is increasing dyspnea associated Anecdotal cases exist of treatment with epidural analgesia, gonado-
with progressive, widespread radiopacities and a partial pressure tropin-releasing hormone agonists, or antiandrogens. No studies
of oxygen in arterial blood (PaO2) of less than 75 mm Hg, exchange have shown evidence of benefit for any of these treatments.
transfusion should be considered. This often results in improve-
ment within 48 hours.
Acute Headache
Avascular Necrosis Acute headache in a patient with sickle cell disease may herald a
neurologic catastrophe. Because an increasing number of children
Avascular necrosis (or ischemic necrosis) is the most commonly with sickle cell disease and silent cerebral infarcts survive into adult-
observed complication of sickle cell disease in adults. The limited hood, the number presenting with aneurysmal bleeds is expected to
terminal artery supply and poor collateral circulation in the femoral increase. Recent studies show that both past thrombotic infarcts
and humeral heads and the vertebral bodies make these areas vul- and the existence of telangiectasias at the basal ganglia (termed
nerable to bone infarction, joint damage, and chronic pain. These ‘‘moya-moya’’ vasculopathy) are risk factors for hemorrhagic
patients often have findings related to infarction on plain radio- stroke in adulthood.
graphs (e.g., ‘‘Lincoln log’’ appearance of the vertebrae). Pain and Neuropathic pain syndromes have also been described in sickle
disability can be quite severe, requiring total joint replacement in cell patients. For example, the mental nerve may be compressed as
advanced forms of the disease. Because of their compromised a result of mandibular bone infarction, leading to numbness of
microvasculature, patients with sickle cell disease have difficulties the chin and mental nerve neuropathy. Other neuropathic pain
recovering from joint replacement surgery. Many orthopedists are syndromes that have been described in sickle cell patients include
understandably reluctant to operate on patients with sickle cell dis- trigeminal neuralgia, acute proximal median mononeuropathy,
ease. As a result, many of these patients end up suffering with entrapment neuropathy, and acute demyelinating polyneuropathy.
chronic pain in degenerating shoulders or hips for years. Patients Although acute painful crisis is the most common type of pain
with sickle disease who report persistent shoulder, hip, or knee pain described in the literature on sickle cell disease, most of the
and have nondiagnostic radiographs should undergo bone scans to pain many adults with sickle cell suffer is chronic bone and joint
look for necrosis. pain whose exacerbations are often framed in terms of acute crisis.
Undertreatment of this chronic pain can lead to unnecessary suf-
fering and even fatal complications. Repeated hospital admissions
Dactylitis for pain are strongly associated with a higher mortality rate.
Dactylitis (hand-foot syndrome) involves acute, painful nonpitting

swelling of one or more extremities. It is usually accompanied by PHARMACOLOGIC MANAGEMENTOF
fever and is also referred to as ‘‘acute osteopathy.’’ Dactylitis usually PAINFUL SYNDROMES
occurs in children between the ages of 6 months and 2 years,
although there have been cases reported up to age 7. The attacks Acute painful crises accounts for most of the emergency department
usually resolve spontaneously within a week but predict future visits by people with sickle cell disease. Treating sickle cell pain is
attacks. Recurrent episodes of dactylitis are a risk factor for early complex, and it requires understanding that much of the pain in
death owing to sickle cell disease. adults with this illness may be chronic (Box 46–2). The frequency of
painful crises may increase as the patient ages and is subject to
progressive damage of bones, joints, and tissues. ‘‘Palliative medi-
Leg Ulceration cine’’ is often a reasonable model of care for these patients with
progressive complex medical problems ranging from recurrent
Leg ulceration occurs in 5% to 10% of adult patients and can be a infection, central nervous system events, leg ulcers, severe bone
painful and disabling complication of sickle cell anemia. These pain, avascular necrosis of multiple joints, acute chest syndrome,
ulcers are probably due to vaso-occlusion in blood vessels in the cardiovascular compromise, renal failure, end-organ damage, and
skin and underlying muscle. Although formal studies of venous eventually, untimely death.
function in sickle cell disease have reached conflicting conclusions, The term palliative should not be interpreted to mean ‘‘nihi-
a case-controlled study in Jamaica demonstrated an association of listic.’’ The clinician faced with a patient with sickle cell disease
venous incompetence with chronic leg ulceration. The cause of should always be aware that a painful crisis may be triggered by
venous incompetence is unknown but may be related to turbidity a dangerous but reversible cause. When faced with a patient in
and impaired linear flow at venous valves, hypoxia-induced sick- painful crisis, consideration must be given to the possibility of
ling, the rheologic effects of high white cell counts, or the abnormal concurrent infection or thrombosis. The patient’s assessment and
activation of the coagulation system. treatment must also take into consideration the possibility of
chronic organ dysfunction owing to pulmonary hypertension, car-
diomyopathy, renal dysfunction, or hepatopathy.
Priapism The general approach to the patient with acute painful crisis
should always include a thorough history and examination, includ-
Priapsim is a painful and prolonged penile erection that affects up ing a patient self-report of the pain, which can be facilitated using
to half of all males with sickle cell disease and can occur as early as one of the numerous validated pain scales available. Crisis pain can
Patients with sickle cell disease who primarily use the emer-
Box 46^2 CURRENT THERAPY gency department to manage their disease often end up with
substandard care, lacking both in continuity and in physicians
Timely Pain Management with the specialized knowledge needed to help manage this ill-
Timely and appropriate doses of opioids are the mainstay of treatment of
moderate to severe pain.
ness. Unfortunately, in the United States, many of these patients
are left with no alternative.
Proper Selection of Analgesic Medications
Repeated doses of meperidine are not recommended.
In patients with renal failure or hepatopathy, morphine can have
exaggerated side effects. Opioids such as fentanyl with limited renal and Selection of Opioid Analgesics
hepatic metabolism and no active metabolites may be the safest choice.
Most opiates have comparable efficacy and safety profiles, with
Assess Anemia and Leukocytosis analgesia and side effects being dose dependent. In patients with
Vascular adherence of leukocytes and accompanying ‘‘vasculitis’’-like sickle cell disease, we have to consider coexistent organ dysfunction
syndrome may contribute to acute ‘‘crisis.’’
May respond to anti-inflammatory or limited and judicious treatment that can alter the metabolism of certain medications. It should also
with steroids. be noted that the baseline level of renal or hepatic dysfunction may
be worsened during an acute crisis. In most cases of acute crisis,
Quick Attention to Possibility of Bacterial Infection most sickle cell centers and pain specialists that treat sickle cell
Wide variety of bacterial infections as is seen in diabetic patients may be
disease favor the intravenous route of opioid administration. One
contributing to painful decompensation.
Presumptive treatment is often required. study that evaluated intravenous versus oral morphine in children
with vaso-occlusive episodes found equal efficacy and safety in both
groups. In another study, oral morphine was used in conjunction
with a nonsteroidal anti-inflammatory agent for the treatment of
be alleviated only by analgesic medications. Analgesics should be acute painful crisis. This regimen reduced admissions to the hospi-
started promptly and titrated to the patient’s report of pain, which tal when compared with historical controls. As mentioned pre-
should always be documented. viously, meperidine has been the most commonly used opioid for
The usual strategies for treating sustained, severe pain with the treatment of painful crisis. The increased risk of seizure (from
opioid analgesics all too often call for intermittent dosing on an accumulation of its metabolite normeperidine) and the skin and
as-needed basis. In this approach, pain medications are given only muscle injury due to its use by intramuscular injection make it
when the pain recurs. The analgesics used are often short acting and relatively contraindicated for repeated use in patients with sickle
given with insufficient frequency. This discontinuous provision of cell disease.
analgesia subjects patients with sustained pain to periods of pain, Although opioid medications can usually control the pain of
anticipation, and anxiety and can generate the pain-avoidance sickle cell disease, many physicians will not prescribe these medica-
behaviors that physicians often characterize as ‘‘manipulative’’ tions or will prescribe them in inadequate dosages because of
and ‘‘drug-seeking.’’ To avoid this, intravenous analgesics can be undue concerns about addiction or side effects such as respiratory
started as continuous infusions or via patient-controlled pumps. depression. In a study that examined the effectiveness of analgesia in
After adequate analgesia is obtained, an oral or transdermal 21 children with vaso-occlusive crisis, 71% did not achieve adequate
sustained-release opioid may be started with a provision made for pain control during the study period. Factors undermining effective
intermittent bolus or ‘‘rescue’’ medication. Uncontrolled pain treatment included lack of pain assessment, improper choice of
accounts for more than 90% of hospital admissions in adults with medication or inadequate dosing, and misconceptions about the
sickle cell disease. In adult patients with frequent episodes of painful nature of painful crisis among physicians and nurses.
crisis, the use of long-acting opioid medications reduced visits to Morphine has long been considered a drug of choice for the
the emergency department and hospitalizations and shortened the treatment of painful crisis, but physicians must be aware that the
lengths of stay in hospital. pharmacokinetics of morphine can vary among patients. One study
A precipitating cause for the painful crisis should always be con- of patients with sickle cell disease reported an eightfold variation in
sidered. Prompt attention to infection in particular can mean the morphine clearance among different individuals. Patients with
difference between life and death for a patient with sickle cell disease. sickle cell disease typically have a more rapid plasma clearance for
Serious infections are usually signaled by fevers, and no patient with a morphine than other patients, such as those with cancer or post-
temperature greater than 1018F should be discharged before the operative pain. In addition, patients with severe symptoms have
source of infection is identified and treated. But radiographs, urina- significantly faster clearances than those with moderate pain. This
lyses, and antibiotics do not relieve pain. Whereas laboratory tests rapid clearance may result in less analgesia in response to com-
and radiographs should be ordered when indicated, they should not monly administered dosages. It should be noted that the clearance
be considered to be routine treatment of painful crisis. of morphine and some of its active metabolites can be significantly
Some medical institutions have reported success with a dedi- reduced in cases of hepatopathy and renal failure, both of which are
cated outpatient facility for the treatment of uncomplicated sickle becoming more frequent among people with sickle cell disease as
cell pain crisis. Use of this special unit reduced the time spent to improved disease management (most notably prevention and treat-
pain relief, increased the number of patients discharged to home, ment of infections) results in an aging of this population.
decreased hospital admission rates, and reduced the use of the Hydromorphone has been useful in the treatment sickle cell
emergency department by patients with sickle cell disease. Over pain. It usually has fewer side effects than morphine owing to the
the 5 years studied, savings amounted to millions of dollars as a lack of the hydroxyl group in position six of morphine that is largely
result of fewer hospital admissions and a shorter length of stay. responsible for morphine-induced nausea. The sustained-release
Until recently, treatment of sickle cell–related pain was limited to preparation of hydromorphone is currently unavailable in the
short-acting opioids administered in emergency departments. The United States, although the recent introduction of sustained-release
most commonly used opioid has been meperidine, which is rela- oxymorphone may hold promise for the effective treatment of
tively contraindicated in these patients who often have significant moderate to severe chronic pain in these patients. Other oral
renal insufficiency. opioids such as methadone, oxycodone, and levorphanol have
been successfully used to treat chronic pain in patients with sickle sickle cell pain found only 1 patient who showed signs of addiction.
cell disease, as has transdermal fentanyl. Another study of 160 patients found that 14 ‘‘made excessive use of
hospital services,’’ tampered with drug delivery systems in the hos-
pital, had a history of illicit drug behavior, or had been involved
Adjuvant Therapy for Acute Pain with the police or courts because of drug-related activities. Despite
this, many of the physicians associated with comprehensive sickle
Nonsteroidal anti-inflammatory medications have been used in cell centers in the United States continue to find that physicians’
combination with opioids or alone for acute episodes of sickle attitudes about addiction and toward patients in crisis result in
cell pain. These include ketorolac, piroxicam, and ibuprofen, undertreatment of pain.
which have been evaluated for monotherapy and in combination The most common manifestation of this problem occurs when
with opiates for vaso-occlusive crisis. Ketorolac may be a successful an adult patient with sickle cell disease seeks care in a hospital
primary treatment for patients unable to tolerate opiates. In single- emergency room. The interaction between patient and caregiver
dose studies, ketorolac did not reduce the opioid requirements can quickly deteriorate into disagreements over how aggressively
of patients with sickle cell pain; however, continued (‘‘around- to treat the pain and can kindle suspicions of substance abuse.
the-clock’’) ketorolac administration may provide increased benefit. Because severe episodes are so regular, patients with sickle cell dis-
In a blinded, cross-over trial with 20 children, ketorolac provided ease often manifest a high degree of concern, anxiety, and distress
superior pain control and had fewer side effects than meperidine. regarding their pain medications, and these may translate into
An obvious concern is the risk of renal failure with ketorolac. behaviors that are often misinterpreted by health professionals as
A more recent study of 70 patients with episodes of pain measuring drug-seeking behaviors.
‘‘7 out of 10’’ (on a numerical rating scale) found that ketorolac The problematic behaviors that are driven by fear and despera-
provided relief in fewer than half the subjects. tion related to unrelieved pain or lack of access to adequate pain
Steroids have also been shown to reduce sickle cell crisis pain. In medication can best be characterized as ‘‘pseudoaddiction’’ (see
a randomized, double-blinded trial of 56 pain episodes in children Section VII, Chapter 54, Opioid Pharmacotherapy). Assessment
and adolescents, methylprednisolone in doses of 15 mg/kg (to a and management of this very complex set of behaviors require con-
maximum dose of 1000 mg) significantly reduced opioid require- siderable clinical sophistication. Inattention to these issues only
ments compared with a placebo-controlled group. Stimulants have worsens the burden and stigma of sickle cell disease.
been used as adjuvant therapy to enhance the effects of opioids,
usually for patients who experience oversedation with their pain
medications. SUGGESTED READINGS
The antidepressants and anticonvulsant medications that are Asher SW. Multiple cranial neuropathies, trigeminal neuralgia, and
typically used for neuropathic pain have not been studied for vascular headaches in sickle cell disease: a possible common
sickle cell pain. One antidepressant to be avoided in males with mechanism. Neurology 1980;30:210–211.
sickle cell disease would be trazodone whose erection-potentiating Ballas SK. Pain management of sickle cell disease. Hematol Oncol Clin
effects could lead to the development of priapism, another common North Am 2005;19:785–802.
complication of sickle cell disease. Beyer J, Platt A, Kinney T, Treadwell M. Practice guidelines for the
assessment of children with sickle cell pain. J Soc Pediatr Nurses
1999;4:61–73.
Brookoff D. A protocol for defusing sickle cell crisis. Emerg Med
Sickle Cell Disease and Opioid Addiction 1992;7:131–140.
Brookoff D, Polomano R. Treating sickle cell–like cancer pain. Ann Intern
One of the most important barriers to care for patients with sickle Med 1992;116:364–368.
cell disease is the exaggerated fear of promoting addiction. Studies Charache S, Lubin B, Reid C. Management and therapy of sickle cell
show that the prevalence of addiction in patients with sickle cell disease (NIH Pub. No. 89-2117). U.S. Department of Health and
disease is lower than that of the surrounding populations and may Human Services. Public Health Services. Washington, DC: U.S.
be as low as 1%. Nonetheless, a survey of caregivers who frequently Government Printing Office, 1989.
Elander J, Lusher J, Bevan D, et al. Understanding the causes of
see patients with sickle cell disease found that 63% of nurses, 53% of
problematic pain management in sickle cell disease: evidence that
emergency department physicians, and 23% of hematologists pseudoaddiction plays a more important role than genuine analgesic
believed that drug addiction is prevalent in patients with sickle dependence. J Pain Symptom Manage 2004;27:156–169.
cell disease. Jacob E, Beyer JE, Miaskowski C, et al. Are there phases to the vaso-
Exaggerated concerns about addiction and physical dependence occlusive painful episode in sickle cell disease? J Pain Symptom Manage
among patients with sickle cell disease has compromised the 2005;29:392–400.
treatment of these patients for a long time. Studies examining the Payne R. Pain management in sickle cell disease: rationale and techniques.
incidence of addiction among patients with sickle cell disease have Ann N Y Acad Sci 1989;565:189–206.
repeatedly shown that it is no greater than that of the general Shaiova L, Wallenstein D. Outpatient management of sickle cell pain with
population and is often significantly lower. A study of 610 patients chronic opioid pharmacotherapy. J Natl Med Assoc 2004;96:984–986.
Yale S, Nagib N, Guthrie T. Approach to the vaso-occlusive crisis in
in London found that none were drug addicts. A study of 198 adults with sickle cell disease. Am Fam Physician 2000;61:1349–1356.
children and adolescents treated with intravenous opiates for
354 Chapter 47 SACROILIAC JOINT PAIN
Chapter 47 3rd decade of life.4 SIJ syndrome is present with right-sided symp-
toms in 45% of patients, left-sided symptoms in 35%, and bilateral
SACROILIAC JOINT PAIN symptoms in the remaining 20%.7
Dave Loomba and Gagan Mahajan

PATHOPHYSIOLOGY
The most common cause of SIJ pain is idiopathic, because studies
have not revealed an accurate correlation between the patients’ his-
tory and the diagnosis of SIJ syndrome.8 Potential pain generators
include hyper-/hypomobility, abnormal joint mechanics, ligamen-
INTRODUCTION tous or capsular tension, compression or shear forces, and myofas-
cial disturbances, all of which can lead to inflammation and pain.
Sacroiliac joint (SIJ) syndrome is defined as pain originating from
the SIJ due to degeneration or altered joint mobility. In 1905, Other potential sources of SIJ pain include9:
Goldwaith and Osgood1 first described the SIJ as a primary pain
n Intra-articular: osteoarthritis, inflammatory spondyloarthro-
generator. Approximately 15% of the population suffers from low
pathies or infection.
back pain and buttock pain originating from the SIJ.2 Owing to its
n Extra-articular: enthesis/ligamentous sprain or osseous/soft
anatomic location and overlapping pain referral patterns, SIJ syn-
tissue trauma.
drome can be difficult to differentiate from other spinal disorders
n Metabolic: gout, hyperparathyroidism, renal osteodystrophy,
(e.g., facet joint arthopathy, degenerative disk disease, and spinal
acromegaly, calcium pyrophosphate crystal deposition dis-
stenosis), hip and pelvis disorders, and myofascial pain syndromes.
ease, or tumor.
Further making the diagnosis challenging, the inherent variability in
n Iatrogenic instability: bone harvesting or pelvic tumor
innervation of the SIJ can cause different pain referral patterns
resection.
among individuals.3
n Pregnancy: SIJ hypermobility or mechanical trauma from
childbirth.
TAXONOMY
The SIJ is a diarthrodial, auricular-shaped joint consisting of an CLINICAL FEATURES
outer, fibrous joint capsule, synovium, synovial fluid, hyaline car-
tilage on the sacral aspect, and fibrocartilage on the iliac aspect. SIJ syndrome can be difficult to differentiate from other concom-
With a surface area of approximately 17.5 cm2, the SIJ is the largest itant spinal disorders (facet joint arthropathy, degenerative disk
axial joint in the human body and supports approximately half of disease, or stenosis), hip and pelvis disorders, and myofascial pain
the trunk weight.4 Although the SIJ exhibits some motion, posses- syndromes because of their overlapping pain referral patterns. In
sing approximately 2 to 3 mms of glide and 38 of rotation, it is addition, patients often have multiple coexisting pain generators,
primarily designed for stability.3 Numerous ligaments (anterior and such as facet joint arthropathy, in conjunction with SIJ syndrome.
posterior sacroiliac, sacrospinous, sacrotuberous, interosseous, and Further making the diagnosis challenging, the inherent variability in
iliolumbar) and muscles (gluteus maximus and medius, latissimus innervation of the SIJ can cause different pain referral patterns
dorsi, biceps femoris, psoas, piriformis, erector spinae, oblique and among individuals.6
transversus abdominis) act to support and stabilize the SIJ. The SIJ syndrome has been commonly associated with referred pain
surface of the joint lies in the direction in which shearing force is located inferior to the ipsilateral posterior iliac spine.10 Pain referral
exerted when an orthostatic load is applied. The SIJ is susceptible to patterns, however, are more extensive than this and can often local-
numerous pathologic processes including degeneration, metabolic ize to the sacral sulcus, low back, and buttock. Slipman and cow-
derangements, infectious diseases, trauma, tumor, and orkers11 found that in their study of 54 subjects, patients reported
inflammation.5 pain in the thigh (48%), leg (28%), groin (14%), foot or ankle
Innervation of the SIJ is highly variable, leading to the wide array (13%), and abdomen (2%). Using self-reported pain drawings,
of pain referral patterns among individuals afflicted with SIJ syn- Dreyfuss and associates12 demonstrated that only 4% of 45 patients
drome. The anterior aspect of the joint is innervated by the lateral with SIJ syndrome indicated pain above L5.
branches of the posterior rami of the L2–S2 nerve roots, and the
posterior aspect is innervated by the lateral branches of posterior
rami of the L4–S3 nerve roots6 (Fig. 47–1). The SIJ receives myeli- EVALUATION
nated and unmyelinated axons that most likely conduct pain and
proprioceptive impulses originating from mechanoreceptors and The International Association for the Study of Pain (IASP)13 has
free nerve endings.6 defined the diagnostic criteria for SIJ syndrome (Box 47–1).
Although there is no validated physical examination maneuver
that definitively identifies SIJ syndrome, a wide array of tests has
EPIDEMIOLOGY been described. Some of the more common examination techniques
include14,15
Although definitive epidemiologic studies of SIJ syndrome are lack-
n Patrick’s test, also known as the FABER test (Fig. 47–2):
ing, the incidence of SIJ syndrome is estimated to range from 13%
With the patient supine, place the affected hip in flexion,
to 30%.3 Moderate degenerative joint changes occur as early as the
Figure 47^2. Patrick’s (FABER) test. (From Benzon H, Raja S,

Barsook D [eds]: Essentials of Pain Medicine and Regional Anesthesia,
2nd ed. Philadelphia: Elsevier Churchill Livingstone, 2005; p 358.)
n Gaenslen’s test (Fig. 47–3): With the patient in the supine

position, the examiner passively flexes the hip and knee of
the unaffected limb toward the trunk while the affected limb
is allowed to slowly fall off the side of the examination table
to passively extend the hip. The test is positive if pain is
produced along the SIJ of the affected limb.
n Yeoman’s test, also called the extension test (Fig. 47–4): With
Figure 47^1. Innervation of the sacroiliac joint. The anterior the patient in the prone position, the examiner places one
aspect of the joint is innervated by the lateral branches of the hand above the anterior aspect of the knee of the affected
posterior rami of the L2^S2 nerve roots, and the posterior aspect of limb and elevates it to passively extend the hip. The other
the joint is innervated by the lateral branches of posterior rami of the hand applies downward pressure over the contralateral iliac
L4 ^S3 nerve roots. (From Benzon H, Raja S, Barsook D [eds]: Essentials crest. The test is positive if pain is provoked along the SIJ of
of Pain Medicine and Regional Anesthesia, 2nd ed. Philadelphia: Elsevier the affected limb.
Churchill Livingstone, 2005; p 361.)
abduction, and external rotation. With the ankle of the

affected limb placed on the contralateral knee, creating
a figure-four position, the examiner applies downward
pressure on the medial aspect of the knee of the affected
limb while simultaneously providing counterpressure on
the contralateral anterior superior iliac spine. The test is
positive if pain is elicited along the SIJ of the affected limb.
Pain referred to the groin is more suggestive of hip joint
pathology.
Box 47^1 CURRENT DIAGNOSIS
Figure 47^3. Gaenslen’s test. (From Benzon H, Raja S, Barsook D

From Merskey H, Bogduk N (eds): Classifications of Chronic Pain: Descriptions of Chronic Pain
Syndrome and Definitions of PainTerms. Seattle: IASP Press,1993; pp 190 ^191.
[eds]: Essentials of Pain Medicine and Regional Anesthesia, 2nd ed.
Philadelphia: Elsevier Churchill Livingstone, 2005; p 358.)
Figure 47^4. Yeomen’s (extension) test. (From Benzon H, Raja S, Barsook D [eds]: Essentials of Pain Medicine and Regional Anesthesia, 2nd ed.
Philadelphia: Elsevier Churchill Livingstone, 2005; p 358.)
n Fortin’s finger test: The patient points to the area of pain with have been used to limit sacroiliac motion and provide improved
one finger. The test is positive if the site is within 1 cm of the proprioception. Unfortunately, prospective studies evaluating the
posterior superior iliac spine. efficacy of physical therapy and bracing are lacking.3 Other conser-
vative treatments include massage, heat, cold, electromyographic
Although pain-provoking maneuvers can be useful tools to aid biofeedback, transcutaneous electrical nerve stimulation, manual
in the diagnosis of SIJ syndrome, their specificity is low.16 Poor muscle therapy, and chiropractic manipulation.
inter- and intrarater reliability have contributed to false-positive If a patient fails to improve with noninvasive therapies, an
rates as high as 20% in asymptomatic individuals.17 Compared SIJ injection should be considered. Nonfluoroscopically guided
with a positive diagnostic SIJ injection, Broadhurst and Bond18 diagnostic and therapeutic SIJ injections have been performed
reported a sensitivity range of 77% to 87% when three examination since 1938, but the use of fluoroscopic guidance did not start
maneuvers were used. until 1979.3 Although some clinicians perform SIJ injections in
Imaging studies have also been inconsistent in providing an office-based settings without image guidance, this approach is
adequate diagnostic assessment of SIJ syndrome. Approximately not recommended owing to an inability to confirm needle place-
24.5% of asymptomatic individuals older than 50 years of age ment within the SIJ. Because of the thickness of the surrounding
have degenerative SIJ changes on x-ray.19 Bone scan has a poor sacroiliac and interosseous ligaments and the convoluted joint
sensitivity, ranging from 12.9% to 65% in patients responding surface, non–image-guided injections will most likely result in
positively to SIJ injections.3 Single-photon emission computed ligamentous or myofascial injections.25 Rosenberg and associ-
tomography (SPECT) demonstrates a sensitivity of only 9.1%.20 ates25 found that without computed tomography (CT) guidance,
Studies assessing the efficacy of magnetic resonance imaging only 22% of needle placements were intra-articular. More con-
(MRI) are inconclusive, with Battafarano and colleagues21 demon- cerning, however, was the finding that 24% were epidural, of
strating a sensitivity of 100%, but Hanly and coworkers22 finding a which 44% were placed in one of the sacral neural foramina.25
sensitivity of only 54%. Because patient history and imaging stu- Although CT and MRI guidance can be utilized for this proce-
dies are not accurate enough to confirm the diagnosis of SIJ syn- dure, it can be safely and accurately performed at lower eco-
drome, the ‘‘gold standard’’ for diagnosing SIJ syndrome remains nomic expense with fluoroscopic guidance.
the reduction of pain after an intra-articular injection of local
anesthetic.23
Intra-articular SIJ Injection26
MANAGEMENT Equipment
Current treatment options are presented in Box 47–2. Surgical n Quincke spinal needle, 22-gauge, 3.5-inch (or 6-inch for a larger
intervention is a treatment of last resort when the pain remains patient)
intractable and less-invasive treatments have failed. n Luer-Lok 1-ml syringe (for iohexol)
The goals of physical therapy include pelvic stabilization, resto-
ration of truncal and lower muscle imbalances, and correction of
gait abnormalities. Biomechanical models have revealed that the Box 47^2 CURRENT THERAPY
abdominal muscles with transversely oriented muscle fibers, espe-
cially the transversus abdominis, significantly decrease the laxity of Pharmacotherapy (non-steroidal anti-inflammatory drugs, acetamino-
phen, neuropathic analgesics, and/or opioids).
the SIJ.24 Thus, precisely controlled, isolated contractions of the
Physical therapy.
transversus abdominis muscle should be incorporated into therapy, Sacroiliac joint (SIJ) injection.
along with strengthening and stretching exercises for the lower Neuromodulation of nerves innervating the sacroiliac joint.
extremity and spine.24 SIJ belts and pelvic stabilization orthoses
n Luer-Lok 3-ml syringe (for injection solution) within 12 hours.27 Bernard and colleagues28 reported prolonged
n Luer-Lok 10-ml syringe with 25-gauge, 1.5-inch needle (for local analgesia lasting 9 months in 81% of patients. In a retrospective
anesthesia) study by Maugers and coworkers,29 79.2% of patients with a sero-
n Povidone-iodine (Betadine) scrub negative spondyloarthropathy suffering from sacroiliitis reported
n Alcohol scrub greater than 70% analgesia for an average of 8.4 months after SIJ
n Sterile drapes, towels, and gloves steroid injection. For those patients who do not obtain long-term
n Sterile gauze analgesia with steroids or for those in whom steroids are contra-
n Adhesive bandages indicated, other treatment options (intra-articular viscosupplemen-
n C-Arm fluoroscopy tation with hyaluronic acid, prolotherapy, and neuromodulation)
n Protective lead apron and goggles have also been reported to provide prolonged pain relief.8
After viscosupplementation of the SIJ with hyaluronic acid,
Srejic and associates30 reported onset of analgesia to be approxi-
Medications mately 45 to 60 minutes, peaking at about 4 to 5 days, and lasting
from 6 to 8 months. Viscosupplementation works by restoring the
n Lidocaine Methylparaben Free (MPF) 1% (5–10 ml) for skin
viscoelastic property of synovial fluid that is reduced in osteoarthri-
wheal and deep tissue anesthetization
tis through the loss of hyaluronan. Elastoviscosity is critical for joint
n Bupivicaine 0.25% (1 ml) and triamcinolone 40 mg (1 ml)
function. In addition, hyaluronic acid has analgesic properties and
n Contrast (0.5 ml)
may delay progression of osteoarthritis by inhibiting the diffusion
of destructive chondrocyte enzymes into joint cartilage.
Prolotherapy focuses on restoring stability to weakened joints
Methodology and ligaments. Using fluoroscopic guidance, an irritant solution—
1. After obtaining informed consent, place the patient in a prone 2 ml of 50% dextrose or 3 ml of P2G (phenol:glycerine:glucose)
position on a fluoroscopic table and prepare and drape the mixed with 1% lidocaine to make a 5-ml solution—is injected into
patient using sterile technique. the ipsilateral iliolumbar and sacroiliac interosseous ligaments. This
2. Identify the target site of injection by rotating the C-arm 258 to can be repeated three times over a 4- to 8-week period.31 This
358 caudally from the axial plane to differentiate the accessible irritant induces a brief stimulation of the inflammatory cascade,
posteroinferior aspect of the SIJ from the inaccessible anterior triggering the release of growth factors, fibroblast chemotaxis, and
aspect of the SIJ and 08 to 308 obliquely to the contralateral side deposition of new collagen into the surrounding ligaments. This
to avoid interference from the ipsilateral iliac crest (Figs. 47–5 to ultimately leads to thickening of the surrounding ligaments and
47–8; Box 47–3). tendons to stabilize a ‘‘hypermobile joint.’’9 Chakraverty and col-
3. Using 1% lidocaine, anesthetize the skin and subcutaneous tissue leagues31 demonstrated 82% improvement in pain at 12 months in
overlying the SIJ. 61% of patients after sacroiliac ligament prolotherapy.
4. Insert a 22-gauge 3.5-inch (or 6-inch for a larger patient) spinal Radiofrequency denervation is commonly used for the treatment
needle through the anesthetized skin surface and advance the of facetogenic pain. Its application as an alternative treatment for
needle in a coaxial direction to the fluoroscopy beam. SIJ pain remains controversial owing to the lack of sufficient stu-
5. Once the posterior aspect of the joint is contacted, advance the dies, lack of consensus regarding the pattern of innervation, and
needle tip 5 to 10 mm through the ligaments and capsule and differences in how the procedure should be performed. Some have
into the joint space. This may be facilitated by angling the needle advocated for denervation of the medial and lateral branch nerves as
tip laterally to follow the natural curve of the joint (Fig. 47–9). they enter into the SIJ, whereas others have proposed denervating
6. Because the SIJ has a limited volume, inject a minimal amount of the nerves as they emerge from the lumbar spine and sacral foram-
contrast (0.2–0.5 ml) to confirm an arthrogram in order to pre- ina.32-34 Furthermore, the dual (anterior and posterior) innervation
serve space for 1 to 2 ml of the active agent (Fig. 47–10). of the SIJ can affect the overall treatment outcome because only the
posterior nerve supply is denervated. For example, whereas a
After an SIJ injection with local anesthetic and steroid, 50% to patient could have clinical and radiographic findings supporting
80% of patients notice immediate relief, and 90% experience relief SIJ syndrome, denervation of the posterior nerve supply may
Figure 47^5. Fluoroscopic positioning for intra-articular sacroiliac joint injection. The C-arm has been rotated 258 ^358 caudally from
the axial plane and 08 ^308 obliquely to the contralateral side. (From Rathmell J [ed]: Atlas of Image-Guided Intervention in Regional Anesthesia and
Pain Medicine. Philadelphia: Lippincott Williams & Wilkins, 2006; p 96.)
A B
Figure 47^6. A, Posteroanterior (PA) radiograph displays the anterior (arrows) and posterior (arrow) aspects of the sacroiliac joint.The asterisk
indicates the point of needle entry. B, PA radiograph displays the anterior (asterisks) and posterior (stars) aspects of the sacroiliac joint. (A and B,
From Fenton D, Czervionke L [eds]: Image-Guided Spine Intervention. Philadelphia: Saunders, 2003; p 131.)
Figure 47^7. Oblique view demonstrates the curvilinear nature of

the sacroiliac joint, resulting in overlying shadows of the anterior and Figure 47^8. PA radiograph displays the curvilinear nature of
posterior aspects of the joint (arrowheads). (From Fenton D, Czervionke anterior (arrowheads) and posterior (arrows) aspects of the sacroiliac
L [eds]: Image-Guided Spine Intervention. Philadelphia: Saunders, 2003; joint. (From Fenton D, Czervionke L [eds]: Image-Guided Spine
p 132.) Intervention. Philadelphia: Saunders, 2003; p 130.)
Box 47^3 TECHNICAL TIPS

1. The SIJ is curvilinear, arcing laterally toward the anterior aspect. This
results in overlying shadows of the anterior and posterior aspects of
the joint (see Figs. 47^7 and 47^ 8).
2. The overlying iliac crest can block access to the SIJ.This can be accom-
modated by using caudal angulation of the C-arm and confining the
injection to the inferior aspect of the SIJ.
provide incomplete analgesia if the pain is partially mediated by the

anterior nerve supply.
Neuromodulation
Radiofrequency Denervation ofthe SIJ23,32

Equipment
n Three 22-gauge, 10-cm (or 15-cm for a larger patient) Sluijter-
Mehta cannula (SMK) needles with 5-mm active tips
n Luer-Lok 3-ml syringe (for injection solution)
n Luer-Lok 12-ml syringe with 25-gauge, 1.5-inch needle (for local
anesthesia)
n Luer-Lok 12-ml syringe with 25-gauge, 1.5-inch needle (for SIJ
Figure 47^10. PA radiograph displays the sacroiliac joint after
anesthesia)
contrast injection (arrows) into the joint.The needle tip is in the
n Providone-iodine scrub
posteroinferior aspect of the sacroiliac joint. (From Fenton D,
n Alcohol scrub
Czervionke L [eds]: Image-Guided Spine Intervention. Philadelphia:
n Sterile drapes, towels, and gloves
Saunders, 2003; pp 132^140.)
n Sterile gauze
n Adhesive bandages
n C-Arm fluoroscopy
n Radiofrequency generator and grounding pad Medications
n Protective lead apron and goggles n Lidocaine MPF 1%, 10 ml
n Lidocaine MPF 2%, 10 ml
Methodology
1. Follow steps 1 to 5 for ‘‘Intra-articular SIJ Injection,’’ earlier.
However, substitute an SMK needle for a spinal needle.
2. Place a second SMK needle 5 to 6 mm above the first needle
and advance to the same depth to ensure that the active tips
lie in the same plane to create a bipolar system (Fig. 47–11).
If both needles are placed greater than 6 mm apart, two dis-
crete unipolar lesions are created as opposed to one bipolar
lesion.
3. After both needles have been placed, connect one needle to the
electrode port of the radiofrequency generator and connect the
other needle to the ground.
4. After confirming absence of lower extremity muscle contraction
at 2 Hz with the motor stimulation turned up to a maximum
of 3 V of motor stimulation, inject lidocaine 2% (0.5 ml)
through each needle prior to performing a bipolar lesion at
908C for 120 seconds. Allow the needle tip to cool to at
least 458C before removing the probe and starting subsequent
lesions.
5. After completion of the first bipolar lesion, place a third needle
NT 5 to 6 mm cephalad to the second one. Follow steps 3 and 4 (of
‘‘Intra-articular SIJ Injection,’’ earlier) to create a second bipolar
lesion. Repeat this ‘‘leapfrog’’ process to perform approximately
six to eight sequential, ‘‘strip’’ lesions along the entire posterior
and inferior aspects of the SIJ.
Figure 47^9. PA radiograph displays the needle tip (NT) in the
posteroinferior aspect of the sacroiliac joint.The anterior joint space Using this technique, Ferrante and coworkers32 demonstrated at
(asterisk) is lateral to the posterior joint space. (From Fenton D, least a 50% reduction in pain with an average duration of analgesia
Czervionke L [eds]: Image-Guided Spine Intervention. Philadelphia: lasting 12 months in 12 of 33 (36%) patients.
Saunders, 2003; p 132.)
Radiofrequency Denervation ofthe L4 Medial Branch Nerve,

L5 Posterior Primary Ramus, and the Lateral Branches ofthe
S1^3 Dorsal Rami26,33
Equipment and Medications
n See ‘‘Radiofrequency Denervation of the SIJ,’’ earlier, except use
five SMK needles.
Methodology
1. After obtaining informed consent, place the patient in a prone
position on the fluoroscopic table and prepare and drape the
patient using sterile technique.
2. Position the C-arm over the lumbosacral spine with 258 to 358 of
ipsilateral oblique angulation and 258 to 308 of caudal angula-
tion. For the L4 medial branch nerve block, identify the L4–5
facet joint and the junction between the L5 superior articular
process and the L5 transverse process (Fig. 47–12). For the L5
posterior primary ramus block, identify the L5–S1 facet joint and
the junction between the S1 superior articular process and the
sacral ala (Fig. 47–13).
3. Using 1% lidocaine, anesthetize the skin and subcutaneous tissue
overlying the insertion site.
Figure 47^11. PA radiograph demonstrates needle positioning in the 4. Insert an SMK needle through the anesthetized skin surface and
sacroiliac joint to perform radiofrequency denervation of the nerves advance toward the target sites of injection.
innervating the sacroiliac joint using a ‘‘leapfrog’’ technique. (From 5. Obtain a lateral view of the lumbosacral spine to ensure the
Ferrante M, King L, Roche E, et al. Radiofrequency sacroiliac joint needle tip is not advanced into the neural foramen.
denervation for sacroiliac syndrome. Reg Anesth Pain Med 2001;26:139.) 6. To perform S1–3 lateral branch nerve blocks, the C-arm is posi-
tioned in a slightly cephalocaudad direction to optimize the view
of the S1–3 foramina.
7. Using 1% lidocaine, anesthetize the skin and subcutaneous tissue
approximately 5 mm lateral to each foramen (Fig. 47–14).
SAP
NT
SAP
P
TP
P
TP
NT
A B
Figure 47^12. A and B, Oblique radiographs demonstrate needle tip (NT) placement at the junction of the superior articulating process (SAP)
and the transverse process (TP) in relation to the pedicle (P). (A and B, From Fenton D, Czervionke L [eds]: Image-Guided Spine Intervention.
Philadelphia: Saunders, 2003; pp 127^140.)
SAP
IAP
S
NT
EC
Figure 47^14. Diagram depicts proper needle positioning for the

performance of radiofrequency denervation of the lateral branches of
Figure 47^13. PA radiograph displays proper needle tip (NT)
the S1, S2, and S3 dorsal rami. Needle tips are placed lateral to the
placement at the L5 dorsal primary ramus.The needle tip is located sacral foramen at the 2 and 4 o’clock positions. (From Cohen S, Abdi S.
at the junction between the S1 superior articular process (SAP) and Lateral branch blocks as a treatment for sacroiliac joint pain: a pilot study.
the sacral ala (S).This is shown in relation to the inferior articular Reg Anesth Pain Med 2003;28:114.)
process (IAP). EC, electrode cable. (From Fenton D, Czervionke L [eds]:
Image-Guided Spine Intervention. Philadelphia: Saunders, 2003;
pp 127^140.)
Postprocedure Care after Intra-articular and
Radiofrequency Procedures
8. At each level, insert an SMK needle through the anesthetized n The patient should be placed in the semirecumbant position in
skin surface and advance toward the target sites of injection. the recovery room and observed for 30 minutes, monitoring
For injections performed on the right side, this corresponds to respiratory rate, heart rate, and blood pressure.
the 2 and 4 o’clock positions lateral to the foramina. For injec- n The patient can be discharged into the care of a responsible
tions performed on the left side, this corresponds to the 8 and person once motor strength has returned to preprocedure
10 o’clock positions lateral to the foramina. strength.
9. After all needles have been placed (Fig. 47–15), connect one n The patient should not drive for 24 hours.
needle to the electrode port of the radiofrequency generator. A
grounding pad should also be placed.
10. Confirmation of correct needle placements is made using
sensory and motor stimulation at 50 and 2 Hz, respectively.
Stimulation in a concordant distribution of pain should be
reproduced at a sensory threshold below 0.6 V. Confirm an
absence of lower extremity muscle contraction with the
motor stimulation turned up to a maximum of 3 V.
11. Inject lidocaine 2% (0.5 ml) through each needle and wait at
least 1 minute before performing a unipolar radiofrequency
lesion at 908C for 120 seconds.
12. Allow the needle tip to cool to at least 458C before removing the
probe and starting subsequent lesions.
Cohen and Abdi33 demonstrated that 13 of 18 patients with SIJ

syndrome obtained significant pain relief with diagnostic L4 medial
branch; L5 posterior primary ramus; and S1, S2, and S3 lateral
branch nerve blocks. Of the 9 patients who underwent continuous
radiofrequency lesioning of the nerves, 89% achieved 50% pain
relief lasting up to 9 months. Using a modification of Cohen and
Abdi’s technique,33 Burnham and Yasui34 reported an average of Figure 47^15. PA radiograph demonstrates proper needle tip
50% pain relief 9 months after radiofrequency strip lesioning of the placement for radiofrequency denervation of the L4 medial branch
L5 posterior primary ramus and S1, S2, and S3 lateral branch nerves nerve, the L5 posterior primary ramus, and the lateral branches of
(Fig. 47–16). However, randomized, controlled trials will need to be the S1^3 dorsal rami. (From Cohen S, Abdi S. Lateral branch blocks as a
done to further evaluate the efficacy of all of these radiofrequency treatment for sacroiliac joint pain: a pilot study. Reg Anesth Pain Med
procedures. 2003;28:115.)
lumbar discography experienced ‘‘good or excellent pain relief fol-

lowing SIJ fusion.’’
CONCLUSIONS
Chronic low back pain affects millions of people worldwide, resulting
in disability to perform daily activities of life, work, exercise, and
other enjoyable activities. SIJ syndrome has been identified as a pri-
mary pain generator in approximately 15% of patients with chronic low
back pain.2 Diagnosing SIJ syndrome can be difficult, given its vari-
able symptom referral patterns and poor sensitivity and specificity of
physical examination maneuvers and imaging studies. Whereas intra-
articular injection of local anesthetic and corticosteroids can be effec-
tive in the treatment of SIJ syndrome, the duration of analgesia is often
short-lived. Because repeated steroid injections are not recommen-
ded as a long-term treatment plan, this has resulted in the application
of novel techniques for treating SIJ pain such as viscosupplementation,
radiofrequency denervation, and implantable devices.
Key Points
n SIJ dysfunction is defined as pain originating from the SIJ due to
degeneration or altered joint mobility.
n Current literature suggests that approximately 15% of the pop-
ulation suffers from low back pain and buttock pain originating
from the SIJ.2
n Owing to its anatomic location, contiguous spinal structures can
cause referred pain to the SIJ, which makes the diagnosis of SIJ
Figure 47^16. Diagram depicts multiple needle tip placements
dysfunction difficult.
utilizing the ‘‘strip-lesioning’’ technique for denervation of the S1, S2,
n Because physical examination maneuvers lack sufficient specific-
and S3 lateral branch nerves. (From Burnham R,Yasui Y. An alternate
ity and sensitivity, intra-articular injection of local anesthetic
method of radiofrequency neurotomy ofthe sacroiliac joint: a pilot study of
remains the gold standard for diagnosing SIJ dysfunction.
the effect on pain, function, and satisfaction. Reg Anesth Pain Med
n Using evidence-based literature, there is a lack of consensus as to
2007;32:14.)
which treatment(s) should be offered and which one(s) provides
the best outcomes.
n The patient should avoid soaking the injection site in water and
should avoid placing heat directly over the injection site for 24 to
48 hours. Showering is okay. REFERENCES
n The patient should be given a contact number if any problems or 1. Goldwaith JH, Osgood RB. A consideration of the pelvic articulations
concerns arise after discharge. from an anatomical, pathological, and clinical standpoint. Boston
n The patient should be seen in follow-up in 2 to 4 weeks to assess Med Surg J 1905;152:593–601.
the response to the procedure. 2. Schwarzer AC, Aprill CN, Bogduk N. The sacroiliac joint in chronic
low back pain. Spine 1995;20:31–37.
3. Slipman CW, Patel RK, Shin CH, et al. Studies probe complexity of
Complications of SIJ injections and radiofrequency denervation sacroiliac joint syndrome. BioMechanics 2000;Apr;67–78.
are uncommon. Patients may experience exacerbation of their pain 4. Shibata Y, Shirai Y, Miyamoto M. The aging process in the sacroiliac
for several days after the procedure owing to distention of the SIJ joint: helical computed tomography analysis. J Orthop Sci 2002;7:12–18.
with intra-articular injections or local trauma from needle place- 5. Calvillo O, Skaribas I, Turnipseed J. Anatomy and pathophysiology of
ment. Other adverse events include drug-related allergic reactions, the sacroiliac joint. Curr Rev Pain 2000;4:356–361.
bleeding, infection, transient lower extremity weakness/paresthesias 6. Grob KR, Neuhuber WL, Kissling RO. Innervation of the sacroiliac
(secondary to partial block of the sciatic nerve), and transient dys- joint of the human. Rheumatology 1995;54:117–122.
7. Bernard TN Jr., Cassidy JD. The sacroiliac joint syndrome:
uria.26 Absolute contraindications to SIJ procedures include patient
pathophysiology, diagnosis and management. In Frymoyer J, Ducker
refusal, coagulopathy, infection, or pregnancy. T, Hadler N, et al (eds): The Adult Spine: Principles and Practice, 2nd
More-invasive therapies should be considered only when pain is ed. New York: Raven, 1997; pp 2343–2366.
intractable and disabling. A case report of implanting a neuro- 8. Pang N, Mahajan G, Fishman SM. Sacroiliac joint dysfunction. In
prosthesis to stimulate the third sacral nerve roots documented Wallace M, Staats P (eds): Pain Medicine and Management: Just the
clinical success for two patients who were determined to have SIJ Facts. New York: McGraw-Hill, 2005; pp 336–341.
syndrome based on a positive diagnostic SIJ injection.35 Surgery 9. Cohen S. Sacroiliac joint pain: a comprehensive review of anatomy,
should be explored when the patient has failed to respond to less- diagnosis, and treatment. Anesth Analg 2005;101:1440–1453.
invasive treatments. Screw fixation of the ilium to the sacrum has 10. Fortin J, Aprill C, Dwyer A, Pier J. Sacroiliac joint: pain referral maps
upon applying a new injection/arthrography technique. Part I:
been described. Waisbrod and associates36 demonstrated a 50%
asymptomatic volunteers. Spine 1994;19:1475–1482.
decrease in pain after SIJ fusions in 11 of 21 patients diagnosed 11. Slipman CW, Jackson HB, Chan KW, et al. Sacroiliac joint pain
with SIJ syndrome based on positive SIJ injections, plain films, CT referral zones. Arch Phys Med Rehabil 2000;81:334–338.
bone scan, and physical examination. A prospective study by 12. Dreyfuss P, Michaelson M, Pauza K, et al. The value of medical
Moore37 reported that 90% of patients diagnosed with SIJ syn- history and physical examination in diagnosing sacroiliac joint pain.
drome based on a positive, double-blind SIJ injection and negative Spine 1996;21:2594–2602.
13. Merskey H, Bogduk N (eds): Classifications of Chronic Pain: 31. Chakraverty R, Dias R. Audit of conservative management of chronic
Descriptions of Chronic Pain Syndrome and Definitions of Pain low back pain in a secondary care setting. Acupunct Med
Terms. Seattle: IASP Press, 1993; pp 190–191. 2004;22:207–213.
14. Waldman S (ed): Sacroiliac joint injection and low back pain. In 32. Ferrante M, King L, Roche E, et al. Radiofrequency sacroiliac joint
Interventional Pain Management. Philadelphia: WB Saunders, 2001; denervation for sacroiliac syndrome. Reg Anesth Pain Med
pp 535–540. 2001;26:137–142.
15. Reider B (ed): Pelvis, hip and thigh. In The Orthopaedic Physical 33. Cohen S, Abdi S. Lateral branch blocks as a treatment for sacroiliac
Examination, Philadelphia: WB Saunders, 2001; pp 195–197. joint pain: a pilot study. Reg Anesth Pain Med 2003;28:113–119.
16. Saal JS. General principles of diagnostic testing as related to painful 34. Burnham R, Yasui Y. An alternate method of radiofrequency
lumbar spine disorders: a critical appraisal of current diagnostic neurotomy of the sacroiliac joint: a pilot study of the effect on pain,
techniques. Spine 2002;27:2538–2546. function, and satisfaction. Reg Anesth Pain Med 2007;32:12–19.
17. Dreyfuss P, Dryer S, Griffin J, et al. Positive sacroiliac screening test 35. Calvillo O, Esses SI, Ponder C, et al. Neuroaugmentation in the
in asymptomatic adults. Spine 1994;19:1138–1143. management of sacroiliac joint pain. Report of two cases. Spine
18. Broadhurst NA, Bond MJ. Pain provocation tests for the assessment 1998;23:1069–1072.
of sacroiliac joint dysfunction. J Spinal Disord 1998;11:341–345. 36. Waisbrod H, Krainick JU, Gerbershagen HU. Sacroiliac joint
19. Vogel JB III, Brown WH, Helms CA, Genant HK. The normal sacroiliac arthrodesis for chronic lower back pain. Arch Orthop Trauma Surg
joint: a CT study of asymptomatic patients. Radiology 1984;151:433–437. 1987;106:238–240.
20. Slipman CW, Sterenfeld EB, Pauza K, et al. Sacroiliac joint syndrome: 37. Moore MR. Results after sacroiliac joint fusion. Presented at Third
the diagnostic value of single photon emission computed tomography. World Interdisciplinary Congress on Low Back Pain and Its Relation
Int Spine Injection Soc 1994;2:2–20. to the Sacroiliac Joint. November 1998,Vienna.
21. Battafarano DF, West SG, Rak KM, et al. Comparison of bone scan,
computed tomography, and magnetic resonance imaging in the
diagnosis of active sacroiliitis. Semin Arthritis Rheum 1993;23:101–176. SUGGESTED READINGS
22. Hanly JG, Mitchell MJ, Barnes DC, MacMillan L. Early recognition
ofsacroiliitis by magnetic resonance imaging and single photon Burnham R, Yasui Y. An alternate method of radiofrequency neurotomy
emission computed tomography. J Rheumatol 1994;21:2088–2095. of the sacroiliac joint: a pilot study of the effect on pain, function, and
23. Rathmell J (ed): Sacroiliac joint injection. In Atlas of Image-Guided satisfaction. Reg Anesth Pain Med 2007;32:12–19.
Intervention in Regional Anesthesia and Pain Medicine. Philadelphia: Calvillo O, Esses SI, Ponder C, et al. Neuroaugmentation in the
Lippincott Williams & Wilkins, 2006; pp 93–100. management of sacroiliac joint pain. Report of two cases. Spine
24. Richardson C, Snijders C, Hides J, et al. The relation between the 1998;23:1069–1072.
transversus abdominis muscles, sacroiliac joint mechanics, and low Calvillo O, Skaribas I, Turnipseed J. Anatomy and pathophysiology of the
back pain. Spine 2002;27:399–405. sacroiliac joint. Curr Rev Pain 2000;4:356–361.
25. Rosenberg JM, Quint TJ, Rosayro AM. CT localization of clinically Cohen S. Sacroiliac joint pain: a comprehensive review of anatomy,
guided SI joint injections.’’ Clin J Pain 2000;16:18–21. diagnosis, and treatment. Anesth Analg 2005;101:1440–1453.
26. Fenton DS. Sacroiliac joint injection. In Fenton D, Czervionke L Cohen S, Abdi S. Lateral branch blocks as a treatment for sacroiliac joint
(eds): Image-Guided Spine Intervention. Philadelphia: Saunders, 2003; pain: a pilot study. Reg Anesth Pain Med 2003;28:113–119.
pp 127–140. Dreyfuss P, Michaelson M, Pauza K, et al. The value of medical history
27. Benzon HT. Pain originating from the buttock: sacroiliac joint and physical examination in diagnosing sacroiliac joint pain. Spine
dysfunction and piriformis syndrome. In Benzon H, Raja S, Barsook 1996;21:2594–2602.
D (eds): Essentials of Pain Medicine and Regional Anesthesia, 2nd ed. Ferrante M, King L, Roche E, et al. Radiofrequency sacroiliac joint
Philadelphia: Elsevier Churchill Livingstone, 2005; pp 357–360. denervation for sacroiliac syndrome. Reg Anesth Pain Med
28. Bernard TN Jr, Kirkaldy-Willis WH. Recognizing specific characteristics 2001;26:137–142.
of nonspecific low back pain. Clin Orthop Rel Res 1987;217:266–280. Grob KR, Neuhuber WL, Kissling RO. Innervation of the sacroiliac joint
29. Maugers Y, Mathis C, Vilon P, Prost A. A corticosteroid injection of of the human. Rheumatology 1995;54:117–122.
the sacroiliac joint in patients with seronegative spondyloarthropathy. Slipman CW, Jackson HB, Chan KW, et al. Sacroiliac joint pain referral
Arthritis Rheum 1992;35:564–568. zones. Arch Phys Med Rehabil 2000;81:334–338.
30. Srejic U, Calvillo O, Kabakibou K. Viscosupplementation: a new Slipman CW, Patel RK, Shin CH, et al. Studies probe complexity of
concept in the treatment of sacroiliac joint syndrome: a preliminary sacroiliac joint syndrome. BioMechanics 2000;April:67–78.
report of four cases. Reg Anesth Pain Med 1999;24:84–88.
Chapter 48 investigations into the relationship between pain and sleep is

that they are reciprocal by nature. Pain can disrupt and decrease
PAIN AND SLEEP the quality of a patient’s sleep, and poor sleep can, in turn, increase
a patient’s perception of pain. Although, in practice, a better
Howard S. Smith, Lynn R. Webster, Christine Gallati, understanding of the interaction between pain and sleep could
potentially reduce pain and increase the quality of life for patients
and Clete A. Kushida suffering from a wide variety of conditions, this field of research
has remained largely untapped and underappreciated. This chapter
first gives an overview of what we currently know about the
interaction of pain and sleep and then discusses some current
interventions available to patients suffering from pain, with spe-
cial attention paid to how these treatments affect sleep. Future
INTRODUCTION studies directed at bridging these two fields of science hold tremen-
dous promise for providing novel therapeutic strategies for
Sleep difficulties and disturbances in pain patients are widespread patients suffering from inadequate sleep, chronic pain, or a combi-
and clinically significant. One axiom that has emerged from nation of both.
13. Merskey H, Bogduk N (eds): Classifications of Chronic Pain: 31. Chakraverty R, Dias R. Audit of conservative management of chronic
Descriptions of Chronic Pain Syndrome and Definitions of Pain low back pain in a secondary care setting. Acupunct Med
Terms. Seattle: IASP Press, 1993; pp 190–191. 2004;22:207–213.
14. Waldman S (ed): Sacroiliac joint injection and low back pain. In 32. Ferrante M, King L, Roche E, et al. Radiofrequency sacroiliac joint
Interventional Pain Management. Philadelphia: WB Saunders, 2001; denervation for sacroiliac syndrome. Reg Anesth Pain Med
pp 535–540. 2001;26:137–142.
15. Reider B (ed): Pelvis, hip and thigh. In The Orthopaedic Physical 33. Cohen S, Abdi S. Lateral branch blocks as a treatment for sacroiliac
Examination, Philadelphia: WB Saunders, 2001; pp 195–197. joint pain: a pilot study. Reg Anesth Pain Med 2003;28:113–119.
16. Saal JS. General principles of diagnostic testing as related to painful 34. Burnham R, Yasui Y. An alternate method of radiofrequency
lumbar spine disorders: a critical appraisal of current diagnostic neurotomy of the sacroiliac joint: a pilot study of the effect on pain,
techniques. Spine 2002;27:2538–2546. function, and satisfaction. Reg Anesth Pain Med 2007;32:12–19.
17. Dreyfuss P, Dryer S, Griffin J, et al. Positive sacroiliac screening test 35. Calvillo O, Esses SI, Ponder C, et al. Neuroaugmentation in the
in asymptomatic adults. Spine 1994;19:1138–1143. management of sacroiliac joint pain. Report of two cases. Spine
18. Broadhurst NA, Bond MJ. Pain provocation tests for the assessment 1998;23:1069–1072.
of sacroiliac joint dysfunction. J Spinal Disord 1998;11:341–345. 36. Waisbrod H, Krainick JU, Gerbershagen HU. Sacroiliac joint
19. Vogel JB III, Brown WH, Helms CA, Genant HK. The normal sacroiliac arthrodesis for chronic lower back pain. Arch Orthop Trauma Surg
joint: a CT study of asymptomatic patients. Radiology 1984;151:433–437. 1987;106:238–240.
20. Slipman CW, Sterenfeld EB, Pauza K, et al. Sacroiliac joint syndrome: 37. Moore MR. Results after sacroiliac joint fusion. Presented at Third
the diagnostic value of single photon emission computed tomography. World Interdisciplinary Congress on Low Back Pain and Its Relation
Int Spine Injection Soc 1994;2:2–20. to the Sacroiliac Joint. November 1998,Vienna.
21. Battafarano DF, West SG, Rak KM, et al. Comparison of bone scan,
computed tomography, and magnetic resonance imaging in the
diagnosis of active sacroiliitis. Semin Arthritis Rheum 1993;23:101–176. SUGGESTED READINGS
22. Hanly JG, Mitchell MJ, Barnes DC, MacMillan L. Early recognition
ofsacroiliitis by magnetic resonance imaging and single photon Burnham R, Yasui Y. An alternate method of radiofrequency neurotomy
emission computed tomography. J Rheumatol 1994;21:2088–2095. of the sacroiliac joint: a pilot study of the effect on pain, function, and
23. Rathmell J (ed): Sacroiliac joint injection. In Atlas of Image-Guided satisfaction. Reg Anesth Pain Med 2007;32:12–19.
Intervention in Regional Anesthesia and Pain Medicine. Philadelphia: Calvillo O, Esses SI, Ponder C, et al. Neuroaugmentation in the
Lippincott Williams & Wilkins, 2006; pp 93–100. management of sacroiliac joint pain. Report of two cases. Spine
24. Richardson C, Snijders C, Hides J, et al. The relation between the 1998;23:1069–1072.
transversus abdominis muscles, sacroiliac joint mechanics, and low Calvillo O, Skaribas I, Turnipseed J. Anatomy and pathophysiology of the
back pain. Spine 2002;27:399–405. sacroiliac joint. Curr Rev Pain 2000;4:356–361.
25. Rosenberg JM, Quint TJ, Rosayro AM. CT localization of clinically Cohen S. Sacroiliac joint pain: a comprehensive review of anatomy,
guided SI joint injections.’’ Clin J Pain 2000;16:18–21. diagnosis, and treatment. Anesth Analg 2005;101:1440–1453.
26. Fenton DS. Sacroiliac joint injection. In Fenton D, Czervionke L Cohen S, Abdi S. Lateral branch blocks as a treatment for sacroiliac joint
(eds): Image-Guided Spine Intervention. Philadelphia: Saunders, 2003; pain: a pilot study. Reg Anesth Pain Med 2003;28:113–119.
pp 127–140. Dreyfuss P, Michaelson M, Pauza K, et al. The value of medical history
27. Benzon HT. Pain originating from the buttock: sacroiliac joint and physical examination in diagnosing sacroiliac joint pain. Spine
dysfunction and piriformis syndrome. In Benzon H, Raja S, Barsook 1996;21:2594–2602.
D (eds): Essentials of Pain Medicine and Regional Anesthesia, 2nd ed. Ferrante M, King L, Roche E, et al. Radiofrequency sacroiliac joint
Philadelphia: Elsevier Churchill Livingstone, 2005; pp 357–360. denervation for sacroiliac syndrome. Reg Anesth Pain Med
28. Bernard TN Jr, Kirkaldy-Willis WH. Recognizing specific characteristics 2001;26:137–142.
of nonspecific low back pain. Clin Orthop Rel Res 1987;217:266–280. Grob KR, Neuhuber WL, Kissling RO. Innervation of the sacroiliac joint
29. Maugers Y, Mathis C, Vilon P, Prost A. A corticosteroid injection of of the human. Rheumatology 1995;54:117–122.
the sacroiliac joint in patients with seronegative spondyloarthropathy. Slipman CW, Jackson HB, Chan KW, et al. Sacroiliac joint pain referral
Arthritis Rheum 1992;35:564–568. zones. Arch Phys Med Rehabil 2000;81:334–338.
30. Srejic U, Calvillo O, Kabakibou K. Viscosupplementation: a new Slipman CW, Patel RK, Shin CH, et al. Studies probe complexity of
concept in the treatment of sacroiliac joint syndrome: a preliminary sacroiliac joint syndrome. BioMechanics 2000;April:67–78.
report of four cases. Reg Anesth Pain Med 1999;24:84–88.
Chapter 48 investigations into the relationship between pain and sleep is

that they are reciprocal by nature. Pain can disrupt and decrease
PAIN AND SLEEP the quality of a patient’s sleep, and poor sleep can, in turn, increase
a patient’s perception of pain. Although, in practice, a better
Howard S. Smith, Lynn R. Webster, Christine Gallati, understanding of the interaction between pain and sleep could
potentially reduce pain and increase the quality of life for patients
and Clete A. Kushida suffering from a wide variety of conditions, this field of research
has remained largely untapped and underappreciated. This chapter
first gives an overview of what we currently know about the
interaction of pain and sleep and then discusses some current
interventions available to patients suffering from pain, with spe-
cial attention paid to how these treatments affect sleep. Future
INTRODUCTION studies directed at bridging these two fields of science hold tremen-
dous promise for providing novel therapeutic strategies for
Sleep difficulties and disturbances in pain patients are widespread patients suffering from inadequate sleep, chronic pain, or a combi-
and clinically significant. One axiom that has emerged from nation of both.
364 Chapter 48 PAIN AND SLEEP
PAIN AND SLEEP DISTURBANCES setting.15 PSG studies of critically ill patients in the intensive care unit
with acute myocardial infraction, congestive heart failure, and stroke
Sleep disturbances (e.g., difficultly initiating sleep, frequent awaken- reported similar findings. Although total sleep time usually returns to
ings, shortened total sleep time, earlier awakening, unrefreshing preoperative levels within 1 week of hospitalization after surgery,15–17
sleep) have been documented in a variety of pain patients, including one study of 57 cardiac and 29 orthopedic patients after elective
cancer patients, noncancer chronic pain patients, patients in the surgery (N = 86) showed near doubling (10%–19%) in the rate of
postsurgery setting, patients hospitalized with acute conditions, insomnia 3 months after discharge.18 The development of sleep dis-
and burn victims. Studies reporting on these populations utilized orders can have long-term, deleterious effects on the recovery and
both objective (actigraphy and polysomnography) and subjective quality of life of patients, aggravating existing medical conditions,
(surveys and questionnaires) measures of sleep disturbance. especially those involving chronic inflammation,19 and in some
The prevalence of sleep disturbances in patients who suffer from cases, leading to the development of chronic pain conditions.20
chronic pain is higher than that in the general population. This fact
was clearly demonstrated in a community-based survey study con-
ducted by Ohayon in 2005.1 The results indicated that there was a THE RECIPROCAL NATURE OF SLEEP
high prevalence of sleep problems in individuals suffering from pain- AND PAIN
ful medical illnesses. Forty-two percent of individuals who reported
insomnia symptoms had at least one type of chronic pain. Approximately two thirds of pain patients complain of sleep pro-
Conversely, 23% of respondents with chronic pain reported at least blems. It appears that the combination of pain and poor sleep may
one symptom of insomnia, which include unrefreshing sleep, diffi- produce more severe consequences than either of these factors
cultly falling asleep, sleep disruptions, and premature awakening.1 could produce by themselves.21 It also seems that pain and poor
Sleep dysfunctions are more common in a number of chronic sleep can serve to bolster each other: pain causing sleep disturbances
pain conditions, such as rheumatoid arthritis, fibromyalgia, chronic and sleep disturbances leading a patient to experience more-intense
headaches, osteoarthritis, and low back pain. Rheumatologic dis- pain.22–25
eases are highly associated with sleep disorders. It is estimated that Many studies have documented enhanced pain perception, in
at least 50% of these patients suffer from chronic insomnia.2 In one both humans and rats, after sleep deprivation. A number of these
study of 101 subjects diagnosed with fibromyalgia, 99% of partici- studies have indicated that REM sleep deprivation, specifically, has
pants reported poor sleep quality.3 In another study of women with the ability to increase pain perception.26–35
fibromyalgia, 48% (n = 29) of the participants reported moderate to Functional neuroimaging studies have shown that sleep and pain
severe difficulty sleeping.4 A survey of 268 patients with chronic may involve opposing neural networks.36–39 When sleep is initiated,
lower back pain found a significant relationship between pain and both the pain neuromatrix and the arousal ascending system are
sleep quality. After the onset of pain, there was a 55% increase in the deactivated. It has, therefore, been hypothesized, conversely, that
proportion of the participants that reported disturbed sleep.5 pain input and activation of the pain neuromatrix can prevent
Primary sleep disorders other than insomnia, such as sleep apnea the onset of sleep by increasing arousal.
and periodic limb movements, are more prevalent in individuals There is a body of evidence that sleep disturbances and pain
suffering from chronic pain conditions. There appears to be a enhance and maintain each other.40,41 It has even been suggested
strong association between chronic headaches and sleep apnea. that sleep disturbances play an etiologic role in the development of
Individuals with obstructive sleep apnea syndrome (OSA) are seven certain chronic pain conditions.20 If these hypotheses hold cre-
times more likely to experience chronic headaches (headaches occur- dence, they make a powerful argument for integrating pain and
ring 15 times or more throughout a month) than the general popu- sleep medicine in the treatment of individuals with chronic pain
lation.6 These headaches usually occur in the morning, and their conditions.42 Optimal analgesic medications may improve patients’
severity shows a direct relationship with the severity of the patient’s sleep and effective treatment of sleep disorders may help to alleviate
OSA.7 There also seems to be a strong connection between fibromy- painful conditions. More research is needed to identify the hall-
algia and sleep apnea. In a study of patients diagnosed with sleep marks of patients with pain and sleep disorders that would stand
apnea, it was found that the rate of fibromyalgia (n = 50) was to benefit most from this type of integrated treatment.
10-fold higher in the study group than in the general public.8
Evidence suggests that OSA may even play an etiologic role in some
cases of fibromyalgia. Sepici and coworkers9 reported on case study in SLEEP: IMPORTANCE, ARCHITECTURE,
which a woman presented with both fibromyalgia and OSA. After the EFFECTS ON PAIN PERCEPTION, AND
patient received nasal continuous positive airway pressure (CPAP)
treatment for her OSA, her fibromyalgia symptoms also showed PHARMACOLOGY
vast improvement.9 It is also well established that fibromyalgia
patients often experience OSA and periodic limb movements.10,11 The Biologic Importance of Sleep
The pain associated with burn injuries has also been shown to
cause sleep disturbances. Burn pain is interesting in that it can Sleep is a highly conserved physiologic process throughout the
disrupt sleep long after the acute pain phase is over.12–14 In a animal kingdom. It is believed to play a role in a wide variety of
study of 82 children and adolescents, researchers found that many biologic processes, including protein synthesis, cellular growth and
of the subjects had at-home sleep disorders over a year after the proliferation, metabolism, and immune function. Sleep is essential
initial burn injury.12 for proper homeostasis. Extreme sleep deprivation has been shown
Individuals who are hospitalized with acute pain often experi- to produce dire results in animals. In a 1983 study, Rechtschaffen
ence sleep disturbances. The prevalence of patients suffering from and associates43a demonstrated that severe reductions in the sleep of
sleep disturbances during hospitalization appears to be variable. rats, via mild physical stimulus, caused serious pathologies and
Studies have found a wide range of values, from 22% to 61%, for death. In a later review of similar studies,43 it was suggested that
acutely ill patients who report sleep disturbances.15–17 one of the ways in which sleep deprivation exerts its deleterious and
Polysomnographic (PSG) studies have confirmed patient reports fatal effects is by interfering with thermoregulation.
of poor sleep quality, showing reduced total sleep time for the first Sleep has also been implicated in the regulation of protein syn-
2 nights after surgery, sleep fragmentation with frequent arousals thesis. The expression of genes associated with the positive regula-
and awakenings, a notable decrease of rapid eye movement (REM) tion of translation is increased by sleep.44 Studies in rats showed that
sleep, as well as reduced slow wave sleep (SWS) in the postsurgical sleep deprivation causes a reduction in the proliferation of cells.45
Sleep is accompanied by a reduction in body temperature and noxious thermal stimuli.30,31,54,55 It has been hypothesized that
metabolism, which has led to the theory that one of sleep’s vital this phenomenon is mediated by a loss of regular opioidergic and
roles is to provide a period of energy conservation.46 It has been monoaminergic descending inhibitory mechanisms.56 Currently,
suggested that this period of metabolic respite can serve to combat only a few parallel studies have been conducted in humans, and
oxidative stress. The higher metabolic rates associated with wake- results from these studies have not consistently mirrored those done
fulness are believed to lead to the accumulation of free radicals. in animals.
Prolonged sleep deprivation in rats resulted in a significant decrease A study of nine healthy men found that total sleep deprivation,
in the levels of superoxide dismutase, a potent, endogenous anti- but not REM deprivation, produced a slight decrease in the thresh-
oxidant in the hippocampus and brainstem that can protect against old for mechanical pain (8%), but no reduction in the threshold
damages wrought by reactive oxygen species (ROS).47 for noxious heat stimuli was seen with either total sleep or selective
Everson and colleagues48 studied glutathione content in the liver, REM sleep deprivation.31 Surprisingly, the largest reduction in
heart, and lung with sleep deprivation because glutathione is consid- the threshold for mechanical pain (15%) was observed when sub-
ered a major free radical scavenger that reflects the degree of oxida- jects were deprived of SWS. These results suggest that SWS sup-
tive stress. They also investigated the activities of major enzymatic pression may be more critical than REM sleep suppression when
antioxidants, including catalase and glutathione peroxidase, as well considering the detrimental effects of selective modulations in sleep
as indexes of glutathione recycling.48 Catalase activity and glutathi- architecture that an analgesic drug could potentially have on a
one content, which normally are tightly regulated, were both patient.31 This conclusion is not consistent with the findings in
decreased in liver by 23% to 36% by 5 and 10 days of sleep depriva- similar animal studies and raises the concern that the relationship
tion.48 The decreases were accompanied by markers of generalized between pain and suppression of different phases of sleep may be
cell injury and absence of responses by the other enzymatic antiox- different and more complex in humans. It should also be noted that
idants under study.48 Recovery sleep normalized antioxidant content no reduction in thermal pain thresholds were observed in this
in liver and enhanced enzymatic antioxidant activities in both the study.
liver and the heart.48 Another similar study, however, showed findings that were
Sleep also appears to be intertwined with immune function. We somewhat consistent with animal studies. This study of 13 healthy
are all familiar with the natural drive to increase our sleep when we subjects—7 participating in a total sleep–deprivation protocol and
are sick. Experimentally, animals also demonstrate increased levels 6 participating in a REM sleep–deprivation protocol—showed that
of sleep when they are presented with infection.49 We also know, sleep loss and specific suppression of REM sleep produced hyper-
through personal experience, that elevated levels of sleep may speed algesic effects the following morning. This study, interestingly,
one’s recuperation. This fact has also been validated in animal found these reductions in pain thresholds by using noxious heat
studies. In rats, infection combined with sleep deprivation, in com- as the pain stimulus. Onen and colleagues’ 2001 study,31 however,
parison with infection alone, is correlated with increased levels of found no reductions in pain thresholds when they used this type of
certain bacteria in the blood and higher mortality rates.50 Sleep stimulus on their sleep deprived patients.
deprivation in rats also leads to elevated levels of immunity-related, Another study looked at the effects of sleep restriction and dis-
inflammatory cytokines, including interleukin (IL)-1 and tumor ruption on pain in 32 healthy females.57 The researchers found that
necrosis factor (TNF),51 which have sleep-promoting properties.52 whereas sleep deprivation had no effect on pain thresholds, dis-
Other studies showed that sleep helps to attenuate proinflammatory turbed sleep (which consisted of forced awakenings during each
immune responses, wherras sleep deprivation can worsen them. hour of sleep) was associated with a loss of pain inhibition and
Sleep disturbances and disorders in individuals with chronic an increase in spontaneous pain. Sleep restriction (reduced total
inflammatory conditions (e.g., rheumatoid arthritis, fibromyalgia) sleep), however, was found to have no effect on pain inhibition
are beleived to exacerbate disease symptoms by dysregulating the or spontaneous pain. These results imply that disruptions in the
immune system.19 continuity of sleep hinder endogenous pain-inhibitory function,
increasing spontaneous pain. This study lends support to the
notion that sleep disturbance may play a role in the development
The Architecture of Sleep and maintenance of chronic pain.57
Currently, strong statements cannot be made about the effects of
During the first stage of non–rapid eye movement (NREM) sleep disturbed and restricted sleep on pain in humans. Animal studies,
(N1), the eyes are closed and PSG readings show a reduction in however, definitively show that the specific suppression of REM
activity. This stage lasts for 5 to 10 minutes and then progresses into sleep causes an increase in mechanical pain perception. This may
N2 (formerly called ‘‘stage 2’’ sleep). N2 sleep is marked by a very well be true of humans, but more studies with large sample
decrease in both body temperature and heart rate. During this sizes are necessary to determine this. The evidence implicating sleep
period of light sleep, PSG readings display sporadic peaks, known disruption in pain inhibition and the suppression of spontaneous
as positive and negative waves, which coincide with intermittent pain, however, is convincing and consistent with the functional
periods of muscle tone and relaxation. From here, the body neuroimaging studies that have shown that sleep and pain involve
enters N3 sleep. N3 (formerly called ‘‘stages 3 and 4’’ sleep) is opposing neural networks.36–39 It is important to note that these
considered ‘‘deep sleep’’ or slow wave sleep (SWS). Once slow studies were conducted on healthy individuals, so even if the sample
waves take over 20% of the electroencephalographic (EEG) pattern, sizes were larger and the results were more authoritative, they would
N3 sleep has been attained. The sleeper may enter REM sleep after not necessarily provide accurate information about the effects of
N3 or N2 sleep. The sleeper will cycle from deep to light sleep and disturbed sleep in pain patients.
REM throughout the night; SWS time decreases while N2 and REM Roehrs and coworkers58 studied 13 healthy pain-free normal
sleep time lengthen as the night progresses. One average sleep cycle sleepers, 7 in a sleep-loss protocol and 6 in a REM sleep–loss pro-
typically lasts 60 to 90 minutes. Most people experience four to six tocol. Finger-withdrawal latency to a radiant heat stimulus tested at
NREM-REM cycles per night, depending on the length of sleep.43,53 10:30 AM and 2:30 PM and the Multiple Sleep Latency Test con-
ducted at 10:00 AM, noon, 2:00 PM, and 4:00 PM were measured
the following day.58 Finger-withdrawal latency was shortened by
Pain Perception 25% after 4 hours of time in bed the previous night relative to
8 hours of time in bed (P < .05), and REM sleep deprivation relative
Animal studies have demonstrated that REM sleep deprivation can to an NREM yoked-control sleep-interruption condition shortened
substantially reduce thresholds for both mechanical pain and finger-withdrawal latency by 32% (P < .02).58 Roehrs and
coworkers58 concluded that the loss of 4 hours of sleep and specific THEORETICAL DRUG-SLEEP
REM sleep loss are hyperalgesic the following day and suggested INTERACTIONS
that pharmacologic treatments and clinical conditions that reduce
total sleep and/or reduce REM sleep time may increase pain. The fact that we have some basal knowledge about the neurochem-
istry associated with wakefulness, the various stages of sleep, and the
transition between these allows us to, in some instances, argue a
The Pharmacology of Sleep rationale or pose a theory as to how a medication affects or will
affect sleep patterns. It is important to keep the following pharma-
Many pain medications affect sleep patterns. In order to understand cologic features of normal wakefulness and sleep in mind: (1) wake-
these drug-induced modulations from a pharmacologic standpoint, fulness is characterized by high cholinergic, serotonergic,
we must first discuss the neurochemical fluctuations that accom- noradrenergic, and histaminergic tone, (2) the transition from
pany wakefulness and normal sleep cycles. wakefulness to light sleep is characterized by a decrease in the
tone of all these neurotransmitters, (3) an increase in GABAergic
tone is responsible for the decline in the tone of these neurotrans-
Wakefulness and theTransition to NREM Sleep
mitters, (4) in NREM sleep, cholinergic tone levels off at an inter-
The hypocretinergic/orexinergic system plays an essential role in the mediate level, whereas the tone of all of the other three
maintenance of wakefulness. The hypocretinergic/orexinergic neurotransmitters continues to decline, and (5) REM sleep is
system consists of a small group of neurons located in the posterior marked by a rebound in cholinergic tone to its original wakeful
and lateral hypothalamus that produce hypocretins/orexins, which levels, and serotonergic, noradrenergic, and histaminergic tone all
are neuropeptides. The loss of these neurons is associated with the remain low during this phase.
development of narcolepsy.59–61 Taking these points into consideration allows us to make a
This system is believed to promote wakefulness by (1) inhibiting number of predictions about the effects different types of pharma-
the ventral pontine tegmentum neurons (thereby suppressing REM ceuticals will have on sleep architecture. Agents with anticholinergic
sleep), (2) directly activating the cerebral cortex, and (3) stimulating activity can be expected to promote SWS but inhibit REM
neuronal clusters in the reticular-activating system that produce sleep. Opioid analgesics are a good example of this type of drug.
histamine, acetylcholine, dopamine, serotonin, and noradrenaline. The mechanism of action behind opioids’ sedative effects involves
Wakefulness is associated with cholinergic, noradrenergic, and his- the inhibition of cholinergic and possibly noradrenergic neurons.69
taminergic tone in key areas of the cerebral cortex.59–62 The onset of Agents that work to increase GABAergic tone will bolster SWS but
sleep is associated with a decrease in the activity of the hypocreti- inhibit the transition into REM sleep. Agents that enhance mono-
nergic/orexinergic neurons, which allows for the generation of REM aminergic tone will promote wakefulness and block the transition
sleep in the ventral pontine tegmetum and inhibits aminergic and into sleep. Some tricyclic antidepressants (TCAs) that are used as
cholinergic neurons of the reticular-activating system,63 which leads analgesics inhibit the reuptake of serotonin and/or nore-
to a decrease in the serotonergic, cholinergic, noradrenergic, and pinepherine after their release into the synaptic cleft. Certain anti-
histaminergic tone in the brain.59,60 The onset of NREM sleep is epileptic drugs increase GABA levels or inhibit its reuptake. In
also associated, specifically, with the inhibition of the noradrenergic general, these predictions hold true, but only in the context of
neurons of the locus ceruleus64 and the histaminergic neurons in healthy subjects. When pain becomes a factor, things become
the tuberomammilary nucleus of the hypothalamus.65 It is hypothe- more confusing because pain itself has the ability to alter sleep
sized that the decreased activity of all of these neurons promotes architecture.
both the initiation and the maintenance of SWS.
It is still not entirely clear what triggers the onset of sleep, but it
has been hypothesized that the accumulation of certain metabolites Current Pharmacologic Pain Treatments and Their
in the brain plays a role in this process.62 One of the suspect meta- Effects on Sleep
bolites is adenosine, which is an end-product resulting from the
breakdown of adenosine triphosphate (ATP). It is speculated that Opioids
as the waking day progresses, ATP is metabolized in the brain,
raising central nervous system) levels of adenosine. Elevated levels In rat and cats, acute administration of morphine results in a dose-
of adenosine then activate adenosine A1 receptors, which suppress related suppression of REM sleep.70–75 In rats, there are variable
neuronal activity in key areas of the central nervous system, includ- effects on SWS after the acute administration of morphine, but
ing the basal forebrain and the reticular-activating system, both of SWS returns to normal if morphine is chronically administered.
which are implicated in the maintenance of wakefulness.66 Other REM sleep, however, remains significantly suppressed throughout
metabolites that could be involved in the promotion of sleep initi- the chronic administration of morphine.72,76 In rats, selective sup-
ation have yet to be identified. pression of REM sleep decreases the effects of both morphine and
enkephalins on pain produced by mechanical stimulus.35 Parallel
studies in humans have shown similar suppression of REM in
REM Sleep
opioid-treated patients.77–81 Recently, a double-blind, multiple
The transition to REM sleep from NREM sleep is associated with a cross-over study was conducted to examine the effects of morphine
profound decrease in aminergic tone as well as an increase in cho- and methadone on the sleep architecture of healthy human subjects
linergic tone as a result of increased cholinergic neuronal activity in (N = 42).82 Morphine sulfate (15 mg), methadone (5 mg), or pla-
the pontine reticular formation.62,67 Thus, wakefulness and REM cebo was administered before sleep. Sleep architecture and distur-
sleep states are both believed to be maintained by enhanced cho- bances were recorded using polysomnography. Both morphine and
linergic tone in the central nervous system. However, during REM methadone significantly reduced N3 sleep and increased N2 sleep.82
sleep, the activity of the noradrenergic and serotonergic neurons is It was stated previously that suppression of REM sleep causes a
minimized, which leads to a significant decrease in central nervous reduction in the threshold for mechanical pain in animals.
system levels of these neurotransmitters during this state. As is the Although these results have yet to be mirrored in parallel human
case for the transition into NREM, the decrease in release of these studies, one could hypothesize that the selective suppression of
monoamine neurotransmitters is mediated through active suppres- REM sleep by morphine and other opiates may reduce their efficacy
sion of neuronal activity through an increase in g-aminobutyric in the treatment of chronic and acute pain by decreasing patients’
acid (GABA)ergic tone.68 pain thresholds.
Along with disrupting sleep architecture through direct neuro- sleep that appears to be sustained for the duration of drug admin-
pharmacology, opioids have also been implicated in disrupting istration.95 Duloxetine also inhibits the uptake of both 5-HT
sleep by causing and promoting sleep apnea. ‘‘Since 2001 there and noradrenaline and, like amitriptyline, seems to significantly
has been an emerging literature that suggests that chronic opioid inhibit REM.96 Selective serotonin reuptake inhibitors (SSRIs),
use is related to central sleep apnea of both periodic and non- including paroxetine, demonstrate a similar tendency toward
periodic breathing types, and occurs in approximately 30% of REM suppression.95,97,98 These TCAs are believed to suppress REM
these subjects.’’83 In a retrospective cohort study that compared sleep by increasing the activation of 5-HT1A and 5-HT2 receptors.
the sleep breathing patterns of 60 patients taking chronic opioids Amitriptyline as well as duloxetine and venlafaxine, the mixed
with 60 matched patients who were not taking opioids, researchers 5-HT–norepinephrine reuptake inhibitors (SNRIs), also inhibit
found a correlation between chronic opioid use and OSA.84 OSA REM sleep through increased activation of the a1-adrenergic
results in fragmented, disrupted sleep, which is associated with the receptors.93
impairment of pain inhibition and increased spontaneous pain. Mirtazapine and nefazodone are two newer antidepressants that
Clinically, opioids are probably less effective than they could be appear to have minimal effects on sleep architecture. Mirtazapine
because they suppress REM sleep, which may reduce patients’ works by blocking a2-adrenergic receptors, 5-HT2 receptors, and
threshold for pain, and they can lead to sleep disruptions that histamine receptors.93 A single dose of mirtazapine before sleep
could work to maintain a condition of chronic pain. increased SWS with little effect on REM sleep in a study of six
Available data and polysomnography were analyzed for 140 healthy males.99 In another study of six clinically depressed patients,
patients on around-the-clock opioid therapy for at least 6 months mirtazapine was administered daily for a 2-week period and showed
with a stable dose for at least 4 weeks.85 The apnea-hypopnea index no significant effects on sleep architecture.100 Nefazodone has lim-
was abnormal ( 5/hr) in 75% of patients (39% had OSA, 4% had ited ability to inhibit the reuptake of 5-HT and norepinephrine and
sleep apnea of indeterminate type, 24% had central sleep apnea, and also acts as an antagonist of 5-HT2 receptors.93 A placebo-con-
8% had both central sleep apnea and OSA); 25% had no sleep trolled, double-blind study of 37 subjects showed that nefazodone
apnea.85 Webster and associates85 found a direct relation between had no significant effect on SWS or REM sleep time.98 An 8-week
the apnea-hypopnea index and the daily dosage of methadone clinical trial of eight women with seasonal affective disorder in
(P = .002) but not to other around-the-clock opioids.85 Webster which nefazodone was administered daily similarly showed no sig-
and associates85 found a direct relation between the central apnea nificant changes in sleep architecture.101 It is believed that these
index and the daily dosage of methadone (P = .008) and also with agents are less disruptive to sleep architecture because they block
benzodiazepines (P = .0004).85 5-HT2 receptors.92,93
Webster and associates85 concluded that sleep-disordered
breathing was common in chronic pain patients on opioids and
Antiepileptics
the dose-response relation of sleep apnea to methadone and to
benzodiazepines called for increased vigilance.85 Many antiepileptic drugs are used to treat chronic pain, including
A limited number of studies have investigated the effects of neuropathic disorders. The drugs most frequently used for these
opiates on sleep architecture in the presence of acute pain in purposes include phenytoin, carbamazepine, valproic acid, lamotri-
humans.14,33,86–88 The results of these studies showed that acute gine, gabapentin, pregabalin, and tiagabine.102–105 These drugs exert
pain caused significant changes in patients’ sleep architecture. It their antiepileptic effects through a variety of mechanisms.
was not clear, however, whether or not opioids suppressed SWS Phenytoin, carbamazepine, and valproic acid act on voltage-
and REM sleep in this context. activated sodium channels, slowing their recovery rate of in a vol-
Morphine delivered via microdialysis to the medullary hypoglas- tage-use–dependent manner.106 Gabapentin and pregabalin
sal nucleus (XII; which innervates genioglassal muscles of the decrease neuronal influx by binding to voltage-dependent calcium
tongue) of anesthetized Wistar rats caused a statistically significant, channels.107–109 Tiagabine has the ability to inhibit the uptake of
concentration-dependent increase in XII acetylcholine (Ach) GABA.110 Lamotrigine acts by both blocking voltage-gated sodium
release.89 The increase in XII Ach release caused by 10 mm morphine channels and inhibiting the release of glutamate.111 Different anti-
was blocked by the m-opioid antagonist naloxone and not blocked epileptic drugs may exert different effects on sleep structure.112
by the k-opioid antagonist norbinaltorphimine.89 Skulsky and col- In general, the older antiepileptic drugs have significant negative
leagues89 suggested that morphine depresses hypoglossal nerve effects on sleep architecture, but it appears that some of the newer
activity, in part, by increasing Ach release in XII. Activation of drugs have minimal effects on sleep and may even improve it in
m-opioid receptors on inhibitory neurons within XII likely disinhi- some cases. A pilot study of epileptic patients (n = 39/agent) com-
bits cholinergic terminals, causing increased Ach release with result- pared the effects of phenytoin, valproic acid, carbamazepine, lamo-
ing inhibited tongue muscle activity, which may contribute to trigine, and gabapentin with untreated controls. Phenytoin
airway obstruction.89 demonstrated notable reductions in both SWS and REM sleep
while increasing N1 sleep. Valproic acid also selectively enhanced
N1 sleep, but it did not reduce SWS as dramatically as phenytoin.
Antidepressants
Carbamazepine and lamotrigine appeared to have no significant
TCAs appear to have continued to demonstrate analgesic efficacy as effects on sleep architecture. Gabapentin showed a selective
a treatment for neuropathic pain.90 They have also shown some enhancement of SWS without any other alterations to sleep
positive results in the treatment of chronic muscle pains, including architecture.113
fibromyalgia.90,91 TCAs act by inhibiting the reuptake of either sero- Gabapentin and pregabalin both promote modest increases SWS
tonin (5-HT) or norepinephrine, or both. Some TCAs can also in healthy adults, and they appear to be able to achieve this without
block a1-adrenergic, muscarinic, cholinergic, and H1-histaminergic affecting REM sleep.113–115 In a placebo-controlled, double-blind,
receptors,92,93 which explains why in human studies many, but cross-over study of gabapetin for the treatment of restless leg syn-
not all, TCAs suppress REM sleep.94 These studies have also drome, researchers found that gabapetin improved the sleep archi-
demonstrated that some TCAs initially enhance SWS and light tecture of patients, but it was believed to attain this by reducing
NREM sleep.95–98 Amitriptyline, duloxetine, and mirtazapine are periodic leg movements rather than by any direct pharmaceutical
all TCAs currently being utilized or investigated for their ability action of the drug.116 A multicenter, double-blind, 8-week, rando-
to relieve chronic pain. mized clinical trial was carried out to examine the efficacy and
Amitriptyline inhibits 5-HT and noradrenaline reuptake safety of pregabalin in the treatment of fibromyalgia. The partici-
almost equally and exhibits a prolonged suppression of REM pants were 529 patients who were scored for their levels of pain,
sleep quality, fatigue, and quality of life. The results suggested that Whereas there is a strong, independent relationship between
pregabalin, when administered at 300 and 450 mg/day, could sleep disturbances and pain,25,130 other pain-related factors, includ-
reduce fatigue by producing significant improvements in sleep ing depression, inactivity, and conditioned hyperarousal, may play a
quality.117 significant role in the pathogenesis of disturbed sleep.22,131–133
In a study of 13 epileptic patients, lamotrigine was shown to These factors are responsive to treatment with cognitive-behavioral
selectively increase REM sleep time in one study, while decreasing therapy (CBT) and, therefore, provide another rationale for the use
the number of REM cycles the sleeper entered.118 Another study of of CBT in pain patients who experience, or are at risk for, sleep
10 epileptics tested the addition of lamotrigine to a regimen of disturbances.
phenytoin or caramazepine. The addition of lamotrigine signifi- Chronic pain patients who experience sleep disturbances
cantly decreased SWS while increasing N2 sleep, without showing often display compensatory behaviors such as increased waking
any effect on REM sleep.119 Lastly, tiagabine was found to increase time spent in the bedroom. It is believed that this behavior can
SWS and improve sleep continuity in a dose-dependent manner in actually exacerbate a patient’s insomnia by abolishing the learned
insomniacs as well as healthy patients, but it was also found to association between the bedroom and sleep, replacing it with the
decrease REM sleep.120,121 association of this environment with anxiety.134 This bedroom
anxiety can spur catastrophic thoughts pertaining to pain or
cause hypersensitivity to environmental stimuli in the bedroom,
Current PharmacologicTreatments: Summary increasing the length of time required for the onset of sleep.
and Discussion Patients who have these kinds of bedroom anxieties show
increased disturbance of sleep continuity.130 CBT techniques tar-
The pharmacologic management of pain does not necessarily geted at these negative bedroom cognitions may prove to be
address the alterations that pain exerts on sleep architecture. In effective in the treatment of insomnia associated with chronic
some cases, the analgesic may mirror and reinforce the alterations. pain.
Opioids are a prime example of this phenomenon. Although there is Two types of CBT are discussed here, CBT for pain (CBT-P) and
little research that addresses the effects of these alterations, one can CBT for insomnia (CTB-I).
easily imagine how they may have deleterious short-term and long-
term effects on the well-being of the patient. Hospitalization and
opioid treatment for an acute pain could lead to the development of CBT-P
a sleep disorder that could affect the overall health of an individual
or even lead to a chronic pain condition. Sleep disorders could CBT-P often includes relaxation training, cognitive therapy, coping
develop during the pharmacologic treatment of a chronic pain con- skills therapy, and techniques to increase activity levels. Although
dition, causing other pathologic conditions or allowing it to linger CBT-P may produce only modest improvements in pain,135,136 it
for a longer period than it would have otherwise. Alternatively, if has been proved to be effective at improving pain-related outcomes,
opioids achieve significant analgesia, overall sleep may actually including successful coping and maintenance of self-efficacy, that
secondarily improve. are crucial to a patient’s quality of life.135,136
Furthermore, it may be difficult to tease out precisely Several studies have assessed the efficacy of CBT-P in patients
which effects are occurring in any individual patient. For example, with fibromyalgia. In a pilot study, CTB-P, which included mind-
amitriptyline may contribute to analgesia and overall clinical fulness meditation and movement therapy in addition to standard
improvement both by direct analgesic effects and via secondary interventions, produced significant reductions in ratings of sleep-
effects from overall sleep improvement. In order to be fully effective, lessness on a visual analog scale (VAS) for patients with fibromy-
the pharmacologic management of pain should always take sleep algia. The results also showed a significant improvement in pain
into account. and depression.137 A different study found that CBT-P failed to
Opioids will undoubtedly remain vital to the management of reduce VAS ratings of ‘‘sleep disturbances’’ in fibromyalgia patients
pain, regardless of their effects on sleep. More research needs to compared with a symptom-monitoring control group.138 A similar
be done to assess the efficacy of antiepileptics, such as gabapentin study also found no significant improvements in pain or the impact
and pregabalin, and antidepressants, including nefazodone, mirta- of pain on sleep in patients with fibromyalgia who participated in
zapine, valproic acid, and carbamazepine in the treat of chronic CBT-P.139
pain conditions. These drugs appear to have minimal or favorable Another study that utilized CBT-P intervention specially
effects on sleep architecture. Further research not only will allow designed for patients with cancer pain produced improvements in
clinicians to properly use these drugs in pain conditions but also sleep and reduced pain interference in both sleep and daytime
will add to our understanding of pain and sleep interactions, per- activities.140 CBT-P reduced pain, increased self-efficacy, and re-
haps leading to pharmaceutical innovations in this field. duced rheumatologist ratings of joint involvement in a study of
female patients with rheumatoid arthritis. CBT-P could not, how-
ever, improve sleep in these patients.141
COGNITIVE-BEHAVIORALTHERAPY
The connection between pain, insomnia, and depression is well CBT-I
established. Chronic painful conditions are usually accompanied
by high rates of depression.122 Depressed individuals often display CBT-I focuses on the key factors that perpetuate insomnia.
symptoms of insomnia: poor overall quality of sleep, difficulties Standard CBT-I usually includes relaxation, stimulus control,
falling asleep, frequent awakenings, and/or premature awaken- sleep restriction, and cognitive therapies. CBT-I and some of its
ing.123,124 Insomnia and other sleep disturbances may interfere components individually can produce considerable improvements
with the efficacy of standard antidepressant therapy. More-severe in sleep time and quality,142–147 which can last for significant per-
insomnia symptoms are correlated with poorer clinical out- iods of time.148–150 Sleep restriction and stimulus control have been
comes,125 and the development or presence of chronic insomnia implicated as two of the most effective components of CBT-I for
may increase the likelihood that patients will have a relapse of treating secondary insomnia in pain patients.142,151
major depression.126 Several studies showed that the response to The results seen with CBT-I are comparable with the results
antidepressant therapy can be expedited if the treatment provides observed after 2 to 5 weeks of sedative hypnotic treatment with
improvements in sleep early on into therapy.127–129 benzodiazepine receptor agonists.147 When CBT-I is used
simultaneously with sedative hypnotics, patients are able to reduce architecture in pain conditions (either through their own direct
their use of these medications.152–154 pharmacologic effects or secondarily via analgesic effects).
Standard CBT-I with the addition of muscle relaxation training CBT in the form of CBT-P or CBT-I may prove to be an impor-
produced positive results on 15 cancer pain patients who had tant adjunct to traditional pharmacologic management of pain and
developed secondary insomnia.155 Dramatic reductions occurred secondary insomnia and perhaps even an effective monotherapy for
in the amount of time spent waiting for the onset of sleep mild pain conditions coexisting with sleep disturbances. Sleep
(from 124 to 29 min). This treatment regimen did not show any restriction and stimulus control appear to be two highly effective
reductions in pain levels, however.155 components that can be included in these interventions. CBTs tai-
A randomized, clinical trial conducted by Endinger and colored for specific conditions hold much promise for the treatment
workers156 found that sleep hygiene, including regular exercise, of a variety of patients. The inclusion of exercise, for example, in
was valuable addition to CTB-I intervention in fibromyalgia CBT for individuals with fibromyalgia may produce dramatic
patients with chronic insomnia. Patients who received standard results.
CBT-I, which included sleep restriction and stimulus control, and These findings build a powerful case for the integration of pain
sleep hygiene treatment had significant reductions in reported and sleep medicine to develop treatments tailored for specific pain
pain. Diaries and actigraphy did not show improvements in sleep conditions. Treatments showing adequate appreciation for the
in this group, but these patients did report global reductions in reciprocal nature of pain and sleep may be able to provide pain
insomnia. patients with greater relief and improved quality of life.
Currie and colleagues157 studied 60 participants with insomnia
secondary to chronic pain who were assigned randomly to either a
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VI
SPECIAL POPULATION
Chapter 49
PEDIATRIC PAIN ASSESSMENT
PAIN IN CHILDREN The American Academy of Pediatrics (AAP) and the American Pain
Society (APS) highlighted several difficulties that can lead to under-
Padma Gulur, Salahadin Abdi, Ashutosh Sharma, and treatment of pain in children6:
Lakshmi Raghavan
n The myth that infants and children do not feel pain, or suffer
less from it than adults.
n Lack of routine pain assessment in children.
n Lack of knowledge regarding newer modalities and proper
dosing strategies for the use of analgesics in children.
n Fears of respiratory depression or other adverse effects of
analgesic medications.
n The belief that preventing pain in children takes too much
time and effort.
INTRODUCTION
Uniform pain assessment for the pediatric population should be
Pediatric pain is less than optimally managed in most practicing mandated in all hospitals. However, many confounding factors
centers, even today.1 A combination of the challenge most care- make the assessment of pain in children challenging. Pediatric
givers face in accurately assessing pain in infants and children due patients may lack previous pain experiences to compare with
to the difficulty this population has in reporting and the belief that their current pain level. In addition, special challenges exist invol-
children with their developing nervous system do not experience as ving children’s interplay of cognitive, behavioral, and psychosocial
much pain as adults has led to underrecognition and undertreat- factors in the pain experience. Also, at different stages of develop-
ment of pain in children. ment from neonates to adolescents, pain responses and behaviors
Children, in fact, have a more profound inflammatory response differ. Validated observational pain scales for neonates and
than adults and data show they lack a central inhibitory response, infants are available to allow pain assessment because they are
leading to pain levels in most cases that are likely higher than those unable to verbalize pain. These scales, although validated, must be
in adults.2,3 Thus, the importance of adequate management of pain taken in the context that causes other than pain, such as hunger,
in the pediatric population cannot be overstated. fear, or anxiety (e.g., from parental separation) can influence the
The importance of establishing appropriate assessment and report.7 There are even scales for preterm neonates.8 Simple
management guidelines in both pediatric and general adult/pedia- self-report scales using facial expressions or a slide rule with varying
tric combined hospitals was highlighted by the Joint Commission color intensity (Fig. 49–1) or small objects to describe pieces of hurt
on Accreditation of Healthcare Organizations. Trends in pediatric (e.g., Poker Chip Tool) have been devised to allow children over age
hospitals have been to emphasize fixed targets on their pain assess- 4 to more accurately describe the intensity of their pain.
ment scales (e.g., visual analog score [VAS] > 4/10) as treatment
triggers.4 Greco and Berde5—citing several pain states that are hard
to manage optimally in the most state-of-the-art setting, given the Observational Pain Scales for Neonates
challenge of optimizing pain control versus respiratory compromi- and Infants
se—raised the level of caution against strict adherence to this prac-
tice. They emphasized the importance of setting realistic goals for Neonates and their response to pain have been studied for a number
such conditions and the need for individual treatment protocols in of years now and led to the development of behavioral pain scales.9
these circumstances as opposed to blanket adherence to standar- These pain assessment scales have been validated in studies of pre-
dized hospital guidelines. term and term neonates and have also led to the development of
Whereas guidelines are helpful, they should not replace caregiver similar observational scales for toddlers and cognitively impaired
assessment and management based on this assessment. As is dis- children. Most use physiologic parameters such as heart rate and
cussed in the following segments, pain assessment tools in them- oxygen saturation with facial expressions (e.g., brow bulge, eye
selves, although very helpful, cannot generate the same objective squeeze, and nasolabial furrow) and body movements to determine
scores in all patients and using a fixed number/point on these the degree of pain experienced.
scales to trigger treatments is not applicable in all cases—and it Commonly used scales in newborns are the Premature Infant
could well be dangerous in some.5 Pain Profile (PIPP)8; Neonatal/Infant Pain Scale (NIPS)9; Neonatal
373
374 Chapter 49 PAIN IN CHILDREN
Eastern Ontario Pain Scale) (Table 49–1), and the Oucher Scale
(Fig. 49–3). The Oucher Scale (www.oucher.org), which is available
in different ethnic versions, permits children to rate their pain
intensity by matching it to photographs of other children’s faces
that depict increasing levels of pain. The Poker Chip Scale asks
children to quantify their pain in ‘‘pieces of hurt,’’ with more
poker chips representing more pain. As school-age children learn
the proportionality of numbers and colors, they can generally use
the same scales as adults (e.g., VAS, numerical rating scale).
Interpreting pain scales can be difficult in young children
because their ratings are based on prior experiences of pain. For
young children, an injury or procedure might be the strongest pain
they have experienced, whereas older children and adults may rate
the same injury as less painful because they have experienced a more
diverse array of pain.11
Several questionnaires have been developed for children with
chronic or persistent pain, for example, the Varni-Thompson
Pediatric Pain Questionnaire,12 and the Children’s Comprehensive
Pain Questionnaire.13
TREATMENTOF PAIN IN CHILDREN

Pain management in pediatric population includes both nonphar-
macologic and pharmacologic approaches. Unfortunately, often the
nonpharmacologic routes are ignored in favor of a heavy reliance
on pharmacologic approaches. Also, alleviation of comorbid factors
such as anxiety is overlooked. Although it is impossible to prevent
Figure 49^1. Pain Intensity Slide Rule. (From McGrath PJ, all sources of pain, safe and effective analgesic modalities are avail-
Johnson G, et al.CHEOPS: A behavioral scale for rating postoperative pain in able for the management of pain in this population.
children. Adv Pain ResTher 1985;9:395 - 402; and Lawrence J, Alcock D,
McGrath P, et al.The developement of a tool to assess neonatal pain.
Neonatal Netw1993;12:59- 66.) Nonpharmacologic Approaches
Pain, Agitation, & Sedation Scale (N-PASS); and the CRIES Nonpharmacologic approaches include psychological strategies,
Postoperative Pain Scales.8–10 The FLACC (Face, Legs, Activity, education and parental support, and other modalities such as trans-
Cry, and Consolability) Scale is a behavioral scale that has been cutaneous electrical nerve stimulation (TENS) units, physical
validated for assessment of postoperative pain in children between therapy, and acupuncture. For children undergoing repeated pain-
the ages of 2 months and 7 years.7 After a child is observed for 1 to ful procedures, cognitive-behavioral therapy interventions, which
5 minutes, a pain score is obtained by reviewing the descriptions of decrease anxiety and distress, can be quite effective.14 Most of
behavior and selecting the number that most closely matches the these techniques take time to learn and master and are more
observed behavior. suitable for children undergoing frequent procedures. Simple
distraction techniques that divert attention away from painful stim-
uli or positive incentives that provide a small reward (e.g., stickers)
Self-report Scales for Children can be effective for children undergoing occasional procedures.
These techniques are designed to decrease anxiety and are good
Children around age 4 are able to self-report pain and, at times, adjuvants, but they are not adequate as the only method of pain
describe its characteristics. Self-report pain scales developed for relief. The TENS unit, acupuncture, and the like have all shown
young children include the Poker Chip Scale, Wong-Baker some benefit as adjuvant therapies, but these need to be further
Faces Scale (Fig. 49–2), the CHEOP scale (Children’s Hospital validated.
0 1 2 3 4 5
NO HURT HURTS HURTS HURTS HURTS HURTS
LITTLE BIT LITTLE MORE EVEN MORE WHOLE LOT WORST
Alternate
coding 0 2 4 6 8 10
Figure 49^2. The Wong-Baker Scale. (From Berde CB, Sethna NP. Analgesics for the treatment of pain in children. N Engl J Med
2002;347:1094 -1103.)
VI SPECIAL POPULATION 375
Table 49^1. Children’s Hospital Eastern Ontario Pain Scale (CHEOPS)*
From McGrath PJ, Johnson G, et al. CHEOPS: A behavioral scale for rating postoperative pain in children. Adv Pain Res Ther 1985;9:395–402; and Lawrence
J, Alcock D, McGrath P, et al. The developement of a tool to asses neonatal pain. Neonatal Netw 1993;12:59–66.
Pharmacologic Approaches
Fear of overdosing, respiratory depression, and other concerns are infants, have delayed maturation of the enzyme systems
primarily behind the undertreatment of pain in children. Although involved in drug conjugation, including sulfation, glucuroni-
there are some special considerations when treating infants and dation, and oxidation. Several of these hepatic enzyme
children, safe and effective dosing of analgesics is achievable in systems, including cytochrome P-450 subtypes and the
most pain states for most children. Nonetheless, it is important to mixed-function oxidases, mature at varying rates over the
keep in mind the following special considerations outlined by the first 1 to 6 months of life.15
American Medical Association (AMA). n Glomerular filtration rates are diminished in the first week of
life, especially in premature infants, but generally are suffi-
ciently mature to clear medications and metabolites by
Special Considerations inTreating Infants and Children (AMA 2 weeks of age.16
Council on Medical Education [CME] on Pediatric Pain) n Newborns have a higher percentage of body weight as water
When treating pain in infants, it is important to understand and less as fat compared with older patients. Water-soluble
that, although most of the major organ systems are anatomically drugs, therefore, often have larger volumes of distribution.
well developed at birth, their functional maturity is often delayed. n Newborns have reduced plasma concentrations of both albu-
In the first months of life in both preterm and full-term newborns, min and a1-acid glycoprotein than older children and adults.
these systems rapidly mature, and most approach a functional For some drugs, this may lead to higher concentrations of
level similar to that of adults before 3 months of age. General unbound drug (active) and, therefore, greater drug effect or
principles of newborn physiology and its effects on the pharmacol- drug toxicity.
ogy of opioids and local anesthetics are described in the following n Newborns, and especially premature infants, have diminished
text: ventilatory responses to hypoxemia and hypercarbia.17,18
These ventilatory responses can be further impaired by cen-
n Most analgesics (including opioids and local anesthetics) are tral nervous system depressant drugs such as opioids and
conjugated in the liver. Newborns, and especially premature benzodiazepines.
infants and children have demonstrated less toxicity with this drug
even in the presence of overdose.19
Acetaminophen is available orally in several tablet and liquid
formulations. Caution must be exercised with infant formulations,
which are concentrated and have more room for dosing errors.
100 Oral dosing of 10 to 15 mg/kg is recommended. Neonates have a
slower elimination half-life, so the drug must be given less fre-
90 quently. Daily maximum oral dosing is recommended to not
exceed 90 mg/kg for children, 60 mg/kg for term neonates younger
80 than 10 days of age, and 45 mg/kg for premature infants older than
34 weeks gestational age. Rectal preparations of acetaminophen are
70 available for infants and toddlers who are unable or unwilling to
take medication orally. A series of studies confirmed that rectal
absorption is slow, somewhat variable, and comparatively ineffi-
60 cient.15 Single rectal doses of 30 to 45 mg/kg produced plasma
concentrations that were generally in the effective range and never
50 in a range associated with hepatotoxicity.15 After these large rectal
doses, there is a comparatively slow decline in plasma concentra-
40 tions. Based on a 24-hour kinetic study, it was recommended that
initial doses of 35 to 40 mg/kg be followed by subsequent doses of
30 20 mg/kg, with the dosing interval extended to at least 6 hours.15 If
a large rectal dose is to be followed by oral dosing, it is also recom-
mended that a first oral dose be given no sooner than 6 hours after
20
the initial dose. Dosage guidelines for acetaminophen and the most
commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in
10 children can be found in Table 49–2.
0 NSAIDs
The pharmacology of NSAIDs in children is comparable with that
Figure 49^3. The Oucher Scale. (Form Berde CB, Sethna NP. in adults.16 In newborns, however, NSAIDs do have a more pro-
Analgesics for the treatment of pain in children. N Engl J Med 2002; longed half-life, and dosing frequency should be appropriately
347:1094 -1103.) adjusted. Children appear to have a lower incidence of renal and
gastrointestinal side effects than adults, even with chronic
administration.17
Acetaminophen
Ibuprofen is frequently chosen for mild to moderate pain
Acetaminophen is the most commonly used analgesic agent in pedi- because it is available in a liquid form, which allows for easy admin-
atric practice. It has an excellent safety profile and lacks significant istration in younger children. It is available over the counter for
side effects. It is used primarily for mild to moderate pain. It is often fever reduction as well as pain relief and has, to date, exhibited a
combined with opioid analgesics (e.g., acetaminophen with reasonable safety profile.
codeine) for patients with more severe pain. A review of short-term ibuprofen use in a large cohort of chil-
Toxicity from acetaminophen is the result of accumulation of dren revealed a nonclinically significant increase in renal or gastro-
N-acetyl-p-benzoquinone imine (NAPQI) and when there is not intestinal side effects compared with those of acetaminophen.17
enough glutathione peroxidase (GSH) to bind to it. Infants and Ketorolac is the only parenteral NSAID currently available in the
children produce high levels of GSH as a part of hepatic growth, United States. It is used primarily for the treatment of postopera-
which seems to provide a protective effect. This may explain why tive pain in children and adolescents.18 One study demonstrated
Table 49^2. Initial Dosage Guidelines for Nonopioid Analgesics
Dose for Patients Dose for Patients Maximal Daily Dose for Maximal Daily Dose for
Drug < 60 kg (mg/kg) 60 kg (mg) Interval (hr) Patients < 60 kg (mg/kg) Patients 60 kg (mg)
Aetaminophen* 10–15 650–1000 4 90* 4000
Oral 20{ 1000 6 120
Rectal
Ibuprofen 5–10 400–600{ 6 40 2400{
Naproxen 5–6 250–375{ 12 24 1000{
Aspirin§ 10–15 650–1000{ 4 80 3600{
Ketorolac (IV) 0.25–0.5 15–30 6 2 120
*Maximum daily doses for acetaminophen should be reduced to 60 mg/kg in term neonates and infants and to 45 mg/kg in preterm neonates.
{
A loading dose of 35–40 mg/kg is recommended when acetaminophen is administered rectally.
{
Higher doses may be used in selected cases for treatment of rheumatologic conditions in children.
§
Aspirin carries a risk of provoking Reye’s syndrome in infants and children. If other analgesics are available, aspirin use should be restricted to
indications for which antiplatelet or anti-inflammatory effect is required, rather than routine analgesic or antipyretic in neonates, infants, or children.
Dosing guidelines for aspirin in neonates have not been established.
From Berde CB, Sethna NP. Analgesics for the treatment of pain in children. N Engl J Med 2002;347:1094–1103.
that the administration of a single dose of 0.8 mg/kg of ketorolac of life have inadequate and sometimes paradoxical ventilatory
could reduce the need for self-administered opioid analgesia by responses to both hypoxia and hypercapnia.22 Cardiorespiratory
approximately 30% in the first 12 hours after surgery, and this monitoring is recommended whenever opioids are administered
showed a significant reduction in urinary retention compared to infants younger than 2 to 3 months. Premature infants and
with opioid analgesia alone.20 Dosage recommendations currently former premature infants with chronic lung disease continue to
are 0.25 to 0.5 mg/kg every 6 hours, with no requirement for a show depressed hypoxic drive for several months and often
loading dose. A review of the short-term use (48 hr) of intravenous require careful monitoring after opioid administration up to 5 to
ketorolac in over 1700 children demonstrated a low rate of 6 months of age.
complications.21
Since 2000, selective cyclooxygenase-2 (COX-2) inhibitors have
Oral Opioids
received much publicity. Cardiovascular toxicity data in adult
patients led to the removal of rofecoxib and valdecoxib from the Codeine as an elixir is the most commonly administered oral opioid
market; only celecoxib is available for oral administration. None of in young children. However, its efficacy as an analgesic is still open
these agents has undergone formal study in pediatric patients. to debate for anything but the mildest of pain. It is usually given in
Intravenous forms of the COX-2 inhibitors (e.g., parecoxib) are combination with acetaminophen. It is available as acetaminophen/
currently under further investigation. codeine elixir in a 10:1 ratio (acetaminophen 120 mg with codeine
12 mg in each 5 ml). Dosage guidelines for codeine and other
opioid analgesics are summarized in Table 49–3.
Opioid Analgesics
Methadone is also available as an oral elixir and, because of its
Dosing of opioid analgesics is dependent on the developmental long half-life, can provide excellent analgesia even with infrequent
stage. In the first week of a newborn’s life, the elimination half- dosing. It has an oral bioavailability of 60% to 90%, so dosage
life of morphine is more than twice as long as that in older chil- ranges for oral and intravenous administration are similar. Owing
dren and adults, mainly due to the immaturity of the newborn to its slow and variable clearance, methadone requires careful
infant’s hepatic enzyme systems. Further, glomerular filtration is assessment and titration to prevent delayed sedation.
reduced in the first week of life, leading to slower elimination of
morphine’s active metabolites. Fentanyl and sufentanil also have
Transdermal route
diminished hepatic metabolism in premature and term neonates.
An understanding of the immaturity of central respiratory control Fentanyl is available in a transdermal patch, which takes about
mechanisms is also important. Infants in the first 3 to 6 months 12 to 24 hours to achieve steady state. This is indicated in
Table 49^3. Initial Dosage Guidelines for Opioid Analgesics*
Usual Starting Intravenous or Usual Starting Oral Doses

Equianalgesic Doses Subcutaneous Doses and Intervals Parenteral: and Intervals
Oral
Drug Parenteral Oral Child < 50 kg Child 50 kg Dose Ratio Child < 50 kg Child 50 kg
Codeine 120 mg 200 mg NR NR 1:2 0.5–1 mg/kg 30–60 mg
q 3–4 hr q 3–4 hr
Morphine 10 mg 30 mg Bolus: 0.1 Bolus: 5–8 mg 1:3 Immediate Immediate
(long term) mg/kg q 2–4 hr q 2–4 hr release: release: 15–20
60 mg Infusion: Infusion: 1.5 mg/hr 0.3 mg/kg mg q 3–4 hr
(single dose) 0.02–0.03 q 3–4 hr Sustained
mg/kg/hr release: 30–45
mg q 8–12 hr
Oxycodone NA 15–20 mg NA NA NA 0.1–0.2 mg/kg 5–10 mg
q 3–4 hr q 3–4 hr
Methadone{ 10 mg 10–20 mg 0.1 mg/kg 5–8 mg q 4–8 hr 1:2 0.1 mg/kg q 10 mg q
4–8 hr 4–8 hr
Fentanyl 100 mcg NA Bolus: 0.5–1.0 Bolus: 25–50 mcg NA NA NA
(0.1 mg) mcg/kg q 1–2 hr q 1–2 hr
Infusion: 0.5–2.0 Infusion: 25–100 mcg
mcg/kg/hr hr
Hydromorphone 1.5–2 mg 6–8 mg Bolus: 0.02 mg Bolus: 1 mg q 2–4 hr 1:4 0.04–0.08 mg/ 100–150 mg
q 2–4 hr Infusion: 0.3 mg/hr kg q 3–4 hr q 3–4 hr
Infusion: 0.006
mg/kg/hr
Meperidine 75–100 mg 300 mg Bolus: 0.8–1.0 Bolus: 50–75 mg 1:4 2–3 mg/kg q 100–150 mg
(pethidine){ mg/kg q 2–3 hr q 2–3 hr 3–4 hr q 3–4 hr
*Doses are for patients over 6 mo of age. All doses are approximate and should be adjusted according to clinical circumstances.
{
See text for information about methadone sliding scale administration.
{
Meperidine should generally be avoided if other opioids are available, especially with chronic use, because its metabolite can cause seizures.
From Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Engl J Med 2002;347:1094–1103.
mostly opioid-tolerant patients such as those being treated for patients are unable to self-administer analgesia. AACA is a
cancer. It provides a good mode for basal opioid administration method of pain control in which a consistently available and com-
but usually needs to be combined with a short-acting break- petent individual is authorized by a prescriber and properly edu-
through medication for optimal pain control. One of the main cated to activate the dosing button of an analgesic infusion pump,
benefits of the fentanyl transdermal patch is in being able to in response to that patient’s pain, when a patient is unable.
avoid both the oral and the intravenous routes.
n NCA: the authorized agent is the nurse responsible for the
patient.
Intravenous opioids n Caregiver-controlled analgesia (CCA): the authorized agent
is a nonprofessional individual (e.g., parent, significant
Intermittent intravenous boluses of morphine, hydromorphone, or
other).
fentanyl can provide rapid pain relief, but their duration of action is
short, resulting in marked fluctuations in serum opioid concentra- The ASPMN position statement described criteria for the use of
tions during the dosage period. The dosing interval for these AACA, guidelines for selection and education of the authorized
opioids, therefore, may need to be hourly as needed and should agent, key prescription and monitoring recommendations during
not be greater than every 2 to 4 hours (unless perhaps if given therapy, and quality-improvement activities to ensure safety and
subcutaneously for morphine or hydromorphone). In order to pro- effectiveness. Furthermore, in the interest of promoting optimal
vide a more steady analgesic effect, continuous opioid infusions and safety for PCA/AACA, it appears that respiratory monitoring with
patient-controlled analgesia (PCA) or nurse-controlled analgesia oximetry and/or capnography is required.26 Specifically, utilizing
(NCA) are commonly used to circumvent these fluctuations in continuous respiratory monitoring and a smart infusion system
plasma concentrations. may be useful in some cases.27
Intramuscular routes of administration are avoided owing to the Basal infusions improve sleep quality, but these have been asso-
associated discomfort with repeated administration and the associ- ciated with episodes of hypoxemia when used for postoperative
ated anxiety of the technique. pain management in children.28 The use of round-the-clock
NSAIDs and/or acetaminophen can be useful. For cancer pain or
palliative care, roughly two thirds of the overall requirement is
Continuous opioid infusions
provided from the basal infusion. ‘‘Enteral PCA’’ may be another
Initial infusion rates in newborns are much lower than in toddlers/ potential option in selected patients.29
older children, as explained earlier, and range from 0.005 to
0.01 mg/kg/hr. For toddlers and children, commonly recommended
Methadone sliding scale
initial morphine infusion rates are roughly 0.025 mg/kg/hr.
Cardiorespiratory monitoring is required for infants younger than A regimen involving intravenous loading doses (usually 0.1–0.2 mg/
3 months of age, and adjustment of these rates should be based on kg) and small bolus doses of methadone has been shown to be very
clinical signs of either inadequate pain relief or increased effective for postoperative analgesia in children.30 Pain is assessed by
somnolence.23 the nursing staff at intervals not exceeding 4 hours (reverse PRN
[nothing by mouth] method), and methadone is administered via a
‘‘sliding scale.’’ If the pain is rated as severe, 0.07 mg/kg is adminis-
PCA or NCA
tered; 0.05 mg/kg is given for moderate pain; and 0.03 mg/kg if the
Children 6 to 7 years of age have been shown to be able to inde- pain is considered mild.
pendently use the PCA pump for postoperative pain relief.24 NCA
may be used for younger children to permit small titrated dosing of
opioids for infants and children unable to use the PCA button.25 Local Anesthetics and Regional Anesthesia
PCA may be administered either alone or in conjunction with a
low-dose continuous infusion. Morphine has been the most exten- Topical anesthetics
sively studied in children, and it is used as a first-line analgesic. Topical anesthetics are primarily used on intact skin to provide
Meperidine is generally not recommended when other opioids are pain relief prior to needle-stick procedures. Several routine med-
available because of the potential for seizures owing to its metabo- ical procedures such as blood draws, immunizations, chemother-
lite normeperidine. apy treatments involve needles, which can cause traumatic stress
Many institutions have previously allowed so-called PCA by in children as well as serious mental discomfort for their par-
proxy, in which either a nurse or a caregiver (typically a parent) ents. Health care providers are implementing procedures to
was empowered to push the PCA button for a patient who was ensure that the issue of pain in children is addressed adequately.
unable owing to incapacity from age, mental status, or other A position statement has been issued jointly by the APS and the
factors. This practice has recently been called into question AAP for adequately addressing acute or short-lived pain.31 The
based on safety concerns that patients may inadvertently receive position statement, which applies to the treatment of children
too much narcotic, with resultant respiratory depression and and adults, calls for health care practitioners to eliminate or
possibly death. Many hospitals are now revising these policies reduce pain caused by medical treatments whenever possible.
either to abolish this practice or to substantially modify it so In fact, the APS and AAP agree that acute pain experienced
that proxy personnel (which may include parents) receive appro- with medical procedures can, in most cases, be substantially re-
priate training before being allowed to push the button for the duced and even prevented. Thus, it is no longer believed that
patient. infants and children cannot feel pain. In fact, clinical research
In a position statement of the American Society for Pain has shown that not only do children feel pain but, when their
Management Nursing (ASPMN)—approved by the ASPMN pain is not addressed adequately, they can become more sensi-
Board of Directors in June 2006—it was stated that ‘‘The ASPMN tive to pain in the future, and it can have a lasting impression
does not support the use of ‘PCA by Proxy’ in which an unauthor- when it comes to seeking medical treatment when they become
ized person activates the dosing mechanism of an analgesic infusion adults.32 Use of topical anesthetics to eliminate pain associated
pump and delivers analgesic medication to the patient, thereby with dermal procedures has been consistently documented clin-
increasing the risk for potential harm.’’ ically to reduce fear and anxiety in patients presenting symptoms
The ASPMN supports the use of authorized agent–controlled of ‘‘needle phobia,’’ a condition defined as the fear and distress
analgesia (AACA) in a variety of patient care settings in which associated with the use of needles.33
EMLA
techniques involve disrupting the stratum corneum, the outermost
EMLA refers to a topical preparation of a eutectic mixture of local layer of the skin, thereby creating the pathway for the drugs to be
anesthetic cream consisting of lidocaine and prilocaine. Also avail- transported, iontophoretic drug delivery systems are one of the very
able is a mixture of lidocaine and tetracaine. Clinical trials have few systems that have been well characterized and successfully
shown the effectiveness of EMLA in reducing the pain or distress developed for commercial use. Several studies of iontophoresis
of a number of common pediatric procedures including venous and its applications are well documented in the literature.43–50
cannulation, venipuncture, lumbar puncture, circumcision, urethral Iontophoresis, as the name suggests, involves the use of a low-
meatotomy and adhesion release, immunizations, arterial cannula- level electrical current to transport drug, usually in the ionic state,
tion, and dermatologic procedures accessing implanted central across the skin. The flux of a drug from electrically assisted trans-
venous access catheters EMLA must be applied in a thick layer port depends on the (1) physicochemical properties of the drug
over intact skin and is most effective if left undisturbed for at (molecular size, ionic charge, drug concentration), (2) the formu-
least 90 to 120 minutes.34 lation (pH, competing ions, type of buffering agents), and (3) elec-
Furthermore, topical anesthetic creams (EMLA and Ametop) trical parameters (amount and duration of electrical current). For a
significantly reduced the anxiety before cannulation and the level given drug and its formulation, the flux is directly proportional to
of discomfort recorded.35 Another means to administer topical the current that can be precisely controlled to deliver the required
anesthetics is by skin infiltration (subcutaneous injection).36 Both dose. The ability of iontophoretic delivery platforms to deliver the
delivery techniques suffer from serious drawbacks however. In the required dose through precise control of current is a unique advan-
case of creams, including EMLA, the time required to reach max- tage that none of the other active transdermal drug delivery systems
imum effect is minimally 1 hour. This time frame is often imprac- possesses. Iontophoretic systems can also be precisely programmed
tical in busy outpatient clinics. Also, the depth of anesthesia to deliver different dose profiles by timing the switching on and off
produced by EMLA tends to be too superficial. Intradermal injec- of the current. Such profiles include a bolus on demand, continuous
tion of anesthetic agents requires a needle, and therefore, the infusion, delivery at regularly timed intervals, or a combination of
administration process itself can be traumatic to the needle- any of these profiles.
phobic patient. There is also pain on injection of the agents, such A typical iontophoretic delivery system consists of a patch that
as lidocaine.36 contains an anode, a cathode, and two reservoirs, one that contains
the drug in the ionic state and the other that contains the return
electrolyte. Positively charged drug ions are delivered from the
Liposomal lidocaine
anode, and the negatively charged ions are delivered from the cath-
Lidocaine can be dispersed in liposomes to facilitate transcutaneous ode (Fig. 49–4). The drug ion transport follows the basic principles
delivery. This formulation (ELA-Max; 4% liposomal lidocaine) is of electricity, namely, like charges repel each other. Cationic trans-
available as an over-the-counter cream and can be massaged into port involves the repulsion of positively charged ions to be moved
the skin, providing skin anesthesia within 30 minutes.37 away from the anode into the skin, then the ions are transported
across the skin into the blood stream for systemic delivery. The
same occurs for the anions that are delivered cathodically. It
Iontophoresis
should be noted that iontophoretic systems can also be used to
In an effort to find techniques with shorter onset times than EMLA, deliver topically by choosing appropriate formulations and current
iontophoresis of lidocaine (Numby Stuff) has been developed, profiles. In designing an optimal iontophoretic drug delivery
which employs an electrical field to drive local anesthetics in their system, careful consideration should be made in the selection of
charged ionic form across the stratum corneum.38 This usually has electrode material, drug reservoir, drug formulation, duration of
an onset time of 10 to 25 minutes. With higher currents (e.g., iontophoresis, and the current density.
4 mA), more tingling of the skin occurs, but analgesia can be
achieved in approximately 10 minutes. Longer application times Vyteris iontophoretic technology: lidosite
(approximately 25–30 min) are needed when lower currents are LidoSite is an iontophoretic system developed to provide topical
used, but the tingling sensation can be made almost undetectable. analgesia for both adult and children in the management of pain
Iontophoresis provides an effective, rapid, needle-free means to associated with procedures such as blood draws, catheter insertions,
deliver topical anesthetics into the skin. The LidoSite patch (devel- and those involving localized surgical procedures. A recent survey
oped and manufactured by Vyteris, Inc., of Fair Lawn, NJ) is a showed that 15 million adults and 5 million children suffer from
preloaded anesthetic patch that delivers lidocaine and epinephrine needle phobia or a high level of discomfort when faced with the
over a 10-minute period using the principle of iontophoresis. prospect of a needle injection or blood draw procedure.51 These
Studies have shown that iontophoretic delivery of topical anes- people tend to avoid going through the procedure, which unavoid-
thetics such as lidocaine is superior to EMLA cream in terms of ably increases public health challenges.
efficacy. Control of pain associated with intravenous cannulation Two prospective, randomized, placebo-controlled trials were
and venipuncture procedures was significantly more effective using conducted to assess the analgesia provided by Vyteris’ lidocaine
iontophoretic delivery than with EMLA in both adults and chil- iontophoretic system during venipuncture and intravenous canula-
dren.39–41 Vyteris has compared the topical anesthetic efficacy of tion.52 The first clinical trial utilized a 10-cm VAS to evaluate
LidoSite with that of EMLA cream. LidoSite was significantly more pain in subjects who were 18 years old or older. The mean (±
effective than EMLA, as determined by the VAS. Iontophoretic standard deviation [SD]) VAS score assessed in 270 subjects was
delivery of lidocaine is equivalent to subcutaneous administration significantly lower (0.8 ± 1.5 cm) than that in the placebo
in terms of efficacy while avoiding the issues associated with injec- group (2.5 ± 2.3 cm). The second trial utilized 256 pediatric sub-
tion of lidocaine.42 jects in the age group of 5 to 17 years; the pain they experienced
The several advantages offered by the transdermal drug delivery was assessed using the Nine Faces Integrated Scale (NFIS).
route are offset by the excellent barrier properties of the skin, which The studies showed lower mean weighted NFIS scores compared
limit the number of drug candidates that can be delivered via this with the placebo. Two more clinical trials were conducted to
route. Several active transdemal drug delivery systems that use assess pain control using an lidocaine iontophoretic system prior
external energy—such as heat, radiofrequency, ultrasonic fre- to minor surgical procedures for the removal of skin lesions
quency, laser ablation, iontophoresis (electrically assisted trans- using laser surgery and incisional/excisional surgery, which demon-
port), and mechanical abrasion—have been evaluated to strated that pain can be better managed when the lidocaine system
overcome the skin barrier. Whereas most of these enhancement is used.
Drug Battery/ Return

reservoir microcomputer reservoir
(saline)
+ –
D+ D+
Skin
Cl– Na+
D+ D+ Blood Vessel
• Drug ions are delivered from the reservoir of similar polarity

• Drug flux increases with applied current
• Drug ions compete for current with extraneous ions
Figure 49^4. Schematic of an iontophoretic system.
Based on these clinical trials, Vyteris developed the first prefilled controls the system indicators. Delivery is initiated by an ‘‘ON’’
lidocaine iontophoretic system, LidoSite, which was approved by button and once started, the profile goes through three stages: cur-
the U.S. Food and Drug Administration (FDA) in 2004. The rent ramp up, constant current delivery, and a ramp down. Light
LidoSite topical system is a drug-device combination product con- emitting diodes are used to indicate normal conditions (green
sisting of a LidoSite Patch (drug) and a LidoSite controller (medical blinking light) and to alert the user of an abnormal condition
device). The drug used in the patch is lidocaine, which is a local (yellow blinking). An audio beeper sounds to indicate self-check
anesthetic, loaded on to a polymer-based hydrogel that acts as the or the end of the delivery. A liquid crystal display shows the
reservoir. Polymer-based hydrogel reservoirs are used because of number of patch applications used for a given controller.
their ability to provide good adherence to the skin and also to
conform to the contours of the body. The electrode material for Opportunities and future potential of iontophoretic systems
the system is made of silver/silver chloride, well known to prevent The LidoSite drug delivery system, developed by Vyteris, Inc.,
drifts in pH during the electrochemical reaction at the electrode. is targeted as a topical anesthetic product to achieve dermal anal-
The patch is for a single use, to be discarded after use (Fig. 49–5). gesia on intact skin prior to dermal procedures such as cannulation,
The portable controller is reusable and can last for up to 99 appli- intravenous puncture, or dermal surgical procedures. Iontophoresis
cations. The controller contains a nonreplaceable battery that pro- for specific medical indications has also been evaluated by the Blue
vides up to hundred 10-minute applications of 1.77 mA direct Cross Blue Shield Association and Kaiser Permanente (Technical
current. An analog circuitry is used to control the delivery of the Evaluation Center [TEC]).53 The assessment summarized published
current to the patch. An embedded microprocessor monitors the evidence from controlled trials that randomly assigned patients to
current application during the operation of the controller and different treatment groups or used a blinding method. The studies
also included placebo-controlled studies. The first goal of the eval-
uation was to determine whether an effect exists beyond placebo
and to compare alternative treatments for the condition. Based on
the available evidence, the Blue Cross and Blue Shield Association
Medical Advisory Panel concluded there was sufficient evidence
Controller
supporting iontophoretic delivery of topical anesthetics (lidocaine
plus epinephrine) as more effective than placebo and that this effect
was equal, or superior, to EMLA cream. Based on this TEC assess-
ment, use of iontophoresis for administration of local anesthesia
prior to a venipuncture or dermatologic procedure is considered
medically necessary by several individual health care provider
Drug reservoir organizations.54,55
(anode) The underlying iontophoresis technology on which LidoSite was
based can be used to develop delivery systems that deliver other
Patch therapeutics in the pain-management category as well as macromo-
lecules that cannot otherwise be delivered transdermally.
Interconnect
tab
The pain associated with children and its management can be
categorized according to the severity of the pain as mild, moderate,
and severe. Mild pain can be managed with NSAIDs, a class of drugs
that are effective for all age groups and can be a viable alternative to
COX-2 inhibitors. The oral dosage forms of NSAIDs can lead to
Return
(cathode)
gastrointestinal ulceration, platelet inhibition and bleeding, and
renal failure if used frequently. Iontophoretic drug delivery systems
can used to control the right doses required for efficacy and have
Figure 49^5. Lidocaine iontophoretic drug delivery system. the advantage of avoiding the first-pass metabolism in the
Consequently, inadequate pain management often leads to persis-

Box 49^1 EPIDURAL INFUSIONS OF LOCAL ANESTHETICS tent behavioral abnormalities as well as to chronic pain status.
WITH/WITHOUT OPIOIDS IN CHILDREN Finally, management of chronic pain should be a multidisciplin-
ary approach. Thus, reliance solely on pharmacologic modes has
Solutions rarely been adequate. Established care models for both the assess-
<1 yr old: 0.1% bupivacaine without fentanyl ment and the treatment of pain in children are available and should
1^7 yr of age: 0.1% bupivacaine with 2 mcg/ml fentanyl be employed. However, the need for further research is clear.
>7 yr of age or adult: 0.1% bupivacaine with 20 mcg/ml hydromorphone
Special indications: fentanyl or hydromorphone without bupivacaine
Rate of Infusion REFERENCES
Starting rate, 0.1 ml/kg/hr of appropriate solution (see earlier)
For increasing pain, increase in increments up to 0.3 ml/kg/hr 1. Schechter NL. The undertreatment of pain in children: an overview.
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For Bolusing Catheter 2. Andrews K, Fitzgerald M. Cutaneous flexion reflex in human
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6 ^15 kg: 2 ml of1% lidocaine with1:200,000 epinephrine characteristics after single and repeated stimuli. Dev Med Child
>15 kg: 5 ml of 1% lidocaine with 1:200,000 epinephrine Neurol 1999;41:696–703.
3. Fitzgerald M, Koltzenburg M. The functional development of
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newborn rat spinal cord. Dev Brain Res 1986;24:261–270.
gastroinestinal tract and, hence, the resultant side effects. Similarly, 4. Schechter NL, et al. The ouchless place, no pain children’s gain.
postoperative pain, which can be classified as moderate to severe, is Pediatrics 1997;99:890–894.
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FDA approved for use to treat acute pain in a medically supervised and management of acute pain in infants, children, and adolescents.
Pediatrics 2001;108:793–797.
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Vapocoolant spray assess neonatal pain. Neonatal Netw 1993;12:59–66.
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In Turk DC, Melzack R (eds): Handbook of Pain Assessment. New
1950s for the treatment of myalgic pain. More recent studies have York: Guilford, 2001; pp 97–117.
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immunization.56 The vapocoolant can be either sprayed directly 13. Ross DM, Ross SA. Children’s Comprehensive Pain Questionnaire
onto the skin or onto a cotton ball and then applied to the injection (CCPQ) (1984). In McGrath PA (ed): Pain in Children: Nature,
site for 15 seconds. Assessment, and Treatment, New York: Guilford, 1990; pp 68–70,
392–400.
14. Walco GA, Halpern SL, Conte PM. Pain in infants and children. In
Infiltration of local anesthetics Tollison CD, Satterthwaithe JR, Tollison JW (eds): Practical Pain
Management. Philadelphia: Lippincott Williams & Wilkins, 2002;
The intradermal injection of these agents prior to painful proce- pp 748–759.
dures is well established but can be associated with a burning pain 15. Birmingham PK, Tobin MJ, Henthorn TK, et al. Twenty-four-hour
of its own. Intradermal injection pain can be significantly lessened pharmacokinetics of rectal acetaminophen in children: an old drug
by the use of a smaller needle and buffering of the local anesthetic with new recommendations. Anesthesiology 1997;87:244–252.
with the addition of sodium bicarbonate (4 ml lidocaine mixed with 16. Berde CB, Sethna NF. Analgesics for the treatment of pain in
1 ml sodium bicarbonate). A bioinjector, which uses compressed children. N Engl J Med 2002;347:1094–1103.
CO2 to inject the lidocaine rapidly beneath the skin, can also be 17. Lesko SM, Mitchell AA. An assessment of the safety of pediatric
used to avoid this. ibuprofen. A practitioner-based randomized clinical trial. JAMA
1995;273:929–933.
18. Bean-Lijewski JD, Hunt RD. Effect of ketorolac on bleeding time and
Neuraxial techniques for analgesia postoperative pain in children: a double-blind, placebo-controlled
comparison with meperidine. J Clin Anesth 1996;8:25–30.
Single-shot caudal injections for short-stay surgeries in young chil- 19. Rumack BH. Acetaminophen overdose in children and adolescents.
dren and continuous epidural analgesia via indwelling catheters Pediatr Clin North Am 1986;33:691–701.
provide excellent postoperative analgesia for infants and children 20. Vetter TR, Heiner EJ. Intravenous ketorolac as an adjuvant to
of all ages undergoing more extensive abdominal and lower extrem- pediatric patient-controlled analgesia with morphine. J Clin Anesth
ity procedures. Further, this technique could be potentially useful if 1994;6:110–113.
the catheter with an injection port is internalized (Box 49–1). 21. Houck CS, Wilder RT, McDermott JS, et al. Safety of intravenous
ketorolac therapy in children and cost savings with a unit dosing
system. J Pediatr 1996;129:292–296.
22. Pasternak GW, Zhang A, Tecott L. Developmental differences between
SUMMARY high and low affinity opiate binding sites: their relationship to
analgesia and respiratory depression. Life Sci 1980;27:1185–1190.
Pain assessment is the first and crucial step in pain management for 23. Lynn A, Nespeca MK, Bratton SL, et al. Clearance of morphine in
children. It is important to acknowledge that pain is experienced by postoperative infants during intravenous infusion: the influence of age
children and the significance of adequate management for the same. and surgery. Anesth Analg 1998;86:958–963.
382 Chapter 50 PAIN IN THE ELDERLY
24. Berde CB, Lehn BM, Yee JD, et al. Patient-controlled analgesia in associated with peripheral intravenous cannulation. J Am Assoc Nurse
children and adolescents: a randomized, prospective comparison with Anesth 2001;69:185–187.
intramuscular administration of morphine for postoperative analgesia. 40. Squire SJ, Kirchhoff KT, Hissong K. Comparing two methods of
J Pediatr 1991;118:460–466. topical anesthesia used before intravenous cannulation in pediatric
25. Monitto CL, Greenberg RS, Kost-Byerly S, et al. The safety and patients. J Pediatr Health Care 2000;14:68–72.
efficacy of parent-/nurse-controlled analgesia in patients less than six 41. Galinkin JL, Rose JB, Harris K, Watcha MF. Lidocaine iontophoresis
years of age. Anesth Analg 2000;91:573–579. verus eutectic mixture of local anesthetics (EMLAÕ ) for IV placement
26. Maddox RR, Williams CK, Fields M. Respiratory monitoring in patient- in children. Anesth Analg 2002;94:1484–1488.
controlled analgesia. Am J Health Syst Pharm 2004;61:2628–2635. 42. Zeltzer L, Regalado M, Nichter LS, et al. Iontophoresis versus
27. Maddox RR, Williams CK, Oglesby H, et al. Clinical experience with subcutaneous injection: a comparison of two methods of local
patient-controlled analgesia using continuous respiratory monitoring anesthesia delivery in children. Pain 1991;44:73–78.
and a smart infusion system. Am J Health Syst Pharm 2006;63:157–164. 43. Burnette RR. Iontophoresis. In Hadgraft J, Guy RH (eds):
28. McNeely JK, Trentadue NC. Comparison of patient-controlled Transdermal Drug Delivery: Developmental Issues and Research
analgesia with and without nighttime morphine infusion following Initiatives New York: Marcer Dekker, 1989; pp 247–291.
lower extremity surgery in children. J Pain Symptom Manage 44. Tyle P. Iontophoretic devices for drug delivery. Pharm Res
1997;13:268–273. 1986;3:318–326.
29. Smith HS, Johnston KR, Fudin J. Enteral patient-controlled analgesia. 45. Kalia YN, Naik A, Garrison J, Guy RH. Iontophoretic drug delivery.
Lancet 1994;344:1092. Adv Drug Deliv Rev 2004;56:619–658.
30. Berde CB, Beyer JE, Bournaki MC, et al. Comparison of morphine 46. Pikal MJ. The role of electroosmotic flow in transdermal
and methadone for prevention of postoperative pain in 3- to iontophoresis Adv Drug Deliv Rev 1992;9:201–237.
7-year-old children. J Pediatr 1991;119:136–141. 47. Degado-Charro MB, Guy RH. Iontophoresis: applications in drug
31. American Academy of Pediatrics. Committee on Psychosocial delivery and noninvasive monitoring. In Hadgraft J, Guy RH (eds):
Aspects of Child and Family Health; Task Force on Pain in Infants, Transdermal Drug Delivery, 2nd ed. New York: Marcel Dekker, 2003;
Children, and Adolescents. The assessment and management of acute pp 199–225.
pain in infants, children, and adolescents. Pediatrics. 2001;108(3): 48. Sage BH, Rivere JR. Model systems in iontophoresis transport
793-797. efficacy. Adv Drug Deliv Rev 1992;9:265–287.
32. Hamilton JG. Needle phobia, a neglected diagnosis. J Fam Pract 49. Phipps JB, Gyory JR. Trandermal ion migration. Adv Drug Deliv Rev
1995;41:169–175. 1992;9:137–176.
33. Willemsen H, Chowdhury U, Briscall L. Needle phobia in children: a 50. Scott ER, Phipps B, Gyory R, Padmanabahan RV. Electrotransport
discussion of aetiology and treatment options. Clin Child Psychol system for transdermal drug delivery: a practical implementation of
Psychiatry 2002;7:609–619. iontophoresis. In Wise DL (ed): Handbook of Pharmaceutical
34. Lander J, Hodgins M, Nazarali S, et al. Determinants of success and Controlled Release Technology. New York: Marcel Dekker, 2000;
failure of EMLA. Pain 1996;64:89–97. pp 617–659.
35. Speirs AF, Taylor KH, Joanes DN, Girdler NM. A randomized, 51. Vyteris, Inc. Available at www.vyteris.com (As per TV Guide study
double-blind, placebo-controlled, comparative study of topical skin conducted in 2006.)
analgesics and the anxiety and discomfort associated with venous 52. Zempsky WT, Sullivan J, Paulson DM, Hoath SB. Evaluation of a
cannulation. Br Dent J 2001;190:444–449. low-dose lidocaine iontophoresis system for topical anesthesia in
36. Szmuk P, Szmuk E, Ezri T. Use of needle-free injection systems to adults and children: a randomized, controlled trial. Clin Ther
alleviate needle phobia and pain at injection. Expert Rev 2004;26:1110–1119.
Pharmacoecon Outcomes Res 2005;5:467–477. 53. Iontophoresis for medical indications. TEC Bull (online)
37. Eichenfield LF, Funk A, Fallon-Friedlander S, Cunningham BB. A 2003;13(20):18-22. Assessment Program. 2003;18:1–44.
clinical study to evaluate the efficacy of ELA-Max (4% liposomal 54. http://medpolicy.unicare.com/policies/guidelines/med/
lidocaine) as compared with eutectic mixture of local anesthetics iontophoresis.html (accessed on December 7, 2006).
cream for pain reduction of venipuncture in children. Pediatrics 55. http://medpolicy.bluecrossca.com/policies/guidelines/MED/
2002;109:1093–1099. iontophoresis.html (accessed on December 7, 2006).
38. Irsfeld S, Klement W, Lipfert P. Dermal anaesthesia: comparison of 56. Zappa SC, Nabors SB. Use of ethyl chloride topical anesthetic to
EMLA cream with iontophoretic local anaesthesia. Br J Anaesth reduce procedural pain in pediatric oncology patients. Cancer Nurs
1993;71:375–378. 1992;15:130–136.
39. Miller KA, Balakrishnan G, Eichbauer G, Betley K. 1% Lidocaine
injection, EMLA cream, or ‘‘Numby Stuff’’ for topical analgesia
Chapter 50 differences from its management in younger subjects. Few would

argue that these differences do not exist, although the definition of
PAIN IN THE ELDERLY when a patient becomes ‘‘elderly’’ is problematic. We all know of
‘‘young’’ patients who are physiologically and medically old,
Gary McCleane whereas others, although chronologically advanced, retain the
health and constitution of others decades younger.
Clearly, many disease states become more common as age
advances. These conditions may cause acute illnesses that need
operative intervention (leading to pain) or may cause more chronic
pain-related disability. But it is about more than just the physical
health of the patient. We can see the physiologic parameters and
INTRODUCTION results of blood screening as we measure them and make alterations
to our treatment plans for that patient, but we can easily forget the
There is little merit in considering the treatment of pain in elderly other issues that contribute to holistic care. The elderly are more
patients as a separate entity unless there are real and practical likely to have sensory impairments, memory difficulties, and lack of
24. Berde CB, Lehn BM, Yee JD, et al. Patient-controlled analgesia in associated with peripheral intravenous cannulation. J Am Assoc Nurse
children and adolescents: a randomized, prospective comparison with Anesth 2001;69:185–187.
intramuscular administration of morphine for postoperative analgesia. 40. Squire SJ, Kirchhoff KT, Hissong K. Comparing two methods of
J Pediatr 1991;118:460–466. topical anesthesia used before intravenous cannulation in pediatric
25. Monitto CL, Greenberg RS, Kost-Byerly S, et al. The safety and patients. J Pediatr Health Care 2000;14:68–72.
efficacy of parent-/nurse-controlled analgesia in patients less than six 41. Galinkin JL, Rose JB, Harris K, Watcha MF. Lidocaine iontophoresis
years of age. Anesth Analg 2000;91:573–579. verus eutectic mixture of local anesthetics (EMLAÕ ) for IV placement
26. Maddox RR, Williams CK, Fields M. Respiratory monitoring in patient- in children. Anesth Analg 2002;94:1484–1488.
controlled analgesia. Am J Health Syst Pharm 2004;61:2628–2635. 42. Zeltzer L, Regalado M, Nichter LS, et al. Iontophoresis versus
27. Maddox RR, Williams CK, Oglesby H, et al. Clinical experience with subcutaneous injection: a comparison of two methods of local
patient-controlled analgesia using continuous respiratory monitoring anesthesia delivery in children. Pain 1991;44:73–78.
and a smart infusion system. Am J Health Syst Pharm 2006;63:157–164. 43. Burnette RR. Iontophoresis. In Hadgraft J, Guy RH (eds):
28. McNeely JK, Trentadue NC. Comparison of patient-controlled Transdermal Drug Delivery: Developmental Issues and Research
analgesia with and without nighttime morphine infusion following Initiatives New York: Marcer Dekker, 1989; pp 247–291.
lower extremity surgery in children. J Pain Symptom Manage 44. Tyle P. Iontophoretic devices for drug delivery. Pharm Res
1997;13:268–273. 1986;3:318–326.
29. Smith HS, Johnston KR, Fudin J. Enteral patient-controlled analgesia. 45. Kalia YN, Naik A, Garrison J, Guy RH. Iontophoretic drug delivery.
Lancet 1994;344:1092. Adv Drug Deliv Rev 2004;56:619–658.
30. Berde CB, Beyer JE, Bournaki MC, et al. Comparison of morphine 46. Pikal MJ. The role of electroosmotic flow in transdermal
and methadone for prevention of postoperative pain in 3- to iontophoresis Adv Drug Deliv Rev 1992;9:201–237.
7-year-old children. J Pediatr 1991;119:136–141. 47. Degado-Charro MB, Guy RH. Iontophoresis: applications in drug
31. American Academy of Pediatrics. Committee on Psychosocial delivery and noninvasive monitoring. In Hadgraft J, Guy RH (eds):
Aspects of Child and Family Health; Task Force on Pain in Infants, Transdermal Drug Delivery, 2nd ed. New York: Marcel Dekker, 2003;
Children, and Adolescents. The assessment and management of acute pp 199–225.
pain in infants, children, and adolescents. Pediatrics. 2001;108(3): 48. Sage BH, Rivere JR. Model systems in iontophoresis transport
793-797. efficacy. Adv Drug Deliv Rev 1992;9:265–287.
32. Hamilton JG. Needle phobia, a neglected diagnosis. J Fam Pract 49. Phipps JB, Gyory JR. Trandermal ion migration. Adv Drug Deliv Rev
1995;41:169–175. 1992;9:137–176.
33. Willemsen H, Chowdhury U, Briscall L. Needle phobia in children: a 50. Scott ER, Phipps B, Gyory R, Padmanabahan RV. Electrotransport
discussion of aetiology and treatment options. Clin Child Psychol system for transdermal drug delivery: a practical implementation of
Psychiatry 2002;7:609–619. iontophoresis. In Wise DL (ed): Handbook of Pharmaceutical
34. Lander J, Hodgins M, Nazarali S, et al. Determinants of success and Controlled Release Technology. New York: Marcel Dekker, 2000;
failure of EMLA. Pain 1996;64:89–97. pp 617–659.
35. Speirs AF, Taylor KH, Joanes DN, Girdler NM. A randomized, 51. Vyteris, Inc. Available at www.vyteris.com (As per TV Guide study
double-blind, placebo-controlled, comparative study of topical skin conducted in 2006.)
analgesics and the anxiety and discomfort associated with venous 52. Zempsky WT, Sullivan J, Paulson DM, Hoath SB. Evaluation of a
cannulation. Br Dent J 2001;190:444–449. low-dose lidocaine iontophoresis system for topical anesthesia in
36. Szmuk P, Szmuk E, Ezri T. Use of needle-free injection systems to adults and children: a randomized, controlled trial. Clin Ther
alleviate needle phobia and pain at injection. Expert Rev 2004;26:1110–1119.
Pharmacoecon Outcomes Res 2005;5:467–477. 53. Iontophoresis for medical indications. TEC Bull (online)
37. Eichenfield LF, Funk A, Fallon-Friedlander S, Cunningham BB. A 2003;13(20):18-22. Assessment Program. 2003;18:1–44.
clinical study to evaluate the efficacy of ELA-Max (4% liposomal 54. http://medpolicy.unicare.com/policies/guidelines/med/
lidocaine) as compared with eutectic mixture of local anesthetics iontophoresis.html (accessed on December 7, 2006).
cream for pain reduction of venipuncture in children. Pediatrics 55. http://medpolicy.bluecrossca.com/policies/guidelines/MED/
2002;109:1093–1099. iontophoresis.html (accessed on December 7, 2006).
38. Irsfeld S, Klement W, Lipfert P. Dermal anaesthesia: comparison of 56. Zappa SC, Nabors SB. Use of ethyl chloride topical anesthetic to
EMLA cream with iontophoretic local anaesthesia. Br J Anaesth reduce procedural pain in pediatric oncology patients. Cancer Nurs
1993;71:375–378. 1992;15:130–136.
39. Miller KA, Balakrishnan G, Eichbauer G, Betley K. 1% Lidocaine
injection, EMLA cream, or ‘‘Numby Stuff’’ for topical analgesia
Chapter 50 differences from its management in younger subjects. Few would

argue that these differences do not exist, although the definition of
PAIN IN THE ELDERLY when a patient becomes ‘‘elderly’’ is problematic. We all know of
‘‘young’’ patients who are physiologically and medically old,
Gary McCleane whereas others, although chronologically advanced, retain the
health and constitution of others decades younger.
Clearly, many disease states become more common as age
advances. These conditions may cause acute illnesses that need
operative intervention (leading to pain) or may cause more chronic
pain-related disability. But it is about more than just the physical
health of the patient. We can see the physiologic parameters and
INTRODUCTION results of blood screening as we measure them and make alterations
to our treatment plans for that patient, but we can easily forget the
There is little merit in considering the treatment of pain in elderly other issues that contribute to holistic care. The elderly are more
patients as a separate entity unless there are real and practical likely to have sensory impairments, memory difficulties, and lack of
social backup that can all interfere with treatment and illness recov- fibers in the elderly. Axonal atrophy is more commonly observed,
ery. As educated practitioners, it is easy for us to suggest treatments and nerve conduction and endoneural blood flow are reduced
that may well have the potential for being effective with that patient. with advancing age, contributing to a reduction in peripheral
However, the patient cannot read the drug label that states the dose nerve function. Even when regeneration of damaged neurons
and dose frequency, cannot open the container because of arthritic occurs, these regenerated fibers have a smaller number of termi-
hands, and cannot get assistance with drug administration because nal and collateral synapses.
she or he lives on her or his own. Therefore, an awareness of all In aged rats, immunochemical studies of the spinal cord
those factors that accompany aging is significantly more important revealed an increase in mRNA content of the neuropeptide
than just the knowledge of how drug treatments for pain differ in tyrosine and galanin in dorsal root ganglia neurons. These ani-
the elderly. mals have decreased cellular content of calcitonin gene–related
As well as increased incidence of illness with advancing years, peptide and substance P compared with younger animals,
problems of communication with older patients can arise. whereas their levels of somatostatin are similar. The labeling
Impairment of sight and hearing can have obvious consequences. intensity for encoding high-affinity tyrosine receptors (TrkA,
Even more problematic are patients with dementia. They suffer pain TrkB, and TrkC) are decreased in the dorsal root ganglia neu-
as much as anyone else but may lack the cognitive function that rons of the aged rats.
allows them to communicate their pain or the response to drug It has also been noted that there is a progressive loss of both
intervention. Their reaction to pain may be to exhibit abnormal serotinergic and noradrenergic neurons in the superficial lamina of
behavior that can be misconstrued as worsening mental function the spinal dorsal horn. These neurons are closely implicated in
or aggression. When dealing with the intricacies of pain diagnosis, descending bulbospinal inhibitory control, and such loss may
the inability of the patient to describe the location, duration, and upset the natural endogenous pain-suppressing mechanisms.
characterization of the pain can make the diagnostic process infi- At supraspinal levels, there is reduced neurotransmitter content
nitely more difficult, with obvious repercussions on the quality of expression, decreased metabolic turnover, and a loss of neurons and
treatment offered. dendritic connections throughout the cerebral cortex, midbrain,
Allied to all of this is the issue of accessibility to treatment. and brainstem.
In terms of chronic pain, the vast majority of pain clinics are hos-
pital based, and a proportion of the treatments they offer are avail-
able only in a hospital environment. With the physical
disability that can accompany aging, accessibility of these services EFFECTOF AGE IN ANIMAL PAIN
may be less easy. Perhaps what we need is an increased understand- MODELS
ing in the primary care environment that would enable effective
treatment to be instituted at home and not necessitate hospital It is known that levels of the neurotransmitter substance P in the
referral. spinal cord are lower in very old rats than in young rats. After
In this chapter, I discuss the evidence for the differing percep- peripheral nerve injury, immunoreactivity to the substance P recep-
tions of, processing of, and responses to pain of elderly versus tor (NK 1, neurokinin 1 receptor) increases in the spinal cord
young patients without dealing with individual conditions or spe- ipsilateral to the injury and the increase correlates to the develop-
cific treatments, both of which are discussed elsewhere. ment of thermal hyperalgesia. After such peripheral nerve injury,
aged rats develop thermal hyperalgesia and tactile allodynia more
slowly than young rats, and the thermally hyperalgesia correlates to
the increase in numbers of NK 1 receptors, with these receptors
AN AGING POPULATION developing more slowly.
In rats having an incision inflicted on one of their paws and
In the year 2000, there were more than 400 million people the consequent mechanical sensitivity and thermal responses
aged 65 and over in the world, with a projected increase to tested, both young and old rats respond in a similar fashion
almost 1.5 billion by the year 2050. This represents a fourfold to the thermal stimulus. However, younger animals appear to
increase compared with the 50% increase for the global population recover more quickly than the older rats from the mechanical
as a whole. By 2050, it is expected that 25% of these elderly peo- allodynia produced by the paw incision. This suggests that mod-
ple will be over the age of 80. Epidemiologic evidence suggests ulation of A-fiber–mediated sensitization differs in young and
that acute pain is similar across all age groups. Chronic pain old rats.
seems to increase in incidence up to the 7th decade, although the Studies on isolated spinal cord neurons show that spontane-
nature and type of this pain may differ from that found in younger ous firing rates are higher and the responsea to thermal stimu-
people. lation are greater in aged than in adult rats. Furthermore, the
Rustøen and coworkers1 surveyed 4000 Norwegian citizens with size of the receptive field area of wide-dynamic range neurons is
a pain and health questionnaire. Of those in the 18- to 39-year-old larger and that of low-threshold neurons smaller in aged than in
group, 19.2% reported pain of greater than 3 months duration; adult rats. The increased nociceptive neuronal activity in older
27.5% of the 40- to 59-year-olds also reported chronic pain; and rats correlates with the finding that paw withdrawal latency is
the figure was 31.2% in the 60- to 81-year-old group. Therefore, in significantly shorter in aged than in adult rats after heat stimu-
this population group, chronic pain was more frequent not only in lation of the paw. This along with the previously mentioned loss
the old but also in the middle-age group compared with younger of serotinergic and noradrenergic fibers in the spinal dorsal horn
adults. of older rats may contribute to the apparent diminution of
descending inhibitory control of nociceptive processing in older
animals.
Pickering and associates2 studied young, old, and senescent rats
NEURAL DIFFERENCES IN THE AGED using a chronic sciatic nerve constriction model. They found that
senescent animals were less sensitive to neuropathic pain than old
Animal studies suggest that aging has a significant effect on or young rats, whereas these senescent animals were more sensitive
aspects of the morphologic and functional operation of the to acute pain than the other groups. All of these findings confirm
peripheral nervous system. A decrease in the major myelin pro- that from a physiologic perspective, definite differences exist
teins contributes to a loss in myelinated and unmyelinated nerve between young adult and older animals.
EFFECTOF AGE INHUMAN PAIN less of them are soaked up by fat tissue. In contrast, water-soluble
MODELS drugs, such as morphine, are less efficiently distributed and higher
plasma concentrations are obtained with equivalent doses and,
It is not easy to equate the results of human experimental pain tests therefore, side effects may be more frequent.
with actual clinical pain conditions. Experimental pain tests exam- Free drug availability may be significantly augmented owing
ine single modalities of pain, whereas in clinical pain practice, a to decreases in serum albumin, particularly in those elderly patients
noxious stimulus often produces pain that has different facets. with chronic disease and malnutrition. Such changes increase the
Perhaps the most clinically relevant issues are those of pain potential for adverse effects associated with highly protein-bound
threshold and pain tolerance. Gibson3 reported on over 50 studies analgesics such as nonsteroidal anti-inflammatory drugs
that examined age differences in sensitivity to experimentally in- (NSAIDs) and antiepileptic agents such as valproate, phenytoin,
duced pain; the majority of these studies focused on pain thresh- and carbamazepine. Levels of a1-acid glycoprotein, the serum
old. Twenty-one studies reported an increase in pain threshold carrier for basic drugs such as meperidine, appear unchanged in
with advancing age, 3 reported a decrease, and 17 cited no older people.
change. When all results were examined meta-analytically, the With increased age, liver and kidney function decrease and they
effect size was 0.74 (P < .0005), indicating definite evidence of become progressively less efficient at drug clearance. Drug half-life,
an increase in pain threshold with advancing age. Thus, there a ratio of the volume of distribution to clearance, is notably
may well be a difference in pain threshold depending on the increased for several benzodiazepines and tricyclic antidepressants.
type of pain inflicted. Lautenbacher and colleagues4 studied 20 Lipid-soluble drugs such as lidocaine and narcotic analgesics
young men with an average age of 27.1 years and compared are good examples of drugs that undergo significant first-pass
them to 20 elderly men with an average age of 71.6 years. The metabolism during passage from the gastrointestinal tract to
authors found that somatosensory thresholds for nonnoxious the liver. Peak plasma concentrations may rise as may the poten-
stimuli increased with age, whereas pressure pain thresholds tial for dose-related side effects. This situation is further com-
decreased and heat pain thresholds showed no age-related pounded when cardiac output is impaired through disease.
changes. These results were confirmed by Lin and coworkers,5 Highly protein-bound drugs are less influenced by first-pass
who found a consistent relationship between sensory thresholds metabolism.
as measured by quantitative sensory testing and age. It seems that hepatic phase I reactions involving oxidation,
When pain tolerance is considered, the 10 studies examining the hydrolysis, and reduction appear more strongly altered by age
effect of age on pain tolerance showed a definite age-related than phase II conjugation processes (acetylation, glucuronidation,
decrease in willingness to endure very strong pain. The decrease sulfation, and glycine conjugation). In general, phase I reactions
in pain tolerance was estimated at –0.45 (P < .001) across these diminish regardless of which microsomal cytochrome P-450
studies. enzyme is involved, although interindividual variation can be sig-
Lasch and associates6 examined the effect of intraesophageal nificant. Acetaminophen and diazepam, both processed through the
balloon dilation in healthy young and older adults. The volume CYP3A4 and 3A5 enzyme routes, are metabolized at equal rates
of air inflated into the balloon before report of pain was mea- regardless of age. Carbamazepine, lidocaine, and fentanyl, in con-
sured. The volume was significantly higher in the older subjects. trast, are subject to reduced metabolism by the same enzyme sys-
Indeed, many of the older subjects failed to report pain even tems in older patients. Glucuronidation of morphine and
after maximal balloon inflation, in marked contrast to the youn- glutathione conjugation of acetaminophen are examples of reduced
ger patients. It certainly seems, using this experimental techni- and unaltered phase II reactions, respectively. Age appears to have
que, that pain threshold does increase with age. But this study no effect on the frequencies of slow- and rapid-metabolizing genetic
also reminds us that pain is not always an entirely negative polymorphisms.
symptom. On many occasions, it provides a timely warning of The most important pharmacokinetic effect of age is the reduc-
impending problems. For example, if a larger volume within a tion in renal clearance. This can be compounded by illnesses that
hollow viscus is required in an elderly patient before pain is further reduce renal function. This can lead to drug toxicity at
experienced, compared with younger subjects, the discomfort dosing levels appropriate for a younger patient with normal renal
caused by an obstructive lesion in the bowel, for example, function. Drugs with a predominant renal mode of excretion, such
may take longer to become symptomatic in older patients, as gabapentin, can accumulate when kidney function fails.
with all the consequences for the treatment and prognosis of
the causative lesion. It is also clinically apparent that the inci-
dence of silent myocardial ischemia increases with age. Whether PHARMACODYNAMIC CHANGES
this is due to an increased pain threshold in the older patient, a
pain-reducing effect of concomitant medication, or the effects of Whether the elderly demonstrate actual changes in intrinsic sensi-
an intercurrent illness is debatable, but all probably have some tivity at the receptor level is controversial in terms of both measur-
effect. Therefore, although our emphasis is on the management able alterations in receptor numbers and the efficiency of signal
of pain in the elderly, we should not lose sight of the fact that transduction after receptor binding. It has been shown that in
thought must also be given to the absence of pain in these elderly rats, the number of m- and k-opioid receptor numbers
patients under circumstances in which it would normally be fall, whereas d-opioid receptor numbers stay unchanged.
present. One factor of practical concern is that of pain tolerance when
opioid drugs are being used. Buntin-Mushock and coworkers7 per-
formed a retrospective chart review of 206 patients who had been
PHARMACOKINETIC ALTERATIONS prescribed strong opioids. These authors found that younger
patients reached a maximum dose of around 450 mg of oral mor-
Physiologic changes in older people affecting fat mass (increased), phine over a 15-month period, whereas the older patients achieved
muscle mass (reduced), and body water (reduced) have important a maximum dose of around 210 mg over 14 months. When dis-
effects on drug distribution. Blood volume may also be reduced charged from the clinic, only the older patients actually had a
owing to concomitant use of diuretics. With the reduction in rel- reduction in the visual analog pain scores. The authors suggested
ative fat mass, those drugs that are highly lipophylic, such as fenta- that perhaps older patients have less chance of developing opioid
nyl and lidocaine, can have an increased duration of effect because tolerance.
From a practical perspective, decline in homeostatic counter- Corran TM, Farrell MJ, Helme RD, Gibson SJ. The classification of
regulatory mechanisms in older patients creates a less-forgiving patients with chronic pain: age as a contributing factor. Clin J Pain
background to drug administration, and it is clear that older 1997;13:207–214.
patients are less able to regain their original physiologic steady Cruce WL, Lovell JA, Crisp T, Stuesse SL. Effect of aging on the substance
P receptor, NK-1 in the spinal cord in rats with peripheral nerve injury.
state after administration of drugs. For example, tricyclic antide-
Somatosens Mot Res 2001;18:66–75.
pressants and opioids can induce orthostatic hypotension and pre- Edwards RR, Fillingham RB. Age-associated differences in responses to
cipitate falls and syncope. Homeostatic changes increase the risk of noxious stimuli. J Gerontol A Biol Sci Med Sci 2001;56:180–185.
gastric irritation and bleeding after exposure to NSAIDs, and data Edwards RR, Fillingham RB. Effects of age on temporal summations and
suggest that the risk of gastric bleeding is four times higher in older habituation of thermal pain. Clinical relevance in healthy older and
individuals than in younger adults. younger adults. J Pain 2001;2:307–317.
Gagliese L, Melzack R. Age differences in nociception and pain behaviour
in the rat. Neurosci Biobehav Rev 2000;24:843–854.
Gagliese L, Melzack R. Age differences in the response to the formalin test
CONCLUSIONS in rats. Neurobiol Aging 1999;20:699–707.
Gibson SJ. Age related differences in pain perception and report. Clin
Experimental testing in both animals and humans and, indeed, Geriatr Med 2001;17:433–456.
practical experience confirm that the experience of pain, its presen- Gibson SJ, Voukeetos X, Ames D, et al. An examination of pain
tation, diagnosis, pathophysiology, and actual treatment change perception and cerebral event-related potentials following carbon
as age progresses. In one sense, the chronological age of the patient dioxide laser stimulation in patients with Alzheimer’s disease age-
is not relevant because it gives an artificial estimate of the indivi- related matched control volunteers. Pain Res Manage 2001;6:126–132.
dual’s health status. What is more important is how that indivi- Gloth FM. Geriatric pain: factors that limit pain relief and increase
dual’s health deviates from what may be considered average for complications. Geriatrics 2000;55:51–54.
an adult. In anesthesiologic practice, for example, the risk of a Harkins SW. Effects of age and interstimulus interval on the brainstem
auditory evoked potentials. Int J Neurosci 1981;15:107–118.
patient undergoing anesthesia is not estimated using age as a
Harkins SW. Geriatric pain; pain perception in the old. Clin Geriatr Med
criteria. Rather, an estimate of risk is made using assessment 1996;12:435–459.
scales, such as the American Society of Anesthesiologists (ASA) Harkins SW, Chapman CR. Detection and decision factors in pain
grading system, that classify the patient’s health using the presence perception in young and elderly. Pain 1976;2:253–264.
or absence of disease states, whether these diseases are mild or Harkins SW, Chapman CR. The perception of induced dental pain in
severe, and whether they represent a constant threat to life. young and elderly women. J Gerontol 1977;32:428–435.
It could be argued, therefore, that one should not base a diagnosis Harkins SW, Davis MD, Bush FM, Kasberger J. Suppression of first pain
and plan a treatment on the basis of that patient’s age alone. For all and slow temporal summation of second pain related to age. J Gerontol
patients, regardless of age, we should have an individual approach A Biol Sci Med Sci 1996;8:35–41.
and construct a diagnostic package and treatment plan based on that Harkins SW, Price DD, Martelli M. Effects of age on pain perception:
thermonociception. J Gerontol 1986;41:58–63.
individual’s situation, taking account of their physical and mental Heft MW, Cooper BY, O’Brien KK, et al. Aging effects on the perception
health, expectations, social circumstances, and general well-being. of noxious and non-noxious thermal stimuli applied to the face. Aging
1996;8:35–41.
Helme RD, Gibson SJ. The epidemiology of pain in elderly people. Clin
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1. Rustøen T, Wahhl AK, Hanestad BR, et al. Age and the experience of Iwata K, Fukuoka T, Kondo E, et al. Plastic changes in nociceptive
chronic pain: differences in health and quality of life among younger, transmission of the rats spinal cord with advancing age. J Neurophysiol
middle-aged, and older adults. Clin J Pain 2005;21:513–523. 2002;10:1086–1093.
2. Pickering G, Jourdan D, Millecamps M, et al. Age-related impact of Jourdan D, Boghossian S, Alloui A, et al. Age related changes in
neuropathic pain on animal behaviour. Eur J Pain 2006;19:749–755. nociception and effect of morphine in the Lou rat. Eur J Pain
3. Gibson SJ. Pain and aging: the pain experience over the adult lifespan. 2000;4:291–300.
In Dostrovsky J, Carr D, Koltlenburg M (eds): Proceedings of the 10th Kenshalio DR. Somesthetic sensitivity in young and elderly humans. J
World Congress on Pain. Seattle: IASP Press, 2003. Gerentol 1986;41:732–742.
4. Lautenbacher S, Kunz M, Strate P, et al. Age effects on pain thresholds, Khalil Z, Ralevic V, Bassirit M, et al. Effects of ageing on sensory nerve
temporal summation and spatial summation of heat and pressure pain. function in rat skin. Brain Res 1994;641:265–272.
Pain 2005;115:410–418. Laporte AM, Doyen C, Nevo IT. Autoradiographic mapping of serotonin
5. Lin YH, Hsieh SC, Chao CC, et al. Influence of aging on thermal and 5HT1A, 5HT1D, 5HT2A and 5HT3 receptors in the aged human spinal
vibratory thresholds of quantitative sensory testing. J Peripher Nerv cord. J Chem Neuroanat 1996;11:67–75.
Syst 2005;10:269–281. Lautenbacher S, Strian F. Similarities in age differences in heat pain
6. Lasch H, Castell DO, Castell JA. Evidence for diminished visceral pain perception and thermal sensitivity. Funct Neurol 1991;6:129–135.
with aging; studies using graded intraesophageal balloon distension. Lucantoni C, Marinelli S, Refe A, et al. Course of pain sensitivity in aging:
Am J Physiol 1997;272:G1–G3. pathogenetical aspects of silent cardiopathy. Arch Gerentol Ger
7. Buntin-Mushock C, Philip L, Moriyama K, Palmer PP. Age dependent 1997;24:281–286.
opioid escalation in chronic pain patients. Anesth Analg Lunenfeld B. The ageing male: demographics and challenges. World J
2005;100:1740–1745. Urol 2002;20:11–16.
Manfredi PL, Breuer B, Meier DE, Libow L. Pain assessment in elderly
patients with severe dementia. J Pain Sympt Manage 2003;25:48–52.
SUGGESTED READINGS Noble RE. Drug therapy in the elderly. Metabolism 2003;52:27–30.
Onodera K, Sakurada S, Furuta S, et al. Age-related differences in forced
Barili P, De Carolis G, Zaccheo D, Amenta F. Sensitivity to ageing of the walking stress induced analgesia in mice. Drugs Exp Clin Res
limbic dopaminergic system: a review. Mech Ageing Dev 1998;106:57–92. 2001;27:193–198.
Bergman E, Johnston H, Zhang X, et al. Neuropeptides and neurotrophin Pakkenberg B, Gundersen HJ. Neocortical neuron numbers in humans:
receptor mRNAs in primary sensory neurons of aged rats. J Comp effects of sex and age. J Comp Neurol 1997;384:312–320.
Neurol 1996;11:303–319. Ririe DG, Vernon TL, Tobin JR, Eisenach JC. Age dependent responses to
Bresler R, Bahl JJ. Principles of drug therapy for the elderly patient. Mayo thermal hyperalgesia and mechanical allodynia in a rat model of acute
Clin Proc 2003;78:1564–1577. postoperative pain. Anesthesiology 2003;99:443–448.
Chakour MC, Gibson SJ, Bradbeer M, Helme RD. The effect of age on A Routledge PA, O’Mahony MS, Woodhouse KW. Adverse drug reactions
delta and C fiber thermal pain perception. Pain 1996;64:143–152. in elderly patients. Br J Clin Pharmacol 2004;57:121–126.
386 Chapter 51 PAIN IN THE PALLIATIVE CARE POPULATION
Tucker MA, Andrew MF, Ogle SJ, Davison JG. Age-associated change in Wong DF, Wagner HN, Dannals RF. Effects of age on dopamine and
pain threshold measured by transcutaneous neuronal electrical serotonin receptors measured by positron tomography in the living
stimulation. Age Ageing 1989;18:241–246. brain. Science 1984;226:1393–1396.
Turnheim K. When drug therapy gets old: pharmacokinetics and Yunus MB, Holt GS, Masi AT, Aldag JC. Fibromyalgia syndrome among
pharmacodynamics in the elderly. Exp Gerontol 2003;38:843–853. the elderly: comparison with younger patients. J Am Geriatr Soc
U.S. Bureau of the Census. International Data Base 2002; Vol 2002. 1988;36:987–995.
Washington, DC: US Department of Commerce, U.S. Bureau of the Zhang YQ, Mei J, Lu SG, Zhao ZQ. Age-related alterations in responses
Census, 2002. of nucleus basalis magnocellular neurons to peripheral nociceptive
Verdu E, Ceballos D, Vilches JJ, Navarro X. Influence of age on peripheral stimuli. Brain Res 2002;948:47–55.
nerve function and regeneration. J Peripher Nerve Syst 2000;5:191–208. Zheng Z, Gibson SJ, Khalil Z, et al. Age-related differences in the time
Vuyk J. Pharmacodynamics in the elderly. Best Prac Res Clin Anaesthesiol course of capsaicin induced hyperalgesia. Pain 2000;85:51–58.
2003;17:207–218.
Chapter 51 CONCEPTOF ‘‘TOTAL PAIN’’ IN

PAIN IN THE PALLIATIVE CARE PATIENTS AT THE END OF LIFE
In the 1960s, Dame Cicely Saunders,3 an English social worker–
POPULATION turned–physician and founder of the modern hospice movement,
coined the term ‘‘total pain’’ to describe the suffering she saw in
Lida Nabati and Janet Abrahm those with terminal illness. She saw that in addition to physical
pain, her patients at the end of life were suffering from emotional,
spiritual, psychological, and existential pain. Although she was an
innovator in the use of scheduled around-the-clock opioids to treat
pain, she determined that listening to a patient’s life narrative was
an equally important therapeutic intervention. She recognized the
value of the multidimensional approach to care for the terminally
ill, and her work provided the foundation on which the field of
palliative medicine has evolved. Palliative medicine has been a
INTRODUCTION recognized medical specialty in the United Kingdom for many
years, and in 2006, the subspecialty of Hospice and Palliative
Palliative care is defined by the World Health Organization Medicine achieved official recognition in the United States by the
(WHO)1 as ‘‘an approach that improves the quality of life of American Board of Medical Specialties.
patients and their families facing the problems associated with
life-threatening illness, through the prevention and relief of suffer-
ing by means of early identification and impeccable assessment BARRIERS TO EFFECTIVE PAIN
and treatment of pain and other problems, physical, psychosocial MANAGEMENTAT THE END OF LIFE
and spiritual.’’ This definition further clarifies that palliative care ‘‘is
applicable early in the course of illness, in conjunction with Pain is one of the most commonly reported sources of distress for
other therapies that are intended to prolong life, such as chemo- patients at the end of life. The Study to Understand Prognoses and
therapy or radiation therapy, and includes those investigations Preferences for Outcomes and Risks of Treatments (SUPPORT)
needed to better understand and manage distressing clinical trial4 found that many patients at the end of life suffered from
complications.1 poorly controlled pain. The Institute of Medicine5 reported on
Whereas the palliative care patient population can include the state of end-of-life care in the United States and documented
patients with cancer, it also comprises those with end-stage heart serious deficiencies in meeting symptom-management needs of
failure, end-stage renal disease, advanced chronic obstructive dying patients. A study of patients with cancer showed that distres-
pulmonary disease, degenerative neurologic disorders, and other sing pain is common at the end of life despite the setting of death,
advanced chronic illnesses. Palliative care patients may suffer whether it is home, hospital, hospice facility, or nursing facility.6
from chronic pain, acute pain, cancer-related pain, or other non- Another study reported that relief of physical symptoms was a
cancer pain syndromes, such as painful diabetic peripheral major concern of patients at the end of life and their families.7
neuropathy. Please see other chapters in this volume for detailed The evidence suggested that a patient’s prioritization of concern
information on treatment of cancer pain. In this chapter, we focus for undertreated pain at the end of life may be justified.
on special considerations for patients with pain near or at the end of Interestingly, undertreatment of pain may not be solely the fault
life, including legal and ethical issues, palliative sedation, and of medical providers: a study of patients with advanced illness
patient and family concerns, among other topics. It is important reporting poorly controlled pain cited patients’ unwillingness to
to reiterate, however. that palliative care is not limited to care near increase analgesics owing to concerns of sedation as a reason for
or at the end of life; palliative care is available to patients from the suboptimal pain control.8 Patient- and family-related barriers to
time of diagnosis of a life-limiting illness and concurrent with dis- effective end-of-life pain management also include fears of addic-
ease-modifying or life-prolonging therapy.2 tion, fears that they will ‘‘use up’’ all available analgesia and be left
Tucker MA, Andrew MF, Ogle SJ, Davison JG. Age-associated change in Wong DF, Wagner HN, Dannals RF. Effects of age on dopamine and
pain threshold measured by transcutaneous neuronal electrical serotonin receptors measured by positron tomography in the living
stimulation. Age Ageing 1989;18:241–246. brain. Science 1984;226:1393–1396.
Turnheim K. When drug therapy gets old: pharmacokinetics and Yunus MB, Holt GS, Masi AT, Aldag JC. Fibromyalgia syndrome among
pharmacodynamics in the elderly. Exp Gerontol 2003;38:843–853. the elderly: comparison with younger patients. J Am Geriatr Soc
U.S. Bureau of the Census. International Data Base 2002; Vol 2002. 1988;36:987–995.
Washington, DC: US Department of Commerce, U.S. Bureau of the Zhang YQ, Mei J, Lu SG, Zhao ZQ. Age-related alterations in responses
Census, 2002. of nucleus basalis magnocellular neurons to peripheral nociceptive
Verdu E, Ceballos D, Vilches JJ, Navarro X. Influence of age on peripheral stimuli. Brain Res 2002;948:47–55.
nerve function and regeneration. J Peripher Nerve Syst 2000;5:191–208. Zheng Z, Gibson SJ, Khalil Z, et al. Age-related differences in the time
Vuyk J. Pharmacodynamics in the elderly. Best Prac Res Clin Anaesthesiol course of capsaicin induced hyperalgesia. Pain 2000;85:51–58.
2003;17:207–218.
Chapter 51 CONCEPTOF ‘‘TOTAL PAIN’’ IN

PAIN IN THE PALLIATIVE CARE PATIENTS AT THE END OF LIFE
In the 1960s, Dame Cicely Saunders,3 an English social worker–
POPULATION turned–physician and founder of the modern hospice movement,
coined the term ‘‘total pain’’ to describe the suffering she saw in
Lida Nabati and Janet Abrahm those with terminal illness. She saw that in addition to physical
pain, her patients at the end of life were suffering from emotional,
spiritual, psychological, and existential pain. Although she was an
innovator in the use of scheduled around-the-clock opioids to treat
pain, she determined that listening to a patient’s life narrative was
an equally important therapeutic intervention. She recognized the
value of the multidimensional approach to care for the terminally
ill, and her work provided the foundation on which the field of
palliative medicine has evolved. Palliative medicine has been a
INTRODUCTION recognized medical specialty in the United Kingdom for many
years, and in 2006, the subspecialty of Hospice and Palliative
Palliative care is defined by the World Health Organization Medicine achieved official recognition in the United States by the
(WHO)1 as ‘‘an approach that improves the quality of life of American Board of Medical Specialties.
patients and their families facing the problems associated with
life-threatening illness, through the prevention and relief of suffer-
ing by means of early identification and impeccable assessment BARRIERS TO EFFECTIVE PAIN
and treatment of pain and other problems, physical, psychosocial MANAGEMENTAT THE END OF LIFE
and spiritual.’’ This definition further clarifies that palliative care ‘‘is
applicable early in the course of illness, in conjunction with Pain is one of the most commonly reported sources of distress for
other therapies that are intended to prolong life, such as chemo- patients at the end of life. The Study to Understand Prognoses and
therapy or radiation therapy, and includes those investigations Preferences for Outcomes and Risks of Treatments (SUPPORT)
needed to better understand and manage distressing clinical trial4 found that many patients at the end of life suffered from
complications.1 poorly controlled pain. The Institute of Medicine5 reported on
Whereas the palliative care patient population can include the state of end-of-life care in the United States and documented
patients with cancer, it also comprises those with end-stage heart serious deficiencies in meeting symptom-management needs of
failure, end-stage renal disease, advanced chronic obstructive dying patients. A study of patients with cancer showed that distres-
pulmonary disease, degenerative neurologic disorders, and other sing pain is common at the end of life despite the setting of death,
advanced chronic illnesses. Palliative care patients may suffer whether it is home, hospital, hospice facility, or nursing facility.6
from chronic pain, acute pain, cancer-related pain, or other non- Another study reported that relief of physical symptoms was a
cancer pain syndromes, such as painful diabetic peripheral major concern of patients at the end of life and their families.7
neuropathy. Please see other chapters in this volume for detailed The evidence suggested that a patient’s prioritization of concern
information on treatment of cancer pain. In this chapter, we focus for undertreated pain at the end of life may be justified.
on special considerations for patients with pain near or at the end of Interestingly, undertreatment of pain may not be solely the fault
life, including legal and ethical issues, palliative sedation, and of medical providers: a study of patients with advanced illness
patient and family concerns, among other topics. It is important reporting poorly controlled pain cited patients’ unwillingness to
to reiterate, however. that palliative care is not limited to care near increase analgesics owing to concerns of sedation as a reason for
or at the end of life; palliative care is available to patients from the suboptimal pain control.8 Patient- and family-related barriers to
time of diagnosis of a life-limiting illness and concurrent with dis- effective end-of-life pain management also include fears of addic-
ease-modifying or life-prolonging therapy.2 tion, fears that they will ‘‘use up’’ all available analgesia and be left
to suffer at the very end of life, fears of hastened death from sedat- irrational fear that their nurse or caregiver is trying to poison
ing medications, and avoidance of unwanted side effects. Limited them. The Confusion Assessment Method is a simple screening
studies confirm that the risk of developing addiction in the setting tool that can be used by physicians and nurses at the bedside.17
of opioid use for pain is very small.9,10 In addition, evidence shows The etiology of delirium is often unknown, but more often, it is
that opioids, when used appropriately to achieve symptom control, multifactorial.18 Etiologies include medications (e.g., opioids,
are not likely to hasten death.11,12 benzodiazepines, and corticosteroids), metabolic abnormalities,
Health care professionals also share fears of causing addiction hypoxia, infection, and central nervous system metastases.
and hastened death and worry about federal regulatory action on Evidence-based recommendations for treatment of delirium at the
prescribing controlled substances. Although physicians who pre- end of life suggest haloperidol as the first-line agent unless contra-
scribe controlled substances in an inappropriate manner may be indicated.19 Atypical antipsychotics such as olanzapine can also be
prosecuted under the Drug Enforcement Agency’s Controlled used. If delirium is believed to be due to opioids, therapeutic inter-
Substances Act of 1996, this should not limit physicians from ventions might include rotation to an alternate opioid, substituting
appropriately using opioids for treatment of pain.13,14 Systemic nonopioid and/or nonpharmacologic management of pain, or
barriers also exist. These may include the requirement of prior reducing the dose along with treating delirium with antipsychotics.
authorizations by insurers, state limitations on dispensable quanti- The triad of myoclonus, hyperalgesia, and delirium would indicate
ties of opioid analgesics allowed, and limited pharmacy stock of neurotoxicity necessitating opioid rotation or dose reduction
commonly used opioids.15 (see ‘‘Neurotoxicity,’’ later).
ASSESSMENTOF PAIN IN THE Psychosocial and Spiritual Sources of Distress

PALLIATIVE CARE POPULATION
Depression is a not-uncommon and treatable condition in patients
Assessment of pain should be frequent in patients at the end of life with advanced illness. The diagnosis can be challenging to make in
because their clinical courses are often unpredictable. This variabil- the setting of advanced illness because the typical somatic signs seen
ity may be due to disease progression or to escalating psychosocial with depression such as anorexia, fatigue, weight loss, and insomnia
or spiritual distress as functional capacity declines and the end of may be attributable to the illness. Targeted assessment of crying or
life approaches. As patient’s oral intake declines and illness anhedonia and feelings of sadness, worthlessness, guilt, hopeless-
advances, shifts in albumin and renal and hepatic function will ness, or helplessness can be more helpful. Asking the following
affect pharmacokinetics of many agents commonly used for symp- questions can help to elicit these sentiments: How do you see
tom control. your future? What do you imagine is ahead for yourself with this
For patients who are nonverbal near the end of life, methods to illness? What aspects of your life do you feel most proud of? Most
assess pain include family report and cues such as grimacing or troubled by?20 Terminally ill patients who answered yes to Are you
moaning. Assessment should address the patient’s subjective depressed? are in fact very likely to be depressed.21
report of pain and acceptability of side effects, particularly sedation Depression can be effectively managed even in the setting of very
and constipation. limited prognosis. Counseling in the form of support from a social
In the setting of advanced illness, the usual reason patients worker, a psychiatrist, a palliative care clinician, pastoral care, or
require escalation of their opioid dose is disease progression other clinician can be provided. Pharmacologic therapy is also often
rather than opioid tolerance. When reassessing pain, one should needed. The psychostimulants modafenil and methylphenidate can
observe for changing character, location, or triggers for pain. have a beneficial effect on mood and energy level within days. If
A previous dull ache from a metastatic lesion to bone that escalates prognosis is longer than several weeks, a selective serotonin reup-
to sharp and severe with any movement may indicate a pathologic take inhibitor (SSRI) should also be added. Tricyclic antidepressants
fracture, whereas sudden change to burning, shooting pain with can have efficacy in pain, although those agents with excessive an-
radiation down an extremity may indicate peripheral nerve involve- ticholinergic and sedating properties such as amitriptyline should
ment by tumor. be avoided in favor of desipramine or nortriptyline. Duloxetine is a
newer antidepressant with selective reuptake of both serotonin and
norepinephrine that has been shown to have an effect on painful
DIFFERENTIAL DIAGNOSIS OF PAIN IN physical symptoms associated with depression.22
THE PALLIATIVE CARE POPULATION Anxiety can present as uncontrolled worry, a sense of impending
doom, restlessness, autonomic hyperactivity (e.g., palpitations,
Given pain’s multidimensional character, particularly in patients at sweating, dry mouth, tightness in the chest), nausea/vomiting, dif-
the end of life, it is important to discuss a differential diagnosis for a ficulty concentrating or relaxing, insomnia, or irritability. Anxiety
complaint of ‘‘pain’’ in this population. can occur in the setting of hypoxia, sepsis, and other medical con-
ditions or in response to psychosocial stressors, which may be pres-
ent at the end of life. Benzodiazepines are helpful in managing
Delirium anxiety, but antipsychotics can also be used to blunt anxiety, and
they are less likely to cause delirium.
Up to 80% of dying patients will experience delirium.16 Delirium is Additional sources of distress for patients are related to the con-
characterized by fluctuations in consciousness as well as cognition cept of personhood and losses of roles in the occupational, relation-
and can be associated with agitation or hypoactivity. Agitation or ship, and financial realms. Patients often have concerns of being a
restlessness can easily be mistaken for pain in a delirious patient. In burden to loved ones and worries over who will take care of their
addition, delirious patients are not likely to be reliable reporters of loved ones after they are gone. Clinicians can help patients find
pain using standard methods of pain assessment. Symptoms of de- solace and closure at the end of life by exploring and listening
lirium include hallucinations, nightmares, anxiety, and difficulty empathetically to religious and spiritual beliefs.23 Helping patients
concentrating. Signs of delirium may include reversal of day/night find meaning in their life and transmit a legacy can be very mean-
cycle, sensitivity to light or sounds, emotional lability, and deficits ingful. Patients and families can be encouraged to bring closure by
of attention and memory. Patients with hypoactive delirium may discussing ‘‘The Five Things:’’ Forgive me; I forgive you; Thank you;
appear depressed or withdrawn and often report fears and a feeling I love you, and Goodbye.24 Many patients and families can view this
of not being safe. They may refuse medication because of the time as one of remembrance, growth, healing, and resolution.25
Chemical Coping addressing issues of pain management at the end of life.30

Deliberative decision making does not assume preexisting patient
Patients being treated with opioid analgesics at the end of life likely values necessary to inform decisions regarding possible treatment
have a low risk of developing addiction. Nonetheless, concerns for options presented by the health care professional. The health care
addiction still exist on the part of clinicians and families. It is professional’s role in caring for someone who is in the end of life
important to educate patients and families on the difference and experiencing pain is not simply to elicit values but to help
between tolerance and physiologic dependence, which are expected patients shape or adapt their values in what is an entirely new
from regular opioid use, and addiction, which implies compulsive and unfamiliar situation for them. Helping patients to articulate
use of a substance despite harm.26 Clinicians should not confuse these values may offer the health care professional an opportunity
these with pseudoaddiction, which is when aberrant behaviors esca- to address misunderstandings and fears about what to expect as life
late as a result of undertreated pain and resolve when pain is ade- draws to a close. Just as the experience of pain is subjective, the
quately treated.27 approach to treating pain at the end of life should be individualized
Patients who engage in a series of behaviors indicating problem- to each patient’s desires and values.30
atic drug taking may report poorly controlled pain and escalating
opioid use. It is important to recognize aberrant drug-taking beha-
viors on a spectrum from less to more suggestive of a substance use MANAGEMENTOF PAIN AT THE END
disorder. Behaviors such as occasional self-escalating doses and OF LIFE
repeated complaining of poorly controlled pain are less suggestive
of a substance use disorder. Injection of oral agents, taking medica- Opioids are the mainstay of treating pain at the end of life, and
tions for boredom or to get ‘‘high,’’ and diversion of prescribed general principles of their use apply. Opioids should not be routi-
drugs for criminal intent are more suggestive of substance use dis- nely decreased for a declining respiratory rate because this may be
order.28 Patients who have used mood-altering substances to cope part of the dying process. If opioids are decreased, the patient
with stressful life events in the past are at greater risk of continuing should be monitored carefully for increasing discomfort.
these maladaptive behaviors and will need to be closely monitored. Naloxone is almost never indicated at the end of life if opioids are
With coordinated multidisciplinary efforts, many patients, even used carefully with guidelines suggested in this chapter, and it is
those actively addicted to illicit drugs, can be effectively and safely likely to cause very distressing opioid withdrawal if given undiluted.
managed with opioid analgesics and other controlled substances at Patient-controlled analgesia (PCA) devices with or without contin-
the end of life.26 uous infusion can be a safe and effective means of allowing patients
to self-administer opioids and limiting the risk of oversedation.
For patients unable to take oral medications, the clinical chal-
Neurotoxicity lenge is to provide both baseline and breakthrough pain control
using alternative routes of opioid delivery. Baseline pain is usually
Opioids can cause neurotoxicity that can manifest with myoclonus, well controlled by continuous intravenous or subcutaneous infu-
hyperalgesia and allodynia, and delirium. Neurotoxicity is typically sions alone or as a basal rate as part of a PCA device, rectal admin-
seen in the setting of a rapid escalation of opioid dose or impair- istration of sustained-release opioid tablets, or in patients with
ment of renal function in the setting of chronic stable use leading to adequate fat stores, transdermal patches. Breakthrough pain can
accumulation of neurotoxic metabolites. Neurotoxicity can be man- be addressed via intravenous or subcutaneous PCA, immediate-
aged with a reduction of the opioid dose, opioid rotation, and release rectal opioid suppositories, and buccal and sublingual
gentle hydration to help clear metabolites. It is speculated that opioids (Table 51–1).
spinal N-methyl-D-aspartate (NMDA) receptors mediate opioid tol- A disturbing, but common, practice in many institutions is to
erance, and methadone may be an effective agent to rotate to in the order continuous opioid infusions with broad parameters (e.g.,
setting of opioid-induced hyperalgesia because it has a unique prop- morphine sulfate 0–20 mg/hr intravenous continuous infusion)
erty of NMDA receptor antagonism. It is the only opioid with this for patients who are very near the end of life and choose comfort
property.29 as the overriding goal of medical care. If the patient had no previous
complaints of pain or dyspnea, a continuous opioid infusion is not
usually indicated in the last days. Nonspecific moaning in such
patients (e.g., when they are touched in a previously nonpainful
ASSESSMENT LIMITED BY BENEFITS/ area or when their lips are moistened) is more often a sign of de-
BURDENS AND SHARED DECISION lirium and is better treated as described previously. If patients do
MAKING appear to be grimacing when turned or cry out at those times, bolus
dosing prior to moving may be more appropriate.
Benefits of diagnostic or therapeutic interventions should be For patients who are thought to benefit from a continuous infu-
weighed against their burdens, and patients or their surrogate decision for pain or dyspnea, the parameters should be narrow (with the
sion makers should be involved in decision making. Patients will highest dose no more than three times the lowest), boluses should
often choose to prioritize comfort at the end of life, and this may be included for pain or dyspnea exacerbations, and clear instruc-
involve limiting burdensome or uncomfortable diagnostic testing. tions should be included for when the boluses should be given and
Empirical treatment of pain and delirium without extensive evalu- the drip increased. If a bolus order is not available, the continuous
ation may be more appropriate if it is consistent with a patient’s infusion is often escalated in response to an acute exacerbation of
goals and values. For example, a patient who is doing reasonably symptoms, yet it may take hours for the patient to experience the
well at home with hospice care who feels she or he has completed full benefit of that titration, causing needless suffering and potential
her or his end of life tasks may develop an acute pain crisis. overdosing of opioid.
Commonly available options for evaluation such as imaging tech- An appropriate order for a patient previously needing morphine
niques are not readily available in the home, and a patient may boluses of 4 mg intravenously every 4 hours would be morphine
decide to forgo work-up and have the pain treated with escalation sulfate 1 to 3 mg/hr continuous infusion (subcutaneously or intra-
of the analgesic regimen, even if sedation is required to achieve venously); morphine sulfate 2 to 6 mg every 2 hours as needed for
comfort. grimacing or other evidence of discomfort. A patient who has an
Deliberative decision making is a form of shared decision acute exacerbation of pain or dyspnea is more likely to get imme-
making that is helpful for health care professionals and patients diate relief (within 15 min) from a bolus infusion and may not
Table 51^1. Nonoral Routes of Opioid Analgesia Pruritus and urinary retention may occur in opioid-naı̈ve
patients if opioids are introduced at the end of life. These side
Route Opioid effects are transient, but patients may need short courses of
diphenhydramine or urecholine, respectively, to treat these
Subcutaneous Morphine, hydromorphone.* fentanyl, complications.31
oxymorphone
Methadone can cause local toxicity
(dexamethasone [Decadron] may prevent)
OPIOIDS FOR RESPIRATORY DISORDERS
Intravenous Fentanyl, morphine, hydromorphone,
methadone, oxymorphone Dyspnea is very common in patients at the end of life. Causes of
Sublingual Morphine or oxycodone concentrates, dyspnea are extensive and include pleural effusions, pulmonary
edema, anemia, extensive ascites, advanced chronic obstructive pul-
methadone
monary disease, pulmonary parenchymal metastases, and metabolic
Buccal Fentanyl acidosis. Benzodiazepines may be helpful for anxiety causing or
Transmucosal Fentanyl resulting from dyspnea. But no matter what the etiology, opioids
Rectal Sustained-release morphine,* sustained- can be used to help with the subjective sensation of breathlessness,
release oxycodone,{ methadone,{ although there is insufficient evidence to support the use of neb-
morphine, oxycodone, oxymorphone ulized opioids.32 Opioids are initiated at the same doses used to
treat pain in an opioid-naı̈ve patient and escalated as needed. There
Nebulized Not recommended
is no evidence that morphine is superior to any other opioid for
Transdermal Fentanyl alleviation of dyspnea. The same opioid the patient is using for pain
(e.g., hydromorphone) can be used to treat the dyspnea. Sustained-
*Hydromorphone is the most potent opioid and is also available in a
release opioid preparations with immediate-release doses available
highly concentrated form.
{ for breakthrough dyspnea are used in the same manner as for pain.
Decreasing the dose from the oral, sustained-release oxycodone
Families and staff must be carefully educated that the purpose of
preparation is suggested.
{ opioids is to control the symptom of dyspnea, not to hasten death.
Methadone rectal dose is probably equivalent to oral dose.
From references 44 to 47.
ALTERNATIVE APPROACHES
require further titration of the continuous infusion. A patient pre-
viously comfortable on 60 mg of oral sustained-release morphine It is estimated that sometime during their course, 10% to 15% of
every 8 hours who becomes unable to take oral medications, how- cancer patients will experience pain refractory to conventional
ever, would need morphine sulfate 7.5 to 22 mg/hr continuous analgesic regimens.33 Interventional approaches to pain manage-
infusion with 15 to 30 mg intravenously every 2 hours as needed ment at the end of life can diminish or obviate the need for
for grimacing or other evidence of discomfort. But this amount of opioids and other analgesics, thereby affording patients control
morphine in a patient with progressive renal insufficiency would of pain without the unwanted side effects of these medications.
likely lead to neurotoxicity from the metabolites, and the volume These approaches include but are not limited to nerve blocks;
required would be difficult to deliver subcutaneously. A conversion peripheral nerve neurolysis with phenol or alcohol; sympathetic
to hydromorphone may be preferable. ganglion blocks; and neuroaxial drug delivery of combinations of
opioids, local anesthetics, and other agents (such as clonidine)
through epidural catheters, catheters connected to implanted sub-
MANAGEMENTOF OPIOID-RELATED cutaneous ports, and totally implanted intrathecal pumps. Patients
SIDE EFFECTS (FOR ‘‘DELIRIUM,’’ SEE with implanted ports or pumps can be managed outside the hos-
EARLIER) pital, even at home.
Systemic radionuclides such as strontium and samarium are
Constipation can be a very significant source of distress and can effective for pain from widespread metastases to bone in patients
cause delirium in patients whose oral intake and mobility decline with a prognosis of at least several months,34 whereas bisphospho-
and who increasingly rely on opioids for comfort. Constipation nates (e.g., zoledronic acid) are effective in about a week. For
needs to be treated in a preventive manner with scheduled use of patients with single metastases to long bones, single fraction radi-
stimulants (senna) and stool softeners (docusate), as well as osmotic ation therapy is effective with minimal burden to the patient and
laxatives (lactulose or polyethylene glycol preparations) as needed. caregivers.35 Central neurolytic approaches such as cordotomy and
Patients who have not had a stool for several days should be cingulotomy are rarely necessary. Close collaboration with an anes-
assessed for fecal impaction and treated with suppositories, mineral thesia pain specialist, interventional radiologist, nuclear medicine
oil retention enema followed by a large-volume water enema, and specialist, and radiation oncologist is important to comprehensive
disimpaction when necessary.31 care of pain in patients at the end of life.
Psychostimulants such as methylphenidate and modafenil can be Nonpharmacologic interventions such as heat, meditation, hyp-
used to counter opioid-induced fatigue and sedation, although nosis, relaxation, physical therapy, acupuncture, and massage
patients should be counseled that they typically develop tolerance should be considered. Family and other caregivers can easily be
to the sedating effect of opioids. taught some of these techniques, which can help them to feel
Antiemetics such as metoclopramide, prochlorperazine, or useful in the care of their loved one.
ondansetron can be used to manage nausea associated with opioids,
although patients should be advised that they typically develop tol-
erance to opioid-induced nausea within several days. Nausea that REQUESTS FOR HASTENED DEATH
develops while on stable chronic opioid dosing is not likely attrib-
utable to opioids. Ondansetron is itself constipating and should be Clinicians caring for patients near the end of life should be com-
used sparingly in this population.31 Other agents with antiemtic fortable identifying and addressing requests for hastened death from
properties such as steroids, scopalamine patch, and aprepitant31 patients and families. Requests for hastened death may take the
may be useful in certain circumstances. form of a request for assisted suicide or euthanasia. These requests
should be viewed as an opportunity to further explore patients’

concerns about debility, dependency, or suffering at the end of Box 51^1 PALLIATIVE SEDATION
life.36
In the United States, physician-assisted suicide is legal only Indications
Intractable suffering in advanced terminal illness despite maximal
in the state of Oregon. Euthanasia, conversely, is an action taken conventional therapy.
with the intent to hasten death and is illegal in the United States.
In the setting of terminal illness, it is acceptable for patients to Criteria
forgo life-sustaining treatment, such as artificial nutrition and Patient has an advanced terminal illness and refractory symptoms.
Do not resuscitate (DNR) order is active.
hydration or mechanical ventilatory support, if they deem their Patient and/or surrogate decision maker desires sedation as acceptable
quality of life to be such that they choose not to have it prolonged. means to achieve symptom control and understands goals of
Such an action is not suicide and is sanctioned not only by a intervention.
consensus of ethical opinion but also by most religious traditions. Palliative care consultation is obtained if available.
Care should be taken to assess patients for depression, demo- Pastoral care and psychiatry consultation are obtained for psychologi-
ralization, or spiritual and psychosocial distress. Psychiatric and cal or spiritual/existential distress.
pastoral care consultation should be obtained to help with this Plan is been discussed with all medical staff involved.
assessment. Discussions and plan are documented in chart.
Suggested Therapy
Midazolam
ETHICAL CONSIDERATIONS 0.5^5 mg IV/SC loading dose followed by 0.5^1mg/hr IV/SC continuous
infusion.
Frequently, patients and families as well as medical providers raise
concerns that opioids or other sedating agents required to treat Pentobarbital
2^3 mg/kg IV loading dose followed by 1 mg/hr IV continuous infusion.
symptoms at the end of life actually hasten death. The ethical prin-
ciple of ‘‘double effect’’ is often invoked when discussing pain con- Phenobarbital
trol at the end of life. Double effect comprises four conditions: a 200 mg IV/SC loading dose followed by 600 mg/day IV/SC continuous
morally neutral act, an intended good outcome and a foreseen but infusion.
unintended outcome, the bad outcome is not the means to the good Chlorpromazine
outcome, and the good effect outweighs the bad effect (also known 10 ^25 mg PO/IV/PR every 2^ 4 hr.
as proportionality). The doctrine of double effect is often raised as
IV, intravenous; PO, oral; PR, per rectum; SC, subcutaneous.
an ethical framework for providing sedating analgesics at the end of Adapted from Rousseau P. Palliative sedation in the management of refractory symptoms.
life. However, because the evidence suggests that death is not likely J Support Oncol 2004;2:181^186.
hastened by opioid analgesics, this construct probably does not
apply.37
PALLIATIVE SEDATION
at the time of diagnosis and concurrent with disease-modifying
Palliative sedation is ‘‘the monitored use of medications to relieve therapy. This is in contrast to hospice care, which is typically lim-
refractory and unendurable symptoms by inducing varying degrees ited to patients who are choosing quality of life as their primary goal
of unconsciousness but not death.’’38 The intent is to alleviate suf- of medical care. Patients are eligible for hospice care when they have
fering, not to hasten death, for patients with advanced terminal a prognosis of 6 months or less if the disease takes its expected
illness who are believed to be near the end of life. For patients course.
who are near death and have intractable suffering despite expert Patients who elect to enter hospice programs typically forgo
evaluation and management, palliative sedation is an ethically and therapies with palliative intent such as total parenteral nutrition,
legally acceptable treatment option. The nature of suffering may be chemotherapy, or radiation. Hospice programs, in fact, operate on a
physical, from pain or dyspnea, or it may be psychological, spiritual, capitated system, receiving a fixed amount per patient per day,
or existential, or a combination of these. approximately $130 a day in 2006.43 The combined funds are
In the case of psychological and spiritual/existential distress, used for operating costs of the hospice to provide multidisciplinary
consultation with psychiatry and pastoral care should be obtained. and comprehensive end-of-life care that includes nursing and home
It is important to obtain consent from patients or surrogate deci- health aide visits, social work and chaplaincy services, as well as
sion makers and have consensus among those involved in the care drugs and durable medical equipment related to the terminal diag-
of a patient to agree on sedation as the only acceptable means of nosis. Hospices provide 24/7 phone coverage by hospice nurses,
relieving intractable suffering.39 A do not resuscitate order should who will also come to the home for emergencies. For short periods
be implemented in this setting. For patients receiving artificial of time, continuous home nursing can be given, as can inpatient
nutrition or hydration, these measures are usually discontinued. hospice care. All patients can spend 5 days every month in a nursing
A discussion should take place with the patient and/or surrogate home to give the caregivers a ‘‘respite’’ from the physical care they
decision maker regarding the burdens and benefits of these thera- require. These services offer much-needed support for patients for
pies at this time.40–42 Preferred medications to induce palliative whom remaining at home with optimal support for them and their
sedation include benzodiazepines and barbiturates (Box 51–1), families is a priority.
and palliative care can be done in a variety of settings, including Primary care physicians and specialist teams (e.g., oncologists)
non–intensive care unit hospital wards and even at home with can maintain communication with the patient and/or family
hospice support. when hospice care is involved. This continuity is very important
in supporting the patients through a difficult time and alleviating
their fears of abandonment. It is important that the patient’s
HOSPICE primary team express support for hospice care as care that is
typically most appropriate to achieving goal of comfort at the
Palliative care programs serve patients with a life-limiting illness end of life. It is not offered merely because ‘‘there is nothing
and can be offered in the hospital, outpatient, or even home setting more that can be done.’’
SUMMARY 20. Block SD. Assessing and managing depression in the terminally ill
patient. Ann Intern Med 2000;132:209–218.
Patients near or at the end of life who report pain should be thor- 21. Chochinov HM, Wilson KG, Enns M, Lander S. ‘‘Are you depressed?’’
oughly assessed for other sources of suffering such as delirium, Screening for depression in the terminally ill. Am J Psychiatry
psychosocial distress, or spiritual distress. These patients are at 1997;154:674–675.
risk of undertreatment of pain or inappropriate management of 22. Goldstein DJ, Lu Y, Detke MJ, et al. Effects of duloxetine on painful
physical symptoms of depression. Psychosomatics 2004;45:17–28.
pain given widespread concerns about ethical issues, a misunder-
23. Lo B, Ruston D, Kates LW, et al. Discussing religious and spiritual
standing of the doctrine of double effect, and excessive fears of issues at the end of life: a practical guide for physicians. JAMA
addiction or legal recourse. In addition, patients and families and 2002;287:749–754.
health care providers harbor misconceptions that pose barriers to 24. Byock I: Dying Well: The Prospect of Growth at the End of Life. New
effective pain management at the end of life. To address these con- York: Riverhead, 1997; pp 139–140.
cerns, we recommend eliciting beliefs and educating patients, 25. Block SD. Psychological considerations, growth, and transcendence at
families, and staff regarding effective pain management near or at the end of life. JAMA 2001;285:2898–2905.
the end of life. When maximal multidisciplinary approaches fail to 26. Passik SD, Kirsh KL. Managing pain in patients with aberrant drug-
relieve suffering, in certain cases palliative sedation is an acceptable taking behaviors. J Support Oncol 2005;3:83–86.
means of alleviating distress. 27. Weissman DE, Haddox JD. Opioid pseudoaddiction—an iatrogenic
syndrome. Pain 1989;36:363–366.
28. Passik SD, Kirsh KL, Portenoy RK. Substance abuse issues in palliative
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392 Chapter 52 PAIN IN THE SUBSTANCE ABUSE POPULATION
Chapter 52 to employ when the riskier agents are being prescribed. Thus, there
is a duty not just to assess patients and treat them as individuals but
PAIN IN THE SUBSTANCE also to assess and know the community and treat patients in the
context of the specific flavor of drug abuse in their community.
ABUSE POPULATION
Steven D. Passik and Kenneth L. Kirsh TREATMENTAND GOOD PRACTICE
Although the concern is identifying and treating patients with pain
and comorbid aberrant drug-taking behaviors appropriately, it is
important to remember the basic tenets of good chronic pain man-
agement, many of which also help with these more complicated
patients (Box 52–2). For instance, any medications chosen to
INTRODUCTION treat the patient should be titrated to effect or toxicity, following
the ‘‘start low, go slow’’ principle.6,7 Also, patient self-report should
The growing problem of prescription drug abuse has forced pain- be respected, even if the patient has been found to be a questionable
management practitioners to take a new look at opioid prescribing source on occasion. We must not naı̈vely accept the patient’s words
and to seek balance in its risks and benefits (Box 52–1). Whereas it and report completely; neither should we dismiss their words out of
is no doubt time to tone down the rhetoric, we should not abandon hand entirely. Further, any pain patient must abide by the rules of
the use of these agents and return to trends of underprescribing. therapy and make a good faith effort to achieve a successful out-
Although it is arguable that the dramatically expanded use of come. Finally, it is important for the clinician to have an ongoing
opioids was undertaken with a paucity of long-term data to justify assessment and thorough documentation of the patient’s function-
it, it is also the case that the complete avoidance of these drugs was ing according to several key domains.
equally unsupported.1 Today, all practitioners involved in pain
management have the dual mission of relieving suffering while
avoiding contributing to drug abuse and diversion. If all practi- THE 4 A’s
tioners can become better acquainted with the principles of addic-
tion medicine as these apply to the world of pain management, pain Passik and Weinreb8 described the ‘‘4 A’s’’ of pain-management
management can be kept safe and available for all who need it. The outcomes—analgesia (pain relief), activities of daily living (psycho-
assessment of aberrant behaviors in patients with chronic pain is social functioning), adverse side effects (side effects), and aberrant
one key aspect of mastering these principles. drug-taking behaviors (addiction-related outcomes)—as a short-
The problem of prescription drug abuse has grown by leaps and hand for the domains that should be assessed and discussed at
bounds since the late 1990s. Whereas initial reports were optimistic every return visit for patients on chronic opioid therapy. Doing
that the increasing production and use of opioids was not accom- so in a detailed manner is time-consuming, and a tool would cer-
panied by a growth in the abuse and diversion of these drugs, as tainly help to upgrade most physicians’ documentation.
time has passed the growth of the problem has become more obvi- Various definitions of abuse that include the phenomena related
ous.2 The media spectacle that has accompanied the misuse of to physical dependence or tolerance are not applicable to patients
sustained-release oxycodone has been only the most visible of the who receive potentially abusable drugs for legitimate medical pur-
multitude of stories on misuse of opioids by well-known celebrities poses. A differential diagnosis should be explored if questionable
and others.3 There is little doubt that much of the reporting of the behaviors occur during pain treatment (Table 52–1).9 A true addic-
problem in the popular press has been inaccurate, sensationalized, tion is only one of several possible explanations, but it is more likely
and unbalanced. The result of this distasteful reporting has been when behaviors such as multiple unsanctioned dose escalations and
that many physicians were initially dismissive of the problem obtaining opioids from multiple prescribers occur.
because the seriousness of the problem was actually obscured for The diagnosis of pseudoaddiction must also be considered if the
them by the media circus. However, it has become abundantly clear patient is reporting distress related to unrelieved symptoms.
via numerous avenues of information (e.g., the Drug Awareness Behaviors such as aggressively complaining about the need for
Warning Network, the Household Survey) that the problem is on higher doses or occasional unilateral drug escalations, which
the rise.4 Prescribers must recognize that there is a deteriorating appear to be addiction on the surface, may be indications that the
environment around opioid use engendered by the substantial patient’s pain is undermedicated. Indeed, one of the most perplex-
public concern and must follow guidelines carefully. The problem ing differential diagnoses is the distinction between addiction (the
of prescription drug abuse nationally is only part of the issue, how- behavior is out of control, continues despite harm) and pseudoad-
ever. Prescribers must also know what drugs are being abused diction (the behavior is driven by inadequate analgesia, resolves
locally, follow the trends, and use medications carefully if these when analgesia is improved).10 No behavior is universally linked
agents happen to be ‘‘hot’’ in their location. to one or another despite how aberrant it might appear on its ‘‘face
For example, we have studied prescription drug abuse in central value’’ (e.g., we have reported a case of prescription forgery that was
and southeastern Kentucky, a locale especially hard hit by prescrip- linked to anxiety related to the caregiver’s vacation and had nothing
tion drug abuse problems.2,5 In both a retrospective and a prospec- to do with abuse/diversion).11 Generally, patients will describe
tive set of studies, we learned a great deal about the abuse of pain uncontrolled pain rather than loss of control from their perspective.
medications in the area (e.g., hot ones like oxycodone and less- Thus, clinicians often have to ‘‘walk the line’’ between the two
popular ones such as fentanyl) and which patients are at particular possibilities by beginning the process of imposing limits while
risk for abuse or diversion.2,5 This understanding colors the deci- titrating drugs upward to effect until the behavior comes under
sions of physicians in the area about choice of agents and strategies control or escalates further before the diagnosis is clinched.
Table 52^1. Differential Diagnosis Considerations

Box 52^1 CURRENT DIAGNOSIS for Assessing Aberrant Drug-taking
The growing problem of prescription drug abuse has forced the
Behaviors
pain-management field to take a new look at opioid prescribing and to
seek balance in its risks and benefits. Differential Diagnosis Explanation
Whereas understanding national trends is important, prescribers
must know what drugs are being abused locally, follow the trends,
Addiction Marked by out-of-control behaviors
and use medications carefully if the agents happen to be ‘‘hot’’ in their and compulsive drug use (use
location. despite harm).
Prescribers must learn to assess for aberrant drug-taking behaviors. Pseudoaddiction Marked by undertreated pain leading
to desperate acting out. Patients
may turn to alcohol, street drugs,
or doctor-shopping to meet their
There is no doubt that the notion of pseudoaddiction was an
important step forward in pain management—a recognition of need for pain relief. These behaviors
the desperation set in motion by unrelieved pain and a somber subside when their pain is
realization that patients can be pushed to uncharacteristic ways of adequately treated.
behaving driven by our failure to optimally treat them. However, it Psychiatric diagnoses
is also crucial to recognize that pseudoaddiction is not an empiri- Organic mental Patients are often confused and have
cally validated notion. The initial paper on the subject was a small syndrome stereotyped drug-taking.
case series.10
Personality disorder Patients are impulsive, have a sense
Impulsive drug use may also indicate the existence of another
psychiatric disorder, diagnosis of which may have therapeutic of entitlement, and may engage in
implications. For example, patients with borderline personality dis- chemical coping behaviors.
orders may be categorized as exhibiting aberrant drug-taking beha- Chemical coping Patients place too much emphasis on
viors if they are utilizing prescription medications to express fear the meaning of their medications.
and anger or improve chronic boredom. Similarly, patients who use They are overly drug focused.
opioids to self-medicate symptoms of anxiety or depression, insom- Depression, anxiety, Patients are marked by their desire to
nia, or problems of adjustment may be classified as aberrant drug and situational self-medicate their mood disorder
takers. Occasionally, aberrant drug-related behaviors appear to be
stressors or current life stress.
causally related to mild encephalopathy, with confusion regarding
the appropriate therapeutic regimen. Problematic behaviors rarely Criminal intent Category is concerned with the subset
imply criminal intent, such as when patients report pain but intend of criminals who are intent on
to sell or divert medications. These diagnoses are not mutually diverting medications for profit.
exclusive, and a thorough psychiatric assessment is vitally important
in an effort to categorize questionable behaviors properly in both
the population without a prior history of substance abuse and the
population of known substance abusers who have a higher inci- short-acting opioid, had a mean value of $47 per pill (4 mg
dence of psychiatric comorbidity. strength) compared with $3 per pill for slow-release morphine.
On a national level, the Drug Abuse Warning Network is in
place to capture data on overdoses in emergency rooms across
UNDERSTANDING STREET VALUES the country.13 Their data reveal that hydrocodone combinations
are accountable for the most overdoses, followed closely by oxyco-
It is important for clinicians who treat chronic pain patients to be done combinations. Methadone and fentanyl combinations are typ-
aware of the street value of the medications they prescribe. Whereas ically lower, but these have occasional fluctuations.
there are national trends, variations will exist based on the location
of the country in which the providers practice as well as the types of
patients they see. As an early attempt to become familiar with the TAILORING THE APPROACH
street values of various opioid analgesics, Brookoff12 asked 130 hos-
pital patients who admitted to abusing medications about their When deciding on treatment plans, clinicians need to utilize the
behaviors. He discovered that, in general, controlled-release pre- findings of their assessment and diagnosis work and plan accord-
parations of opioids had less value than other opioids and even ingly. The categories of patients (the Uncomplicated Patient, the
some nonopioid formulations. As an example, hydromorphone, a Patient with Comorbid Psychiatric and Coping Difficulties, and the
Patient with Addiction), along with a description and recommen-
dation for who is qualified to treat them, are listed in Table
52–2.14,15 Cookie-cutter approaches and overconfidence about the
ability to treat anyone under any circumstances needs to be replaced
Box 52^2 CURRENT THERAPY by a sober assessment of whom a particular practitioner can treat in
his or her practice setting given the practitioner’s time, expertise in
Good pain-management practices (e.g., making slow and gradual dose
changes, having proper documentation) work for all patients, including complex psychiatric issues, and resources. Learning whom one can
those with substance use problems. treat alone, whom they can treat with help, and whom they should
Continue to utilize patient self-report, but realize it will be less accu- refer out is crucial for pain management to be done safely.
rate in problematic patients.Try to confirm self-report through corro- Therefore, health care providers should obtain consultations as
borating channels when possible. needed. In addition, when drug therapy is begun, it should be
Multidisciplinary approach is absolutely necessary to manage patients done in the context of a treatment plan based on informed consent
with pain and comorbid substance use problems. If necessary, physi- of the risks and benefits of all medicines prescribed. Health care
cians need to reach out to the community and develop informal providers owe it to their patients to discuss realistic expectations
‘‘teams’’ of experts, including mental health practitioners.
about pain reduction and help formulate functional goals to be
394 Chapter 52 PAIN IN THE SUBSTANCE ABUSE POPULATION
Table 52^2. Categories of Patients with Chronic Pain and Their Accompanying Levels of Care Required
Patient Categorization Requirements for Care

Uncomplicated patient Acceptable to use minimally monitored drug-only therapy.
Has no documented comorbid psychiatric problems or connection to drug subculture.
Routine medical management generally sufficient.
Suggested practice includes 30-day supply of medications with liberal rescue dose policy.
Monthly follow-ups.
Primary care physicians can monitor and follow.
Patient with comorbid Behavior resembles that of addicts with a central focus on obtaining drugs.
psychiatric and coping Needs structure, psychiatric input, and drug treatments that decentralize the pain medication
difficulties from the patient’s coping.
Decentralize meaning: reduce the meaning of medications, undo conditioning, and undo the
socialization around the drug.
Best accomplished via use of pain-related psychotherapy.
Primary care physicians can monitor and follow as long as other involvement (e.g., physical
therapy, occupational therapy, social work, psychology) is maintained.
Patient with addiction Requires the most structure including frequent visits.
Active abuser Give a limited supply of medications.
In drug-free recovery Drug choices should be tailored for long-acting opioids with little street value.
In methadone Rescues offered judiciously.
maintenance Implement use of urine toxicology screening and follow-up on results.
Require patient to be in active recovery programs or psychotherapy
Primary care physicians should typically refer these patients to specialists, unless these
physicians have a strong interest and training in this area.
achieved by prescribing rational pharmacology. Helping the patient functioning. Becoming familiar with the family may help the phy-
understand how success or failure is to be measured—not only in sician or staff to identify family members who are themselves drug
terms of pain control (hopefully, a meaningful reduction in pain abusers and who may potentially divert the patient’s medications,
intensity) but also in terms of function (stabilized or improved), resulting in the patient’s noncompliance.
toxicities (manageable or none), and aberrant behaviors (few or
none)—is crucial for gaining compliance and understanding of
the goals of therapy. The health care provider must, of course, URINE TOXICOLOGY SCREENING
prescribe all medications consistent with state and federal regula-
tions. This assertion then begs the question, ‘‘What does the phy- Urine toxicology screening has the potential to be a very useful tool
sician owe the patient/community,’’ in which initiation of an opioid to the practicing clinician both for diagnosing potential abuse pro-
trial is concerned. The physician must perform a thorough assess- blems and for monitoring patients with an established history of
ment of the patient’s risk for aberrant behavior and then match this abuse. Recent work suggests that urine toxicology screens are
risk to a level of structure in opioid treatment that is appropriate. If employed infrequently in tertiary care centers.16 When screens are
a patient were found to be at high risk, multiple precautions can be ordered, documentation tends to be inconsistent regarding the rea-
employed to mitigate this risk (see later); this assessment should not sons for ordering as well as any follow-up recommendations based
be used as a basis for categorical exclusion of that patient as a on the results. The survey found that nearly 40% of the charts
candidate for opioid therapy. However, if a given practice venue surveyed listed no reason for obtaining the urine toxicology
cannot provide the appropriate level of structure, referral to a more- screen and the ordering physician could not be identified nearly
specialized setting may be necessary. 30% of the time.16
GENERALTREATMENT ISSUES INTERDISCIPLINARY TREATMENT

A written agreement or consent document between the treatment Ultimately, a multidisciplinary team approach, with an interdisci-
team and the patient helps to provide structure to the treatment plinary focus (e.g., collaborative, holistic/focused on the mind-body
plan, establishes clear expectations of the roles played by both par- relationship, and embodying the tenets of the biopsychosocial
ties, and outlines the consequences of aberrant drug taking. The model) is recommended for the management of substance abuse
inclusion of spot urine toxicology screens in the contract can be and misuse in the medical care setting. Mental health professionals
useful in maximizing treatment compliance. Expectations regarding with specialization in the area of addiction are usually instrumental
attendance of clinic visits and the management of one’s supply of here, given their expertise in developing and executing strategies for
medications should also be stated. In addition, the physician should behavioral management and treatment compliance. Unfortunately,
limit the amount of drug dispensed per prescription and make these skilled professionals are not often readily available to clini-
refills contingent upon clinic attendance. One should also consider cians working in private practice or other medical agencies.
requiring the patient to attend 12-step programs and have the Therefore, it is beneficial for clinicians in independent practice to
patient document her or his attendance as a condition for ongoing establish a collective of complementary practitioners in their geo-
prescribing. In addition, family members and friends should be graphic locale to whom they can refer patients for the purpose of
involved in the treatment to help bolster social support and receiving supplementary services for pain control and maintain a
modicum of team-based support. Clinicians practicing in isolation 3. Hancock CM. OxyContin use and abuse. Clin J Oncol Nurs
can quickly experience feelings of anger, defensiveness, and frustra- 2002;6:109.
tion in relation to medical patients with chronic pain. Such feelings 4. Office of Applied Studies of the Substance Abuse and Mental Health
can unintentionally compromise the level and quality of health care Services Administration. Results from the 2005 National Survey on
Drug Use and Health: National Findings. Department of Health and
and contribute to a perceived sense of alienation, hopelessness, and
Human Services. Publication No. SMA 06-4194. Available at: http://
rejection on the part of the patient. Structured, interdisciplinary www.oas.samhsa.gov/NSDUH/2k5NSDUH/2k5results.htm (Accessed
treatment (e.g., to include addiction, behavioral medicine, rehabil- July 10, 2008).
itation medicine, social work, and/or psychiatry team members) is 5. Hays L, Kirsh KL, Passik SD. Seeking drug treatment for oxycontin
the most effective approach toward facilitating staff understanding abuse: a chart review of consecutive admissions to a substance abuse
of each patient’s needs, provides a forum for necessary venting and treatment facility in the bluegrass region of Kentucky. J Natl Compr
strategizing, and aids in the development and administration of Cancer Netw 2003;1:423–428.
efficacious and empathetic interventions for optimizing pain con- 6. Lamberg L. New guidelines on managing chronic pain in older
trol and minimizing aberrant substance use. Regular staff meetings persons. JAMA 1998;280:311–312.
can also help to establish both patient-specific and team-based 7. Verhaak PFM, Kerssens JJ, Dekker J, et al. Prevalence of chronic
benign pain disorder among adults: a review of the literature. Pain
treatment goals, facilitate consistency and confidence in the provi- 1998;77:231–239.
sion of services, foster patient compliance, and maximize the like- 8. Passik SD, Weinreb HJ. Managing chronic nonmalignant pain:
lihood that clinical objectives are met. overcoming obstacles to the use of opioids. Adv Ther 2000;17:70–80.
9. Rinaldi RC, Steindler EM, Wilford BB, Goodwin D. Clarification and
standardization of substance abuse terminology. JAMA 1988;259:555.
10. Weissman DE, Haddox JD. Opioid pseudoaddiction—an iatrogenic
CONCLUSION syndrome. Pain 1989;36:363–366.
The health care provider who does pain management needs to first 11. Hay JL, Passik SD. The cancer patient with borderline personality
disorder: suggestions for symptom-focused management in the
recognize that the problem of prescription drug misuse is not
medical setting. Psychooncology 2000;9:91–100.
simply media hype nor is it confined to remote areas like eastern 12. Brookoff D. Abuse potential of various opioid medications. J Gen
Kentucky. The particular sociology of areas like Appalachia may Intern Med 1993;8:688–690.
have made them the most vulnerable early on, but it is now every- 13. Drug Abuse Warning Network. Emergency department trends from
one’s problem. Today, a tactical and humane approach is required the drug abuse warning network, preliminary estimates January-June
in the treatment of pain. The health care provider needs to perform 2002. Drug Abuse Warning Network Series. National Clearinghouse
an appropriate evaluation of the patient before writing the first for Alcohol and Drug Information, Rockville, MD. Available at:
prescription for a controlled substance to treat pain. This evaluation http://www.samhsa.gov/oas/dawn/TrndED/2001/Text/TrndEDtxt.pdf
is a medical evaluation of the pain complaint but also includes a (Accessed July, 2008).
vulnerability assessment for misuse or aberrant drug-related behav- 14. Savage SR, Kirsh KL, Passik SD. Challenges in using opioids to treat
pain in persons with substance use disorders. Addict Sci Clin Pract
ior. Thus, an understanding of the patient’s potential risk factors in 2008;4:4–25. Available at: http://www.drugabuse.gov/PDF/ascp/
the areas of chemical dependency history, psychiatric comorbidities, vol4no2/Challenges.pdf
social and familial situation, genetic loadings, and spirituality must 15. Engel GL. The clinical application of the biopsychosocial model.
be reached. The results of this assessment are not to be used to Am J Psychiatry 1980;137:535–544.
categorically exclude patients from opioid therapy, but they may 16. Passik SD, Schreiber J, Kirsh KL, Portenoy RK. A chart review of the
dictate the level of agreed-upon boundaries that need to be put in ordering and documentation of urine toxicology screens in a cancer
place or the outside help that might be required to effectively center: do they influence patient management? J Pain Symptom
manage a patient. Manage 2000;19:40–44.
REFERENCES
1. Kirsh KL, Passik SD. Patients with a history of substance abuse. In
Smith HS (ed): Opioid Therapy in the 21st Century. New York:
Oxford University Press, 2008; pp 155–161.
2. Passik SD, Hays L, Eisner N, Kirsh KL. Psychiatric and pain
characteristics of prescription drug abusers entering drug
rehabilitation. J Pain Palliat Care Pharmacother 2006;20:5–13.
VII
PHARMACOLOGIC
APPROACHES TO PAIN
MANAGEMENT
Chapter 53 Despite the tremendous advances in pain pharmacotherapy, it is

still not possible to choose a single best pain medication based solely
A MECHANISM-BASED on precise mechanistic considerations. Thus, several important fac-
tors must be weighed when choosing the medication or medications
with which to begin a course of therapy. Besides anticipated efficacy,
APPROACH TO PAIN the reasons for selecting particular medications include tolerability
and safety, the potential for disease-modifying action, familiarity to
PHARMACOTHERAPY: the prescribing physician, cost to the patient, and compliance. This
chapter focuses on those factors that contribute to anticipated effi-
TARGETING PAIN MODALITIES cacy, drawing on a mechanism-based approach to rational pharma-
cotherapy. The other factors guiding therapy selection are also
addressed. The material in this chapter exclusively addresses systemic
FOR OPTIMAL TREATMENT pharmacotherapy for pain. There are many other treatment
approaches that are essential to the comprehensive management of
EFFICACY pain both pharmacologic (e.g., injection analgesia, topical agents)
and nonpharmacologic (especially physical therapy, acupuncture,
massage, exercise, and clinical psychological approaches).
Beth B. Murinson
PHARMACOTHERAPY BASED ON
ANTICIPATED EFFICACY
INTRODUCTION
The ultimate goal of rational therapeutics is to precisely tailor a
There has been a tremendous expansion in the range and diversity pharmacologic treatment to a condition based on matching the
of pharmacologic agents available for the treatment of pain. therapy to a specific disease mechanism. In the field of pain, tre-
Whereas previous generations of physicians were limited to a few mendous progress toward this goal has been made, and even though
opioids, some aspirin-like compounds, and a small number of local this goal has yet to be obtained, the concept of matching pain
anesthetic techniques, the modern practitioner faces an expanding mechanisms to treatment remains an appealing approach for
array of choices for treating pain. As the choices in pain pharma- many. In the world of basic and preclinical research in pain, there
cotherapy have become increasingly complex, the potential for sub- has been extensive controversy over the categorization of pain.
stantially improving quality of life with tolerable side effects has Clearly, the success of investigational research depends heavily on
made quantum leaps forward. The key is to match the patient obtaining groups of study subjects who are highly homogeneous;
with the right medication, and for this reason, guidelines for select- the same pressures apply to clinical trials. Thus, pain research and
ing the best therapy for pain have become essential. An approach to the associated pain literature have an inherent bias toward studies
selecting those agents most likely to improve pain is outlined in this with united external validity. In actual clinical practice, however, it
chapter. This approach to pain pharmacotherapy relies on the con- is valuable to consider broad classes of pain mechanisms and match
cept that certain classes of medication are most effective for certain those with medication classes for the current therapy of pain.
broad mechanistic modalities of pain. Thus, the chapter begins by Another impetus for applying a broad classification scheme is that
explaining the categorization of pain conditions into mechanistic there are still few diseases for which the choice of treatment is essen-
modalities and then focuses on how to match medication class to tially mandated by the diagnosis (e.g. carbamazepine for the treat-
pain modality. Also included is the idea that between-class combi- ment of trigeminal neuralgia). For most pain-associated conditions,
nations of pain medications can be a powerful strategy for increased the process of matching disease to treatment is most effectively
safety and anticipated pain efficacy. based on broad categories of suspected disease mechanism, referred
397
398 Chapter 53 A MECHANISM-BASED APPROACH TO PAIN PHARMACOTHER APY
to here as mechanistic modalities. For the purposes of selecting a Table 53^1. Mechanistic Modalities of Pain: Examples
treatment regimen, the most useful classification of pain is as follows: of Pain Conditions Attributable to One
n Nociceptive: Nociceptive pain arises in direct response to an or More Mechanistic Modalities
injury.It is usually acute in onset and commensurate with the
degree of injury. Nociceptive pain signals bodily injury. It Mechanistic Modality Pain Condition
plays the clearest ‘‘positive’’ role in protecting the well- Nociceptive Simple incision, initial pain
being of the species. of a burn
n Inflammatory: Inflammatory pain arises in the setting of an
up-regulation of inflammatory mediators. In this setting, the Inflammatory Osteoarthritis, pain of a
nerve endings can be hypersensitized to normally nonpainful sunburn
stimuli such as mild pressure or warmth. The degree of Neuropathic Carpal tunnel, meralgia
inflammatory pain can vary from patient to patient, and paresthetica
not all the factors contributing to this phenomenon can be Nociceptive + inflammatory Incision of an abscess
measured in the clinical setting. Nociceptive + neuropathic Amputation of a limb
n Neuropathic: Neuropathic pain arises from nerve injury or
dysfunction. Although patients with neuropathic pain are not Inflammatory + neuropathic Cervical spondylosis with
as prevalent as patients experiencing nociceptive or inflam- radiculopathy
matory pain, neuropathic pain is often characterized by Nociceptive + inflammatory + Acute spine injury with
intensity and treatment resistance, leading to an increased neuropathic degenerative joint disease
level of physician visits, degree of impairment of function, and radiculopathy
and use of multiple pharmacologic therapies.
Pain May Be Produced by One or

More Mechanisms or surmised. Two approaches are possible. One is patient-centered
and involves gaining an awareness of mechanistic modalities
The ‘‘mechanisms’’ previously discussed are not, precisely speaking, through interviewing the patient carefully in order to ascertain
actual, specific mechanisms that explain step-by-step how a partic- the qualities and characteristics of her or his pain; the qualities of
ular pain event is signaled by the nociceptive processing system but, a pain are often characteristic of a particular mechanistic modality,
rather, are broad classes of mechanisms or mechanistic modalities of as is discussed later. The second approach is diagnosis-centered and
pain. The usefulness of these mechanistic modalities lies in their involves recognizing a pain condition or diagnosis based on exten-
application to the diagnosis and treatment of pain. Understanding sive clinic experience and knowing that certain conditions typically
the mechanistic modalities of a pain condition may be useful for encompass particular mechanistic modalities of pain. This approach
several reasons: is also discussed later. Both the patient-centered approach and the
diagnosis-centered approach rely on specific types of clinical skill
1. The mechanistic modalities are often ascertainable based on
and medical expertise.
the qualities or characteristics of pain that a patient is
experiencing.
2. Understanding the mechanistic modalities involved in a pain
problem can contribute to making a specific diagnosis. The Patient-centered Approach to Identifying the
3. In planning treatment, the mechanistic modalities of pain Mechanistic Modalities of Pain
associated with a particular condition may be used to guide
Using the approach of carefully eliciting from the patient the qua-
the selection of a most-effective regimen (modality-matching).
lities of his or her pain requires particular skill at taking a medical
Each of these points is explored in more detail later. Perhaps the history. The traditional clinical qualities used for characterizing
most important aspect of the mechanism-based approach to pain is symptoms such as pain are remembered using the mnemonic
to recognize that some pain conditions may occur through single QRST (quality, region, severity, and timing). The experienced prac-
mechanisms whereas others occur through activation of multiple titioner will recognize that, in many cases, patients have multiple
mechanistic modalities (Table 53–1). As an example, the pain as- pain symptoms that require assessment. Characterizing the various
sociated with an acute incision is clearly nociceptive. Other condi- features of each pain symptom increases the time required for the
tions such as rheumatoid arthritis and diabetic neuropathy are history-taking part of the clinical visit. Nonetheless, it is possible to
more complex. It is noted that there are other classification strate- formulate hypotheses about mechanistic modalities of pain
gies that are used to describe pain. These other classification involved in a condition based on information obtained from the
schemes focus on various aspects of pain (e.g., cancer vs. noncancer, patient’s history. For example, the patient who describes a shocklike
visceral vs. somatic, acute vs. chronic), but these classification stra- pain, shooting through the leg, that is intense and transient is
tegies are of limited utility in guiding the design of treatment. almost certainly experiencing neuropathic pain. When all else fails
Furthermore, it can be seen that conditions categorized by these and a patient’s diagnosis is not immediately clear, the patient-
approaches actually occur owing to one or more mechanistic mod- centered approach to pain diagnosis and treatment can be very
alities, for example, cancer pain may consist of neuropathic pain to useful in guiding the first choices in treatment. Table 53–2 lists
the extent that a tumor is infiltrating into a nerve, as well as having several examples of how the qualities of a particular pain can be
a component of inflammatory pain. used to identify a specific mechanistic modality likely responsible
for that pain.
In addition, when reassessing and managing patients in follow-
up, especially those whose pain is only partially controlled or those
Identifying the Mechanistic Modalities Underlying with pain that worsens, inquiring about the specific pain character-
a Pain Condition istics will help to guide the modifications to an existing pain regi-
men. As described later, with the diagnosis-centered approach,
Using the approach of mechanistic modalities to guide treat- various aspects of the physical examination as well as blood tests,
ment presupposes that the mechanistic modalities are known diagnostic imaging, and electrophysiologic studies provide valuable
VII PHARMACOLOGIC APPROACHES TO PAIN MANAGEMENT 399
Table 53^2. Pain CharacteristicsThat Are Useful in must yield a diagnosis of ‘‘idiopathic.’’ Nonetheless, in those cir-
Discerning Mechanistic Modality of Pain cumstances in which the diagnosis is immediately obvious, it is
possible to apply additional expert knowledge to anticipate which
mechanistic modalities will contribute to a specific pain condition.
Quality For example, in the case of acute lumbar radiculopathy, the relevant
Nociceptive pain Initially sharp, dull when less severe, mechanistic modalities of pain may include nociceptive pain asso-
sharp with increased intensity. ciated with an annular tear of the disk; inflammatory pain associ-
Inflammatory pain Aching, dull to sharp, can be stabbing in ated with the inflammation of the disk, nearby nerve endings, or
quality. degenerative joint disease; and neuropathic pain associated with
impingement upon the nerve root. Further examples of this diag-
Neuropathic pain Burning, squeezing, numb/tingling,
nosis-centered approach to ascertaining the mechanistic modalities
sharp, shooting, shocklike. of pain can be found by reviewing Table 53–1, this time reading
Region/Pattern from right to left.
Nociceptive pain Pattern of pain is related to area of
injury or trauma, although this may Selecting Medications Based on
include referred pain.
‘‘Modality Matching’’
Inflammatory pain Most typically localized to the body part
that is inflamed or infected. However, Having established the mechanistic modalities associated with a
when severe, the perceived area of particular pain condition makes it possible to select pain treatment
involvement may expand based on anticipated efficacy. The clinician needs to ask two ques-
tions: Does a particular medication have efficacy against a mecha-
Neuropathic pain Often radiates both proximally and
nistic modality contributing to this patient’s pain? Given the pain
distally from the site of nerve damage. modalities involved and the intensity of pain of this type, is the
This pain may be especially difficult to medication chosen strong enough to be effective? The first question
localize; however, there are several regards the use of medications for particular pain conditions. Each
established neuropathic pain of the broad classes of pharmacologic therapies is likely to be effec-
syndromes with known patterns of tive for pain arising from particular mechanistic modalities.
presentation. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) are
highly effective against nociceptive and inflammatory pain but are
Severity not at all useful in the treatment of neuropathic pain. Detailed
Nociceptive pain Varies widely between individuals. examples of this are provided in Table 53–3.
Specific stimuli are widely recognized The second question regards the selection of medication for a
as provoking intense pain (e.g., specific mechanistic modality of pain. It is well established that
nociceptive pain responds to traditional analgesic medications. For
thoracotomy, childbirth).
nociceptive pain that is mild to moderate, agents such as acetamin-
Inflammatory pain May vary and can significantly disrupt ophen or NSAIDs are sufficient. For nociceptive pain that is mod-
functioning. erate in intensity, combination analgesic agents may be necessary.
Neuropathic pain Often described as extremely intense; Many combinations of acetaminophen with opioids and NSAIDs
lancinating pains are particularly with opioids are widely used for the treatment of moderate acute
profound.
Timing
Table 53^3. Classes of Analgesic Medications and
Nociceptive pain Often temporally correlated with an Their Potential Efficacy against
injury. Particular Mechanistic Modalities
Inflammatory pain Progressively worsening with time, of Pain
sometimes relieved transiently after
activity or rest. Medication Class Efficacy against Mechanistic Modalities
Neuropathic pain Often begins insidiously but can worsen NSAIDs Nociceptive and inflammatory pain.
over time; individuals can suffer with
Opioids All forms of pain, although hyperalgesia has
this pain for years.
resulted from sustained administration in
animal models of pain.
Anticonvulsants Neuropathic pain is targeted by most
clues to identifying the mechanistic modalities contributing to a anticonvulsants, and some evidence
pain problem. suggests that selected agents may attenuate
postoperative opioid use (gabapentin).
Antidepressants Neuropathic pain, possibly beneficial for
The Diagnosis-centered Approach to Identifying inflammatory pain
the Mechanistic Modalities of Pain Centrally acting Variable. Acetaminophen is not beneficial
Many experienced practitioners approach the diagnostic process analgesics for neuropathic pain; however, baclofen
using what is called ‘‘compiled medical knowledge.’’ In this setting, may be.
the experienced clinician uses a targeted history and examination to Local anesthetics Nociceptive, neuropathic, and to some
elicit precisely those points that will lead to a diagnosis. This level of degree, inflammatory.
practice requires extensive experience, and sometimes, even the
most astute clinician is stumped by a patient’s presentation and NSAIDs, nonsteroidal anti-inflammatory drugs.
400 Chapter 53 A MECHANISM-BASED APPROACH TO PAIN PHARMACOTHER APY
Table 53^4. Choosing Pharmacotherapy Based on the Mechanistic Modalities of Pain
Pain Modality
Pain Intensity Nociceptive Inflammatory Neuropathic

Mild Acetaminophen or NSAID NSAID Low-dose neuromodulating
Moderate Acetaminophen/opioid or NSAID/opioid combination High-dose neuromodulating
NSAID/opioid combination
Severe Opioid Disease-modifying therapy + Multidrug regimen
analgesic
NSAID, nonsteroidal anti-inflammatory drug.
nociceptive pain. For nociceptive pain that is more severe in inten- the coadministration of timed-release opioids with short-acting
sity, opioids or N-methyl-D-aspartate (NMDA) inhibitors may be (rescue) opioids requires close coordination of the dosing regimen
useful. For nociceptive pain, this approach closely parallels the in order to prevent undesirable consequences such as excessive
World Health Organization (WHO) pain ladder approach for can- sedation and respiratory suppression. Although the combination
cer pain. For inflammatory pain, a similar approach can be adopted of anticonvulsants is in widespread use at neurology referral centers
in which medications active against inflammatory pain and of vari- for the treatment of refractory epilepsy, such combinations are rare
able potency are selected based on pain intensity. For neuropathic in the treatment of pain. The combination of pain-active antide-
pain, it is also important to assess pain intensity prior to beginning pressants is a strategy sometimes employed in academic pain prac-
treatment, but the effective agents are dramatically different. tices. This strategy requires exceptional caution because the use of
Neuromodulating agents, including anticonvulsants, pain-active these agents in concert runs the risk of excessive serotonergic tone.
antidepressants, channel-active agents, and medications from
other classes, have all been shown to have some efficacy against
neuropathic pain. In low- to moderate-intensity neuropathic pain, TOLERABILITY AND SAFETY AS
modest doses of single neuromodulating agents may be FACTORS IN TREATMENT SELECTION
sufficient. In moderate-intensity neuropathic pain, increased doses
of single neuromodulating agents may be sufficient to restore func- Patient preference, dose-related side effects, and potentially fatal
tion without troublesome side effects such as sedation and cognitive adverse reactions all play a role in determining the course of treat-
impairment. However, when neuropathic pain is severe, it is often ment for pain. Although many patients exposed to opioids in the
necessary to combine neuromodulating agents with opioid analgesia context of episodic nociceptive pain will report dysphoria and other
in order to obtain the desired clinical effects. An approach to mul- adverse effects and readily discontinue these agents, in one direct-
tiagent therapy is discussed later. The approach to treatment based comparison study, opioids were preferred over tricyclic antidepres-
on modality matching is outlined in Table 53–4. sants in the treatment of neuropathic pain. Most patients will read-
ily report that a medication produces unpleasant side effects, and
for somatically focused patients, the experience of even minor
Treating Pain Consisting of Multiple Mechanistic alterations of perception can present a significant barrier to suc-
Modalities cessful pharmacotherapy.
Dose-related side effects are prevalent among medications, and
In conditions that consist of pain due to more than one mechanistic side effects such as constipation (opioids), sedation (antidepres-
modality, it is sometimes possible to find a single agent that is active sants), and weight gain (anticonvulsants) can have serious conse-
for both types of pain. An example is NSAIDs, which are active for quences for patients depending on the side effect severity, the rate at
both nociceptive and inflammatory pain. Opioids can be effective which medication changes are implemented, and the willingness of
for nociceptive, inflammatory, and neuropathic pain, but because of the patient to adapt to a new lifestyle. As a rule of thumb, if patients
the potential for physical dependence, tolerance, and addiction, experience symptoms that are bothersome but not dangerous, it is
these agents must be prescribed with care and attention to the reasonable restart a medication at the lowest possible dose and
well-being of the whole person. As often as not, conditions that
consist of multiple pain mechanisms will require polypharmacy. Table 53^5. Examples of between-class
The challenge of advancing therapy by adding additional medica-
Combinations
tions presupposes that the clinician has carefully checked for med-
ication interactions, taking into consideration all of the medications
a patient is exposed to. That said, a potentially effective approach to Class
combining therapies lies in choosing medications from different Combinations Specific Example Example of Usage
classes, bearing in mind which mechanistic modalities are likely Centrally acting Acetaminophen + Nociceptive pain
to respond to medications in that class. For example, in a patient analgesic + codeine
with chronic degenerative joint disease who has had an acute, inop- opioid
erable disk injury with a strongly symptomatic nerve impingement,
NSAID + opioid Ibuprofen + Inflammatory
an NSAID/opioid combination might be best augmented with a
pain-active anticonvulsant. Examples of between-class medication oxycodone pain
combinations and the clinical settings that might apply are provided Anticonvulsant + Gabapentin + Neuropathic pain
in Table 53–5. Additional indications for combination therapy opioid morphine
include severe, treatment-resistant pain. Anticonvulsant + Gabapentin + Neuropathic pain
In comparison with between-class combinations, within-class antidepressant amitriptyline
combinations of pain medications require additional care and
expertise. Even commonly used within-class combinations such as NSAID, nonsteroidal anti-inflammatory drug.
gradually ramp up with weekly or biweekly incremental increases. management of arthritis with NSAIDs. In fact, severe inflammatory
During medication titration, the patient should be encouraged to pain is often managed with a combination of pain-active/disease-
maintain a detailed pain and symptom calendar, which will facili- modifying agents and pain-inactive agents that alter pain through
tate discussion if difficulties are encountered. treating underlying painful disease itself. Examples of disease-
Most worrisome are the adverse reactions. These are often idio- modifying agents in the setting of inflammatory disease include
syncratic, but some of the deleterious effects can be mitigated with tumor necrosis factor inhibitors, etanercept and infliximab; inter-
careful plans for monitoring. Examples of life-threatening idiopath- leukin-1 (IL-1) inhibitors, anakinra; and T-cell activation inhibitors
ic reactions include (1) the rash associated with lamotrigine such as abatacept. Rituximab binds CD20, resulting in a functional
(Lamictal), which requires that the drug be started at low dose depletion of B-cells. All of these agents significantly attenuate spe-
and tapered up slowly; the patient must be carefully instructed in cific inflammatory responses but were not developed to specifically
monitoring for rashes; (2) the hyponatremia and bone marrow and predominantly act on the nociceptive processing system.
suppression that can occur with carbamazepine (Tegretol), which Chronic pain conditions are often accompanied by other ill-
require that a monitoring plan be in place and that baseline labo- nesses that exacerbate the perception of pain and limit the patient’s
ratory values be obtained; (3) the gastrointestinal bleeding risks ability to actively make her or his pain better (e.g., interference with
associated with NSAIDs, which mandate that frequent administra- coping skills). These illnesses include depression, anxiety, and
tion be time-limited (e.g., ibuprofen three times daily for no more sometimes substance abuse. Because several antidepressants are
than 2 weeks) and that NSAID dosages are the lowest that will pain-active, namely duloxetine (Cymbalta), venlafaxine (Effexor),
produce acceptable pain relief. There are also side effects that and several of the tricyclic antidepressants, there are multiple ways
become especially harmful when exposure occurs over the long to approach the treatment of depression that is comorbid with
term, in contrast to relative safety during an acute treatment chronic pain, especially neuropathic pain. When symptoms of
course; examples include weight gain and xerostomia. Some of depression or decreased coping are detected in patients with pain,
the pain-active medications require special dosing in the setting it is very important to rapidly engage either a psychiatrist, a clinical
of renal failure or hepatic insufficiency; classic examples of this psychologist, or a clinical social worker as appropriate in order to
include limiting NSAIDs for renal failure and avoiding acetamino- provide adequate support for patients struggling under the weight
phen in the setting of other insults to the liver. of two potentially life-threatening conditions that have strong
Finally, it is necessary to consider the safety of pain-active med- potential to be worse in combination. The treatment of comorbid
ications when used in combination. Given the wide prevalence of anxiety is more challenging because the agents for generalized anx-
polypharmacy, especially in the pain-prone elderly, it is a sound iety disorder are less likely to be pain active and the treatment of
practice to check for drug interactions using a database resource comorbid substance abuse disorder presents exceptional challenges
such as Micromedex. The advantage of the between-class combina- to individual clinicians, the health care system, and society at large.
tion approach described in this chapter is that many of these com- In looking to the future of disease-modifying therapy, it is
binations are well tolerated when the drugs are used at low to important to consider the use of novel treatments for painful
moderate dosages. peripheral neuropathy: Given the long-established role of nerve
growth factor (NGF) as a neurotrophin, it is not surprising that
clinical trials of NGF against peripheral neuropathy were planned
DISEASE-MODIFYING POTENTIAL AS A with great optimism. However, given that NGF is potently induced
FACTOR IN TREATMENT SELECTION in the setting of inflammation and is known to promote pain sen-
sing, it is also not surprising that the clinical trials of NGF were
Given the diversity of pain-active pharmacologic agents, it is terminated owing to unacceptable levels of local and systemic pain
reasonable to ask whether a pain treatment regimen can include phenomena including intense myalgias. Indeed, although it is clear
medications that have disease-modifying potential. In the setting from human loss-of-function mutations in the NGF signaling path-
of pain treatment, disease-modifying can mean one of several ways that NGF is necessary for normal pain sensitivity, it has been
things including (1) the modification of nociceptive processing proposed that some patients might benefit from interference with
events that lead to a subsequent amplification of pain signals, NGF signaling either through administration of antibodies to NGF
(2) the modification of an underlying condition that directly results or through interruption of signaling through the NGF receptor,
in a patient’s pain, and (3) the modification of a comorbid illness TrkA (e.g., TrkA antagonists).
that may heighten the patient’s perception of pain or interfere with
pain coping. Indeed, each of these is possible and are discussed with
reference to the mechanistic modalities approach to pain treatment PRIOR EXPERIENCE AS A FACTOR IN
previously described. TREATMENT SELECTION
The elimination of intense pain may prevent alterations in
nociceptive processing that worsen later pain experiences. These Familiarity to the treating physician can be an excellent criterion
pronociceptive (pain-enhancing) alterations are believed to occur in choosing a medication for pain treatment. Indeed, the observa-
through several mechanisms including long-term potentiation, tion that several of the neuromodulating agents, especially the
wind-up, and sprouting. Many pain expert clinicians have advanced anticonvulsants, possess a significant risk for idiosyncratic and
the notion that the aggressive treatment of severe pain will prevent potentially fatal adverse reactions is a strong argument in support
the development of chronic pain in certain individuals. Consistent of using a limited set of medications with which the prescribing
with this, good evidence suggests that careful attention to intraoper- physician is very familiar. New medicines for the treatment of pain
ative analgesia, as distinct from solely maintaining anesthesia; during are currently in development, and an important challenge is to
surgery has a major impact on reducing the use of pain. medications incorporate new medicines into clinical practice. This challenge is
after surgery. This type of disease-modifying therapy most closely compounded by the rampant use of direct-to-consumer advertising.
relates to the treatment of nociceptive pain, and the medications It should be noted that even with increased levels of regulatory
that have been recommended for use in the prevention of altered stringency, the numbers of patients exposed to a medication prior
pain processing are the medications that treat intense nociceptive to U.S. Food and Drug Adminiatration (FDA) approval is dwarfed
pain: opioids, NMDA blockers, and focal analgesic techniques. by the thousands of patients who will take a medication in the first
Pain-active agents that are also disease modifying for an under- few months after its release to the market. Except in rare circum-
lying painful condition are widely used in the treatment of arthritis stances of severe refractory pain unresponsive to existing medica-
and other inflammatory conditions. An example of this includes the tions, careful attention to the early clinical experience with new
402 Chapter 54 OPIOID PHARMACOTHER APY
medications may inform the clinician of future precautions in including acetaminophen, NSAIDs, and opioids work reasonably
actual clinical use. well for nociceptive pain as well as for mild to moderate inflamma-
tory pain, the management of severe inflammatory pain often
requires disease-modifying therapies. The management of neuro-
pathic pain typically requires the use of neuromodulating agents.
COSTAND COMPLIANCE AS FACTORS Other factors influencing the selection of particular medications
IN MEDICATION SELECTION include tolerability and safety, the potential for disease-modifying
action, familiarity to the prescriber, cost to the patient, and
The costs associated with a medication are an important factor in compliance.
selecting the best therapy for a specific patient. Recent studies sug-
gests that patients with pain are less willing to take their medication
when the copayments rose. Conversely, most pain care clinicians ACKNOWLEDGMENTS
have the experience that their patients are willing to endure signif-
icant financial hardship to alleviate pain, but at the same time, Thanks to Drs. John W. Griffin and James N. Campbell for many
this can create a significant psychosocial stressor. It is important valuable discussions of this subject. Thanks to Ms. Claudia
to be sensitive to a patient’s financial situation and inquire about Berrondo and Dr. Lawrence Vidaver for reading and commenting
mechanisms for covering the cost of medications at the time when on this manuscript.
the patient seems comfortable enough to answer this question with-
out embarrassment. As a general guideline, the newer medications
and the timed-release formulations are more expensive than more SUGGESTED READINGS
established medications and generic formulations. Aida S. The challenge of pre-emptive analgesia. Pain: Clin Updates
A final crucial factor involved in successful pharmacologic ther- 2005;13:1–4.
apy for pain is patient compliance. The best analgesic cocktail is Campbell JN. Nerve lesions and the generation of pain. Muscle Nerve
meaningless if the patient does not or cannot take it in the appro- 2001;24:1261–1273.
priate manner. strong evidence favors simple regimens. Clinical Gilron I. Morphine, gabapentin, or their combination for neuropathic
studies show a marked drop-off in compliance when medication pain. N Engl J Med 2005;352:1324–1334.
Heughan CE, Sawynok J. The interaction between gabapentin and
frequency rises above twice daily; further decreases in compliance
amitriptyline in the rat formalin test after systemic administration.
are seen with even more frequent dosing schedules. Therefore, Anesth Analg 2002;94:975–980.
route, frequency, and even taste should be weighed when optimiz- Indo Y. Molecular basis of congenital insensitivity to pain with anhidrosis
ing care for specific patients. (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene
encoding the receptor tyrosine kinase for nerve growth factor. Hum
Mutat 2001;18:462–471.
Mantyh PW, et al. Molecular mechanisms of cancer pain. Nature Rev
SUMMARY Cancer 2002;2:201–209.
Multiple factors must be considered in designing a treatment plan Raja SN, et al. Opioids versus antidepressants in postherpetic neuralgia: a
for patients with pain, and anticipated efficacy is paramount. This randomized, placebo-controlled trial. Neurology 2002;59:1015–1021.
Sator-Katzenschlager SM, et al. Chronic pelvic pain treated with
chapter has described a process of first identifying the mechanistic gabapentin and amitriptypline: a randomized controlled pilot study.
modalities of pain associated with a particular condition and then Wien Klin Wochenschr 2005;117:761–768.
selecting medications based on anticipated efficacy. The mechanistic Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of
modalities of pain are nociceptive pain, inflammatory pain, and neuropathic pain: an update and effect related to mechanism of drug
neuropathic pain. Taken alone or in combination, these modalities action. Pain 1999;83:389–400.
underlie all pain conditions. It is possible to ascertain the mecha- Woolf CJ, et al. Towards a mechanism-based classification of pain? Pain
nistic modalities involved using either patient-centered or diagnos- 1998;77:227–229.
tic-centered approaches. Although the traditional analgesic agents
Chapter 54 A series of well-written and useful clinical practice guidelines have

been published, beginning with the Agency for Health Care Policy
OPIOID PHARMACOTHERAPY and Research (AHCPR) guidelines on management of acute pain
and cancer pain.1,2 Prior to these sentinel documents, the World
Kenneth C. Jackson, II Health Organization (WHO) published an analgesic ladder for
cancer pain that included opioid analgesics on steps 2 and 3 of
the 3-step ladder.3 It is well accepted that opioids play a vital and
significant role in managing the pain that presents in settings of
acute and cancer pain. Most clinicians feel comfortable with the use
of opioids in palliative care settings, especially when patients face
INTRODUCTION pain during terminal illness.
In contrast, much confusion and inconsistency remain when
Opioid analgesics maintain a significant role in the treatment of a examining the role of opioids in the larger context of chronic,
host of painful conditions in modern clinical practice. Despite a nonmalignant pain conditions. Indeed, much has been written to
long history of utility, opioids remain an enigma to many clinicians. describe both the value and the concerns associated with opioid use
medications may inform the clinician of future precautions in including acetaminophen, NSAIDs, and opioids work reasonably
actual clinical use. well for nociceptive pain as well as for mild to moderate inflamma-
tory pain, the management of severe inflammatory pain often
requires disease-modifying therapies. The management of neuro-
pathic pain typically requires the use of neuromodulating agents.
COSTAND COMPLIANCE AS FACTORS Other factors influencing the selection of particular medications
IN MEDICATION SELECTION include tolerability and safety, the potential for disease-modifying
action, familiarity to the prescriber, cost to the patient, and
The costs associated with a medication are an important factor in compliance.
selecting the best therapy for a specific patient. Recent studies sug-
gests that patients with pain are less willing to take their medication
when the copayments rose. Conversely, most pain care clinicians ACKNOWLEDGMENTS
have the experience that their patients are willing to endure signif-
icant financial hardship to alleviate pain, but at the same time, Thanks to Drs. John W. Griffin and James N. Campbell for many
this can create a significant psychosocial stressor. It is important valuable discussions of this subject. Thanks to Ms. Claudia
to be sensitive to a patient’s financial situation and inquire about Berrondo and Dr. Lawrence Vidaver for reading and commenting
mechanisms for covering the cost of medications at the time when on this manuscript.
the patient seems comfortable enough to answer this question with-
out embarrassment. As a general guideline, the newer medications
and the timed-release formulations are more expensive than more SUGGESTED READINGS
established medications and generic formulations. Aida S. The challenge of pre-emptive analgesia. Pain: Clin Updates
A final crucial factor involved in successful pharmacologic ther- 2005;13:1–4.
apy for pain is patient compliance. The best analgesic cocktail is Campbell JN. Nerve lesions and the generation of pain. Muscle Nerve
meaningless if the patient does not or cannot take it in the appro- 2001;24:1261–1273.
priate manner. strong evidence favors simple regimens. Clinical Gilron I. Morphine, gabapentin, or their combination for neuropathic
studies show a marked drop-off in compliance when medication pain. N Engl J Med 2005;352:1324–1334.
Heughan CE, Sawynok J. The interaction between gabapentin and
frequency rises above twice daily; further decreases in compliance
amitriptyline in the rat formalin test after systemic administration.
are seen with even more frequent dosing schedules. Therefore, Anesth Analg 2002;94:975–980.
route, frequency, and even taste should be weighed when optimiz- Indo Y. Molecular basis of congenital insensitivity to pain with anhidrosis
ing care for specific patients. (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene
encoding the receptor tyrosine kinase for nerve growth factor. Hum
Mutat 2001;18:462–471.
Mantyh PW, et al. Molecular mechanisms of cancer pain. Nature Rev
SUMMARY Cancer 2002;2:201–209.
Multiple factors must be considered in designing a treatment plan Raja SN, et al. Opioids versus antidepressants in postherpetic neuralgia: a
for patients with pain, and anticipated efficacy is paramount. This randomized, placebo-controlled trial. Neurology 2002;59:1015–1021.
Sator-Katzenschlager SM, et al. Chronic pelvic pain treated with
chapter has described a process of first identifying the mechanistic gabapentin and amitriptypline: a randomized controlled pilot study.
modalities of pain associated with a particular condition and then Wien Klin Wochenschr 2005;117:761–768.
selecting medications based on anticipated efficacy. The mechanistic Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of
modalities of pain are nociceptive pain, inflammatory pain, and neuropathic pain: an update and effect related to mechanism of drug
neuropathic pain. Taken alone or in combination, these modalities action. Pain 1999;83:389–400.
underlie all pain conditions. It is possible to ascertain the mecha- Woolf CJ, et al. Towards a mechanism-based classification of pain? Pain
nistic modalities involved using either patient-centered or diagnos- 1998;77:227–229.
tic-centered approaches. Although the traditional analgesic agents
Chapter 54 A series of well-written and useful clinical practice guidelines have

been published, beginning with the Agency for Health Care Policy
OPIOID PHARMACOTHERAPY and Research (AHCPR) guidelines on management of acute pain
and cancer pain.1,2 Prior to these sentinel documents, the World
Kenneth C. Jackson, II Health Organization (WHO) published an analgesic ladder for
cancer pain that included opioid analgesics on steps 2 and 3 of
the 3-step ladder.3 It is well accepted that opioids play a vital and
significant role in managing the pain that presents in settings of
acute and cancer pain. Most clinicians feel comfortable with the use
of opioids in palliative care settings, especially when patients face
INTRODUCTION pain during terminal illness.
In contrast, much confusion and inconsistency remain when
Opioid analgesics maintain a significant role in the treatment of a examining the role of opioids in the larger context of chronic,
host of painful conditions in modern clinical practice. Despite a nonmalignant pain conditions. Indeed, much has been written to
long history of utility, opioids remain an enigma to many clinicians. describe both the value and the concerns associated with opioid use
in this setting. The use of opioids outside acute and cancer pain maintain a dose ceiling effect that can limit their potential for
paradigms was not considered standard practice by most clinicians dose escalation.
until well into the 1990s. Indeed, the use of opioids in chronic, Narcotic: A term historically used to describe opium and its deri-
nonmalignant pain was not considered mainstream despite numer- vatives. The word derives from a Greek word meaning
ous published studies that chronicled the safety and efficacy of ‘‘benumbing.’’ In modern society, the word narcotic has
opioids in the management of a variety of chronic, nonmalignant become a legal term that includes a wide range of sedating
pain states.4 The American Academy of Pain Medicine and the and potentially abused substances, and it is no longer limited
American Pain Society published a joint consensus statement in to opioid analgesics. This term maintains an extremely negative
1997 entitled ‘‘The Use of Opioids for the Treatment of Chronic connotation and should be avoided by clinicians when discuss-
Pain.’’5 Soon after, the Federation of State Medical Boards of the ing opioid therapy with patients and other clinicians.
United States published Model Guidelines for the Use of Controlled Opiate: By definition, this is a term used to describe substances that
Substances in the Treatment of Pain, which have recently been derive from opium. The term opiate is often incorrectly used
updated.6 These hallmark publications provided a foundation for interchangeably with opioid.
prudent and reasonable approaches to the use of opioids across the Opioid: By definition, an opioid is an opium-like substance. In the
entire health care continuum, including the setting of chronic, non- past, opioid was used to describe endogenous opium-like sub-
malignant pain. stances and the term opiate was used to describe drugs that
derived from opium. Today, opioid has become the preferred
term in both clinical and scientific dialogue to describe this
analgesic class of medications.
TAXONOMY (DEFINITIONS) Opioiphobia: The irrational fear by clinicians and/or patients
related to appropriate opioid analgesic use for analgesic
Addiction: A complex psychological phenomenon characterized by purposes.
loss of control over drug use and compulsive use of the drug Partial Opioid Agonists: Medications that partially occupy and
despite harm from that use.7 Regarding opioids, it has been activate the m region of the opioid receptors. These agents are
suggested that the patient becomes preoccupied with obtaining known to maintain a dose-ceiling effect that can limit their
these substances even with the presence of adequate analgesia. potential for dose escalation.
Iatrogenic addiction from opioid analgesia in patients experien- Pseudoaddiction: Appropriate drug-seeking behavior for the pur-
cing pain is exquisitely rare. pose of pain relief, not abuse or substance misuse.8
Controlled substances: Medications, such as opioids, and other Characterized by a demand for more medication for analgesic
substances that have been determined to pose a risk of addiction. purposes but in which behaviors (e.g., anger, hostility) appear
The rating scale includes Schedules I to V. Schedule I substances similar to behaviors seen in addicted patients. Pseudoaddiction
have no approved medical use, but they may be available for use can be differentiated from drug misuse by increasing the dose by
in research settings. In the United States, Schedule I substances an appropriate amount and determining whether the complaints
include heroin and marijuana. Schedule II substances are abate.
deemed to have high addiction potential and include most Pseudotolerance: A situation in which dose escalation occurs with
full-agonist opioid analgesics. Schedule III substances are those opioids that appears consistent with pharmacologic tolerance
with moderate abuse potential and include products that con- but, after a thoughtful evaluation, is better explained by a variety
tain either codeine or hydrocodone in combination with aceta- of other variables.9 These may include increased analgesic
minophen or nonsteroidal anti-inflammatory drugs (NSAIDs). requirements owing to progressive disease, presence of new
Schedule IV substances are listed as those with low abuse poten- pathology, or increased or excessive physical activity. Patients
tial and include the mixed agonist-antagonist opioids. Finally, may also become noncompliant, have drug interactions, or
Schedule V substances are considered to be those controlled even divert medications in a manner that incorrectly produces
substances with the lowest abuse potential and include the par- the appearance of tolerance.
tial agonist buprenorphine. Tolerance: A pharmacologic concept in which there is a diminished
Dependence: A physical or pharmacologic phenomenon character- drug effect from drug exposure over time. In the setting of
ized by an abstinence syndrome upon abrupt drug discontinua- tolerance, there would be an increasing need for increased
tion, substantial dose reduction, or administration of an dosing to maintain the initial effects of a medication over
antagonist.7 Dependence is nearly universal among patients time. There is no connection between the phenomenon of tol-
receiving continual opioid therapy for a week or more. erance and addiction.
Dependence is a common phenomenon that occurs with numer-
ous medication classes (e.g., glucocorticoids).
Dose Ceiling: The highest dose of a mixed agonist-antagonist or
partial agonist opioid analgesic that can be expected to produce EPIDEMIOLOGY
an analgesic response. Doses in excess of the dose ceiling are
known to produce no further analgesia; however, continued Opioid analgesic use has increased substantially in recent years.
dose escalation can be expected to produce additional or more This probably is a natural reflection of the increasing acceptance
severe adverse effects. for use of opioids in a variety of settings as well as the increased
Full Opioid Agonists: Medications that fully occupy and activate availability of newer formulations of a variety of opioid agents.
the m and k regions of opioid receptors. In theory these agents From 1999 to 2002, opioid prescription use in the United States
do not maintain an analgesic dose ceiling. Based on a patient’s increased substantially for three commonly used medications:
response and adverse effect profile, dosing for these agents fentanyl prescriptions increased 150%, morphine 60%, and oxy-
becomes a function of a functional dose ceiling. codone 50%.10 From 1997 to 2002, the total grams dispensed of
Functional Dose Ceiling: The upper limit of analgesic dosing from several opioids increased significantly: morphine 73.3%, hydro-
a full-agonist opioid analgesic prior to the appearance of signif- codone 117.1%, oxycodone 402.9%, and methadone 410.8%.11
icant adverse effects that limit further dose escalation. Taken in combination, these data indicate both increased utili-
Mixed Opioid Agonist-Antagonists: Medications that block activ- zation and, potentially, a trend to increased dose escalation.
ity at m opioid receptors and fully occupy and activate the It has been estimated that upward of 90% of patients being seen
k region of the opioid receptor. These agents are known to in pain-management practices are using opioids for chronic
management of a pain disorder.11,12 Many of these patients were Table 54^1. Opioid Analgesics Classified by
initially prescribed these medications prior to referral to a pain- Mechanism of Activity
management practice.12 Many of these patients may receive multi-
ple opioid prescriptions, often a long-acting agent in addition to a Full (Pure) Partial Mixed Agonist-
shorter-acting opioid for as-needed use. Of note, it has been sug- Agonists Agonists Antagonists
gested that certain medical specialties (e.g., rheumatology, family
practice, internal medicine) are more likely than their colleagues Codeine Buprenorphine Butorphanol
(e.g., surgery, neurology) to prescribe opioids in the setting of Fentanyl Nalbuphine
chronic pain. Hydromorphone Pentazocine
Levorphanol
Meperidine
PHARMACOLOGY Methadone
Opioid receptors are found primarily within the central nervous Morphine
system (CNS) and gastrointestinal (GI) tract, but they are known Oxycodone
to be located in other peripheral tissues. Analgesia produced by Oxymorphone
opioid analgesics has traditionally been considered an action of
Propoxyphene
receptor activation within the CNS. However, more-recent evidence
indicates that peripheral mechanisms may play a role in certain set-
tings.13-15 The basic framework for the role of opioid analgesic phar-
macology can be based on our understanding of the interaction that
occurs between endogenous opioid peptides (e.g., dynorphins, CLINICAL FEATURES
endorphins, and enkephalins) and opioid receptors. There are
three currently accepted opioid receptors, the m-, k-, and d-receptors. There does not appear to be any substantial difference in the phar-
Opioid receptors are composed of glycoproteins found in macodynamic activity within each class of opioid analgesic, for
cellular membranes and are coupled to G proteins that modulate example, full agonist. Clinically, it is known that patients have a
electrolyte conduction. The activation of a m- or d-receptor opens wide variability in response to opioids within each class, from both
a potassium ion channel that promotes an increase in potassium an analgesic and an adverse effect perspective. A growing body of
conductance. k-Receptor activation appears to inhibit calcium reen- literature suggests a potential genetic influence on the composition
try via a calcium ion channel mechanism. The resulting hyperpo- of opioid receptor subclasses.17 There are reports of wide variability
larization produced by these receptor interactions inhibits neuronal in opioid dosing for similar pain stimuli in both acute and cancer
activity. Opioid receptor activation provides for a decrease in signal pain populations.18,19
transmission from the primary peripheral afferent nerves to the As noted previously, full-agonist opioids maintain the most
higher CNS centers as well as processing of the pain stimulus. robust dosing profile among the opioid analgesic classes. Dose esca-
m, k, and d opioid receptors are located throughout the CNS and lation remains a function of patient tolerability because there is no
are known to have numerous subtypes. From a clinical perspective, predefined maximum dose for the full-agonist opioid analgesics. To
our understanding of the actions and toxicity is linked to our rudi- utilize this class effectively clinicians must titrate opioid regimens,
mentary understanding of the m1 and m2 subtypes, and to a lesser keeping an eye toward balancing analgesia with acceptable levels of
extent k-receptor subtypes. The clinical implications of the adverse effects and functionality. This particular analgesic profile
d-receptor and its subtypes remain poorly elucidated at this time, leads to substantial variability across the patient care continuum
but may play a role in promoting analgesia mediated by the and, for many clinicians, can prove frustrating owing to this poten-
m-receptors. It is commonly held that m1 activation produces tial. In essence, severe adverse effects become a functional dose
supraspinal analgesia and m2 activation is responsible for many ceiling. It is of value to note that codeine, a full agonist, maintains
adverse effects associated with opioid analgesic administration. a consistent functional dose ceiling for most patients. Individual
Peripheral opioid receptors have been described and manifest a codeine doses larger than 100 mg or a total daily dose greater
direct analgesic effect through anti-inflammatory and antihyperal- than 400 mg cause such severe constipation that further dosing is
gesic activity.16 Peripheral opioid administration via topical or often unacceptable to patients.20 No other full agonist maintains a
intra-articular routes has produced analgesic activity that appears known, consistent functional dose ceiling.
to be separate from any CNS-mediated effects. The full-agonist class maintains the best utility in treating most
Opioid analgesics have traditionally been classified into three opioid-responsive pain, especially in the setting of chronic disease.
pharmacologic classes: full agonists, partial agonists, and mixed The partial and mixed agonist-antagonists are best avoided in most
agonist-antagonists (Table 54–1). The distinction of these classes chronic pain owing to an analgesic ceiling that can limit their utility
arises from our understanding of how these substances occupy in all avenues of pain management.
and activate primarily the m and k regions of the opioid receptor
complex described earlier. Full agonists fully occupy and activate
the m and k regions of the opioid receptor complex and, as such, Addiction and Dependence
have the potential for an unlimited dose response. Partial agonists
function by occupying only part of the m region of an opioid recep- One of the disconcerting aspects of opioid analgesia for many clin-
tor and produce a lesser degree of analgesia than a full agonist. icians is the concern about addiction, a most common misconcep-
Mixed agonist-antagonist opioids activate k-receptors and either tion related to opioid therapy. Addiction is the compulsive use of a
block or antagonize the m-receptor region, yielding a lesser degree substance that results in physical, psychological, or social harm to
of analgesia than full agonists. In the case of partial agonists and an individual and continued use despite this harm.7 In isolation,
mixed agonist-antagonists, a dose-ceiling effect occurs. These two drug-seeking behaviors do not necessarily indicate an addiction
classes fail to fully occupy and activate the m and k regions and are disorder. Most of our knowledge about opioid-induced addiction
known to clinically have a maximal analgesic effect at their U.S. has been based on the experience of drug abusers, not on patients
Food and Drug Administration (FDA)–labeled maximum dose. with pain. Analysis of the incidence of iatrogenic opioid-induced
Unfortunately, the adverse effect profile for these two classes con- addiction shows that it is quite rare. Many patients who may appear
tinues to worsen when patients use doses in excess of the maximum. to have addictive traits may actually suffer from pseudoaddiction,
an iatrogenic syndrome of drug-seeking behavior resulting from patient’s pain, current and past pain treatments (e.g., prescrip-
inadequate analgesia, not substance abuse.8 tion, nonprescription, dietary, and herbal), and underlying or
Many clinicians determine that patients are abusing opioids coexisting diseases and conditions. The effect of pain on physical
when there are complaints of a new pain after an initial pain prob- and psychological function should be assessed as well as a review
lem is treated. In the setting of chronic pain, multiple pain foci of current or past substance abuse. In addition, a physical exam-
appear to be common. Twycross and Fairfield21 reported that ination must occur and should be recorded in the patient’s
among 955 advanced cancer patients evaluated, 34% experienced medical record.
two or more different types of pain, and 80% of patients reported Treatment plan: Clinicians should prepare a written treatment
pain due to two or more different etiologies. Clinically, it appears plan, complete with objectives, to determine successful opioid-
that more severe pain masks pain of lesser intensity, such that the associated outcomes. Outcomes of note may include analgesic
now-unmasked pain may require additional medication or other response and physical and psychosocial function. The plan
treatments. Fortunately for many patients, treating the unmasked should discuss the potential for adjusting opioid pharmacother-
pain appropriately causes aberrant behaviors to subside. apy in the future and whether further diagnostic evaluations or
treatments may be necessary in the future.
Informed consent/agreement for treatment: Good clinical
Tolerance care requires that a discussion of risks and benefits related to opi-
oid pharmacotherapy be discussed and documented
Opioid analgesic tolerance is widely believed to be a serious limitation with patients or a patient’s surrogate or guardian where appro-
to effective use, yet clinical experience does not support this belief. priate. Many patients, and especially those at high risk for
Analgesic tolerance has been reported consistently in animal studies,22 abuse with opioids, may benefit from the use of a written
but it does not appear to be a common problem in humans. Tolerance agreement between physician, pharmacist, and patient outlining
sometimes does occur in the first week or two of opioid therapy, often the responsibilities of all involved in this process. These agree-
requiring dose increases. With effective dose titration, the clinical ments may include information on the use of urine/serum
implications of tolerance can be nullified. In nonescalating chronic medication levels screening; the number and frequency of all
pain, opioid doses often remain stable over long periods of time. In prescription refills; and reasons for which opioid pharmacother-
cases of poorly treated chronic pain, what is assumed to be tolerance is apy may be discontinued (e.g., violation of agreement).
often better described as suboptimal pain relief. Periodic review: Continuation or modification of opioid pharma-
When stable opioid regimens become ineffective or suboptimal, cotherapy requires reassessment of patient progress in relation to
clinicians should thoroughly reevaluate patients. The change in the treatment plan. This requires an analysis of subjective pain
analgesic efficacy may actually signal increasing or new pathology; information as well as objective functional data. This process is
increased or excessive physical activity secondary to previous pain necessary to evaluate the appropriateness of continued opioid
relief; drug interactions; noncompliance; or other nonpharmacolo- pharmacotherapy.
gic factors. This phenomenon has been defined as pseudotolerance.9 Consultation: Clinicians involved in managing opioid pharmaco-
Tolerance to the constipation effect of opioids does not occur.20 therapy may require and should consider the services of
Activation of m-opioid receptors, found in the colon, leads to an additional health care professionals to aid in the evaluation and
inhibition of peristalsis. As noted previously, stimulant laxatives treatment of patients requiring opioid pharmacotherapy. This
(e.g., senna, bisacodyl) are often required to induce colonic empty- may be especially true for patients at risk for opioid abuse or
ing. Stool softeners (e.g., docusate), when given alone, are normally diversion as well as those with comorbid psychiatric disorders.
ineffective. Prophylaxis with a stimulant laxative is indicated when Prescription process: Patients should receive opioid prescriptions
an opioid is initiated. from one physician and one pharmacy whenever possible. In
states in which prescription-monitoring programs exist and pro-
vide patient-specific reporting, it is advisable to consider using
these reports as part of the clinician’s monitoring process. In this
EVALUATION (HISTORY, PHYSICAL situation, a copy of the report would be a useful addition to the
EXAMINATION, LABORATORY medical record.
TESTING) Documentation/medical records: Clinicians should maintain accu-
rate and complete medical records that comply with state and
Opioid analgesics are controlled substances in the United States and, federal requirement surrounding the provision of controlled
as such, require additional levels of vigilance when used in appro- substances in clinical practice. These records should include all
priate therapeutic paradigms. Currently, the best guidance for clin- of the data mentioned previously. Maintenance of thorough
icians is provided by the Federation of State Medical Boards, who in medical records provides access to the rationale and justification
2004 published an updated Model Policy for the Use of Controlled for the use of opioid-based analgesia. These records provide
Substances for the Treatment of Pain.6 This document provides an other clinicians and regulatory authorities with a complete pic-
excellent resource for clinicians caring for patients who require ture surrounding the decisions to initiate, continue, modify, or
opioids as part of their overall pain treatment approach. Good clin- discontinue therapy with an opioid analgesic.
ical practice is a constant when reviewing and analyzing the model
policy, as is the concept of compliance with laws and regulations
related to controlled substances. Whereas this document emphasizes MANAGEMENT
physicians’ roles, it provides useful guidance to all involved in mana-
ging patients with opioid pharmacotherapy. Readers are encou- The WHO has published specific guidance on general principles for
raged to visit the Federation’s website to review this information opioid use in cancer pain in relation to the 3-step analgesic ladder.3
in more detail. The following information, in large part, draws for These important principles have been validated in numerous studies
the model guidelines and offers information that should be useful to in undeveloped, developing, and developed countries. Although
clinicians contemplating the use of opioid pharmacotherapy. developed initially for cancer pain, these principles are often
useful in other facets of pain management:
Patient evaluation: Clinicians should obtain a complete medical
1. Use the oral (or other noninvasive) routes when possible.
history that includes a thorough medication history. The history
2. Titrate doses to individual response.
should include commentary on the nature and intensity of the
3. Utilize analgesics as described on the analgesic ladder. Doses should be increased to response. Appropriate dose incre-
4. Maintain effective drug concentrations while noxious stimu- ments are normally 50% of the dose and can be increased every 5
lus is present. half-lives. This percent increase applies no matter what the prior
5. Use adjuvant medications when indicated. dose. Often, it is better to err slightly in the direction of too
much opioid rather than too little. Initially, sedation may be
Dosing of opioids in subacute and chronic settings is often best advantageous for anxious patients or those with sleep deficits.
facilitated by using oral, long-acting opioids to provide what can be In addition to time-contingent opioid doses, supplemental
described as time-contingent dosing. This approach provides consis- rescue doses of short-acting opioids should be available for break-
tent levels of the opioid analgesic over an extended time period and through pain. Rescue doses can be calculated based on the total
is preferred over the more frequent dosing of shorter-acting daily time-contingent dose used and generally should be 5% to
opioids. In addition to providing more consistent analgesia, this 15% of the total daily time-contingent dose administered. Because
approach facilitates compliance and minimizes serum level fluctua- of the nature of breakthrough pain, it is inappropriate to use a
tions. Time-contingent dosing may decrease the adverse conse- controlled-release dosage form as a rescue dose. When a patient
quences related to repeated stimulation of afferent neuronal tissue with chronic pain requires more than two to three rescue doses
(e.g., physiologic wind-up and neuronal plasticity) and, thus, may for more than 2 to 3 consecutive days, an increase in the time-
assist in minimizing the occurrence of hyperalgesia. contingent dose should be considered. This is done most simply
There are two main types of oral long-acting opioid analgesics by increasing the regularly scheduled dose by 50% once steady-state
(Table 54–2). The most commonly utilized are the pharmaceutically serum levels are achieved. Alternatively, calculating the actual uti-
enhanced opioid analgesics. A second group of long-acting opioids lized daily opioid requirement (e.g., time-contingent dose + break-
comprises methadone and levorphanol, two agents with inherently through doses) may provide a basis for a new time-contingent dose.
long-acting pharmacokinetic profiles. In general, the pharmaceuti- Opioid selection can be significantly affected by metabolic con-
cally modified agents are much easier to dose and titrate. These siderations. Opioid metabolites may directly cause neurotoxicity as
agents typically can be managed in most primary care settings well as displace the parent opioid from receptor sites. Patients with
with little special training. Methadone and levorphanol, conversely, impaired renal function and those receiving high-dose and/or long-
have much less consistency across populations and have been the term opioid pharmacotherapy are at a higher risk for toxicity.
subject of much controversy. Methadone pharmacokinetics are dif- Morphine-3-glucuronide (M3G) and morphine-6-glucuronide
ficult to anticipate, primarily owing to a biphasic elimination pat- (M6G) are two major morphine metabolites. As much as 50% of
tern. This pattern provides an analgesic window that ranges from the parent drug may be renally excreted as M3G, whereas M6G
6 to 12 hours after a dose with chronic use. The elimination phase is accounts for about 5%. Both compounds are water-soluble glucur-
highly variable and provides low levels of methadone for 24 to onides that require renal elimination for clearance. M3G appears to
36 hours in younger, healthy patients but in excess of 150 hours be antinociceptive and has been associated with hyperalgesia and
in some populations.23 These low levels seen during the neurotoxicities. M6G possesses analgesic properties and may be
b-elimination phase accumulate over time and may cause severe significantly more potent than morphine. Accumulation of both
CNS toxicity, especially when aggressive dose titration related to metabolites, as a function of poor renal status, predisposes patients
analgesia is attempted. Upward dose titration for most patients to toxicity as well as poor pain control.
should not be attempted for at least 5 to 7 days after a previous Opioids have the potential to interact with a variety of medica-
dose initiation of titration. Levorphanol appears to have a similar tions (Table 54–3). The majority of interactions are pharmacodynam-
pharmacokinetic profile, but to date, it has not been fully elucidated. ic in nature. Sedation is common with opioids, especially when
There remains no standard correct dose for any opioid analgesic administered with alcohol, benzodiazepines, butyrophenones, phe-
for a given patient or indication. Individual dose titration remains nothiazines, sedative-hypnotics, and tricyclic antidepressants.
the only useful way to determine an appropriate analgesic dose. Analgesic activity may be impaired by use of benzodiazepines through
Opioid analgesic doses should be increased as is appropriate for nec- inhibitory effects on the descending inhibitory control pathways.
essary analgesia within the constraints of an acceptable adverse effect Methadone withdrawal is a prime example of potential pharma-
profile. Initial dosing for moderate to severe pain should be conser- cokinetic opioid-drug interactions. Withdrawal has been precipi-
vative, especially in the elderly or those with renal impairment. When tated by a number of agents that induce microsomal enzymes and
indicated, analgesic doses should be increased as soon as steady-state increase the metabolism of methadone. Conversely, inhibition of
serum levels are reached. In the case of short half-life opioids such as methadone metabolism has been seen with coadministration of
morphine and oxycodone, a half-life of about 2 hours would provide substances that increase methadone levels.
steady-state levels within approximately 10 hours. In this setting, It should be noted that opioid-drug interactions are not solely
upward dose titration could occur rapidly without concern for accu- due to changes in the activity of the opioid. Various opioids may
mulative toxicity. As noted earlier, inherently long-acting opioids inhibit the metabolism of other agents, producing an increase in
such as methadone must be titrated more slowly and carefully. serum levels and activity of the interacting drug. The tricyclic anti-
Many clinicians use very conservative dose increments when esca- depressant desipramine has been shown to have increased serum
lating opioid therapy. This, unfortunately, can lead to treatment failure. levels when coadministered with methadone or morphine.
Table 54^2. Long-acting Opioids

COMPLICATIONS/OUTCOMES
Pharmacologically Long-Acting Pharmaceutically Long-Acting
Opioids are typically well tolerated in both acute and chronic set-
Levorphanol (Levo-Dromoran) Hydromorphone (Palladone) tings. Adverse CNS and GI effects should be anticipated and
(no longer available in the preemptively managed in most ‘‘opioid-naı̈ve’’ patients who initi-
United States) ate opioids for either acute or chronic pain management.
Methadone (Dolophine) Morphine sulfate (Kadian, Tolerance to a variety of bothersome opioid-related adverse effects
Morphine ER, MS Contin, (e.g., nausea and sedation) commonly occurs within a few days of
Oramorph SR) initiating therapy or subsequent dose escalation. Similarly, tolerance
Oxycodone (Oxycontin) to respiratory depression typically occurs within 7 to 10 days of
initiating a regularly scheduled opioid regimen. There is no toler-
Oxymorphone (Opana ER) ance to the constipating effects of opioids. Most patients using
Table 54^3. Opioid-Drug Interactions
Opioid(s) Interacting Drug(s) Description

Opioids Antihistamines, haloperidol, tricyclic Increased sedation
antidepressants
Controlled-release opioids Erythromycin, metoclopramide Earlier peak plasma concentration; increased sedation
Codeine Quinidine Decreased conversion to morphine; decreased analgesia
Meperidine Monoamine oxidase inhibitors Seizures, arrhythmias, hyperpyrexia, and coma; potentially fatal
interaction
Meperidine, morphine Cimetidine Inhibition of opioid metabolism; increased opioid effects
Methadone Carbamazepine Increased opioid metabolism; may induce withdrawal
Erythromycin
Phenytoin
Methadone, morphine Desipramine Inhibition of desipramine metabolism; toxicity possible
Propoxyphene Carbamazepine Increased carbamazepine levels, potential for toxicity
Propoxyphene Doxepin Increased doxepin levels, potential for toxicity
Propoxyphene Metoprolol, propranolol Increased plasma levels of these b-blockers
Adapted from Jackson KC, Lipman AG. Opioid analgesics. In Tollison CD, Satterwhite JR, Tollison JW (eds): Practical Pain Management, 3rd ed.
Philadelphia: Lippincott, Williams & Wilkins, 2002; pp 216–230.
opioids on a regular basis will require an aggressive bowel regimen selection and utilization of opioid pharmacotherapy are available
that includes stimulant laxatives such as bisacodyl or senna. to the practicing clinician. With continuing efforts to discuss the
Osmotic and saline laxatives are typically ineffective as alternatives potential benefits and potential pitfalls surrounding opioid analge-
for a prophylactic bowel regimen owing to the marked reduction in sics, hopefully, the past will illuminate the future with respect to
peristalsis that is manifested from activation of opioid receptors in appropriate and rational opioid pharmacotherapy.
the intestinal tract. Stool softeners may be useful adjuncts for
patients using a stimulant laxative in which the presence of hard,
dry stools is problematic. Use of monotherapy with stool softeners
is of no benefit in promoting evacuation of the narcotized gut and REFERENCES
should be avoided. Fiber or bulk-forming laxatives should be used
1. Acute Pain Management Guideline Panel. Acute pain management:
with extreme caution, if at all, for opioid-treated patients. These operative or medical procedures and trauma. Clinical Practice
agents are unable to promote laxation in the narcotized gut and can Guideline (AHCPR Pub. No. 92-0032). Rockville, MD: Agency
promote colicky pain or, worse, may promote a concrete mass that for Health Care Policy and Research, Public Health Service,
may require surgical extraction. U.S. Department of Health and Human Services, 1992.
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fied as a potential problem, especially for patients receiving high Clinical Practice Guideline No. 9 (AHCPR Publication No.
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generalized myoclonus, hyperalgesia, allodynia, and seizures. These Health Service, 1994.
3. WHO: Cancer Pain Relief: With a Guide to Opioid Availability,
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use of morphine, likely the result of accumulation of the neurotoxic 4. Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review
metabolite M3G.24 Other opioids such as hydromorphone and fen- of the critical issues. J Pain Symptom Manage 1996;11:203–217.
tanyl have also been reported to manifest significant CNS toxicity, 5. Haddox JD, Joranson DE, Angarola RT, et al. The use of opioids for
probably related to various metabolite accumulations. the treatment of chronic pain. Consensus Statement from the
Opioids do not produce the end-organ toxicity commonly seen American Academy of Pain Medicine and American Pain Society.
with NSAIDs on the GI tract and kidneys nor the hepatotoxicity Clin J Pain 1997;13:6–8.
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remarkably safe drugs when used chronically in appropriate doses guidelines for the use of controlled substances for the treatment of
pain. May 2004. http://www.fsmb.org/pdf/
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7. Rinaldi R, Steindler E, Wilford B, et al. Clarification and
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8. Weissman DE, Haddox JD. Opioid pseudoaddiction—an iatrogenic
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Unfortunately, a variety of barriers, ranging from societal to educa- Care Pain Symptom Control 1998;6:95–98.
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The most common misconceptions among clinicians and the abuse and illicit drug use in chronic pain patients: an evaluation of
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clinicians. Similarly, key concepts related to the appropriate inflammatory effects of opioids. Z Rheumatol 2001;60:416–424.
408 Chapter 55 OPIOIDS ISSUES
14. Ribeiro MDC, Joel SP, Zeppetella G. The bioavailability of morphine 20. Jackson KC, Lipman AG. Opioid analgesics. In Tollison CD,
applied topically to cutaneous ulcers. J Pain Symptom Manage Satterwhite JR, Tollison JW (eds): Practical Pain Management, 3rd ed.
2004;27:434–439. Philadelphia: Lippincott, Williams & Wilkins, 2002; pp 216–230.
15. Gallagher RE, Arndt DR, Hunt KL. Analgesic effects of topical 21. Twycross R, Fairfield S. Pain in far-advanced cancer. Pain
methadone: A report of four cases. Clin J Pain 2005;21:190–192. 1982;14:303–310.
16. Collins E, Poulain P, Gauvin-Piquard A, et al. Is disease progression 22. Haddox JD, Joranson D, Angarola RT. The use of opioids for the
the major factor in morphine ‘‘tolerance’’ in cancer pain treatment? treatment of chronic pain. A consensus statement of the American
Pain 1993;55:319–326. Academy of Pain Medicine and the American Pain Society. The
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18. Twycross R. Morphine and diamorphine in the terminally ill patient. August 21, 2008.)
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Chapter 55 analgesic neurotransmitters; as well as effects on G protein–

activated inwardly rectifying potassium (GIRK) channels.
OPIOIDS ISSUES An ‘‘analgesic ladder’’ approach to the selection of analgesic
drugs for cancer pain has been popularized by the World Health
Howard S. Smith and Gary McCleane Organization (WHO)2 and is now widely accepted as a broad
guideline and educational tool. No such universally accepted and
validated simplistic guideline or stepwise algorithm exists for per-
sistent noncancer pain (PNCP). However, similar principles of ther-
apy exist, initiating treatment conservatively with progressive
titration of doses and the addition of more-aggressive strategies in
the face of a lack of responsiveness.
According to the analgesic ladder, selection of an analgesic
INTRODUCTION should be guided by the usual severity of pain: patients with mild
pain usually are first treated with a nonopioid analgesic (e.g., ace-
Opioids are potent analgesic agents that have remained controver- taminophen or a nonsteroidal anti-inflammatory drug [NSAID]).
sial over many years. These analgesics have helped numerous This may be combined with one or more adjuvant drugs if a specific
patients to regain significantly improved quality of life by indication for one exists. These adjuvants include drugs to treat a
alleviating pain/suffering, yet many health care providers are still side effect of the analgesic (e.g., laxatives) and drugs with analgesic
not comfortable prescribing opioids for severe intractable pain. effects (the so-called adjuvant analgesics).
Clinicians should be familiar with risk-management strategies for Patients with moderate pain (including those with insufficient
assessing drug-taking behaviors; adverse effects of opioids; and relief after a trial of acetaminophen or an NSAID) are treated with
analgesic/functional outcomes associated with opioid therapy. an opioid conventionally used for moderate pain (Table 55–1).
Understanding and employing the concept of ‘‘balance’’ (i.e., pro- Patients with severe pain (including those who fail to achieve
viding medical availability and instructions on the appropriate use adequate relief after appropriate administration of drugs on the
of opioids as well as risk-management plans designed to prevent the second rung of the analgesic ladder) receive an opioid convention-
abuse or misuse of these agents) may increase the level of comfort of ally selected for severe pain (Table 55–2). This treatment may also
various clinicians prescribing opioids for pain relief. be combined with acetaminophen or an NSAID or an adjuvant
drug as indicated.
Although in some painful scenarios (e.g., severe intractable
OPIOID ACTIONS cancer pain) opioids may be a suitable first-line analgesic, in
other pain scenarios (e.g., moderate, human immunodeficiency dis-
Opioids are among the best broad-spectrum analgesics currently ease [HIV]–associated pain) opioids may be more appropriately
available to treat a wide variety of painful conditions. The broad reserved as a second- or third-line analgesic agent.3
spectrum of action and efficacy of opioids may perhaps be due in
part to the multiple sites of action at which opioids may produce
analgesic effects (e.g., peripheral, spinal, supraspinal).1 Opioids pro- ASPECTS OF INDIVIDUALOPIOIDS
duce analgesic effects by binding to membrane-bound opioid recep-
tors and initiating activation of G protein–coupled receptors Transdermal Buprenorphine
(GPCRs). m Opioid receptor agonist binding causes conformational
changes resulting in intracellular protein activation and inhibition Transdermal buprenorphine (although currently unavailable in the
of the activity of adenylyl cyclase. The subsequent m opioid receptor United States) is increasingly being utilized in the management of
agonist decrease in cyclic adenosine monophosphate (cAMP) may pain both related and unrelated to cancer. It appears to have sig-
indirectly lead to inhibition of voltage-dependent calcium channels nificant antihyperalgesic effects that increase its utility in the treat-
on presynaptic neurons, with subsequent diminished release of ment of neuropathic pain. Sittl4 suggested that the conventional
14. Ribeiro MDC, Joel SP, Zeppetella G. The bioavailability of morphine 20. Jackson KC, Lipman AG. Opioid analgesics. In Tollison CD,
applied topically to cutaneous ulcers. J Pain Symptom Manage Satterwhite JR, Tollison JW (eds): Practical Pain Management, 3rd ed.
2004;27:434–439. Philadelphia: Lippincott, Williams & Wilkins, 2002; pp 216–230.
15. Gallagher RE, Arndt DR, Hunt KL. Analgesic effects of topical 21. Twycross R, Fairfield S. Pain in far-advanced cancer. Pain
methadone: A report of four cases. Clin J Pain 2005;21:190–192. 1982;14:303–310.
16. Collins E, Poulain P, Gauvin-Piquard A, et al. Is disease progression 22. Haddox JD, Joranson D, Angarola RT. The use of opioids for the
the major factor in morphine ‘‘tolerance’’ in cancer pain treatment? treatment of chronic pain. A consensus statement of the American
Pain 1993;55:319–326. Academy of Pain Medicine and the American Pain Society. The
17. Pasternak GW. Molecular biology of opioid analgesia. J Pain American Academy of Pain Medicine and the American Pain Society,
Symptom Manage 2005;29(5 suppl):S2–S9. Glenview, IL. 1997. www.painmed.org/pdf/opioids.pdf (accessed
18. Twycross R. Morphine and diamorphine in the terminally ill patient. August 21, 2008.)
Acta Anaesth Scand 1984;74:128–134. 23. Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone.
19. Beeton A, Upton P, Shipton E. The case for patient-controlled J Pain Palliat Care Pharmacother 2005;19:13–24.
analgesia. Inter-patient variation in postoperative analgesic 24. Andersen G, Christup L, Sjogren P. Relationships among morphine
requirements. S Afr J Surg 1992;30:5–6. metabolism, pain and side effects during long-term treatment: An
update. J Pain Sympton Manage 2003;25:74–91.
Chapter 55 analgesic neurotransmitters; as well as effects on G protein–

activated inwardly rectifying potassium (GIRK) channels.
OPIOIDS ISSUES An ‘‘analgesic ladder’’ approach to the selection of analgesic
drugs for cancer pain has been popularized by the World Health
Howard S. Smith and Gary McCleane Organization (WHO)2 and is now widely accepted as a broad
guideline and educational tool. No such universally accepted and
validated simplistic guideline or stepwise algorithm exists for per-
sistent noncancer pain (PNCP). However, similar principles of ther-
apy exist, initiating treatment conservatively with progressive
titration of doses and the addition of more-aggressive strategies in
the face of a lack of responsiveness.
According to the analgesic ladder, selection of an analgesic
INTRODUCTION should be guided by the usual severity of pain: patients with mild
pain usually are first treated with a nonopioid analgesic (e.g., ace-
Opioids are potent analgesic agents that have remained controver- taminophen or a nonsteroidal anti-inflammatory drug [NSAID]).
sial over many years. These analgesics have helped numerous This may be combined with one or more adjuvant drugs if a specific
patients to regain significantly improved quality of life by indication for one exists. These adjuvants include drugs to treat a
alleviating pain/suffering, yet many health care providers are still side effect of the analgesic (e.g., laxatives) and drugs with analgesic
not comfortable prescribing opioids for severe intractable pain. effects (the so-called adjuvant analgesics).
Clinicians should be familiar with risk-management strategies for Patients with moderate pain (including those with insufficient
assessing drug-taking behaviors; adverse effects of opioids; and relief after a trial of acetaminophen or an NSAID) are treated with
analgesic/functional outcomes associated with opioid therapy. an opioid conventionally used for moderate pain (Table 55–1).
Understanding and employing the concept of ‘‘balance’’ (i.e., pro- Patients with severe pain (including those who fail to achieve
viding medical availability and instructions on the appropriate use adequate relief after appropriate administration of drugs on the
of opioids as well as risk-management plans designed to prevent the second rung of the analgesic ladder) receive an opioid convention-
abuse or misuse of these agents) may increase the level of comfort of ally selected for severe pain (Table 55–2). This treatment may also
various clinicians prescribing opioids for pain relief. be combined with acetaminophen or an NSAID or an adjuvant
drug as indicated.
Although in some painful scenarios (e.g., severe intractable
OPIOID ACTIONS cancer pain) opioids may be a suitable first-line analgesic, in
other pain scenarios (e.g., moderate, human immunodeficiency dis-
Opioids are among the best broad-spectrum analgesics currently ease [HIV]–associated pain) opioids may be more appropriately
available to treat a wide variety of painful conditions. The broad reserved as a second- or third-line analgesic agent.3
spectrum of action and efficacy of opioids may perhaps be due in
part to the multiple sites of action at which opioids may produce
analgesic effects (e.g., peripheral, spinal, supraspinal).1 Opioids pro- ASPECTS OF INDIVIDUALOPIOIDS
duce analgesic effects by binding to membrane-bound opioid recep-
tors and initiating activation of G protein–coupled receptors Transdermal Buprenorphine
(GPCRs). m Opioid receptor agonist binding causes conformational
changes resulting in intracellular protein activation and inhibition Transdermal buprenorphine (although currently unavailable in the
of the activity of adenylyl cyclase. The subsequent m opioid receptor United States) is increasingly being utilized in the management of
agonist decrease in cyclic adenosine monophosphate (cAMP) may pain both related and unrelated to cancer. It appears to have sig-
indirectly lead to inhibition of voltage-dependent calcium channels nificant antihyperalgesic effects that increase its utility in the treat-
on presynaptic neurons, with subsequent diminished release of ment of neuropathic pain. Sittl4 suggested that the conventional
Table 55^1. WHO Step 2 Analgesic Agents
Oral Agents Bioavailability (%) Half-life (hr) Onset (min) Peak Effect (min) Duration (hr)
Codeine 40 (12–84) 2.5–3.5 30–60 45–60 4–6
Dihydrocodeine 20 3–4 30 45–60 3–4
Tramadol 75 6 30 180 4–6
Hydrocodone 39 3.8 (2.0–4.5) 20–30 1.3 (1–2) 3–6
From Smith HS. Optimizing pharmacologic outcomes: Individualization of therapy. In Smith HS (ed): Opioid Therapy in the 21st Century. New York:
Oxford University Press, 2008; p 72.
conversation ratio of morphine to transdermal buprenorphine of Transdermal Fentanyl

75:1 is questionable and should be changed to 100:1.
Fentanyl is a synthetic phenylpiperidine m opioid receptor agonist.
It is Approximately 80 times more potent than morphine, is highly
Morphine lipophilic, and binds avidly to plasma proteins. After intramuscular
administration of fentanyl citrate, the analgesic onset time is
Morphine is the prototype exogenous mu opioid receptor (MOR) approximately 7 to 15 minutes; the time to peak analgesia may be
agonist. It is relatively hydrophilic, and 90% of its molecules are extremely variable but could be approximated by 15 to 45 minutes;
ionized at normal oral pH. The onset of oral morphine takes about the analgesic duration is about 1 to 2 hours; and the elimination
20 to 39 minutes with a time to peak analgesia of 60 to 90 minutes half-life is about 2 to 4 hours.5 Fentanyl is largely metabolized by
and a duration of 3 to 6 hours. The oral bioavailability of morphine piperidine N-dealkylation to norfentanyl via hepatic microsomal
is approximately 35% with a half-life of 1.5 to 4.5 hours. Long- cytochrome P-450 (CYP450) CYP3A4.5
acting morphine may be available as MS Contin, Oramorph, Langford and colleagues,6 in their study of 596 patients with
Kadian, and Avinza. defined osteoarthritis of the hip or knee who were randomized to
During oral or systemic administration of morphine in humans, receive either transdermal fentanyl or placebo, reported that trans-
glucuronidation (i.e., conjugation with glucuronic acid) at the phe- dermal fentanyl was shown to have a statistically significant pain-
nolic and alcoholic hydroxyl groups at positions 3 and 6 occurs to a reducing effect over placebo.
large extent in the liver. UGT was identified as the enzyme respon- Oral transmucosal fentanyl citrate (OTFC) is a candid matrix for-
sible for production of glucuronides from morphine. UGT exists as mulation administered orally as a palatable lozenge on a stick. OTFC
a multigene family resulting in a range of isoenzymes, and at least appears to be particularly well suited for breakthrough pain (which is
11 different forms of UGT have been identified. The functional present in about two thirds of cancer patients with pain) owing to its
heterogeneity also has been observed between the isoenzymes rapid onset. Meaningful analgesia may occur between 5 and 10 min-
responsible for the glucuronidation of morphine in the 3 and 6 utes after initiating OTFC use. Peak plasma concentrations are
positions. The liver is the major site of metabolism of morphine, achieved at 20 minutes, and the duration of analgesia is about 2
but evidence of extrahepatic glucuronidation has been reported.4a hours.7 The U.S. Food and Drug Administration (FDA) issued an
Morphine-6-glucoronide (M6G) was shown to be more potent approvable letter for Fentora (Fentanyl buccal tablet) in June 2006.
than morphine when injected intrathecally to patients. However, Fentanyl effervescent buccal tablets enhance buccal delivery of fenta-
opioid effects attributed to M6G develop with a remarkable delay nyl, utilizing the OraVescent drug delivery system, achieving an abso-
from the rise of M6G plasma concentrations caused by slow and lute bioavailability of 65%. The onset of pain relief in some patients is
incomplete transfer of M6G through the blood-brain barrier; there- within 15 minutes, with analgesic duration of up to 60 minutes.8,9
fore, results may be variable after oral administration. An iontophoretic fentanyl HCl patient-controlled transdermal
In contrast to M6G, morphine-3-glucoronide (M3G) shows no system (Ionsys) has been developed for the management of post-
affinity for the m- and d opioid receptors and is presumed to be devoid operative pain. The self-contained, needle-free system is about the
of analgesic activity. Despite this apparent lack of activity, however, size of a credit card (5 x 7.5 cm); it attaches to the upper arm or
intracerebroventricular or intraperitoneal M3G has been reported to chest and delivers a set amount of fentanyl (40 mg) when an imper-
induce allodynia and hyperalgesia, and progressively higher doses of ceptible, low-intensity electric current is initiated by quickly
M3G produce behavioral excitation, myoclonus, and seizures.4b double-clicking the dose-activation button.10
Table 55^2. WHO Step 3 Opioids
Oral Agents Bioavailability (%) Half-life (hr) Onset (min) Peak Effect (min) Duration (hr)
Morphine sulfate IR 25–35 (15–64) 2–3 20–30 60–90 3–6
Oxycodone IR 75 (60–87) 2.0–3.5 20–30 60–120 3–6
Hydromorphone IR 37–62 2.5 (2–3) 30 1–2 3–6
Oxymorphone IR 10 7.3–9.4 15–23 45–90 4–6
Methadone 80 (12–150) 30–90 2–4 For analgesia 6–8; for suppressing
opioid withdrawal 24–48
Levorphanol Uncertain 11–16 20–60 1–2 3–6
Chronic dosing
(30)
IR, immediate-release/short-acting; SS, steady state.
From Smith HS. Optimizing pharmacologic outcomes: Individualization of therapy. In Smith HS (ed): Opioid Therapy in the 21st Century. New York:
Oxford University Press, 2008; p 72.
Oxycodone Hydrocodone
Oxydocone (14-hydroxydihydrocodeinone) is a potent MOR ago- In terms of the number of pain pills dispensed, hydrocodone-
nist that appears to have effects at the k opioid receptor as well. It is containing formulations are likely the most common opioid anal-
available as a controlled-release formulation and as a short-acting gesic prescribed in the United States. Hydrocodone is a codeine
analgesic alone in various strengths as well as in combination with derivative and, because of high bioavailability (> 50%), is available
acetaminophen or aspirin. The opioid effects of oxycodone are as oral formulations, mostly in combination with nonopioid
related to the parent drug and not to its metabolites.11 analgesics (e.g., acetaminophen, ibuprofen). Hydrocodone in sim-
Watson and coworkers12 studied patients with painful diabetic ilar doses is equivalent in effectiveness to morphine after oral
neuropathy. Patients were treated for 4 weeks with controlled- administration. It possesses analgesic and antitussive activity, and
release oxycodone or placebo. The only side effects that occurred its half-life is similar to that of codeine. Hydrocodone undergoes
on a statistically more significant basis in the oxycodone-treated extensive hepatic conjugation and oxidative degradation to a variety
group were dry mouth and constipation.12 of metabolites, which are excreted mainly in urine.5
Marshall and associates13 assessed the cost of producing pain The major metabolites of hydrocodone excreted into urine are
relief in patients with osteoarthritis of the hip or knee when dihydrocodeine and nordihydrocodeine (both conjugated to
controlled-release oxycodone or a combination of acetaminophen approximately 65%). The O-demethylation to dihydromorphine
and oxycodone are used. They found that 62% of patients (DHM) conversion is mediated by the polymorphically expressed
receiving controlled-release oxycodone alone had pain relief versus CYP2D6 enzyme; however, DHM is produced in minor amounts
46% taking the combination of that drug and acetaminophen. and 85% is conjugated further. Traces of nordihydromorphine
Consequently, from an economic perspective, controlled-release and hydrocodone have been confirmed, and other metabolites of
oxycodone alone was more cost effective than the combination dihydrocodeine can be detected. Some of the hydrocodone meta-
product.13 bolites (DHM, hydromorphone, dihydrocodeine) are pharmaco-
Webster and colleagues,14 in a randomized, controlled trial of logically active at the opioid receptors and may contribute in
patients with low back pain, reported that Oxytrex (oxycodone plus various degrees to the analgesic activity of hydrocodone or pro-
ultra–low-dose naltrexone, an investigational drug) minimized duce unexpected side effects (e.g., renal dysfunction) when their
physical dependence while providing effective analgesia. excretion is impaired.5
One major question that continues to be of major relevance is
whether individual opioids have distinct advantages over other
members of this class. Staahl and coworkers15 compared the effects OPIOID ADVERSE EFFECTS
of morphine and oxycodone in healthy human volunteers. They
utilized a cross-over study design, so each subject received mor- Common opioid side effects may include: nausea and vomiting,
phine and an equinalgesic dose of oxycodone. They showed that pruritus, sedation, and constipation. Potential future agents such
both oxycodone and morphine are equipotent in pain modulation as methylnaltrexone or avilmopan may offer promise in the manage-
of induced skin and muscle pain. In contrast, when used for ment of opioid analgesic effects (e.g., opioid-induced constipation).
mechanically and thermally induced visceral pain of the esophagus, Other adverse effects may include cognitive disturbances, per-
oxycodone produced significantly superior analgesia.15 Conversely, ceptual distortions, myoclonus, urinary retention, headache and/or
the ACTION study (and its extension phase)16—a randomized, dizziness, fatigue, anorexia, dry mouth, sweating, decreased sexual
open-label, multicenter trial comparing once-a-day to twice-a-day desire (libido), abdominal discomfort/cramping/bloating, and infre-
controlled-release oxycodone hydrochloride (OxyContin) for the quent respiratory depression. Opioid toxicity will vary between indi-
treatment of chronic, moderate to severe low back pain—suggested viduals. Individuals do not develop every adverse effect/toxicity and
that extended-release morphine was significantly better than differ greatly in the magnitude of various effects and in how much
controlled-release oxycodone for reducing pain and improving distress they cause the individual. In general, tolerance develops to
sleep and physical functioning at a lower daily opioid dose. most side effects but often may not develop to constipation.26
Opioids appear to differ to a certain extent in the incidence and
frequency of side effects associated with their use. Staats and associ-
Oxymorphone ates27 retrospectively studied 1836 patients receiving treatment with
transdermal fentanyl, sustained-release oxycodone, and sustained-
Oxymorphone, a 3-O-demethylation metabolite of oxycodone, is a release morphine. Those receiving transdermal fentanyl had a
potent opioid that has a three to five times higher m opioid receptor lower risk of developing constipation than those taking either of the
affinity than that of morphone.17 Oxymorphone has been studied other two strong opioids (3% vs. 6% risk with oxycodone and 5%
for postsurgical pain in an oral, immediate-release formulation and with morphine).27 This lower incidence of constipation with trans-
appears to be effective.17 It has also been studied as an oral, extend- dermal fentanyl is supported by other studies.28,29 Multiple approaches
ed-release formulation, and it appears that oxymorphone may be are available for the management of opioid-induced constipation,
effective for moderate to severe pain secondary to osteoarthritis.18 opioid-induced nausea/vomiting, opioid-induced sedation, opioid-
In June 2006, the FDA approved Opana (oxymorphone hydrochlor- induced pruritus, and opioid-induced respiratory depression.30
ide) tablets (5 mg, 10 mg), and Opana (oxymorphone hydrochlor- A recurrent anxiety associated with chronic strong opioid
ide) extended-release tablets (5 mg, 10 mg, 20 mg, 40 mg). It also administration is its effect on cognition and motor tasks as exem-
seems that oxymorphone extended-release may be equianalgesic to plified by driving safety. Schindler and colleagues31 examined this
oxycodone controlled-release at half the milligram daily dosage issue in opioid addicts (not with chronic pain) using an Austrian
(with comparable safety)19,20 and may be more potent than standard test battery for measurement of performance related to
morphine at equianalgesic doses.21 Oxymorphone extended-release driving ability, the Act & React Test (ART) system. Subjects were
uses the TIMERx delivery system22 to provide pharmacokinetic taking either methadone or buprenorphine and were compared
characteristics consistent with 12-hour dosing.23 Major metabolites with healthy controls. They found that those taking these strong
of oxymorphone include 6-OH-oxymorphone-3-glucuronide. It opioids did not differ significantly from the healthy controls in the
appears that oxymorphone extended-release does not affect majority of the ART standard tests.31
CYP2C9 or CYP3A4 metabolic pathways.24 Noroxymorphone Similarly, Sabatowski and coworkers32 measured attention, reac-
demonstrated a 3- and 10- fold higher affinity for the m opioid tion, visual orientation, motor coordination, and vigilance in 30 sub-
receptor than oxycodone and noroxycodone, respectively.25 jects using a stable dose of transdermal fentanyl for noncancer pain
and compared them with 90 healthy volunteers. None of the results n In rotating opioids, consider all medical factors that may be
from the measures differed significantly between the fentanyl-treated relevant (e.g., renal function, liver function, age, comorbidities),
and the volunteer subjects, and the authors concluded that in patients and adjust equianalgesic dose based on these factors.
treated with stable doses of transdermal fentanyl, the threshold for n In rotating to an opioid other than methadone or fentanyl,
fitness to drive did not differ significantly between the groups.32 decrease the equianalgesic dose by 25% to 50%.
Longer-term administration of opioids may be complicated by n In rotating to methadone, reduce the dose by 75% to 90%.
other factors that can influence their long-term tolerability. For n In rotating to trandermal fentanyl, maintain the equianalgesic
example, acute administration of opioids increases prolactin, dose.
growth hormone, thyroid-stimulating hormone, and adrenocorti- n In rotating because of uncontrolled pain, consider a lesser than
cotropic hormone while inhibiting luteinizing hormone (LH) usual dose reduction.
release.33–35 When administered on a long-term basis, different n Ensure that appropriate rescue/breakthrough doses are available.
endocrine results are observed. Abs and associates36 extensively Use 5% to 15% of the total daily opioid dose as a guide, and
investigated 73 patients receiving an average duration of reassess and retitrate the new opioid.
26 months of intrathecal opioids for chronic nonmalignant pain.
Decreased libido and impotence were present in 23 of the 24 men Although these recommendations encourage the utilization of
studied. Nine of the men had a significantly reduced testosterone an opioid equianalgesic conversion table, health care providers
level, and most had a decreased LH level. All of the premenopausal must keep in mind that there is significant variability among
females had either amenorrhea or an irregular cycle, with ovulation opioids and significant differences among patients. Clinicians
in only 1 patient as well as decreased LH and follicle-stimulating need to ‘‘practice medicine’’ and ‘‘actively decide’’ the most appro-
hormone levels compared with controls. The 24-hour urinary cor- priate opioid dose to start with, tailoring their decisions to specific
tisol excretion was significantly lower in the study subjects than individual patients, rather than simply ‘‘robotically’’ calculating an
controls in 14 of the 73 patients. Fifteen percent of all patients opioid dose and prescribing this amount while deciding whether
developed growth hormone deficiency. Therefore, in patients any adjustments are needed. Subsequent close patient follow-up
receiving intrathecal opioids on a long-term basis, the majority and careful opioid titration should ensue in attempts to achieve
of men and all women developed hypogonadotrophic hypogonad- optimal analgesia with minimal adverse effects.
ism, 15% developed central hypocorticism, and about 15%
developed growth hormone deficiency.36
A variety of miscellaneous potential opioid adverse effects may CLINICALUSE OF OPIOIDS:THE
have clinical significance including issues of tolerance and opioid- EVIDENCE
induced hyperalgesia. It appears that sleep-disordered breathing
(e.g., sleep apnea) may be associated with long-term opioid therapy The last few years have seen the publication of a number of sys-
(LTOT).37,38 A single case report highlights a different possible side tematic reviews concerning various aspects of the effects of
effect of fentanyl use. Kokko and colleagues39 reported apparent opioids.40,41 To a large extent, these offer no surprises, but rather
inappropriate antidiuretic hormone (ADH) release in a patient reassure that the widespread use of opioids in clinical practice is
with a known lung tumor treated with fentanyl. Withdrawal of based on hard scientific evidence (Table 55–4).
fentanyl terminated the ADH release, whereas reinstitution of fen- What is lacking is any firm indication that any particular opioid
tanyl at a later date triggered a further inappropriate ADH release.39 has demonstrable superiority over others. One is, therefore, left to
select an opioid for clinical use based on personal experience and
familiarity with the various drugs and their formulations and
OPIOID ROTATION unique special characteristics in different clinical circumstances.
Olsen and coworkers42 assessed the opioid use by American
Some patients may experience intolerable side effects before ade- primary care physicians and found that opioids were prescribed
quate analgesia is reached or, more rarely, do not benefit at all. in 5% of all visits between 1992 and 2001. The rate was 4.1% in
Several strategies can be employed to reduce toxicity and improve 1992 to 1993 and rose to 6.3% in 1998 to 1999. Subscribing to
pain control, including more aggressive treatment of side effects, Medicaid or Medicare and receiving an NSAID increased the
use of coanalgesics or intravenous or anesthetic procedures, and use chances of receiving an opioid, whereas being of Hispanic origin,
of nonpharmacologic interventions. An alternative approach is to being enrolled in a health maintenance organization, or living in the
change to another opioid in an attempt to allow titration to ade- Northeast or Midwest mitigating against opioid prescription.42
quate pain control while limiting side effects. With such use of opioids for severe pain, particularly in the long
The practice of changing from one opioid to another, referred to term, questions of their effects with protracted use arise. At least
as opioid rotation, is most commonly undertaken when adequate some of the evidence is conflicting. Won and associates43 reported
analgesia is limited by the occurrence of problematic side effects. their findings of a study of 10,372 nursing home residents with
The principle of rotation is based on the observation that a patient’s persistent pain. They found that 18.9% were taking short-acting
response can vary from opioid to opioid, for both analgesia and opioids whereas 3.3% were taking long-acting opioids. They
adverse effects. An inadequate response or the occurrence of intol- noted that there were no changes in cognitive status, mood
erable side effects with one opioid does not necessarily predict a status, or increased risk of depression with use of opioid analgesics.
similar response to another. Furthermore, they found a decreased risk of falls with opioid use.43
Eisenberg and colleagues40 published a systematic review and
meta-analysis of trials evaluating the safety and efficacy of opioid
agonists in the treatment of neuropathic pain of nonmalignant
Key Points for Opioid Rotation
origin. Eisenberg and colleagues40 examined 22 studies that met
n Utilize an opioid equianalgesic table that is appropriate/relevant inclusion criteria and were classified as short-term (<24 hr; n = 14)
for your practice and use it consistently (Table 55–3). or intermediate-term (median = 28 days; range = 8–56 days; n = 8)
n In deciding on an alternative opioid, consider all patient factors trials. They reported that the short-term trials had contradictory
(e.g., What is the best route of drug delivery in this patient? results. However, all 8 intermediate-term trials demonstrated
Which drug is most convenient for the patient/treating team? opioid efficacy for spontaneous neuropathic pain. A fixed-effects
Is cost going to be an issue? Is the new drug available in the model meta-analysis of 6 intermediate-term trials showed mean
community?). post-treatment visual analog scale scores of pain intensity after
Table 55^3. Equianalgesic ConversionTable
Equianalgesic Dose
Name Oral (mg) Parenteral Comments Precautions and Contraindications

Morphine 30 10 mg Standard of comparison for opioid Clearance of parent drug and active
analgesics. metabolite is prolonged in renal failure
Hydromorphone 4–6 1.5 mg Exact dose equivalence unclear
Hydrocodone 20 N/A 1.5:2 hydrocodone:morphine dose Available in United States combined
equivalence with acetaminophen; maximum daily
dose of acetaminophen is 4 g
Oxycodone 15–20 5–10 mg* 1.0–1.5:2 oxycodone:morphine dose Clearance is prolonged in hepatic failure
equivalence
Methadone{ 10–20 (single N/A Long plasma half-life (24–36 hr), Accumulates with repeated dosing,
dose; may unique characteristics, considerable unpredictable pharmacology in
vary widely) interindividual difference in individual patients, use with caution
pharmacokinetics, cannot be titrated
in the same manner as other opioids
Buprenorphine Available in 3- and 7-day transdermal
formulations{ (see manufacturer’s
recommendations for morphine dose
equivalence range)
Oxymorphone§ 10 1–1.5 mg* Limited availability
Fentanyl N/A 200 mg Available in transdermal preparation Considered reasonably safe in patients
(see manufacturer’s with renal impairment
recommendations for morphine dose
equivalence range)
*Parenteral not available in United States.
{
It is extremely important to monitor all patients closely when converting from methadone to other opioid agonists. The ratio between methadone and
other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and tends to accumulate in the plasma.
{
Transdermal not available in United States.
§
The approximate equivalent doses in this conversion table are to be used only for the conversion from current opioid therapy to oxymorphone extended
release (Opana ER). Add the total daily dose for the opioid and use the approximate equivalent doses to calculate the oxymorphone total equianalgesic
daily dose. For patients on a regimen of mixed opioids, calculate the approximate oral oxymorphone dose for each opioid and add the total to estimate
the total daily equianalgesic oxymorphone dose. The dose of oxymorphone extended release (Opana ER) can be gradually adjusted, preferably at
increments of 10 mg every 12 hours every 3–7 days, until adequate pain relief and acceptable side effects have been achieved.
From McCarberg BH, Smith HS. Optimizing pharmacologic outcomes. Principles of opioid rotation. In Smith HS (ed): Opioid Therapy in the 21st
Century. New York: Oxford University Press, 2008; p 65.
opioids to be 14 units lower on a scale from 0 to 100 than after Watson and coworkers12 surveyed 102 patients with PNCP in a
placebo (95% confidence interval [CI] –18 to –10; P < .001). neurologic practice followed by a neurologist every 3 months for
Because the mean initial pain intensity recorded from 4 of the 1 year or more (median 8 yr; range 1–22 yr). They reported that
intermediate-term trials ranged from 46 to 69, this 14-point dif- approximately one third of patients (34 out of 102) had a change in
ference was considered to correspond to a 20% to 30% greater their pain status from either severe or moderate pain, as mea-
reduction with opioids than with placebo.40 sured by a 0 to 10 numerical rating scale (NRS) (mild = 1–3, mod-
Kalso and coworkers41 analyzed data from 1145 patients initially erate = 4–7, severe = 8–10), by category scale (absent, mild,
randomized in 15 placebo-controlled trials of potent opioids used moderate, severe, very severe), and by considering pain with move-
in treatment of severe pain for efficacy and safety in chronic non- ment. They queried patients as to whether they were satisfied with
cancer pain.41 Four studies tested intravenous opioids in neuro- pain relief despite adverse events. Forty-five patients (44%)
pathic pain in a cross-over design with 115 of 120 patients answered that they were satisfied, and 57 (56%) replied that they
completing the protocols. Using either pain-intensity difference or were not satisfied with their pain relief. However, of the 86 patients
pain relief as the end-point, all 4 intravenous studies reported aver- assessed for disability, 47 patients (54%) had significant improve-
age pain relief of 30% to 60% with opioid. Eleven studies (1025 ment in their disability status on opioids. Also, there was some
patients) compared oral opioids with placebo for 4 days to 8 weeks. pain improvement on opioids in 78 (91%) of 102 patients, and
Six of the 15 trials included had an open-label follow-up of 6 to 24 the patients chose to continue therapy for some analgesia despite
months. The mean decrease in pain intensity in most studies was at adverse effects.12
least 30% with opioids and was comparable in neuropathic and
musculoskeletal pain. Approximately 80% of patients noted at
least one adverse effect. The most common adverse effects were
constipation (41%), nausea (32%), and somnolence (29%). Only LTOT FOR PNCP
44% of 388 patients on open-label treatments were still on opioids
after therapy for between 7 and 24 months. Adverse effects and lack Practicing in the ‘‘middle of the road’’ by employing the appropriate
of efficacy were two common reasons for discontinuation.41 use of opioids in the context of good medical practice as well as giving
Table 55^4. Recent Systematic Reviews Concerning Opioid Use (Published in 2004^2006)
Trials
Clinical Scenario Analyzed (N) Patients (N) Outcome
NSAIDs ± opioids in cancer 42 3084 NSAID + opioid: no difference (4 of 14 papers); statistically
pain insignificant benefit (1 of 14 papers); slight but statistically
significant benefit (9 of 14 papers)
Oxycodone for cancer pain 4 * Efficacy and tolerability of oxycodone similar to those of
morphine
Oral transmucosal fentanyl for 4 393 Effective for cancer breakthrough pain
breakthrough pain in cancer
Efficacy of epidural 31 1343 72% of patients obtained ‘‘excellent’’ pain relief
Subarachnoid 28 722 62% of patients obtain ‘‘excellent’’ pain relief
Intracerebroventricular opioids 13 337 73% of patients obtained ‘‘excellent’’ pain relief
in pain due to cancer
Long-term oral opioids for 16 1427 None of the studies were of good quality; insufficient evidence to
chronic noncancer pain produce conclusion
Opioids for chronic noncancer 41 6019 Weak and strong opioids outperformed placebo for all types of
pain chronic noncancer pain
Tramadol for neuropathic pain 5 161 NNT of tramadol compared with placebo (3.4); NNH of
tramadol compared with placebo (7.7)
Opioids for noncancer pain 15 1145 Short-term efficacy of opioids were good for both neuropathic
and musculoskeletal pain; 80% of patients experienced at least
one adverse event with opioid use; only 44% of 388 patients on
open-label treatment were still taking the opioid between 7 and
24 months after commencement
Analgesic in postherpetic 31 * Strong opioids and tramadol were effective, codeine was
neuralgia ineffective
Opioids in neuropathic pain 22 * Opioids showed effectiveness, high incidence of adverse effects
treatment
m Agonists in treatment of 9 * Dynamic allodynia significantly reduced; no consistent effect on
evoked neuropathic pain static allodynia, small number of studies hindered interpretation
NSAIDs and opioids for renal 20 1613 NSAIDs more effective than opioids in reducing pain; higher
colic incidence of adverse events with opioids compared with NSAIDs
Intra-articular morphine after 46 * Few well-controlled studies; no added analgesic effect of intra-
knee arthroscopy articular morphine compared with saline
{ {
Opioid switching Opioid switching results in improvement in more than 50% of
patients who have chronic pain with poor response to one opioid
Opioid side effects in chronic 34 5546 Dry mouth in 25% of patients; nausea in 21%; constipation in
nonmalignant pain 15%; 22% withdrew from opioid therapy because of side effects
NNH, numbers needed to harm; NNT, numbers needed to treat; NSAIDs, nonsteroidal anti-inflammatory drugs.
*Number of patients not indicated in review paper.
{
There was generally a low quality of 31 reports meeting inclusion criteria—with data pooled from 23 articles with 732 patients.
From McCleane G, Smith HS. Opioids for persistent noncancer pain. Med Clin North Am 2007;91:177-197.
appropriate attention to the risk assessment and management of Perhaps one of the most important principles as a clinician in
opioid abuse (being cognizant of potential abuse, addiction, and initiating and maintaining LTOT for PNCP is to ‘‘know where you
diversion) has become known as ‘‘balance.’’44–46 are and where you are going.’’ Goal-directed therapy agreements
Issues that surround the initiation (and/or maintenance) phase (GDTA) may be helpful when initiating LTOT for PNCP.47
of LTOT for PNCP include the use of opioid ‘‘contracts’’ or agree- Clinicians are sometimes faced with patients in whom opioids
ments; the use of goal-directed therapy agreements47; the use of a were started and/or exculpated in efforts to achieve analgesia with-
substance abuse history and/or ‘‘screening tool’’ for substance out clearly defined end-points. This may raise patient and clinician
misuse; the use of urine testing, unscheduled pill counts, and opti- expectations and in an attempt to make expected treatment out-
mally, some form of psychological assessment (which could be an comes more finite and concrete, the use of some form of GDTAs
assessment by the provider) documentation tools as well as some may possess potential utility. As with opioid treatment agreements,
sense of how reasonable the doctor-patient relationship is. Each GDTAs are not necessarily advocated for all patients or all practices,
clinic/clinician may utilize different items/tools in their practices— but are merely suggested in situations in which clinicians deem
and there are no requirements for what some authors have referred them appropriate.
to as risk-management plans (RMPs) or risk management action GDTAs should be tailored to each individual patient, clear and
plans (risk MAPs).46a concise, reasonable for the patient to attain over a finite period of
time, and optimally, agreed upon by both patient and clinician. 6. Prescribing LTOT for PNCP remains very much an art that
Examples may include increasing daily ambulation by a defined may be used successfully alone or in conjunction with other
amount and instituting opioid therapy (clinicians can set defined therapeutic options but typically not as a first-line agent for
criteria to be met in order to continue opioid therapy). In this patients who have not tried previous treatment.
manner, patients may be expected to reach certain reasonably
attainable functional goals (which may need to be documented by
their physical and/or behavioral therapist) in order to continue IDENTIFYING PATIENTS AT RISK FOR
opioid therapy. The specific defined goals should be clearly stated ANALGESIC MISUSE
in the GDTA. It appears optimal to institute the GDTA prior to
instituting opioid therapy. The GDTA is essentially believed to be a All clinicians who treat pain with opioids should assess for patient
‘‘contractually’’ agreed-upon realistic target of translational analge- characteristics that may increase a patient’s risk of the potential for
sia47 that should be realized in order to continue therapy as is. abuse. One way to help clinicians is through the use of tools to
Although prior to LTOT there may not be any specific need for screen patients for substance abuse issues.
psychological/psychiatric evaluations or psychological testing, it Two brief screening tools for alcohol and drug abuse are the
seems prudent that clinicians should ‘‘know’’ a patient and have CAGE-AID (‘‘Adapted to Include Drugs’’)49 and the Two-Item
an established provider-patient relationship before initiating LTOT Conjoint Screen (TICS)50—(1) In the last year have you ever
for PNCP. Wasan and colleagues48 reported that high levels of psy- drunk or used drugs more than you meant to? (2) Have you felt
chopathology (comprising mainly depression, anxiety, and high you wanted or needed to cut down on your drinking or drug abuse
neuroticism) are associated with diminished opioid analgesia in in the last year? However, these are not opioid specific.
patients with discogenic low back pain. CAGE is a standard screening tool which does not stand for
Many issues surround LTOT for PCNP. One possibly practical anything but is named from the 4 questions:
way of classifying various issues (although artificial and not precise)
1. Tried to Cut down or Change your pattern of drinking (or
is to categorize issues into three phases (analogous to the three phases
drug use)?
of delivering an anesthetic [induction, maintenance, emergence]):
2. Been Annoyed or Angry by others’ concern about your drink-
1. Initiation (induction). ing (or drug use)?
2. Maintenance. 3. Felt Guilty about the consequences of your drinking (or drug
3. Reassessment (increase dose, continue same dose, decrease use)?
dose, taper to off [emergence]). 4. Had a drink or used a drug in the morning (Eye-opener) to
decrease hangover or withdrawal symptoms?
Decisions regarding the timing of initiation and whether to ini-
tiate LTOT for PNCP must be made on a case-by-case basis. The Opioid-specific tools include the Prescription Drug Use Question-
various factors that may enter into the clinician’s decision making naire (PDUQ), the Screening Instrument for Substance Abuse Poten-
process may include the patient’s age, prognosis, documentation of tial (SISAP), the Screener and Opioid Assessment for Patients with
diagnosis, previous treatments, the patient’s willingness to change Pain (SOAPP), and the Opioid Risk Tool (ORT). Compton and co-
(e.g., behavior), pain duration and intensity, history of substance workers51 developed an interview-screening tool for assessment of
use and mental health issues, patient/clinician goals, and the par- addiction in patients with chronic pain and ‘‘problematic’’ substance
ticular physician-patient relationship. use. The PDUQ was created to identify subjects who are likely to be
It is crucial that the clinician has a reasonable dynamic picture of nonaddicted, substance abusing, or substance dependent. The PDUQ
the intensity of the patient’s pain as well as its impact on social is a 42-item interview in which data are obtained regarding the
domain (e.g., family, relationships, and recreational activities), patient’s pain condition, opioid use, social and family history, and
emotional domain (e.g., mood), and functional domain (e.g., phys- any psychiatric issues.51 Unfavorable features include the fact that the
ical functioning, activities of daily life, occupational issues) before semistructured interview instrument takes significant time to admin-
starting opioid therapy. It is also vital that the clinician continues to ister and is geared for use by trained mental health professionals.
evaluate the patient’s status in each of these domains. If, in fact, the The SISAP is a five-item screen that assesses the risk of opioid
patient does not improve or deteriorates during LTOT, it may be abuse based on a patient’s alcohol consumption, marijuana use,
appropriate at some point to change to a different opioid or taper tobacco use, and age52 (Box 55–1).
the patient slowly to a lower dose of LTOT or completely off Two instruments designed to help clinicians decide what level of
opioids and attempt different treatments. The pre–opioid-prescrib- monitoring would be best for particular patients on opioids are the
ing period (POPP; before initiating opioid therapy) is a critically SOAPP and ORT. The SOAPP, a survey tool used to predict opioid
important time for patient education/informed consent; assessment
of baseline pain, function, and risk factors for opioid misuse; and
discussions with the patient regarding expectations/goals of therapy Box 55^1 SCREENING INSTRUMENT FOR SUBSTANCE ABUSE
as well as the rules of the pain clinic (e.g., signing opioid agreements POTENTIAL (SISAP)
and discussions of urine drug testing (UDT), unscheduled pill
counts, refills, ‘‘violations’’ leading to discontinuation of opioid SISAP Questions
therapy). 1. If you drink alcohol, how many drinks do you have on a typical day?
Overall, the use of LTOT for PNCP may provide significant 2. How many drinks do you have in a typical week?
3. Have you used marijuana or hashish in the past year?
analgesia in patients with minimal side effects for many years.
4. Have you ever smoked cigarettes?
However, it must be kept in mind that 5. What is your age?
1. LTOT may not be optimal for all patients. Interpretation of SISAP Results
2. LTOT does not provide good or excellent analgesia in all Use caution when prescribing opioids for the following patients:
patients. 1. Men who exceed 4 drinks per day or 16 drinks per week.
3. LTOT is not devoid of side effects. 2. Women who exceed 4 drinks per day or 12 drinks per week.
4. LTOT should be monitored in efforts to assess efficacy, side 3. A patient who admits to marijuana or hashish use in the past year.
effects, and aberrant drug behavior. 4. A patient under 40 who smokes.
5. LTOT can be successfully withdrawn in selected patients who Adapted from Coambs RB, Jarry JL:The SISAP: a new screening instrument for Identifying poten-
tial opioid abusers in the management of chronic nonmalignant pain in general medical practice.
may do better without opioids. Pain Res Manage 1996;1:155-162.
abuse, is available as a 5-, 14-, or 24-item questionnaire.53 The

Box 55^2 SCREENER AND OPIOID ASSESSMENT FOR major benefit in using the 14- or 24-item questionnaire is that
PATIENTS wITH PAIN (SOAPP) they have increased sensitivity and specificity over the 5-item
short form (Box 55–2).
Please answer the question below using the following scale: 0 = never; To score, add the ratings (0-4) of each of the fourteen questions.
1 = seldom; 2 = sometimes; 3 = often; 4 = very often. The 14-item SOAPP uses a cutoff score of 8 or above (out of a
1. How often do you have mood swings? possible 56); a score of 8 or higher indicates that the subject may
2. How often do you smoke a cigarette within an hour after you
wake up? have a potential increased risk of opioid abuse. Therefore, the
3. How often have any of your family members, including parents and patient may require additional or special precautions and/or mon-
grandparents, had a problem with alcohol or drugs? itoring when treated with LTOT (e.g., giving prescriptions at inter-
4. How often have any of your close friends had a problem with alcohol vals [days or weeks] with limited tablets). Information on the
or drugs? SOAPP as well as the Current Opioid Misuse Measure (COMM;
5. How often have others suggested that you have a drug or alcohol a tool to aid in the identification of patients on LTOT with aberrant
problem? drug-taking behavior)54 is available at http://www.painedu.org/
6. How often have you attended an Alcoholics Anonymous or Narcotics index.asp.
Anonymous meeting?
The ORT is a five-question, self-administered assessment that
7. How often have you taken medication other than the way it was
prescribed?
can be completed in less than 5 minutes on a patient’s initial visit.14
8. How often have you been treated for an alcohol or drug problem? The ORT assesses for personal and family history of substance
9. How often have your medications been lost or stolen? abuse, age, history of preadolescent sexual abuse, and the pres-
10. How often have others expressed concern over your use of ence of depression, attention deficit disorder (ADD), obsessive-
medication? compulsive disorder (OCD), bipolar disorder, and schizophrenia.14
11. How often have you felt a craving for medication? The ORT accurately predicted which patients were at highest and
12. How often have you been asked to give a urine screen for substance lowest risk for exhibiting aberrant, drug-related behaviors associat-
abuse? ed with abuse or addiction14 (Table 55–5).
13. How often have you used illegal drugs (e.g., marijuana, cocaine) in the The Severity of Opiate Dependence Questionnaire (SODQ) is
past 5 years?
14. How often, in your lifetime, have you had legal problems or been
not an initial screen but is essentially meant to be used as an indi-
arrested? cator of opiate dependence.51 It consists of five sections of multiple-
Adapted from Butler SF, Budman SH, Fernandez K, et al. Validation of a screener and opioid
choice questions addressing patterns of use, degree of withdrawal
assessment measure for patients with chronic pain. Pain 2004;112:65-75. symptoms, and other signs of physical and psychological depen-
dence.51 Three items from the SODQ appeared to be especially
important in identifying serious concerns of opioid dependency:
n The tendency to increase analgesic dose or frequency.
n The tendency to have a preferred route of administration.
51
n The tendency to consider oneself addicted.
Table 55^5. The Opioid RiskTool (ORT)
Mark Each Box Item Score if Item Score

Item That Applies Female if Male
1. Family history of substance abuse
Alcohol [] 1 3
Illegal drugs [] 2 3
Prescription drugs [] 4 4
2. Personal history of substance abuse
Alcohol [ ] 3 3
Illegal drugs [ ] 4 4
Prescription drugs [ ] 5 5
3. Age (mark box if 16–45) [ ] 1 1
4. History of preadolescent sexual abuse [ ] 3 0
5. Psychological disease
Attention deficit disorder, Obsessive-compulsive disorder, bipolar, [] 2 2
schizophrenia
Depression [] 1 1
Total ORT Score (sum of 1–5)
Interpretation of ORT Score

Low risk 0–3
Moderate risk 4– 7
High risk 8
From Webster LR, Butera PG, Moran LV, et al. Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in
low back pain. J Pain 2006;7:937–946.
RMPs English and Spanish on their website at www.painmed.org/product-

pub/statements (Fig. 55–1).
No one behavior is pathognomonic of a substance use disorder. Practicing in the middle of the road by employing the appro-
Thus, there is no foolproof instrument to reliably assess the risk priate use of opioids in the context of good medical practice, as well
of opioid addiction.55 Because the prevalence of addiction in the as appropriate attention to the risk assessment and management of
general population is not insignificant, it seems prudent to utilize opioid abuse (being cognizant of potential abuse, addiction, and
the 10 steps of ‘‘universal precautions’’ in patients for LTOT56: diversion), has become known as balance.44–46
In the interest of both balance and documentation, many have
1. Reasonable attempts to make a diagnosis with appropriate
advocated utilizing an RMP when prescribing LTOT. Currently, no
differential.
specific elements are required to be part of any particular RMP.
2. Comprehensive patient assessment including risk of addic-
However, popular RMP elements may include opioid treatment
tive disorders.
agreements, unscheduled pill counts, and UDT.
3. Informed consent.
4. Treatment agreement.
5. Pre- and postintervention assessment of pain level and ‘‘Contracts’’/Agreements
function.
‘‘Opioid contracts’’ are also very reasonable when prescribing LTOT
6. Appropriate trial of opioid therapy ± ‘‘adjunctive’’
for patients with PNCP. However, they may not be necessary for all
medications.
patients in all settings. Therefore, the use of opioid contracts should
7. Reassessment of pain score and level of function.
be left to clinician judgment and/or policies.
8. Regularly assessment of the ‘‘Four A’s’’ (analgesia, activities
Elements of opioid contracts may include (Fig. 55–2)
of daily living, adverse effects, and aberrant drug-related
behaviors) of pain medicine. n Only one physician prescribing opioids while a patient is
9. Periodic review of pain diagnosis and comorbid conditions, being treated at a pain clinic.
including addictive disorders. n Use of only one pharmacy for medications.
10. Documentation. n Allow random drug (blood or urine) screens and/or pill counts.
The American Academy of Pain Medicine (AAPM) has a sample n Refill requests need to be made according to pain clinic policy
informed consent, ‘‘Consent for Chronic Opioid Therapy,’’ in both and not on nights or weekends.
Figure 55^1. (From American Academy of Pain

Medicine, Glenview, IL.)
Figure 55^1. cont’d (From American Academy of

Pain Medicine, Glenview, IL.)
n Selling, trading, or sharing opioids with anyone constitutes incorrectly utilized at times in a punitive manner to ‘‘catch’’ the
grounds for discontinuation of opioids and possible patient with an inappropriate positive or negative test. Unfortuna-
dismissal. tely, this often results in dismissal of the patient from the practice.
n Forged or abused prescriptions constitute grounds for dis- Whereas drug testing can be used in a variety of ways, it is most com-
continuation of opioids and dismissal. monly used for two quite different purposes: to identify substances
n Use of any illegal controlled substances (e.g., marijuana, that should not be present in the urine (forensic testing) and to detect
cocaine) constitutes grounds for discontinuation of opioids the presence of prescribed medications (compliance testing).
and possible dismissal. The use of UDT in efforts to monitor patients on LTOT treated
n Safeguarding opioids from loss or theft (lost or stolen opioids in a pain clinic is reasonable. UDT is not mandatory for all patients
will not be replaced). on LTOT in all settings. UDT should be utilized based on the clin-
n Agreement to take medications exactly as prescribed. ical judgment of the prescribing clinicians. However, some clini-
n All unused opioid medication are to be brought to the pain cians and/or clinics test all patients on LTOT sporadically based on
clinic at every visit. the policies of the pain clinic. Katz and Fanciullo58 proposed that,
although further research is needed, it may be easier and more
The AAPM has a sample treatment agreement, ‘‘Long-term uniform to conduct routine urine toxicology testing in patients
Controlled Substances Therapy for Chronic Pain,’’ in both with chronic pain treated with opioids.58 By adopting a uniform
English and Spanish on their website at www.painmed.org/product- policy of testing, stigma is reduced while ensuring that those per-
pub/statements. An extension of the traditional contract is the use sons dually diagnosed with pain and substance use disorders may
of a trilateral opioid contract, which is seen, agreed upon, and receive optimal care. With careful explanation of the purpose of
signed by the pain specialist, patient, and patient’s primary care testing, any patient concerns can be easily addressed.59,60 Caveats to
physician57 (see Fig. 55–2). the use of UDT include
1. Ensuring the proper collection, handling, and documentation
of the urine specimen (temperature [within 4 min of voiding]
UDT 908F to 1008F; urinary pH: 4.5 to 8.0; urinary creatinine
> 20 mg/dl)
The use of UDT in a noncancer pain practice is more common than
2. Being knowledgeable regarding interpretation of UDT results.
in oncology or primary care settings. However, it seems to be
3. Knowing exactly what your patient consumed and when it is Caution must be exercised when interpreting UDT results in
consumed prior to the urine collection. a pain practice. True-negative urine results for prescribed medica-
4. Knowing what you are looking for and what you will do tions may indicate a pattern of bingeing rather than drug diversion.
when various results come back. Time of last use of the drug(s) can be helpful in interpreting UDT
results.
One of the most common urinary drug ‘‘screens’’ involves flu- In certain cases, UDT may detect traces of unexplained opioids
orescence polarization immunoassay (FPIA), which detects the secondary to drug metabolism. For example, a patient taking
‘‘Federal Five’’ of marijuana, cocaine, opiates, phencyclidine, and codeine may show trace quantities of hydrocodone (11%) that is
amphetamines/methamphetamines. This test has a relatively low unrelated to hydrocodone use.62 Detection of minor amounts of
sensitivity for semisynthetic and synthetic opioids (e.g., hydroco- hydrocodone in urine containing a high concentration of codeine
done, oxycodone, fentanyl). Therefore, if the test on the patient’s should not be interpreted as evidence of hydrocodone misuse. In the
urine is negative for the presence of the drug, it does not exclude case of a patient who is prescribed hydrocodone, quantities of hy-
patient use. Furthermore, even if the test is positive for a specific dromorphone may also be detected owing to hydrocodone metab-
drug, a confirmatory test should follow. The confirmatory urine olism.59 Morphine may be metabolized to produce small amounts of
drug test is based on principles of gas chromatography and mass hydromorphone (10%) through a minor metabolic pathway.63
spectrometry (GC-MS), or high-performance liquid chromatogra-
phy (HPLC). GC-MS is considered to be the ‘‘gold standard.’’
The health care professional must know which drugs to test Aberrant Drug-Taking Behaviors
for and by what methods, as well as the expected use of the results.
If the purpose of testing is to find unprescribed or illicit drug use, Although aberrant drug-taking behaviors should not automatically
combination techniques such as GC-MS or HPLC are the most point clinicians toward suspecting addiction, ongoing assessments
specific for identifying individual drugs or their metabolites.61 of drug-taking behavior (one of the Four A’s), in part by ‘‘keeping
Figure 55^2. (From American Academy of Pain

Medicine, Glenview, IL.)
Figure 55^2. cont’d (From American Academy of

Pain Medicine, Glenview, IL.)
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opioid side effects in cancer-related and chronic noncancer pain: a 51. Compton P, Darakjian J, Miotto K. Screening for addiction in
systematic review. J Pain 2003;4:231–256. patients with chronic pain and a ‘‘problematic’’ substance use:
27. Staats PS, Markowita J, Schein J. Incidence of constipatiom associated evaluation of a pilot assessment tool. J Pain Symptom Manage
with long-acting opioid therapy: a comparative study. South Med 1998;16:355–363.
J 2004;97:129–134. 52. Coambs RB, Jarry JL. The SISAP: a new screening instrument for
28. Van Seventer R, Smit JM, Schipper RM, et al. Comparison of identifying potential opioid abusers in the management of chronic
TTS-fentanyl with sustained-release oral morphine in the treatment nonmalignant pain in general medical practice. Pain Res Manage
of patients not using opioids for mild-to-moderate pain. Curr Med 1996;1:155–162.
Res Opin 2003;19:457–468. 53. Butler SF, Budman SH, Fernandez K, Jamison RN. Validation of a
29. Allan L, Richarz U, Simpson K, et al. Transdermal fentanyl sustained screener and opioid assessment measure for patients with chronic
release oral morphine in strong-opioid naı̈ve patients with chronic pain. Pain 2004;112:65–75.
back pain. Spine 2005;30:2484–2490. 54. Butler SF, Budman SH, Fernandez KC, et al. Development and
30. Smith HS, McCleane G. Optimizing pharmacologic outcomes: validation of the Current Opioid Misuse Measure. Pain
assessing and managing opioid side effects. In Smith HS (ed): 2007;130:144–156.
Opioid Therapy in the 21st Century, New York: Elsevier, 2008; 55. Gourlay D, Heit H. Universal precautions: a matter of mutual trust
pp 47–58. and responsibility. Pain 2006;7:210.
31. Schindler SD, Ortner R, Peternell A, et al. Maintenance therapy 56. Gourlay DL, Heit HA. Universal precautions in pain medicine: a
with synthetic opioids and driving aptitude. Eur Addict Res rational approach to the treatment of chronic pain. Pain Med
2004;10:80–87. 2005;6:107.
32. Sabatowski R, Schwalen S, Rettig K, et al. Driving ability under long- 57. Fishman SM, Mahajan G, Jung SW, et al. The trilateral opioid contract.
term treatment with transdermal fentanyl. J Pain Sympt Manage Bridging the pain clinic and the primary care physician through the
2003;25:38–47. opioid contract. J Pain Symptom Manage 2002;24:335–344.
58. Katz N, Fanciullo G. Role of urine toxicology testing in the 64. Wu SM, Compton P, Bolis R, et al. The Addiction Behaviors
management of chronic opioid therapy. Clin J Pain 2002;18:576–582. Checklist: validation of a new clinician-based measure of
59. Urine Drug Testing in Primary Care: dispelling the myths & designing inappropriate opioid use in chronic pain. J Pain Symptom Manage
strategies. Pharmacom Grp, 2002. Available at http:// 2006;32:342–351.
www.familydocs.org/assets/Professional_Development/CME/UDT.pdf
60. Heit HA, Gourlay DL. Urine drug testing in pain medicine. J Pain SUGGESTED READINGS
Symptom Manage 2004;27:260–267.
61. Vandevenne M, Vandenbussche H, Verstraete A. Detection time of Smith HS (ed). Opioid Therapy in the 21st Century. New York: Oxford
drugs of abuse in urine. Acta Clin Belg 2000;55:323–333. University Press, 2008.
62. Oyler JM, Cone EJ, Joseph RE Jr, Huestis MA. Identification of Smith HS, Passik SD (eds). Pain and Chemical Dependency. New York:
hydrocodone in human urine following controlled codeine Oxford University Press, 2008.
administration. J Anal Toxicol 2000;24:530–535. Smith HS, Fine PG, Passik SD (eds). Opioid Risk Management: Tools and
63. Cone EJ, Heit HA, Caplan YH, et al. Evidence of morphine Tips-Pocket News. New York: Oxford University Press, 2008.
metabolism to hydromorphone in pain patients chronically treated
with morphine. J Anal Toxicol 2006;30:1–5.
Chapter 56 of opioid receptors, such that the response to a given con-

centration of an opioid analgesic is reduced. Increasing
OPIOID TOLERANCE, evidence suggests that at least a critical part of the
mechanism related to this type of tolerance involves the
N-methyl-D-aspartate (NMDA) receptor.1-7
DEPENDENCE, AND n Pharmacokinetic tolerance refers to changes in the distribu-
tion or metabolism of an opioid after its repeated admin-
HYPERALGESIA istration that results in reduced opioid concentrations in
the blood and/or at the sites of drug action. The most
Lucy Chen and Jianren Mao common mechanism of this phenomenon is an increased
rate of opioid metabolism. Of note is that pharmacokinetic
factors may also contribute to an increased or prolonged
opioid analgesic effect through the active metabolites of
opioids such as morphine.
n Learned tolerance refers to a reduction in the opioid effects
resulting from conditioned or associative tolerance. This
INTRODUCTION form of tolerance is a learned mechanism that develops
when environmental cues are consistently paired with the
Over the last several decades, opioids have been successfully used opioid administration. If the opioid is taken under a novel
for the management of acute pain as well as chronic and cancer- circumstance, its effect might be enhanced and the learned
related pain. However, a number of issues with opioid therapy have tolerance would be reduced.
presented practical challenges in the clinical setting. Concerns
regarding side effects, tolerance, dependence, addiction, and The clinical relevance and utility of these classifications remain to be
opioid-induced hyperalgesia have somewhat limited the use of seen. However, understanding various aspects of opioid toler-
opioids for the management of pain. ance may aid the investigation into the mechanisms of opioid
tolerance.
Dependence: Physical dependence is characterized by a constella-
tion of clinical symptoms and signs upon withdrawal (absti-
CURRENT DIAGNOSIS AND nence) from opioids after their use. Physical dependence on
DEFINITIONS (Box 56–1) opioids should not be confused with addiction.
Addiction: Opioid addiction is a subset of substance abuse disorders
characterized by the symptoms manifesting as persistent use of
Tolerance: Opioid tolerance is a pharmacologic phenomenon in the opioid despite significant substance-related problems. In the
which repeated exposure to an opioid results in a decreased context of pain treatment, patients with opioid addiction may
therapeutic effect or the need for a higher dose to maintain demonstrate any of the following: (1) impaired ability to control
the same effect. There are several aspects of opioid analgesic the use of opioid; (2) using opioids for an effect other than pain
tolerance: relief; (3) requesting opioids or opioid dose escalation despite
n Innate tolerance is related to the genetically determined sen- the evidence of adequate analgesia; (4) drug-seeking behaviors
sitivity, or lack of sensitivity, to an opioid observed during the (e.g., multiple opioid prescription providers, unexplainable loss
first administration. of opioid prescriptions, or multiple episodes of early refills).
n Acquired tolerance can be divided into pharmacodynamic, Pseudoaddiction: Pseudoaddiction refers to ‘‘abnormal behaviors’’
pharmacokinetic, and learned tolerance. as a direct consequence of inadequate pain control. These beha-
viors are similar to those seen with addiction. Some physicians
n Pharmacodynamic tolerance refers to the adaptive changes consider this term to be a description of an iatrogenic cause of
within the systems affected by an opioid, including opioid- inadequate pain management with opioid analgesics. The pseu-
induced changes in the receptor density or desensitization doaddiction developed through three characteristic phases
58. Katz N, Fanciullo G. Role of urine toxicology testing in the 64. Wu SM, Compton P, Bolis R, et al. The Addiction Behaviors
management of chronic opioid therapy. Clin J Pain 2002;18:576–582. Checklist: validation of a new clinician-based measure of
59. Urine Drug Testing in Primary Care: dispelling the myths & designing inappropriate opioid use in chronic pain. J Pain Symptom Manage
strategies. Pharmacom Grp, 2002. Available at http:// 2006;32:342–351.
www.familydocs.org/assets/Professional_Development/CME/UDT.pdf
60. Heit HA, Gourlay DL. Urine drug testing in pain medicine. J Pain SUGGESTED READINGS
Symptom Manage 2004;27:260–267.
61. Vandevenne M, Vandenbussche H, Verstraete A. Detection time of Smith HS (ed). Opioid Therapy in the 21st Century. New York: Oxford
drugs of abuse in urine. Acta Clin Belg 2000;55:323–333. University Press, 2008.
62. Oyler JM, Cone EJ, Joseph RE Jr, Huestis MA. Identification of Smith HS, Passik SD (eds). Pain and Chemical Dependency. New York:
hydrocodone in human urine following controlled codeine Oxford University Press, 2008.
administration. J Anal Toxicol 2000;24:530–535. Smith HS, Fine PG, Passik SD (eds). Opioid Risk Management: Tools and
63. Cone EJ, Heit HA, Caplan YH, et al. Evidence of morphine Tips-Pocket News. New York: Oxford University Press, 2008.
metabolism to hydromorphone in pain patients chronically treated
with morphine. J Anal Toxicol 2006;30:1–5.
Chapter 56 of opioid receptors, such that the response to a given con-

centration of an opioid analgesic is reduced. Increasing
OPIOID TOLERANCE, evidence suggests that at least a critical part of the
mechanism related to this type of tolerance involves the
N-methyl-D-aspartate (NMDA) receptor.1-7
DEPENDENCE, AND n Pharmacokinetic tolerance refers to changes in the distribu-
tion or metabolism of an opioid after its repeated admin-
HYPERALGESIA istration that results in reduced opioid concentrations in
the blood and/or at the sites of drug action. The most
Lucy Chen and Jianren Mao common mechanism of this phenomenon is an increased
rate of opioid metabolism. Of note is that pharmacokinetic
factors may also contribute to an increased or prolonged
opioid analgesic effect through the active metabolites of
opioids such as morphine.
n Learned tolerance refers to a reduction in the opioid effects
resulting from conditioned or associative tolerance. This
INTRODUCTION form of tolerance is a learned mechanism that develops
when environmental cues are consistently paired with the
Over the last several decades, opioids have been successfully used opioid administration. If the opioid is taken under a novel
for the management of acute pain as well as chronic and cancer- circumstance, its effect might be enhanced and the learned
related pain. However, a number of issues with opioid therapy have tolerance would be reduced.
presented practical challenges in the clinical setting. Concerns
regarding side effects, tolerance, dependence, addiction, and The clinical relevance and utility of these classifications remain to be
opioid-induced hyperalgesia have somewhat limited the use of seen. However, understanding various aspects of opioid toler-
opioids for the management of pain. ance may aid the investigation into the mechanisms of opioid
tolerance.
Dependence: Physical dependence is characterized by a constella-
tion of clinical symptoms and signs upon withdrawal (absti-
CURRENT DIAGNOSIS AND nence) from opioids after their use. Physical dependence on
DEFINITIONS (Box 56–1) opioids should not be confused with addiction.
Addiction: Opioid addiction is a subset of substance abuse disorders
characterized by the symptoms manifesting as persistent use of
Tolerance: Opioid tolerance is a pharmacologic phenomenon in the opioid despite significant substance-related problems. In the
which repeated exposure to an opioid results in a decreased context of pain treatment, patients with opioid addiction may
therapeutic effect or the need for a higher dose to maintain demonstrate any of the following: (1) impaired ability to control
the same effect. There are several aspects of opioid analgesic the use of opioid; (2) using opioids for an effect other than pain
tolerance: relief; (3) requesting opioids or opioid dose escalation despite
n Innate tolerance is related to the genetically determined sen- the evidence of adequate analgesia; (4) drug-seeking behaviors
sitivity, or lack of sensitivity, to an opioid observed during the (e.g., multiple opioid prescription providers, unexplainable loss
first administration. of opioid prescriptions, or multiple episodes of early refills).
n Acquired tolerance can be divided into pharmacodynamic, Pseudoaddiction: Pseudoaddiction refers to ‘‘abnormal behaviors’’
pharmacokinetic, and learned tolerance. as a direct consequence of inadequate pain control. These beha-
viors are similar to those seen with addiction. Some physicians
n Pharmacodynamic tolerance refers to the adaptive changes consider this term to be a description of an iatrogenic cause of
within the systems affected by an opioid, including opioid- inadequate pain management with opioid analgesics. The pseu-
induced changes in the receptor density or desensitization doaddiction developed through three characteristic phases
422 Chapter 56 OPIOID TOLER ANCE, DEPENDENCE, AND HYPER ALGESIA
5. Opioid actions may be negatively modulated by cholecysto-

Box 56^1 CURRENT DIAGNOSIS kinin, an endogenous neuropeptide, within the central ner-
vous system. In animal studies, morphine-6-glucuronide
Tolerance (M6G) and morphine-3-glucuronide (M3G), two active mor-
Opioid tolerance is a pharmacologic phenomenon in which repeated
exposure to an opioid results in a decreased therapeutic effect or the phine metabolites, may potentiate and reduce the analgesic
need for a higher dose to maintain the same effect. effects of m opioid agonists, respectively.
6. Recently, an interesting observation has been made with
Dependence regard to the relationship between opioid tolerance and neu-
Physical dependence is characterized by a constellation of clinical symp-
ropathic pain.4,5 A number of studies indicated similarities in
toms and signs upon withdrawal (abstinence) from opioids after their
use.Withdrawal symptoms and signs include the cellular and molecular mechanisms between opioid tol-
erance and neuropathic pain.5 Those findings may explain, at
least in part, the reduced efficacy of opioid analgesics in
Fatigue Coryza Lacrimation treating neuropathic pain and a possible increase in pain
Yawning Pupillary dilatation Piloerection sensitivity after a prolonged exposure to opioid analgesics.
Diaphoresis Increased anxiety Tachycardia These studies also raise the possibility that clinically available
Nausea Diarrhea Abdominal cramping NMDA receptor antagonists may be beneficial for reducing
pathologic pain and preventing opioid tolerance.4,5
Vomiting Insomnia Increased sensitivity to pain
Opioid-induced Hyperalgesia
Opioid administration may induce a paradoxical increase in pain sensitiv-
ity including hyperalgesia (enhanced painful response to noxious stimuli)
and/or allodynia (painful response elicited by innocuous stimuli). CLINICAL FEATURES OF OPIOID
TOLERANCE, DEPENDENCE,
AND HYPERALGESIA
including (1) inadequate prescription of analgesics to meet the In the clinical setting, apparent tolerance to opioids is reflected by
primary pain stimulus; (2) escalation of analgesic demands by a reduction of the opioid analgesic effect, which results in the esca-
the patient associated with behavioral changes to convince lation of the opioid dose in order to achieve equal analgesic effects.7
others of the severity of pain; and (3) a crisis of mistrust between Besides analgesic tolerance, tolerance to the side effects of opioids
the patient and the health care team. such as constipation and respiratory depression can also occur,
Opioid-induced hyperalgesia: Opioid administration may induce a although tolerance to side effects appears to be less likely than anal-
paradoxical increase in pain sensitivity including hyperalgesia gesic tolerance.7 However, not all increases in opioid use are due to
(enhanced painful response to noxious stimuli) and/or allodynia the development of pharmacologic tolerance. For example, disease
(painful response elicited by innocuous stimuli). This phenom- progression and/or psychological issues (e.g., anxiety or depression)
enon may be seen with acute or chronic administration of could lead to the escalation of opioid use as well.
opioids, particularly in high doses. Physical dependence is a reflection of neurophysiologic adapta-
tion, believed to occur at peripheral and central neurons as a result
of changes induced in opioid receptors. Clinical symptoms and
signs of physical dependence usually appear after explicit or implicit
MECHANISMS OF OPIOID TOLERANCE withdrawal from opioids (see Box 56–1).
AND DEPENDENCE These symptoms and signs often peak at about 6 to 12 hours for
short-acting opioids and 48 to 72 hours for long-acting opioids
Over the last several decades, much seminal progress has been made after the initial withdrawal.7 Although life-threatening withdrawals
in exploring the mechanisms of opioid tolerance and dependence. rarely occur, withdrawal symptoms can be extremely uncomfortable
Some of the major findings are summarized as follows. and worrisome. In those patients receiving mixed opioid and ben-
zodiazepine treatment, possible withdrawal from benzodiazepines
1. Three major subtypes of opioid receptors, namely m-, d-, and
should always be considered because life-threatening seizures may
k-receptors, have been cloned. These receptors belong to a
occur in such circumstances.7
super family of G protein–coupled receptors. G-protein acti-
It is important to recognize that opioid withdrawal can be iatro-
vation serves as a coupling mechanism between opioid recep-
genic in many cases including (1) inappropriate dose conversion
tors and rectifying K+ channels, leading to cell membrane
from one opioid to another or from one route of drug administration
hyperpolarization under most circumstances. Accordingly,
to another, (2) too large a reduction of an opioid dose during a
the uncoupling between G protein and opioid receptors has
tapering process, (3) use of an opioid with mixed agonist-antagonist
been implicated in the mechanisms of opioid tolerance.1-7
properties after a prolonged opioid therapy, (4) abrupt discontinua-
2. Opioid receptors may be down-regulated after a prolonged
tion of an opioid, and (5) administration of an opioid antagonist.8-10
exposure to opioid receptor agonists. This may be seen as
It is challenging to distinguish pharmacologic tolerance from
changes in both receptor density and receptor affinity.
hyperalgesia when the efficacy of analgesia is usually based on sub-
3. The cyclic adenosine monophosphate (cAMP) and protein
jective pain scores. However, several features of opioid-induced
kinase A system may be up-regulated during the development
hyperalgesia observed in animal and human studies would be help-
of opioid tolerance as well as the process of opioid withdrawal.
ful in making some distinction between opioid-induced hyperalge-
4. Activation of the NMDA receptor, a subgroup of excitatory
sia and preexisting pain4,5,7:
glutamate receptors, has been implicated in the development
of opioid tolerance and dependence.7 Among three major 1. Because opioid-induced hyperalgesia would conceivably
opioid receptor subtypes, the role of the NMDA receptor in exacerbate a preexisting pain condition, pain intensity would
m opioid tolerance has been better established. The NMDA be increased above the level of preexisting pain after opioid
receptor–mediated activation of intracellular cascades such as treatment in the absence of apparent disease progression.
protein kinase C and nitric oxide may play a pivotal role in 2. Opioid-induced hyperalgesia would be diffuse, less defined in
the development of opioid tolerance and dependence.7 quality, and beyond the distribution of a preexisting pain
state, given that the underlying mechanisms of opioid-

induced hyperalgesia involve neural circuits and extensive Box 56^2 CURRENT THERAPY
cellular and molecular changes.
3. Quantitative sensory testing may reveal changes in pain Management of Opioid Tolerance
1. Increase the opioid dose by 15%^20% at each dose adjustment until a
threshold, tolerability, and distribution patterns associated good analgesia effect is achieved.
with the development of hyperalgesia. These parameters 2. Use opioid rotation.
may also help make distinctions between the exacerbation 3. Add a clinically available N-methyl-D-aspartate (NMDA) receptor
of preexisting pain and opioid-induced pain. antagonist.
4. Undertreatment of a preexisting pain or the development 4. Use adjuvant medications to target analgesia at different pain
of pharmacologic tolerance may be overcome by a trial of mechanisms.
opioid dose escalation. To the contrary, opioid-induced hyper- Management of Opioid-induced Hyperalgesia
algesia could be worsened after the increase in opioid doses. 1. Slowly decrease the opioid dose until hyperalgesia improves.
2. Consider opioid rotation.
The factors that may influence the development of opioid- 3. Use adjuvant pain medications to minimize the amount of opioid,
induced hyperalgesia remain to be investigated. First, the opioid thereby reducing the risk of worsening hyperalgesia.
dose range leading to opioid-induced hyperalgesia remains to be 4. Use clinically available NMDA receptor antagonists.
determined. Second, there may be differences between different Management of Withdrawal Signs and Symptoms
categories of opioid medications (e.g., morphine vs. methadone) 1. Restart the same opioid at the previous dose if the withdrawal symp-
or individual opioids in the same categories in terms of their ability toms are apparent.
to induce hyperalgesia. Third, the onset of opioid-induced hyper- 2. Gradually taper the opioid dose at a rate of 15%^20% every 3^7 days
algesia needs to be analyzed in the clinical setting. Conceivably, to prevent withdrawal if the treatment plan is to discontinue the
opioid-induced hyperalgesia would be more likely to develop in opioid.
3. Clonidine could be used to prevent and treat some withdrawal symp-
patients receiving high opioid doses with a sustained treatment toms and signs.
course. Fourth, if hyperalgesia occurs after treatment with one 4. Avoid using an opioid with mixed agonist-antagonist properties after
opioid, it would be of interest to know whether cross-hyperalgesia prolonged opioid therapy.
will occur to other opioids. 5. Avoid abruptly discontinuing opioids or administering an opioid antag-
onist during opioid therapy unless titrating ‘‘ultra-low’’ doses for the
treatment of opioid side effects.
APPROACH TOA PATIENTON AN

OPIOID REGIMEN WITHOUT
ADEQUATE PAIN RELIEF
dose adjustments may depend on the half-life of the opioid
In evaluating a patient on opioids but with inadequate pain relief, it and the disease state.
is important to consider several aspects of the differential diagnosis. 2. Use opioid rotation. It is believed that the cross-tolerance from
The clinical assessment of opioid tolerance, physical dependence, or one opioid to another may be incomplete in most cases. A dif-
opioid induced hyperalgesia should rely on (1) carefully evaluating ferent opioid could be used to replace the previous opioid.
the potential of disease progress, (2) reviewing the details of a pain- Empirically, the equipotent analgesia dose for the new opioid
medication regimen and compliance, (3) documenting other med- may be decreased by 30% to 40%.
ications potentially interacting with opioids, and (4) exploring pre- 3. A clinically available NMDA receptor antagonist (e.g., dextro-
existing progressed or newly developed psychiatric problems and methorphan, memantine, amantadine, and ketamine) could be
social issues. used in conjunction with an opioid. The dose of dextrometho-
Although it may prove difficult to determine clear clinical dis- phan could be 30 to 60 mg by mouth every 6 to 8 hours and
tinctions between true opioid pharmacologic tolerance and titrated up as tolerated to achieve the effect. Methadone is a
increased opioid demand secondary to other factors, every effort unique opioid that possesses an NMDA receptor antagonist
should be made to investigate the underlying causes. For example, effect. In some cases, methadone might be a better choice than
an increased pain state due to disease progression may be curtailed other long-acting opioids.
by appropriate adjunctive therapies such as radiation therapy in 4. The use of adjuvant medications to target different pain mechan-
cancer patients rather than increasing the opioid dose. In general, isms is also recommended, including acetaminophen, nonster-
escalation of opioid doses should not be made based simply on oidal anti-inflammatory drugs (NSAIDs), antidepressants,
changes in pain score. anticonvulsants, topical agents, and other neuropathic pain
At present, the differentiation between pharmacologic tolerance medications.8-10 For cancer-related pain, radiation therapy
and opioid-induced hyperalgesia remains unclear. It will not be and/or chemotherapy are often effective adjunctive therapies.
unreasonable to give a trial of opioid dose escalation if pain
is not under control with the current regimen. If the patient’s
pain improves, the cause of the pain is more likely to be
tolerance. However, if the patient’s pain worsens or does not con-
sistently respond to the dose escalation, it could be a result of MANAGEMENTOF OPIOID-INDUCED
opioid-induced hyperalgesia and the dose should be decreased or HYPERALGESIA (see Box 56–2)
weaned off.
1. Slowly decrease the opioid dose by 10% to 15% every 3 to 7 days
until hyperalgesia has improved.
2. Consider opioid rotation. Patients may get better pain relief
MANAGEMENTOF OPIOID TOLERANCE using a different opioid analgesic, often at a lower equianalgesic
(Box 56–2) dose.
3. Use adjuvant pain medications as stated previously to minimize
1. Increase the opioid dose by 15% to 20% at each dose adjustment the amount of opioid, thereby reducing the risk of worsening
until a good analgesia effect is achieved. The interval of such hyperalgesia. Such medications include acetaminophen, NSAIDs,
424 Chapter 57 GASTROINTESTINAL DYSFUNCTION WITH OPIOID USE
antidepressants, anticonvulsants, topical agents, and other neu- increased pain require a systematic evaluation of possible etiologies.
ropathic pain medications. There should be awareness that increasing opioid doses may not
4. Use clinically available NMDA receptor antagonists as discussed always be the answer to increased pain. Under certain circum-
previously. stances, less opioid may be more effective in achieving pain reduc-
tion. This approach may be combined with opioid rotation and/or
addition of nonopioid adjuvant medications. In addition, opioid
tolerance and opioid-induced hyperalgesia need to be differentiated
MANAGEMENTOF PHYSICAL from physical dependence, addiction, pseudoaddiction, and abuse.
DEPENDENCE AND WITHDRAWAL
SYMPTOMS (see Box 56–2) REFERENCES
1. Restart the same opioid at the previous dose if withdrawal symp- 1. Jaffe JH. Drug addiction and drug abuse. In Gilman AG, Goodman
toms are apparent. If the plan is to continue the opioid therapy LS, Rall TW, Murad F (eds): The Pharmacological Basis of
for pain management, the opioid dose may be adjusted to Therapeutics, 7th ed. New York: Macmillan, 1985; pp 532–581.
achieve adequate analgesia. 2. O’Brien CP. Drug addiction and drug abuse. In Hardman JG,
2. Gradually taper the opioid dose at a rate of 15% to 20% every Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis
3 to 7 days to prevent withdrawal if the treatment plan is to of Therapeutics, 9th ed. New York: McGraw-Hill, 1995; pp 557–577.
discontinue the opioid. 3. Weissman DE, Haddox JD. Opioid pseudoaddiction—an iatrogenic
3. Clonidine (Catapres; an a2-agonist; oral dose 0.2–0.4 mg/day; syndrome. Pain 1989;36:363–366.
transdermal dose 0.1–0.3 mg once every 7 days) can be used 4. Mao J, Price DD, Mayer DJ. Mechanism of hyperalgesia and opioid
tolerance, a current review of their possible interactions. Pain
to prevent and treat withdrawal symptoms and signs at an oral
1995;62:259–274.
dose of 0.2 to 0.4 mg/day (transdermal dose 0.1–0.3 mg once 5. Mao J. NMDA and opioid receptors: their interactions in
every 7 days). This treatment can be continued for 4 days for antinociception, tolerance and neuroplasticity. Brain Res Rev
short-acting opioids or up to 14 days for long-acting opioids. 1999;30:289–304.
4. Avoid using an opioid with mixed agonist-antagonist properties 6. Mao J, Chen L. Opioid tolerance and dependence. In Smith HS (ed):
after prolonged opioid therapy. Drugs for Pain. Philadelphia: Hanley & Belfus, 2002; pp 153–156.
5. Avoid abruptly discontinuing opioids or administering an 7. Chang G, Chen LL, Mao J. Opioid tolerance and hyperalgesia. Med
opioid antagonist during opioid therapy unless titrating ‘‘ultra- Clin North Am 2007;91:199–211.
low’’ doses for the treatment of side effects. 8. Elliott JA, Opper SE. Opioids: adverse effects and their management.
In Smith HS (ed): Drugs for Pain. Philadelphia: Hanley & Belfus,
2002; pp 133–151.
9. Savage SR. Opioid use in the management of chronic pain. Med Clin
SUMMARY North Am 1999;83:761–786.
10. Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-
In summary, opioid tolerance, dependence, and opioid-induced maintained former opiate addicts: effect of long-acting maintenance
hyperalgesia have been documented and contribute to the decreased agent. Drug Alcohol Depend 2001;63:139–146.
analgesic efficacy of opioids. In the clinical setting, complaints of
Chapter 57 and allow patients to benefit from opioid-induced analgesia.

Because the analgesic and gastrointestinal effects of opioids are
GASTROINTESTINAL mediated through the same classes of receptors, that is, m, d, and
k, it has been challenging to dissociate their beneficial analgesic
DYSFUNCTION WITH effects from the untoward gastrointestinal effects. The chapter
reviews the underlying pathophysiologic mechanisms of specific
gastrointestinal adverse effects of opioids and describes the possible
OPIOID USE treatment options to reduce these effects.
Sangeeta R. Mehendale and Chun-SuYuan

NAUSEA AND VOMITING
Nausea and vomiting are severe adverse effects of opioid adminis-
tration. Nausea is an essential component of the vomiting sensation;
however, it may occur without vomiting. Of the patients being
treated with opioids, 8% to 35% reported nausea and 14% to
INTRODUCTION 40% suffered from vomiting.
Opioids act at the chemoreceptor trigger zone (CTZ; area post-
Opioids are potent analgesics used extensively for treating moderate rema in the medulla), triggering emetic mechanisms mediated by
to severe pain caused by cancer or surgery. Although opioids offer the vomiting center in the medulla (Fig. 57–1). The area postrema is
excellent pain relief, their use is associated with bowel-related essential for opioid-induced vomiting, as demonstrated by animal
adverse effects, such as nausea, vomiting, and constipation, that studies in which ablation of the area postrema eliminated the emetic
severely compromise patients’ quality of life. It is, therefore, impor- response to opioids. The blood-brain barrier in the area postrema is
tant to reduce the impact of these adverse effects on patients’ lives not complete, and therefore, the area postrema is pharmacologically
antidepressants, anticonvulsants, topical agents, and other neu- increased pain require a systematic evaluation of possible etiologies.
ropathic pain medications. There should be awareness that increasing opioid doses may not
4. Use clinically available NMDA receptor antagonists as discussed always be the answer to increased pain. Under certain circum-
previously. stances, less opioid may be more effective in achieving pain reduc-
tion. This approach may be combined with opioid rotation and/or
addition of nonopioid adjuvant medications. In addition, opioid
tolerance and opioid-induced hyperalgesia need to be differentiated
MANAGEMENTOF PHYSICAL from physical dependence, addiction, pseudoaddiction, and abuse.
DEPENDENCE AND WITHDRAWAL
SYMPTOMS (see Box 56–2) REFERENCES
1. Restart the same opioid at the previous dose if withdrawal symp- 1. Jaffe JH. Drug addiction and drug abuse. In Gilman AG, Goodman
toms are apparent. If the plan is to continue the opioid therapy LS, Rall TW, Murad F (eds): The Pharmacological Basis of
for pain management, the opioid dose may be adjusted to Therapeutics, 7th ed. New York: Macmillan, 1985; pp 532–581.
achieve adequate analgesia. 2. O’Brien CP. Drug addiction and drug abuse. In Hardman JG,
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Chapter 57 and allow patients to benefit from opioid-induced analgesia.

Because the analgesic and gastrointestinal effects of opioids are
GASTROINTESTINAL mediated through the same classes of receptors, that is, m, d, and
k, it has been challenging to dissociate their beneficial analgesic
DYSFUNCTION WITH effects from the untoward gastrointestinal effects. The chapter
reviews the underlying pathophysiologic mechanisms of specific
gastrointestinal adverse effects of opioids and describes the possible
OPIOID USE treatment options to reduce these effects.
Sangeeta R. Mehendale and Chun-SuYuan

NAUSEA AND VOMITING
Nausea and vomiting are severe adverse effects of opioid adminis-
tration. Nausea is an essential component of the vomiting sensation;
however, it may occur without vomiting. Of the patients being
treated with opioids, 8% to 35% reported nausea and 14% to
INTRODUCTION 40% suffered from vomiting.
Opioids act at the chemoreceptor trigger zone (CTZ; area post-
Opioids are potent analgesics used extensively for treating moderate rema in the medulla), triggering emetic mechanisms mediated by
to severe pain caused by cancer or surgery. Although opioids offer the vomiting center in the medulla (Fig. 57–1). The area postrema is
excellent pain relief, their use is associated with bowel-related essential for opioid-induced vomiting, as demonstrated by animal
adverse effects, such as nausea, vomiting, and constipation, that studies in which ablation of the area postrema eliminated the emetic
severely compromise patients’ quality of life. It is, therefore, impor- response to opioids. The blood-brain barrier in the area postrema is
tant to reduce the impact of these adverse effects on patients’ lives not complete, and therefore, the area postrema is pharmacologically
Several other therapeutic and experimental alternatives

OPIOIDS
have been proposed to reduce the incidence of opioid-induced
nausea and vomiting (e.g., aprepitant). The use of opioid antago-
nists that block only the peripheral actions of opioids have shown
Limit peripheral
action Peripheral
reduction in the severity of nausea. Intrathecal use of highly lipo-
Central
e.g. peripheral actions actions philic opioid agents such as lofentanil results in rapid local absorp-
opioid antagonist tion of the drug, which could reduce the adverse effects of opioids.
Supplementing emesis-inducing opioids with k opioid agonists may
be a possible alternative to providing analgesia while reducing
CTZ ↓ Gastrointestinal Sensory nausea and vomiting. k-agonists appear not only to be devoid of
stimulation motility input to emetic effects but also to possess antiemetic activity and have been
μ+, δ+ μ+, δ+, κ? brainstem used clinically to treat nausea in dyspeptic patients.
CONSTIPATION
Vomiting center
μ–, κ– Constipation, a major symptom of bowel malfunction, manifests
as straining, difficulty in evacuation of stools, hardened dried
stools, and abdominal distention. Opioid-induced constipation is
Nausea and
found in 40% to 50% of patients who are treated with morphine,
vomiting making it a significant adverse effect of opioids.
Opioid-induced constipation is seen even with a single admin-
Figure 57^1. Opioids mediate nausea and vomiting by peripheral istration of morphine. The dose of opioids that induces constipa-
and central mechanisms.Various components of the pathway may tion is much smaller than that required for analgesia; thus,
be affected by specific opioid receptors. Other factors outside the using lower doses of opioids will not prevent constipation. With
gastrointestinal system (not included in the schematic) such as repeated exposure to morphine, tolerance does not develop to con-
opioid-induced increased vestibular sensitivity may also stimulate stipation as it does to other effects such as analgesia. Tolerance
nausea and vomiting. +, denotes that receptor stimulation stimulates development may be linked to the existence of subtypes of
effect; ^, denotes that receptor stimulation inhibits effect; CTZ, m-receptors that mediate various pharmacologic actions. It appears
chemoreceptor trigger zone. Higher concentrations of m agonists that tolerance develops more readily to m1-dependent actions than
demonstrate both emetic and antiemetic actions. to non–m1-dependent actions. Another hypothesis suggests that
P glycoprotein (the drug efflux protein) up-regulation is required
for tolerance development. Morphine induces P glycoprotein
considered a peripheral compartment. Thus, opioid antagonists up-regulation in the brain, but it does not up-regulate intestinal
with peripherally restricted action could block the emetic effect of P glycoprotein.
morphine without compromising the analgesic effect. m-receptors Centrally administered opioid peptides influence colonic activ-
present in the CTZ probably mediate the response to opioid com- ity; however, opioid-induced peripheral regulation of colonic func-
pounds, although research in this area has been sparse. d-receptors tion appears to be more important. Prolonged retention of
could also partly mediate the emetic response because receptors to morphine in the intestinal tissue after intravenous administration
enkephalin, an endogenous d-opioid receptor agonist, have been suggests that it may exert local effects on the enteric nervous system
demonstrated in the CTZ in dogs. Interestingly, m-agonists, at and intestines. The overall constipating effect of opioids results
higher doses, and k-agonists serve as antiemetics by acting down- from reduced intestinal motility and increased fluid reabsorption
stream from the area postrema on the vomiting center. The mech- in the intestines. These effects are, to a great extent, mediated by
anism of opioid-induced emesis is still not completely clear and stimulation of opioid receptors in the enteric nervous system. The
may involve release of neurotransmitters such as dopamine in the increased contractile activity of the circular muscle layer of colon,
CTZ. Also, opioids such as morphine are known to increase vestib- owing to the presence of receptors on myocytes in this layer, results
ular sensitivity, which may in turn cause nausea and vomiting and in frequent segmenting, nonpropulsive contractions and in
also explain the higher incidence of these symptoms in ambulatory increased intestinal transit time. The inhibitory effect of opioid
patients. agonists on the ileocecal sphincter and defecation reflexes also con-
In addition to the effect of opioid agonists on the CTZ, the other tributes to opioid-induced constipation.
actions of opioids result in inhibition of gastric motility and delay m-agonists decrease intestinal motility when administered cen-
in gastric emptying, with a predominant m-receptor involvement. trally and spinally. Central d- and k-receptors mediate the inhibi-
Morphine, even at lower doses, slows gastric emptying in humans. tion of colonic motility in different species. Also, when
Like morphine, d-agonists also cause delayed gastric emptying. administered intrathecally, k-opioid receptor agonists are effective
Effects of k-agonists on gastric emptying appear to be unclear. in inhibiting intestinal motility. In cats, prejunctional inhibitory
Overall, the inhibitory gastric effects of opioid agonists could con- d-receptors, present on the sacral parasympathetic outflow to
tribute to nausea and vomiting by activating gastrointestinal colon, caused inhibition of colonic activity. Thus, when opioids
mechanoreceptors that convey signals to the vomiting center via are administered centrally or intrathecally, they mediate inhibition
the vagal afferents. The vagal input to the vomiting center may be of colonic motility irrespective of the class of opioid receptor
only complementary to the direct stimulation of the CTZ by opioids evaluated.
in producing nausea and vomiting. The effects of peripherally administered opioids on the large
Opioid-stimulated nausea and vomiting is mainly of concern intestine vary according to the species and the segment of the
only with acute or short-term opioid administration, becuase tol- colon studied. m-agonists administered peripherally generally inhi-
erance develops to this effect within days. Generally, it is considered bit intestinal motility. Peripherally administered d- and k-agonists
advisable to reduce the risk of causing these opioid-induced symp- decreased colonic activity in rabbits and guinea pigs; however,
toms by avoiding medications with side effects of nausea and vom- k-agonists do not inhibit intestinal transit in rats, suggesting a
iting. Opioid-induced nausea and vomiting is prevented by species-dependent distribution of specific opioid receptors.
dexamethasone or droperidol and treated by 5HT-3 antagonists. Differential distribution of m-, d-, and k-receptors in human
intestines has also been demonstrated and may result in varied has been suggested to reduce constipation. Nitric oxide precursor,
intestinal responses to specific agonists. Opioid receptor distribu- which reverses morphine-induced constipation by acting locally in
tion locally in the intestines and their significant involvement in the the gut, has been proposed to combat opioid-induced constipation
mediation of the pharmacologic effects of opioids afford a mecha- without interference with its central analgesic activity.
nism to modulate those effects without compromising analgesia
(primarily a central opioid effect).
This understanding of the pathophysiologic mechanism of Newer Opioid Compounds
opioid-induced constipation has led to novel therapeutic possibili-
ties for improving the slow gastrointestinal transit. In addition to Two selective peripheral opioid receptor antagonists, methylnal-
currently used opioid rotation and mixed agonists-antagonists, trexone and alvimopan, are currently being investigated for their
other possibilities are enumerated later in this section. efficacy in reducing gastrointestinal adverse effects of opioid
analgesics.
The effect of methylnaltrexone was investigated in chronic
Route of Administration methadone subjects with opioid-induced constipation in a con-
trolled clinical trial. Intravenous administration of methylnaltrex-
Use of transdermal fentanyl patch, when compared with oral mor- one induced bowel movement and significantly decreased
phine, produced a decrease in constipation, as suggested by reduced the orocecal transit time compared with the placebo group
laxative use in the fentanyl-treated group. Thus, a change in the (Fig. 57–2). The dose of 0.1 mg/kg methylnaltrexone used in the
route of administration of this lipophilic opioid agonist may min- study was effective in methadone users versus 0.45 mg/kg in opioid-
imize constipation by reducing the peripheral adverse effects while naı̈ve subjects observed in earlier trials. Knowing that chronic
maintaining analgesic efficacy. opioid users have increased sensitivity to opioid antagonists
is important in clinical practice. To date, two successful phase
3 methylnaltrexone trials have been completed in chronic opioid
Combination with Other Medications users with advanced medical illness. Subcutaneous methylnaltrex-
one significantly reversed chronic opioid-induced constipation, and
Opioids could be used in smaller doses when combined with other no opioid withdrawal symptoms and no reduction of opioid anal-
classes of drugs, such as clonidine, that complement their analgesic gesic effects were observed. These results further demonstrate that
activity. Use of adjuncts such as selective serotonin reuptake inhi- methylnaltrexone is a peripheral actively opioid antagonist, and
bitors can increase morphine-induced analgesia while countering constipation is predominantly a peripherally mediated mechanism
constipation by increasing concentration of serotonin in the gut in humans.
(increased serotonin could, however, stimulate nausea and vomit- Newer agonist compounds like dihydroetorphine hydrochloride
ing). The use of adjuvant drugs, which reduce pain through non- reduce the incidence of constipation significantly. Using highly
opioid pathways (e.g., non-steroidal anti-inflammatory drugs, lipid-soluble opioid agonists for spinal anesthesia has been pro-
antipsychotics, and benzodiazepines) as a supplement to morphine posed to minimize the central gastrointestinal effects of opioids.
210 210
180 180
Oral-cecal transit time (min)
Oral-cecal transit time (min)
150 150
120 120
90 90
60 60
30 30
A Baseline After placebo
Baseline B After MNTX
Figure 57^2. Changes in oral-cecal transit time measured using hydrogen breath test (after a lactulose meal) in chronic
methadone subjects. The transit times in subjects in the placebo group (A) and methylnaltrexone group (B) at baseline and after injection are
shown.The average change in transit time (thick line) in the methylnaltrexone group was significantly greater than that in the placebo group.
(A and B, Adapted fromYuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone for reversal ofconstipation due to chronic methadone use: a randomized
controlled trial.JAMA 2000;283:367^372.)
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Chapter 58 prostaglandin production was 10 times more sensitive to inhibition

by APAP than spleen prostaglandin production. Simmons and cow-
ACETAMINOPHEN orkers in 19995 published the discovery of a new COX isoenzyme
(COX-3) (a novel COX-1 splice variant) in canine that was puta-
Howard S. Smith and Mike A. Royal tively the specific target of APAP. This was quickly generalized to
humans and rodents without critical evaluation of the data, and
COX-3 was advanced by some to be the mechanism of action for
APAP.6 Although COX-3 may have COX activity in canines, and
this activity may be inhibited by APAP, its low expression level and
the kinetics make clinical relevance in humans uncertain and con-
INTRODUCTION troversial.6 Ayoub and associates7 still maintain that the mechan-
isms of APAP-induced analgesia in rodents are mediated in part
Acetaminophen (APAP) is one of the most widely used of all drugs from inhibition of COX-3.
and is still considered a first-line analgesic agent for treating many APAP’s proposed actions as a weak inhibitor of prostaglandin
mild to moderate acute and chronic pain states. APAP has been the synthesis have been advanced from work in broken cell systems8;
overwhelming favorite first-line drug for the pain of osteoarthritis, however, it appears that therapeutic concentrations of APAP sig-
despite many currently available therapeutic options, and remains nificantly inhibit prostaglandin synthesis in intact cells and tissues.
the top-selling over-the-counter antipyretic and analgesic drug in Graham and Scott9 reported that the pharmacologic effects of
the United States. APAP are similar to those of selective COX-2 inhibitors and pro-
It often is used both as a sole agent for pain relief and in con- posed that the target of APAP is COX-2. Kis and colleagues10 con-
junction with other analgesics (e.g., opioids, nonsteroidal anti- curred with this view and found that APAP dose-dependently
inflammatory drugs [NSAIDs]). Clinicians also tend to favor inhibited both basal and lipopolysaccharide (LPS)-induced prosta-
APAP over aspirin or NSAIDs in patients with aspirin-sensitive glandin E2 (PGE2) production in cerebral endothelial cells
asthma or a history of aspirin or NSAID hypersensitivity, at signif- with inhibitory concentration of 50% (IC50) values of 15.5 and
icant increased risk of gastrointestinal mucosal insult, at increased 6.9 mM, respectively. LPS stimulation increased the expression of
risk of bleeding, with multiple concurrent drug therapy, and at COX-2 (but not COX-1 or COX-3), and the selective COX-2 inhib-
increased risk of renal insult. itor NS398 was equally as effective as APAP in blocking
Clinical research has shown efficacy for APAP in multiple pain LPS-induced PGE2 production.10 Kis and colleagues6,10 suggested
states including arthritis pain, headache, post–oral surgery pain, that APAP acts against COX-2 (but not COX-1 or COX-3).
episiotomy pain, orthopedic surgery pain, menstrual pain or dys- Therefore, it seems that at least one mechanism contributing to
menorrhea, postimmunization muscle aches and pain, cancer pain, APAP’s analgesic qualities may be its preferential inhibition of
and osteoarthritis.1 The American Geriatrics Society Clinical COX-2. Lee and coworkers11 suggested that APAP is a selective
Practice Guidelines2 for the management of chronic pain in older COX-2 inhibitor in vivo. The molecular mechanism of APAP’s
persons recommend APAP as the drug of choice for relieving mild COX-2 inhibition remains uncertain. It may be that, at least in
to moderate musculoskeletal pain. No dose adjustment is necessary part, APAP reduces the ‘‘active’’ oxidized form of COX back to
in the elderly (maximum daily dose is 4000 mg).2 the catalytically inactive state.12,13 Thus, environments with high
APAP was developed as a drug by von Mehring in 1893, but it levels of oxidants (e.g., inflamed tissue with high levels of perox-
did not become widely used until 1949. APAP (known in Europe as idase) would tend to decrease this effect (perhaps accounting in part
paracetamol) is an aniline derivative. Aniline derivatives (occasion- for the even weaker anti-inflammatory effects of APAP in inflam-
ally referred to as coal tar analgesics) are strong antipyretics that mation). Conversely, environments with low levels of oxidants
may exert their antipyretic effects on the thermoregulatory center of (e.g., brain) would tend to potentiate APAP’s selective COX-2
the hypothalamus. Aniline can lead to formation of methemoglobin inhibition. Multiple investigators advanced the theory that nitric
and methemoglobinemia in large doses. The hydroxylated anilines oxide generation and/or serotonergic mechanisms play a role in
(ortho [o], meta [m], and para [p]) are known as aminophenols. the analgesia produced from APAP. Bonnefont and colleagues14
p-Aminophenol (a metabolite of aniline) is the least toxic of the proposed that the inhibition of COX activities is not the exclusive
three. Early attempts to reduce toxicity of p-aminophenol (phena- mechanism involved in APAP-induced antinociception and sug-
cetin) involved the acetylation of the amine group, yielding gested that the serotonergic system (via spinal mechanisms) may
N-acetyl-p-aminophenol (APAP) (Fig. 58–1). This compound has contribute to APAP-induced analgesia. They proposed that the
seemed to be the safest; however, it still contains the free amino mechanisms of APAP-produced antinociception may involve
group, and the production of methemoglobin is possible if APAP is APAP indirect stimulation of 5-HT1A receptors with subsequent
ingested in supraphysiologic doses. modulation of the spinal ERK1/2 pathway.15
Another possible contributing mechanism of APAP is that it
could exert effects on COX-1 indirectly via free radical uptake
MECHANISMS OF ACTION scavenging (free radicals seems to be needed for COX activity).
Modulation of the serotonergic (5-hydroxytryptamine [5-HT])
APAP possesses potent antipyretic and analgesic activity yet only system by APAP has been suggested on the basis of biochemical and
weak anti-inflammatory activity.3 Although the precise mechanisms behavioral studies supporting an indirect serotonergic effect.
of action of APAP remain uncertain, the manner in which APAP Indeed, based on work by Tjølsen and colleagues,16 serotonin was
works is becoming somewhat clearer. It has traditionally been held suspected to play a part in the central analgesic mechanism of APAP
that APAP acts centrally and is a weak inhibitor of cyclooxygenase after a down-regulation of this effect was observed after injury to
(COX)-1 and COX-2.3 APAP’s central actions have been touted the serotonergic bulbospinal pathways in rats. Thus, APAP may
since 1972 when Flower and Vane4 reported that brain stimulate the descending 5-HT activity that reduce nociceptive
430 Chapter 58 ACETAMINOPHEN
H Hydroxylation
(at para position) 3-OH-APAP A E 3-Methoxy APAP
H N HO APAP
H APAP-sulfate
D
Aniline P-aminophenol
R
H Cytochrome C
Acetylation P450
HO N CH3
C
Macromolecules
O APAP-glucuronide NAPQI Hepatotoxicity
Acetaminophen
Figure 58^1. Chemical structure of APAP. Glutathione F
signaling in the spinal cord.17–19 In addition, in a recent human NAPQI/GSH

pain study, Pickering and coworkers20 showed that tropisetron and
granisetron, serotonin-3 (5-HT3) antagonists, can block the analge- G H
sic effect of a single dose of APAP. The significance of these obser-
vations is unknown.
Cysteine Mercapturic
Data from rats demonstrate that two cannabinoid CB1 receptor
acid conjugates
antagonists can prevent the analgesic effect of APAP.21 A study
performed on mice also suggested that endogenous opioids are con- Figure 58^2. APAP metabolism.
tributors to the central antinociceptive action of APAP because the
effect can be reduced by several selective antagonists to specific Mechanisms of Toxicity
opioid receptor subtypes.22 APAP may also have an analgesic
effect modulated by N-methyl-D-aspartate (NMDA), an excitatory The minor route of APAP metabolism by the CYP2E1-dependent
amino acid receptor complex that modulates calcium influx and mixed-function oxidase yields a reactive arylating metabolite,
seems to be involved in ‘‘wind-up’’ phenomenon and perpetuation NAPQI (Fig. 58–2). NAPQI can be produced by direct two-electron
of chronic neuropathic pain states and an ability to modulate central oxidation of APAP by CYP450 or by a one-electron oxidation to
substance P levels.23 In addition, an analgesic effect of APAP has N-acetyl-p-benzo-semi-quinone imine by peroxidase, prostaglandin
been suggested through an inhibitory action on spinal nitric oxide H synthetase, or CYP450.27 NAPQI may deplete the mitochondrial
mechanisms.23–25 The significance of these observations is unknown. and cytosolic pools of reduced GSH. Without reduced GSH present,
NAPQI directly arylates and oxidizes cellular proteins, leading
to inhibition of enzyme activities. GSH peroxidase and thiol trans-
APAP TOXICITY ferase are two specific enzymes inhibited in APAP-treated animals.
Thus, GSH provides a protective measure against NAPQI. The
The liver receives the major insult from APAP toxicity, with the rate-limiting step in the production of reduced GSH is glutamyl-
predominant lesion being acute centrilobular hepatic necrosis. cysteine synthetase. Glutamylcysteine synthetase and glutathione
Severe liver damage (arbitrarily defined as elevated plasma alanine synthetase as well as many other antioxidant enzymes are regulated
or aspartate aminotransferase activity > 1000 U/L) may result from by antioxidant-responsive elements–mediated gene expression. In
a single dose of 150 to 250 mg/kg, but there is marked individual GSH-depleted states, the risk of hepatotoxicity seems to be greater.
variation. Standard weight-based therapeutic dosing (10–15 mg/kg) APAP hepatotoxicity traditionally has been viewed as dependent
is more than 10-fold below these potentially toxic levels. on the balance between the rate of formation of NAPQI and the
rate of GSH conjugation. In addition, NAPQI production is
determined in part by the rate of absorption of APAP (first-pass
APAP Metabolism metabolism), the environmental and genetic determinants of
CYP-metabolizing machinery, and the degree of APAP elimination
APAP primarily is metabolized in the liver by first-order kinetics through the primary pathways (i.e., glucuronide and sulfate con-
and involves three principal separate pathways: conjugation with jugation). Toxicity is diminished by inhibiting APAP oxidation and
glucuronide; conjugation with sulfate; and oxidation via the cyto- stimulation of GSH synthesis. Alternatively, toxicity is augmented
chrome P-450 (CYP450)–dependent, mixed-function oxidative by increased APAP oxidation (e.g., increased levels of CYP2E1 or
enzyme pathways. The primary metabolic pathway is via hepatic 1A2) and depletion of hepatic GSH stores (e.g., low-protein diet).
conjugation with glucuronic acid (55%), conjugation with Alcoholics and diabetic patients who do not respond well to insulin
sulfuric acid (35%), or conjugation with cysteine (3%). may possess increased levels of hepatic CYP2E1.
Mercapturate and free APAP make up approximately 3% and 4% At low doses, most APAP is readily conjugated with glucuronic
of urine metabolites. Small amounts of hydroxylated and deacety- acid and sulfate via the action of uridine diphosphate
lated metabolites have been found in the urine. The CYP450 system (UDP)–glucuronsyltransferase (50%–60%) and sulfotransferases
forms a reactive intermediate metabolite that conjugates with glu- (25%–35%), then eliminated.28 Approximately 3% to 5% of
tathione (GSH) and is metabolized further to form cysteine and APAP is excreted unchanged in the urine, and less than 1% is
mercapturic acid conjugates. The principal CYP isoenzyme involved recovered in bile. A small amount (< 10%) of APAP is converted
seems to be CYP2E1.26 CYP3A4 and CYP1A2 provide additional, to NAPQI. Exposure to high APAP doses may overwhelm the glu-
but minor, pathways.26 Medications that affect other CYP systems curonidation and sulfation pathways and deplete the glutathione
(e.g., 2D6 or 3A4) or that are nonspecific hepatic enzyme inducers pool, resulting in excess NAPQI capable of binding to intracellular
do not appear to significantly affect N-acetyl-p-benzoquinone imine macromolecules.
(NAPQI) production and would not be expected to increase the Significant covalent binding of NAPQI to cellular macromole-
potential for APAP hepatotoxicity. cules (e.g., DNA) results in hepatic cell death; however, this is not
expected until hepatic GSH concentrations are depressed to 20% of low molecular weight permit easy access through the blood-brain
control values or lower. The most common scenarios of relative barrier. The peak concentration of APAP in cerebrospinal fluid
GSH depletion include liver disease (e.g., hepatic cirrhosis), alcohol (CSF) is attained after 2 to 3 hours.33
abuse, and abuse or use of a-adrenergic agonists (which may lower APAP is distributed relatively uniformly throughout most body
hepatic GSH significantly).29 With chronic alcohol misuse (defined fluids. Plasma protein binding may be variable. Ninety percent to
as 3 or more drinks per day) may result in significant GSH deple- 100% of the drug may be recovered in the urine within the first day
tion, although values do not usually decrease to 20% of control. after administration.
However, as a general rule, one probably should not ingest 4 g of In adults, most APAP is conjugated with glucuronic acid (a
APAP per day on a long-term basis in this situation. lesser extent is conjugated with sulfate). Interestingly, with
The patient with frank APAP toxicity may exhibit nausea and APAP dose escalation or chronic dosing, induction of glucuronida-
vomiting (within a few hours of ingestion); abdominal pain and tion occurs and results in a decrease in NAPQI production as
tenderness secondary to swelling of Glisson’s capsule (18–72 hr); measured by urine metabolites.34 The glucuronide-derived, sul-
oliguria, renal failure, and back pain (24–48 hr); and fulminant fate-derived, and glutathione-derived metabolites lack biologic
hepatic failure (3rd–6th day). Other potential complications of activity. The biologic half-life of APAP in normal adults is 2 to
toxic APAP overdose include disseminated intravascular coagula- 3 hours with usual therapeutic dosing. The half-life tends to be
tion, acute pancreatitis, impaired carbohydrate tolerance, myocar- slightly longer in full-term neonates and infants and in patients
ditis, and hypophosphatemia.30 with cirrhosis. The elimination half-life is about 3 hours for the
extended-release product. The elimination half-life of APAP in
the CSF is 3.2 hours, according to pooled data.
Treatment of Toxicity Pineiro-Carrerro and Pineiro35 noted that young children are
actually more resistant to APAP-induced hepatotoxicity than
Prescott and coworkers31 advocated the early use of the glutathione adults as a result of metabolism differences: sulfation predominates
precursor of N-acetylcysteine for the treatment of APAP intoxica- over glucuronidation and the CYP system is immature, leading to a
tion in efforts to maintain hepatic reduced glutathione concentra- reduction in NAPQI. Young children also appear to have increased
tions (reduced GSH cannot be given because it does not cross the glutathione stores in the liver compared with those of adults, which
plasma membrane). N-Acetylcysteine may be beneficial in APAP confers an additional degree of protection (more glutathione is
intoxication via multiple mechanisms. available to deactivate any NAPQI that may be formed).
Optimal treatment time seems to be 8 to 10 hours or less from Arana and colleagues36 reviewed the available data on APAP
ingestion; the clinician should not wait past 8 hours for the results metabolism in neonates and infants compared with older children
of plasma concentrations. N-Acetylcysteine may have theorectical and noted substantial differences:
advantages over other therapeutic options, such as oral methionine.
n A rate constant for APAP glucuronidation that increases
N-Acetylcysteine has a therapeutic effect in established APAP liver
with age.
failure. If N-acetycysteine was appropriately administered within
n A rate constant for APAP sulfation that is larger than in adults.
8 to 10 hours of ingestion of the APAP overdose, it was virtually
n A higher percentage of excretion of unchanged APAP in
100% effective in preventing severe liver damage, renal failure, and
neonates (25%) compared with older children and adults
death. The incidence of severe liver damage varied from 8% to 53%
(3%–5%).
when treatment was delayed for 10 to 24 hours. Anaphylactoid-type
n A longer elimination half-life in neonates with reports as high
reactions to N-acetylcysteine that may occur are believed to be
as 11 hours in preterm neonates (28–32 wk), 4.8 hours in
dose-related and mediated by histamine release, but severe bronch-
those 32 to 36 weeks old, and 3.5 hours for term neonates
ospasm, angioedema, and hypotension may occur (especially in
compared with approximately 2 to 3 hours in adults.
atopic individuals and asthmatics). In patients who are vomiting
n A lower incidence of liver failure after APAP overdose in
and those who have been given emetics or oral activated charcoal,
neonates than in adults owing to markedly reduced rates of
intravenous (IV) N-acetylcysteine (N-acetylcysteine is available
metabolism by the CYP system and a greater ability to syn-
only orally in the United States). It may be prudent to treat
thesize glutathione.
chronic alcoholics at a lower threshold than usual. Jones and associ-
ates32 addressed the question of whether it would help diminish Supporting the observation by Arana and colleagues36 that neo-
the clinical hepatotoxicity seen in the United Kingdom if methio- nates and infants are unlikely to develop hepatotoxicity from acet-
nine were added to every APAP tablet (e.g., combination in the aminophen, van der Marel and coworkers37 studied APAP
same tablet) and concluded that it would not be wise because the pharmacokinetics using an oral elixir or suppository (loading
risks (e.g., long-term effects) are not well known. dose of 33–59 mg/kg and 19–45 mg/kg every 6, 8, or 12 hr) in
47 infants (mean age 11.8 ± 2.5 mo) undergoing major craniofacial
surgery. Using a nonlinear, mixed-effects model (NONMEM)
CLINICALUSE OF APAP methodology to estimate APAP and metabolite clearance, the
authors37 confirmed the age-related effects reviewed by Arana and
APAP (C8H9NO2) is a white crystalline powder with a molecular colleagues36 and confirmed the absence of detectable levels of
weight of 151.16 and a pKa of 9.51 at 258C (it is stable at a pH NAPQI metabolites in the urine of the infants studied. Sulfate
between 4 and 7 at 258C) and is generally stable for 3 years in solid metabolism accounted for 50% of APAP clearance. No accumula-
formulations and 2 years in liquid formulations. Oral APAP is tion with repeated dosing was seen in this study.
absorbed rapidly and almost completely from the gastrointestinal
tract by passive transport, primarily in the small intestine. The rel-
ative bioavailability ranges from 85% to 98%; however, absorption PHARMACOKINETICS
of APAP is significantly dependent on gastric emptying. Clinicians
should be aware of this when administering APAP to patients APAP is available for oral administration in multiple forms (liquid
with medical conditions or medications promoting gastroparesis. and solid). Tablets, caplets, and capsules are available. The capsules
APAP absorption may also be impaired in vegetarians. contain tasteless granules that can be emptied onto a teaspoon
A relatively small amount of APAP (10%–25%) is bound to containing a small amount of applesauce. Care should be taken to
plasma proteins. APAP seems to be widely distributed with most ensure full dissolution of drug if the capsule is emptied into a glass
body fluids except fat. Acetaminophen’s low protein binding and of liquid because large numbers of granules may adhere to the side
of the glass. The liquid should be at room temperature because because there was no significant difference in adverse events
mixing the granules with a hot beverage can yield a bitter taste. between the groups.
The recommended adult dosage of APAP is 325 to 650 mg every In an open-label, four-period, randomized, cross-over study
4 hours, 325 to 500 mg every 3 hours, or 650 to 1000 mg every comparing the pharmacokinetics of 1 g IV and oral APAP admin-
6 hours, with a maximum daily dose of 4 g in 24 hours. APAP is istration (q4h and Q6h regimens; 8 doses in each 48-hr treatment
absorbed rapidly and almost completely from the gastrointestinal period) in 32 healthy adult male volunteers,40 it was demonstrated
tract. The concentration in plasma reaches a peak in 30 to that the IV time of maximum concentration (Tmax) is earlier
60 minutes, and the plasma half-life is approximately 2 hours after and the maximum concentration (Cmax) is approximately 60%
administration. Pharmacokinetic linearity has been demonstrated higher than that seen with oral dosing. No accumulation was seen
with oral APAP doses up to 8 g daily for 72 hours in a recent study.34 in this repeated dose study. IV APAP was well tolerated, and there
Rectal bioavailability of APAP is approximately half of the oral were no significant differences between the IV and the oral dosing
dose. If using a suppository and it is soft, cold water should be run groups.
over it while it is still in foil or it should be refrigerated for A multiple-dose study to evaluate the pharmacokinetics and
30 minutes. The foil is removed, the suppository is moistened safety of IV APAP in healthy subjects (n = 26 for safety analysis
with cold water, and the suppository is pushed well up into the and n = 24 for pharmacokinetics; aged 18–40 yr, inclusive) was
rectum with a finger while the patient lies on his or her side. performed to evaluate the pharmacokinetic data of a 2-g starting
In the United States, adult APAP generally comes in regular- dose followed by four 1-g doses administered at 6-hour intervals.41
strength 325-mg tablets or caplets or extra-strength 500-mg gel The time to reach Cmax corresponded to the end of the 15-minute
caps, gel tabs, caplets, or tablets. Tylenol Arthritis Extended Relief infusion. After the 2-g infusion, the mean Cmax was 67.9 ± 21.8 mcg/
is a 650-mg caplet. Tylenol adult liquid is alcohol-free, and each ml with the maximum observed individual value of 115 mcg/ml. The
15 ml (0.5 fl. oz. or 1 tbsp) contains 500 mg of APAP (also comes in Cmax after the second and fifth1-g infusions were comparable and
honey lemon and cherry flavors and multiple other forms [e.g., approximately 35% lower than that seen after the first infusion of
pediatric]). The various pediatric preparations include Tylenol 2 g. There was no evidence for accumulation. No serious adverse
Infants’ Drops (80 mg/0.8 ml). Children’s Tylenol elixir (160 mg/ events were reported, and no subject discontinued for safety reasons.
5ml), Children’s Tylenol suspension liquid (160 mg/5 ml),
Children’s Tylenol chewable tables (80 mg), Tylenol Junior
Strength chewable tables (160 mg), and Tylenol Junior Strength PHARMACODYNAMICS
caplets (160 mg). Of the forms mentioned, only regular-strength
Tylenol tablets, Tylenol Arthritis Extended Relief caplets, and max- Clinical studies in the context of postoperative pain have shown
imum-strength Tylenol sore throat honey-lemon-flavored adult that, at an equivalent dosage, the IV route is more effective than the
liquid do not contain FD&C Red #40 in the inactive ingredients, oral route, which in turn is superior to the rectal route.42 For
which may be important for individuals known to be allergic to example, after oral surgery, IV APAP had a faster onset of analgesia
FD&C Red #40. and was more effective in reducing pain intensity in the first hour of
Although not available in the United States, an IV form of the treatment than oral APAP.43 Similar results were obtained after
APAP prodrug propacetamol was available in Europe from 1985 to orthopedic surgery.44
2001. Propacetamol is rapidly converted to APAP by plasma Whereas there is no direct correlation between the analgesic and
esterases with a 2-g IV dose being equivalent to a 1-g dose of the antipyretic activity of APAP and its plasma concentration at any
IV acetaminophen. In 2001, an IV form of APAP (Perfalgan, given time,45 the analgesic profile of the drug is almost parallel to its
Bristol-Myers Squibb Company) was approved for use in Europe concentration-time curve in the CSF, reproducing that seen in the
and is currently approved and used in approximately 50 countries plasma, but delayed in terms of time.33
worldwide. IV APAP has been extensively studied in clinical trials in In a pharmacokinetic single-dose study of IV acetaminophen,
Europe and is currently in phase III testing in the United States. Kumpulainen and coworkers46 studied the CSF penetration of a
More than 200 million 1-g doses have been distributed since its single dose of IV APAP 5 mg/kg in 32 children (aged 3 mo–12
approval in 2001. yr, median 55 mo) who were undergoing lower body surgery with
The results from a randomized, placebo-controlled, multicenter spinal anesthesia. Median Cmax was 14 mcg/ml (range 2.4–33.0)
study by Sinatra and associates38 performed in a postoperative compared with median peak CSF concentration of 7.2 (range was
orthopedic (total hip and total knee arthroplasty) pain model below the limit of quantification to 18.0). CSF penetration through
showed that pain relief and pain-intensity differences from baseline an intact blood brain-barrier appeared to occur readily with APAP
(PID) were significantly greater for IV APAP compared with and peaked at approximately 1 hour. IV APAP was well tolerated in
placebo from the earliest time point measured, 15 minutes, through this study.
6 hours (P values were .017 at 15 min, .016 at 30 minutes, .0001 at Although it seems that oral APAP also appears in CSF readily,
all time points from 45 min through 3 hr, .0008 at 4 hr, .0013 at the peak CSF concentration was not observed until 210 minutes in a
5 hr, and .0005 at 6 hr). IV APAP also provided greater efficacy study by Anderson and associates47 rather than in 57 minutes as
when compared with placebo as measured by the sum of pain relief observed by Kumpulainen and coworkers.46 Similarly, in a study of
scores and the sum of PID scores (P < .0001). Moreover, the rectal APAP 30 mg/kg in 41 children undergoing insertion or revi-
median time to rescue medication was significantly longer for the sion of a ventriculoperitoneal shunt or insertion of a ventricular
IV APAP group than for the placebo group (4 vs. 1.6 hr, P < .05). drain, peak CSF (and plasma) APAP levels were observed 2 hours
A more-recent randomized, double-blind, placebo-controlled after administration.48 These studies suggest that a rapid and higher
study used IV APAP as part of an adjunctive, multimodal treatment Cmax produces more rapid and higher CSF peak APAP levels.
program (with IV tramadol continuous infusion) for pain over Anderson and colleagues45 performed a pharmacodynamic
72 hours after elective cardiac surgery (mostly coronary artery assessment of APAP analgesia in 120 children undergoing outpatient
bypass grafting or valve replacement) in 113 patients.39 Cattabriga tonsillectomy who were administered either oral (n = 20) or rectal
and colleagues39 reported that at 12, 18, and 24 hours after the end (n = 100) APAP within an hour of induction of anesthesia. No other
of the operation, patients who received IV APAP (plus tramadol) analgesic agents were administered in this study. APAP pharmaco-
had significantly less pain at rest than those who received placebo kinetic parameters and pain scores (0–10) were measured over a
(plus tramadol) (P = .0041, P = .0039, and P = .0044, respectively). 4-hour period postoperatively and analyzed using a NONMEM
The IV APAP group also required less cumulative morphine than model in order to calculate the EC50 (the plasma concentration of
the placebo group (48 vs. 97 mg). IV APAP was well tolerated APAP producing 50% of Emax or greatest possible pain relief).
Based on the results in this study, an EC50 of 10 mcg/ml is necessary placebo in a single-dose administration of 5.6 (95% confidence
to achieve a mean post-tonsillectomy pain score of 3.6 out of 10. interval [CI], 3.9–9.5); at 600 mg or 650 mg, the NNT was
In a follow-on study, Anderson and coworkers49 studied the 5.3 (95 CI, 4.1–7.2); at 1 g, the NNT was 4.6 (95 CI, 3.9–5.4);
analgesic pharmacodynamics of APAP elixir 40 mg/kg (n = 12) or and at 1500 mg, the NNT was 5.0 (95 CI, 3.3–11).57
100 mg/kg (n = 20) vs. placebo (n = 30) given 30 to 60 minutes APAP 1 g has an overall NNT of 4.6 for at least 50% pain relief
preoperatively in children (aged 9 ± 3 yr) who were undergoing compared with placebo in single-dose administration.57 This means
elective tonsillectomy. No other analgesic agents were administered that one out of every five patients with moderate to severe pain
in this study. APAP’s pharmacokinetic parameters and pain scores intensity would obtain at least 50% pain relief with APAP over
(0–10) were measured over a 4-hour period postoperatively, and placebo.57 The equivalent NNT value for either 600 or 650 mg
these data were pooled with the prior study (summarized earlier) was 5.3 and for 1500 mg was 5.0, suggesting a lower efficacy,
and analyzed using a NONMEM model in order to calculate the although the dose response was not significant.
EC50. An EC50 of 10 mcg/ml is expected to produce a pain reduc- Moore and coworkers,58 in a more recent update of the Cochrane
tion of 2.6 units with the placebo model in this study, accounting Review, published data that were essentially unchanged but based on
for a maximum pain reduction of 5.6 units at 3 hours. Based on 40 trials (4717 patients) of APAP versus placebo for moderate to
these data, an oral dose of 40 mg/kg given preoperatively resulted in severe acute pain. Through all these studies and data, the safety of
pain scores below 4 units for 5 hours postoperatively, and the APAP in appropriate dosing was shown, because there were no seri-
higher dose of 100 mg/kg was no more effective. ous adverse events that necessitated withdrawal from any study.
It appears that APAP’s CSF penetration is more rapid in children The results confirm that APAP is an effective and safe analgesic,
than in adults, which may explain the much higher EC50 level and that for single-dose administration for moderate to severe pain,
observed in adults of 17 mcg/ml50 compared with 10 mcg/ml 1 g may be the optimal dose for most patients. In a prospective,
seen in children. For example, Bannwarth and associates33 evaluated open, single-blind, randomized study, intravenous propacetamol
CSF penetration of IV propacetamol 2 g (equivalent to IV APAP (the prodrug to APAP), tramadol, and diclofenac were equally effi-
1 g) in 43 healthy adults having a lumbar puncture for myelogra- cacious for emergency analgesic treatment of peripheral trauma.59
phy; at this dose (corresponding to 15 mg/kg in children), peak CSF Multiple combination products exist of APAP combined with other
concentrations were observed at 45 minutes but were half that agents. Caffeine, an agent found combined with APAP in multiple
observed by Kumpulainen and coworkers.46 products, accelerates absorption and enhances the analgesic effects
In the treatment of acute pain, onset time is an issue, so rectal of APAP.60
APAP administration is suboptimal because there is slow and erra- APAP is generally safe to use with most medical conditions.
tic ongoing absorption that does not peak within 4 hours after Some brands of APAP contain aspartame, which potentially could
administration.51 Although not available in the United States, the worsen phenylketonuria. APAP should be used with caution in
time of onset with effervescent APAP 1 g was significantly faster patients who have been malnourished, have active alcohol abuse,
than with tablet APAP 1 g in a single-dose study with median time or have significant renal or hepatic disease.
to analgesia onset of 20 minutes (effervescent) versus 60 minutes APAP crosses the placenta; it generally is considered safe for
(tablet).52 This difference may be due to significantly faster absorp- use during pregnancy if a medication is believed to be required.
tion with the effervescent form.53 After maternal ingestion of therapeutic doses, APAP crosses the
The duration was longer with the tablet at 4 hours after admin- placenta to the fetal circulation in 30 minutes (serum concentration
istration, and the pain relief was significantly better with tablet differences between maternal and cord blood are not statistically
APAP than with effervescent APAP.52 In treatment regimens for significant).61 APAP is metabolized effectively via sulfate conjuga-
chronic pain, a sustained-release preparation seems well suited for tion in the fetus.62
many patients. APAP has been formulated in controlled-release The American Academy of Pediatrics considers APAP use to be
sprinkles, which are not currently available in the United States, compatible with breast-feeding. Amounts in milk range from 0.1%
and the extended-release Tylenol Arthritis Extended Relief caplets, to 1.85% of the ingested maternal dose.63–65 The nursing infant
which are available in the United States. This 650-mg caplet is a receives less than 2% of the maternal dose even at the moment of
unique, patented bilayer: the first layer dissolves quickly (roughly peak APAP concentration.
about half the dose, e.g., similar to taking a regular-strength APAP was believed to interfere with some blood glucose tests in
Tylenol, 325 mg), whereas the second layer is time-released to pro- the past; however, at recommended doses, it does not seem to
vide 8 hours of relief. If an overdose of this caplet is taken, it may be interfere with glucose analysis using currently marketed blood glu-
appropriate to repeat an additional plasma APAP level 4 to 6 hours cose meters. At therapeutic doses, APAP may interfere with the
after the initial level. determination of 5-hydroxyindoleacetic acid, leading to false-
In vitro data suggest that two 650-mg extended-release caplets positive results. False determinations should be eliminated by
(1300 mg) of acetaminophen release 88% and 95% of the drug avoiding APAP administration for several hours before and
within 3 and 5 hours.54 After one dose of two 650-mg extended-release during the collection of the urine specimen.66
caplets, the average Cmax occurred within 0.5 to 3 hours after ingestion. APAP has essentially no major clinically significant drug interac-
The package label instructs patients not to take APAP for more tions. It may produce a small, transient rise in the International
than 10 days (for fever, 5 days) unless directed by their physi- Normalized Ratio in patients taking anticoagulation medication
cians; however, clinical experience has borne out that with appro- and in patients with APAP poisoning without hepatic injury, which
priate monitoring and caution, APAP can be used long-term for appear to be caused by inhibition of vitamin K–dependent activation
chronic conditions. The use of 4 g of APAP in adults with osteo- of coagulation factor (i.e., reducing functional factor VII).67
arthritis of the knee was evaluated for 4 weeks.55 Williams and Concomitant administration of APAP with diflunisal produces
colleagues56 evaluated treatment with APAP in doses of 2600 mg/ about a 50% increase in the plasma levels of APAP in normal
day for 2 years. In these studies, APAP was well tolerated. volunteers. Isoniazid probably has no clinically significant effects
McQuay and Moore57 did a systematic review of APAP for anal- on acetaminophen; however, it is possible that some acetylation
gesia in moderate to severe acute pain states. A total of 37 accept- genotypes may alter the activity of CYP2E1 (which primarily meta-
able studies (with 2530 patients given APAP and 1594 given bolizes acetaminophen), and theoretically, inhibition or induction
placebo) were analyzed. Combining data across conditions, the of CYP2E1 may occur on discontinuation of isoniazid or after con-
pooled relative benefits for all doses of APAP versus placebo were comitant administration of isoniazid and acetaminophen.
significant.57 At a dose of 500 mg, APAP had a number needed to Although rare, severe adverse reactions (including anaphyla-
treat (NNT) value to achieve at least 50% pain relief compared with ctic-type reactions) can occur with APAP. An immunoglobulin
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436 Chapter 59 STEROIDS
73. Rocha GM, Michea LF, Peters EM, et al. Direct toxicity of the National Kidney Foundation from an Ad Hoc Committee of the
nonsteroidal anti-inflammatory drugs for renal medullary cells. Proc National Kidney Foundation. Am J Kidney Dis 1996;27:162–165.
Natl Acad Sci U S A 2001;98:5317–5322. 75. Schnitzer TJ. Update of ACR Guidelines for Osteoarthritis: role of the
74. Henrich WL, Agodoa LE, Barrett B, et al. Analgesics and the kidney: Coxibs. J Pain Symptom Manage 2002;23:524–530.
summary and recommendations to the Scientific Advisory Board of
Chapter 59 PHARMACODYNAMICS OF
STEROIDS GLUCOCORTICOIDS
Muhammad A. Munir, Sanjeev Agarwal, and

Mechanism of Action
Jun-Ming Zhang
Glucocorticoids interact with specific receptor proteins in target
tissues to regulate the expression of glucocorticoid-responsive
genes, thereby changing the levels and array of proteins synthesized
by the various target tissues. Most effects of glucocorticoids are not
immediate but become apparent after several hours. This fact is of
clinical significance because a delay is generally seen before the
INTRODUCTION beneficial effects of corticosteroid therapy become manifest.
The receptors for glucocorticoids are members of the nuclear
The adrenocortical hormones are steroid molecules produced and receptor family of transcription factors that transduce the effects of
released by the adrenal cortex. The adrenal cortex synthesizes two a diverse array of small, hydrophobic ligands. In the absence of the
types of steroids: the corticosteroids, and the androgens. The actions hormonal ligand, glucocorticoid receptors (GR) are primarily cyto-
of corticosteroids are described as glucocorticoid (carbohydrate plasmic, in oligomeric complexes with heat shock proteins. Free
regulating) and mineralocorticoid (electrolyte regulating), reflecting hormone from the plasma and interstitial fluid enters the cell and
their preferential activities. In humans, cortisol (hydrocortisone) is binds to the receptor, inducing conformational changes that allow it
the main glucocorticoid and aldosterone is the main to dissociate from the heat shock proteins. After the GR dissociates
mineralocorticoid. from its associated proteins and translocates to the nucleus, it inter-
Secretion of adrenocortical steroids and aldosterone are con- acts with specific DNA sequences within the regulatory regions of
trolled, respectively, by adrenocorticotropic hormone (ACTH) affected genes. The short DNA sequences that are recognized by the
and angiotensin. activated GR are called glucocorticoid responsive elements (GREs)
The effects of corticosteroids include alterations in carbohydrate, and provide specificity to the induction of gene transcription by
protein, and lipid metabolism; maintenance of fluid and electrolyte glucocorticoids (Fig. 59–1).
balance; and preservation of normal function of the cardiovascular, In addition to binding to GREs, the ligand-bound receptor also
immune, renal, endocrine, nervous, and musculoskeletal systems. forms complexes with and influences the function of other tran-
The adrenal cortex is an important source of both corticoster- scription factors, such as AP1 and nuclear factor kB (NF-B), which
oids and androgens. However, patients with adrenal insufficiency act on non–GRE-containing promoters, to contribute to the regu-
can be restored to normal life expectancy by replacement therapy lation of transcription of their responsive genes. These
with corticosteroids alone. In this chapter, glucocorticoids are dis- transcription factors have broad actions on the regulation of
cussed in detail, followed by brief overview of mineralocorticoids growth factors, proinflammatory cytokines, and others and to
and androgens. a great extent mediate the antigrowth, anti-inflammatory, and
immunosuppressive effects of glucocorticoids. Recent reports
describe steroidal and nonsteroidal compounds that exhibit anti-
CORTICOSTEROIDS inflammatory actions but have little effect on blood glucose, sug-
gesting that such selective glucocorticoid agonists may emerge
Corticosteroids are grouped according to their relative potencies in from ongoing research.
Na+ retention, effects on carbohydrate metabolism, and anti- Some of the effects of glucocorticoids can be attributed to their
inflammatory effects. In general, potencies of steroids as judged binding to aldosterone receptors. Mineralocorticoid effects of
by their ability to sustain life in adrenalectomized animals closely cortisol are not significant in some tissues (particularly in the
parallel those determined for Na+ retention, ande potencies based kidney, colon, and salivary glands) owing to expression of
on effects on glucose metabolism closely parallel those for anti- 11b-hydroxysteroid dehydrogenase type 2, the enzyme responsible
inflammatory effects. for biotransformation to its 11-keto derivative (cortisone), which
The corticosteroids traditionally are divided into mineralocorti- has minimal affinity for aldosterone receptors.
coids and glucocorticoids; estimates of potencies of representative
steroids in these actions are listed in Table 59–1. Some steroids that
are classified predominantly as glucocorticoids (e.g., cortisol) also Physiologic Effects
possess modest but significant mineralocorticoid activity and, thus,
may affect fluid and electrolyte handling in the clinical setting. In The effects of corticosteroids include alterations in intermediary
contrast, aldosterone is an exceedingly potent mineralocorticoid metabolism; maintenance of fluid and electrolyte balance; and
that has no significant glucocorticoid activity at normal rates of preservation of normal function of the kidney and skeletal muscle
secretion. and the cardiovascular, immune, endocrine, and nervous systems.
73. Rocha GM, Michea LF, Peters EM, et al. Direct toxicity of the National Kidney Foundation from an Ad Hoc Committee of the
nonsteroidal anti-inflammatory drugs for renal medullary cells. Proc National Kidney Foundation. Am J Kidney Dis 1996;27:162–165.
Natl Acad Sci U S A 2001;98:5317–5322. 75. Schnitzer TJ. Update of ACR Guidelines for Osteoarthritis: role of the
74. Henrich WL, Agodoa LE, Barrett B, et al. Analgesics and the kidney: Coxibs. J Pain Symptom Manage 2002;23:524–530.
summary and recommendations to the Scientific Advisory Board of
Chapter 59 PHARMACODYNAMICS OF
STEROIDS GLUCOCORTICOIDS
Muhammad A. Munir, Sanjeev Agarwal, and

Mechanism of Action
Jun-Ming Zhang
Glucocorticoids interact with specific receptor proteins in target
tissues to regulate the expression of glucocorticoid-responsive
genes, thereby changing the levels and array of proteins synthesized
by the various target tissues. Most effects of glucocorticoids are not
immediate but become apparent after several hours. This fact is of
clinical significance because a delay is generally seen before the
INTRODUCTION beneficial effects of corticosteroid therapy become manifest.
The receptors for glucocorticoids are members of the nuclear
The adrenocortical hormones are steroid molecules produced and receptor family of transcription factors that transduce the effects of
released by the adrenal cortex. The adrenal cortex synthesizes two a diverse array of small, hydrophobic ligands. In the absence of the
types of steroids: the corticosteroids, and the androgens. The actions hormonal ligand, glucocorticoid receptors (GR) are primarily cyto-
of corticosteroids are described as glucocorticoid (carbohydrate plasmic, in oligomeric complexes with heat shock proteins. Free
regulating) and mineralocorticoid (electrolyte regulating), reflecting hormone from the plasma and interstitial fluid enters the cell and
their preferential activities. In humans, cortisol (hydrocortisone) is binds to the receptor, inducing conformational changes that allow it
the main glucocorticoid and aldosterone is the main to dissociate from the heat shock proteins. After the GR dissociates
mineralocorticoid. from its associated proteins and translocates to the nucleus, it inter-
Secretion of adrenocortical steroids and aldosterone are con- acts with specific DNA sequences within the regulatory regions of
trolled, respectively, by adrenocorticotropic hormone (ACTH) affected genes. The short DNA sequences that are recognized by the
and angiotensin. activated GR are called glucocorticoid responsive elements (GREs)
The effects of corticosteroids include alterations in carbohydrate, and provide specificity to the induction of gene transcription by
protein, and lipid metabolism; maintenance of fluid and electrolyte glucocorticoids (Fig. 59–1).
balance; and preservation of normal function of the cardiovascular, In addition to binding to GREs, the ligand-bound receptor also
immune, renal, endocrine, nervous, and musculoskeletal systems. forms complexes with and influences the function of other tran-
The adrenal cortex is an important source of both corticoster- scription factors, such as AP1 and nuclear factor kB (NF-B), which
oids and androgens. However, patients with adrenal insufficiency act on non–GRE-containing promoters, to contribute to the regu-
can be restored to normal life expectancy by replacement therapy lation of transcription of their responsive genes. These
with corticosteroids alone. In this chapter, glucocorticoids are dis- transcription factors have broad actions on the regulation of
cussed in detail, followed by brief overview of mineralocorticoids growth factors, proinflammatory cytokines, and others and to
and androgens. a great extent mediate the antigrowth, anti-inflammatory, and
immunosuppressive effects of glucocorticoids. Recent reports
describe steroidal and nonsteroidal compounds that exhibit anti-
CORTICOSTEROIDS inflammatory actions but have little effect on blood glucose, sug-
gesting that such selective glucocorticoid agonists may emerge
Corticosteroids are grouped according to their relative potencies in from ongoing research.
Na+ retention, effects on carbohydrate metabolism, and anti- Some of the effects of glucocorticoids can be attributed to their
inflammatory effects. In general, potencies of steroids as judged binding to aldosterone receptors. Mineralocorticoid effects of
by their ability to sustain life in adrenalectomized animals closely cortisol are not significant in some tissues (particularly in the
parallel those determined for Na+ retention, ande potencies based kidney, colon, and salivary glands) owing to expression of
on effects on glucose metabolism closely parallel those for anti- 11b-hydroxysteroid dehydrogenase type 2, the enzyme responsible
inflammatory effects. for biotransformation to its 11-keto derivative (cortisone), which
The corticosteroids traditionally are divided into mineralocorti- has minimal affinity for aldosterone receptors.
coids and glucocorticoids; estimates of potencies of representative
steroids in these actions are listed in Table 59–1. Some steroids that
are classified predominantly as glucocorticoids (e.g., cortisol) also Physiologic Effects
possess modest but significant mineralocorticoid activity and, thus,
may affect fluid and electrolyte handling in the clinical setting. In The effects of corticosteroids include alterations in intermediary
contrast, aldosterone is an exceedingly potent mineralocorticoid metabolism; maintenance of fluid and electrolyte balance; and
that has no significant glucocorticoid activity at normal rates of preservation of normal function of the kidney and skeletal muscle
secretion. and the cardiovascular, immune, endocrine, and nervous systems.
Table 59^1. Some Commonly Used Natural and Synthetic Corticosteroids
Activity
Agent Anti-inflammatory* Salt-retaining* Equivalent Oral Dose (mg)

Short- to Medium-acting Glucocorticoids
Hydrocortisone (cortisol) 1 1 20
Prednisone 4 0.3 5
Prednisolone 5 0.3 5
Methylprednisolone 5 0 4
Cortisone 0.8 0.8 25
Intermediate-acting Glucocorticoids
Triamcinolone 5 0 4
Fluprednisolone 15 0 1.5
Paramethasone 10 0 2
Long-acting Glucocorticoids
Betamethasone 25–40 0 0.6
Dexamethasone 30 0 0.75
Mineralocorticoids
Fludrocortisone 10 250 2
Desoxycorticosterone acetate 0 20
*Anti-inflammatory and salt-retaining activity described in relation to hydrocortisone (cortisol).
CYTOPLASM
Hsp70 Hsp70
GR
Hsp90 (Unstable) Hsp90
CBG
S
GR Hsp70
Hsp90
S S
S S
GR GR
S DNA
CBG S GR
Response
GRE
S GR
NUCLEUS
Protein
Transcription
machinery
pre- (RNA polymerase,
mRNA
mRNA etc)
Figure 59^1. Mechanism of glucocorticoid action. CBG, corticosteroid-binding globulin or transcortin; GR, glucocorticoid receptor; GRE,
glucocorticoid-response element; HSP, heat shock proteins; S, steroid.
The major metabolic consequences of glucocorticoid secretion Other Effects

or administration are due to direct actions of these hormones in
the cell. However, some important effects are the result of homeo- The major action of glucocorticoids on the cardiovascular system is
static responses by insulin and glucagon. Many of the effects of to enhance vascular reactivity to other vasoactive substances.
glucocorticoids are dose-related and become magnified when Hypoadrenalism is associated with reduced response to vasocon-
large amounts are administered for therapeutic purposes. strictors such as norepinephrine and angiotensin II. Hypertension
However, there are also certain other effects known as ‘‘permissive’’ seen with either endogenous or exogenous excess of glucocorticoids
effects, in the absence of which many normal functions become is generally resistant to Na+ restriction.
deficient. Glucocorticoids have important effects on the nervous system.
Hypoadrenalism is associated with depression. Hyperadrenalism is
often initially responsible for insomnia, and euphoria and, later, for
Carbohydrate and Protein Metabolism depression. Glucocorticoids given chronically suppress the pituitary
release of ACTH, growth hormone, thyroid-stimulating hormone,
Corticosteroids stimulate the liver to form glucose from amino and luteinizing hormone.
acids and glycerol and to store glucose as liver glycogen. In the Diminished work capacity is a prominent sign of adrenocortical
periphery, glucocorticoids diminish glucose utilization, increase insufficiency, and glucocorticoid excess over prolonged periods may
protein breakdown and the synthesis of glutamine, and activate cause skeletal muscle wasting.
lipolysis, thereby providing amino acids and glycerol for gluco- Large doses of glucocorticoids may cause peptic ulcer, promote
neogenesis. The net result is to increase blood glucose levels. fat redistribution, and antagonize the effect of vitamin D on calcium
Because of their effects on glucose metabolism, glucocorticoids absorption. In addition to their effects on leukocytes, they increase
can worsen glycemic control in patients with overt diabetes and the number of platelets and red blood cells.
can precipitate the onset of hyperglycemia in predisposed In the absence of physiologic amounts of cortisol, renal function
patients. (particularly glomerular filtration) is impaired, vasopressin secre-
Although glucocorticoids stimulate protein and RNA synthesis tion is augmented, and there is an inability to excrete a water load
in the liver, they have catabolic and antianabolic effects in lymphoid normally.
and connective tissue, muscle, fat, and skin. Supraphysiologic Glucocorticoids have important effects on the development of
amounts of glucocorticoids lead to decreased muscle mass and the fetal lungs, including the stimulation of production of surfactant.
weakness and thinning of the skin. Catabolic and antianabolic
effects on bone are the cause of osteoporosis in Cushing’s syndrome
and impose a major limitation in the long-term therapeutic use of PHARMACOKINETICS OF
glucocorticoids. In children, glucocorticoids reduce growth, and GLUCOCORTICOIDS
this effect may be partially prevented by administration of growth
hormone in high doses. The synthesis and secretion of hydrocortisone are tightly regulated
by the central nervous system, which is very sensitive to negative
feedback by the circulating cortisol and exogenous (synthetic) glu-
Lipid Metabolism cocorticoids. Cortisol is synthesized from cholesterol.
The rate of secretion of cortisol is 10 to 20 mg/day, whereas that
The effects of corticosteroids include the dramatic redistribution of of aldosterone is 0.125 mg/day. The rate of secretion of cortisol
body fat that occurs in settings of endogenous or pharmacologically follows a circadian rhythm governed by pulses of ACTH that peak
induced hypercorticism, such as Cushing’s syndrome. Permissive in the early morning hours and after meals. In contrast, concentra-
facilitation of the lipolytic effect of other agents, such as growth tion of aldosterone remains constant throughout the day under
hormone and a-adrenoceptor agonists, results in an increase in free usual circumstances and varies with water and electrolyte balance.
fatty acids after glucocorticoid administration. Fat redistribution In plasma, cortisol is bound to circulating proteins.
leads to increased fat in the back of the neck (‘‘buffalo hump’’), Corticosteroid-binding globulin (CBG) binds 90% of the circulat-
face (‘‘moon facies’’), and supraclavicular area and loss of fat in the ing hormone and the remainder (about 5%–10%) is free or loosely
extremities. bound to albumin ( 5%). CBG is increased in pregnancy, with
estrogen administration, and in hyperthyroidism. It is decreased by
hypothyroidism, genetic defects in synthesis, and protein deficiency
Anti-inflammatory and Immunosuppressive states. Albumin has a large capacity but low affinity for cortisol.
Actions Synthetic corticosteroids such as dexamethasone are largely bound
to albumin rather than CBG.
Glucocorticoids reduce the manifestations of inflammation via their The half-life of cortisol in the circulation is normally about 60 to
profound effects on the concentration, distribution, and function of 90 minutes. The half-life may be increased after administration of
peripheral leukocytes; and suppressive effects on the inflammatory large amounts of hydrocortisone or during stress, hypothyroidism,
cytokines, chemokines, and other lipid and glucolipid mediators of or liver disease. Only 1% of cortisol is excreted unchanged in the
inflammation. Corticosteroids profoundly alter the number and urine as free cortisol; about 20% of cortisol is converted to corti-
immune responses of lymphocytes. These effects are an important sone by 11-hydroxysteroid dehydrogenase in the kidney and other
facet of the anti-inflammatory and immunosuppressive actions of tissues with mineralocorticoid receptors before reaching the liver.
the glucocorticoids. They can prevent or suppress inflammation in Most cortisol is inactivated in the liver by reduction and subsequent
response to multiple inciting events. conversion to tetrahydrocortisol and tetrahydrocortisone by
Glucocorticoids also influence the inflammatory response by 3-hydroxysteroid dehydrogenase. There are small amounts of
reducing the prostaglandin, leukotriene, and platelet-activating other metabolites. About one third of the cortisol produced daily
factor synthesis that results from activation of phospholipase A2. is excreted in the urine as dihydroxy ketone metabolites and is
Finally, glucocorticoids reduce expression of cyclooxygenase-2 measured as 17-hydroxysteroids.
(COX-2) in inflammatory cells. Synthetic steroids with an 11-keto substituent, such as cortisone
The anti-inflammatory and immunosuppressive effects of these and prednisone, must be enzymatically reduced to the correspond-
agents are widely useful therapeutically but are also responsible for ing 11b-hydroxy derivative before they are biologically active.
some of their most serious adverse effects. The type 1 isozyme of 11b-hydroxysteroid dehydrogenase catalyzes
this reduction, predominantly in the liver but also in specialized ACTH-secreting pituitary adenoma (Cushing’s disease) but occa-
sites such as adipocytes, bone, eye, and skin. In settings in which sionally is due to tumors or nodular hyperplasia of the adrenal
this enzymatic activity is impaired, it is prudent to use steroids that gland or ectopic production of ACTH by other tumors. The mani-
do not require enzymatic activation (e.g., hydrocortisone and pred- festations are those associated with the chronic presence of excessive
nisolone rather than cortisone or prednisone). Such settings glucocorticoids. This disorder is treated by surgical removal of the
include severe hepatic failure and patients with the rare condition tumor producing ACTH or cortisol, irradiation of the pituitary
of cortisone reductase deficiency, who are unable to activate the tumor, or resection of one or both adrenals. These patients
11-keto steroids because of a partial loss of 11HSD1 activity and must receive large doses of cortisol during and after the surgical pro-
a relative deficiency in the enzyme hexose-6-phosphate dehydro- cedure. If adrenalectomy has been performed, long-term mainte-
genase, which supplies reducing equivalents to the 11-hydroxyster- nance is similar to that outlined previously for adrenal insufficiency.
oid dehydrogenase.
Nonendocrine Disorders
CLINICAL PHARMACOLOGYOF Because of their ability to suppress inflammatory and immune
GLUCOCORTICOIDS responses, the synthetic analogues of cortisol are useful in the treat-
ment of a diverse group of diseases unrelated to any known distur-
bance of adrenal function.
Therapeutic Uses Because the corticosteroids are not usually restorative, the
Replacement Therapy pathologic process may progress while clinical manifestations are
suppressed. Therefore, chronic therapy with these drugs should be
Chronic Adrenal Insufficiency (Addison’s Disease). Chronic undertaken with great concern and only when the consequence of
adrenocortical insufficiency may result in fatigue, weight loss, hypo- the disorder warrants their use and less dangerous measures have
tension, hyperpigmentation, and inability to maintain the blood been exhausted.
glucose level during fasting. Minor noxious stimuli may produce In general, attempts should be made to bring the disease process
acute adrenal insufficiency with circulatory shock and even death in under control using medium- to intermediate-acting glucocorti-
such individuals. coids such as prednisone and prednisolone, as well as all supple-
In primary adrenal insufficiency, about 20 to 30 mg of hydro- mentary measures possible to keep the dose low. Whenever
cortisone must be given daily, with increased amounts during per- possible, alternate-day therapy should be utilized and should not
iods of stress. Hydrocortisone may be supplemented by a suitable be decreased or stopped abruptly. When prolonged therapy is
amount of a salt-retaining hormone such as fludrocortisone. anticipated, it is helpful to obtain chest x-rays and a tuberculin
test to detect reactivation of the dormant disease.
Acute Adrenal Insufficiency. The treatment for acute adreno-
cortical insufficiency must be instituted immediately. Therapy con- Rheumatic Disorders. Glucocorticoids are a mainstay in the
sists of correction of fluid and electrolyte abnormalities and treatment of systemic lupus erythematosus, polyarteritis nodosa,
treatment of precipitating factors in addition to large amounts of Wegener’s granulomatosis, Churg-Strauss syndrome, and giant
parenteral hydrocortisone. cell arteritis. Initially, prednisone (1 mg/kg per day in divided
Hydrocortisone sodium succinate or phosphate in doses of doses) is often used, generally followed by consolidation to a
100 mg intravenously is given every 8 hours until the patient is single daily dose, with subsequent tapering to a minimal effective
stable. The dose is then gradually reduced, achieving maintenance dose as determined by clinical variables. Prednisone and methyl-
dosage within 5 days. The administration of salt-retaining hormone prednisolone are generally preferred over longer-acting steroids to
is resumed when the total hydrocortisone dosage has been reduced facilitate drug tapering.
to 50 mg/day. In noninflammatory degenerative joint diseases (e.g., osteoar-
thritis) or in a variety of regional pain syndromes (e.g., tendinitis
Congenital Adrenal Hyperplasia. Congenital adrenal hyperpla- or bursitis), glucocorticoids may be administered by local injection
sia is characterized by specific defects in the synthesis of for the treatment of episodic disease flare-up.
cortisol. The most common defect is a decrease in or lack of
21b-hydroxylase activity. A lack of 21b-hydroxylase would lead to Bronchial Asthma and Other Pulmonary Conditions.
a reduction in cortisol synthesis and produce a compensatory Corticosteroids are used commonly in bronchial asthma and are
increase in ACTH release. The gland becomes hyperplastic and sometimes employed in chronic obstructive pulmonary disease,
produces abnormally large amounts of precursors such as particularly when there is some evidence of reversible obstructive
17-hydroxyprogesterone that can be diverted to the androgen path- disease. In severe asthma attacks requiring hospitalization, intrave-
way, leading to virilization. nous administration of 60 to 120 mg of methylprednisolone (or
If the defect is in 11-hydroxylation, large amounts of deoxycor- equivalent) every 6 hours is used initially, followed by daily oral
ticosterone are produced, and because this steroid has mineralocor- doses of prednisone (30–60 mg) as the acute attack resolves. The
ticoid activity, hypertension with or without hypokalemic alkalosis dose is then tapered gradually, with withdrawal planned for 10 days
ensues. When 17-hydroxylation is defective in the adrenals and to 2 weeks after initiation of steroid therapy.
gonads, hypogonadism is also present. However, increased amounts Less severe, acute exacerbations of asthma often are treated with
of 11-deoxycorticosterone are formed, and the signs and symptoms brief courses of oral glucocorticoids. Upon resolution of the acute
associated with mineralocorticoid excess such as hypertension and exacerbation, the glucocorticoids generally can be rapidly tapered
hypokalemia are also observed. without significant deleterious effects. Any suppression of adrenal
The management of congenital adrenal hyperplasia is beyond function usually dissipates within 1 to 2 weeks. The lowest effective
the scope of this chapter. However, the infant should be treated dose is used for long-term therapy.
using appropriate electrolyte solutions and an intravenous prepara- Inhaled steroids (e.g., beclomethasone dipropionate, triamcino-
tion of hydrocortisone in stress doses under the supervision of a lone acetonid, fluticasone, flunisolide, or budesonide) are effective
pediatric endocrinologist. in reducing bronchial hyperreactivity with less suppression of
adrenal function. Side effects such as dysphonia or oropharyngeal
Postsurgical Replacement. Cushing’s syndrome is usually candidiasis can be reduced substantially by use of spacers and
the result of bilateral adrenal hyperplasia secondary to an mouth rinsing.
Lung maturation in the fetus is regulated by the fetal secretion of trauma or cerebrovascular accidents, controlled clinical trials do
cortisol. Treatment of the mother with large doses of glucocorticoid not support their use in these settings.
reduces the incidence of respiratory distress syndrome in infants
delivered prematurely. When delivery is anticipated before 34
The Analgesic Effects of Glucocorticoids
weeks of gestation, intramuscular betamethasone 12 mg followed
by an additional dose of 12 mg 18 to 24 hours later is commonly used. Glucocorticoids have been used systemically as well as via injections
(e.g., perineural, spinal) to achieve analgesia. Although precise
Allergic Disease. Patients with severe allergic reactions such as antinociceptive mechanisms of glucocorticoids remain uncertain,
anaphylaxis require immediate therapy with epinephrine because of multiple effects have been proposed including
the delayed onset of action of glucocorticoids. The manifestations of
1. Anti-inflammatory effects: Phospholipase A2 (PLA2) inhibi-
allergic diseases can be suppressed by adequate doses of glucocorti-
tion with decreased prostaglandin/leukotriene generation,
coids given as supplements to the primary therapy. In allergic rhi-
decreased proinflammatory cytokine, decreased adhesion
nitis, intranasal steroids are considered the drug of choice by many
molecules, decreased leukocyte/mast cell chemotaxis/accumu-
experts.
lation, stabilization of inflammatory cell membranes (with
resultant decreased release of inflammatory mediators),
Infectious Diseases. Glucocorticoids are indicated in the therapy
decreased NF-kB activity with diminished expression of COX-
of specific infectious pathogens such as Pneumocystis carinii pneu-
2 in inflammatory cells, decreased reactive oxygen species.
monia associated with moderate to severe hypoxia. Glucocorticoid
2. Diminished spontaneous ectopic neural activity.
addition to the antibiotic regimen increases oxygenation and lowers
3. Decreased perineural edema.
the incidence of respiratory failure and mortality. Similarly, gluco-
4. Membrane stabilization: Decreased adenosine triphosphate
corticoids clearly decrease the incidence of long-term neurologic
use for plasma membrane ion cycling with resultant
impairment associated with Haemophilus influenzae type B menin-
decreased cytosolic calcium concentrations.
gitis in infants and children 2 months of age or older. Use of glu-
5. Restoration of balance of neurotrophic factors (#nerve
cocorticoids in septic shock remains controversial.
growth factor [NGF]/"glial cell line–derived neurotrophic
factor [GDNF]).
Renal Diseases. Glucocorticoids are the first-line treatment in
6. Decreased disinhibition (decreased inhibition of glycinergic
nephrotic syndrome secondary to minimal change disease. Initial
neurotransmission).
daily doses of prednisone are 1 to 2 mg/kg for 6 weeks are followed
by a gradual tapering of the dose over 6 to 8 weeks, although some Infrequent but significant irreversible neurologic deficits have
nephrologists advocate alternate-day therapy. Objective evidence of occurred from transforminal epidural steroid spinal injections,
response, such as diminished proteinuria, is seen within 2 to 3 which have been attributed to undetected intra-arterial penetration
weeks in 85% of patients, and more than 95% of patients will of the procedure needle. Furthermore, it has been proposed that
have remission within 3 months. Research with other forms of steroid suspensions that are the most particulate may lead to the
renal disease, such as membranous and membranoproliferative glo- worst neurologic insult. Of the commercially available formula-
merulonephritis and focal sclerosis, has provided contradictory data tions commonly used for epidural injection, methylprednisolone
on the role of glucocorticoids. (Depo-Medrol) has the largest particulate size, followed by triam-
cinolone (Kenalog), followed by betamethasone (Celestone
Skin Diseases. Glucocorticoids are remarkably effective in the Soluspoan; containing 3.0 mg betamethasone sodium phosphate
treatment of a wide variety of inflammatory dermatoses, and topical [soluble ester that provides prompt activity] and 3.0 mg betameth-
application of 1% hydrocortisone ointment during an eczematous asone acetate [only slightly soluble, which has a slower onset but
eruption is an effective treatment. Glucocorticoids are administered affords some sustained activity]). Some practitioners use a com-
systemically for severe episodes of acute dermatologic disorders and pounding pharmacy to prepare a pure betamethasone sodium
for exacerbations of chronic disorders. phosphate (3.0 mg) formulation, which essentially provides a non-
particulate formulation.
Gastrointestinal Diseases. Glucocorticoid therapy is indicated
in selected patients with inflammatory bowel disease such as
Miscellaneous Diseases and Conditions
chronic ulcerative colitis and Crohn’s disease. In mild ulcerative
colitis, hydrocortisone (100 mg) can be administered as a retention Corticosteroids are also used in the management of sarcoidosis,
enema with favorable effects. In more severe acute exacerbations, thrombocytopenia, autoimmune destruction of erythrocytes,
oral prednisone (10–30 mg/day) is often employed and higher doses organ transplantation, and spinal cord injury.
can be used for severely ill patients.
Hepatic Diseases. More than 75% of patients with autoimmune Diagnostic Uses of Glucocorticoids
hepatitis show histologic remission when treated with prednisone.
However, use of corticosteroids in hepatic disease has been highly It is sometimes necessary to suppress the production of ACTH
controversial, and the role of corticosteroids in alcoholic liver dis- in order to identify the source of a particular hormone or to
ease is not fully defined. establish whether its production is influenced by the secretion of
ACTH.
Malignancies. Glucocorticoids are employed, because of their The dexamethasone suppression test is used for the diagnosis of
antilymphocytic effects, in the chemotherapy of acute lymphocytic Cushing’s syndrome and has also been used in the differential diag-
leukemia and lymphomas. Most commonly, glucocorticoids are one nosis of depressive psychiatric states.
component of combination chemotherapy administered under
scheduled protocols.
MINERALOCORTICOIDS AND
Cerebral Edema. Corticosteroids are of value in the reduction ANDROGENS
or prevention of cerebral edema associated with neoplasms, espe-
cially those that are metastatic. Although corticosteroids are fre- The principal mineralocorticoid in humans is aldosterone.
quently used for the treatment of cerebral edema caused by Aldosterone is synthesized primarily in the zona glomerulosa of
the adrenal cortex. The rate of aldosterone secretion is subject to Steroid Withdrawal
several influences. ACTH produces a modest stimulation of its
release, and even in the absence of ACTH, aldosterone secretion The most serious complication associated with steroid withdrawal is
falls only to about half the normal rate, indicating that other factors, acute adrenal insufficiency, which results from overly rapid with-
such as angiotensin, are important in regulating its secretion. drawal of corticosteroids after prolonged therapy owing to suppres-
Aldosterone and other steroids with mineralocorticoid proper- sion of the hypothalamic-pituitary-adrenal (HPA) axis. Many
ties promote the reabsorption of sodium from the distal convoluted patients recover from glucocorticoid-induced HPA suppression
and cortical collecting renal tubules, loosely coupled to the excre- within several weeks to months; however, in some individuals, the
tion of potassium and hydrogen ion. Sodium reabsorption in other time to recovery can be 1 year or longer. Patients who have received
organs such as sweat and salivary glands, gastrointestinal mucosa, supraphysiologic doses of glucocorticoids for a period of 2 to
and across cell membranes is also increased. Extreme levels of 4 weeks within the preceding year should be considered to have
aldosterone produced by tumors or overdosage with synthetic some degree of HPA impairment in settings of acute stress and
mineralocorticoids lead to hypernatremia, hypokalemia, metabolic should be treated accordingly.
alkalosis, increased plasma volume, and hypertension. In addition to this most severe form of withdrawal, a character-
Mineralocorticoids act by binding to the mineralocorticoid istic glucocorticoid withdrawal syndrome consists of fever,
receptor in the cytoplasm of target cells, especially principal cells myalgias, arthralgias, and malaise, which may be difficult to differ-
of the distal convoluted and collecting tubules of the kidney. The entiate from some of the underlying diseases for which steroid
drug-receptor complex activates a series of events similar to those therapy was instituted. Finally, pseudotumor cerebri, a clinical syn-
described previously for the glucocorticoids. It is of interest that this drome that includes increased intracranial pressure with papille-
receptor has the same affinity for cortisol, which is present in much dema, is a rare condition that is sometimes associated with
higher concentrations in the extracellular fluid. The specificity for reduction or withdrawal of corticosteroid therapy. In some cases,
mineralocorticoids at this site, as pointed out earlier, is due to the large doses of glucocorticoids may induce increased intracranial
presence of the enzyme 11b-hydroxysteroid dehydrogenase, which pressure as well.
converts cortisol to inactive cortisone.
Aldosterone is secreted at the rate of 0.125 mg/day in normal
individuals with a moderate dietary salt intake. The half-life of Prolonged Glucocorticoid Use
aldosterone injected in tracer quantities is 15 to 20 minutes, and
it does not appear to be firmly bound to serum proteins. The Other complications associated with prolonged therapy include iat-
metabolism of aldosterone is similar to that of cortisol, about half rogenic Cushing’s syndrome, fluid and electrolyte abnormalities,
of it appearing in the urine as conjugated tetrahydroaldosterone. hypertension, hyperglycemia, increased susceptibility to infection,
A small proportion is excreted free or as the 3-oxo glucuronide. osteoporosis, myopathy, behavioral disturbances, visceral fat
Small amounts of deoxycorticosterone (DOC) are also formed deposition, osteoporosis, myopathy, impaired wound healing, asep-
and released. Its actions, effects, and metabolism are qualitatively tic necrosis of hip, cataracts, growth arrest, and the characteristic
similar to those of aldosterone. DOC, which is also a precursor of habitus of steroid overdose, including fat redistribution, striae, and
aldosterone, is normally secreted in amounts of about 0.2 mg/day. ecchymoses.
Its half-life when injected into the human circulation is about Other serious side effects include peptic ulcers, masking of
70 minutes. The control of its secretion differs from that of aldos- bacterial and mycotic infections, nausea, dizziness, hypomania or
terone in that the secretion of DOC is primarily under the control acute psychosis, depression, hypokalemia, hypochloremic alkalosis,
of ACTH. glaucoma, heart failure in patients with heart disease, benign intra-
The other class of steroids synthesized by adrenal cortex is cranial hypertension, and growth retardation in children.
androgens. The principal androgen secreted is dehydroepiandroster- In general, the dosage should be kept as low as possible, and
one (DHEA); smaller amounts of androstenedione and testosterone intermittent administration (e.g., alternate-day) should be
are also secreted. The androgens contribute to the normal matura- employed when satisfactory therapeutic results can be obtained
tion process, but they do not stimulate or support major androgen- on this schedule. Even patients maintained on relatively low doses
dependent pubertal changes in humans. DHEA and its sulfate of corticosteroids may require supplementary therapy at times of
(DHEAS) may have other important physiologic actions owing to stress such as surgery, serious illness, or accidents.
the peripheral conversion of DHEA to more potent androgens or to These agents must be used with great caution in patients with
estrogens and to interaction with androgen and estrogen receptors, peptic ulcer disease, heart disease, or hypertension with heart failure
respectively. DHEA in patients with systemic lupus erythematosus and certain infectious illnesses such as varicella and tuberculosis,
may show beneficial effects with significant improvement of the psychoses, diabetes, osteoporosis, or glaucoma.
disease. DHEA replacement in adrenal insufficiency may produce
sense of well-being in female patients. The androgenic or estrogenic
actions of DHEA could explain the effects of the compound in both
situations. CLINICAL SUMMARY
Steroids are administered in multiple formulations for a variety of
TOXICITY disorders that share an inflammatory or immunologic basis.
However, steroids are not curative and rather provide palliative
Toxic effects result either from withdrawal of steroid therapy or care for most nonendocrine and nonreplacement uses. The deci-
from continued use at supraphysiologic doses. The side effects sion to start any particular patient with steroid therapy must be
from both categories are potentially life threatening and mandate weighed very carefully, considering the number and severity of side
a careful assessment of the risks and benefits in each patient. effects. In determining the dosage regimen to be used, the physi-
When the glucocorticoids are used for short periods (< 2 wk), it cian must consider the seriousness of the disease, the amount of
is unusual to see serious adverse effects even with moderately large drug likely to be required to obtain the desired effect, and the
doses. However, insomnia, behavioral changes (primarily hypoma- duration of therapy. However, a single dose of steroid, even a
nia), and acute peptic ulcers are occasionally observed even after large one, is virtually without harmful effects, and a short course
only a few days of treatment. Acute pancreatitis is a rare but serious of therapy is unlikely to cause harm in the absence of specific
acute adverse effect of high-dose glucocorticoids. contraindications.
442 Chapter 60 NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND CYCLOOXYGENASE-2 INHIBITORS
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Bamberger CM, et al. Glucocorticoid receptor-beta, a potential
Hochberg Z, Pacak K, Chrousos GP. Endocrine withdrawal syndromes.
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Meduri GU, et al. Prolonged methylprednisolone treatment suppresses
Bentley AM, et al. Prednisolone treatment in asthma: reduction in the
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Scheinman RI, et al. Role of transcriptional activation of I kBa in
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Shupnik M, Chrousos G, Siragy H: Glucocorticoids and
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Molecular to Clinical, 3rd ed. Mosby, 1998; pp 485–497.
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Chapter 60 underlying pathologic process, owing to its ability to suppress pro-

duction of inflammatory prostaglandins. NSAIDs are both analgesic
NONSTEROIDAL and anti-inflammatory and may also be useful for the treatment of
pain not involving inflammation.4
ANTI-INFLAMMATORY DRUGS NSAIDs differ from opioid analgesics in certain important
regards. These differences should be realized to provide the most
effective care to acute pain patients and include
AND CYCLOOXYGENASE-2 1. There is a ceiling effect to the dose-response curve of
INHIBITORS NSAIDs; therefore, after achieving an analgesic ceiling,
increasing the dose increases the side effects without resulting
in additional analgesia.
Muhammad A. Munir, Eli Cianciolo, and Jun-Ming Zhang 2. NSAIDs do not produce physical or psychological depen-
dence, and therefore, sudden interruption in treatment does
not cause a drug withdrawal syndrome.
3. NSAIDs are antipyretic.
INTRODUCTION NSAIDs are underrated for the treatment of chronic pain and
unnecessarily omitted for patients with chronic pain and those
Nonsteroidal anti-inflammatory drugs (NSAIDs) are often over- unable to take oral medications. Parental, topical, and rectal dosage
looked or dismissed for the treatment of moderate to severe pain. forms are available for some NSAIDs that are often underutilized.
NSAIDs can be used very effectively for the treatment of mild to All NSAIDs, including the subclass of selective cyclooxygenase
moderate pain or as the foundation for moderate to severe pain (COX)-2 inhibitors, are anti-inflammatory, analgesic, and antipy-
treatment regimens. NSAIDs with different mechanisms of action retic. NSAIDs are a chemically heterogeneous group of compounds,
can be attempted before advancing to the addition of opioid analge- often chemically unrelated, that nevertheless share certain therapeu-
sics. Unless contraindicated, any analgesic regimen for acute pain tic actions and adverse effects. Aspirin also inhibits the COX
should include an NSAID, even when pain is severe enough to enzymes but in a manner molecularly distinct from the competitive,
require the addition of an opioid.1 reversible, active site inhibitors and is often distinguished from the
NSAIDs.
NSAIDS
Pharmacokinetics and Pharmacodynamics
NSAIDs are useful for acute and chronic pain due to a variety of
disease processes including trauma, arthritis, surgery, and cancer.2,3 Most of the NSAIDs are rapidly and completely absorbed from the
NSAIDs are indicated for pain that involves inflammation as an gastrointestinal tract, with peak concentrations occurring within
SUGGESTED READINGS Dorr HG, Sippell WG. Prenatal dexamethasone treatment in pregnancies
at risk for congenital adrenal hyperplasia due to 21-hydroxylase
Axelrod L. Perioperative management of patients treated with
deficiency: effect on midgestational amniotic fluid steroid levels. J Clin
glucocorticoids. Endocrinol Metab Clin North Am 2003;32:367–383.
Endocrinol Metab 1993;76:117.
Annane D, Cavaillon JC. Corticosteroids in sepsis: from bench to bedside?
Franchimont D, et al. Glucocorticoids and inflammation revisited: the
Shock 2003;20:197–207.
state of the art. Neuroimmunomodulation 2002;10:247.
Bamberger CM, et al. Glucocorticoid receptor-beta, a potential
Hochberg Z, Pacak K, Chrousos GP. Endocrine withdrawal syndromes.
endogenous inhibitor of glucocorticoid action in humans. J Clin Invest
Endocrine Rev 2002–2003;24:523.
1995;95:2435.
Kalantaridou S, Chrousos GP. Clinical review 148: monogenic disorders
Barnes PJ, Adcock I. Anti-inflammatory actions of steroids: molecular
of puberty. J Clin Endocrinol Metab 2002-2003;87:2481.
mechanisms. Trends Pharmacol Sci 1993;14:436.
Meduri GU, et al. Prolonged methylprednisolone treatment suppresses
Bentley AM, et al. Prednisolone treatment in asthma: reduction in the
systemic inflammation in patients with unresolving ARDS: evidence for
numbers of eosinophils, T cells, tryptase-only positive mast cells, and
inadequate endogenous glucocorticoid secretion and inflammation-
modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression
induced immune cell resistance to glucocorticoids. Am J Resp Crit Care
within the bronchial mucosa. Am J Resp Crit Care Med 1996;153:551.
Med 2002;165:983.
Chin R. Adrenal crisis. Crit Care Clin 1991;7:23.
Morales AJ, et al. Effects of replacement dose of dehydroepiandrosterone
Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-
in men and women of advancing age. J Clin Endocrinol Metab
mediated inflammation. N Engl J Med 1995;332:1351.
1994;78:1360.
Saag KG. Glucocorticoid-induced osteoporosis. Endocrinol Metab Clin
and inhaled corticosteroid therapy. 1. General principles.
North Am 2003;32:135–157.
Scheinman RI, et al. Role of transcriptional activation of I kBa in
mediation of immunosuppression by glucocorticoids. Science
and inhaled corticosteroid therapy. 2. Review of the literature.
1995;270:283.
Shupnik M, Chrousos G, Siragy H: Glucocorticoids and
Coursin DB, Wood KE. Corticosteroid supplementation for adrenal
mineralocorticoids. In Brondy G, et al (eds): Human Pharmacology:
insufficiency. JAMA 2002;287:236–240.
Molecular to Clinical, 3rd ed. Mosby, 1998; pp 485–497.
Coghlan MJ, Elmore SW, Kym PR, Kort ME. The pursuit of differentiated
Tappy L, et al. Mechanisms of dexamethasone-induced insulin resistance
ligands for the glucocorticoid receptor. Curr Top Med Chem
in healthy humans. J Clin Endocrinol Metab 1994;79:1063.
2003;3:1617–1635.
Chapter 60 underlying pathologic process, owing to its ability to suppress pro-

duction of inflammatory prostaglandins. NSAIDs are both analgesic
NONSTEROIDAL and anti-inflammatory and may also be useful for the treatment of
pain not involving inflammation.4
ANTI-INFLAMMATORY DRUGS NSAIDs differ from opioid analgesics in certain important
regards. These differences should be realized to provide the most
effective care to acute pain patients and include
AND CYCLOOXYGENASE-2 1. There is a ceiling effect to the dose-response curve of
INHIBITORS NSAIDs; therefore, after achieving an analgesic ceiling,
increasing the dose increases the side effects without resulting
in additional analgesia.
Muhammad A. Munir, Eli Cianciolo, and Jun-Ming Zhang 2. NSAIDs do not produce physical or psychological depen-
dence, and therefore, sudden interruption in treatment does
not cause a drug withdrawal syndrome.
3. NSAIDs are antipyretic.
INTRODUCTION NSAIDs are underrated for the treatment of chronic pain and
unnecessarily omitted for patients with chronic pain and those
Nonsteroidal anti-inflammatory drugs (NSAIDs) are often over- unable to take oral medications. Parental, topical, and rectal dosage
looked or dismissed for the treatment of moderate to severe pain. forms are available for some NSAIDs that are often underutilized.
NSAIDs can be used very effectively for the treatment of mild to All NSAIDs, including the subclass of selective cyclooxygenase
moderate pain or as the foundation for moderate to severe pain (COX)-2 inhibitors, are anti-inflammatory, analgesic, and antipy-
treatment regimens. NSAIDs with different mechanisms of action retic. NSAIDs are a chemically heterogeneous group of compounds,
can be attempted before advancing to the addition of opioid analge- often chemically unrelated, that nevertheless share certain therapeu-
sics. Unless contraindicated, any analgesic regimen for acute pain tic actions and adverse effects. Aspirin also inhibits the COX
should include an NSAID, even when pain is severe enough to enzymes but in a manner molecularly distinct from the competitive,
require the addition of an opioid.1 reversible, active site inhibitors and is often distinguished from the
NSAIDs.
NSAIDS
Pharmacokinetics and Pharmacodynamics
NSAIDs are useful for acute and chronic pain due to a variety of
disease processes including trauma, arthritis, surgery, and cancer.2,3 Most of the NSAIDs are rapidly and completely absorbed from the
NSAIDs are indicated for pain that involves inflammation as an gastrointestinal tract, with peak concentrations occurring within
1 to 4 hours. Aspirin begins to acetylate platelets within minutes of NSAIDs but fewer adverse effects with respect to bleeding and the
reaching the presystemic circulation. The presence of food tends to gastrointestinal tract. COX-2–selective NSAIDs are no safer to the
delay absorption without affecting peak concentration. Most kidneys than nonselective NSAIDs. As of mid-2003, three members
NSAIDs are extensively protein-bound (95%–99%) and undergo of the initial class of COX-2 inhibitors, the coxibs, were approved
hepatic metabolism and renal excretion. In general, NSAIDs are for use in the United States and Europe. Both rofecoxib and valde-
not recommended in the setting of advanced hepatic or renal dis- coxib have now been withdrawn from the market in view of their
ease owing to their adverse pharmacodynamic effects (Table 60–1). adverse event profile. None of the coxibs has established clinical
efficacy over NSAIDs.
Aspirin covalently modifies COX-1 and COX-2, irreversibly
Mechanism of Action inhibiting COX activity. This is an important distinction from all
the NSAIDs because the duration of aspirin’s effects is related to the
All NSAIDs inhibit the enzyme COX, thereby inhibiting prostaglan- turnover rate of COXs in different target tissues. The duration of
din synthesis.5 In addition to peripheral effects, NSAIDs exert a effect of nonaspirin NSAIDs, which competitively inhibit the active
central action at the brain or spinal cord level that could be impor- sites of the COX enzymes, relates more directly to the time course of
tant for their analgesic effect.6 More than 30 years ago, the existence drug disposition. The importance of enzyme turnover in relief from
of multiple isoforms of COX were hypothesized. In the 1990s, the aspirin action is most notable in platelets, which, being anucleate,
second form (COX-2) was isolated. COX-1, the originally identified have a markedly limited capacity for protein synthesis. Thus, the
isoform, is found in platelets, the gastrointestinal tract, kidneys, and consequences of inhibition of platelet COX-1 last for the lifetime of
most other human tissues. COX-2 is found only in certain organs the platelet. Inhibition of platelet COX-1–dependent thromboxane
such as the kidneys and central nervous system (CNS) and is A2 (TXA2) formation, therefore, is cumulative with repeated doses
induced in peripheral tissues by noxious stimuli that cause inflam- of aspirin (at least as low as 30 mg/day) and takes roughly 8 to 12
mation and pain. The inhibition of COX-1 is associated with the days, the platelet turnover time, to recover once therapy has been
well-known gastrointestinal bleeding and renal side effects that can stopped.
occur with NSAID use. The therapeutic effects of NSAIDs are In addition, some NSAIDs may have prostanoid-independent
believed to be due predominantly to COX-2 and not the COX-1 inhibitory effects on neutrophil functions. Kankaanranta and cow-
inhibition. Until recently, all available NSAIDs nonselectively inhib- orkers7 examined the effects of acetylsalicyclic acid, diclofenace,
ited the COX-1 and COX-2 isoforms. Drugs that do so are termed indomethacin, ketoprofen, piroxicam, and tolfenamic acid on leu-
nonselective or traditional NSAIDs. Most NSAIDs inhibit both kotriene B4 (LTB4)–induced chemotaxis of human polymorphonu-
COX-1 and COX-2 with little selectivity, although some (conven- clear leukocytes (PMNs) in vitro. Tolfenamic acid inhibited LTB4-
tionally thought of as nonselective NSAIDs, diclofenac, meloxicam, induced chemotaxis (inhibitory concentration of 50% [IC50] 59
and nimesulide) exhibit a preference for COX-2 that is close to that microM), whereas the other compounds were ineffective. About
of celecoxib in vitro (but not across all dose ranges). Indeed, mel- 25% reduction in the chemotactic response was achieved with ther-
oxicam achieved approval in some countries as a selective inhibitor apeutic concentrations of tolfenamic acid.7 Kankaanranta and cow-
of COX-2. orkers7 suggested that the inhibition of PMN chemotaxis is an
COX-2–selective NSAIDs, which first became available in the additional mechanism in the anti-inflammatory action of tolfe-
late 1990s, provide all of the beneficial effects of nonselective namic acid and that this action is not ligand specific. NSAIDs
(e.g., diclofenac) appeared to increase kynurenate concentrations
in the spinal cord and diencephalons.8 Antagonism by kynurenate
of glutamate effects at the allosteric gylcine site of N-methyl-D-
Table 60^1. NSAIDs Potential Side Effects aspartate (NMDA) receptors may contribute to the antinociceptive
effects of NSAIDs.8
Bizzarri and associates9 showed that R- and S-ketoprofen, inde-
Cardiovascular NSAIDs: Hypertension, decreased pendently of their potency as prostaglandin inhibitors, proved
effectiveness of antihypertensive very efficacious in selective inhibition of interleukin-8 (IL-8)
medications, inhibition of platelet chemotaxis. Reduction of IL-8 migration by ketoprofen isomers
activation, propensity for bruising and was paralleled by selective inhibition of PMN response in terms
hemorrhage of intracellular calcium concentration (Ca2+i), increase and extra-
COX-2: Myocardial infarction, stroke, cellular signal–regulated kinase (ERK)–2 activation, two intracellu-
thromboembolic events lar mediators reported to be critical for PMN activities.9 Bizzarri
and associates9 concluded that inhibition of IL-8–induced PMN
Gastrointestinal Ulcers, anemia, gastrointestinal hemorrhage, chemotaxis may contribute to the anti-inflammatory activity of
perforation, diarrhea, nausea, anorexia, NSAIDs.
abdominal pain Another potential analgesic mechanism of NSAIDs is that they
Renal Deterioration of kidney function, analgesic may directly block recombinant and native (independent of COX
nephropathy, salt and water retention, inhibition) acid-sensing ion channels (ASICs).10,11 Ibuprofen and
edema, decreased effectiveness of diuretic flurbiprofen inhibit ASIC1a-containing channels and aspirin
medication, decreased urate excretion, ASIC3-containing channels and, thus, prohibit sensory neurons in
hyperkalemia an acidic environment triggering action potentials.11 Furthermore,
glucocorticoids or NSAIDs completely prevent the usual 6- to
CNS NSAIDs: Headache, dizziness, vertigo, 15-fold increase in mRNA levels of ASICs with inflammation,11
confusion, depression which largely occurs via the increase in nerve growth factor
Salicylates: Lowering of seizure threshold, (NGF) associated with inflammatory pain.12
hyperventilation
Hypersensitivity Vasomotor rhinitis, asthma, urticaria,
flushing, hypotension, shock Clinical Uses
CNS, central nervous system; COX-2, cyclooxygenase-2; GI, All NSAIDs, including selective COX-2 inhibitors, are analgesic,
gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs. anti-inflammatory, and antipyretic.
which NSAIDs or aspirin may cause ulceration is by local irritation

Analgesic
from contact of orally administered drug with the gastric mucosa.
When employed as analgesics, these drugs usually are effective only Coadministration of the PGE1 analogue misoprostol or proton
against pain of low to moderate intensity, such as dental pain. pump inhibitors in conjunction with NSAIDs can be beneficial in
Although their broad-spectrum maximal analgesic efficacy is gen- the prevention of duodenal and gastric ulceration.14
erally less than that of the opioids, NSAIDs lack the unwanted
adverse effects of opiates in the CNS, including respiratory depres-
Cardiovascular
sion and the development of physical dependence. NSAIDs do not
change the perception of sensory modalities other than pain. Selective inhibitors of COX-2 depress PGI2 formation by endothe-
Chronic postoperative pain or pain arising from inflammation is lial cells without concomitant inhibition of platelet thromboxane.
controlled particularly well by NSAIDs. Experiments in mice suggest that PGI2 restrains the cardiovascular
effects of TXA2, affording a mechanism by which selective inhibitors
might increase the risk of thrombosis.15,16 This mechanism should
Anti-inflammatory
pertain to individuals otherwise at risk of thrombosis, such as those
NSAIDs have their key application as anti-inflammatory agents in with rheumatoid arthritis, because the relative risk of myocardial
the treatment of musculoskeletal disorders, such as rheumatoid infarction is increased in these patients compared with patients with
arthritis and osteoarthritis. In general, NSAIDs provide only symp- osteoarthritis or no arthritis. The incidence of myocardial infarction
tomatic relief from pain and inflammation associated with the and stroke is increased in such at-risk patients when COX-2
disease and do not arrest the progression of pathologic injury to inhibitors are utilized as well as with traditional NSAIDs.17
tissue. Placebo-controlled trials have now revealed an increased incidence
of myocardial infarction and stroke in patients treated with rofe-
coxib,18 valdecoxi,19 and celecoxib,20 which appears consistent with
Antipyretics
a mechanism-based cardiovascular hazard for the class.17
NSAIDs reduce fever in most situations, but not the circadian vari-
ation in temperature or the rise in response to exercise or increased
Blood Pressure, Renal, and Renovascular Adverse Events
ambient temperature. It is important to select an NSAID with rapid
onset for the management of fever associated with minor illness in Traditional NSAIDs and COX-2 inhibitors have been associated
adults. Owing to the association with Reye’s syndrome, aspirin and with renal and renovascular adverse events.21 NSAIDs have little
other salicylates are contraindicated in children and young adults effect on renal function or blood pressure in normal human sub-
less than 12 years old with fever associated with viral illness. jects. However, in patients with congestive heart failure, hepatic
cirrhosis, chronic kidney disease, hypovolemia, and other states of
activation of the sympathoadrenal or renin-angiotensin systems,
Other Clinical Uses
prostaglandin formation becomes crucial in model systems and in
In addition to analgesic, antipyretic, and anti-inflammatory effects, humans.22
NSAIDs are also used for closure of patent ductus arteriosus in
neonates, to treat severe episodes of vasodilatation and hypotension
Analgesic Nephropathy
in systemic mastocytosis, treatment of biochemical derangement of
Bartter’s syndrome, chemoprevention of certain cancers such as Analgesic nephropathy is a condition of slowly progressive renal
colon cancer, and prevention of flushing associated with the use failure, decreased concentrating capacity of the renal tubule, and
of niacin. sterile pyuria. Risk factors are the chronic use of high doses of
combinations of NSAIDs and frequent urinary tract infections. If
recognized early, discontinuation of NSAIDs permits recovery of
Adverse Reactions of NSAID Treatment renal function.
Adverse effects of aspirin and NSAID therapy are listed in

Hypersensitivity
Table 60–1 and are considerably common in elderly patients.
Caution is warranted in choosing an NSAID for pain management Certain individuals display hypersensitivity to aspirin and NSAIDs,
in the elderly. as manifested by symptoms that range from vasomotor rhinitis with
profuse watery secretions, angioedema, generalized urticaria, and
bronchial asthma to laryngeal edema, bronchoconstriction, flush-
Gastrointestinal
ing, hypotension, and shock. Aspirin intolerance is a contraindica-
The most common symptoms associated with these drugs are tion to therapy with any other NSAID because cross-sensitivity can
gastrointestinal, including anorexia, nausea, dyspepsia, abdominal provoke a life-threatening reaction reminiscent of anaphylactic
pain, and diarrhea. These symptoms may be related to the shock. Despite the resemblance to anaphylaxis, this reaction does
induction of gastric or intestinal ulcers, which is estimated to not appear to be immunologic in nature.
occur in 15% to 30% of regular users. The risk is further increased Although less common in children, this syndrome may occur
in those with Helicobacter pylori infection, heavy alcohol consump- in 10% to 25% of patients with asthma, nasal polyps, or chronic
tion, or other risk factors for mucosal injury, including the concur- urticaria and in 1% of apparently healthy individuals.
rent use of glucocorticoids. All of the selective COX-2 inhibitors
have been shown to be less prone to induce endoscopically visua-
lized gastric ulcers than equally efficacious doses of traditional
NSAIDs.13 Selected Nonopioid Analgesics: Clinical Pearls
Gastric damage by NSAIDs can be brought about by at least two
distinct mechanisms. Inhibition of COX-1 in gastric epithelial cells (Table 60 ^2)
depresses mucosal cytoprotective prostaglandins, especially prosta-
1. Propionic acids: Ibuprofen and naproxen are the most com-
glandin I2 (PGI2) and PGE2. These eicosanoids inhibit acid secretion
monly used NSAIDs in the United States. These are available
by the stomach, enhance mucosal blood flow, and promote the secre-
without a prescription in the United States. The relative risk of
tion of cytoprotective mucus in the intestine. Another mechanism by
Table 60^2. NSAIDs: Comparative Pharmacology
Average Oral Dose Maximal

Proprietary Names Analgesic Dose Interval Daily Dose Analgesic Efficacy Compared with Plasma
Drug (not all-inclusive) (mg) (hr) (mg) Standards Half-Life (hr) Comments
Propionic Acids
Ibuprofen Motrin, Rufen, Nuprin, 200–400 4–6 2400 Superior at 200 mg to aspirin 2.0–2.5 Most commonly used NSAID in
Advil, Medipren, 650 mg United States; available without
others prescription
Naproxen Naprosyn 500 initially, 6–8 1,500 — 12–15 Better tolerated than
Naprolan 250 subsequently indomethacin and aspirin
Naproxen sodium Anaprox 550 initially, 6–8 1650 275 mg comparable with aspirin
275 subsequently 650 mg, with slower onset and
longer duration; 550 mg superior
to aspirin 650 mg
Naproxen sodium Aleve 220 8–12 — Comparable with aspirin 2-3 —
Fenoprofen Nalfon 200 4–6 3200 Superior at 25 mg to aspirin 1.5 SR preparation available
Ketoprofen Orudis 25–50 6–8 300 650 mg
Ketoprofen OTC Actron, Orudis-K+ 12.5–25 4–6 —
Oxaprozin Daypro 600 12–24 1200 24–69

Pyrrolacetic Acids
Ketorolac Toradol 30 or 60 IM or 6 150 first In the range of 6–12 mg of 6 Limit treatment to 5 days; may
30 IV initially, day, 120 morphine precipitate renal failure in
15 or 30 IV thereafter dehydrated patients; average
or IM dose in elderly 10–15 IM/IV q6h
subsequently
Indolacetic Acids
Indomethacin Indocin Comparable with aspirin 650 mg 2 Not routinely used because of
Indocin, SR high incidence of GI and CNS
Indochron ER side effects; rectal and SR oral
forms available for adults
Salicylates
Acetylated
Aspirin Numerous 500–1000 4–6 4000 0.25 Because of risk of Reye’s
syndrome, do not use in
children under 12 with possible
viral illness; rectal suppository
available for children and adults;
SR preparation available
Continued
Table 60^2. NSAIDs: Comparative Pharmacologyçcont’d
Average Oral Dose Maximal

Proprietary Names Analgesic Dose Interval Daily Dose Analgesic Efficacy Compared with Plasma
Drug (not all-inclusive) (mg) (hr) (mg) Standards Half-Life (hr) Comments
Modified
Diflunisal Dolobid 1000 initially, 8–12 1500 500 mg superior to aspirin 8–12 Dose in elderly 500–1000 mg/day.
500 subsequently 650 mg, with slower onset and does not yield salicylate
longer duration; an initial dose
of 1000 mg significantly shortens
time to onset
Salicylate Salts
Choline magnesium Trilisate 1000–1500 12 2000–3000 Longer duration of action than 9–17 Unlike aspirin and NSAIDs, does
Trisalicylate Tricosal aspirin 650 mg not increase bleeding time
Sulindac Clinoril 150 12 400 7.8 active
metabolite
= 16
Etodolac Lodine 300–400 8–12 1000 More potent than sulindac and
naproxen; less potent than
indomethacin
Tolmetin Tolectin 200–600 8 1800 5
Anthranilic Acids
Mefenamic acid Ponstel 500 initially, 6 1500 Comparable with aspirin 650 mg 2 In United States use is restricted
250 subsequently to interval of 1 wk
Phenylacetic Acids
Diclofenac potassium Cataflam 50 8 150 Superior in efficacy and analgesic More selective for COX-2 than
duration to aspirin 650 mg COX-1
Enolic Acids
Meloxicam Mobic 7.5–15 24 15 15–20 Tenfold selective for COX-2
Piroxicam Feldene 20–40 24 40 50
Naphthylalkanone
Nabumetone Relafen 1000 initially, 8–12 2000 Pain relief equal to aspirin, 24 Fewer GI side effects
500–750 indomethacin, naproxen, and
subsequently sulindac
COX-2 Selective
Celecoxib Celebrex 200–400 12–24 400 Anti-inflammatory and analgesic 11 Only COX-2 selective not
effect similar to naproxen withdrawn from U.S. market.
CNS, central nervous system; COX, cyclooxygenase; GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; OTC, over the counter.
myocardial infarction is unaltered by ibuprofen, but it is reduced 7. Phenylacetic acid: Diclofenac potassium has been shown to be
by about 10% by naproxen, compared with a reduction of 20% superior in efficacy and analgesic duration to aspirin and also
to 25% by aspirin. Ibuprofen and naproxen are better tolerated somewhat selectively inhibits COX-2 more than COX-1.
than aspirin and indomethacin and have been used in patients 8. Enolic acids: Meloxicam has long half-life and roughly 10-fold
with a history of gastrointestinal intolerance to other NSAIDs. COX-2 selectivity on average in ex vivo assays.27 There is sig-
2. COX-2 selective: Three members of the initial class of COX-2 nificantly less gastric injury compared with piroxicam (20 mg/
inhibitors, the coxibs, were approved for use in the United day) in subjects treated with 7.5 mg/day of meloxicam, but the
States. Both rofecoxib and valdecoxib have now been withdrawn advantage is lost with 15 mg/day.28
from the market in view of their adverse event profile. 9. Naphthylalkanone: Nabumetone is a prodrug; it is absorbed
Valdecoxib has been associated with a threefold increase in car- rapidly and is converted in the liver to one or more active meta-
diovascular risk in two studies of patients undergoing cardiovas- bolites, principally 6-methoxy-2-naphtylacetic acid, a potent
cular bypass graft surgery.23 Based on interim analysis of data nonselective inhibitor of COX.29 There is no significant exposure
from the Adenomatous Polyp Prevention on Vioxx (APPROVe) from enterohepatic circulation. The incidence of gastrointestinal
study,19 which showed a significant (twofold) increase in the ulceration appears to be lower than with other NSAIDs.30
incidence of serious thromboembolic events in subjects receiving
25 mg of rofecoxib relative to placebo, rofecoxib was withdrawn
from the market worldwide.24 The U.S. Food and Drug
Administration (FDA) advisory panel agreed that rofecoxib SUMMARY
increased the risk of myocardial infarction and stroke and that
the evidence accumulated was more substantial than that for NSAIDs are useful analgesics for many pain states, especially those
valdecoxib and appeared more convincing than that for celecox- involving inflammation. Their use is frequently overlooked in
ib. Effects attributed to inhibition of prostaglandin production patients with postoperative and chronic pain. Unless there is a
in the kidney (hypertension and edema)occur with nonselective contraindication, the use of an NSAID should be routinely consid-
COX inhibitors and also with celecoxib. Studies in mice and ered to manage acute pain and certain chronic cancer and noncan-
some epidemiologic evidence suggest that the likelihood of cer pain states.
hypertension on NSAIDs reflects the degree of inhibition of
COX-2 and the selectivity with which it is attained. Thus, the
risk of thrombosis, hypertension, and accelerated atherogenesis
may be mechanistically integrated. The coxibs should be avoided
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bances and bleeding are common adverse effects with therapeu- 15. McAdam BF, Catella-Lawson F, Mardini IA, et al. Systemic
tic doses of aspirin. Because of the possible association with biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human
Reye’s syndrome, aspirin should not be used for children youn- pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci
ger than the age of 12 with viral illness, particularly influenza. U S A 1999;96:272–277.
448 Chapter 61 ANTIDEPRESSANTS
16. Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of specific 25. Ehrlich G. Primary drug therapy: aspirin vs. the nonsteroidal anti-
inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, inflammatory drugs. Postgrad Med 1983 May; Spec:9–17.
and vasoactive eicosanoids. J Pharmacol Exp Ther 1999;289:735–741. 26. Stuart JJ, Pisko EJ. Choline magnesium trisalicylate does not impair
17. FitzGerald GA. COX-2 and beyond: approaches to prostaglandin platelet aggregation. Pharmatherapeutica 1981;2:547–551.
inhibition in human disease. Nat Rev Drug Discov 2003;2:879–890. 27. Panara MR, Renda G, Sciulli MG, et al. Dose-dependent inhibition
18. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events of platelet cyclooxygenase-1 and monocyte cyclooxygenase-2 by
associated with rofecoxib in a colorectal adenoma chemoprevention meloxicam in healthy subjects. J Pharmacol Exp Ther
trial. N Engl J Med 2005;352:1092–1102. 1999;290:276–280.
19. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of 28. Patoia L, Santucci L, Furno P, et al. A 4-week, double-blind, parallel-
COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. group study to compare the gastrointestinal effects of meloxicam
N Engl J Med 2005;352:1081–1091. 7.5 mg, meloxicam 15 mg, piroxicam 20 mg and placebo by means of
20. Solomon SD, McMurray JV, Pfeffer MA, et al. Cardiovascular risk faecal blood loss, endoscopy and symptom evaluation in healthy
associated with celecoxib in a clinical trial for colorectal adenoma volunteers. Br J Rheumatol 1996;35:61–67.
prevention. N Engl J Med 2005;352:1071–1080. 29. Patrignani P, Panara MR, Greco A, et al. Biochemical and
21. Cheng HF, Harris RC. Cyclooxygenases, the kidney, and hypertension. pharmacological characterization of the cyclooxygenase activity of
Hypertension 2004;43:525–530. human blood prostaglandin endoperoxide synthases. J Pharmacol Exp
22. Patrono C, Dunn MJ. The clinical significance of inhibition of renal Ther 1994;271:1705–1712.
prostaglandin synthesis. Kidney Int 1987;32:1–12. 30. Scott DL, Palmer RH. Safety and efficacy of nabumetone in
23. Furberg CD, Psaty BM, FitzGerald GA. Parecoxib, valdecoxib and osteoarthritis: emphasis on gastrointestinal safety. Aliment Pharmacol
cardiovascular risk. Circulation 2005;111:249. Ther 2000;14:443–452.
24. FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med
2004;351:1709–1711.
Chapter 61 efficacy for depression and anxiety disorders, their use is limited in
pain medicine, because they have limited analgesic properties.3 One
ANTIDEPRESSANTS caveat is that the SSRIs are particularly effective for anxiety disor-
ders and should be considered a second-line agent in treating anx-
Ajay D.Wasan,Howard S. Smith, and Charles E. Argoff iety disorders in patients with chronic pain. The SNRIs are effective
analgesics for neuropathic pain and are an effective anxiety treat-
ment in those without pain (i.e., analgesia independent of mood
effects). Thus, the SNRIs are the first-line choice for those patients
with neuropathic pain and an anxiety disorder.
INTRODUCTION TCAS
Antidepressants, a heterogeneous group of drugs, also have broad Cyclic antidepressants have been in use for nearly 50 years and are
efficacy for a range of conditions other than depression, particularly generally as effective as SSRIs for depression. Of all the antidepres-
anxiety disorders (e.g., panic disorder, generalized anxiety disorder, sant classes, their use in pain medicine has been the best studied.
social anxiety, post-traumatic stress disorder, and obsessive- However, they have a more problematic side effect profile and may
compulsive disorder), eating disorders, attention deficit hyperactiv- be lethal in overdose. The term tricyclic signifies a shared chemical
ity disorders, premenstrual dysphoric disorder, and chronic pain. structure with two joined benzene rings. Imipramine, the first TCA,
Many of the antidepressant classes may exhibit analgesia for a broad was approved for the treatment of depression over 25 years ago.
range of pain conditions independent of their effects on mood, being Advantages of TCAs include their lower cost (compared with
effective in those with and without psychiatric comorbidity (function SSRIs) and the fact that they are well studied. Also, TCAs can be
is varied and related in part to structure) (Fig. 61–1).1 efficacious in SSRI nonresponders for depression. Some evidence
Antidepressant medications may be classified as follows2: favors the use of TCAs in patients with severe melancholic depres-
sion.4 In addition, TCAs have a more established track record than
1. Cyclic antidepressants, including the tricyclic antidepressants
SSRIs in treating a variety of chronic pain conditions, including
(TCAs) and tetracyclic antidepressants (e.g., maprotiline).
neuropathies, fibromyalgia, and migraine,5,6 and have been demon-
2. Selective serotonin reuptake inhibitors (SSRIs).
strated to possess far superior analgesic qualities than most other
3. Serotonin-norepinephrine reuptake inhibitors (SNRIs).
classes of antidepressants in both preclinical and clinical studies.
4. Dopamine-norepinephrine reuptake inhibitors (DNRIs).
Disadvantages of TCAs include a wide range of adverse effects
5. Norepinephrine reuptake inhibitors (NRIs).
such as anticholinergic effects, orthostatic hypotension, effects on
6. Monoamine oxidase inhibitors (MAOIs).
the cardiac conduction system, weight gain, sedation, sexual dys-
7. The miscellaneous category of ‘‘atypical antidepressants.’’
function, restlessness, ‘‘jitteriness,’’ heightened anxiety on initial
This chapter focuses on three classes of antidepressants that are dosing, and cardiotoxicity in overdose. Before starting a TCA, in
commonly used and have analgesic properties, the TCAs, SNRIs, those patients older than 45 years or in any patient with a history of
and DNRIs. The NRIs and MAOIs, although they do have analgesic cardiac disease, the QTc interval on an electrocardiogram (ECG)
properties, are rarely prescribed anymore, except perhaps for treat- should be checked to see if it is less than 450 msec. Using TCAs in
ment-resistant depression or anxiety disorders. Although the SSRIs patients with QTc intervals higher than 450 msec places them at a
are the most frequently prescribed class of antidepressants and have greater risk of developing torsades de pointes arrhythmia, even
16. Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of specific 25. Ehrlich G. Primary drug therapy: aspirin vs. the nonsteroidal anti-
inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, inflammatory drugs. Postgrad Med 1983 May; Spec:9–17.
and vasoactive eicosanoids. J Pharmacol Exp Ther 1999;289:735–741. 26. Stuart JJ, Pisko EJ. Choline magnesium trisalicylate does not impair
17. FitzGerald GA. COX-2 and beyond: approaches to prostaglandin platelet aggregation. Pharmatherapeutica 1981;2:547–551.
inhibition in human disease. Nat Rev Drug Discov 2003;2:879–890. 27. Panara MR, Renda G, Sciulli MG, et al. Dose-dependent inhibition
18. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events of platelet cyclooxygenase-1 and monocyte cyclooxygenase-2 by
associated with rofecoxib in a colorectal adenoma chemoprevention meloxicam in healthy subjects. J Pharmacol Exp Ther
trial. N Engl J Med 2005;352:1092–1102. 1999;290:276–280.
19. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of 28. Patoia L, Santucci L, Furno P, et al. A 4-week, double-blind, parallel-
COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. group study to compare the gastrointestinal effects of meloxicam
N Engl J Med 2005;352:1081–1091. 7.5 mg, meloxicam 15 mg, piroxicam 20 mg and placebo by means of
20. Solomon SD, McMurray JV, Pfeffer MA, et al. Cardiovascular risk faecal blood loss, endoscopy and symptom evaluation in healthy
associated with celecoxib in a clinical trial for colorectal adenoma volunteers. Br J Rheumatol 1996;35:61–67.
prevention. N Engl J Med 2005;352:1071–1080. 29. Patrignani P, Panara MR, Greco A, et al. Biochemical and
21. Cheng HF, Harris RC. Cyclooxygenases, the kidney, and hypertension. pharmacological characterization of the cyclooxygenase activity of
Hypertension 2004;43:525–530. human blood prostaglandin endoperoxide synthases. J Pharmacol Exp
22. Patrono C, Dunn MJ. The clinical significance of inhibition of renal Ther 1994;271:1705–1712.
prostaglandin synthesis. Kidney Int 1987;32:1–12. 30. Scott DL, Palmer RH. Safety and efficacy of nabumetone in
23. Furberg CD, Psaty BM, FitzGerald GA. Parecoxib, valdecoxib and osteoarthritis: emphasis on gastrointestinal safety. Aliment Pharmacol
cardiovascular risk. Circulation 2005;111:249. Ther 2000;14:443–452.
24. FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med
2004;351:1709–1711.
Chapter 61 efficacy for depression and anxiety disorders, their use is limited in
pain medicine, because they have limited analgesic properties.3 One
ANTIDEPRESSANTS caveat is that the SSRIs are particularly effective for anxiety disor-
ders and should be considered a second-line agent in treating anx-
Ajay D.Wasan,Howard S. Smith, and Charles E. Argoff iety disorders in patients with chronic pain. The SNRIs are effective
analgesics for neuropathic pain and are an effective anxiety treat-
ment in those without pain (i.e., analgesia independent of mood
effects). Thus, the SNRIs are the first-line choice for those patients
with neuropathic pain and an anxiety disorder.
INTRODUCTION TCAS
Antidepressants, a heterogeneous group of drugs, also have broad Cyclic antidepressants have been in use for nearly 50 years and are
efficacy for a range of conditions other than depression, particularly generally as effective as SSRIs for depression. Of all the antidepres-
anxiety disorders (e.g., panic disorder, generalized anxiety disorder, sant classes, their use in pain medicine has been the best studied.
social anxiety, post-traumatic stress disorder, and obsessive- However, they have a more problematic side effect profile and may
compulsive disorder), eating disorders, attention deficit hyperactiv- be lethal in overdose. The term tricyclic signifies a shared chemical
ity disorders, premenstrual dysphoric disorder, and chronic pain. structure with two joined benzene rings. Imipramine, the first TCA,
Many of the antidepressant classes may exhibit analgesia for a broad was approved for the treatment of depression over 25 years ago.
range of pain conditions independent of their effects on mood, being Advantages of TCAs include their lower cost (compared with
effective in those with and without psychiatric comorbidity (function SSRIs) and the fact that they are well studied. Also, TCAs can be
is varied and related in part to structure) (Fig. 61–1).1 efficacious in SSRI nonresponders for depression. Some evidence
Antidepressant medications may be classified as follows2: favors the use of TCAs in patients with severe melancholic depres-
sion.4 In addition, TCAs have a more established track record than
1. Cyclic antidepressants, including the tricyclic antidepressants
SSRIs in treating a variety of chronic pain conditions, including
(TCAs) and tetracyclic antidepressants (e.g., maprotiline).
neuropathies, fibromyalgia, and migraine,5,6 and have been demon-
2. Selective serotonin reuptake inhibitors (SSRIs).
strated to possess far superior analgesic qualities than most other
3. Serotonin-norepinephrine reuptake inhibitors (SNRIs).
classes of antidepressants in both preclinical and clinical studies.
4. Dopamine-norepinephrine reuptake inhibitors (DNRIs).
Disadvantages of TCAs include a wide range of adverse effects
5. Norepinephrine reuptake inhibitors (NRIs).
such as anticholinergic effects, orthostatic hypotension, effects on
6. Monoamine oxidase inhibitors (MAOIs).
the cardiac conduction system, weight gain, sedation, sexual dys-
7. The miscellaneous category of ‘‘atypical antidepressants.’’
function, restlessness, ‘‘jitteriness,’’ heightened anxiety on initial
This chapter focuses on three classes of antidepressants that are dosing, and cardiotoxicity in overdose. Before starting a TCA, in
commonly used and have analgesic properties, the TCAs, SNRIs, those patients older than 45 years or in any patient with a history of
and DNRIs. The NRIs and MAOIs, although they do have analgesic cardiac disease, the QTc interval on an electrocardiogram (ECG)
properties, are rarely prescribed anymore, except perhaps for treat- should be checked to see if it is less than 450 msec. Using TCAs in
ment-resistant depression or anxiety disorders. Although the SSRIs patients with QTc intervals higher than 450 msec places them at a
are the most frequently prescribed class of antidepressants and have greater risk of developing torsades de pointes arrhythmia, even
N N
C H C H C
H C
H H
CH3
CH2 CH2 C CH2
H
CH2 CH2 CH2 CH2
N N N N
CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3

Amitriptyline Imipramine Trimipramine Doxepin
C H H
C C C
H H H
H CH2 CH2 CH2 CH2
CH2 CH2 CH2 CH2
N N N N
H CH3 H CH3 H CH3 H CH3

Nortriptyline Desipramine Protryptyline Maprotiline
Figure 61^1. Chemical structures of tricyclic antidepressants (TCAs). First row, Tertiary amineTCAs. Second row, Secondary amine
TCAs. (From SudohY, Cahoon EE, Gerner P, Wang GK.Tricyclic antidepressants as long-acting local anesthetics. Pain 2003;103:49^55.)
when lower doses of TCAs are used (10–75 mg), as is common in the most potent effects on the noradrenergic system is desipramine
pain medicine. The combined direct and indirect cost of care with (nortriptyline also exhibits preferential inhibition of NE reuptake
TCAs may be higher than with SSRIs because of the need for more over 5-HT reuptake).
frequent visits.7 The secondary amine TCAs include
n Nortriptyline (Pamelor).
n Desipramine (Norpramin).
TCA Categories n Protriptyline (Vivactil).
n Amoxapine (Asendin).
The TCAs can be divided into amines and their demethylated sec-
ondary amine derivatives. In addition, maprotiline (Ludiomil) is
classified as a tetracyclic. Categorization of Side Effects
The tertiary amine TCAs include
Of the TCAs, nortripyline has the lowest incidence of side effects
n Amitriptyline (Elavil).
and, thus, is the preferred TCA for use in chronic pain patients, for
n Imipramine (Tofranil).
treatment of either pain or depression. Whereas nortriptyline is
n Trimipramine (Surmontil).
more sedating than desipramine, it has a lower incidence of ortho-
n Clomipramine (Anafranil).
static hypotension and dizziness. Nortriptyline also has a rate of
n Doxepin (Sinequan).
analgesia comparable with that of amitriptyline, despite the latter
Although clomipramine has been considered by some to possess perhaps having broader effects on multiple analgesic mechanisms,
a relatively balanced inhibition of serotonin (5-HT) and norepi- as discussed later.
nephrine (NE) reuptake, clomipramine is generally regarded as
the TCA with the most potent effects on the serotonergic system,
Anticholinergic Effects
followed by amitriptyline and imipramine. Few clinical studies have
evaluated clomipramine as an analgesic agent. Among the TCAs, Anticholinergic side effects result from the affinity of TCAs for
amitriptyline has the most potent anticholinergic effects and desi- muscarinic cholinergic receptors. Anticholinergic symptoms
pramine has the least, and thus is the least sedating. The TCA with include dry mouth, blurred vision, constipation, urinary hesitancy,
tachycardia, and ejaculatory difficulties. Secondary amine TCAs Table 61^1. Elimination Half-lives of Antidepressants
tend to cause fewer anticholinergic effects than tertiary amine
TCAs. Desipramine is likely the least anticholinergic of this group. Antidepressant Elimination Half-life (hr)
Paroxetine 21
Antihistaminergic Effects Fluoxetine 87
Antihistaminergic side effects result largely from histaminergic Sertraline 26
H1-receptor blockade. Common side effects include sedation, car- Fluvoxamine 19
bohydrate craving, and weight gain. Weight gain with TCAs can be Citalopram 35
substantial, averaging 1 to 3 pounds per month of treatment. Clomipramine 23
Secondary amine TCAs tend to cause less sedation than tertiary Imipramine 28
amine TCAs. Doxepin is the most potent antihistaminergic antide- Amitriptyline 21
pressant. Doxepin has potent effects on H1- as well as H2-receptors. Desipramine 21
It has been formulated as a topical agent for itching (e.g., H1), and it
Amoxapine 8
has been shown to be able to reduce mean basal gastric acid output
by 46% (e.g., H2).8 Doxepin 17
Orthostatic hypotension results from a1-adrenergic receptor Venlafaxine 3.6
antagonism (amitriptyline may be the worst in this regard). Duloxetine 12
Secondary amine TCAs (e.g., nortriptyline) are generally believed Reboxetine 13
to be less likely to cause orthostatic hypotension than tertiary amine Nefazodone 3
TCAs. Mirtazapine 30
Bupropion 12
Cardiac Effects
Data from Richelson E. Pharmacology of antidepressants. Mayo Clin Proc
Cardiac toxicity may occur in susceptible individuals and after TCA 2001;76:511–527.
overdose. The TCAs should be avoided in patients with bifascicular
heart block, left bundle branch block, or a prolonged QT interval,
because they may slow conduction through the atrioventricular
node. TCAs have quinidine-like effects on cardiac conduction and
are classified as class I antiarrhythmics. Caution should be used
when coadministering TCAs with other drugs from this antiar-
rhythmic class, including quinidine, procainamide, and disopyr- treatment are effective.13 But there is a subset of patients who will
amide. Follow-up ECGs should be performed appropriately and have analgesia only if doses in the antidepressant range are used.
compared with baseline pre–TCA-therapy ECGs. Hence, one should consider using antidepressant doses (100–400
mg/day) in conjunction with blood level monitoring if lower-dose
TCAs are not effective for pain.
Large interindividual variation in the pharmacokinetics of TCAs
CLINICAL PHARMACOLOGYOF exists. A 30-fold range in steady-state plasma concentrations on
ANTIDEPRESSANTS identical doses has been reported for imipramine,15 with similar
variations (on this order or lower) for other TCAs (e.g., amitripty-
line, desipramine, nortriptyline, and clomipramine).16–20 This
Elimination Half-life and Blood Levels of appears largely due to the presence/activity of the sparteine/debri-
Antidepressants soquine oxygenase (cytochrome P-450 [CYP450] CYP2D6).21
About 7% of whites are poor metabolizers of sparteine (devoid of
The elimination half-lives of several antidepressants are presented in hepatic CYP2D6)22,23; fast extensive metabolizers with high activity
Table 61–1. These data refer only to the parent compound. Active of CYP2D6 also exist.
metabolites can significantly prolong the half-life of antidepressants.
For example, fluoxetine’s active metabolite norfluoxetine has a half-
life of 7 to 15 days. Furthermore, coadministration of an SSRI (e.g., Drug-Drug Interactions Involving the
fluoxetine) and a TCA (e.g., amitriptyline) may lead to significant CYP450 Isoenzymes
increases in SSRI and TCA serum concentration.
Compounds with a half-life between 12 and 36 hours can be CYP450 isoenzymes, including 1A2, 2C, 2D6, 3A3/4, are located on
given once per day and maintain steady-state levels. Drugs with microsomal membranes throughout the body. Their mechanism of
shorter half-lives have to be administered several times per day or metabolism is best known in the liver and bowel wall, where they
once per day in extended-release formulations. Fluoxetine, which oxidatively metabolize medications as well as prostaglandins, fatty
has a half-life of 4 days (87 hr) and a longer half-life (7–15 days) for acids, and steroids. Alteration in function of these isoenzymes may
its metabolite, is available in a weekly formulation for maintenance cause clinically significant pharmacokinetic drug-drug interactions
therapy.9 via changes in drug levels.
Large individual variability exists in the blood levels obtained CYP450 2D6 full or partial inhibition by one of several antide-
with a fixed dose of an antidepressant owing to individual variabil- pressants (fluoxetine, paroxetine, sertraline, duloxetine, and bupro-
ity in the activity of hepatic drug-metabolizing enzymes.10 Thus, pion) may lead to increased levels of TCAs, b-blockers,
some patients, particularly the elderly who may have impaired antiarrthythmics, and several narcotic analgesics (codeine, hydro-
hepatic enzyme systems, can have toxic levels of TCAs at low xycodone, oxycodone, tramadol, and dextromethorphan), which
doses, such as 25 mg. A relationship between blood levels and clin- are substrated for this enzyme. Also, a potential consequence is
ical depression response has been established only for TCAs.11 For inhibition of the conversion of codeine to its active form (mor-
TCAs, monitoring trends of blood levels can be used to avoid tox- phine), with subsequent reduction of its efficacy. However, there
icity.12 If the TCA is used for pain treatment, most studies have are yet no data indicating that those patients on antidepressants
found that doses typically less than those used for depression and opioids experience less or more opioid effectiveness.
Indeed, evidence indicates that pain patients with untreated depres- 1. TCAs have analgesic effects in patients who have pain with-
sion or anxiety disorders, regardless of whether they are on an out depression associated with: painful diabetic peripheral
antidepressant, experience less opioid analgesia compared with neuropathy,29,30 postherpetic neuralgia (PHN),31,32 central
matched controls.24 poststroke pain,33 arthritis,34 and migraine headaches.35,36
CYP450 3A4 inhibition by nefazodone and fluoxamine has 2. TCAs generally exhibit analgesic effects within a week or so,
potential consequences in increased levels of numerous commonly whereas antidepressive effects may be seen gradually over
prescribed substrates, including carbamazepine, cyclosporine, about 3 to 8 weeks.37
alprazolam, midazolam, zolpidem, zaleplon, calcium channel 3. The TCA dose to achieve analgesia is generally much lower
blockers, statins, sildenafil, oral contraceptives, and pimozide than doses need to achieve antidepressive effects. In an imip-
(arrhythmia risk). By interacting with cisapride or pimozide, ramine dose-titration study of patients with chronic painful
CYP450 3A4 inhibitors may lead to QT prolongation and torsades diabetic peripheral neuropathy, plasma drug concentrations
de pointes. of imipramine plus its active metabolite desipramine needed
CYP450 1A2 inhibition by fluvoxamine may lead to toxicity on to be at or above 400 nM in order to obtain 95% of individ-
clozapine, theophylline, and other 1A2 substrates. ual maximal responses in the majority of patients.38
CYP450 2C inhibition by fluoxetine, fluvoxamines, sertraline,
tranylcypromine, ketoconazole, and fluconazole has a potential TCAs appear to exhibit acute analgesic effects in experimental
for increased levels of anticoagulant (warfarin) and diazepam. For human studies39 as well as animal models.40–43
a more detailed list of inhibitors and substrates for the CYP450 Amitriptyline, a TCA, has been labeled a ‘‘dirty drug’’ because it
isoenzymes, see Table 61–2.25–28 hits multiple receptors. This may contribute to its many side effects
It is currently well accepted that selected antidepressants possess as well as its good analgesic efficacy.
independent analgesic effects for peripheral neuropathic pain, A meta-analysis of 39 placebo-controlled trials of antidepressant
which may occur totally irrespective of their antidepressant effects. analgesia in chronic pain revealed that a larger effect size occurs
Multiple threads of evidence have led to these conclusions with agents that combine effects on both serotonergic and noradren-
regarding the analgesic effects of TCAs: ergic systems rather than the more specific agents.44
Table 61^2. Inhibitors and Substrates for the Cytochrome P- 450 Isoenzymes
Isoenzyme Substrates Inhibitors Inducers

2D6 TCAs, b-blockers, antiarrhythmics Fluoxetine, paroxetine, sentraine,
(mexiletine, flecainide, propafenone, bupropion, phenothiazines, cocaine,
encainide), diltiazem, nifedipine, methadone, yohimbine, quinidine,
nisoldipine, codeine, hydroxycodone, protease inhibitors, antimalarials,
oxycodone, tramadol, odansetron, cimetidine, lansoprazole, antifungal
phenothiazines, risperidone, (terbinafine)
dextromethorphan, mCPP
3A Pimozide, alprazolam, modazolam, Nefazodone, fluvoxamine, fluoxetine, Carbamazepine, phenytoin,
zolpidem, zapelon, buspirone, sertraline, antifungals, macrolide oxcarbazepine, phenobarbital,
carbamazepine, tertiary TCAs, quetiapine, antibiotics, antiretrovirals, ritonavir (chronic), efavirenz
clozapine, ziprasadone, haloperidol, quinuprisin/dalfopristin, calcium (also inhibitor), rifampin,
cisapride, ergotamines, alfentanil, fentanyl, channel blockers, grapefruit juice, St. John’s wort
methadone, sildenafil, H1- blockers, cimetidine
sibutramine, montelukast, oral
contraceptive pills, testosterone, Ca2+
channel blockers, cyclosporine, tacrolimus,
HMG-CoA reductase inhibitors,
amiodarone, propafenone, quinidine,
antiretrovirals
1A2 Clozapine, olanzapine, haloperidol, tertiary Fluvoxamine, fluroquinolones, Omeprazole, cigarette smoking,
TCAs, tacrine, theophylline, aminophylline, (ciprofloxacin and others), charred meats
caffeine, R-warfarin, cyclobenzaprine, cimetidine, antiarrhythmics (arylhydrocarbons),
phenacetin, pro-carcinogens (mexiletine, propafenone), cruciferous vegetables
zafirlukast (e.g., Brussel sprouts)
2C subfamily Doazepam, tertiary TCAs, phenytoin, THC, Fluoxetine, fluvoxamine, sertraline, Rifampin, phenobarbital,
S-warfarin, NSAIDs, celecoxib, piroxicam, tranylcypromine, omeprazole, carbamazepine
dapsone, proprandol, mephenytoin, valproate, isoniazid, ketoconazole,
tolbutamide, glyburide, glipizide, fluconazole, ritonavir,
rosiglitazone, tamoxifen, angiotensin-2 sulfaphenazole, ticlopidine,
blockers (losartan, valsartan) zafirlukast, fluvastatin, cimetidine
HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; mCPP, metachlorophenylpiperazine; NSAIDs, nonsteroidal anti-inflammatory drugs; TCAs, tricyclic
antidepressants; THC, tetrahydrocannabinol.
Modified from references 25–28.
ANTIDEPRESSANT MECHANISMS OF Rats differ from sheep or humans; topical administration differs
ANALGESIA from intrathecal or perineural application; and motor function dif-
fers from proprioception or nociception. However, in efforts to
Inhibition of Monoamine Reuptake have a very rough idea of local anesthetic potency, N-phenylethyl
amitriptyline is about 50 times as potent as lidocaine, amitriptyline
Amitriptyline inhibits the reuptake of both 5-HT and NE45,46 but is about 8 times as potent as lidocaine, and bupivacaine is about 4
also interacts with opioid47,48 and adenosine receptors49 and blocks times as potent as lidocaine. However, N-phenylethyl amitriptyline
a2-adrenergic,49 N-methyl-D-aspartate (NMDA),50,51 nicotinic,49 appears to have a narrow therapeutic index.65 N-Methyl amitripty-
muscarinic cholinergic,49 and histaminergic receptors. In addition, line is similar to amitriptyline but with a much longer duration of
amitriptyline blocks various voltage-gated ion channels (e.g., K+, action.61 Furthermore, N-methyl amitriptyline appears to exhibit
Na+, Ca2+)52,53 and induces apoptosis as well as inhibits the mito- significant differential blockade (i.e., selective block of specific
chondrial inner membrane anion uniporter.49 [pain-transmitting] nerve fiber group) and greater than amitripty-
Multiple mechanisms of action contribute to the analgesic line bupivacaine (lidocaine) in sheep.61
effects of antidepressants, and these may be different for different Because amitriptyline blocks persistently open sodium channels
antidepressants, which may involve peripheral as well as central at low plasma concentrations, amitriptyline (with a significantly
mechanisms, and are multifactorial, modulating receptor effects longer half-life) may have utility in the perioperative period.
and channel effects. Lidocaine has been demonstrated to be effective for chronic neuro-
Although it has become apparent that agents with mechanisms pathic pain states66 and has also been shown to diminish acute
of action that block reuptake of NE are important in antinocicep- postoperative pain as well as facilitate return of normal bowel func-
tion, it appears that serotonergic mechanisms are important as well. tion.67 Preclinical evidence also seems to support this notion.
Preliminary observations seem to indicate that so-called NRIs (also Amitriptyline demonstrates antinocicepetive effects in experimental
known as NARIs) appear to have less antinociceptive activity than mouse models of pain states.68 In addition, amitriptyline in com-
SNRIs. So, affecting both serotonergic and noradrenergic systems bination with morphine had better analgesic effects that morphine
may be important for maximal antinociception. Matsuzawa- alone.68
Yanagida and coworkers54 proposed that agents that block the re- Fridrich and associates69 investigated the adverse effects of
uptake of 5-HT may have important pain modulating mechanisms preoperative intravenous amitriptyline (not currently approved by
in the cortex, with effects ameliorating the emotional experience of the U.S. Food and Drug Administration [FDA]) infused over 1 hour
pain and its concomitant anxiety when modulating serotonergic for 25 mg, 50 mg, and 100 mg (n = 5 per group). Plasma levels of
neurotransmission in the basolateral amygdala and anterior cingu- amitriptyline/nortriptyline were determined, and adverse effects
lated cortex. In addition, it seems that these agents may exhibit were recorded in a predetermined symptom list. Infusion of
antinociceptive effects when inhibiting the 5-HT transporter in 25- and 50-mg amitriptyline appears to be well tolerated; however,
the primary somatosensory cortex (S1).54 study of higher doses was terminated when 1 subject in the 100-mg
Furthermore, from preclinical evidence, Zhao and colleagues55 group developed severe bradycardia. Intravenous infusion of
revealed a likely significant role of the central serotonergic system in amitriptyline (25–50 mg over 1 hr) did not create side effects
mediating the analgesic effects of antidepressant medications. It beyond dry mouth, drowsiness, and dizziness in 2 of our 10 other-
has been proposed that chronic TCA treatment may lead to up- wise healthy participants receiving the 25- to 50-mg dose. An
regulation of 5-HT1A and/or down-regulation of 5-HT1A receptors, appropriately powered future trial is necessary to determine a
which may explain a mild increased antinociceptive efficacy after potential role of amitriptyline in decreasing postoperative pain.69
several weeks of treatment with a stable dose.56,57 However, as
noted, the SSRIs have not been shown to be effective analgesics.
NMDA Antagonist Activity
Sodium Channel (Na+) Blockade Repetitive small afferent nociceptive input into the dorsal horn of
the spinal cord may lead to facilitated processing of nociceptive
Sodium channel blockade may contribute to the analgesic efficacy signals involving NMDA receptor complexes, which may be appre-
of antidepressants.58 Amitriptyline appears to be the most potent ciated behaviorally as hyperalgesia.70,71 The processes previously
TCA in its ability to block sodium channels with doxepin as second discussed may be ameliorated by the intrathecal administration of
best, though both were superior to bupivacaine. Desipramine was NMDA antagonists.72
somewhat less effective than bupivacaine, and nortriptyline was The intrathecal administration of NMDA induces a thermal
one of the least effective TCAs at blocking sodium channels.1 hyperalgesia, which may be reversed by NMDA antagonists73 as
Sudoh and colleagues59 concluded that N-methyl doxepin is a well as by intrathecal amitriptyline.74 Also, NMDA antagonists
potent Na+ channel blocker and a long-acting local anesthetic for and amitriptyline may diminish the hyperalgesia phase 2 (but not
rat sciatic nerve blockade. phase 1 [the acute nociceptive component]) of the formalin-
Although amitriptyline is more potent than bupivacaine in a induced tissue injury model.75 Intrathecal amitriptyline acts func-
subcutaneous infiltration model60 and in intrathecal administration tionally as an NMDA antagonist in the presence of rat cutaneous
in rat and sheep,61 when amitriptyline was evaluated for ulnar nerve inflammation-induced thermal hyperalgesia.74 Intrathecal NMDA
blockade in healthy human volunteers, it was found to be less effec- antagonists and intrathecal amitriptyline have been demonstrated
tive than bupivacaine, contrary to the results of a large number of to reduce thermal hyperalgesia (rodent Bennett model) and tactile
animal studies.62 This may be due to the thicker nerve sheaths allodynia (rodent Chung model).76
present in humans compared with rats, presenting more of a barrier
for amitriptyline to penetrate into the nerve.62,63 Local anesthetics
and TCAs both bind more tightly to the inactivated state of the Opioid Receptor Interactions
sodium channel.64 Thus, neural blockade with amitriptyline (like
local anesthetics) is use-dependent.52 Preclinical evidence has suggested that there is some type of inter-
Potency is extremely difficult to assess because differences exist action of TCAs with central opioid receptors that may contribute to
in different agents, different routes of administration, different the mechanisms of TCA-induced analgesia40,41,47,48 despite the low
environments, different species, different sodium channels, and dif- affinity of TCAs for the opioid receptors47–49 because TCA antino-
ferent measurements. ciceptive effects are partially reversed by naloxone.40,41,47,48
Downstream signaling resulting from antidepressants binding to the mechanism of intrathecal lidocaine reversing established tactile
receptors may have similarities with that of downstream signaling allodynia. It is conceivable that inhibiting phosphorylation of
resulting from opioids binding to receptors. Gherlardini and extracellular signal–regulated kinase (ERK) generation may be one
coworkers77 administered mice intracerebroventricular antisense of the analgesic mechanisms that some antidepressants may possess.
oligonucleotides (aODN), complementary to the sequence of the
mRNA sequence of the a-subunit of Gi1, Gi2 and Gi3 proteins,
18 to 24 hours prior to the hot plate test. Treatment with aODN CLINICALUSE OF ANTIDEPRESSANTS
against Gi-a, Gi2-a and Gi3-a dose-dependently reduced the anal-
gesia induced by both amitriptyline (15 mg/kg subcutaneously) and A study of TCA utilization patterns in 1145 patients found that
clomipramine (25 mg/kg subcutaneously).77 Ghelardini and cow- TCAs were used in 25% of patients referred to a multidisciplinary
orkers77 stated that their results indicated that amitriptyline and pain center.83 Seventy-three percent of the patients were treated with
clomipramine induce their analgesic effect by activating all three low doses (the equivalent of 50 mg of amitriptyline),83 and only
subtypes of the Gi-proteins. 34 (12%) with full doses (the equivalent of at least 150 mg of ami-
Benbouzid and colleagues78 suggested that d opioid receptors are triptyline). The remaining 43 (15%) received intermediate doses.
critical for TCA antinociceptive actions in the preclinical treatment Amitriptyline was the most commonly used drug (58%).83
of neuropathic allodynia. Benbouzid and colleagues78 used a murine Evidence-based guidelines have recommended three groups of
model of neuropathic pain induced by sciatic nerve constriction via first-line analgesic agents for patients with nonfocal neuropathic
implantation of a cuff (a 2-mm section of split PE-20 polyethylene pain, including
tubing) to produce neuropathic-induced mechanical allodynia. After
1. TCAs.
2 weeks of treatment, nortriptyline reversed the neuropathic-induced
2. SNRIs.
allodynia in wild-type mice; however, nortriptyline treatment was
3. Calcium channel a2d ligands (i.e., gabapentin and pregabalin)
ineffective in a Delta opioid receptor (DOR)-deficient line of DOR
(Box 61–1).84
knockout mutant mice even after 5 weeks of treatment.78 Also, acute
injections of naltrindole (a specific DOR antagonist) at doses of 1 or Other articles have also endorsed TCA antidepressants as first-
5 mg/kg, respectively, partially or totally suppressed the antinocicep- line agents for the treatment of peripheral neuropathic pain,85–88
tive benefit of 21 days of nortriptyline treatment in neuropathic despite the fact that TCAs are not FDA approved for peripheral
mice.78 Benbouzid and colleagues78 hypothesized that chronic TCA neuropathic pain.
treatment may increase DOR expression level, alter their membrane Overall, antidepressants exhibited a number needed to treat
localization, boost their functionality/activity, or perhaps lead to (NNT) of 3.1 (85% confidence interval [CI] 2.2–5.1) and a relative
oligomerization between DOR and adrenergic receptors. risk (RR) of 2.2 (95% CI 1.5–3.1).84 For diabetic neuropathy, the
NNT for effectiveness was 1.3 (85% CI 1.2–1.5) with an RR of 12.4
(95% CI 5.2–29.2) (five studies), and for PHN, NNT of 2. (95% CI
a-Adrenergic Receptor Blockade 2.0–4.1) and an RR of 2.2 (95% CI 1.6–3.1) (four studies).84 There
was some limited evidence that TCAs may not be effective in
Other potential mechanisms that may conceivably contribute to human immunodeficiency virus (HIV)–related neuropathies. The
TCA-induced analgesia include TCA effects leading to blockade of number needed to harm (NNH) for major adverse effects, defined
a2-adrenergic receptors. Ozdoğan and associates79 tested the acute as an event leading to withdrawal from a study, was 28 (95% CI
analgesic effects of amitriptyline and the a2-adrenoceptor agonist 17.6–68.9) for amitriptyline and 16.2 (95% CI 8.0–436.0) for venla-
clonidine in wild-type control and in a2A-adrenoceptor knockout faxine. The NNH for minor adverse effects was 6 (95% CI 4.2–10.7)
mice in hot-plate and tail-flick tests. Amitriptyline-induced analge- for amitriptyline and 9.6 (95% CI 3.5–13.0) for venlafaxine.84
sia was lost in a2A-adenoceptor knockout mice, which led Ozdoğan Both TCAs and SNRIs (e.g., venlafaxine and duxloxetine) have
and associates79 to conclude that a2A-adrenoceptors appear to have NNTs of approximately 3.84 This means that for approximately
a significant role in amitriptyline-induced acute analgesia in mice. every three patients with neuropathic pain who are treated with
Ghelardini and colleagues80 also suggested that antinociception
induced by amitriptyline and imipramine is mediated by a2A-
adrenoceptors.
BOX 61^1 TREATMENT SELECTION CONSIDERATIONS
FOR FIRST-LINE MEDICATIONS AND FOR
TRPV1 Receptors OPIOID AGONISTS
Another potential analgesic mechanism of TCAs may involve TCA Secondary AmineTCAs
modulation of TRPV1 receptors. Oláh and coworkers81 performed Nortriptyline, desipramine (use a tertiary amineTCA only if a secondary
amineTCA is not available)
functional assays on TRPV1-expressing cells that support direct,
dose-dependent inhibition of vanilloid-induced 45Ca2+-uptake at SSNRIs
micromolar concentrations: calmidazolium (broad range) is greater Duloxetine*
than or equal to trifluoperazine. Venlafaxine
Calcium Channel a2-d Ligands
Gabapentin
Inhibition of Extracellular Signal^Regulated Kinase Pregabalin*
Phosphorylation Topical Lidocaine
Opioid Agonists{
Attenuation of phosphorylation of p38 mitogen-activated pro-
Morphine, oxycodone, methadone, levorphanol
tein kinase (MAPK) in the activated microglial may reveal a Tramadol
new mechanism for intrathecal lidocaine reversing tactile *Lack long-term clinical experience and safety data because new to market.
allodynia after chronic constriction injury in rats. Gu and associ- {
First-line only in certain circumstances.
ates82 studied the chronic constriction injury in rats and demon- SSNRIs, selective serotonin-norepinephrine reuptake inhibitors; TCAs, tricyclic antidepressants.
strated that attenuating phosphorylation of p38 MAPK in the From Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic
activated microglia of spinal cord may at least contribute to pain: evidence-based recommendations. Pain 2007;132;237^251.
either of these antidepressants, one will get at least moderate pain include dry mouth, sweating, dizziness, orthostatic hypotension,
relief.84 There is evidence to suggest that other antidepressants may fatigue, constipation, and problems with micturation. The SSRIs
be effective but numbers of participants are insufficient to calculate and SNRIs with side effects including nausea, vomiting, and dys-
robust NNTs.84 SSRIs are generally better tolerated by patients; pepsia are generally better tolerated than TCAs. Drop-outs owing to
however, only limited evidence exists for analgesic efficacy. adverse effects during clinical studies for antidepressants in neuro-
pathic pain can be utilized to help calculate NNH as the reciprocal
value of the difference in drop-out rate on active and placebo treat-
ment, and this provides a very rough estimate of tolerability of the
PHARMACOLOGIC MANAGEMENTOF medications. The overall NNHs are roughly 13.6 for TCAs, 19 for
SSRIs, and 21.5 for SNRIs as well as bupropion.
NEUROPATHIC PAIN
TCAs DNRIs
NNT represents the number of patients who need to be treated to Semenchuk and coworkers97 performed a single-center, outpatient,
obtain one patient with more than 50% pain relief. NNTs have been randomized, double-blind, placebo-controlled, cross-over study
calculated from pooled data from randomized, placebo-controlled bupropion for neuropathic pain. It consisted of two phases:
trials and used by some investigators to give a very rough estimate Forty-one nondepressed patients with neuropathic pain spent
of the efficacy of different antidepressants for the treatment of neu- 6 weeks in each phase in random order and received identical
ropathic pain.89 The NNT of TCAs for peripheral neuropathic pain tables of 150 mg bupropion SR or placebo.97 Patients were
has been reported to be 2.3 (95% CI 2.1–2.7).89 TCAs with balanced instructed to take 1 tablet once daily for 1 week followed by
effects on the serotonergic and noradrenergic systems (e.g., amitrip- 1 tablet twice daily for 5 weeks. While the patients took bupropion
tyline) have an NNT of 2.2, whereas TCAs with predominant effects SR, neuropathic pain relief was improved or much improved in
on the noradrenergic system (e.g., desipramine) have an NNT of 30 (73%) patients, and 1 of these patients became pain-free.97
2.5, SNRIs (e.g., venlafaxine) have an NNT of 4.6, and SSRIs have The mean average pain score at baseline was 5.7, which remained
an NNT of 6.8.89 unchanged at the end of week 6 with placebo but decreased by
Various TCAs have been studied for neuropathic pain condi- 1.7 points to 4.0 (P < .001) during therapy with bupropion SR.
tions with NNTs of 2.3 for PHN,90 2.3 for PHN,91 and 2.1 for Pain relief with bupropion SR was significant at week 2 (P < .05)
PHN92 comparing favorably with oxycodone 2.8 for PHN, pregab- and continued throughout weeks 3 through 6 (P < .001).97 A sig-
alin for PHN 3.4, and gabapentin for PHN 3.2. In diabetic neuro- nificant decrease in interference of pain on quality of life was
pathy, NNT was 1.4 in a study with optimal doses of imipramine observed while patients were receiving bupropion SR compared
versus 2.4 in other studies on the entire group of TCAs.91 with placebo. Side effects experienced with bupropion SR were
Furthermore, the NNT of TCAs remains low across different neu- not dose-limiting and consisted primarily of dry mouth, insomnia,
ropathic pain conditions ranging from 1.791 to 3.4.92 headache, gastrointestinal upset, tremor, constipation, and
O’Connor and coworkers93 compared the net health effects and dizziness.97
costs resulting from treatment with different first-line PHN medi- A surprisingly low NNT of 1.6 was calculated for the DNRI
cations. Desipramine appeared to be more effective and less expen- bupropion in one relatively small group of 41 patients with a range
sive than gabapentin or pregabalin for the treatment of older of different etiologies of peripheral neuropathic pain.97 However,
patients with PHN in whom it is not contraindicated.93 anecdotal clinical experience does not match these results. Owing
Saarto and Wiffen94 updated their original Cochrane Review to bupropion’s inhibition of NE and dopamine, Katz and associates98
published in Issue 3 (2005) of the Cochrane Library. To determine studied it in nonneuropathic chronic low back pain but did not find
the analgesic efficacy and safety of antidepressant drugs in neuro- evidence for efficacy.
pathic pain, Saarto and Wiffen94 reviewed 61 trials of 20 antide- Although bupropion may not yield optimal analgesia, it may still
pressants (3293 participants) that were considered eligible. Saarto have benefits in treating patients with chronic pain. In animal
and Wiffen94 found that TCAs are effective for at least moderate models, chronic administration of bupropion (2 or 5 mg/kg)
relief of neuropathic pain and, overall, have an NNT of 3.6 (95% CI during the induction phase (days 1–9) of morphine administration
3.0–4.5) with an RR of 2.1 (95% CI 1.8–2.5). delayed the development of tolerance to the antinociceptive action
Staiger and associates95 concluded that TCAs and tetracyclic of morphine and also reversed naloxone-precipitated (2 mg/kg)
antidepressants appear to produce moderate symptom reductions withdrawal jumps.99 Conversely, acute administration of bupropion
for patients with chronic low back pain independent of depression (2 or 5 mg/kg) on day 10 (i.e., during the expression phase of
status. morphine dependence) reduced the incidence of naloxone-precipi-
To assess the efficacy of nortriptyline, a TCA, as an analgesic in tated withdrawal jumps without affecting tolerance to the analgesic
chronic back pain without depression, Atkinson and colleagues96 effect.99 Joshi and colleagues99 suggested a potential use of bupro-
conducted a randomized, double-blind, placebo-controlled, 8-week pion in opioid tolerance and dependence.
trial of patients recruited from primary care and general orthopedic Furthermore, even preclinical evidence suggests that combined
settings who had chronic low back pain (pain at T6 or below on a reuptake inhibition of 5-HT and NE appears to confer a greater
daily basis for 6 mo). Reduction in pain-intensity scores was degree of antinociception in animal models of experimental pain
significantly greater for subjects randomized to nortriptyline (dif- than drugs that inhibit only the reuptake of 5-HT or NE.100,101 In
ference in mean change 1.68, 95% –0.001, CI –3.36, P = .050) who fact, the selective attenuation of mechanical allodynia by bupropion
experienced a reduction of pain by 22% compared with a 9% suggests that the additional reuptake of dopamine may further
reduction for subjects on placebo.96 Subgroup analyses of subjects enhance 5-HT and NE reuptake-mediated antinociception after
who completed the study with radicular pain on nortriptyline (n = nerve injury.101
5) had significantly (P < .05) better analgesia and overall outcome
than did those on placebo (n = 6). Atkinson and colleagues reported
that their results suggest noradrenergic mechanism may be relevant SNRIs
to analgesia in back pain.96
TCAs should be avoided in patients with cardiac conduction This section summarizes evidence for the use of three SNRI agents,
disturbances, cardiac decompensation, and epilepsy. Side effects duloxetine, venlafaxine, and minalcipran, as analgesics. Currently,
minalcipran is not FDA approved for any indication, but it is used Table 61^3. Selective Serotonin-Norepinephrine
in other countries. Reuptake Inhibitors
Several published studies as well as multiple published guidelines
support the use of duloxetine for the management of diabetic Agent Selectivity 5 -HT:NE
peripheral neuropathic pain (DPNP). The results of three multi-
center, randomized, controlled studies concluded that duloxetine at Venlafaxine 30:1
a dose of 60 mg daily and 60 mg twice daily may effectively relieve Duloxetine 10:1
pain in patients with DPNP. As would be expected, discontinua- Milnacipran 1:1
tions owing to adverse effects were more common in duloxetine-
treated patients than in those who received placebo.102–104 The 5-HT, serotonin; NE, norepinephrine.
efficacy of duloxetine has also been emphasized in a number of
different published guidelines for neuropathic pain.84,96,105
Three published studies examined the potential benefit of dulox-
etine for the treatment of fibromyalgia. Each of these multicenter, coworkers121 published a study of 24 healthy volunteers investigated
randomized, controlled studies examined the effect of duloxetine on in a placebo-controlled crossover design that showed that reboxe-
patients with fibromyalgia with or without depression. In one study, tine is superior to placebo in controlling capsaicin-evoked human
duloxetine-treated patients improved signicantly more on the total pain (reducing the N1 and P2 components of laser somatosensory
Fibromyalgia Impact Questionnaire (FIQ) score than placebo- (nociceptive)-evoked potentials (this may not be a particularly good
treated patients but did not specifically improve more on the FIQ model of chronic human neuropathic pain).
pain component of this tool.106 Duloxetine-treated patients did
experience greater reductions in the Brief Pain Inventory (BPI)
average pain severity score compared with placebo-treated SUMMARY
patients.106 In a second study, patients treated with fibromyalgia
who were treated with duloxetine 60 mg daily or 60 mg twice Antidepressants are a heterogeneous group of agents, some of which
daily had significantly greater improvements in the BPI pain sever- are not only useful for the treatment of major depressive disorders
ity and interference score, the FIQ, the Clinical Global Impression but also independently possess analgesic qualities that may have
of Severity, and the Patient Global Impression of Improvement utility in the therapeutic regimen of a number of painful conditions.
compared with placebo.107 The results of a recently published 6-
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458 Chapter 62 ANTIEPILEPTIC DRUGS
115. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of treatment of major depressive disorder. Eur Neuropsychopharmacol
minalcipran in patients with fibromyalgia. J Rheumatol 2008;18:122–127.
2005;32:1975–1985. 119. Canavero S, Bonicalzi V, Paolotti R. Reboxetine for central pain:
116. Ito M, Yoshida K, Kimura H, et al. Successful treatment of a single-blind prespective study. Clin Neuropharmacol
trigeminal neuralgia with minalcipran. Clin Neuropharmacol 2002;25:238–239.
2007;30:183–185. 120. Aragona M, Bancheri L, Perinelli D, et al. Randomized double-blind
117. Andreoli V, Caillard V, Deo RS, et al. Reboxetine, a new comparison of serotonergic (Citalopram) versus noradrenergic
noradrenaline selective antidepressant, is at least as effective as (Reboxetine) reuptake inhibitors in outpatients with somatoform,
fluoxetine in the treatment of depression. J Clin Psychopharmacol DSM-IV-TR pain disorder. Eur J Pain 2005;9:33–38.
2002;22:393–399. 121. Schüler P, Seibel K, Chevts V, Schaffler K. Analgesic effect of the
118. Papakostas GI, Nelson JC, Kasper S, Möller HJ. A meta-analysis of selective noradrenalin reuptake inhibitor reboxetine. Nervenartz
clinical trials comparing reboxetine, a norepinephrine reuptake 2002;73:149–154.
inhibitor, with selective serotonin reuptake inhibitors for the
Chapter 62 can be effective for these conditions, whereas many AEDs can be
effective for NP of a different etiology. Indeed, patients with post-
ANTIEPILEPTIC DRUGS herpetic neuralgia and trigeminal neuralgia represent only a small
proportion of those with NP, and only a fraction of the use of
Gary McCleane gabapentin and pregabalin is actually for postherpetic neuralgia.
Therefore, to maximize the chances of therapeutic success when
treating patients with NP, one should not be constrained to using
only those AEDs with a specific indication for that condition.
Rather, therapy should be guided by a logical appreciation of the
pharmacologic properties of members of the AED class, the
patient’s broad medical condition, and an understanding of cur-
INTRODUCTION rently available trial evidence.
It is now over 60 years since the first description of the use of an
It is not unusual for patients to be surprised and even shocked when AED in NP management. In the original case report, phenytoin was
a suggestion is made that an antiepileptic drug (AED) be used in the used in the management of trigeminal neuralgia. Since that time,
treatment of their pain. Some find it hard to comprehend the logic many other AEDs have had an analgesic effect attributed to them.
that suggests the use of AEDs in pain treatment, and yet a failure to What now seems apparent is that those AEDs with an effect on
explain the rationale of AED use may cause problems when the nerve fiber can reduce NP whereas those with primarily synaptic
patient goes on to read the packet insert that often accompanies effects do not. That leaves a large, and increasing, number of com-
her or his AED medication. Has the doctor made a mistake by pounds in the AED class that have variable effects on NP. These
suggesting an epilepsy drug? Are these drugs safe? Will I have an drugs are unified by their antiepileptic and anti-NP effects but differ
epileptic fit if I suddenly stop the medication, as is often suggested to some extent in their modes of action. Therefore, from a clinical
in the packet insert? Communication and explanation may help to perspective, if one AED fails to help a patient with NP (or if it is not
reduce patient anxiety, improve compliance, and reassure the tolerated because of side effects), it is often logical to try a different
patient that her or his treating physician knows what he or she AED with an alternative mode of action.
are talking about. Before considering individual AEDs, some principles of treat-
From a medical perspective, less concern about AED use should ment must be established. Every time an AED is tried for pain
be apparent. Neuropathic pain (NP) arises when there is injury treatment, it should be part of a ‘‘therapeutic trial.’’ That is to say,
or insult to neural tissue and may be compounded by attempts by the drug is initiated at an appropriate dose, and with knowledge of
the central nervous system to reduce the effects of the stimulus by its half-life, a dose escalation schedule is implemented until either a
activating descending inhibitory and excitatory drives. These effects useful effect is produced or intolerable side effects are experienced
can produce pain in the absence of a painful stimulus or can produce (Table 62–1). When dose escalation to a ceiling level is achieved,
an excessive pain response to a normally innocuous event. Given after a short time, a judgment should be made as to the drug’s effi-
that neural overactivity is a cardinal feature of NP and epilepsy, the cacy or, more precisely, its effect on the patient’s quality of life. If no
use of AEDs becomes logical. That said, we might be better served if pain relief, insufficient pain relief, or intolerable side effects are
these agents were described as ‘‘neuropathic pain analgesics’’ or produced, the drug should be stopped and an alternative considered
something similar, particularly because some of the emerging after a washout period. AEDs, when used at appropriate doses, have
AEDs are being developed for NP treatment and not epilepsy. an almost immediate effect, so there is no place for sustained therapy
One of the advances in pain therapy apparent in the last two in the absence of pain relief, particularly because withdrawal of some
decades is the increasing number of AEDs with official NP indica- AEDs can be complicated by withdrawal reactions when used over a
tions. For example, both gabapentin and pregabalin have posther- protracted period. Too often, one meets patients who have been
petic neuralgia as an indication, whereas historically, carbamazepine taking pain drugs, including AEDs, for protracted periods despite
had an indication for the treatment of trigeminal neuralgia in the the fact that they have obtained no analgesic benefit. This may result
United Kingdom. These indications are a reflection of the hard from lack of appropriate medical follow-up and assessment of treat-
evidence of AEDs’ beneficial effects in a proportion of patients ment effects or from ignorance of the treating doctor, because there
with these conditions. However, it does not necessarily mean that seems to be an attitude in some that if a drug has an indication that
AEDs are the best drugs for the management of these types of NP. suggests a pain-relieving effect in a particular condition, then
Clinical experience and some trial evidence suggest that other AEDs despite the patient’s claim that no relief is being produced, he or
115. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of treatment of major depressive disorder. Eur Neuropsychopharmacol
minalcipran in patients with fibromyalgia. J Rheumatol 2008;18:122–127.
2005;32:1975–1985. 119. Canavero S, Bonicalzi V, Paolotti R. Reboxetine for central pain:
116. Ito M, Yoshida K, Kimura H, et al. Successful treatment of a single-blind prespective study. Clin Neuropharmacol
trigeminal neuralgia with minalcipran. Clin Neuropharmacol 2002;25:238–239.
2007;30:183–185. 120. Aragona M, Bancheri L, Perinelli D, et al. Randomized double-blind
117. Andreoli V, Caillard V, Deo RS, et al. Reboxetine, a new comparison of serotonergic (Citalopram) versus noradrenergic
noradrenaline selective antidepressant, is at least as effective as (Reboxetine) reuptake inhibitors in outpatients with somatoform,
fluoxetine in the treatment of depression. J Clin Psychopharmacol DSM-IV-TR pain disorder. Eur J Pain 2005;9:33–38.
2002;22:393–399. 121. Schüler P, Seibel K, Chevts V, Schaffler K. Analgesic effect of the
118. Papakostas GI, Nelson JC, Kasper S, Möller HJ. A meta-analysis of selective noradrenalin reuptake inhibitor reboxetine. Nervenartz
clinical trials comparing reboxetine, a norepinephrine reuptake 2002;73:149–154.
inhibitor, with selective serotonin reuptake inhibitors for the
Chapter 62 can be effective for these conditions, whereas many AEDs can be
effective for NP of a different etiology. Indeed, patients with post-
ANTIEPILEPTIC DRUGS herpetic neuralgia and trigeminal neuralgia represent only a small
proportion of those with NP, and only a fraction of the use of
Gary McCleane gabapentin and pregabalin is actually for postherpetic neuralgia.
Therefore, to maximize the chances of therapeutic success when
treating patients with NP, one should not be constrained to using
only those AEDs with a specific indication for that condition.
Rather, therapy should be guided by a logical appreciation of the
pharmacologic properties of members of the AED class, the
patient’s broad medical condition, and an understanding of cur-
INTRODUCTION rently available trial evidence.
It is now over 60 years since the first description of the use of an
It is not unusual for patients to be surprised and even shocked when AED in NP management. In the original case report, phenytoin was
a suggestion is made that an antiepileptic drug (AED) be used in the used in the management of trigeminal neuralgia. Since that time,
treatment of their pain. Some find it hard to comprehend the logic many other AEDs have had an analgesic effect attributed to them.
that suggests the use of AEDs in pain treatment, and yet a failure to What now seems apparent is that those AEDs with an effect on
explain the rationale of AED use may cause problems when the nerve fiber can reduce NP whereas those with primarily synaptic
patient goes on to read the packet insert that often accompanies effects do not. That leaves a large, and increasing, number of com-
her or his AED medication. Has the doctor made a mistake by pounds in the AED class that have variable effects on NP. These
suggesting an epilepsy drug? Are these drugs safe? Will I have an drugs are unified by their antiepileptic and anti-NP effects but differ
epileptic fit if I suddenly stop the medication, as is often suggested to some extent in their modes of action. Therefore, from a clinical
in the packet insert? Communication and explanation may help to perspective, if one AED fails to help a patient with NP (or if it is not
reduce patient anxiety, improve compliance, and reassure the tolerated because of side effects), it is often logical to try a different
patient that her or his treating physician knows what he or she AED with an alternative mode of action.
are talking about. Before considering individual AEDs, some principles of treat-
From a medical perspective, less concern about AED use should ment must be established. Every time an AED is tried for pain
be apparent. Neuropathic pain (NP) arises when there is injury treatment, it should be part of a ‘‘therapeutic trial.’’ That is to say,
or insult to neural tissue and may be compounded by attempts by the drug is initiated at an appropriate dose, and with knowledge of
the central nervous system to reduce the effects of the stimulus by its half-life, a dose escalation schedule is implemented until either a
activating descending inhibitory and excitatory drives. These effects useful effect is produced or intolerable side effects are experienced
can produce pain in the absence of a painful stimulus or can produce (Table 62–1). When dose escalation to a ceiling level is achieved,
an excessive pain response to a normally innocuous event. Given after a short time, a judgment should be made as to the drug’s effi-
that neural overactivity is a cardinal feature of NP and epilepsy, the cacy or, more precisely, its effect on the patient’s quality of life. If no
use of AEDs becomes logical. That said, we might be better served if pain relief, insufficient pain relief, or intolerable side effects are
these agents were described as ‘‘neuropathic pain analgesics’’ or produced, the drug should be stopped and an alternative considered
something similar, particularly because some of the emerging after a washout period. AEDs, when used at appropriate doses, have
AEDs are being developed for NP treatment and not epilepsy. an almost immediate effect, so there is no place for sustained therapy
One of the advances in pain therapy apparent in the last two in the absence of pain relief, particularly because withdrawal of some
decades is the increasing number of AEDs with official NP indica- AEDs can be complicated by withdrawal reactions when used over a
tions. For example, both gabapentin and pregabalin have posther- protracted period. Too often, one meets patients who have been
petic neuralgia as an indication, whereas historically, carbamazepine taking pain drugs, including AEDs, for protracted periods despite
had an indication for the treatment of trigeminal neuralgia in the the fact that they have obtained no analgesic benefit. This may result
United Kingdom. These indications are a reflection of the hard from lack of appropriate medical follow-up and assessment of treat-
evidence of AEDs’ beneficial effects in a proportion of patients ment effects or from ignorance of the treating doctor, because there
with these conditions. However, it does not necessarily mean that seems to be an attitude in some that if a drug has an indication that
AEDs are the best drugs for the management of these types of NP. suggests a pain-relieving effect in a particular condition, then
Clinical experience and some trial evidence suggest that other AEDs despite the patient’s claim that no relief is being produced, he or
Table 62^1. Suggested Dosing Regimens for Antiepileptic Drugs
Route of Rate of Dose Total Daily

AED Administration Unit Dose Increase Dose (mg)
Phenytoin IV/IM 200 mg Stat dose
Fosphenytoin IV/IM 500 PEs Stat dose
Carbamazepine Oral 100 mg From 100 mg twice daily 800
increasing by 200 mg q 2nd day
Oxcarbazepine Oral 150 mg Increasing by 150 mg q 3rd day 600
Gabapentin Oral 300 mg q 3rd day 1800–2400
Pregabalin Oral 75 mg q.a.d. 600
Lamotrigine Oral 50 mg q wk 300
Clonazepam Oral 0.5 mg q 2nd day 1.5
PEs, phenytoin equivalent units.
she are in fact incorrect and the drug is doing something. This Phenytoin is also available in a parenteral formulation, and a
ignores the fact that even with those drugs with strong evidence of single trial suggests that the intravenous infusion of phenytoin can
analgesic actions, relief is produced is some, and not all, patients reduce NP. The potential value of such parenteral use is that it gives
treated. A further principle of treatment is that individual AEDs an option for NP treatment when the oral route of administration is
should be selected after full consideration of the patient’s medical unavailable. However, although the parenteral formulation of phen-
condition and situation. For example, the danger of the ‘‘fetal ytoin is inexpensive, it contains among its diluents sodium hydro-
valproate syndrome’’ should dictate that valproate not be used in xide, which gives it a highly alkaline pH. Therefore, if there is
females of child-bearing potential, whereas sedative AEDs are inap- extravasation of the phenytoin infusate, the danger of localized
propriate when the patient operates machinery or wishes to drive. skin necrosis is ever present.
Mechanistically, phenytoin has a sodium channel blocking effect
(as have a number of the other AEDs, local anesthetic drugs, and
INDIVIDUAL AEDS tricyclic antidepressants). We now know that the sodium channel is
not a single entity, but rather a family of receptors, and it is likely
An increasing number of AEDs are now available in the market- that the effect of phenytoin is on different sodium channels than
place. With some, the evidence of an anti-NP effect is, at best, these other agents.
anecdotal, whereas with others, it is substantial. As previously sug-
gested, with those agents for which evidence is lacking, this may be
due to their having a lesser analgesic effect or a reflection of the lack Fosphenytoin (Fig. 62^2)
of studies examining their potential pain-reducing actions.
We now look at some of the currently available AEDs and high- Fosphenytoin, a water-soluble ester prodrug of phenytoin, has a
light their individual characteristics, remembering that what is pro- near-normal pH and, therefore, lacks the dangers associated with
duced is a list and not in any order of supposed efficacy. intravenous phenytoin use.
Fosphenytoin is presented in a parenteral, not an oral, formu-
Phenytoin (Fig. 62^1) lation. It has been shown to reduce NP when given intramuscularly
and intravenously, and therefore, like phenytoin, it can be used
Phenytoin (diphenylhydantoin) was first synthesized by the German when an immediate effect is desired or when the oral route of
Heinrich Biltz in 1908, and its anticonvulsant effects were first administration is unavailable. Side effects, apart from those related
noted in 1938. to pH, are much the same as with phenytoin. Fosphenytoin is
Historically, the first reported AED to be used in pain manage- ‘‘activated’’ by phosphatases, and this reaction can cause an intense,
ment with some evidence of an analgesic effect was used in patients but short-lived, burning perineal discomfort that patients need to
with painful diabetic neuropathy. Unfortunately, long-term use is be warned about.
associated with a number of side effects including tachyphylaxis, Fosphenytoin is not a milligram-for-milligram equivalent to
gingival hyperplasia, somnolence and cognitive impairment, and phenytoin, and therefore, to avoid inappropriate dosing, it is
folate and calcium disorders that preclude it being of value in NP
treatment.
O H
H N
N O
NH
O N O OH
O P
OH
O
Figure 62^2. Fosphenytoin, q water-soluble ester prodrug of
Figure 62^1. Phenytoin (diphenylhydantoin). phenytoin.
N
O NH2
Figure 62^3. Carbamazepine.
O NH2
Figure 62^4. Oxcarbazepine.
measured in phenytoin equivalent units (PEs). Each PE is equal to 1
mg of phenytoin. Although fosphenytoin would appear safer than
phenytoin when used intravenously, it is also considerably more risk of inducing adverse events, it should be used in preference to
expensive. carbamazepine.
Carbamazepine (Fig. 62–3) SodiumValproate (Fig. 62–5)

Carbamazepine was discovered by chemist Walter Schindler in Some evidence suggests that sodium valproate may have some effect
1953, who then went on to synthesize the drug in 1960. In 1962, on NP and is well tolerated. Particular care should be taken when it
it was shown to help trigeminal neuralgia and was licensed for the is used in females of child-bearing potential, in view of the danger
treatment of epilepsy in the United Kingdom in 1965, although it of the so-called fetal valproate syndrome. Sodium valproate can also
did not receive this indication in the United States until 1974. cause straight hair to grow curly, a side effect that may be welcomed
Carbamazepine was, until recently, the most frequently utilized by some!
AED in clinical pain management. Its sodium channel blocking
effect seems to be important to its analgesic effect. Interestingly, it
has a tricyclic structure analogous to that of the tricyclic Ethosuxamide (Fig. 62–6)
antidepressants.
The side effects of carbamazepine use, many of which are dose It is postulated that ethosuxamide acts as a T-type calcium channel
related, include nausea, drowsiness, lethargy, hyponatraemia, and blocker. Its place is not well established in NP management,
agranulocytosis, among many others. although emerging animal evidence suggests that it can have an
The difficulty in tolerating a therapeutic dose for sustained per- antinociceptive effect in taxol-induced neuropathy, a model of
iods may encourage patients to reduce the dose when an episode of NP mimicking that seen in chemotherapy-induced NP.
NP lessens; therefore, they would not benefit from the potential of a
preventive effect if such a larger dose were continued in the longer
term. One stratagem that has the potential for increasing tolerability Clonazepam (Fig. 62–7)
is conversion from immediate- to extended-release carbamazepine.
Miller and colleagues studied 61 patients treated for greater than Clonazepam, a g-amino butyric acid (GABA) receptor agonist, has
1 year with immediate-release carbamazepine for epilepsy. On con- sedative, anticonvulsant, and amnesic properties. Anecdotal evi-
version to an equal dose of extended-release Carbamazepine, the dence suggests that it may also have pain-relieving and muscle-
incidence of central nervous system–related side effects fell from relaxant potential.
49% to 20%.
McQuay and coworkers, in their 1995 systematic review of the
use of AEDs in pain management, concluded that the numbers Lamotrigine (Fig. 62–8)
needed to treat (NNTs) for adverse effects using carbamazepine
in the treatment of trigeminal neuralgia is 3.4 and for severe adverse Lamotrigine seems to have an effect by virtue of its actions on
effects is 24 as opposed to an NNT of 2.6 for pain relief. When the voltage-gated cation channels and on glutamate release. Whereas
same drug is used for the treatment of painful diabetic neuropathy, it does not have a specific NP indication, a range of controlled
the NNT for adverse effects is 3.1, for severe adverse effects 20, and trials and case reports testify to an anti-NP effect. Potential advan-
for pain relief 2.5. tages with its use include its lack of sedative effect and propensity
not to cause weight gain (in contrast to many other agents of
differing classes used in NP pain management). Perhaps its major
Oxcarbazepine (Fig. 62–4) disadvantage is its tendency to cause skin rash, with this effect
Oxcarbazepine, a keto derivative of carbamazepine, was originally

O
synthesized in 1966, approved for use as an anticonvulsant in
Denmark in 1990, approved for use in all European Union coun-
CH3
tries as an anticonvulsant in 1999, and approved in the United ONa
States in 2000.
Evidence is beginning to accrue of a useful analgesic effect in
patients with NP. The potential advantage of oxcarbazepine is the
lesser risk of side effects when compared with carbamazepine,
although somnolence, dizziness, nausea, and hyponatraemia may
still all occur. It could be argued that, although no comparative CH3
studies with carbamazepine have been reported, given its lesser Figure 62^5. Sodium valproate.
H having a direct relationship to the rate of dose escalation. Therefore,

N a relatively slow increase in dosing is necessary, and it may be that
O O this effect will not be apparent until a dose of greater than 200 mg
daily is reached.
Evidence from females taking lamotrigine for epilepsy who go
on to give birth suggests that the incidence of fetal malformation
is no different from those not taking an AED. It may, therefore,
be that this agent should be chosen in females of child-bearing
potential. Lymphadenopathy and breast tenderness may also com-
Figure 62^6. Ethosuxamide.
plicate use.
Gabapentin (Fig. 62–9)

O
Gabapentin has an effect on the ad2-subunit of a calcium channel
rather than on GABA, as its name would suggest. Gabapentin has
HN overtaken carbamazepine in terms of volume of sales for use in NP.
Substantial evidence exists for a pain-relieving effect in NP, with
N this evidence being strongest for postherpetic neuralgia and painful
diabetic neuropathy. That said, the weight of available evidence
CI suggests that this effect is replicated in many other NP conditions.
Dose escalation to an effective dose is necessary, with the reassur-
ance of a wide safety margin even in overdose. That said, side effects
are not all that uncommon and include weight gain, somnolence,
O2N dizziness, and nausea. Some of these can become less problematic
with sustained use. Withdrawal reactions have been reported when
Figure 62^7. Clonazepam. gabapentin treatment is discontinued. Doses of up to 2400 to 3600
mg daily may be required to produce pain relief.
Pregabalin (Fig. 62–10)
H2N N NH2 Pregabalin has recently received an indication for the treatment of
postherpetic neuralgia in the United States and a license for use in
peripheral NP in the United Kingdom. We are told that it works by
a mechanism of action similar to that of gabapentin but has about
N five times the receptor affinity. For this reason, like gabapentin, it
N could be expected to have a pain-relieving effect in a broad range of
NP conditions, although this is speculative and is yet to be sub-
stantiated by a sufficient number of clinical studies.
CI If pregabalin does indeed differ from gabapentin in terms of its
receptor affinity, but not the receptor at which it is active, the
CI question arises whether is there any logic to a trial of gabapentin
Figure 62^8. Lamotrigine.
if pregabalin fails to help. Intuitively, one would have thought not.
In clinical use, pregabalin appears to be both better tolerated and
more efficacious than gabapentin. Its effect is quickly observed, and
if not apparent, then quick dose escalation can take place.
Ultimately, if no effect is apparent when the maximum recom-
mended tolerated dose is reached, the drug should be discontinued.
Among the side effects of pregabalin use are nausea, dizziness, and
H2N COOH
somnolence, which all tend to lessen with sustained use. Weight
gain can complicate long term treatment.
Topiramate (Fig. 62–11)

Figure 62^9. Gabapentin. Chemically, topiramate is a sulfamate-substituted monosaccharide
related to fructose. About 70% of an ingested dose is excreted
unchanged in the urine. A number of case reports and a few studies
suggest that topiramate does have pain-reducing properties,
although side effects may reduce compliance. In a report by Lee
and associates, a significant number of patients taking this drug for
NH2
epilepsy continued to have cognitive impairment subsequent to its
H O use after one years use. In the study by Donofrio and colleagues
examining the use of topiramate in painful diabetic neuropathy, it
was found that a useful proportion of patients gained pain relief but
OH that 39.5% of patients discontinued its use most frequently because
Figure 62^10. Pregabalin. of side effects.
O O
CH3
SO2NH2 O
O O
NH2
H3C CH3 N
O O
H3C CH3
O
Figure 62^11. Topiramate. Figure 62^13. Levetiracetam.
Therefore, although topiramate does seem to share the anti-NP tolerability of the AEDs and that which does exist largely relates
effect of other AEDs, it probably cannot be considered as a first-line to the use of AEDs in the epilepsy field.
choice in the AED class. When the AEDs are compared in terms of propensity to alter
body weight, Biton stated that carbamazepine and valproate
Lacosamide increase weight, topiramate and felbamate decrease it, and lamotri-
gine, levetiracetam, and phenytoin are weight neutral.
Formerly known as harkoseride and SPM 927, this AED is still in As with much of the data on other potential side effects, the effect
the experimental phase of its development and is not clinically of AEDs on cognition is based on work done largely in subjects
available. Its mode of action remains uncertain. Case reports of with epilepsy. Given that epilepsy may itself cause central nervous
open-label use suggest analgesic efficacy, and we await the report system abnormalities owing both to the underlying cause of the
of larger controlled studies to better define its potential. epilepsy and to the effect of previous seizures, the interpretation of
this data is problematic. That said, it can give some insight into the
Vigabatrin (Fig. 62–12) possible central nervous system side effects in patients with, for
example, NP. Aldenkamp and associates suggested that oxcarbaze-
Vigabatrin has a GABAergic mode of action. A single animal study pine and lamotrigine do not affect cognitive function in either
suggests that it can have an antinociceptive effect in a noxious healthy volunteers or epilepsy patients, and Hirsch and coworkers
thermal stimulus test. Its place in human pain management is not suggest that sodium valproate produces few cognitive side effects.
established. Martin and colleagues examined the possible effects on cognitive
function produced by topiramate, gabapentin, and lamotrigine in
Tiagabine healthy young volunteers. They found that topiramate did have an
effect on cognitive function, whereas lamotrigine and gabapentin
Tiagabine is a potent selective inhibitor of the principal neuronal had little effect. The finding that lamotrigine and gabapentin have
GABA transporter (GAT-1) in the cortex and hippocampus. By little effect on cognitive function is confirmed in a review by
slowing the reuptake of synaptically released GABA, it prolongs Goldberg and Burdick. Aldenkam compared phenytoin, Carbama-
the inhibitory postsynaptic potentials. zepine, and sodium valproate. The cognitive impairment produced
Animal studies suggest some antinociceptive potential with tia- by phenytoin was greater than that produced by carbamazepine or
gabine treatment, and a single human study suggests that lowdose sodium valproate.
tiagabine does have some effect on painful sensory neuropathy Besag reviewed the data pertaining to the behavioral side effects
when used at low doses, with larger doses giving rise to an increased of nine of the more recently introduced AEDs. Vigabatrin and
number of adverse events. Low doses may also have some effect on topiramate have been associated with both psychosis and depres-
muscle spasm–related pain. It would be fair to say that tiagabine is sion. He suggested that lamotrigine is largely associated with
not considered an effective AED in human NP pain treatment. improvement rather than deterioration in mood and behavior,
while gabapentin has relatively little effect on behavior. The data
Levetiracetam (Fig. 62–13) on tiagabine and oxcarbazepine are too limited to allow useful
interpretation.
Some evidence exists of an antinociceptive effect when levetiracteam Overall, after review of the literature, LaRoche and Helmers
is administered to rats with induced NP. A single human experi- stated that the more recently introduced AEDs have, overall, a
mental study suggests that this effect may be replicated in humans, better tolerability than the older members of this class.
and a case series of three patients obtaining relief with levetiracetam
has been reported. However, we await more detailed and compre-
hensive evidence of its effect in NP. CONCLUSIONS
The AEDs form a disparate group of compounds that are unified by
COMPARATIVE TOLERABILITY the anticonvulsant effects, and in the case of those whose mode of
action is other than a synaptic one, by an anti-NP effect. The range
The use of an AED is guided both by the supposed potential of of evidence that underpins their use varies from compound to
individual agents to give pain relief and by their propensity to cause compound, and little comparative work has been done to establish
side effects. Unfortunately, we are hampered by the relatively small their relative merits in terms of analgesia and their relative demerits
volume of published evidence that examines the comparative in terms of side effect profile. What little evidence is available on
this latter is not well documented.
One should not be constrained to consider only those AEDs that
H2N COOH hold a specific indication for a particular type of NP. If one were so
constrained, there would be several choices for the treatment of, for
example, postherpetic heuralgia and none, for example, for the
treatment of intercostal neuralgia. Some insight into the modes of
action of AEDs will allow a rational approach to treatment choice.
Figure 62^12. Vigabatrin. If a particular AED fails to produce analgesia, it is acceptable to
move on and try another with a different mode of action, and it Flatters SJ, Bennett GJ. Ethosuxamide reverses paclitaxel- and vincristine-
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Lamotrigine
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Ther 1999;288:1026–1030. Sabatowski R, Galvez R, Cherry DA, et al. and the 1008-045 Study Group.
Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain Pregabalin reduces pain and improves sleep and mood disturbance
in Guillain-Barré syndrome: a double blind, placebo controlled, in patients with post-herpetic neuralgia: results of a randomised,
crossover study. Anesth Analg 2002;95:1719–1723. placebo-controlled clinical trial. Pain 2004;109:26–35.
Partridge BJ, Chaplan SR, Sakamoto E, Yaksh TL. Characterization of the Topiramate
effects of gabapentin and 3-isobutyl gamma amino butyric acid on Van Seventer R, Feister HA, Young JR, et al. Efficacy and tolerability of
substance P induced thermal hyperalgesia. Anesthesiology 1998;88:196–205. twice-daily pregabalin for treating pain and related sleep interference in
Patel J, Naritoku DK. Gabapentin for the treatment of hemifacial spasm. postherpetic neuralgia: a 13-week, randomized trial. Curr Med Res
Clin Neuropharmacol 1996;19:185–188. Opin 2006;22:375–385.
Rosner H, Rubin L, Kestenbaum A. Gabapentin adjunctive therapy in Donofrio PD, Raskin P, Rosenthal NR, et al. and the CAPSS-141 Study
neuropathic pain states. Clin J Pain 1996;12:185–188. Group. Safety and effectiveness of topiramate for the management of
Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment painful diabetic peripheral neuropathy in an open-label extension
of postherpetic neuralgia. A randomized controlled trial. JAMA study. Clin Ther 2005;27:1420–1431.
1998;280:1837–1842. Khoromi S, Patsalides A, Parada S, et al. Topiramate in chronic lumbar
Samkoff LM, Daras M, Tuchman AJ, Koppell BS. Amelioration of radicular pain. J Pain 2005;6:829–836.
refractory dysesthetic limb pain in multiple sclerosis by gabapentin. Lee HW, Jung DK, Suh CK, et al. Cognitive effects of low-dose
Neurology 1997;49:304–305. topiramate monotherapy in epilepsy patients: a 1-year follow up.
Schachter SC, Carrazana EJ. Treatment of facial pain with gabapentin. J Epilepsy Behav 2006;8:736–741.
Epilepsy 1997;10:148–149. Raskin P, Donofrio PD, Rosenthal NR, et al. and the CAPSS-141 Study
Schacter SC, Sauter MK. Treatment of central pain with gabapentin. Group. Topiramate vs placebo in painful diabetic neuropathy: analgesic
J Epilepsy 1996;9:223–226. and metabolic effects. Neurology 2004;63:865–873.
Lacosamide Aldenkamp AP, De Krom M, Reijs R. Newer antiepileptic drugs and

McCleane GJ, Koch B, Rauschkolb C. Does SPM 927 have an analgesic cognitive issues. Epilepsia 2003;44S:21–29.
effect in human neuropathic pain: an open label study. Neurosci Lett Besag FM. Behavioural effects of the newer antiepileptic drugs: an update.
2003;352:117–120. Expert Opin Drug Saf 2004;3:1–8.
Stohr T, Krause E, Selve N. Lacosamide displays potent antinociceptive Biton V. Effect of antiepileptic drugs on bodyweight: overview and
effects in animal models for inflammatory pain. Eur J Pain clinical implications for the treatment of epilepsy. CNS Drugs
2006;10:241–249. 2003;17:781–791.
Vigabatrin Goldberg JF, Burdick KE. Cognitive side effects of anticonvulsants. J Clin
Alves ND, de Castro-Costa CM, de Carvalho AM, et al. Possible analgesic Psychiatry 2001;62S:27–33.
effect of vigabatrin in animal experimental chronic neuropathic pain. Hirsch E, Schmitz B, Carreno M. Epilepsy, antiepileptic drugs (AEDs) and
Arq Neuropsiquiatr 1999;57:916–920. cognition. Acta Neurol Scand 2003;108S:23–32.
Tiagabine Martin R, Kuzniecky R, Ho S, et al. Cognitive effects of topiramate,
Kast RE. Tiagabine may reduce bruxism and associated gabapentin, and lamotrigine in healthy young adults. Neurology
temperomandibular joint pain. Anesth Prog 2005;52:102–104. 1999;52:321–327.
Laughlin TM, Tram KV, Wilcox GL, Birnbaum AK. Comparison of Martin R, Meador K, Turrentine L, et al. Comparative cognitive effects of
antiepileptic drugs tiagabine, lamotrigine, and gabapentin in mouse carbamazepine and gabapentin in healthy senior adults. Epilepsia
models of acute, prolonged, and chronic nociception. J Pharmacol Exp 2001;42:764–771.
Ther 2002;302:1168–1175. General
Meldrum BS, Chapman AG. Basic mechanisms of gabatril (tiagabine) and Backonja MM. Anticonvulsants (antineuropathics) for neuropathic pain
future potential developments. Epilepsia 1999;40S:2–6. syndromes. Clin J Pain 2000;S16:67–72.
Novak V, Kanard R, Kissel JT, Mendell JR. Treatment of painful Dickenson AH, Mathews EA, Suzuki R. Neurobiology of neuropathic
sensory neuropathy with tiagabine: a pilot study. Clin Auton Res pain: mode of action of anticonvulsants. Eur J Pain 2002;6S:51–60.
2001;11:357–361. Jensen T. Anticonvulsants in neuropathic pain: rationale and clinical
Levetiracetam evidence. Eur J Pain 2002;6S:61–68.
Ardid D, Lamberty Y, Alloui A, et al. Antihyperalgesic effects of LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review.
levetiracetam in neuropathic pain models in rats. Eur J Pharmacol JAMA 2004;291:605–614.
2003;473:27–33. Macdonald RL, Kelly KM. Antiepileptic drug mechanisms of action.
Enggaard TP, Klitgaard NA, Sindrup SH. Specific effect of Epilepsia 1995;36S:2–12.
levetiracetam in experimental human pain models. Eur J Pain McQuay H, Carroll D, Jadad AR, et al. Anticonvulsant drugs for
2006;10:193–198. management of pain: a systematic review. BMJ 1995;311:1047–1052.
Price MJ. Levetiracetam in the treatment of neuropathic pain: three case Soderpalm B. Anticonvulsants: aspects of their mechanisms of action. Eur
studies. Clin J Pain 2004;20:33–36. J Pain 2002;6S:3–9.
Side Effects of AEDs
Aldenkamp AP. Effects of antiepileptic drugs on cognition. Epilepsia
2001;42S:46–49.
Chapter 63 HISTORICAL CONTEXT

LOCAL ANESTHETICS Around 700 BC, and probably even further back, inhabitants of
Bolivia and the Andean region cultivated the cocoa plant. In
Gary McCleane 1653, the Spanish Jesuit Bernabé Cobo (1582–1657) authored the
first publication in which the anesthetic properties of the cocoa
leaf were recorded. In 1855, Gaedicke extracted the alkaloid
erythroxyline from cocoa leaves, and 5 years later, Albert
Niemann discovered that erythroxyline contained cocaine and
that was what caused the numbing effect of cocoa leaves.
Thomas Moreno Maı̈z, a Peruvian, recorded that injection of
cocaine solution caused a numbing effect in a variety of animals.
Human use was popularixed by Sigmund Freud, who published
INTRODUCTION results of his work in 1884.
Whereas the term local anesthetics could previously have applied

only to those therapeutic entities that produced anesthesia when MECHANISMS OF ACTION
administered by local injection, it now applies to a broad range of
drugs that are administered in a wide and diverse range of methods. Local anesthetics inhibit nerve function by blocking sodium chan-
What unifies them as a class is their ability to block sodium channels located along the nerve membranes by inhibiting the inward
nels. In the case of local injection, the sodium channel blockade can surge of sodium that causes nerve depolarization. These local anes-
be sufficient to produce skin anesthesia, whereas when used orally thetics do not alter resting transmembrane potential or threshold
and intravenously, the degree of sodium channel blockade is but rather create a nondepolarizing (stabilizing) type of block.
enough to produce a therapeutic effect (i.e., pain reduction) but Local anesthetics alone have limited access to binding sites on
insufficient to numb tissue. In this chapter, we discuss the local sodium channels because the drug must cross through the outer
anesthetics as a group and consider their place in modern pain lipophilic portion of the nerve to access the inner or axoplasmic
management. pore, where it can bind. To reach this inner site, local anesthetics are
Lacosamide Aldenkamp AP, De Krom M, Reijs R. Newer antiepileptic drugs and

McCleane GJ, Koch B, Rauschkolb C. Does SPM 927 have an analgesic cognitive issues. Epilepsia 2003;44S:21–29.
effect in human neuropathic pain: an open label study. Neurosci Lett Besag FM. Behavioural effects of the newer antiepileptic drugs: an update.
2003;352:117–120. Expert Opin Drug Saf 2004;3:1–8.
Stohr T, Krause E, Selve N. Lacosamide displays potent antinociceptive Biton V. Effect of antiepileptic drugs on bodyweight: overview and
effects in animal models for inflammatory pain. Eur J Pain clinical implications for the treatment of epilepsy. CNS Drugs
2006;10:241–249. 2003;17:781–791.
Vigabatrin Goldberg JF, Burdick KE. Cognitive side effects of anticonvulsants. J Clin
Alves ND, de Castro-Costa CM, de Carvalho AM, et al. Possible analgesic Psychiatry 2001;62S:27–33.
effect of vigabatrin in animal experimental chronic neuropathic pain. Hirsch E, Schmitz B, Carreno M. Epilepsy, antiepileptic drugs (AEDs) and
Arq Neuropsiquiatr 1999;57:916–920. cognition. Acta Neurol Scand 2003;108S:23–32.
Tiagabine Martin R, Kuzniecky R, Ho S, et al. Cognitive effects of topiramate,
Kast RE. Tiagabine may reduce bruxism and associated gabapentin, and lamotrigine in healthy young adults. Neurology
temperomandibular joint pain. Anesth Prog 2005;52:102–104. 1999;52:321–327.
Laughlin TM, Tram KV, Wilcox GL, Birnbaum AK. Comparison of Martin R, Meador K, Turrentine L, et al. Comparative cognitive effects of
antiepileptic drugs tiagabine, lamotrigine, and gabapentin in mouse carbamazepine and gabapentin in healthy senior adults. Epilepsia
models of acute, prolonged, and chronic nociception. J Pharmacol Exp 2001;42:764–771.
Ther 2002;302:1168–1175. General
Meldrum BS, Chapman AG. Basic mechanisms of gabatril (tiagabine) and Backonja MM. Anticonvulsants (antineuropathics) for neuropathic pain
future potential developments. Epilepsia 1999;40S:2–6. syndromes. Clin J Pain 2000;S16:67–72.
Novak V, Kanard R, Kissel JT, Mendell JR. Treatment of painful Dickenson AH, Mathews EA, Suzuki R. Neurobiology of neuropathic
sensory neuropathy with tiagabine: a pilot study. Clin Auton Res pain: mode of action of anticonvulsants. Eur J Pain 2002;6S:51–60.
2001;11:357–361. Jensen T. Anticonvulsants in neuropathic pain: rationale and clinical
Levetiracetam evidence. Eur J Pain 2002;6S:61–68.
Ardid D, Lamberty Y, Alloui A, et al. Antihyperalgesic effects of LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review.
levetiracetam in neuropathic pain models in rats. Eur J Pharmacol JAMA 2004;291:605–614.
2003;473:27–33. Macdonald RL, Kelly KM. Antiepileptic drug mechanisms of action.
Enggaard TP, Klitgaard NA, Sindrup SH. Specific effect of Epilepsia 1995;36S:2–12.
levetiracetam in experimental human pain models. Eur J Pain McQuay H, Carroll D, Jadad AR, et al. Anticonvulsant drugs for
2006;10:193–198. management of pain: a systematic review. BMJ 1995;311:1047–1052.
Price MJ. Levetiracetam in the treatment of neuropathic pain: three case Soderpalm B. Anticonvulsants: aspects of their mechanisms of action. Eur
studies. Clin J Pain 2004;20:33–36. J Pain 2002;6S:3–9.
Side Effects of AEDs
Aldenkamp AP. Effects of antiepileptic drugs on cognition. Epilepsia
2001;42S:46–49.
Chapter 63 HISTORICAL CONTEXT

LOCAL ANESTHETICS Around 700 BC, and probably even further back, inhabitants of
Bolivia and the Andean region cultivated the cocoa plant. In
Gary McCleane 1653, the Spanish Jesuit Bernabé Cobo (1582–1657) authored the
first publication in which the anesthetic properties of the cocoa
leaf were recorded. In 1855, Gaedicke extracted the alkaloid
erythroxyline from cocoa leaves, and 5 years later, Albert
Niemann discovered that erythroxyline contained cocaine and
that was what caused the numbing effect of cocoa leaves.
Thomas Moreno Maı̈z, a Peruvian, recorded that injection of
cocaine solution caused a numbing effect in a variety of animals.
Human use was popularixed by Sigmund Freud, who published
INTRODUCTION results of his work in 1884.
Whereas the term local anesthetics could previously have applied

only to those therapeutic entities that produced anesthesia when MECHANISMS OF ACTION
administered by local injection, it now applies to a broad range of
drugs that are administered in a wide and diverse range of methods. Local anesthetics inhibit nerve function by blocking sodium chan-
What unifies them as a class is their ability to block sodium channels located along the nerve membranes by inhibiting the inward
nels. In the case of local injection, the sodium channel blockade can surge of sodium that causes nerve depolarization. These local anes-
be sufficient to produce skin anesthesia, whereas when used orally thetics do not alter resting transmembrane potential or threshold
and intravenously, the degree of sodium channel blockade is but rather create a nondepolarizing (stabilizing) type of block.
enough to produce a therapeutic effect (i.e., pain reduction) but Local anesthetics alone have limited access to binding sites on
insufficient to numb tissue. In this chapter, we discuss the local sodium channels because the drug must cross through the outer
anesthetics as a group and consider their place in modern pain lipophilic portion of the nerve to access the inner or axoplasmic
management. pore, where it can bind. To reach this inner site, local anesthetics are
466 Chapter 63 LOCAL ANESTHETICS
attached to lipophilic bases that serve as carriers through the lipid lidocaine and prilocaine, and amethocaine gel. These are conven-
nerve membrane. With bound local anesthetic, the channel perme- tionally used to anesthetize skin prior to intravenous cannula inser-
ability to sodium does not increase, resulting in a slow rate of tion, but they may also be used to reduce the pain of a number
depolarization such that the threshold potential cannot be breached of other procedures such as lumbar puncture, bone marrow biopsy,
in a timely fashion and the action potential cannot be initiated or and nerve blocks. In addition to being used to anesthetize skin,
propagated. they can reduce pain from a diverse range of conditions including
Sodium channels progress through activated-open, inactivated- burns, postherpetic neuralgia, and skin bruises. Use of EMLA cream
closed, and resting-closed states during an action potential. In the should not be prolonged in view of the potential complication of
resting nerve membrane, sodium channels are distributed in equi- methemoglobinaemia associated with prilocaine use.
librium between the rested-closed (tonic) and inactivated-closed Topical anesthesia of the mucous membrane is often used to
states. Each open sodium channel closes a short time after it facilitate various procedures. For example, lidocaine is sprayed
opens, even though the membrane remains depolarized. The chan- over the upper respiratory tract to anesthetize that membrane
nel remains closed for a brief period, allowing the cell membrane to while fiberoptic bronchoscopy is carried out. When local anesthetic
recover from the influx of sodium. During this phase, sodium is applied on a once-off basis, its duration of effect is limited owing
channels are not permeable to sodium, and therefore, conduction to the vascularity of the membrane. One alternative for this proce-
of nerve impulses as propagated action potentials is not possible. dure is described by Ayoub and Baraka, who suggested the use of a
The rested-close and the activated-open channels have the lidocaine lollipop as a method of local anesthetic application prior
potential of conducting nerve impulses. Selective binding of local to bronchoscopy.
anesthetics to channels in the inactivated-closed phase prevents the One particularly unpleasant accompaniment of cancer and
channel proceeding to either the rested-closed or the activated-open cancer chemotherapy is the presence of oral mucous membrane
configurations despite nerve impulses, thus preventing impulse ulcers, which can be intensely painful. To give sustained relief,
conduction. local anesthetic lollipops (containing, e.g., lidocaine or cocaine)
can be used to give more prolonged relief. Indeed, the tricyclic
antidepressant (TCA) doxepin has been suggested as a method of
CLINICALUSE providing pain relief for painful oral ulcers and for reducing dysuria
when used as a mouth rinse or instilled into the urethra, respec-
With advances in our understanding of pain and its treatment, it is tively. Presumably, the local anesthetic effect of this TCA produces
now clear that when a local anesthetic is used, a numbing effect is the pain relief via sodium channel blockade. Clearly, when local
not necessary for pain relief to be produced. Therefore, there is anesthetic is used in the oral cavity and pharynx, one has to be
opportunity to utilize agents that are classified as local anesthetics careful that the gag reflex has returned before food or oral fluid is
in situations in which the aim is not to produce skin or tissue given to the patient.
anesthesia (Table 63–1). The local anesthetic can be administered The lidocaine 5% patch (Lidoderm) is U.S. Food and Drug
by a variety of routes to achieve a drug concentration at the targeted Administration (FDA) approved for the treatment of postherpetic
neural structure to produce pain relief. neuralgia (PHN), whereas in clinical practice, it has been shown to
reduce the pain of a spectrum of disorders. Katz and colleagues
reported their study of 332 patients with PHN who used up to
Topical three Lidoderm patches for 12 hours each day. Sixty-six percent
of the study population reported reduced pain intensity with
Topical application of a local anesthetic can be used to produce repeated patch application after 7 days. By 14 days after commence-
pain relief or tissue anesthesia. Two local anesthetic preparations are ment of treatment, 43% of the remaining patients experienced re-
commonly used to achieve the latter. These include EMLA duced pain intensity.
(i.e., eutectic mixture of local anesthetics) cream, which contains Meier and coworkers reported use of the Lidoderm patch in the
treatment of focal neuropathic pain syndromes such as PHN,
mononeuropathies, and intercostal and ilioinguinal neuralgia.
Table 63^1. Classification of Local Anesthetics They found that the patch reduced pain over the first 8 hours of
use. This and many other reports confirm that significant side
Ester-linked Local Anesthetics effects are not associated with use of this patch. Therefore, whereas
Cocaine the effect of this lidocaine-containing patch is well evidenced for a
Procaine number of neuropathic pain conditions, extensive clinical experi-
ence would suggest that its potential uses extend greatly beyond
Procaine analogues those neuropathic conditions. It may be used on a site of localized
Tetracaine pain and is associated with local tissue tenderness or allodynia. One
Benzocaine example of this is the suggestion by Nalamachu and associates of
the use of the Lidoderm patch for pain relief in patients with carpal
Amide-linked Local Anesthetics
tunnel syndrome. Whether or not uses in these other conditions
Aminoacyl amides will be formally recognized as an indication for its use is debatable.
Lidocaine
Prilocaine
Etidocaine Perineural
Pipecolyl xylidides
Widespread use is made of local anesthetics in anesthesiologic prac-
Mepivacaine
tice. Epidural and spinal anesthetics are used to enable surgical
Bupivacaine procedures to be carried out, whereas epidural techniques are
Ropivacaine used to provide postoperative pain relief along with analgesia
Aminoalkyl amides during childbirth and in patients who have, for example, sustained
Procainamide rib fractures.
Dibucaine When spinal and epidural techniques are used, it is common-
place for an opioid to be added to the local anesthetic both to
enhance the quality and duration of the subsequent block and to The second highly relevant finding was that the effect was related
allow a reduction in the concentration of local anesthetic used. By to the speed of lidocaine administration rather than the total dose.
doing this, it is possible to block pain while retaining a degree of When a given dose was administered slowly, little reduction in
motor function. In some circumstances, long-term intrathecal baseline, preinfusion allodynia was observed. However, when
delivery of drugs is appropriate and low doses of local anesthetic exactly the same dose was given more rapidly, a pronounced and
are occasionally included. prolonged antiallodynic effect was recorded.
Nerve blocks can be used to treat acute pain and chronic pain Further fascinating insight into the effect of systemic lidocaine is
and to determine which nerve or group of nerves is involved in a given by the work of Araujo and coworkers. They examined rats
pain process. In the postoperative situation, a local anesthetic such that underwent spinal nerve ligation and suffered from consequent
as bupivicaine is often used on its own. The duration of relief is allodynia. Lidocaine infusions were compared with saline infusions,
then equivalent to the duration of effect of the local anesthetic. and the effect on allodynia was measured. They also examined the
When longer relief is desired, a catheter can be inserted adjacent timing of infusions, with some being given on the 2nd day after
to the nerve, with continuous infusion or intermittent injection of ligation and others 7 days after this procedure. They were able
boluses of local anesthetic through the cannula. to show that response to lidocaine had three phases: (1) There
In chronic pain treatments, it seems that addition of corticos- was an acute reduction of allodynia during lidocaine infusion that
teroid, and usually a depot preparation (such as depomedrol or disappeared within 30 to 60 minutes after the end of the infusion.
triamcinolone acetonide), is made in an attempt to prolong pain (2) There was a transient reduction in allodynia several hours after
relief. Whereas this is well established in clinical practice, there is infusion. (3) A sustained reduction developed slowly over 24 hours
no great base of evidence to support this use of steroid. The after infusion and was maintained over the following 21-day study
effect of steroid in prolonging the action of local anesthetic period.
may be related to its effects as an anti-inflammatory agent as Their second major finding was that infusion given 2 days after
well as its membrane-stabilizing effect and its action on dorsal spinal nerve ligation was more effective in reducing allodynia than
root ganglia. infusion of an equal dose on postoperative day 7.
In practice, the only factor limiting which nerves can be blocked Three major conclusions can, therefore, be gleaned from these
is their accessibility. If adjacent to fixed landmarks, their location animal studies. First, intravenous lidocaine reduces the animal signs
can more easily be determined. Further reassurance can be gained of neuropathic pain in a dose-dependent fashion. Second, the rate
with a nerve stimulator and/or imaging techniques (e.g., ultra- of infusion has a significant effect on consequent antinociception.
sound, fluoroscopy). The exact methods of performing nerve Third, the antinociception can persist for a period far in excess of
blocks are beyond the scope of this chapter, and the practicalities the plasma half-life of the lidocaine.
of performing these procedures are well covered elsewhere. If we accept that the animal evidence strongly supports the con-
tention that the intravenous administration of lidocaine can reduce
pain, the issue of the safety of such administration becomes crucial.
Intravenous Most practitioners would have an instinctive reluctance to consider
the intravenous use of any local anesthetic. Many would associate
Few therapeutic acts go against the grain as much as injection of a the use of intravenous local anesthetics with a significant potential
local anesthetic agent deliberately into a vein. We have all been for cardiovascular suppression or even collapse. Perhaps one of the
brought up to carefully aspirate before injection of any local anes- reasons for this fear is the historical use of intravenous lidocaine in
thetic to avoid inadvertent systemic administration of the sub- the treatment of arrhythmias associated with acute myocardial
stance. And yet the concept to be outlined involves the deliberate infarction. In this scenario, infarcted and hypoxic myocardium
injection of what will seem like an enormous amount of local anes- produces an impairment of ventricular performance and lessening
thetic by the intravenous route. of cardiac output along with a propensity for dysrhythmia. The
Reference to the intravenous use of local anesthetic dates back to issue is, therefore, whether lidocaine used in this type of patient
over 60 years ago. Many subsequent reports of pain relief in a wide contributes to the cardiac dysfunction or is merely tarnished by
variety of clinical scenarios have appeared in the literature since association. Reference to the literature, which itself is based largely
then, often as case reports. on animal experimentation, gives a mixed picture, with some
A strong body of evidence from animal studies supports the papers suggesting a negative inotropic effect of lidocaine and
contention that systemic lidocaine reduces neuropathic pain. The others suggesting an improvement in coronary blood flow, an
reduction in pain appears to be dose dependent. Indeed, the anti- increase in myocardial oxygenation, and a reduction in arrhythmia
nociceptive effect may not be confined to neuropathic pain. Ness potential.
reported that intravenous lidocaine inhibits visceromotor and car- Clinical use of lidocaine in pain management also gives an indi-
diovascular reflexes and the evoked and spontaneous activity of cation of safety. Anecdotal reports of use in over 7000 cases without
neurons excited by colorectal distention in a rat model, with the untoward cardiovascular events should increase confidence in use.
implication that systemic lidocaine may be useful in the treatment Strangely, the major side effect of intravenous lidocaine is in fact
of human visceral pain conditions. inflammation of the vein through which the lidocaine is adminis-
Significant insight into the potential clinical use of intravenous tered. This can be severe enough to require premature withdrawal
lidocaine is gained by examination of the work of Chapman and of the administration cannula. This propensity to cause venous
colleagues. They examined the effect of intravenous lidocaine in a irritation is related to the concentration of the lidocaine infused
rat spinal nerve ligation model of neuropathic pain and confirmed and, strangely, to the proprietary brand of lidocaine. It does not
the findings of others who had observed a reduction in tactile appear to be related to the pH or the presence of preservatives. One
allodynia when lidocaine is administered in this fashion. Two fur- method of reducing infusion-related pain and inflammation is to
ther highly significant results were also obtained. First, when lido- place a glyceryl trinitrate patch above the infusion site. This nitrate
caine is given by the intravenous route over a short infusion period, possesses local anti-inflammatory properties sufficient to negate the
the reduction of tactile allodynia observed persists for significantly chances of this particular complication.
longer than the half-life of the drug. Indeed, in this experiment, Several published studies have examined the effect of systemic
21 days after the lidocaine infusion, 30% to 40% of the maximum lidocaine on human experimental pain. In one, Koppert and
possible reduction in tactile allodynia persisted. When they applied associates compared the effect of lidocaine administered systemi-
lidocaine intrathecally and regionally, no such reduction in allodyn- cally and by a regional technique on the pain and secondary
ia was observed. hyperalgesia produced by intradermal injection of capsaicin.
468 Chapter 63 LOCAL ANESTHETICS
Lidocaine administered in both fashions slightly reduced the pain clinicians experienced in its use will testify to a predictable and
produced by capsaicin injection. However, only systemically admi- very real pain-relieving effect when it is used in a diverse range of
nistered lidocaine had a significant effect on the secondary hyper- pain conditions. Two recent systematic reviews examined the avail-
algesia, as measured by pinpricks. This suggests a central mode of able evidence relating to the effect of intravenous lidocaine.
action for lidocaine when used in this fashion. Challapalli and associates concluded that ‘‘Lidocaine and oral ana-
Mattson and colleagues examined the effect of systemic lidocaine logues were safe drugs in controlled clinical trials for neuropathic
on the tissue response to partial-thickness burns. When compared pain, were better than placebo, and were as effective as other
with placebo infusion, lidocaine had no effect in the first 4 hours analgesics.’’
after the burn was inflicted. However, by 12 hours after the burn,
the lidocaine-treated subjects had a significantly quicker resolution
of residual erythema than the control subjects.
Historically, the first report of the successful use of an intrave-
Oral
nous local anesthetic dated from 1943, reporting analgesia in burns Mexiletine
patients when intravenous novocaine was used. We have already
seen that human experimental investigation supports the conten- Probably the most widely used oral local anesthetic is mexiletine,
tion that intravenous local anesthetics may be analgesic when used although it could also be argued that other agents with known
in burns patients, with the added advantage of quickening the res- sodium channel blocking effects such as the TCAs, carbamaze-
olution of the erythematous flare surrounding the site. Jonsson and pine/oxcarbazepine, lamotrigine, and phenytoin/fosphenytoin are
coworkers reported successful use of intravenous lidocaine in more widely used but not classified as local anesthetics.
patients immediately after hospital admission with a burn and con- Electrophysiologic studies in rats suggest that spinally adminis-
firmed that the use of intravenous lidocaine can significantly reduce tered mexiletine has a predominant effect on spinal Ad- and
the need to give rescue opioid analgesia. C-fibers, with little effect on Ab-fibers. Whereas we instinctively
The evidence confirming a potential analgesic effect of intrave- associate the use of drugs such as mexiletine with neuropathic
nous lidocaine is perhaps strongest in the case of neuropathic pain. pain, animal studies suggest that it may also have an effect on
Even then, certain contraindications arise. Attal and associates other types of pain. For example, one model of chronic inflamma-
reported a significant reduction in central nervous system pain tory pain is the formalin test. In this type of study, formalin is
when intravenous lidocaine was compared with placebo infusion, applied to the paw and the behavioral reaction to the irritation
whereas Galer and colleagues found that intravenous lidocaine had produced is measured by counting the number of times the
significantly less analgesic effect in patients with central nervous animal flinches. Mexiletine has been shown to reduce the flinching
system pain than in those with peripheral nervous system injury. behavior in such a formalin test.
Their results are nevertheless impressive. Fifty-eight percent of Erichsen and colleagues, in a rat model of neuropathic pain,
patients with peripheral nervous system injury pain gained relief, showed that mexiletine significantly reduced mechanical allodynia,
83% of patients with trigeminal neuralgia, 78% of those with lum- whereas lidocaine had no such effect. Therefore, despite the fact that
bosacral arachnoiditis, and 70% of those with polyneuropathy. both lidocaine and mexiletine are active on sodium channels, in this
Baranowski and coworkers examined the effect of an intravenous experimental paradigm, their effect was different. In a similar vein,
infusion of lidocaine (1 and 5 mg kg–1) given over 2 hours and Xu and coworkers examined the effects of mexiletine, carbamaze-
compared it with saline (placebo) infusions in patients who suffered pine (also known to be active at sodium channels), morphine,
from PHN. They found that both pain and allodynia were reduced baclofen, and muscimol in a rat model of ischemic spinal cord
in the active treatment group and that, in this scenario, the higher- injury. The allodynia produced by this injury was resistant to treat-
dose infusion conferred no additional benefit. ment with carbamazepine (and morphine, baclofen, and muscimol)
It also seems that the pain of diabetic neuropathy can respond to but did respond to mexiletine. The logic, therefore, of using a small
intravenous lidocaine and that the duration of relief can extend to dose of intravenous lidocaine to test the likely responsiveness to oral
21 days after infusion. Wu and associates compared the effect of mexiletine is not necessarily based on scientific evidence.
intravenous lidocaine to intravenous morphine infusion in patients A number of human studies have been performed examining the
with phantom limb and stump pain. They found that intravenous effect of mexiletine in a variety of pain conditions. Dejgard and
lidocaine reduced stump, but not phantom, pain. Several studies colleagues examined subjects with chronic painful diabetic neurop-
have assessed the efficacy of intravenous lidocaine in the treatment athy and showed that mexiletine reduced pain significantly more
of fibromyalgia. Infusions up to 500 mg of lidocaine were used and than placebo. They also showed that there were no changes in
response rates as high as 48% have been reported. Indeed, in the tendon reflexes, vibration threshold levels, beat-to-beat variation
study by Raphael and colleagues, the duration of relief after infusion in heart rate during deep breathing, or postural blood pressure
was prolonged. Twenty-one out of 50 ‘‘responders’’ had relief that changes during mexiletine treatment. Other studies examined the
extended for between 13 and 18 weeks. effect of mexiletine in spinal cord injury dysesthetic pain (at a lower
As long ago as 1961, Bartlett and Hutaserani reported significant dose than that used in the painful diabetic neuropathy study) and
alleviation of postoperative pain with intravenous lidocaine when found no significant reduction in measured pain parameters. In
doses up to 800 mg were used. Eighty-five percent of patients practice, mexiletine has a narrow therapeutic window, and there-
reported either no or mild pain after intravenous lidocaine use fore, the effective dose may be close to or the same as a dose that
compared with only 31% in the control group. Groudine and co- provokes side effects (side effects being largely related to the gas-
workers reported that intravenous lidocaine was associated with a trointestinal and central nervous systems).
significantly reduced time to first flatulence, more rapid return of
normal bowel function, and a shorter stay in hospital of 1.1 days in
Flecainide
patients undergoing radical retropubic prostatectomy.
In a report on the use of intravenous lidocaine in patients with This antiarrhythmic drug has sodium channel blocking effects sim-
chronic daily headache, Hand and Stark reported that 82% of their ilar to those of mexiletine and lidocaine. Little clinical evidence
19 patients had relief of symptoms. exists for its effect on neuropathic pain, and many practitioners
It can be seen, therefore, that therefore lidocaine has been may be put off from using it because of lack of experience in its
reported to have an effect in many pain conditions, although the use and because of reports of withdrawal arrhythmias when it is
clinical trial support for its use could not be described in any other suddenly stopped in patients who have been using it for its antiar-
way than being suggestive and not conclusive. Nevertheless, those rhythmic properties. That said, from an anecdotal clinical
perspective, it is both more effective and better tolerated than mex- Bartlett EE, Hutaserani O. Xylocaine for the relief of postoperative pain.
iletine. In an isolated study, Ichimata and associates showed Anesth Analg 1961;40:296–304.
that flecainide significantly reduced pain of PHN when studied Bennett MI, Tai TM. Intravenous lignocaine in the management of
over a 1-month period. primary fibromyalgia syndrome. Int J Pharm Res 1995;15:115–119.
Boas RA, Covino BG, Shahnarian A. Analgesic responses to IV lidocaine.
Br J Anaesth 1982;54:501–505.
Butterworth JF, Strichartz GR. Molecular mechanisms of local anesthesia.
CONCLUSIONS A review. Anesthesiology 1990;72:711–734.
Catterall WA. Common modes of drug action on Na+ channels:
Those drugs with sodium channel blocking effects, conventionally local anesthetics, antiarrhythmics and anticonvulsants. Trends
classified as local anesthetics, have an effect when administered Pharmacol Sci 1987;8:57–65.
topically, perineurally, orally, and parenterally. They can be effec- Chabal C, Russell LC, Burchill KJ. The effect of intravenous lidocaine,
tive for a wide range of conditions. Those applied topically can tocainide, and mexiletine on spontaneously active fibers originating in
reduce pain that is localized, whereas those administered intrave- rat sciatic neuromas. Pain 1989;38:333–338.
nously can alleviate both localized and diffuse pain. Although the Challapalli V, Tremont-Lukats IW, McNichol ED, et al. Systemic
administration of local anesthetic agents to relieve neuropathic pain.
use of local anesthetics by local infiltration into tissue and around Cochrane Database Syst Rev 2005;4:CD003345.
nerve and topically is widespread and well evidence-based, when Chapman SR, Bach FW, Shafer SL, Yaksh TL. Prolonged alleviation
administered systemically, the use of lidocaine in particular is of tactile allodynia by intravenous lidocaine in neuropathic pain.
based on a low level of clinical trial evidence. Yet, those who use Anesthesiology 1995;83:775–785.
systemic lidocaine find it a useful and practical option for a variety De Jong RH, Nace RA. Nerve impulse conduction during intravenous
of pain conditions. lidocaine injection. Anesthesiology 1968;29:22–28.
Devor M, Wall PD, Catalan N. Systemic lidocaine silences ectopic
neuromas and DRG discharge without blocking nerve conduction. Pain
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results of an enriched enrolment study. Pain 1999;80:533–538. the return of bowel function, decreases postoperative pain, and shortens
Katz NP, Davis MW, Dworkin RH. Topical lidocaine patch produces a hospital stay in patients undergoing radical retropubic prostatectomy.
significant improvement in mean pain scores and pain relief in treated Anesth Analg 1998;86:235–239.
PHN patients: results of a multicenter open-label trial. J Pain Hand PJ, Stark RJ. Intravenous lignocaine infusions for severe chronic
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Ackerman WE, Colclough GW. Juneja MM, Bellinger K. The management Kopert W, Ostermeier N, Sittl R, et al. Low dose lidocaine reduces
of oral mexiletine intravenous lidocaine to treat chronic painful secondary hyperalgesia by a central mode of action. Pain
symmetrical distal diabetic neuropathy. J Ky Med Assoc 1991;89:500–501. 2000;85:217–224.
Abdi S, Lee DH, Chung JM. The anti-allodynic effects of amitriptyline, Mao J, Chen LL. Systemic lidocaine for neuropathic pain relief. Pain
gabapentin, and lidocaine in a rat model of neuropathic pain. Anesth 2000;87:7–17.
Analg 1998;87:1360–1366. Masset GV, Pedigo S, Dunn NL, et al. Continuous lidocaine infusion for
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experimental mechanical allodynia by systemic lidocaine: responses to cancer patient. J Pediatr Hematol Oncol 2002;24:566–568.
early and late infusions. Pain 2003;103:21–29. Matos L, Hankoczy J, Torok E. Effects of lidocaine on myocardial
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Baranowski AP, De Courcey J, Bonello E. A trial of intravenous lidocaine Mattsson U, Cassuto J, Tarnow P, et al. Intravenous lidocaine infusion in
on the pain and allodynia of postherpetic neuralgia. J Pain Symptom the treatment of experimental human skin burs—digital color image
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470 Chapter 64 MUSCLE RELAX ANTS
Ness TJ. Intravenous lidocaine inhibits visceral nociceptive reflexes and Mexiletine
spinal neurons in the rat. Anesthesiology 2000;92:1685–1691. Blackburn-Munro G, Ibsen N, Erichsen HK. A comparison of the anti-
Peleg R, Shvartzman P. Low dose intravenous lidocaine as treatment for nociceptive effects of voltage-activated Na+ channel blockers in the
proctalgia fugax. Reg Anesth Pain Med 2002;27:97–99. formalin test. Eur J Pharmacol 2002;445:231–238.
Raphael JH, Southall JL, Treharne GJ, Kitas GD. Efficacy and adverse Chapman V, Ng J, Dickenson AH. A novel spinal action of mexiletine in
effects of intravenous lignocaine therapy in fibromyalgia syndrome. spinal somatosensory transmission of nerve injured rats. Pain
BMC Musculoskel Disord 2002;3:21–29. 1998;77:289–296.
Smith LJ, Shih A, Miletic G, Miletic V. Continual systemic infusion of Chiou-Tan FY, Tuel SM, Johnson JC, et al. Effect of mexiletine on spinal
lidocaine provides analgesia in an animal model of neuropathic pain. cord injury dysesthetic pain. Am J Phys Med Rehabil 1996;75:84–87.
Pain 2002;97:267–273. Dejgard A, Petersen P, Kastrup J. Mexiletine for treatment of chronic
Strichartz G. Protracted relief of experimental neuropathic pain by painful diabetic neuropathy. Lancet 1988;8575:9–11.
systemic local anesthetics. Anesthesiology 1995;83:654–655. Erichsen HK, Hao J-X, Xu X-J, Blackburn-Munro G. A comparison of the
Tanelian DL, Brose WG. Neuropathic pain can be relieved by drugs that antinociceptive effects of voltage-activated Na+ channel blockers in two
are use-dependent sodium channel blockers: lidocaine, carbamazepine, rat models of neuropathic pain. Eur J Pharmacol 2003;458:275–282.
and mexiletine. Anesthesiology 1991;74:949–951. Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q. The analgesic effect of
Tanelian DL, MacIver MB. Analgesic concentrations of lidocaine suppress gabapentin and mexiletine after breast surgery for cancer. Anesth Analg
tonic A delta and C fiber discharges produced by acute injury. 2002;95:985–991.
Anesthesiology 1991;74:934–936. Kamei J, Hitosugi H, Kawashima N, et al. Antinociceptive effect of
Tanelian DL, Victory RA. Sodium channel blocking agents. Their use in mexiletine in diabetic mice. Res Commun Chem Pathol Pharmacol
neuropathic pain conditions. Pain Forum 1995;4:75–80. 1992;77:245–248.
Tremont-Lukats IW, Challapalli V, McNichol ED, et al. Systemic Kamei J, Zushida K. Effect of mexiletine on thermal allodynia and
administration of local anesthetics to relieve neuropathic pain: a hyperalgesia in diabetic mice. Jpn J Pharmacol 2000;84:89–92.
systematic review and meta-analysis. Anesth Analg Wallace MS, Magnuson S, Ridgeway B. Efficacy of oral mexiletine for
2005;101:1738–1749. neuropathic pain with allodynia: a double-blind, placebo-controlled,
Tremont-Lukats IW, Hutson PR, Backonja MM. A randomized, crossover study. Reg Anesth Pain Med 2000;25:459–467.
double-masked, placebo-controlled pilot trial of extended IV lidocaine Xu XJ, Hao JX, Seiger A, et al. Systemic mexiletine relieves chronic
infusion for relief of ongoing neuropathic pain. Clin J Pain allodynia like symptoms in rats with ischemic spinal cord injury.
2006;22:266–271. Anesth Analg 1992;74:649–652.
Woolf CJ, Wiesenfeld-Hallin Z. The systemic administration of local Flecainide
anaesthetics produces a selective depression of C afferent fibre evoked Ichimata M, Ikebe H, Yoshitake S, et al. Analgesic effects of flecainide on
activity in the spinal cord. Pain 1985;23:361–374. postherpetic neuralgia. Int J Clin Pharmacol Res 2001;21:15–19.
Wu CL, Tella P, Staats PS, et al. Analgesic effects of intravenous lidocaine
and morphine on postamputation pain: a randomized double-blind,
active placebo-controlled, crossover trial. Anesthesiology
2002;96:841–848.
Chapter 64 ventilation of the lungs. Our focus is on those drugs used to reduce
muscle spasm either by direct action on the muscle, by acting on the
MUSCLE RELAXANTS neural innervation of the muscle, or by acting on the central neural
mechanisms that control muscle function but that do not paralyze
Gary McCleane the muscle.
The presence of muscle spasm and pain is suggested by the
presence of palpable increases in muscle tone over defined muscle
groups. Stretching these muscles can exacerbate pain, and in a sim-
ilar fashion, causing these muscles to contract against resistance can
also increase pain. Muscle spasm may be constant or intermittent;
in the latter case, one must distinguish between painful muscle
INTRODUCTION spasm and the lancinating pain associated with neuropathic pain.
Further suggestive factors of muscle spasm are that it is often re-
Muscle spasm and consequent pain are common accompaniments duced by the application of heat, it radiates in a direction not seen
of many conditions ranging from direct muscle trauma to neuro- with radicular pain, the muscle can be ‘‘loosened’’ by exercise, and
logic disorder. When the muscle spasm and pain are present on enthetic pain (i.e., the pain arising from areas in which muscle
their own, appropriate use of muscle-relaxant and anti-inflamma- adheres to bone) is present. Because muscle spasm may be inter-
tory medications can be curative. In contrast, when muscle spasm is mittent, muscle spasticity during nonspasm phases may be sug-
precipitated by other conditions, unless these are treated, muscle- gested by the presence of enthetic pain in the absence of spasm.
relaxant medication will at best palliate, and not cure, the muscle When muscle spasm is present, patients often complain of a heavi-
spasm and pain. ness and weakness in the area of spasm. Normal joint movement
In this chapter, we consider the available range of muscle-relax- relies on the coordinated action of muscle groups that act and
ant drugs and how they can be used to achieve optimal outcomes. It counteract each other’s effects. If one muscle, or group of muscles,
is important at an early stage to draw a contrast between the muscle is malfunctioning, the unbalanced action of surrounding muscles
relaxants used to alleviate muscle spasm and those used in anesthe- can reduce function and be perceived by the patient as weakness.
siology practice that induce a complete and reversible paralysis of When muscle spasm is located in particular muscle groups, well-
muscles and whose use would be fatal in the absence of mechanical defined clinical syndromes can be observed. For example, spasm of
Ness TJ. Intravenous lidocaine inhibits visceral nociceptive reflexes and Mexiletine
spinal neurons in the rat. Anesthesiology 2000;92:1685–1691. Blackburn-Munro G, Ibsen N, Erichsen HK. A comparison of the anti-
Peleg R, Shvartzman P. Low dose intravenous lidocaine as treatment for nociceptive effects of voltage-activated Na+ channel blockers in the
proctalgia fugax. Reg Anesth Pain Med 2002;27:97–99. formalin test. Eur J Pharmacol 2002;445:231–238.
Raphael JH, Southall JL, Treharne GJ, Kitas GD. Efficacy and adverse Chapman V, Ng J, Dickenson AH. A novel spinal action of mexiletine in
effects of intravenous lignocaine therapy in fibromyalgia syndrome. spinal somatosensory transmission of nerve injured rats. Pain
BMC Musculoskel Disord 2002;3:21–29. 1998;77:289–296.
Smith LJ, Shih A, Miletic G, Miletic V. Continual systemic infusion of Chiou-Tan FY, Tuel SM, Johnson JC, et al. Effect of mexiletine on spinal
lidocaine provides analgesia in an animal model of neuropathic pain. cord injury dysesthetic pain. Am J Phys Med Rehabil 1996;75:84–87.
Pain 2002;97:267–273. Dejgard A, Petersen P, Kastrup J. Mexiletine for treatment of chronic
Strichartz G. Protracted relief of experimental neuropathic pain by painful diabetic neuropathy. Lancet 1988;8575:9–11.
systemic local anesthetics. Anesthesiology 1995;83:654–655. Erichsen HK, Hao J-X, Xu X-J, Blackburn-Munro G. A comparison of the
Tanelian DL, Brose WG. Neuropathic pain can be relieved by drugs that antinociceptive effects of voltage-activated Na+ channel blockers in two
are use-dependent sodium channel blockers: lidocaine, carbamazepine, rat models of neuropathic pain. Eur J Pharmacol 2003;458:275–282.
and mexiletine. Anesthesiology 1991;74:949–951. Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q. The analgesic effect of
Tanelian DL, MacIver MB. Analgesic concentrations of lidocaine suppress gabapentin and mexiletine after breast surgery for cancer. Anesth Analg
tonic A delta and C fiber discharges produced by acute injury. 2002;95:985–991.
Anesthesiology 1991;74:934–936. Kamei J, Hitosugi H, Kawashima N, et al. Antinociceptive effect of
Tanelian DL, Victory RA. Sodium channel blocking agents. Their use in mexiletine in diabetic mice. Res Commun Chem Pathol Pharmacol
neuropathic pain conditions. Pain Forum 1995;4:75–80. 1992;77:245–248.
Tremont-Lukats IW, Challapalli V, McNichol ED, et al. Systemic Kamei J, Zushida K. Effect of mexiletine on thermal allodynia and
administration of local anesthetics to relieve neuropathic pain: a hyperalgesia in diabetic mice. Jpn J Pharmacol 2000;84:89–92.
systematic review and meta-analysis. Anesth Analg Wallace MS, Magnuson S, Ridgeway B. Efficacy of oral mexiletine for
2005;101:1738–1749. neuropathic pain with allodynia: a double-blind, placebo-controlled,
Tremont-Lukats IW, Hutson PR, Backonja MM. A randomized, crossover study. Reg Anesth Pain Med 2000;25:459–467.
double-masked, placebo-controlled pilot trial of extended IV lidocaine Xu XJ, Hao JX, Seiger A, et al. Systemic mexiletine relieves chronic
infusion for relief of ongoing neuropathic pain. Clin J Pain allodynia like symptoms in rats with ischemic spinal cord injury.
2006;22:266–271. Anesth Analg 1992;74:649–652.
Woolf CJ, Wiesenfeld-Hallin Z. The systemic administration of local Flecainide
anaesthetics produces a selective depression of C afferent fibre evoked Ichimata M, Ikebe H, Yoshitake S, et al. Analgesic effects of flecainide on
activity in the spinal cord. Pain 1985;23:361–374. postherpetic neuralgia. Int J Clin Pharmacol Res 2001;21:15–19.
Wu CL, Tella P, Staats PS, et al. Analgesic effects of intravenous lidocaine
and morphine on postamputation pain: a randomized double-blind,
active placebo-controlled, crossover trial. Anesthesiology
2002;96:841–848.
Chapter 64 ventilation of the lungs. Our focus is on those drugs used to reduce
muscle spasm either by direct action on the muscle, by acting on the
MUSCLE RELAXANTS neural innervation of the muscle, or by acting on the central neural
mechanisms that control muscle function but that do not paralyze
Gary McCleane the muscle.
The presence of muscle spasm and pain is suggested by the
presence of palpable increases in muscle tone over defined muscle
groups. Stretching these muscles can exacerbate pain, and in a sim-
ilar fashion, causing these muscles to contract against resistance can
also increase pain. Muscle spasm may be constant or intermittent;
in the latter case, one must distinguish between painful muscle
INTRODUCTION spasm and the lancinating pain associated with neuropathic pain.
Further suggestive factors of muscle spasm are that it is often re-
Muscle spasm and consequent pain are common accompaniments duced by the application of heat, it radiates in a direction not seen
of many conditions ranging from direct muscle trauma to neuro- with radicular pain, the muscle can be ‘‘loosened’’ by exercise, and
logic disorder. When the muscle spasm and pain are present on enthetic pain (i.e., the pain arising from areas in which muscle
their own, appropriate use of muscle-relaxant and anti-inflamma- adheres to bone) is present. Because muscle spasm may be inter-
tory medications can be curative. In contrast, when muscle spasm is mittent, muscle spasticity during nonspasm phases may be sug-
precipitated by other conditions, unless these are treated, muscle- gested by the presence of enthetic pain in the absence of spasm.
relaxant medication will at best palliate, and not cure, the muscle When muscle spasm is present, patients often complain of a heavi-
spasm and pain. ness and weakness in the area of spasm. Normal joint movement
In this chapter, we consider the available range of muscle-relax- relies on the coordinated action of muscle groups that act and
ant drugs and how they can be used to achieve optimal outcomes. It counteract each other’s effects. If one muscle, or group of muscles,
is important at an early stage to draw a contrast between the muscle is malfunctioning, the unbalanced action of surrounding muscles
relaxants used to alleviate muscle spasm and those used in anesthe- can reduce function and be perceived by the patient as weakness.
siology practice that induce a complete and reversible paralysis of When muscle spasm is located in particular muscle groups, well-
muscles and whose use would be fatal in the absence of mechanical defined clinical syndromes can be observed. For example, spasm of
paracervical muscles gives rise to torticollis, whereas spasm of the O

piriformis muscle may give rise to the so-called piriformis syn-
drome, which includes worsening of the pain on internal rotation
of the hip, during defecation, and as a result of pressure over the CH3
N
sciatic notch, and is confirmed by palpable spasm of the piriformis N
muscle on digital rectal examination
Whereas muscle-relaxant drugs can have useful effects in
patients with muscle spasm, their effects may be enhanced by copre-
scription of other agents. For example, muscle spasm is often
accompanied by inflammation. Muscle relaxants do not have
anti-inflammatory effects, and therefore, the use of a nonsteroidal
anti-inflammatory drug (NSAIDs) can complement the effects of
the muscle-relaxant drugs. Conversely, any muscle-relaxant effect of CI
an NSAID is minimal, and the addition of a muscle relaxant to an Figure 64^2. Diazepam.
NSAID can enhance the effect of the NSAID when muscle spasm is
present.
Less well defined is the use of muscle-relaxant drugs in the pres-
ence of neuropathic pain. Muscle spasm can certainly accompany
neuropathic pain, with the spasm occurring as a protective reflex BENZODIAZEPINES
around the area where the neuropathic pain is felt. One would
expect a muscle-relaxant drug to help in this situation. But what Benzodiazepines bind to benzodiazepine receptors located in the
happens if the muscle spasm is the result of neural irritation of a terminals of primary fibers, leading to increased chloride flux
motor nerve? Is it logical to use a muscle-relaxant drug or would it across the terminal membrane with resultant increase in membrane
be better to use an antiepileptic drug or some other agent that one potential.
would use if that neural irritation caused pain? Side effects of the benzodiazepines group as a whole includes
When considering individual muscle-relaxant drugs, one is sedation, cognitive impairment, and with prolonged use, with-
hampered by the lack of clinical studies examining effectiveness. drawal reactions on discontinuation of the drug. Diazepam (Fig.
Therefore, insight into the potential utility of these drugs is based 64–2) is frequently used as a muscle relaxant, but in this casse, its
on anecdotal evidence, albeit anecdotal evidence based on consid- use should be short term and only for flare-ups of muscle spasm.
erable clinical experience. Clonazepam (Fig. 64–3) appears to possess analgesic and per-
haps amnesic properties but has a long drug half-life so it may
accumulate.
BACLOFEN (Fig. 64–1) Lorazepam (Fig. 64–4) has some advantage from a pharmaco-
kinetic perspective, having a shorter half-life than diazepam or clo-
Baclofen is the p-chlorophenyl derivative of g-aminobutyric acid nazepam, and it may be used in preference to these, particularly in
(GABA). It achieves its therapeutic effect by being a GABAB ago- the elderly.
nist and includes sedation and confusion among its side effects.
Abrupt cessation of long-term treatment can be associated with a
withdrawal reaction. That said, baclofen is usually well tolerated, BOTULINUM TOXIN
has a relatively quick onset of action, and can be effective in the
treatment of muscle spasm. Some evidence also suggests that it The German physician and poet Justinus Kerner called botulinum
can reduce the neuropathic pain associated with trigeminal toxin ‘‘sausage poison’’ because the bacterium that produces it,
neuralgia. Clostridium botulinum, can be found in badly managed meat pro-
The exact mechanisms of action of baclofen are not known for ducts. Poisoning by C. botulinum was named botulism (from the
certain but seem to involve both pre- and postsynaptic GABAB Latin botulus [sausage]) by another German physician, Muller. The
receptor actions. At the presynaptic site, baclofen decreases calcium toxin of C. botulinum was first isolated by Emile Schantz, with
conductance with resultant decreased neurotransmitter and excita- A.S.V. Burgen discovering that botulinum toxin blocks neuromus-
tory amino acid uptake. At the postsynaptic site, baclofen increases cular transmission in 1949.
potassium conductance with resultant neuronal hyperpolarization Of the seven known immunologically distinct serotypes of botu-
and may also inhibit the release of substance P. Baclofen is available linum toxin (A, B, C, D, E, F, and G), types A and B are the only
in both an oral formulation and a form used for intrathecal infusion types available for routine clinical use. Whereas each of these neu-
in patients with refractory spasticity. rotoxins is similar in that they are proteins, they vary with respect to
OH HN
H2N
N
O
CI
O2N
CI
Figure 64^1. Baclofen. Figure 64^3. Clonazepam.
H O reported chart review compared type A with type B toxin for the
N treatment of myofascial pain syndrome and concluded that type A–
treated patients had a longer duration of benefit and fewer side
effects.
OH
Two randomized studies concluded either that local anesthetic
trigger point injections are equally effective as botulinum toxin
N
CI injections for myofascial pain or that small doses of botulinum
toxin fail to provide notable relief compared with placebo injec-
tions. In their study of the use of botulinum toxin type A injections
CI into cervical paraspinal, trapezius, and thoracic paraspinal muscles,
Wheeler and coworkers3 were not able to detect any significant
differences in pain reduction between treated and placebo patients.
In contrast, Freund and Schwartz’s randomized, controlled study of
Figure 64^4. Lorazepam.
26 patients with chronic neck pain after whiplash-type injuries4
demonstrated a significant reduction in pain for those patients
treated with botulinum toxin type A versus placebo.
Improvements were noted within 4 weeks of treatment. Cheshire
molecular weight, mechanism of action, duration of effect, and and associates5 injected myofascial trigger points with both botuli-
adverse effects. The bacteria synthesize each toxin initially as a num toxin type A and saline in a cross-over design in six patients
single-chain polypeptide, after which bacterial proteases ‘‘nick’’ with cervical or shoulder girdle pain. Four of the six patients expe-
both type A and type B proteins, resulting in a di-chain structure rienced at least a 30% pain reduction with botulinum toxin but not
consisting of one heavy and one light chain. Type A is nicked more saline injection.
than type B, and there is less than 50% homology between the two Utilizing a novel injection technique, injecting the whole muscle
toxins. girdle in a gridlike pattern instead of the areas of tenderness only,
Botulinum toxin blocks the release of acetylcholine from cho- and using doses of botulinum toxin type A ranging form 20 to 600
linergic nerve terminals. In addition, botulinum toxin inhibits the units, Lang6 reported that 60% of patients experienced good to
release of glutamate, substance P, and calcitonin gene–related pep- excellent results 22 to 60 days after injection.
tide and reduces afferent input to the central nervous system In a single-blinded study, Porta7 evaluated the differences
through effects of the toxins on muscle spindles. between lidocaine/methylprednisolone injections and botulinum
To achieve the effect on acetylcholine, the toxin must be inter- toxin type A injections in affected myofascial trigger points within
nalized into the synaptic terminal. The first step in this process is the psoas, piriformis, or scalenus anterior muscles. Eighty to 150
the binding of the toxin to a receptor on the axon terminals. Each units of toxin were used. Each group experienced benefit, but the
botulinum toxin serotype binds specifically to its own receptor toxin-treated patients experienced greater duration of relief. De
irreversibly, and neither serotype binds to or inhibits the other Andres and colleagues8 also confirmed the treatment of myofascial
serotype’s receptor. After the toxin is bound, an endosome is pain with botulinum toxin type A in an open-label study.
formed that carries the toxin into the axon terminal. The final Several case reports suggest that use of type B toxin in the man-
step involves cleavage of one of the known synaptic proteins that agement of chronic myofascial pain can give equally good results.
are required for acetylcholine to be released by the axon. Botulinum The use of botulinum toxin in the management of chronic low
toxins B, D, F, and G cleave synaptobrevin, also known as vesicle- back pain has also been explored. In a randomized, controlled study
associated membrane protein. Botulinum toxin type C also cleaves involving 31 patients with chronic low back pain, Foster and cow-
syntaxin. orkers9 studied the effect of 200 units of botulinum toxin type A
In 1989, botulinum toxin type A (Botox) became the first botu- (five sites in the paravertebral levels L1–5 or L2–S1, 40 units/site)
linum toxin to be approved by the U.S. Food and Drug compared with placebo injections. Pain and extent of disability were
Administration (FDA) for use in the United States. Although orig- noted at baseline as well as at 3 and 8 weeks using the VAS as well as
inally FDA approved for the treatment of strabismus, blepharos- the Owestry Low Back Pain Questionnaire. At both 3 and 8 weeks,
pasm, and hemifacial spasm, it was subsequently approved for the more patients who had received botulinum toxin injections (73.3%
treatment of cervical dystonia and most recently for the treatment and 60%, respectively) experienced 50% or more pain relief than
of glabellar wrinkles and axillary hyperhidrosis. Botulinum toxin the placebo-treated group (25% and 12.5%, respectively). At 8
type B, the only other botulinum toxin to be currently FDA weeks, there was less disability in the botulinum-treated group
approved, is approved only for cervical dystonia. than in the placebo-treated group. Knüsel and associates10 treated
Botulinum toxin treatment has been shown to have beneficial patients with low back pain associated with painful muscle spasm
effects in a number of musculoskeletal conditions. One of these is with different doses of type A toxin and noted that only those
temporomandibular pain. Freund and Schwartz1 studied 46 treated with the highest dose (240 units) experienced greater relief
patients with this condition and injected botulinum toxin type A than placebo-treated patients.
into both masseter muscles (50 units each side) and into the tem- Botulinum toxin treatment has been reported as having benefi-
poralis muscles (25 units each) under electromyographic guidance. cial effects in other conditions such as piriformis syndrome, plantar
Pain levels as assessed by visual analog scores (VASs), interincisal fasciitis, and lateral epicondylitis.
oral opening, and tenderness to palpation were among the out-
comes measured that showed improvement. Approximately 60%
of those treated experienced at least 50% improvement in these CANNABINOIDS
areas. In contrast, Nixdorf and colleagues2 studied a broadly similar
patient group and injected similar doses of botulinum toxin. They It is contended that the psychoactive ingredient in cannabis, d-9-
utilized a cross-over study design and found no statistically signif- tetrahydrocannabinol (THC), and cannabinoids in general can
icant differences between the active and the placebo-treated groups. reduce muscle spasm and pain. It appears that the cannabinoid
That said, only 15 patients entered, and of those, only 10 completed (CB1) receptors in the central nervous system mediate these effects
the study. in the central nervous system. Human evidence of a muscle-relaxant
A number of studies have examined the role of botulinum toxin effect in patients with multiple sclerosis is somewhat mixed. Wade
in the treatment of chronic cervical or thoracic pain. One recently and colleagues11 studied 160 patients with multiple sclerosis (MS)
who were significantly troubled by a variety of MS-related pro- O

blems, including muscle spasm. These authors conducted their O
study using ‘‘cannabis-based medicinal extract’’ containing equal H N
parts of THC and cannabidiol. When all symptoms were consid- N
ered, there was an equal decrease after active and placebo treatment. O
O
However, when spasticity scores were analyzed separately, a signif- N
O N
icant decrease was observed when active treatment was compared
with placebo. In Vaney and coworkers’ study of 57 patients with
Figure 64^6. Dantrolene.
MS-related spasticity,12 analysis of their intention-to-treat set
showed no reduction with THC/cannabidiol treatment. In their
per-protocol set, reductions in muscle spasms were seen. Zajicek
and associates13 studied 667 patients with MS-related muscle spas- used in the treatment of malignant hyperpyrexia, a condition occa-
ticity and compared the effect of THC with that of placebo. sionally triggered by anesthetic agents and in which intense muscle
Treatment with this cannabinoid was not shown to have any ben- spasm is a predominant feature. In those individuals believed to be
eficial effect on spasticity, using their chosen muscle spasticity mea- susceptible to malignant hyperpyrexia, dantrolene can be used in a
surement tool. However, patients did seem to report some benefit prophylactic fashion.
with active treatment. This same group14 reported the results of When dantrolene is employed in the treatment of muscle spasm
continued treatment for a 12-month period with THC. They and spasticity, a gradual escalation of dose to an effective level is
found limited evidence for a longer-term treatment effect with used. Consequently, dantrolene is of little use in the immediate
cannabinoids. treatment of a flare up of muscle spasm, but rather, has value in
the longer-term management of muscle-based spasm. Dantrolene
can affect liver function, and therefore, periodic blood sampling
CARISOPRODOL (Fig. 64–5) should be carried out to assess liver function.
This agent is metabolized primarily in the liver, with multiple meta-

bolites including meprobamate. Because metabolism depends on METAXALONE
deacetylation via the liver microsomal enzyme cytochrome P-450
(CYP) CYP 2C19, which a proportion of the population is deficient This oxazolidone derivative can have a muscle-relaxant effect when
in, ‘‘poor metabolizers’’ of this drug are at increased risk of experi- there is a peripheral musculoskeletal condition but not when there
encing concentration-based side effects such as drowsiness, hypo- is spasticity secondary to a neurologic disorder. It is generally well
tension, and central nervous system depression at otherwise tolerated but shares the potential side effect of sedation of many
‘‘normal’’ doses. There is some risk of respiratory depression with other muscle-relaxant drugs.
carisoprodol, which is increased by the coadministration of pro-
poxyphene. Although the exact mode of action of carisoprodol is
not established, flumazenil may have a role in reversing carisopro- METHOCARBAMOL
dol toxicity.
Methocarbamol is a carbamate derivate of guaifenesin and is struc-
turally related to mephenesin. It is available in both oral and
CYCLOBENZAPRINE parenteral formulations.
Cyclobenzaprine has a tricyclic structure very similar to that of

amitriptyline. Not surprisingly, therefore, it shares a propensity to ORPHENADRINE
cause anticholinergic side effects with the tricyclic antidepressants.
It can be of use in patients with acute and intermittent musculo- Orphenadrine is a monomethylated derivative of diphenhydramine.
skeletal conditions including low back pain, muscle spasm, and Centrally acting antihistamines such as this exhibit muscle-relaxant
fibromyalgia. and analgesic properties, although the muscle-relaxant effect of or-
phenadrine may also be attributable to its modulating effect on the
raphe-spinal serotinergic system.
DANTROLENE (Fig. 64–6) Orphenadrine also seems to exhibit the characteristics of an
N-methyl-D-aspartate (NMDA) receptor antagonist, which may
Dantrolene is unusual among the muscle-relaxant drugs in that it account for some of its possible analgesic effects. Side effects asso-
works directly on skeletal muscle and achieves its effect by an action ciated with orphenadrine use are partially related to its anticholin-
on calcium uptake by the sarcoplasmic reticulum. Dantrolene is ergic action and include dry mouth, urinary retention, confusion,
blurred vision, agitation, and restlessness.
Orphenadrine is often presented in combination with acetami-
CH3 nophen, aspirin, and NSAIDs.
TIZANIDINE
O O O
Tizanidine is an imidazoline derivative structurally related to clo-
O H3C nidine. Like clonidine, it is an a2-adrenoreceptor agonist. Its effect,
H3C
mediated by this receptor, is to cause a direct inhibition of release of
N NH2 excitatory amino acids and a concomitant inhibition of facilitory
H
coeruleospinal pathways. Epidural and spinal administration of
H3C
clonidine with local anesthetic and opioid combinations is associ-
Carisoprodol ated with enhanced analgesia, and it would, therefore, be expected
Figure 64^5. Carisoprodol. that tizanidine may also have analgesic properties.
Somnolence is one of the most frequent side effects of tizanidine injection into affected muscle can give rise to sustained symptom
use. Its elimination half-life is between 1 and 3 hours, so it can be relief.
administered up to four times daily with a greater proportion of the Unfortunately, whereas considerable clinical experience exists
total daily dose given at night to augment sleep both because of its with the use of many of the muscle relaxants described, perhaps
hypnotic properties and because muscle relaxation and pain relief only in the case of botulinum toxin is use built on solid study
may allow a more uninterrupted night’s rest. Meythaler and collea- evidence. With many of the other agents, evidence supporting
gues15 reported a randomized, double-blind, cross-over study of their use is anecdotal. Furthermore, we have yet to establish, with
17 patients with spasticity owing to acquired brain injury. They any degree of confidence, the optimal muscle-relaxant agent to use
reported that tizanidine significantly reduced muscle tone (and in particular circumstances and to define how we can reduce muscle
also increased motor strength), that its effect was directly related spasm most effectively when it is caused by injury to structures
to the dose used, but that there were limitations with its use owing other than muscle.
to the drowsiness it caused.
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476 Chapter 65 a2 -AGONISTS
Chapter 65 subtype may also be implicated in the development of some

forms of hyperalgesia, particularly thermal hyperalgesia.
a2-Agonists a2C-Receptors are also involved in spinal antinociception. Both
a2A- and a2C-receptor subtypes may be involved in the synergistic
Jennifer A. Elliott interaction between a2-adrenergic agonists and opioids. It has been
demonstrated that the binding affinity of a2-agonists at spinal
a2-receptors correlates with their spinal antinociceptive potency,
regardless of their route of administration. On this basis, dexmede-
tomidine is the most potent of the currently available a2-agonists,
whereas tizanidine is the least potent. Most of the analgesic action
we associate with a2-agonists likely occurs via stimulation of
INTRODUCTION a2-receptors in the dorsal horn of the spinal cord, with resultant
reduced nociceptive neurotransmitter release. However, there may
a2-Agonists are well known for their role in the management of also be diminished neurotransmitter release from peripheral sym-
hypertension. Over the past few decades, a new role has been estab- pathetic nerve terminals, and an overall reduction in sympathetic
lished for these drugs in the treatment of pain and as adjuvants for outflow both centrally and peripherally may contribute to analgesia.
general anesthesia. These agents are appealing because they provide
analgesic synergy and have opioid-sparing effects. a2-Agonists have
been used in the management of a wide range of painful conditions
including acute surgical pain, cancer-related pain, neuropathies, PHARMACOLOGYAND METABOLISM
headaches, and myofascial pain, to name a few. The most well- OF CLINICALLYAVAILABLE
recognized of these agents is clonidine. Tizanidine and dexmedeto- a2-AGONISTS
midine represent newer a2-agonists available for clinical use. Several
other a2-agonists are currently undergoing study in animal models, Three a2-agonists, clonidine, tizanidine, and dexmedetomidine, are
and they may prove beneficial for use in humans as well. Tizanidine currently available for use in anesthesia and pain-management
has been found useful in the management of spasticity and painful practice in the United States. Among these agents, clonidine has
muscle disorders associated with muscle spasm. Dexmedetomidine seen the most widespread application in the management of pain. It
is a sedative analgesic that does not create respiratory depression or is available in the United States for oral, transdermal, and neuraxial
central nervous system disinhibition which have been associated administration. It has also been used as an additive to regional
with traditional sedative agents used for anesthesia. a2-Agonists anesthetics and has been instilled intra-articularly for postoperative
can be administered by several routes. Clonidine may be delivered pain control. Tizanidine is used orally and is primarily employed in
orally, transdermally, or neuraxially. It has also been used as an the management of spasticity and painful muscle disorders.
additive to regional anesthetics. Tizanidine is used via the oral Dexmedetomidine is given intravenously and is indicated for
route, and dexmedetomidine has been administered primarily by short-term (< 24 hr) sedation in the intensive care unit. It is also
intravenous infusion. These agents act through G-protein–linked being evaluated as an adjuvant for perioperative pain and has been
receptors to reduce sympathetic outflow and decrease the release used as a major component of operative anesthesia in several
of neurotransmitters from neurons involved in pain signaling. As studies.
might be expected owing to their utility in the management of
hypertension, one prime undesired effect related to the use of
a2-agonists in the management of pain is hypotension. This side Clonidine
effect may result in dose limitations in certain patients. Sedation is
another frequently-observed adverse effect of these agents. In the treatment of pain, clonidine has been administered both
a2-Agonists play an important role in pain management and systemically and neuraxially. It has also been used as an additive
anesthesia, and as newer agents in this class continue to be devel- in regional anesthetic blocks and instilled into joints for postoper-
oped, it is likely that further applications for these drugs will evolve. ative pain. In the United States, clonidine preparations available for
systemic use include oral tablets and a transdermal delivery system.
After oral administration, peak plasma clonidine levels are achieved
a2-RECEPTORS in 3 to 5 hours; it has an elimination half-life of 12 to 16 hours.
With transdermal use, it takes up to 2 days to achieve peak plasma
a2-Receptors are G-protein–linked receptors whose activation clonidine levels after patch application. Epidurally administered
results in various cellular effects in the target neuron. These effects clonidine (Duraclon) reaches peak concentrations at 19 minutes
include opening of potassium channels, resulting in potassium in the plasma and at 26 minutes in the cerebrospinal fluid. After
efflux, and hyperpolarization of the neuronal membrane. In addi- absorption, approximately 50% of the clonidine dose undergoes
tion, decreased calcium conductance and inhibition of cyclic aden- hepatic metabolism, whereas the remainder is eliminated
osine monophosphate (cAMP) formation occur with a2-receptor unchanged in the urine within 24 hours. Dose adjustment may be
activation. These changes lead to decreased neurotransmitter release advisable in the setting of hepatic or renal insufficiency. Oral clo-
and neuronal impulse transmission. Activation of a2-receptors may nidine is typically started at a dose of 0.1 mg twice daily or three
also affect sodium/hydrogen ion exchange and cause increased times daily and can be titrated up to 2.4 mg total daily dose. The
phospholipase A2 levels. Three a2-receptor subtypes, a2A, a2B, and transdermal patch starting dose is 0.1 mg (the daily delivered dose;
a2C, have been identified. a2A-Receptors appear to be the predom- Catapres-TTS-1 patch) and can be titrated up to 0.6 mg. The trans-
inant receptor subtype responsible for the antinociceptive effects dermal patch is changed on a weekly basis. Epidural infusions of
associated with the use of a2-agonists. Ironically, this receptor clonidine are typically started at a rate of 30 mcg/hr and can be
titrated to 40 mcg/hr (little information is available regarding use of Dexmedetomidine

higher infusion rates). Single epidural bolus doses of up to 700 mcg
of clonidine have been administered. Dexmedetomidine is available in the United States for parenteral
administration. It acts as an agonist at a2-receptors, but can exhibit
a1-receptor agonism when infused rapidly or in high doses. The
Tizanidine distribution half-life of dexmedetomidine is 6 minutes, and its ter-
minal elimination half-life is 2 hours. As with tizanidine, dexmede-
Tizanidine is available in the United States in the form of tablets tomidine undergoes hepatic metabolism via the CYP450 enzyme
and capsules for oral administration. Tizanidine is almost com- system and glucuronidation. Very little dexmedetomidine is
pletely absorbed after oral administration and has a bioavailability excreted unchanged in the urine and feces. Dose reduction is indi-
of 40% owing to its extensive first-pass effect. Peak plasma con- cated in patients with significant hepatic disease owing to decreased
centrations occur approximately 1 hour after dosing in the fasted clearance of the drug with hepatic impairment. This may also be
state, and it has a half-life of 2 to 2.5 hours. Nearly 95% of the true in patients with significant renal impairment, because sedation
drug is metabolized, primarily by the hepatic cytochrome P-450 may be prolonged after dexmedetomidine administration even
(CYP450) enzyme CYP1A2. Tizanidine has inactive metabolites though the terminal elimination half-life of the drug does not
with half-lives of 20 to 40 hours. It appears that elimination of appear to be increased in the presence of renal dysfunction. Dose
tizanidine after its metabolism occurs via both renal (60%) and reduction may also be necessary in older patients because there is an
fecal (20%) routes. When tizanidine is consumed in the presence increased incidence of bradycardia and hypotension with the use of
of food, its pharmacokinetics are altered over its use in the fasted dexmedetomidine in this patient population compared with youn-
state. When tablets are taken with food, the peak plasma concen- ger individuals. When initiating treatment with dexmedetomidine,
trations of tizanidine increase by 30% and the time to peak a loading dose of 1 mcg/kg should be administered over 10 minutes,
plasma concentrations are delayed by approximately 30 minutes. followed by a continuous infusion of 0.2 to 0.7 mcg/kg/hr for main-
In contrast, when capsules of tizanidine are consumed with food, tenance. Currently, dexmedetomidine use is not recommended for
mean plasma concentrations are decreased by 20% and the periods exceeding 24 hours, and it is primarily restricted to peri-
median time to reach peak concentrations is 3 hours (a delay operative and intensive care unit use. However, several case reports
of 2 hours vs. the fasted state). Tizanidine clearance may be re- have been published regarding use of dexmedetomidine for more
duced substantially in the setting of significant renal or hepatic extended periods without indications of serious adverse events after
disease. Its use in patients with severe hepatic dysfunction is not its discontinuation (Table 65–1).
recommended, and dose reduction is advised in the presence of
renal impairment (especially when creatinine clearance < 25 ml/
min). Tizanidine clearance is also affected by the use of oral
contraceptives and other drugs that are inhibitors of CYP1A2. CLINICAL APPLICATIONOF
Examples of such drugs include fluvoxamine, ciprofloxacin and a2-AGONISTS IN ANESTHESIA AND
other fluoroquinolones, cimetidine, famotidine, acyclovir, ticlopi- PAIN MEDICINE
dine, and several antiarrhythmic agents (amiodarone, mexiletine,
propafenone, and verapamil). It is generally advised that caution Clonidine has been widely used in a variety of pain syndromes
be exercised when tizanidine is used in combination with any of including complex regional pain syndrome, neuropathic pain syn-
these drugs. Typically, tizanidine is initiated at a dose of 4 mg dromes, chronic headaches, and cancer pain. It has also been com-
and is titrated in 2- to 4-mg increments until symptoms are bined with local anesthetics as a component of regional anesthesia.
adequately controlled. The maximum recommended daily dose Tizanidine has been administered primarily in the management of
for tizanidine is 36 mg, typically administered in three divided myofascial pain and spasticity, but it has also been used for other
doses. Limited experience exists for the use of individual tizani- painful conditions such as headaches. Dexmedetomidine has been
dine doses exceeding 8 to 12 mg per dose and total daily doses of employed for short-term sedation in the intensive care unit and also
24 to 36 mg/day. as an anesthetic and analgesic adjuvant in the perioperative setting.
Table 65^1. Current Therapy: Pharmacologic Properties of a2-Agonists
Drug Clonidine Tizanidine Dexmedetomidine

Formulations Oral (Catapres) Oral: tablet, capsule (Zanaflex) Intravenous (Precedex)
available Transdermal (Catapres TTS)
Epidural (Duraclon)
Time to peak effect Oral: 3–5 hr 60 min
Transdermal: 48 hr 1 hr (fasted state)
Epidural: 19 min 1.5–3 hr (fed state)
T=1
2 Elimination: 12–16 hr 2–2.5 hr Distribution: 6 min
Elimination: 2 hr
Route of metabolism/ Hepatic: 50% Hepatic: 95% with renal (60%) and Hepatic (nearly 100%)
elimination Renal: 40%–60% fecal (20%) excretion of metabolites
Dosage Oral: 0.2–2.4 mg/day 4–36 mg total per day (limited Loading: 1 mcg/kg
Transdermal: 0.1–0.6 mg/day information exists for long-term use Maintenance: 0.2–0.7 mcg/
Epidural: 30–40 mcg/hr; maximum of single doses > 8–12 mg or total kg/hr
single dose 700 mcg daily doses > 24–36 mg)
478 Chapter 65 a2 -AGONISTS
Clonidine part of a detoxification regimen to assist with analgesic withdrawal

in patients exhibiting analgesic rebound headaches. Based on
Extensive scientific literature documents the utility of clonidine in animal studies, it also appears that tizanidine may provide benefit
the management of a variety of painful conditions. Clonidine has in the perioperative period and in the management of neuropathic
been frequently used for the management of pain in the perioper- pain, in accordance with the effects of clonidine under similar cir-
ative period and treatment of intractable cancer associated pain, cumstances. One study in humans demonstrated a nearly 20%
especially that neuropathic in nature. Other conditions for which decrease in the minimum alveolar concentration of sevoflurane
clonidine has been effective include complex regional pain syn- when 4 mg of oral tizanidine was administered preoperatively.
drome, postherpetic neuralgia, trigeminal neuralgia, and chronic This, in conjunction with the fact that tizanidine is not as potent
headaches. Clonidine has been utilized with benefit in peripheral as clonidine in its antihypertensive effects, may allow for more
nerve blocks, retrobulbar blocks, plexus anesthesia, intravenous widespread use than clonidine. Use of tizanidine for perioperative
regional anesthesia, labor analgesia, intra-articular administration anesthetic and analgesic-sparing effects may prove especially bene-
after arthroscopy, and topically for neuropathies. Clonidine has also ficial if it becomes available for neuraxial use in humans.
demonstrated opioid-sparing effects and synergistic action with
opioids, local anesthetics, glutamate receptor antagonists, and
gabapentin. Use of oral clonidine in conjunction with epidural or Dexmedetomidine
intrathecal morphine has enhanced analgesia in the postoperative
period. It is clear, however, that the greatest degree of analgesia Dexmedetomidine is currently U.S. Food and Drug Administration
occurs with neuraxial administration of clonidine. In fact, one (FDA) approved for use in short-term (< 24 hr) sedation in the
study using epidural clonidine as the sole analgesic agent intrao- intensive care unit in the mechanically ventilated patient. Aside
peratively and in the first 12 hours postoperatively demonstrated from its use in sedation of the critically ill patient, it has also
that administration of a clonidine bolus of 8 mcg/kg/hr followed by been evaluated for use perioperatively and in the management of
a continuous infusion of 2 mcg/kg/hr provided substantial analge- pain. Dexmedetomidine has been used as an anesthetic adjunct for a
sia. Another study compared the use of epidural clonidine or bupi- variety of surgical procedures and has demonstrated reduction in
vacaine as the sole analgesic agent during and after abdominal the hemodynamic responses associated with procedures such as
surgery. In this study, high-dose epidural clonidine exhibited anal- tracheal intubation and surgical incision. This is desirable because
gesia superior to two dosing regimens of epidural bupivacaine. the tachycardia and hypertension that often accompany such stim-
The potency of clonidine when administered intrathecally is uli may induce myocardial ischemia in susceptible individuals, such
approximately 10 times that of epidural clonidine when used to as patients with underlying coronary artery disease. Because dexme-
treat acute thermal pain, whereas it is approximately twice as detomidine also allows for sedation without significant impact on
potent when used to manage mechanical hyperalgesia and allodyn- respiration, it has been employed in the perioperative management
ia. In addition to its beneficial effects on acute postoperative pain, of patients at risk of opioid-induced respiratory depression, such as
intrathecal clonidine has been demonstrated to reduce postopera- the morbidly obese. Several studies have shown a reduction in peri-
tive secondary hyperalgesia as determined in a group of patients operative opioid requirements when dexmedetomidine was incor-
undergoing colonic resection. It was noted that the area of hyper- porated into the anesthetic plan, further indicating the potential
algesia around the incision site was much smaller in diameter in utility of this agent in selected patient populations such as those
patients receiving 300 mcg of intrathecal clonidine than in those with obstructive sleep apnea. In addition, dexmedetomidine does
receiving saline. The patients given intrathecal clonidine as part of not create the central nervous system disinhibition typically seen
their perioperative anesthetic also had less residual pain in their with other sedative agents such as propofol. Instead, because of its
surgical wounds and surrounding tissue at 2 weeks, 1 month, and action on the locus ceruleus, the sedation seen with dexmedetomi-
6 months than those patients who had received intrathecal saline dine resembles that seen during normal sleep. This property allows
placebo. Intrathecal clonidine is also being used with regularity in for rapid patient arousal and cooperation, which may be important
the treatment of chronic nonmalignant pain and intractable cancer especially when intraoperative assessment of neurologic function is
pain, typically in combination with an opioid with or without a essential. Situations in which this drug might be particularly bene-
local anesthetic, and supplied via an implanted intrathecal drug ficial include use during awake carotid endarterectomy or craniot-
delivery system. omy. Many studies have shown reduction in anesthetic
requirements when dexmedetomidine is used intraoperatively,
including reduced needs for thiopental, isoflurane, and fentanyl.
Tizanidine At this point, a few case studies exist in which dexmedetomidine
has been used for longer than 24 hours, the manufacturer’s maxi-
Tizanidine had been used predominantly in the management of mum recommended duration of infusion. Thus far, no reports of
spasticity; however, it has also proved useful for a variety of painful significant withdrawal phenomena have been reported with pro-
conditions. As to its efficacy in the management of spasticity, tiza- longed dexmedetomidine use, but this remains a concern and
nidine compares favorably with both baclofen and diazepam and must be considered when contemplating use divergent from its
seems to cause less muscle weakness than baclofen and a lower labeled indications.
incidence of sedation than diazepam. In treating spasticity related
to multiple sclerosis and cerebrovascular disorders such as stroke,
tizanidine doses of approximately 24 mg/day are average, with max-
imal doses in the range of 32 to 36 mg daily. It appears that muscle PRECAUTIONS AND ADVERSE EFFECTS
strength is fairly well preserved in patients taking tizanidine for ASSOCIATED WITH a2-AGONIST
spasticity or muscle spasm, because less weakness is associated THERAPY
with use of this drug compared with baclofen or diazepam.
Tizanidine has been successfully used in the treatment of paraver- a2-Agonists appear to have beneficial effects on hemodynamics in
tebral muscle spasm in association with acute low back pain as well patients at risk for myocardial ischemia, especially in the perioper-
and is frequently employed in the management of myofascial pain. ative period. However, because hypotension is a frequent side effect
Another major indication for the use of tizanidine is in the man- of these agents, caution must be observed when using them in
agement of headache disorders. Tizanidine has been found effective patients with cerebrovascular disease, chronic renal insufficiency,
in the treatment of chronic daily headache and has been given as and in those who have had a recent myocardial infarction. Use of
these drugs in the elderly also warrants care because there may be an This may manifest as severe hypertension and can result in myo-
increased incidence of orthostatic hypotension in this patient pop- cardial or cerebral infarction in some patients. It is recommended
ulation. Orthostatic hypotension can result in syncope with atten- that clonidine doses be gradually tapered prior to its discontinua-
dant fall-related injuries such as fractures. Use of a2-agonists in tion. Thus far, no reports of similar withdrawal phenomena have
combination with b-blockers, calcium channel blockers, or digitalis been reported for tizanidine or dexmedetomidine (Table 65–2).
may increase the potential for significant bradycardia or atrioven-
tricular block. Some cases of sinus arrest have occurred with rapid
infusion of dexmedetomidine. It may be advisable to avoid these FUTURE DEVELOPMENTS IN
drugs in patients with preexisting cardiac conduction defects. All
the a2-agonists currently available for clinical use are considered
a2-AGONIST THERAPY
category C drugs for use in pregnancy. Common adverse effects The use of a2-agonists in pain management may expand in the
seen with administration of all of the a2-agonists include dry future, especially as newer agents become available that demonstrate
mouth, sedation, dizziness, fever, and nausea. New-onset or exac- reduced adverse effects such as undesired sedation. In addition,
erbation of preexisting depression may occur with use of clonidine dexmedetomidine and tizanidine may have expanded applications
and tizanidine. Asthenia is a fairly frequent side effect of tizanidine, in the treatment of pain in the future if they are made available for
whereas hallucinations have been infrequently reported with this neuraxial administration. Two a2-agonists undergoing study in
drug. Of most significant concern with the use of tizanidine is the animal models of pain show promise for future use in humans.
potential for hepatotoxicity. Approximately 5% of patients who Moxonidine, like clonidine, has been found to provide analgesic
receive this drug will manifest increases in liver function tests synergy when administered with morphine intrathecally in an
(aspartate transaminase [AST]/alanine aminotransferase [ALT]) to animal model and appears to be less sedating than clonidine.
greater than three times the upper limit of normal. Most of these Moxonidine may act at a different a-receptor subtype than cloni-
cases have been asymptomatic, and the abnormalities in liver func- dine. It is possible that combinations of a2-agonists that exert their
tion tests resolved rapidly after discontinuation of tizanidine. There effects at different receptor subtypes may further enhance analgesic
have been, however, several fatalities related to fulminant hepatic synergism and may thereby allow reduction in total analgesic
failure in patients on tizanidine therapy. It is, therefore, recom- requirements and attendant side effects. Moxonidine is available
mended that liver function tests be monitored at initiation of treat- outside the United States for the management of hypertension.
ment with tizanidine and at 1, 3, and 6 months after it is started. Radolmidine, another a2-agonist in development, has been com-
Additional monitoring of liver function tests on a periodic basis pared with dexmedetomidine to evaluate antinociceptive properties
thereafter may also be necessary, depending on clinical indicators. when administered intrathecally in a rat model. It was demon-
Lastly, a withdrawal syndrome has been reported with abrupt dis- strated that these two agents were equipotent in antinociceptive
continuation of clonidine, even after epidural administration. effects, but radolmidine resulted in less reduction in rat locomotor
Table 65^2. Current Therapy: Drug Interactions, Precautions, and Adverse Effects of a2-Agonists
Drug interactions General: Sedatives (enhanced sedation); b-blockers, calcium channel blockers, digitalis (increased risk of heart
block)
Clonidine: Local anesthetics (prolonged sensory and motor block); cyclosporine (increased serum levels of
cyclosporine/cyclosporine toxicity); tricyclic antidepressants (decreased antihypertensive action of clonidine)
Tizanidine: Oral contraceptives, fluvoxamine, ciprofloxacin, zileuton, amiodarone, mexiletine, propafenone,
verapamil, cimetidine, famotidine, acyclovir, ticlopidine (increased serum tizanidine levels, decreased
tizanidine clearance owing to CYP1A2 inhibition)
Dexmedetomidine: No specific interactions (except as above in general drug interactions with a2-agonists)
Precautions General: Pregnancy (category C), use in patients with known cardiac conduction defects
Clonidine: Potential for rebound hypertension with abrupt discontinuation regardless of route of
administration; cautious use in obstetric patients owing to potential for hypotension; cautious use in patients
with cerebrovascular disease, chronic renal failure, coronary artery disease, or recent myocardial infarction
(owing to potential for hypotension)*
Tizanidine: Dose reduction is advised in patients using oral contraceptives, renal insufficiency (owing to
decreased clearance of tizanidine); avoid use in the presence of liver disease (owing to risk of hepatotoxicity)
Dexmedetomidine: Use for periods exceeding 24 hr is not recommended (although several reports of use for
longer periods have been described); owing to its ability to blunt sympathetically mediated blood pressure
and heart rate responses, may be increased risk of failure to detect signs of awareness under anesthesia if this
drug is incorporated into an anesthetic regimen
Adverse effects General: Hypotension, bradycardia, heart block, sedation, dizziness, dry mouth, asthenia, orthostasis, rash,
nausea
Clonidine: Depression, constipation, nervousness/agitation
Tizanidine: elevation of LFTs (5%) with rare incidence of fulminant hepatic failure, hallucinations, muscle
spasm, fever, abdominal pain, diarrhea, dyspepsia, depression
Dexmedetomidine: Sinus arrest, hypertension (with rapid infusion or loading dose administration); fever,
tachycardia, anemia, hypoxia, atrial fibrillation
*This may apply to a2-agonists in general, but it is especially relevant to the use of clonidine.
CYP, cytochrome P-450; LFTs, liver function tests.
480 Chapter 66 GLUTAMATE RECEPTOR ANTAGONISTS
activity, suggesting that it causes less sedation than dexmedetomi- De Kock M, Wiederkher P, Laghmiche A, Scholtes J-L. Epidural clonidine
dine. This effect was possibly related to the inability of radolmidine as the sole analgesic during and after abdominal surgery.
to cross the blood-brain barrier, thus resulting in fewer central Anesthesiology 1997;86:285–292.
effects. Thus, it appears that if radolmidine becomes available for Dunbar SA. Alpha2-adrenoceptor agonists in the management of chronic
pain. Baillieres Clin Anesthesiol 2000;14:471–481.
human use in the future, it may allow for substantial analgesia in
Eisenach JC, DuPen S, Dubois M, et al. Epidural clonidine analgesia for
the absence of significant effects on consciousness. intractable cancer pain. Pain 1995;61:391–399.
Eisenach JC, Hood DD, Curry R. Relative potency of epidural to
intrathecal clonidine differs between acute thermal pain and capsaicin-
CONCLUSION induced allodynia. Pain 2000;84:57–64.
Gabriel JS, Gordin V. Alpha 2 agonists in regional anesthesia and
The use of a2-agonists has expanded into the fields of anesthesia analgesia. Curr Opin Anesthesiol 2001;14:751–753.
and pain management over the past few decades. These agents Hall JE, Uhrich TD, Barney JA, et al. Sedative, amnestic, and analgesic
provide analgesia and can be administered by a variety of routes. properties of small-dose dexmedetomidine infusions. Anesth Analg
a2-Agonists have provided benefit in the treatment of acute pain 2000;90:699–705.
Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor
related to surgery, cancer-associated pain, headaches, neuropathies, agonists: their pharmacology and therapeutic role. Anaesthesia
complex regional pain syndromes, myofascial pain, and spasticity. 1999;54:146–165.
They also provide analgesic synergy and opioid- and anesthetic- Lataste X, Emre M, Davis C, Groves L. Comparative profile of tizanidine
sparing effects. Clonidine is the oldest and most widely used of in the management of spasticity. Neurology 1994;44(suppl 9):S53–S59.
the a2-agonists. Tizanidine has found a role in the treatment of Saper JR, Winner PK, Lake AE III. An open-label dose-titration study
spasticity and associated muscle pain, whereas dexmedetomidine of the efficacy and tolerability of tizanidine hydrochloride tablets
demonstrates utility in the perioperative and critical care patient in the prophylaxis of chronic daily headache. Headache
populations. Newer agents such as moxonidine and radolmidine are 2001;41:357–368.
Semenchuk MR, Sherman S. Effectiveness of tizanidine in neuropathic
being evaluated for future use in pain-management applications in
pain: an open-label study. J Pain 2000;1:285–292.
humans and appear to show promise with regards to reduction in Smith H, Elliott J. Alpha2 receptors and agonists in pain management.
dose-limiting side effects. It, therefore, appears that the role of Curr Opin Anesthesiol 2001;14:513–518.
a2-agonists in anesthesia and pain management will continue to Smith TR. Low-dose tizanidine with nonsteroidal anti-inflammatory drugs
broaden in the future. for detoxification from analgesic rebound headache. Headache
2002;42:175–177.
Unlugenc H, Gunduz M, Guler T, et al. The effect of pre-anesthetic
SUGGESTED READINGS administration of intravenous dexmedetomidine on postoperative pain
Aantaa R, Jalonen J. Perioperative use of alpha2-adrenoceptor agonists in patients receiving patient-controlled morphine. Eur J Anesthesiol
and the cardiac patient. Eur J Anesthesiol 2006;23:361–372. 2005;22:386–391.
Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of Wajima Z, Yoshikawa T, Ogura A, et al. Oral tizanidine, an alpha2-
dexmedetomidine versus morphine for postoperative analgesia after adrenoceptor agonist, reduces the minimum alveolar concentration of
major inpatient surgery. Anesth Analg 2004;98:153–158. sevoflurane in human adults. Anesth Analg 2002;95:393–396.
De Kock M, Gautier P, Pavlopoulou A, et al. Epidural clonidine or Waldman SD. Recent advances in analgesic therapy—tizanidine. Pain Dig
bupivacaine as the sole analgesic agent during and after abdominal 1999;9:40–43.
surgery. Anesthesiology 1999;90:1354–1362. Yildiz M, Tavlan A, Reisli R, et al. Effect of dexmedetomidine on
De Kock M, Lavand’homme P, Waterloos H. The short-lasting analgesia haemodynamic responses to laryngoscopy and intubation. Drugs
and long-term antihyperalgesic effect of intrathecal clonidine in patients 2006;7:43–52.
undergoing colonic surgery. Anesth Analg 2005;101:566–572.
Chapter 66 This is in part due to glutamate’s contribution to the normal

function of physiology and processes as diverse as cognition, sensa-
GLUTAMATE RECEPTOR tion, and memory.1 However, excessive activation by glutamate
is believed to contribute to neuronal damage in a variety of neuro-
logic disorders ranging from acute hypoxic-ischemic brain injury
ANTAGONISTS and spinal cord injury to diseases such as Alzheimer’s, Parkinson’s,
Huntington’s, and amyotrophic lateral sclerosis. This dual role
Howard S. Smith, James P. Wymer, and of glutamate significantly affects therapeutic strategies for neuro-
Christine N. Sang pathic pain and diseases. Disruption of abnormal glutamate func-
tion must be achieved without interference with normal neuronal
processes.
The glutamate receptors are classified into two major groups
based on action: ionotropic and metabotropic. The ionotropic
receptors function as ion channels and are named after the
agonists that selectively bind to them. This group includes N-
INTRODUCTION methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-iso-
xazole propionate (AMPA), and kainate receptors The metabotropic
Confirming the preclinical data that show a role for glutamate receptors are directly coupled to intracellular signal transduction
in neuropathic pain has proved to be a significant clinical challenge. systems via G proteins such as protein kinase C and cyclic
activity, suggesting that it causes less sedation than dexmedetomi- De Kock M, Wiederkher P, Laghmiche A, Scholtes J-L. Epidural clonidine
dine. This effect was possibly related to the inability of radolmidine as the sole analgesic during and after abdominal surgery.
to cross the blood-brain barrier, thus resulting in fewer central Anesthesiology 1997;86:285–292.
effects. Thus, it appears that if radolmidine becomes available for Dunbar SA. Alpha2-adrenoceptor agonists in the management of chronic
pain. Baillieres Clin Anesthesiol 2000;14:471–481.
human use in the future, it may allow for substantial analgesia in
Eisenach JC, DuPen S, Dubois M, et al. Epidural clonidine analgesia for
the absence of significant effects on consciousness. intractable cancer pain. Pain 1995;61:391–399.
Eisenach JC, Hood DD, Curry R. Relative potency of epidural to
intrathecal clonidine differs between acute thermal pain and capsaicin-
CONCLUSION induced allodynia. Pain 2000;84:57–64.
Gabriel JS, Gordin V. Alpha 2 agonists in regional anesthesia and
The use of a2-agonists has expanded into the fields of anesthesia analgesia. Curr Opin Anesthesiol 2001;14:751–753.
and pain management over the past few decades. These agents Hall JE, Uhrich TD, Barney JA, et al. Sedative, amnestic, and analgesic
provide analgesia and can be administered by a variety of routes. properties of small-dose dexmedetomidine infusions. Anesth Analg
a2-Agonists have provided benefit in the treatment of acute pain 2000;90:699–705.
Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor
related to surgery, cancer-associated pain, headaches, neuropathies, agonists: their pharmacology and therapeutic role. Anaesthesia
complex regional pain syndromes, myofascial pain, and spasticity. 1999;54:146–165.
They also provide analgesic synergy and opioid- and anesthetic- Lataste X, Emre M, Davis C, Groves L. Comparative profile of tizanidine
sparing effects. Clonidine is the oldest and most widely used of in the management of spasticity. Neurology 1994;44(suppl 9):S53–S59.
the a2-agonists. Tizanidine has found a role in the treatment of Saper JR, Winner PK, Lake AE III. An open-label dose-titration study
spasticity and associated muscle pain, whereas dexmedetomidine of the efficacy and tolerability of tizanidine hydrochloride tablets
demonstrates utility in the perioperative and critical care patient in the prophylaxis of chronic daily headache. Headache
populations. Newer agents such as moxonidine and radolmidine are 2001;41:357–368.
Semenchuk MR, Sherman S. Effectiveness of tizanidine in neuropathic
being evaluated for future use in pain-management applications in
pain: an open-label study. J Pain 2000;1:285–292.
humans and appear to show promise with regards to reduction in Smith H, Elliott J. Alpha2 receptors and agonists in pain management.
dose-limiting side effects. It, therefore, appears that the role of Curr Opin Anesthesiol 2001;14:513–518.
a2-agonists in anesthesia and pain management will continue to Smith TR. Low-dose tizanidine with nonsteroidal anti-inflammatory drugs
broaden in the future. for detoxification from analgesic rebound headache. Headache
2002;42:175–177.
Unlugenc H, Gunduz M, Guler T, et al. The effect of pre-anesthetic
SUGGESTED READINGS administration of intravenous dexmedetomidine on postoperative pain
Aantaa R, Jalonen J. Perioperative use of alpha2-adrenoceptor agonists in patients receiving patient-controlled morphine. Eur J Anesthesiol
and the cardiac patient. Eur J Anesthesiol 2006;23:361–372. 2005;22:386–391.
Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of Wajima Z, Yoshikawa T, Ogura A, et al. Oral tizanidine, an alpha2-
dexmedetomidine versus morphine for postoperative analgesia after adrenoceptor agonist, reduces the minimum alveolar concentration of
major inpatient surgery. Anesth Analg 2004;98:153–158. sevoflurane in human adults. Anesth Analg 2002;95:393–396.
De Kock M, Gautier P, Pavlopoulou A, et al. Epidural clonidine or Waldman SD. Recent advances in analgesic therapy—tizanidine. Pain Dig
bupivacaine as the sole analgesic agent during and after abdominal 1999;9:40–43.
surgery. Anesthesiology 1999;90:1354–1362. Yildiz M, Tavlan A, Reisli R, et al. Effect of dexmedetomidine on
De Kock M, Lavand’homme P, Waterloos H. The short-lasting analgesia haemodynamic responses to laryngoscopy and intubation. Drugs
and long-term antihyperalgesic effect of intrathecal clonidine in patients 2006;7:43–52.
undergoing colonic surgery. Anesth Analg 2005;101:566–572.
Chapter 66 This is in part due to glutamate’s contribution to the normal

function of physiology and processes as diverse as cognition, sensa-
GLUTAMATE RECEPTOR tion, and memory.1 However, excessive activation by glutamate
is believed to contribute to neuronal damage in a variety of neuro-
logic disorders ranging from acute hypoxic-ischemic brain injury
ANTAGONISTS and spinal cord injury to diseases such as Alzheimer’s, Parkinson’s,
Huntington’s, and amyotrophic lateral sclerosis. This dual role
Howard S. Smith, James P. Wymer, and of glutamate significantly affects therapeutic strategies for neuro-
Christine N. Sang pathic pain and diseases. Disruption of abnormal glutamate func-
tion must be achieved without interference with normal neuronal
processes.
The glutamate receptors are classified into two major groups
based on action: ionotropic and metabotropic. The ionotropic
receptors function as ion channels and are named after the
agonists that selectively bind to them. This group includes N-
INTRODUCTION methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-iso-
xazole propionate (AMPA), and kainate receptors The metabotropic
Confirming the preclinical data that show a role for glutamate receptors are directly coupled to intracellular signal transduction
in neuropathic pain has proved to be a significant clinical challenge. systems via G proteins such as protein kinase C and cyclic
adenosine monophosphate.2 In this chapter, we review currently neuron’s response to subsequent stimuli.3,4 These events are
available data on the role of antagonism at the NMDA, AMPA/ believed to at least partially contribute to the development of
kainate, and metabotropic sites in neuropathic pain. mechanical hyperalgesia that may follow peripheral nerve injury
or tissue inflammation.5
Antagonism of the NMDA channel can be categorized pharma-
THE NMDA RECEPTOR cologically according to the site of action on the receptor-channel
complex (Fig. 66–1). These include drugs acting at the agonist
NMDA receptors (NMDARs) are composed of subunits known as (NMDA) or coagonist (glycine) sites, the channel pore site, and
NR1, NR2 (A, B, C, D), and NR3 (A and B). The NR1 binds glycine, the modulatory sites. Competitive NMDA and glycine antagonists
and NR2 binds glutamate. Normally, the NMDAR has a resting are effective in models of glutamate-mediated neurotoxicity.3–5
membrane potential of –65 mV, and the NMDAR is blocked by Moreover, systemic administration of NMDAR antagonists in
magnesium ion and is thus unresponsive to glutamate. After a sig- patients with neuropathic pain can reduce spontaneous pain and
nificant depolarization of the AMPA or kainate receptors by gluta- hyperalgesia in experimental,6 acute postoperative,7 and chronic
mate, at the neurokinin-1 receptor by substance P, at the neuropathic pain.8,9 Unfortunately, however, memory impairment,
neurokinin-2 receptor by neurokinin A, or at the trkB receptor by sedation, psychotomimetic effects, ataxia, and motor incoordina-
brain-derived neurotropic factor (BDNF), the NMDAR becomes tion are also potential results with the potential to effectively limit
responsive to glutamate. maximal doses achievable in patients.10 This is because glutamate is
also responsible for processes important to normal cognition.
Functional inhibition of the NMDAR complex can be achieved
NMDAR ANTAGONISTS through indirect actions at the channel pore sites (phencyclidine
[PCP]; polyamine site [NR2B selective], and magnesium), and
In neuropathic pain, prolonged firing of peripheral C-fiber noci- modulatory sites such as the S-nitrosylation site where nitric
ceptors causes the release of glutamate centrally, which then acts on oxide (NO) reacts with critical cysteine thiol groups (see Fig.
NMDARs in the spinal cord dorsal horn. Activation of these recep- 66–1). Some investigations suggest that targeting the channel pore
tors then triggers influx of calcium into the cell and initiates a and modulatory sites may provide superior analgesia with the
number of events that enhance secondary messenger pathways, potential of a better side effect profile, especially in patients with
causes rearrangement of receptors in the spinal cord, and alters neuropathic pain. Selective antagonists to the NR2B subunit have
the transcription of genes. Ultimately, this process will alter the become available and also may open new therapeutic opportunities
NMDA RECEPTOR COMPLEX
Outer Glycine site

membrane NMDA
surface Zn ++
site
Polyamine site
SNO
Ca++ SNO-cysteine sulfhydral group (-SH)

reacting with nitrogen oxide species
NO-Nitric Oxide
Na++ ROS-Reactive Oxygen Species
nNOS neuronal Nitric oxide synthase
LA Local Anesthetic
PCP site K+ BDNF Brain derived neurotrophic factor
Membrane = Inhibitory
= Facilatory
NMDA = N-methyl-D-aspartate
Zn++ = Zinc
Mg++ = Magnesium
NR1 NR2 PCP = Phencyclidine
Na++ = Sodium ions
K+ = Potassium ions
Mg++
Ca++ = Calcium ions
Inner membrane surface
Tyr 1472 P Fyn kinase

Mitochondria
Ca++ EP1
Src
ROS
PKC
ERK nNOS
TrkB LA PGE 2
BDNF
Figure 66^1. N-methyl-D-aspartate receptor (NMDAR) complex.
in the clinical management of pain.11 Currently available NMDAR ketamine may have a better therapeutic ratio for analgesia than
antagonists include ketamine, dextromethorphan (DM), amanta- parenteral ketamine.47–49 Oral ketamine, however, has been associ-
dine, memantine, magnesium sulfate, and certain opioids such as ated with hepatic damages, gastric ulcer, and memory impairment50
methadone. Drugs of other classes, such as amitriptyline, also have and may have problems related to tolerance with long-term
affinity for the NMDA channels,12,13 and different antidepressants administration.
may have differing affinities.14 However, these agents are not
discussed.
Nasal Ketamine
Spinal interleukin-1b (IL-1b) produced by astrocytes enhances
NR1 phosphorylation to promote inflammatory pain.15 IL-1 recep- Carr and coworkers51 reported a small, double-blind, randomized,
tor antagonists (IL-1ras) produce antiallodynic effects in rat models controlled, cross-over trial of intranasal ketamine as rapid delivery
of neuropathic pain16,17 and attenuate inflammatory hyperalgesia for systemic administration for the management of breakthrough
likely via inhibiting NR1 phosphorylation15 (perhaps by inhibiting pain. Intranasal ketamine was found to produce reasonably effective
the activation [i.e., phosphorylation] of extracellular receptor–acti- analgesia (more effective than placebo) with an onset of analgesia
vated kinase [ERK]).18 This may be similar to one of the potential within 10 minutes.
postsynaptic mechanisms by which bupivacaine produces The peak effect of analgesia occurred at 40 minutes, with an
analgesia.18,19 analgesia duration of over an hour. The predominant adverse effects
included fatigue, dizziness, altered taste, and feelings of unreality.
Ketamine Neuraxial Ketamine

Ketamine is a phencyclidine-like drug with noncompetitive He and coworkers demonstrated that the combined injection of
NMDAR antagonist activity. It inhibits the NMDA receptor by ketamine and clonidine can produce synergistic analgesia without
binding to the PCP site in the open state and thus provides use- obvious side effects when compared with ketmaine alone in the
dependent blockade of the NMDA channel.20 Ketamine exhibits a chronic construction injury (CCI) rate model.52 Case reports and
phenomenon called ‘‘trapping’’ of NMDA blockade, which pro- case series suggest that the administration of intrathecal and epidu-
duces accumulation of the antagonist, resulting in supramaximal ral ketamine is effective for the treatment of pain. However, keta-
blockade (in situations in which there is repetitive NMDAR stimu- mine has been associated with histopathologic changes of the spinal
lation) and correlating with a narrow therapeutic index.21 In addi- cord. Stotz and associates53 reported a patient with intractable
tion to this, ketamine may function via secondary effects of cancer pain who obtained pain relief after ketamine was added to
enhanced peripheral monoaminergic transmission, inhibition of an intrathecal mixture of bupivacaine, morphine, and clonidine.
central and peripheral cholinergic transmission, and possibly, effects Although the patients did not develop neurologic deficits, focal
on voltage-gated calcium currents lymphocytic vasculitis was observed close to the intrathecal catheter
Animal analgesic studies suggest that ketamine reduces nocicep- postmortem. Karpinski and colleagues54 reported postmortem
tive behaviors and spinal dorsal horn neuronal activity in response changes of subpial spinal cord vacuolation in a terminally ill
to tissue injury.22–25 In humans, ketamine has been reported to cancer patient who developed a wide-based gait after receiving a
relieve glossopharyngeal and neuralgia and cancer pain in subanes- continuous infusion of intrathecal ketamine for pain control.
thetic doses.8,26,27 Placebo-controlled trials in patients suffering Murali Krishna and coworkers55 concluded that low doses of mid-
from postherpetic neuralgia,28,29 acute postoperative hyperalge- azolam and ketamine with bupivacaine intrathecally result in pro-
sia,7,29 phantom pain,30 acute and chronic orofacial pain,31 spinal longed analgesia and fewer hemodynamic fluctuations.
cord injury,32 chronic post-traumatic pain,33 chronic ischemic
pain,34 and mixed neuropathic pain syndromes8,28 have shown
that ketamine can relieve neuropathic pain and hyperalgesia. In 3 -(2-Carboxypiperazin- 4 -yl)
most cases, however, appreciable symptomatic relief from ketamine propyl-1-phosphonic Acid
develops only after the onset of unpleasant psychotomimetic side
effects. Ketamine administered by the subcutaneous and intrave- 3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) is a
nous routes causes dose-dependent nausea, confusion, hallucina- potent and selective competitive antagonist of the NMDAR. CPP is
tions, visual disturbances, unpleasant dreams, delirium, and other not clinically available, and there is little evidence supporting its use
psychotomimetic adverse effects.35 The activity of ketamine in the for the management of clinical pain. Kristensen and associates56
cortex and limbic systems has been implicated in the development described the use of CPP in on patient with intractable
of such symptoms. Ketamine has anecdotally been administered for neuropathic pain. In this patient, intrathecal administration of
the treatment of refractory complex regional pain syndrome.36,37 CPP abolished the spread of pain evoked by low-threshold mechan-
Although some studies are unable to find significant utility to ical and thermal stimuli to areas outside the territory of the injured
support the perioperative use of ketamine,38 multiple studies exist nerve. However, continuous deep pain and allodynia in the terri-
that support a perioperative benefit to ketamine administration.39–42 tory of the injured nerve were unchanged. The authors suggested
that CPP modulates pathologic pain at the spinal level. The
patient developed psychotoimimetic ketamine-like side effects,
Oral Ketamine
which were attributed to the hydrophilicity and rostral spread
A number of case reports and case series have shown the successful of CPP.
use of oral ketamine in experimental ischemic arm pain, posther-
petic neuralgia, neuropathic pain, and postamputation pain.43–46
The administration of oral ketamine results in higher serum con- LOW-AFFINITYCHANNEL BLOCKING
centrations of norketamine, the main metabolite of ketamine. NMDAR ANTAGONISTS
Norketamine is a noncompetitive NMDAR antagonist and is equi-
potent to its parent drug in the second phase of the formalin test. Low-affinity NMDAR antagonists such as DM, dextrorphan (DX),
The potency of norketamine, the shorter duration of psychomotor remacemide, amantadine, memantine, and other adamantine ana-
effects of oral ketamine, and the relatively high levels of norketa- logues produce fewer neuropsychologic side effects than the higher-
mine in the brain (the norketamine-to-ketamine area under the affinity antagonists. The improved side effect profile of these
curve [AUC] ratio in the brain may reach 2.9) suggest that oral compounds has been attributed to their low micromolar affinity
for the NMDAR. The faster rates of block and unblock contribute in showed that DM prevented the development of tolerance to the
part to their more-favorable toxicity profile.20 antinociceptive effects of morphine and attenuated signs of nalox-
one-precipitated physical dependence on morphine.
DM
Amantadine
DM is a dextrorotatory analogue of levorphanol, a low-affinity
noncompetitive antagonist of the NMDA-sensitive ionotropic Amantadine has been used as an antiviral agent and for the treat-
glutamate receptor. In addition, it is also a sigma-1 receptor ment of Parkinson’s disease. Until recently, the mechanism of
agonist, suppressing the release of excitatory,8 and may act on the action of amantadine was speculated to be related to dopaminergic
N-type calcium channel. Unlike ketamine, DX (and likely DM) and anticholinergic activity. Several human postmortem and in
interacts with NMDA-binding sites that are distinct from that of vitro studies have demonstrated that memantine may produce its
ketamine or MK801, and ability to the bind to a closed channel pharmacologic effects through noncompetitive binding to the PCP
exists (with DX and probably DM).57 Initial human studies yielded site of the NMDAR complex.71–74 Investigations of the analgesic
conflicting results,22,58–60 probably due to inadequate dosing. efficacy of amantadine have yielded conflicting results. Eisenberg
McQuay and colleagues29 found that DM did not relieve pain in and Pud75 reported three patients in whom a single dose of intra-
patients with different chronic neuropathic pain syndromes at venous amantadine resulted in the complete resolution of sponta-
doses of 81 mg/day. Duedahl and colleagues61 administered intra- neous pain, mechanical allodynia, and hyperalgesia. Pud and
venous DM in normal volunteers and found significantly reduced associates76 also randomized 25 cancer patients with surgical neu-
areas of secondary hyperalgesia after both capsaicin and thermal ropathic pain to receive either placebo or 200 mg of intravenous
stimulation. Nelson and coworkers9 compared high doses of amantadine. Mean pain intensity remained significantly lower
DM and DX to placebo in patients with diabetic neuropathy and during the 48 hours after amantadine treatment compared with
postherpetic neuralgia. Patients with diabetic neuropathy, but not the 48 hours prior to treatment, whereas no such effect was
postherpetic neuralgia, reported better pain relief with DM. Sang found with the placebo. However, amantadine was not analgesic
and associates62 compared DM with the active placebo lorazepam in subsequent studies by Medrik-Goldberg and colleagues77 and
and obtained similar results to those of Nelson’s group,9 using doses Taira78 in patients with sciatica and different types of neuropathic
as high as 920 mg/day (mean doses 400 mg/day). DM produces pain. Amantadine produces fewer psychotomimetic side effects than
dose-dependent side effects, depending on the rate of titration and ketamine and is usually well tolerated. Dose-dependent side effects
cytochrome P-450 (CYP) 2D6 metabolizer status. Single, over- include dizziness, lethargy, sleep disturbances, headache, hallucina-
the-counter doses of 30 to 60 mg produce mild side effects in tions, and nausea and vomiting.
fewer than 10% of patients. Reported adverse effects to DM include
dizziness, fatigue, confusion, lightheadedness, depression, gastroin-
testinal disturbances, and nystagmus. Memantine
DM is extensively metabolized to DX, primarily by CYP2D6 and
is rapidly protein bound. The disposition of DM is, therefore, sub- Memantine has been used for the treatment of dementia and
stantially influenced by the CYP2D6 enzyme. Seven percent to 10% Parkinson’s disease.79 A number of studies have looked at meman-
of whites and 1% of Asians have mutations in both copies of the tine for the treatment of different neuropathic pain syndromes.
CYP2D6 gene. These patients accumulate higher DM levels than Sang and associates62 compared memantine with the active placebo
normal (poor metabolizers). Most patients have two normal lorazepam for the treatment of diabetic neuropathy and posther-
copies of the CYP 2D6 gene (extensive metabolizers), and some petic neuralgia and were unable to detect a treatment effect.
patients may have multiple copies of the intact genes (ultrarapid Eisenberg and coworkers,80 in a double-blind, randomized,
metabolizers). The median elimination half-life is 2.4 hours in placebo-controlled trial, administered memantine at a dose of
extensive metabolizers and 19.1 hours in poor metabolizers.63–66 10 mg/day and 20 mg/day to patients with postherpetic neuralgia.
Patients can be pharmacologically converted to poor metabolizer Reduction in spontaneous pain, mechanical and cold allodynia,
status by administering drugs such as quinidine, which is a potent mechanical hyperalgesia, and wind-up–like pain was found in
CYP2D6 inhibitor.67 However, the parent drug, DM, has a higher both groups, but there were no significant differences between the
affinity for the sigma-1 opioid receptor than DX, which may placebo and the treatment group. Schifitto and associates81 studied
contribute to differences in effects between the parent drug and 45 subjects with human immunodeficiency virus (HIV)–associated
its metabolite. In an open-label study of subjects with painful symptomatic DSP (SDSP) in a randomized, multicenter, 16-week,
diabetic peripheral neuropathy, quinidine in combination with placebo-controlled study of memantine. Memantine was well toler-
antitussive doses of DM (30 and 120 mg/day) was well tolerated ated; however, no trend toward clinical benefit was observed.
in patients with pain associated with diabetic peripheral neuropa- Results were similar to those of other pilot studies of memantine
thy. Twenty-three of 33 subjects were able to tolerate 120 mg of DM for neuropathic pain unrelated to HIV, suggesting that memantine
in combination with 120 mg of quinidine. The most commonly is ineffective for the symptomatic treatment of HIV-associated
reported adverse events were nausea (27.8%), dizziness (25.0%), SDSP.81 In spite of these studies, certain clinicians believe that
and headache (25.0%). Studies that have compared the effects of patients exist with difficult-to-treat pain syndromes often associated
either single doses68 or chronic oral dosing69 in poor and rapid with cortical reorganization (e.g., phantom limb syndrome, com-
metabolizers show that high doses of DM are better tolerated in plex regional pain syndrome) that may benefit from memantine
rapid metabolizers than in poor metabolizers. Moreover, Carlsson therapy.82–85 Memantine is associated with dizziness, lethargy,
and colleagues68 found a differential effect of DM efficacy in favor sleep disturbances, headache, nausea, and vomiting. In addition,
of rapid metabolizers that correlated with higher plasma DX taking advantage of memantine’s preferential binding to open
concentrations. channels and the fact that excessive NMDAR activity can be
Finally, animal and human studies have suggested that the com- down-regulated by S-nitrosylation, combination drugs called
bination of DM with opiate analgesics may be useful for preventing NitroMemantines have been developed.86 These drugs use meman-
opiate tolerance and dependence while enhancing both peak and tine as a homing signal to target NO to hyperactivated NMDARs in
duration of opioid analgesia, even at subanalgesic doses of DM. order to avoid systemic side effects of NO such as hypotension (low
Mao and coworkers,70 in a study to evaluate the practical feasibility blood pressure). These second-generation mematine derivatives,
of the combined oral administration of morphine sulfate with DM, although not currently available, are designed as pathologically
activated therapeutics and, in preliminary studies, appear to have Numerous investigators have described the successful use of meth-
even-greater neuroprotective properties than memantine.86 adone in the treatment of cancer pain, especially for pain refractory
to high doses of other opioids.101–106
Magnesium
NMDAR 2B SUBUNITANTAGONISTS
A number of investigators have suggested that the administration of
magnesium might be useful as an analgesic.87 Magnesium ions pre- The NMDAR complex encompasses many protein subunits, includ-
vent extracellular calcium ions from entering the cell by blocking ing NMDA R1 (NR1) and NR 3 (NR2A-NR2D). Spinal NMDAR 2B
the ion channel coupled to the NMDAR. Dubray and colleagues88 (NR2B) subunit–increased expression plays an important role in
showed that dietary restriction of magnesium decreased mechanical the facilitation and maintenance of the persistent pain state due
nociceptive thresholds in rats. In the same study, decreased pain to peripheral nerve injury.107 Animal studies have demonstrated
threshold was reversed by the administration of MK-801, an that the NR2B subunit is restricted to the forebrain and distributed
NMDAR antagonist. Xiao and Bennett89 demonstrated that spinal in the laminae I and II of the spinal cord dorsal horn and, therefore,
or subcutaneous administration of magnesium significantly reduces might induce antinociception without motor dysfunction. Rivat
heat hyperalgesia and mechanical allodynia in a model of neuro- and associates108 reported that a polyamine-deficient (PD) diet
pathic pain. In another animal study, Takano and coworkers87 for 7 days prevented the enhancement of tyrosine phosphorylation
found that intrathecal administration of magnesium sulfate of the spinal NR2B subunit–containing NMDAR associated with
caused a dose-dependent suppression of phase 2 of the formalin inflammation in rats. A PD diet strongly reduced long-lasting hy-
test. Koinig and associates,90 in a randomized, double-blind study, peralgesia induced by inflammation or incision, especially in fenta-
administered magnesium to patients undergoing arthroscopic knee nyl-treated rats. Moreover, a PD diet also prevented the exaggerated
surgery and found that intravenous magnesium sulfate administra- hyperalgesia induced by a second inflammation performed 7 days
tion reduced intraoperative and postoperative analgesic require- after the first one. A PD diet also opposed paradoxical hyperalgesia
ments. However, Felsby and colleagues28 were unable to induced by nonnociceptive environmental stress in rats with pain
demonstrate a statistically significant reduction of pain and allo- and opioid experiences. A PD diet reversed pain hypersensitivity
dynia in patients with peripheral neuropathic pain. associated with monoarthritis or neuropathy and restored the
Acute and chronic administration of magnesium is well toler- analgesic effect of morphine.108 CP101,606 [(1S, 2S)-2-(4-hydro-
ated. Reported adverse effects include a flushed feeling, heat sensa- xyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol], a selec-
tion and pain at the injection site, and sedation. tive NR2B subunit antagonist, was demonstrated to be
antihyperalgesic in neuropathic rats without impairing rotarod
performance.109 Nakazato and colleagues110 suggested that the
Riluzole antiallodynia effect of CP-101,606 is ascribable to blockade of
NR2B receptors at the brain, but not the spinal cord. In contrast,
Riluzole has been used for the treatment of amyotrophic lateral intrathecal injection of a nonselective NMDA antagonist, mem-
sclerosis. The exact mechanism of action of riluzole noncompeti- antine, significantly inhibited CCI-induced mechanical allodynia
tively inhibits the NMDAR and kainite receptor91 as well as sodium at a dose of 300 nmol, indicating the difference in the site of
channels.92 Analgesic studies with riluzole have not been encoura- action between the nonselective NMDA antagonist and the
ging. Hammer and coworkers93 examined the acute analgesic effect NR2B-specific NMDA antagonist.110 Spinal administration of
of riluzole in a human model of inflammatory pain induced by a the NMDA-2B receptor antagonist Ro 25-6981 had a clear anti-
thermal injury in 20 healthy volunteers. Riluzole had no acute anal- nociceptive effect at the spinal level after high-frequency stimu-
gesic effects in normal or hyperalgesic skin. lation (HFS) (P < .05, C-fiber–evoked responses in baseline).111
Moreover, spinal administration of this antagonist clearly attenu-
ated the magnitude of spinal cord long-term potentiation (LTP)
OPIOIDS WITHNMDAR ACTIVITY after HFS conditioning (P < .05, C-fiber–evoked responses after
HFS vs. C-fiber–evoked responses after 8 mm Ro 25-6981 +
Methadone, dextropropoxyphene, and meperidine have demon- HFS.111 (–)-6-[2-[4-(3-Fluorophenyl)-4-hydroxy-1-piperidinyl]-
strated low affinity for the PCP site of the NMDAR.94–97 The dual 1-hydroxyethyl]-3, 4-dihydro-2(1H)-quinolinone was identified
action of this opioid over the NMDAR and m-receptors might have as an orally active NR2B subunit–selective NMDAR antagonist.112
important clinical implications in the treatment of neuropathic It has very high selectivity for NR2B subunits containing
pain. Because of its long half-life, excellent bioavailability, and low NMDARs versus the HERG-channel inhibition (therapeutic
cost, methadone has received particular attention in recent years. index = 4200 vs. NR2B binding inhibitory concentration of
50% [IC50]). This compound has improved pharmacokinetic
properties compared with the prototype CP-101,606.112 In fact,
Methadone it is theoretically conceivable and has been proposed113 that the
analgesic effects of intrathecal glucocorticoids in certain pain
Methadone is a racemic mixture of levorotatory (L) and dextroro- states114 may be due in part to their ability to induce significant
tatory (D) methadone. Animal studies have shown that both D- and up-regulation of neuronal NO synthase and NR2B subunit
L-methadone have NMDAR antagonist and that both isomers expression in the spinal dorsal horn.115 Wang and colleagues107
bind specifically to the noncompetitive site of the NMDAR. showed the feasibility of oral immunization with rAd5/NR2B in
However, D-methadone does not produce opioid-like locomotor efforts to potentially prevent neuropathic pain.
activity in mice,98 is inactive after intraventricular administration
in rats,99 and is a 50-fold less potent analgesic in humans than
L-methadone. These findings suggest that D-methadone does not
NON-NMDAR ANTAGONISTS
have opioid analgesic properties and that its analgesic activity
might be mediated through the NMDAR. Evidence has been accumulating that the AMPA channels also
Besides its NMDAR activity, methadone differs from other play a role in the development and maintenance of neuropathic
opioids because of its long half-life, excellent absorption after oral pain. During the sensitization process, excessive C-fiber stimulation
and rectal administration, and lack of known active metabolites.100 enhances influx through AMPA as well as NMDA. With AMPA
channels known to show dense expression in the superficial lamina Selective mGluR5 antagonists, such as 2-methyl-6-(pheny-
of the spinal cord, they are a potential site of intervention. The lethynyl)-pyridine (MPEP) and 3-[(2-methyl-1, 2-thiazol-4-yl)ethy-
anticonvulsant topiramate inhibits activity of glutamate at AMPA/ nyl] pyridine (MTEP), have shown analgesic properties in several
kainate receptors with no effect on NMDA-evoked currents. animal modes of inflammatory and neuropathic somatic pain.131–139
Topiramate blocks kainate-evoked currents in patch clamp studies Lindström and associates140 concluded that mGluR5 antagonists
of hippocampal neurons by allosterically modulating channel con- (e.g., MPEP and MTEP) inhibit colorectal distention–evoked vis-
ductance116–119 likely by binding to phosphorylation sites on AMPA ceromotor and cardiovascular changes in conscious rats through
and kainate receptors in their dephosphorylated states.120 It has an effect, at least in part, at peripheral afferent mechanically
been U.S. Food and Drug Administration (FDA) approved for evoked visceral nociception in the gastrointestinal tract. Lee and
use in migraine prophylaxis, and in three open-label studies, 44 colleagues141 demonstrated that intra-articular MPEP is more effec-
subjects with mixed peripheral neuropathies received topiramate tive than AIDA on nonevoked pain as well as mechanical hyperalge-
doses of 250 to 300 mg/day and demonstrated reduction in visual sia in both the induction and the maintenance phase in knee joint
analog score (VAS) of 65%, 30%, and 60% in 14, 8, and 22 subjects, inflammation. Both preoperative and postoperative administration
respectively.116 Placebo-controlled trials have had less success.121 of 10 mg/kg–1 MPEP blocked mechanical hypersensitivity induced by
AMPA-specific antagonists have been developed, and in the abdominal surgery (P < .01 vs. vehicle treatment).142
experimental animal CCI model, these agents have shown antiallo-
dynic activity. Human trials of AMPA-specific agents have had lim-
ited benefit in migraines but are currently under way for other types CONCLUSIONS
of pain.
Kainate receptors have been associated with pain path- The NMDAR complex has been implicated to play a crucial role in
ways.122,123 Recent studies in humans suggest that the mixed wind-up phenomena and activity-dependent central sensitization of
AMPA/kainate antagonist LY293558 can prevent capsaicin-induced nociceptive afferent input into the spinal cord dorsal horn. Thus, it
hyperalgesia and allodynia with no effect on physiologic nocicep- seemed to follow that the NMDAR complex may be involved in the
tion.124 Similar results were reported in animal studies in which development and/or maintenance of many persistent pain states.
formalin-induced,125 but not acute physiologic,126 nociceptive However, the clinical use of NMDAR antagonists as sole analgesics
responses were reduced by kainite/GluR5-selective decahydrosio- or coanalgesics has not been found to be as effective as had origi-
quinolines. In a randomized, controlled clinical trial, Gilron and nally been hoped. This discrepancy is probably due in part to the
coworkers compared the analgesic efficacy of the AMPA/kainite relatively low potency of clinically available agents at the NMDAR
antagonist LY293558 with that of intravenous ketorolac trimetha- complex and the relative low doses of NMDAR antagonists utilized.
mine and placebo after oral surgery. Study drugs were administered This is largely due to the unfavorable side effect profile (PCP-
at the onset of moderate pain; pain intensity and relief were mea- like cognitive effects [e.g., feelings of intoxication or delirum, dis-
sured for 240 minutes. LY293558 and ketorolac trimethamine were sociative effects, and/or vivid dreams]) seen with clinically available
superior to placebo for pain evoked by mouth opening and in one NMDAR antagonists when used at higher doses. Despite the con-
of several measures of spontaneous pain. The potential therapeutic cerns previously raised, many patients have achieved adequate anal-
value of non-NMDAR depends on the continued development of gesia with NMDA antagonists alone or in combination with other
subtype-selective non-NMDAR antagonists. analgesic agents (e.g., opioids, a2-adrenergic receptor agonists) in
certain neuropathic pain states. Among clinically available oral
NMDA antagonists utilized for persistent pain, DM appears to be
the most useful agent for analgesia, especially when titrated slowly
METABOTROPIC GLUTAMATE to higher doses in combination with other analgesics. Future
ANTAGONISTS research in this area may aim for developing oral NMDA antago-
nists with higher potency and a more favorable side effect profile
The metabotropic glutamate receptor antagonists (mGluRs) repre- (perhaps by focusing on selective agents targeting specific NMDA
sent G protein–coupled receptors. Eight mGluR subtypes have been subunit sites).
cloned to date and are classified into groups I (mGluRs 1 and 5), II
(mGluRs 2 and 3), and III (mGluRs 4, 6, 7, and 8) based on their
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Chapter 67 Speywood, United Kingdom. The BTX-B formulation is named

Myobloc in the United States and Neurobloc in Europe (Elan
BOTULINUM TOXINS FOR THE Pharmaceuticals).
Although the clinical effects of BTX-A and -B are similar, types
TREATMENT OF PAIN -A and -B toxins are distinct antigenically. Neutralizing antibodies
to BTX-A do not block type B toxin effects. This allows patients
who develop neutralizing antibodies to BTX-A and no longer obtain
Catalina Apostol, Salahadin Abdi,Tobias
satisfactory muscle relaxation to continue treatment with the
Moeller-Bertram, Howard S. Smith,Charles E. Argoff, immunologically different BTX-B. At least 4% and perhaps more
and Mark Wallace than 7% of patients treated with BTX-A may develop neutralizing
antibodies to it.1
BTX inhibits the release of Ach from cholinergic terminals of
motor neurons, leading to a temporary flaccid muscle paralysis, and
also inhibits release of Ach from preganglion sympathetic and para-
sympathetic neurons and postganglionic parasympathetic nerves.2
Understanding how Ach works in the autonomic system and
INTRODUCTION skeletal muscle is important in appreciating the wide potential of
clinical applications for BTX. Normally, Ach binds to nicotinic
Botulinum toxins (BTXs) have been used to relax muscles with receptors on skeletal muscles to increase intracellular calcium and
severe abnormal spasticity or increased tone but appear to possess produce contraction. BTX cleaves a synaptosomal protein of 25 kDa
independent analgesic qualities as well. Major uses of BTXs for that mediates the fusion of Ach vesicles with the axon terminal. A
painful conditions include headache, low back pain, and painful potent biologic substance, BTX inhibits proteins that mediate the
myofascial and muscle disorders. This chapter gives an overview fusion of Ach vesicles with the axon terminal and thus interferes
of the use of BTX in various painful conditions. with vesicle exocytosis. Inhibition of the release of glutamate, sub-
stance P, and calcitonin gene–related peptide, reduced afferent
input to the central nervous system through effects of the toxins
HISTORICAL PERSPECTIVE on muscle spindles, and other possible effects on pain transmission
independent of the effect on cholinergic transmission of these neu-
Historically, the existence of Clostridium botulinum has been known rotoxins have been proposed based upon the results of many lab-
for centuries. Its application as a treatment for skeletal disorders oratory experiments.3–5
started in 1817 when Christian Andreas Justinius Kerner first recog- The inhibition of neurotransmitter release by BTX occurs in a
nized the toxin’s ability to paralyze skeletal muscle. Purified forms multistep process that is initiated when the heavy chain of BTX binds
were developed through research by Dr. Herman Sommer in the to specific acceptors/receptors on cholinergic neurons.6,7 Each sero-
1920s and later by Dr. Edward J. Schantz in 1946. In 1950, type appears to require different acceptors, and each acceptor com-
Dr. Vernon Brooks discovered that BTX-A injected in hyperactive prises a ganglioside and a protein component.8–19 For serotypes
muscle stops the release of acetylcholine (Ach). In the 1960s. Dr. B and G, the protein component of the acceptor has been identified
Allan B. Scott, MD, of the Smith-Kettlewell Eye Research as synaptotagmin,19–23 but the target protein for serotype A has not
Foundation, injected BTX in ocular muscles of monkeys and been fully characterized nor confirmed. Fernandex-Salas and co-
humans and observed that he was able to correct strabismus. workers24 tentatively identified FGFR3 as the putative protein com-
Allergan acquired rights to distribute Dr, Scott’s product, ponent for the serotype A receptor. However, it is not known whether
Oculinum, in 1989 and started conducting clinical trials of the this protein associates with any soluble N-ethylmaleimide–sensitive
drug’s effectiveness for other indications. In 1989, the U.S. Food factor attachment protein receptor (SNARE) proteins,25–27 or other
and Drug Administration (FDA) approved BTX-A (Botox) for membrane proteins, to form a complex that would work with the
treatment of strabismus, essential blepharospasm, and hemifascial ganglioside to provide high-affinity binding of BTX-A.
spasm in patients 12 years or older. BTXs share a common structure, being di-chain proteins of
150 kDa, consisting of a heavy chain (HC) of 100 kDa cova-
lently joined by a single disulfide bond to a light chain (LC) of 50
STRUCTURE AND MECHANISM kDa.28 The HC consists of two domains, each of 50 kDa. The
C-terminal domain (HC) is required for the high-affinity neuronal
BTX is produced by the gram-negative anaerobic bacterium binding,29,30 whereas the N-terminal domain (HN) is proposed to
C. botulinum. The bacterium culture is fermented in order to lib- be involved in membrane translocation.31 The LC is a zinc-
erate a toxin that is further precipitated, purified, and crystallized. dependent metalloprotease responsible for the cleavage of the sub-
The resulting complex contains a single-chained 150-kDa peptide strate SNARE protein.32 BTX is believed to gain access to SNARE
and associated proteins. This form has low potency and requires proteins and block vesicle exocytosis at the neuromuscular junction
modification of its tertiary structure before it can inhibit exocytosis via a three-stage process: (1) an initial binding stage leading to
of Ach from vesicles at the neuromuscular junction. internalization via endocytosis; (2) a membrane translocation
There are seven distinct neurotoxin types (A through G) that stage; and (3) a secretion blockade stage (Fig. 67–1).33
share a general structure and function but differ in potency and Lectins from the leguminous Erythrina species have been iden-
duration. BTX-A and -B are the only forms approved by the FDA tified to bind such galactose-containing carbohydrates and the
after they were shown to be safe and effective in double-blind clin- lectin from E. cristagalli (ECL) was selected to test the hypothesis
ical trials for the treatment of dystonia. BTX-A is marketed in the that BTX endopeptidases could be retargeted selectively to
United States as Botox by Allergan and in Europe as Dysport by nociceptive afferents.34,35 After intrathecal administration of the
490 Chapter 67 BOTULINUM TOXINS FOR THE TREAT MENT OF PAIN
3 neuroexocytosis machinery.46,47 BTXs and TeNT, BTX-B, BTX-D,

BTX-F and BTX-G cleave vesicle-associated membrane protein
(VAMP), a protein of the synaptic vesicle membrane, at different
single peptide bonds; BTX-C cleaves both syntaxin and SNAP-25,
H⫹ two proteins of the presynaptic membrane; BTX-A and BTX-E
4 cleave SNAP-25 at different sites within the COOH-terminus.47,48
The core of the membrane fusion machinery is the SNARE
complex, which consists of three major proteins, including
Vesicle N-ethylmaleimide–sensitive factor (NSF), a-soluble NSF attach-
2 ment protein (a-SNAP), synaptobrevin/VAMP, and syntaxin 1A
(syntaxin).
SNAREs function at both constitutive and regulated stages in the
secretory pathway, for example, in both the constitutive transport
5 required for cell growth and the highly regulated release of neuro-
transmitters on stimulation by an action potential. They are present
SNARE on vesicle (v-SNAREs) and target membranes (t-SNAREs) and form
complex a parallel four-helical bundle complex (with two SNAP-25 proteins,
1
synaptobrevin/VAMP, and syntaxin) that bridges the membranes
Pre-synaptic inside the cell.49 In the neuron, the SNAREs are synaptobrevin/
membrane VAMP on the synaptic vesicle membrane and syntaxin 1A and
Figure 67^1. Schematic of neurotoxin action at presynaptic SNAP-25 on the presynaptic plasma membrane. Assembly of
nerve terminal. (1) Botulinum neurotoxin binds to receptor(s) at the SNARE complexes requires exquisite spatial and temporal regula-
presynaptic membrane via (Hc) (providing very selective target tion to prevent inappropriate membrane fusion.
specificity). (2) Receptor with bound neurotoxin undergoes Synaptotagmin I (synaptotagmin) is the main Ca2+ sensor in neu-
endocytosis. (3) Endosome acidifies, leading to insertion of neurotoxin rons, where it is essential for the fast, synchronous fusion of synaptic
heavy chain (HN) into the membrane and translocation of the vesicles after Ca2+ influx.50–53 Synaptotagmins generally consist of an
neurotoxin into the neuronal cytosol. (4) Neurotoxin, or light chain, amino-terminal transmembrane domain and two Ca2+-binding con-
in the cytosol. (5) Neurotoxin light chain cleaves specific soluble served region 2 of protein kinase C (C2) domains.54–56
N-ethylmaleimide ^ sensitive factor attachment protein receptor SNARE complexes assemble when synaptic vesicles dock at the
(SNARE) protein at unique peptide bond. (From Foster KA. A new presynaptic membrane. Complexin is believed to clamp SNARE
wrinkle on pain relief: re-engineering clostridial neurotoxins for analgesics. complexes and prevent membrane fusion. Synaptotagmin recog-
Drug Discov 2005;10:563^569.) nizes and binds to the complexin–SNARE complex in the absence
of Ca2+. After Ca2+ influx, synaptotagmin binds to both Ca2+ and
ECL-LHN/A conjugate into the lumbar region of the spinal cord of membranes, leading to conformational changes that release com-
rats, sensory inputs by primary nociceptive afferents were signifi- plexin, and the shape of the membrane-inserted, Ca2+–synaptotag-
cantly attenuated.34,35 The ability of ECL-LHN/A to block neuro- min–SNARE complex might buckle the membranes outward to
transmitter release from nociceptive afferent neurons for prolonged complete fusion.57–60 Owing to its ability to interfere with exocy-
periods in vitro is, therefore, retained in vivo. Intrathecal adminis- tosis of cholinergic vesicles, BTX produces a temporary chemode-
tration of ECL-LHN/A into the lumbar region of the spinal cord of nervation of 3 to 4 months that reduces muscle tone, clonus, and
mice resulted in a prolonged withdrawal latency in a model of other forms of muscle overreactivity.
thermal pain, thus demonstrating the analgesic activity of the con- Antonucci and associates61 demonstrated that catalytically active
jugate.36 This effect was sustained for more than 30 days postadmi- BTX-A is retrogradely transported by central neurons and moto-
nistration of the conjugate, whereas morphine in the same model neurons and is then transcytosed to afferent synapses, in which it
ceased to demonstrate analgesic activity within less than a day. The cleaves SNAP-25.61 Also, SNAP-25 cleavage by BTX-A was observed
ECL-LHN/A conjugate, intrathecal or subcutaneous, has also been in the contralateral hemisphere after unilateral BTX-A delivery to
shown to inhibit phase II inflammatory pain in the rat formalin the hippocampus. However, they did not demonstrate that this was
model.37 a specific uptake. It is known from cell culture studies that you can
Specifically, a novel protein consisting of the LHN domains of ‘‘force’’ uptake by increasing the concentration and exposure time
BTX-C and epidermal growth factor (EGF) that is able to inhibit (Roger Aoki, personal communication).
secretion of mucus from epithelial cells is reported. Such a molecule In preclinical pain models, in vivo, pretreatment with BTX-A
has the potential to prevent mucus hypersecretion in asthma and (3.5–30 U/kg subcutaneously) prevents formalin-induced pain (in
chronic obstructive pulmonary disease.38 phase 2 only) and the release of glutamate from the rat hind-
BTX is internalized by the cell through an energy-dependent paw.62,63 BTX-A pretreatment also prevents the development of
process and the LC is translocated across the vesicle membrane thermal hyperalgesia, mechanical allodynia, increased blood flow,
into the cytosol.6,7,39 The translocation domain may form a channel WDR activation, and Fos-like immunoreactivity (Fos-LI) [as mea-
to facilitate the release of the LC from the endosome.40–42 In the sure of fos protein expression].64,65 In addition, BTX-A (15 U/kg
cytoplasm, the LC of the BTX-A molecule acts as an enzyme, cleav- subcutaneously) reversed established allodynia in a diabetic rat
ing a specific bond on synaptosomal-associated protein of 25 kDa model.64 Multiple studies have evaluated the antinociceptive effects
(SNAP-25), one of the proteins essential for the exocytosis of Ach. of BTX-A in human experimental models of pain, with mixed
The LCs of each of the seven BTX serotypes (and that of tetanus results.66–71 One study, from the Arendt-Nielson laboratory,
toxin) cleave a distinct peptide bond on one or more SNARE pro- demonstrated a positive antinociceptive effect with BTX-A.71 Cui
teins such that no two serotypes act at exactly the same target sub- and colleagues62 proposed a BTX antinociceptive hypothesis that
strate site. Once in the cytosol, clostridial neurotoxin (CNT) LCs BTX-A is expected to prevent peripheral nerve sensitization induced
exploit their catalytic activity, which was revealed following the by neurotransmitter (neuromodulator) release and, due to an agent
discovery that they contain the His-Glu-Xaa-Xaa-His zinc-binding or stimulus, indirectly attenuate central sensitization (e.g., allodynia
motif of zinc endopeptidases.43–45 BTXs and TeNT are remark- and/or hyperalgesia).
ably specific proteases that recognize and cleave only three proteins, The inhibition of the release of pronociceptive transmitters is
the so-called SNARE proteins, which form the core of the also the proposed mechanism behind pain reduction seen from
intra-articular injections described for knee, shoulder, hip, and vehicle-placebo.80 Injection sites were standardized and located in
sacroiliac joints.72,73 the bilateral frontalis, glabellar, and temporalis muscles. Patients
kept daily diaries recording migraine frequency, severity, and occur-
rence of migraine-associated symptoms. In the second study month,
PHARMACODYNAMICS the 25-U BTX-A group showed significant reductions in EM fre-
quency and severity, acute medication use, and associated vomiting
Peak effect is seen within 2 weeks from injection. Duration is lim- symptoms when compared with the placebo group. Additional
ited to 3 months when neuronal sprouting and molecular turnover improvements were observed in EM frequency in both treatment
at the neuromuscular junction return. Function is completely groups when these parameters were measured at 3 months.
restored within 6 months. The long-term efficacy of BTX was eval- Although the 25-U group seemed to derive a greater degree of
uated by Mejia and coworkers74 in a study of 45 patients who had benefit, the 75-U BTX-A group showed significant improvement
received BTX treatment for at least 12 consecutive years for dystonia in global assessment scores at month 2 when compared with pla-
or blepharospasm. The peak effect and duration of response did not cebo. Treatment-related adverse effects included blepharoptosis,
change over time. The dose per visit did increase, as did the dura- diplopia, and injection site weakness. These adverse effects were
tion of response. Twenty-two patients exhibited less than satisfac- all transient and may have been initially and primarily related to
tory response to BTX-A and were tested for antibodies. Only injector inexperience and technique, which reportedly improved.80
4 patients had confirmed blocking antibodies and started treatment
with BTX-B. Sixteen patients were antibody-negative and
responded to dose adjustments of BTX-A. Two antibody-negative Clinical Studies
patients were nonrespondent to dose changes in BTX-A and under-
BTX-A for theTreatment of EM
went treatment with BTX-B or BTX-F. It has been observed that if
immunoresistance to BTX-A is going to develop, it occurs within Evers and associates81 examined the effect of BTX-A on headache
the first 4 years of treatment. frequency and other migraine-related parameters in 60 patients
with migraine. This relatively small study population was divided
into three groups: one group was given BTX-A to the frontalis and
APPLICATIONS temporalis muscles at a total dose of 16 U; one group was given
BTX-A to the cranial muscles, with additional injections to the neck
In 1989, the FDA approved BTX-A for treatment of strabismus, muscles, for a total dose of 100 U; and the third was given placebo.
blepharospasm, and hemifacial spasm. Numerous other off-label Patients were allowed to receive migraine-preventive drugs
uses of BTX have been published, including achalasia, anismus, throughout the study period. At 3 months, there were no significant
cervical dystonia, detrussor sphincter abnormalities, dysynergia, differences in the reduction of migraine headache frequency or in
essential tremor, and hyperhydrosis. Novel uses for BTX continue the use of acute pain medications between the groups. The only
to evolve and include its preliminary research use in newborns with significant effect of BTX-A was in reducing migraine-associated
CHARGE (coloboma, heart disease, atresia choanae, retarded symptoms in the 16-U BTX-A group. Possible explanations for
growth and retarded development and/or central nervous system the mostly negative results of this study are the small number of
abnormalities, genital hyperplasia, and ear anomalies and/or deaf- patients and the low BTX-A doses given to the cranial muscles
ness) syndrome in efforts to facilitate extubation and avoid (although no study to date has shown a dose-dependent effect of
tracheotomy.75 CHARGE syndrome may be associated with hyper- BTX-A on headache).
stimulated salivary glands, which may secrete excessive fluids/saliva In a large multicenter trial by Aurora and colleagues and the Botox
with the potential for aspiration. Injection of BTX may block nerve North American Episodic Migraine Study Group,82 809 adult EM
activity in the nerves stimulating the salivary glands, thereby patients were screened with 369 randomized to placebo or BTX-A.
reducing salivary gland secretions to a normal level.75 BTX has The mean BTX-A dose was 190.5 U. The BTX-A group had a mean
also been employed for its cosmetic properties as a temporary treat- change from baseline of -4.0 headache episodes at day 180 compared
ment of facial wrinkles. Some of the popular uses of BTX are with -1.9 headache episodes in the placebo group (P = .048).
discussed in more detail. Both BTX-A and placebo groups experienced a reduced number of
headaches, but BTX-A was not superior to placebo.
A European migraine study by Relja and coworkers83 evaluated
Treatment of Headache BTX-A in 495 adults in a randomized, double-blind, placebo-con-
trolled design. The doses used were 75, 150, or 225 U. At 180 days,
The antinociceptive effect of BTX for the treatment of headaches the mean number of migraine events was decreased in all groups
may be due to the ability of BTX-A to block substance P release, including placebo, with no statistically significant differences noted
demonstrated using an in vitro culture system (20%). Other studies between groups.
showed that BTX-A can inhibit the release of glutamate and other Saper and associates84 conducted a randomized, double-blind,
neurotransmitters, including neuropeptides, from synaptosomes.76 placebo-controlled study of 232 patients with a history of four to
BTX-A has also been shown to decrease peripheral sensitization of eight moderate to severe migraines per month, with or without
nociceptive sensory nerve fibers by inhibiting the release of gluta- aura. Patients were randomized to placebo or one of four BTX-A
mate and substance P.77 Furthermore, BTX-A was shown to sup- groups that received injections into different muscle regions: frontal
press the secretion of calcitonin gene–related peptide, a (10 U), temporal (6 U), glabellar (9 U), or all three areas (total dose
neuropeptide involved in migraine pathophysiology, from rat tri- 25 U).84 For 3 months after a single treatment, patients recorded
geminal ganglia neurons.78 Oshinsky79 demonstrated that injection migraine-related variables in a daily diary.84 BTX-A and placebo
of BTX-A into the foreheads of rodents prevents central sensitiza- produced comparable decreases from baseline in the frequency of
tion of wide dynamic range neurons in the trigeminal nucleus cau- migraines (P .411).84
dalis induced by administering an ‘‘inflammatory soup’’ onto the
dura.
BTX-A for theTreatment of Chronic Daily Headache
A double-blind, placebo-controlled clinical study of 123 patients
with a history of two to eight moderate to severe episodic migraine The evidence that BTX helps patients with chronic daily headache
(EM) headaches per month were randomly divided into groups that (CDH) is reasonable but not robust. Mathew and colleagues85 eval-
received a single injection of either 25 or 75 U of BTX or the uated the effect of BTX-A on 355 patients with CDH in a
randomized, placebo-controlled study using the ‘‘follow-the-pain’’ and interventional therapies, including oral antidepressants, mem-
approach. Patients were injected three times at 3-month intervals. brane stabilizers, opioids, and traditional occipital nerve blocks
Injections of BTX-A were associated with a significant decrease without significant relief. This group then underwent occipital
in headache frequency compared with placebo (at day 180 –7.1 nerve blocks using the BTX-A 50 U for each block (100 U if
vs. –3.7 headache days per month with BTX-A and with placebo, bilateral).95 Significant decreases in pain on visual analog scale
respectively). Fifty-four percent of patients treated with BTX-A (VAS) scores and improvement in Pain Disability Index (PDI)
reported at least a 50% decrease from baseline in migraine headache were observed at 4 weeks follow-up in five out of six patients
frequency at day 180 compared with 38% of placebo-treated after BTX-A occipital nerve block. The mean VAS score changed
patients. Injections of BTX-A nonsignificantly increased the from 8 ± 1.8 (median score of 8.5) to 2 ± 2.7 (median score of 1),
number of headache-free days from baseline and decreased the use whereas PDI improved from 51.5 ± 17.6 (median 56) to 19.5 ± 21
of acute pain medications more than placebo. A subgroup analysis of (median 17.5), and the duration of the pain relief increased to an
these study results for patients who were not taking other migraine- average of 16.3 ± 3.2 weeks (median 16) from an average of 1.9 ±
preventive drugs showed a significantly greater decrease in headache 0.5 weeks (median 2) compared with diagnostic 0.5% bupivacaine
frequency (–7.8 vs. –4.5 headache days per month on day 180) and in block.95 After block resolution, the average VAS scores and PDIs
mean headache severity in the BTX-A group compared with pla- returned to levels similar to those before BTX-A block. Kapural
cebo.86 The number of headache-free days per month increased and colleagues95 concluded that BTX-A occipital nerve blocks pro-
significantly more in the BTX-A group compared with placebo vided a much longer duration of analgesia than diagnostic local
(+10.0 vs. +6.7 days, respectively).86 Only 4 of the patients discon- anesthetics. The functional capacity improvement measured by
tinued BTX-A because of adverse effects, which were mild and gen- PDI was profound enough in the majority of the patients to
erally consisted of localized pain at the injection site.86 allow them to resume their regular daily activities for a period
Ondo and coworkers87 studied the effect of BTX-A on of time.95
60 patients with CDH. Using the follow-the-pain approach, patients
were given 200 U of BTX-A or placebo at different sites. Between
Whiplash Injuries
weeks 8 and 12, a significantly higher increase in headache-free days
occurred in the BTX-A group than in the placebo group, and there Two randomized, placebo-controlled trials showed that BTX was
was a strong tendency for this effect to continue over the entire not clinically beneficial for the treatment of neck pain and whiplash
study period. Both subjects’ and investigators’ global impressions (WI)–associated disorders. Statistically significant effects were not
were significantly better for the BTX-A group compared than for achieved in a study of 15 participants.96 In a subsequent study of 25
the placebo group. Women tended to respond better than men to participants, no specific benefits could be identified. Participants
BTX-A. An open-label extension of the study showed a possible treated with normal saline showed outcomes comparable with
cumulative beneficial effect of BTX-A on headache. those treated with BTX over 4 months.97 However, Braker and
In a randomized, placebo-controlled study of 702 patients, coworkers98 studied 20 patients with cervical myofascial pain, 2
Silberstein and associates88 studied the efficacy and tolerability of to 48 weeks after WI, who were randomly assigned to receive
BTX-A for CDH prevention using a ‘‘fixed-site’’ protocol at a total either 200 U of BTX-A or placebo at four tender points and were
dose of 75 U, 150 U, or 225 U. Patients were given three BTX-A seen during the follow-ups at 3, 6, 9, 12, and 24 weeks after the
treatments over a 9-month period. Patients overused pain medica- injections. Outcome measures included the intensity of pain as
tion 42% of the time. Patients received additional masked treat- evaluated by a 10-cm VAS and a 5-point verbal rating scale
ments at 90 and 180 days. Patients were assessed every 30 days for (VRS), quality of life as evaluated by the Short Form 36-item
9 months. The primary efficacy end-point was a mean change from (SF-36) questionnaire, treatment efficacy as per the global assess-
baseline in frequency of headache-free days at day 180 compared ment of the physician and patient, intensity of pain in response to
with the placebo nonresponder group. This primary efficacy mechanical pressure, range of cervical motion, and use of other
end-point was not met; all groups responded to treatment. therapies and their adverse effects.98
However, the 225- and 150-U groups experienced a greater decrease A time-dependent improvement in all the parameters was found
in headache frequency than the placebo group at day 240.88 Pooled in both groups, which was consistently larger in the BTX-A–treated
analysis showed that at day 240, patients who received 225-U BTX- group but mostly not at a significant level.98 Significant differences
A and 150-U BTX-A had significantly fewer headaches than those between the groups were found only in the percentages of patients
who received placebo. A subgroup analysis was done of 231 patients who achieved 50% or more of reduction in intensity (VAS and
(33%) who at baseline had (1) no concurrent headache-preventive average VRS) at 24 weeks (50% vs. 0%, P > .05 and 70% vs.
medications; (2) 15 days or longer with headache lasting 4 or more 11%, P > .05, respectively).98 Thus, Braker and coworkers98 sug-
continuous hours per day; (3) 50% or more of the headache days as gested that BTX-A treatment has some efficacy when administered
migraine/probable migraine days; and (4) 4 or more headache within 1 year of the WI; however, a large, well-designed clinical trial
episodes per month that lasted 4 or more continuous hours. A is needed to draw final conclusions.
reduction in headache days favoring the three BTX-A treatment
arms was seen at all post-treatment time points with significant
differences observed at several time points.89 Facial Pain
Several anecdotal reports exist of the utility of BTX in treating tri-
ChronicTension-type Headache
geminal neuralgia.99–104 In these various reports, injection of the
No good evidence exists for the efficacy of BTX-A in the treatment BTX is targeted peripherally at the region surrounding the trigger
of chronic tension-type headache (CTTH). In fact, four placebo- zone for the neuralgic pain or into the region of the zygomatic
controlled studies that examined its efficacy in CTTH were negative, arch101 with a variable dose (e.g., 100 U101). Although some authors
and one study showed a beneficial effect of BTX-A only on a sec- seem optimistic, the results have been promising but not definitive.
ondary outcome measure.90–94 One major side effect of treatment with BTX is the weakening of
muscles of facial expression proximate to the injected trigger zones,
resulting in a temporary cosmetic paresis. In cases of intractable
Occipital Neuralgia
pain that is unresponsive to first-line oral medications, BTX may
Kapural and colleagues95 retrospectively describes a series of six offer a safe and logical next therapeutic option owing to its
patients with severe occipital neuralgia who received conservative reversibility.
The most significant joint of the face is the temporomandibular BTX-A group and 5.7 years for the control group (range
joint (TMJ). This joint can exhibit a multitude of pathologic con- 6 mo–30 yr). Each patient’s baseline level of pain and degree of dis-
ditions collectively referred to as temporomandibular disorders ability were documented using the VAS and the Oswestry Low Back
(TMD). These pathologic conditions involve pathology of various Pain Questionnaire (OLBPQ) and reevaluated at 3 and 8 weeks
components of the TMJ, as for any joint in the body. Many of these (VAS) and at 8 weeks (OLBPQ). At 3 weeks, 11 of 15 patients who
disorders are painful, and some have reportedly been treated suc- received BTX (73.3%) had greater than 50% pain relief versus 4 of
cessfully with BTX.105 16 (25%) in the control group (P = .012). At 8 weeks, 9 of 15 (60%) in
A potential mechanism for diminishing inflammation of a joint the BTX group and 2 of 16 (12.5%) in control group had relief (P =
secondary to trauma is via decreasing joint loading. The muscles of .009). Repeat OLBPQ at 8 weeks showed improvement in 10 of
mastication are primarily jaw-closing muscles. The masseter, tem- 15 (66.7%) in the BTX group versus 3 of 16 (18.8%) in the control
poralis, and medial (internal) pterygoid muscles are the largest and group (P = .011). None of the patients experienced any side effects.
most powerful facial muscles. Reducing the strength of contraction Foster and colleagues110 concluded that paraspinal administration of
of these muscles with BTX over a prolonged period of time may BTX-A in patients with chronic low back pain can relieve pain and
lead to decreased joint loading and thus, diminished inflammation, improve function at 3 and 8 weeks after treatment.110
joint pain, and joint damage. The dual benefit of muscle injection of Jabbari and coworkers111 prospectively studied the effect of
BTX in TMD lies in its ability to diminish primary muscle pain BTX-A on 75 patients with chronic low back pain refractory to
associated with muscle hyperactivity as well as to potentially dimin- medical or surgical treatment over a period of 14 months.
ish TMJ inflammation.105 BTX dosing is dependent on the size of Patients with bilateral low back pain were also included in this
the muscle, with typical range for each masseter muscle from 25 to study. The patients had a mean age of 46.1 years (range 21–79)
50 U and for the temporalis muscle from 12.5 to 25 U.106,107 and a mean pain duration of 9.2 years (range 7 mo–50 yr).
Twenty-one of 75 patients were female, and 84% of the entire
cohort had bilateral pain. Other factors noted among the cohort
Interstitial Cystitis were previous back surgery (n = 14), root pain (n = 20), epidural
steroids injections (n = 19), and opioid analgesic use (n = 36).
A total of 19 patients with interstitial cystitis (IC) were treated with Magnetic resonance imaging (MRI) showed a variety of low back
100 U or 200 U of intravesical BTX-A injections followed by cys- pathology but mostly chronic degeneration of the spine, canal ste-
toscopic hydrodistention 2 weeks later. Bladder mucosa biopsies nosis, and chronic disk protrusions. Patients were instructed not to
were performed before BTX-A injection and immediately after change their analgesic medications and to continue with their phys-
hydrodilation and in 12 controls. At 3 months, 14 patients had ical therapy during the course of the study.
symptomatic improvement (responders) and 5 did not (nonrespon- Pain intensity (VAS), pain frequency (pain days measured by the
ders). The nerve growth factor (NGF) mRNA levels at baseline Pain Impact Questionnaire [PIQ]), and perceived functional status
in the overall IC patient group were significantly greater than by patients (OLBPQ) were assessed at baseline and at 3 weeks and 2,
those in the controls (0.65 ± 0.33 vs. 0.42 ± 0.25, P = .046). At 4, 6, 8, 10, 12 and 14 months. BTX-A was injected into the para-
2 weeks after BTX-A treatment, the NGF mRNA levels had spinal muscles at four to five levels (between L1 and S1) unilaterally
decreased to 0.47 ± 0.23 (P = .002, compared with baseline) and or bilaterally, and an extra dose was administered laterally into the
were no longer significantly different from those of the controls. bulk of the erector muscles at the level of most discomfort. The dose
The NGF mRNA levels decreased significantly in responders and per site varied from 40 to 50 U. The total dose per session ranged
were significantly decreased after BTX-A in 11 patients with a VAS from 200 to 500 U. Reinjections were performed at 4 months if pain
reduction of 2 or more. The immunoreactivity study of bladder returned. Most patients had reinjections every 4 months.111
tissue from patients with IC showed greater NGF density at baseline At 3 weeks 40 patients (53%) and at 2 months 39 patients (52%)
compared with controls, but the difference was no longer significant reported significant pain relief.111 The change in mean VAS, mean
after successful BTX-A treatment. Intravesical BTX-A injections OLBPQ score, and mean pain days was significant compared with
plus hydrodistetsion reduce bladder pain in patients with IC.108 baseline at 2 months after each injection period (P < .005) and
Three men and 12 women were prospectively given injections of remained so over subsequent treatments.111 Among initial respon-
200 U commercially available BTX-A diluted in 20 ml 0.9% saline ders, 91% continued to be responders over the length of the study.
submucosally in the bladder trigone and lateral walls under cysto- In 9 of 20 patients (45%) with ‘‘root’’ (radicular) pain, the pain
scopic guidance.109 A voiding chart and the VAS for pain were used, improved significantly after BTX treatment of the paraspinal
and urodynamics were performed before treatment and 1, 3, 5, and muscle. After the first treatment, 3 patients (4%), had mild flulike
12 months later. Overall, 13 patients (86.6%) reported subjective symptoms that lasted 2 to 5 days.111 No other side effects were
improvement at the 1- and 3-month follow-ups. The mean VAS noted.111
score and daytime and nighttime urinary frequency were signifi- Eighteen women and 42 men, ages 21 to 79 years (mean 46.6 yr),
cantly decreased (P < .05, < .01, and < .05, respectively).109 At the with low back pain of a mean duration of 9.1 years, were injected in
5-month follow-up, the beneficial effects persisted in 26.6% of the lower back with BTX-A and followed prospectively over 6
cases, but increased daytime and nighttime urinary frequency and months.112 Significant improvement in back and radicular pain
an increased VAS score were observed compared with baseline. At occurred at 3 weeks in 60% and at 2 months in 58% of the
12 months after treatment, pain recurred in all patients. cohort. Beneficial clinical response to the first injection predicted
Giannantoni and associates109 concluded that intravesically injected response to reinjection in 94%. A significant minority of patients
BTX-A is effective for short-term management of refractory painful had a sustained beneficial effect from the first injection at 4 (16.6%)
bladder syndrome. and 6 (8.3%) months. Two patients had a transient flulike reaction
after the initial treatment.112 The patient’s response to BTX-A was
considered beneficial and significant when improvement occurred
Low Back Pain in least two of the following ratings: (1) VAS (average) showed 50%
or more decrease in pain intensity; (2) OBLPQ showed a two-grade
Foster and colleagues110 studied 31 consecutive patients with chronic or more improvement in the pain subset and one or more of the
low back pain, with 15 patients receiving a total of 200 U of BTX-A 40 functional subsets; and (3) CLBPQ showed a 30% or more decrease
U/site at five lumbar paravertebral levels on the side of maximum in the number of pain days from baseline.112
discomfort and another 16 patients receiving the same volume of BTX-A, concentrated at 100 U/ml, was injected with a 1-ml
normal saline. The mean duration of pain was 8.1 years for the tuberculin syringe through a 0.75- or 1.5-inch needle, depending
on the degree of subject adiposity. Four or five injection sites per triamcinolone acetonide 30 mg with 1.5 ml of 2% lidocaine) into
side from L2 to S1 were determined by the physician and the patient the motor point of the piriformis muscle. The electromyography
based on deep finger pressure to locate trigger points or muscle (EMG)-guided injection of BTXs (300 U BTX-A or 12,500 U BTX-
spasm. Injections were done without electromyographic guidance B) may have advantages over traditional local anesthetic and steroid
owing to the size of the muscles involved, the additional expense injections that may include more pain relief faster, longer duration,
and equipment costs, and the relative ease of clinically determining fewer relapses, fewer side effects (especially in diabetic and immu-
painful or overactive sites of paravertebral muscles. The dose per nocompromised patients).123,124
site was 40 to 50 U, and the total dose per session did not exceed
500 U for bilateral pain.112
Plantar Fasciitis
BTX injections were to occur at the time of entry into the study.
The duration of effect was assumed to decline by 4 months. A The plantar fascia runs from the medial tubercle of the calcaneus to
second set of injections would be given at 4 months if the patient the transverse ligaments of the metatarsal heads of the foot. Because
had a significant beneficial response at 2 months. Patients with the plantar fascia is relatively rigid in nature, repetitive stretching/
continued clinical benefit past 4 months would be allowed to overuse insult may lead to microtears at its origin.125 These and
defer reinjection. Follow-up was to occur at 3 weeks after the initial other processes may result in myxoid degeneration with fibrocyte
injection and at 2-month intervals thereafter. Failure to respond at necrosis, chondroid metaplasia, and angiofibroblastic proliferation,
3 weeks or 2 months warranted no further follow-up.112 Overall, the replacing the normal cellular matrix.125 This degenerative thickened
number needed to treat for BTX for low back pain is 2.1.113 fascia is mechanically inefficient and contracts during the night as
the foot rests in the equinus position. The first step out of bed in the
morning stretches the fascia acutely, leading the irritation and pain.
The pain of plantar fasciitis generally diminishes with activity but
Musculoskeletal/Myofascial Disorders may be reaggravated after prolonged sitting, standing, or walking
Muscle Spasm long distances.125
Other findings that may be associated with plantar fasciitis
Muscle spasm refers to pain after muscle injury. Commonly known include taut, tender muscle structures around the arch; decreased
as a muscle cramp, muscle spasm starts as an involuntary contrac- ankle or hallux dorsiflexion; aggravation with heel raises or toe-
tion triggered by irritable muscle spindles or secondary to electro- walking; heel spurs (about 70%); and heel pain reproduced with
lyte imbalance seen with dehydration or exercise. Chronic forms of passive dorsiflexion of the toes (especially while the patient is
muscle spasm such as paraspinal muscle spasm account for some weight-bearing).125
forms of low back pain. BTX injection into these muscles reduced The differential diagnosis may include stress fracture, retrocal-
pain for a period of 6 to 12 weeks according to a study by Knusel caneal bursitis, plantar fascia rupture, calcaneal apophysitis (in ado-
and associates.114 lescents [Sever’s disease]), sacral radiculopathy, fat pad necrosis,
tarsal tunnel syndrome, entrapment of the medial calcaneal
branch of the posterior tibial nerve, and irritation of the nerve to
Dystonia
the abductor digiti quinti.125
Dystonia is another type of movement disorder in which involun- Treatment of plantar fasciitis may include physical medicine
tary muscular contraction results in bizarre twisting postures. techniques (stretching and strengthening exercises [e.g., ankle dor-
Unlike spasticity, it is not linked with upper motor neuron disor- siflexion stretch, great toe stretch, wall stretches, gastrocnemius
ders. Up to 70% of cervical dystonia patients experience pain.115 In stretch, soleous stretch, can roll, towel curl]). Cold therapy (ice
a study by Janovic and Schwartz,116 76.4% of patients with cervical massage) can be employed. Anti-inflammatory agents perhaps
dystonia had complete relief after BTX injections. Surprisingly, clin- with analgesic adjuncts may be used. Orthotics including heel
ical observation indicates that in patients with cervical dystonia, cups and night splints may help certain patients. Some clinicians
pain relief due to BTX outweighs the benefit obtained from have used steroid injections, iontophorosis with glucocorticoids
motor block of affected muscles.116 and/or acetic acid, surgery, or extracorporeal shock wave therapy
in refractory cases.125
Babcock and colleagues126 studied the effects of BTX-A injection
Piriformis Syndrome
for refractory plantar fasciitis in a randomized, placebo-controlled,
Piriformis syndrome is considered to be a reversible compression prospective, short-term clinical trial. They used a 27-gauge 0.75-
of the sciatic nerve by the piriformis muscle that may lead to inch needle to inject group A with 40 U (0.4 ml) in the tender
deep and severe pain in the buttock, hip, and sciatic nerve, with region of the heel medial to the base of the plantar fascia insertion
radiation into the thigh, leg, foot, and toes. Pirformis muscular and 30 U (0.3 ml) in the most tender point of the arch of the foot
tension could compress the sciatic nerve anteriorly and inferiorly (between an inch anterior to the heel and the middle of the foot);
against the sharp tendinous edge of other muscles (e.g., gemellus group B received injections of saline in the same sites.126
superior, obturator internus), which may result in peripheral nerve Main outcome measures included pain VASs, Maryland foot
insult.117 score, pain relief VAS, and pressure algometry response. Patients
Diagnostic signs include tenderness in the buttock between the were assessed prior to injection and at 3 and 8 weeks. Compared
medial edge of the greater sciatic foramen and the greater trochan- with saline, the BTX-A group showed statistically significant
ter,118 weakness in resisted abduction of the flexed thigh,119 pain on improvements in all measures: pain VAS (P < .005), Maryland
passive adduction and internal rotation of the extended thigh,120 foot score (P = .001), pain relief VAS (P < .0005), and pressure
buttock pain with passive adduction of the flexed thigh,121 and pain algometry response (P = .003); without significant side effects.126
in voluntary flexion adduction and internal rotation of the
hip.117,122
Furthermore, electromyographic testing may help to support the Myofascial Pain Syndrome
diagnosis of PS if the flexion, adduction, and internal rotation posi-
tion (the FAIR test) brings more than a 3–standard deviation delay Myofascial pain syndrome (MPS) presents as acute or chronic skel-
of the H-reflex (1.86 msec).117 A significant component of treat- etal muscle pain that originates in specific trigger points and affects
ment involves physical therapy approaches. Interventional surrounding soft tissue and fascia. Although the etiology of MPS is
approaches include injection of steroid and local anesthetic (e.g., still unclear, muscle spasm resulting from increased release of Ach
at dysfunctional end motor plates may play a fundamental role. be localized with EMG, electrical stimulation can be used to find
Contracted fibers cannot relax, leading to pain, stiffness, and fati- motor points and injection can be undertaken because the two usu-
gue. Symptoms are reported by up to 21% of patients presenting to ally coincide. Motor points may be localized with peripheral nerve
orthopedic clinics and 85% to 93% of patients seen in pain-man- stimulators whose electrodes are connected over the muscle belly and
agement centers.127 when 5 to 10 mA and 0.5 sec duration are applied.130
The high incidence of MPS and the growing body of evidence
linking this disorder to excessive muscle spasm have made BTX a
Dosage
promising treatment (Table 67–1). BTX allows taut muscle bands to
regress to a latent, asymptomatic phase by inhibiting Ach release at The severity and chronicity of disease, number of muscles involved,
motor nerve endings. This has led to FDA approval of BTX-A in previous response, and coexisting conditions affect the dosing.
1989 for conditions involving abnormal muscle contraction such as Optimally, BTX is used in the least amount needed to achieve
essential blepharospasm and hemifacial spasm. Its use in MPSs, muscle relaxation and improve range of motion without causing
however, remains off label, and currently, no definitive studies weakness or other side effects. Administration is proportionate to
have established the efficacy of BTX for the treatment of MPS or body mass. Potency is expressed in mouse units (MU) that were
fibromyalgia.128 determined according to a standard Swiss-Webster mouse of 20 g.
Generally, 1 MU is the median lethal dose (LD50) that has been
determined across several animal species. No specific studies were
Evaluation
done in humans. Human LD50 is approximately 3000 MU for a 70-
Unlike the diagnosis of fibromyalgia, an international diagnostic kg adult. Large muscle groups receive anywhere between 60 and 400
criteria for MPS does not exist. However, identification of trigger MU per treatment, although the recommended ceiling dose is closer
points is an important first step. Trigger points are found by gentle to 360 MU given 12 weeks apart.131
palpation in the direction of the muscle fibers. They have a char-
acteristic nodularity, and palpation is extremely painful. Clinical
Preparations
reliability in identifying trigger point varies considerably unless
examiners are consistently trained. In a study by Sciotti and cow- BOTOX is dispensed in 100U vials, whereas Dysport contains 500
orkers,129 four blinded examiners who were trained together were U. The potency of the two forms differs with a 1:4 conversion rate
able to agree up to 80% of the time on the location of trigger points for BOTOX to Dysport. Most practitioners dilute BOTOX with 1 to
in the upper trapezius muscle. 4 ml of preservative-free saline for a concentration of 2.5 to 10 U/
0.1 ml. The preparation is best used within 4 hours of reconstitu-
tion. The pH should be maintained from 4.2 to 6.8, and the tem-
Management perature kept at less than 208C. BTX-B is available in vials of
various volumes, each at a concentration of 5000 U/ml. It is recom-
Adjunct Therapies
mended that this be stored at between 28C and 88C.
Traditional therapies for MPS include, but are not limited to, phar-
amacotherapy and injection therapies. Nonsteroidal anti-inflamma-
Complications and Side Effects
tory drugs, steroids antidepressants, a-adrenergic agonists,
vasodilators, skeletal muscle relaxants, and opioids in conjunction Owing to its specific mechanism of action, specific side effects are
with massage, physical therapy, and transcutaneous electrical nerve uncommon and systemic effects are even less common. Short-lived
stimulation have been employed with some success. Injection ther- flulike symptoms of soreness, headache, fever, chills, lightheaded-
apy with local anesthetics, with or without steroids, or simply dry ness, hypertension, diarrhea, and abdominal pain have been
needling has been shown to be beneficial. BTX has only recently reported. Muscular weakness, however, remains the predominant
been introduced as a possible treatment modality for MPS. side effect that patients should be made aware of prior to BTX
injections. Clinicians should have a clear understanding of the func-
Injection Protocols. Therapy with BTX is individualized accord- tional consequence of injecting particular muscles when these mus-
ing to specific patient indications. There is variation between injec- cles serve crucial functions such as swallowing (Table 67–2).
tion techniques, dosing, and number of injections. Ultimately, the Recently, some reports of adverse events including death have
technique should be adapted to the patient’s specific situation. been linked to the use of BTX in children, leading to a warning by
Injections into deep compartments of the back generally require the FDA.132 According to the FDA, adverse events suggesting bot-
the use of special imaging techniques and/or electromyographic ulism and felt to be potentially associated with distant spread gen-
guidance, whereas superficial injections can be undertaken without erally occurred at relatively high dosages of 100 to 700 U in BTX-A
monitoring (Figs. 67–2 to 67–4). recipients and 10,000 to 20,000 U in BTX-B recipients.132 Botulism
cases in children younger than 16 years, who were treated for limb
EMG. EMG or motor point stimulation is useful for monitoring muscle spasticity associated with cerebral palsy, were associated
the injection of limb muscles, such as the small forearm muscles. with adverse events including dysphagia, respiratory insufficiency
EMG is a useful guide in identifying the anatomy of the muscles requiring use of gastric feeding tubes and ventilatory support, hos-
to be injected. It is based on the observation that trigger points pitalization, and death. Doses in these cases ranged from 6.25 to 32
are found in the proximity of motor endplates. Motor endplates U/kg for BTX-A (some > 20 U/kg max) and from 388 to 625 U/kg
occur predictably in bands throughout the muscle where small for BTX-B. Public Citizen, a consumer advocacy group, stated that
motor nerves terminate. EMG is typically connected to a needle its investigation of the FDA’s adverse event database indicates that
electrode that is used to search for the characteristic noise of the 16 BTX recipients (the majority receiving BTX-B), including 4 chil-
motor endplate. Upon finding the motor endplate, a low-voltage dren, died after being injected with the products; although the FDA
(10–40 mV) increase in the baseline will occur, and the EMG device has not determined whether these deaths were caused by the use of
produces a sound similar to that heard in a seashell held up to the products or were attributable to other causes.132
one’s ear. There are irregularly firing spikes, and the patient experi-
ences a deep pain over these points.
Absolute Contraindications
Motor endplates coincide with motor points, the areas at
which motor nerves terminate in the muscles and where phenol BTX-A is contraindicated in the presence of infection at the pro-
and alcohol blocks typically take place. If a motor endplate cannot posed site of injection or hypersensitivity to any ingredient in the
Table 67^1. Medline Search for ‘‘Myofascial Pain’’ and ‘‘BTX’’ Spanning 1966^2006
StudiesThat Show No Significant Pain Improvement after BTX Treatment

Muscles
Reference Study N Affected Outcome Measures Doses BTX-A Results
Querama Double-blind, 30 Infraspinatus EMG 50 U vs. saline BTX-A decreases motor
et al135 placebo-controlled, Pressure algometry control endplate activity and
parallel Flexibility tests influences EMG pattern
but does not change pain
level
Tuula Double-blind, 31 Neck, shoulder Pressure point 15–35 U No difference between small
et al136 randomized, threshold BTX doses and saline
controlled (dolorimeter) injections
questionnaires
Grabowski Randomized, 17 Neck, shoulder, hip, Likert format VAS 25 U vs. 0.5% P =0.3
et al137 double-blind back questionnaires bupivacaine BTX VAS 2.705 ± 3.31
(cost estimations) Bupivacaine 0.5% 2 ± 2.03
Ferrante Randomized, 132 Cervical/shoulder VAS 10, 25, 50 U Improved pain with placebo
et al138 double-blind, Pressure algometry BTX-A and BTX but no increased
placebo-controlled Need for rescue benefit from BTX vs.
medications saline
StudiesThat Show a Decrease in Myofascial Pain after BTX Treatment

Outcome
Reference Study N Muscles Affected Measures Doses BTX Results
Lew et al139 Randomized, 29 Neck and upper back VAS for pain BTX-A (50 U) per Minimally positive study
double-blind, NDI site (not exceeding improved SF-36 bodily
placebo-controlled, SF-36 200 U per pain scale at 2 and 4 mo
single-center, treatment and and mental health scale at
prospective 100 U per side) vs. 1 mo
saline
De Andres Open-label, 77 Various muscles VAS 10–20 U BTX-A Baseline VAS of 8.1
et al140 interventional, EMG vs. 1 ml 0.5% improved to 6.47 at
prospective Oswestry lidocaine vs. 15 days after BTX;
Questionnaire control: dry VAS at 30 days: 5.84
needling VAS at 90 days: 5.97
Lang141 Retrospective, 91 Levator muscle, VAS VAS BTX-A BTX-A VAS down by
open-label, splenius capitis, Patient global (100–600 U) 2.7 (better pain relief
single-center, chart semispinalis capitis, assessment VAS BTX-B than BTX-B and longer
review, comparing piriformis (9000 U) pain relief)
BTX-A vs. BTX-B BTX-B VAS down by 1.8
Argoff142 Observational study 11 Sternocleidomastoid, Questionnaire 25–50 U Improved burning and
of CRPS patients trapezius, splenius dysesthesia
who also have capitis, levator Normalization of skin color
myofascial pain scapular, etc.
Foster Randomized, 28 Paravertebral VAS 40 U Pain relief at 3 and 8 wk
et al143 double-blind Oswestry Low Back
Questionnaire
Porta144 Single-center, 40 Iliopsoas VAS BTX-A 80-150 U + Results at 30 days:
randomized Piriformis bupivacaine 0.5% vs. nonsignificant at 60 days:
Scalenus anterior methylprednisolone VAS decreased by 5.5 for
80 mg + 0.5% BTX vs. 2.5 for steroid
bupivacaine
Wheeler Randomized, double- 33 Cervicothoracic BTX-A 50 U vs. All groups with pain relief
et al145 blind, prospective paraspinal muscles 100 U vs. saline but no difference among
BTX and saline (UNLESS
a second 100-U injection
is done, then
improvement seen with
BTX)
Table 67^1. Medline Search for ‘‘Myofascial Pain’’ and ‘‘BTX’’ Spanning 1966^2006çcont’d
Outcome
Reference Study N Muscles Affected Measures Doses BTX Results
Cheshire Randomized, double- 6 Cervical paraspinal VAS 50 U BTX-A >30% improvement with
et al146 blind, placebo- muscles Verbal pain BTX-A but not with saline
controlled, cross- Shoulder girdle descriptors
over muscles (Gracely)
Pressure algometry
BTX, botulinum toxin; CRPS, complex regional pain syndrome; EMG, electromyographic; N, number of patients; NDI, Neck Disability Index; SF-36,
Short Form 36-item questionnaire (Medical Outcomes Study); VAS, visual analog scale.
BTX formulation. Hypersensitivity reactions are rare but may be transmission (e.g., tubocurarine, tetracyclines, lincomycin) or
accompanied by serious reactions such as anaphylaxis, soft tissue drugs that interfere with the intraneuronal concentrations of
edema, and dyspnea. If a hypersensitivity reaction is suspected, calcium.133,134
BTX-A injection should be discontinued immediately and appro-
priate medical intervention instituted.
CONCLUSION
Relative Contraindications
Recent advances in understanding the antinoniceptive properties of
Relative contraindications are administration to individuals who BTX, its inhibition of substance P, and its ability to inhibit muscle
cannot understand the risks and benefits of BTX-A and treatment spasm have made this product a credible treatment for MPS.
in patients with neuromuscular disorders or myopathies character- Lacking FDA guidelines for its use in MPS, BTX continues to be
ized by generalized muscle weakness. Patients with amyotrophic used clinically by practitioners. Based on current published studies,
lateral sclerosis, myasthenia gravis, or Lambert-Eaton syndrome
should receive BTX treatment only with caution. The toxin may
be potentiated by aminoglycoside antibiotics, spectinomycin, or any
other drug that might interfere with the neuromuscular
Figure 67^3. Biceps muscle injection. Muscle function: primary

function is to move the forearm toward the shoulder (elbow flexion).
Figure 67^2. Sternocleidomastoid muscle injection. Muscle The secondary function is supination of the forearm (turning the hand
function: contralateral neck torsion, anterior flexion. Recommended from a palms-down to a palms-up position). Recommended BTX dose:
botulinum toxin (BTX) dose: 50 mouse units (MU). 100 MU in 2 ml saline injected at two sites.
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129. Sciotti VM, Mittak VL, et al. Clinical precision of myofascial trigger 138. Ferrante FM, Bern L, et al. Evidence against trigger point injection
point location in the trapezius muscle. Pain 2001;93:259–266. technique for the treatment of cervicothoracic myofascial pain with
130. Childers MK, Wilson JW, Simison D. Equipment and injection botulinum toxin type A. Anesthesiology 2005;103:377–383.
techniques. In Childers MK, Wilson JW, Simison D (eds): Use of 139. Lew HL, Lee EH, Castaneda A, et al. Therapeutic use of botulinum
Botulinum Toxin Type A in Pain Management. New York: Demos toxin type A in treating neck and upper-back pain of myofascial
Medical Publishing, 1999; pp 64–92. origin: a pilot study. Arch Phys Med Rehabil 2008;89:75–80.
131. Brin MF, Lew MF, Adier CH, et al. Safety and efficacy of NeuroBloc 140. De Andres J, Cerda-Olmedo G, et al. Use of botulinum toxin in the
(botulinum toxin type B) in type A-resistant cervical dystonia. treatment of chronic myofascial pain. Clin J Pain 2003;19:269–275.
Neurology 1999;53:1431–1438. 141. Lang AM. A preliminary comparison of the efficacy and tolerability
132. U.S. Food and Drug Administration (2008;February 10). Botox of botulinum toxin serotypes A and B in the treatment of myofascial
linked to respiratory failure and death, FDA advises. Science Daily. pain syndrome: a retrospective, open-label chart review. Clin Ther
Available at http://www.sciencedaily.com-/releases/2008/02/ 2003;25:2268–2278.
080209090530.htm (retrieved April 10, 2008). 142. Argoff C. A focused review of the use of botulinum toxins for
133. Dysport [Product information]. Glen Waverly, Victoria, Australia: neuropathic pain. Clin J Pain 2002;18:S177–S181.
IPSEN Pty Ltd. 143. Foster L, Clapp L, et al. Botulinum toxin A and chronic low back
134. Botox [Product information]. Gordon, New South Wales, Australia: pain, a randomized, double blind study. Neurology
Allergan Australia Pty Ltd, 2002. 2001;56:1290–1293.
135. Querama E, Fuglsang-Frederiksen A, et al. A double-blind, 144. Porta M. A comparative trial of botulinum toxin type A in and
controlled study of botulinum toxin A in chronic myofascial pain. methylprednisolone for the treatment of myofascial pain syndrome
Neurology 2006;67:241–245. and pain from chronic muscle spasm. Pain 2000;85:101–105.
136. Tuula O, Arokoski JPA, et al. The effect of small doses of botulinum 145. Wheeler AH, Goolkasian P, et al. A randomized, double-blind,
toxin A on neck-shoulder myofascial pain syndrome: a double-blind, prospective pilot study of botulinum toxin injection for refractory,
randomized, and controlled crossover trial. Clin J Pain 2006;1:90–96. unilateral, cervicothoracic, paraspinal myofascial pain syndrome.
137. Grabowski CL, Gray DS, et al. Botulinum toxin A versus bupivicaine Spine 1998;23:1662–1666.
trigger point injections for the treatment of myofascial pain 146. Cheshire WP, Abashian S, et al. Botulinum toxin in the treatment of
syndrome: a randomized double blind crossover study. Pain myofascial pain syndrome. Pain 1994;59:65–69.
2005;118:170–175.
Chapter 68 reflection of its perception of market potential and patient prefer-

TOPICAL ANALGESIC AGENTS ence. To many patients, it seems logical and sensible to put the
painkiller where the pain is, rather than ingesting a substance that
travels everywhere even though the pain is felt in a relatively small
Gary McCleane and well-defined area. Fortunately, we are now often in a position to
rationalize why many topically applied agents achieve their thera-
peutic effect. This more detailed understanding of the pathophysiol-
ogy and pharmacology of pain has also allowed some to suggest
novel, topically applied treatments. Examples are provided later of
some old drugs, previously systemically administered, but now
INTRODUCTION known to have a peripheral mode of action. This does not, unfortu-
nately, mean that they will become prominent in pain practice. Being
As medical science progresses, physicians seem to become more and old drugs, the patent protection surrounding their use—and allow-
more specialized and to utilize increasingly invasive techniques in ing the pharmaceutical companies to invest in their verification and
attempts to achieve therapeutic goals. One cannot help but be licensing while protecting the financial investment—has long since
impressed by the technological advances that allow access, visuali- expired. Therefore, it is unlikely that the companies will invest
zation, and opportunity for treatment in areas of the body long resources in seeking an indication for the topical use of these drugs.
considered too delicate or inaccessible for intervention. But this
does not mean that the more complex interventions are necessarily
more efficacious than simpler ones. Nothing is fundamentally NONSTEROIDAL ANTI-INFLAMMATORY
wrong with utilizing the simplest modalities of treatment and reser- DRUGS
ving the more complex treatments for situations in which thera-
peutic failure has occurred with less complex treatments. Therefore, A bewildering array of topical nonsteroidal anti-inflammatory
we cannot forget about simple methods of administration of drugs agents (NSAIDs) is available for purchase either over the counter
and should remember that, in many cases, their use is founded not or through medical prescription. These agents are known to reduce
only on solid scientific evidence of effectiveness but also, in some the production of prostaglandins that sensitize nerve endings at the
cases, on generations’ worth of clinical use. site of injury. This effect occurs through inhibition of the cyclooxy-
When drugs are applied to the skin, they may either have a local genase (COX) enzyme that converts arachidonic acid, liberated
effect (topical analgesics) or be absorbed transdermally but have a from the phospholipid membrane by phospholipases, to prosta-
systemic mode of action. In this chapter, our consideration is on the noids such as prostaglandin. At least two forms of COX are believed
former. When these topical analgesics are considered, they may be to be important. COX-1 is normally expressed in tissues such as
long-established topical agents, old pharmaceutical entities that have those of the stomach and kidneys and plays a physiologic role in
recently been shown to have a peripheral mode of action, or entirely maintaining tissue integrity. A second form, COX-2, plays a role in
new and novel agents. That the pharmaceutical industry still sees the pain and inflammation. The analgesic effects of NSAIDs can be
merit in producing topical and transdermal analgesic agents is a dissociated from their anti-inflammatory effects, and this may
129. Sciotti VM, Mittak VL, et al. Clinical precision of myofascial trigger 138. Ferrante FM, Bern L, et al. Evidence against trigger point injection
point location in the trapezius muscle. Pain 2001;93:259–266. technique for the treatment of cervicothoracic myofascial pain with
130. Childers MK, Wilson JW, Simison D. Equipment and injection botulinum toxin type A. Anesthesiology 2005;103:377–383.
techniques. In Childers MK, Wilson JW, Simison D (eds): Use of 139. Lew HL, Lee EH, Castaneda A, et al. Therapeutic use of botulinum
Botulinum Toxin Type A in Pain Management. New York: Demos toxin type A in treating neck and upper-back pain of myofascial
Medical Publishing, 1999; pp 64–92. origin: a pilot study. Arch Phys Med Rehabil 2008;89:75–80.
131. Brin MF, Lew MF, Adier CH, et al. Safety and efficacy of NeuroBloc 140. De Andres J, Cerda-Olmedo G, et al. Use of botulinum toxin in the
(botulinum toxin type B) in type A-resistant cervical dystonia. treatment of chronic myofascial pain. Clin J Pain 2003;19:269–275.
Neurology 1999;53:1431–1438. 141. Lang AM. A preliminary comparison of the efficacy and tolerability
132. U.S. Food and Drug Administration (2008;February 10). Botox of botulinum toxin serotypes A and B in the treatment of myofascial
linked to respiratory failure and death, FDA advises. Science Daily. pain syndrome: a retrospective, open-label chart review. Clin Ther
Available at http://www.sciencedaily.com-/releases/2008/02/ 2003;25:2268–2278.
080209090530.htm (retrieved April 10, 2008). 142. Argoff C. A focused review of the use of botulinum toxins for
133. Dysport [Product information]. Glen Waverly, Victoria, Australia: neuropathic pain. Clin J Pain 2002;18:S177–S181.
IPSEN Pty Ltd. 143. Foster L, Clapp L, et al. Botulinum toxin A and chronic low back
134. Botox [Product information]. Gordon, New South Wales, Australia: pain, a randomized, double blind study. Neurology
Allergan Australia Pty Ltd, 2002. 2001;56:1290–1293.
135. Querama E, Fuglsang-Frederiksen A, et al. A double-blind, 144. Porta M. A comparative trial of botulinum toxin type A in and
controlled study of botulinum toxin A in chronic myofascial pain. methylprednisolone for the treatment of myofascial pain syndrome
Neurology 2006;67:241–245. and pain from chronic muscle spasm. Pain 2000;85:101–105.
136. Tuula O, Arokoski JPA, et al. The effect of small doses of botulinum 145. Wheeler AH, Goolkasian P, et al. A randomized, double-blind,
toxin A on neck-shoulder myofascial pain syndrome: a double-blind, prospective pilot study of botulinum toxin injection for refractory,
randomized, and controlled crossover trial. Clin J Pain 2006;1:90–96. unilateral, cervicothoracic, paraspinal myofascial pain syndrome.
137. Grabowski CL, Gray DS, et al. Botulinum toxin A versus bupivicaine Spine 1998;23:1662–1666.
trigger point injections for the treatment of myofascial pain 146. Cheshire WP, Abashian S, et al. Botulinum toxin in the treatment of
syndrome: a randomized double blind crossover study. Pain myofascial pain syndrome. Pain 1994;59:65–69.
2005;118:170–175.
Chapter 68 reflection of its perception of market potential and patient prefer-

TOPICAL ANALGESIC AGENTS ence. To many patients, it seems logical and sensible to put the
painkiller where the pain is, rather than ingesting a substance that
travels everywhere even though the pain is felt in a relatively small
Gary McCleane and well-defined area. Fortunately, we are now often in a position to
rationalize why many topically applied agents achieve their thera-
peutic effect. This more detailed understanding of the pathophysiol-
ogy and pharmacology of pain has also allowed some to suggest
novel, topically applied treatments. Examples are provided later of
some old drugs, previously systemically administered, but now
INTRODUCTION known to have a peripheral mode of action. This does not, unfortu-
nately, mean that they will become prominent in pain practice. Being
As medical science progresses, physicians seem to become more and old drugs, the patent protection surrounding their use—and allow-
more specialized and to utilize increasingly invasive techniques in ing the pharmaceutical companies to invest in their verification and
attempts to achieve therapeutic goals. One cannot help but be licensing while protecting the financial investment—has long since
impressed by the technological advances that allow access, visuali- expired. Therefore, it is unlikely that the companies will invest
zation, and opportunity for treatment in areas of the body long resources in seeking an indication for the topical use of these drugs.
considered too delicate or inaccessible for intervention. But this
does not mean that the more complex interventions are necessarily
more efficacious than simpler ones. Nothing is fundamentally NONSTEROIDAL ANTI-INFLAMMATORY
wrong with utilizing the simplest modalities of treatment and reser- DRUGS
ving the more complex treatments for situations in which thera-
peutic failure has occurred with less complex treatments. Therefore, A bewildering array of topical nonsteroidal anti-inflammatory
we cannot forget about simple methods of administration of drugs agents (NSAIDs) is available for purchase either over the counter
and should remember that, in many cases, their use is founded not or through medical prescription. These agents are known to reduce
only on solid scientific evidence of effectiveness but also, in some the production of prostaglandins that sensitize nerve endings at the
cases, on generations’ worth of clinical use. site of injury. This effect occurs through inhibition of the cyclooxy-
When drugs are applied to the skin, they may either have a local genase (COX) enzyme that converts arachidonic acid, liberated
effect (topical analgesics) or be absorbed transdermally but have a from the phospholipid membrane by phospholipases, to prosta-
systemic mode of action. In this chapter, our consideration is on the noids such as prostaglandin. At least two forms of COX are believed
former. When these topical analgesics are considered, they may be to be important. COX-1 is normally expressed in tissues such as
long-established topical agents, old pharmaceutical entities that have those of the stomach and kidneys and plays a physiologic role in
recently been shown to have a peripheral mode of action, or entirely maintaining tissue integrity. A second form, COX-2, plays a role in
new and novel agents. That the pharmaceutical industry still sees the pain and inflammation. The analgesic effects of NSAIDs can be
merit in producing topical and transdermal analgesic agents is a dissociated from their anti-inflammatory effects, and this may
502 Chapter 68 TOPICAL ANALGESIC AGENTS
reflect additional spinal and supraspinal actions of NSAIDs to inhi- NITRATES

bit various aspects of central pain processing. Recent evidence sug-
gests that a third COX, COX-3, which is predominantly centrally Conventionally used in the treatment of ischemic heart disease, it
distributed, may also have a significant role in NSAID action. now seems that nitrates have potent analgesic and anti-inflamma-
When NSAIDs are applied topically, bioavailability and plasma tory effects as well. It is known that exogenous nitrates stimulate the
concentrations are 5% to 15% of those achieved by systemic deliv- release of nitric oxide (NO). This substance is known to be a potent
ery. In human experimental pain models, topically applied NSAIDs mediator in a wide variety of cellular systems such as the endothe-
produce analgesia in models of cutaneous pain and muscle pain. In lium and both the peripheral and the central nervous systems. NO
terms of clinical use, three major reviews—one examining use in is released from the endothelium and from neutrophils and macro-
musculoskeletal and soft tissue pain, another reviewing data phages, all known to be intimately involved in the inflammatory
accrued in over 10,000 patients in 86 trials, and the third looking process. It appears that NO exerts its effect by stimulating increases
primarily at chronic rheumatic disease—all concluded that there in guanylate cyclase, thereby increasing levels of cyclic guanidine
was clear and significant evidence that topical NSAIDs do have monophosphate. Cholinergic drugs, such as acetylcholine, produce
pain-relieving properties. analgesia in a similar fashion by releasing NO and increasing NO at
When NSAIDs are applied topically, relatively high concentra- the nociceptor level.
tions occur in the dermis, whereas levels in adjacent muscle are as In addition to this action, NO may activate adenosine tripho-
high as when the agent is given systemically. Gastrointestinal side sphate–sensitive potassium channels and peripheral antinocicep-
effects occur less frequently than when the drug is given orally but tion. Endogenous NO levels may be increased if glutamate levels
are still more likely in patients who have previously demonstrated are increased. Glutamate is known to be an excitatory amino acid
such responses to oral medication. that activates N-methyl-D-aspartate (NMDA) receptors, thereby
Work is ongoing to develop alternative formulations of various initiating sensitization and protracting the pain process.
NSAIDs that will give enhanced dermal penetration, provide a more Topical nitrate, in the form of glyceryl trinitrate (GTN), has
measured dose, or be easier to use. For example, Mazieres and been shown to effectively reduce the pain of osteoarthritis, supras-
coworkers1 reported the study of the use of a topical ketoprofen pinatus tendinitis, Achilles tendinopathy, extensor tendinosis of the
patch in the treatment of tendinitis. They found a 56% reduction in elbow, and infusion-related thrombophlebitis. In addition, GTN
pain with its use versus a 37% reduction with a placebo patch. may reduce the pain and inflammation caused by sclerosant treat-
Adverse effects were reported in approximately equal numbers in ment of varicose veins and may even be useful in the treatment of
both the active- and the placebo-treatment groups. A topical diclo- vulvar pain. A number of reports suggested that topical nitrates may
fenac patch is also under investigation, with Allessandri and associ- enhance the analgesic effectiveness of strong opioids, but it is likely
ates2 reporting that it gives significantly more pain relief than a that this effect is due to systemic absorption of the nitrate and a
placebo patch in patients undergoing laparoscopic gynecologic sur- consequent central action.
gery. Niethard and colleagues3 reported that topical diclofenac From a practical perspective, GTN can be considered for any
diethylamine gel was effective in the treatment of osteoarthritis of relatively well-localized inflammatory condition. Therefore, in addi-
the knee. Spacca and coworkers4 reported that the use of topical tion to the conditions mentioned previously, GTN can be used with
diclofenac epolamine was efficacious in the treatment of lateral epi- effect in any joint pain (e.g., osteoarthritis, rheumatoid arthritis),
condylitis and shoulder periarthritis. They suggested that this tenosynovitis, enthetic pain, muscle pain, fracture pain (e.g., frac-
diclofenac salt has enhanced potential for cutaneous penetration tured rib, finger), around painful skin ulcers, and even in the man-
and that it is carried by a lecithin gel, which also aids penetration. agement of postoperative pain. In this latter situation, the patch or
Unfortunately, with both these studies, an inactive placebo was segments of patch are placed close to the operative wound.
used. More insight could have been gained if they had used con- Presumably, in addition to reducing inflammation and pain, the
ventional diclofenac gel and investigated whether their study pre- patch can enhance low tissue blood flow with all the benefits that
parations did offer benefit over currently available formulations. can bring in terms of wound healing.
A multicenter, randomized, placebo-controlled, double-blind The predominant side effect associated with topical nitrate use is
study of patients (N = 134) with minor ankle sprain was conducted headache. Currently, patch formulations deliver a relatively large
using a Flector Patch or placebo patch for 7 consecutive days. amount of nitrate, and therefore, the incidence of headache is
The primary efficacy variable was pain on active mobilization, high. Should lower-dose patches become available, the utility of
self-evaluated on a visual analog scale (VAS). The mean pain this treatment would be increased. GTN is also available in an oint-
score revealed 78% improvement at day 3 over baseline in the treatment formulation. The measurement and consistency of dosing are
ment group compared with a 59% improvement in the placebo problematic with the ointment formulation, and because there is
group (P < .0001). The mean pain score revealed an 88% improve- only a small difference between a potentially analgesic dose and one
ment at day 7 over baseline in the treatment group compared with a that causes headache, GTN ointment is less practical than the patch.
74% improvement in the placebo group (P < .0001). Topical nitrate can, therefore, be considered when pain is local-
Another multicenter, randomized, double-blind, placebo-con- ized and particularly in those patients in whom NSAIDs are contra-
trolled study of patients (N = 418) with a variety of soft tissue indicated. Topical nitrate is devoid of the renal, gastrointestinal,
injuries was performed. Patients applied dictofenac epolamine top- and hematologic side effects of NSAIDs.
ical patches (1.3%) twice daily for 14 days or until pain resolution.
The primary end-point was self-evaluated pain on a VAS assessed
twice daily. The mean pain score revealed a 41% improvement at
day 3 versus Vaseline in the treatment group compared with a 33%
improvement in the placebo group. The mean pain score revealed a
LOCAL ANESTHETICS
79% improvement over the entire treatment period over baseline in
the treatment group compared with a 73% improvement in the Gels/Creams
placebo group (P = .009).
Perhaps the greatest danger of topical NSAID use is the risk of Several topical local anesthetic preparations are available in gel,
polypharmacy. A number of over-the-counter topical and oral cream, and patch forms. Amethocaine is available as a gel, and
NSAIDs are now available, and the risk of overdosing with several lidocaine/prilocaine is provided as EMLA cream. EMLA cream con-
different preparations taken at the same time, all of which contain tains a eutectic mixture of lidocaine and prilocaine; it has been used
an NSAID, is very real. to anesthetize skin prior to cannula insertion. It also has
demonstrable benefit in reducing the pain of other procedures conditions. Their pain-relieving effect is independent of their anti-
including lumbar puncture, intramuscular injections, and circum- depressant effect. Unfortunately, their use is also associated with a
cision. Although EMLA cream is not U.S. Food and Drug significant risk of side effects, including dry mouth, sedation, uri-
Administration (FDA) approved for any neuropathic pain condi- nary retention, and weight gain, which reduces compliance. In con-
tion, several studies have been undertaken in patients with posther- trast, when TCAs are applied topically, side effects are relatively rare
petic neuralgia (PHN). Two of these were uncontrolled and showed and a very real chance of pain relief exists. Any relief obtained by
a pain-reducing effect, whereas a randomized, controlled study in topical TCA use can be offset by their possible peripheral actions
the same condition failed to show any benefit. Caution should be (Table 68–1).
taken with long-term use of this preparation because prilocaine has
been associated with the onset of methemoglobinemia.
Adenosine Receptors
Patches At peripheral nerve terminals in rodents, adenosine A1-receptor

activation produces antinociception by decreasing, while adeno-
Lidocaine is available in a topically applied patch in a 5% strength sine A2-receptor activation produces, pronociception by increasing
(Lidoderm). Lidoderm is approved by the FDA for the treatment of cyclic adenosine monophosphate levels in the sensory nerve term-
PHN. Its efficacy in this pain condition is supported by several trials inals. Adenosine A3-receptor activation produces pain behaviors
that also confirm that it is well tolerated. Not only can pain levels in through the release of histamine and serotonin from mast cells
patients with PHN be reduced, but measures of quality of life also and subsequent actions on the sensory nerve terminal. Caffeine
show improvement. In one study of patients with PHN, 66% of acts as a nonspecific adenosine receptor antagonist. When sys-
subjects reported reduced pain intensity when up to three Lidoderm temic caffeine is administered with systemic amitriptyline, the
patches were used for 12 hours each day. normal effect on thermal hyperalgesia is blocked. When amitripty-
Whereas Lidoderm is indicated for use in PHN, it may also be line is administered into a paw with neuropathic pain, an anti-
efficacious in other pain conditions. One controlled study con- hyperalgesic effect is recorded (but not when it is given into the
firmed a pain-reducing effectin the treatment of focal neuropathic contralateral paw). This antihyperalgesic effect is blocked by caf-
pain conditions, such as mononeuropathies and intercostal and il- feine, suggesting that at least part of the effect of peripherally
ioinguinal neuralgia. In an open-label study of 16 patients with applied amitriptyline is mediated through peripheral adenosine
‘‘refractory’’ neuropathic pain (including post-thoracotomy pain, receptors.
complex regional pain syndrome, postamputation pain, neuroma
pain, painful diabetic neuropathy, meralgia parasthetica, and post-
mastectomy pain), 81% of subjects experienced notable pain relief. Sodium Channels
Refractory was defined in those patients who had either failed to
gain pain relief or experienced unacceptable side effects with opi- Sudoh and associates5 administered various TCAs by a single injec-
ates, anticonvulsants, antidepressants, or antiarrhythmic agents. tion into rat sciatic notches. They measured the duration of com-
Lidoderm patches, therefore, offer a low-risk strategy for the plete sciatic nerve blockade and compared it with that of
treatment of a variety of conditions. Many other pain conditions bupivicaine. They found that amitriptyline, doxepin, and imipra-
could probably be effectively treated with Lidoderm patches. mine produced a longer complete sciatic nerve block than bupivi-
One wonders how the postoperative pain may respond if the caine, whereas trimipramine and desipramine produced a shorter
patch is applied over the operative wound and changed on an inter- block. Nortriptyline and maprotiline failed to produce any block.
mittent basis. The topical application of amitriptyline produced longer cutaneous
analgesia than lidocaine.
Similarly, Gerner and colleagues6 found that intrathecal doxe-
CAPSAICIN pin was not significantly different in its motor or proprioceptive
effects from those of intrathecal bupivicaine at a concentration of
Capsaicin achieves its pain-relieving effect by reversibly deplet- 0.75%.
ing sensory nerve endings of substance P and by reducing the den- These studies suggest that from a mode-of-action perspective,
sity of epidermal nerve fibers, again in a reversible fashion. peripherally applied TCAs could have an analgesic effect.
When capsaicin is used clinically, the major impediment to
better compliance is the intense burning sensation associated
with use. This is generally reduced with repeated administration,
although if capsaicin cream is applied outside the normal
area of application, discomfort will once again be apparent.
Coadministration of GTN can reduce the discomfort associated
with application and enhance the analgesic effect of capsaicin. Table 68^1. Modes of Action of Tricyclic
Alternatively, preapplication of EMLA cream can also reduce appli- Antidepressants
cation-associated discomfort.
Occasional patients experience bouts of sneezing when capsaicin
is used. Normally, this is caused by overapplication, drying of the Central Peripheral
cream on the skin, and nasal inhalation of the capsaicin dust from Serotonergic effect Adenosine receptor effect
the application site. Care always needs to be taken that capsaicin is Noradrenergic effect Sodium channel blocking effect
not applied to moist areas because this is associated with an Adenosine receptor effect ?? Opioidergic effect
increased burning sensation.
Sodium channel blocking effect
Opioidergic effect
TRICYCLIC ANTIDEPRESSANTS NMDA receptor effect
Calcium channel effect
Tricyclic antidepressants (TCAs) taken orally have a long history in
pain management. Their use is established for a broad range of pain NMDA, N-methyl-D-aspartate.
Animal Evidence of an Antinociceptive Effect of GLUTAMATE RECEPTOR ANTAGONISTS

Peripherally Applied TCAs It has recently become apparent that glutamate receptors are
Neuropathic Pain expressed on peripheral nerve terminals and that these may con-
tribute to peripheral nociceptive signalling. Both ionotropic and
Amitriptyline applied to rodent paws made neuropathic by a metabotropic glutamate receptors are present on membranes of
chronic nerve constriction injury produced an antinociceptive unmyelinated peripheral axons and axon terminals in the skin,
effect. When amitriptyline was applied to the contralateral paw, and peripheral inflammation increases the proportions of both
no antinociceptive effect was observed in the paw on the injured unmyelinated and myelinated nerves expressing ionotropic gluta-
side. When desipramine and the selective serotonin reuptake inhib- mate receptors. Local injections of NMDA and non-NMDA glu-
itor fluoxetine were studied, desipramine had a similar antinocicep- tamate receptor agonists to the rat hindpaw or knee joint
tive effect when applied topically, whereas fluoxetine did not. enhance pain behaviors, generating hyperalgesia and allodynia.
Injections of metabotropic glutamate receptor agonists produce
similar actions. Conversely, local application of glutamate recep-
FormalinTest
tor antagonists inhibits pain behavior after formalin application.
When amitriptyline and desipramine are coadministered peripher- In humans, ketamine, a noncompetitive NMDA receptor
ally with formalin, both the first- and the second-phase responses antagonist, enhances the local anesthetic and analgesic effects of
are reduced. When amitriptyline is administered peripherally along bupivicaine in acute postoperative pain by a peripheral mecha-
with formalin, Fos immunoreactivity in the dorsal region of the nism. When a thermal injury was inflicted on volunteers, one
spinal cord is significantly lower than in animals in which formalin study suggested that subcutaneous injection of ketamine produces
is administered alone. long-lasting reduction in hyperalgesia, whereas another failed to
confirm this result. That said, any analgesic effect produced by
peripheral ketamine application may be due to more than its
Visceral Pain
glutamate receptor activity. Ketamine can also block voltage-sen-
Using a noxious colorectal distention model in the rat, Su and sitive calcium channels, alter cholinergic and monoaminergic
Gebhart7 showed that the TCAs imipramine, desipramine, and clo- actions, and interfere with opioid receptors.
mipramine reduced the response to noxious colorectal distention by Isolated case reports suggest that topical ketamine can reduce
20%, 22%, and 46%, respectively, compared with control-treated sympathetically maintained pain and pain of malignant origin,
animals. again suggesting that glutamate receptor antagonists may have
some analgesic effect when applied topically.
A study by Poyhia and Vainio8 reported that topically adminis-
Thermal Injury
tered ketamine reduces capsaicin-evoked mechanical hyperalgesia,
Thermal hyperalgesia is produced by exposing a rodent hindpaw to although they suggested that the effect they observed was due to a
528C for 45 seconds. Locally applied amitriptyline at the time of reduction in central sensitization caused by systemic ketamine
thermal injury produces both antihyperalgesic and analgesic effects, absorption.
depending on the concentration. When the amitriptyline is applied
after the injury, the analgesic, but not the antihyperalgesic, effect is
retained. a-ADRENORECEPTOR ANTAGONISTS
Clonidine, an a2-adrenoreceptor agonist, is available in both cream
Human Pain
and patch formulations. It can have both a peripheral and a central
Human evidence of an analgesic effect with the topical application action when applied topically. Clonidine patches have been
of TCAs is limited. A small randomized, placebo-controlled trial of reported to reduce the hyperalgesia associated with sympathetically
40 subjects with neuropathic pain of mixed etiology produced a maintained pain, but not that in patients with sympathetically
reduction of 1.18 on a 0 to 10 linear VAS relative to placebo use independent pain. Clonidine cream may also have some pain-
with the application of doxepin 5% cream. Minor side effects were relieving effect in orofacial neuralgia–like pain. The effect of clo-
seen in only 3 subjects. A larger randomized, controlled trial invol- nidine in sympathetically maintained pain may be related to its
ving 200 subjects, again with neuropathic pain of mixed etiology, effect of reducing presynaptic norepinephrine release from sympa-
suggested that 5% doxepin cream reduced the linear VAS by thetic nerves. In patients with sympathetically maintained pain and
approximately 1 relative to placebo and that the time to effect in those with peripheral nerve injury and postherpetic neuralgia,
was about 2 weeks. Again, side effects were minor and infrequent. localized norepinephrine injection worsens the mechanical and
A pilot study examining the effect of topical amitriptyline applica- thermal hyperalgesia in some patients. When clonidine is injected
tion failed to produce any pain relief, but the maximum therapy into the knee joint after arthroscopy, pain relief can be observed.
duration was 7 days; therefore, the study may have been terminated When injected in combination with bupivicaine and morphine, the
before the time to maximal effect had been reached. analgesic effect of these drugs are enhanced.
Case studies have provided results of a useful reduction in pain
when 5% doxepin cream was applied topically in subjects with
complex regional pain syndrome type I and when doxepin was CANNABINOIDS
used as an oral rinse in patients with oral pain as a result of
cancer or cancer therapy. Cannabinoids can act at peripheral sites to produce analgesia by
Whereas the human evidence of an analgesic effect with top- virtue of their effect on cannabinoid (CB) CB1 and CB2 receptors.
ical doxepin is interesting, more study is needed to verify this In animal models, peripheral administration of agents selective for
and other TCA effects for this route of administration. The evi- CB1 receptors produces local analgesia in the formalin test, the
dence suggests that the effect of topically applied doxepin is local carrageenan hyperalgesia model, and the nerve injury model. This
and that the consequences of systemic administration and, hence, effect may be obtained because of the action of these agents on the
systemic side effects can be substantially reduced. Doxepin in a sensory nerve terminal to inhibit release of calcitonin gene–related
5% cream formulation is currently available as Zonalon, which is peptide or by inhibiting effects of nerve growth factor. CB2 recep-
indicated for the treatment of itch associated with eczema. tor mechanisms may play a prominent role in inflammatory pain.
OPIOIDS 3. Niethard FU, Gold MS, Solomon GS, et al. Efficacy of topical
diclofenac diethylamine gel in osteoarthritis of the knee. J Rheumatol
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vehiculated diclofenac epolamine gel in shoulder periarthritis and
and buprenorphine have been introduced. Although they are
lateral epicondylitis: a placebo-controlled, multicenter, randomized,
applied to skin, it is likely that their predominant effect is double-blind clinical trial. Drugs Exp Clin Res 2005;31:147–154.
central. Tricyclic Antidepressants
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From the human clinical perspective, a number of reports sug-
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508 Chapter 69 TR AMADOL
Chapter 69 none for k- or d-receptors. The reported affinity for the m-receptor
is 10 times less than that of codeine and 6000 times less than that of
Tramadol morphine. The major active metabolite M1 (O-desmethyl-trama-
dol) has a modestly higher affinity at 300 times less than morphine
David J. Skinner, Jonathan Epstein, and (Fig. 69–2). The affinities for tramadol and its metabolites com-
Marco Pappagallo pared with other opioids are listed in Table 69–1. Alone, the opioid-
related activity of tramadol would not be expected to produce a
significant analgesic effect. In addition, the administration of the
opioid antagonist naloxone can only partially reverse the analgesic
effects of tramadol.
The other mechanism of action of tramadol is inhibition of the
neuronal reuptake of the neurotransmitters norepinephrine and
INTRODUCTION serotonin. This activity modulates the normal descending inhibitory
pathways of pain. Of note is that tramadol analgesia can be
The rungs of the World Health Organization (WHO) analgesic decreased by ondansetron, an antiemetic that is a selective seroto-
ladder provide the guidelines for the selection of ‘‘weak or nin-3 (5-HT3)–receptor antagonist and has actions in both central
strong’’ opioids according to the severity of cancer pain. The and peripheral sites. The (+) enantiomer has an approximately
ladder has been used by many practitioners not only in the man- fourfold greater effect on serotonin reuptake, whereas the (–) en-
agement of cancer pain but also in the care of noncancer pain. On antiomer has a greater effect on norepinephrine reuptake. Evidence
the second rung are the so-called weak opioids such as tramadol, has also shown that the (+) enantiomer and (±) tramadol increase
hydrocodone, and codeine. Tramadol, despite being classified with the presynaptic efflux of serotonin in the central nervous system. It
other opioids, is an atypical member of this group. It is a unique is known that medications causing reuptake inhibition of these
analgesic compound that demonstrates a dual mechanism of action neurotransmitters, such as the tricyclic antidepressants (TCAs),
with both opioid and monoaminergic actions. It generally has fewer are effective for pain.
side effects and better tolerability than oral nonsteroidal anti- The analgesic effects of tramadol are also completely reversed by
inflammatory drugs (NSAIDs) or traditional opioids. Tramadol coadministration of naloxone and the a2-adrenoceptor antagonist
was introduced to the U.S. market in 1995 as an alternative to yohimbine. Therefore, the reduction in pain produced by tramadol
NSAIDs. It was developed in 1962 by the German pharmaceutical is the result of the complementary and synergistic actions of its
company Grunenthal and entered the West German market in 1977 enantiomers.
under the trade name Tramal. Since that time, it has been used by
over 100 million patients and is available in 100 countries.
Tramadol is usually marketed as the hydrochloride salt (tra- Absorption, Distribution, Metabolism, and
madol hydrochloride) and is available in injectable (intravenous Elimination
and/or intramuscular), oral, and rectally administered preparations.
In the United States, however, only the oral formulation is available Tramadol has an oral absorption of 100%, with a mean bioavaila-
for use. It is available in 50- and 100-mg tablets as well as a 37.5-mg bility of 70% owing to a 20% to 30% first-pass metabolism after a
tramadol/acetaminophen combination. There is also a 24-hour, single oral dose. After multiple oral dosing, the bioavailability may
sustained-release preparation produced in 100-, 200-, and 300-mg increase to 90% to 100%, which may be the result of a saturated
strengths. The immediate-release forms are marketed as Ultram and first-pass hepatic metabolism. The bioavailability of tramadol after
Ultracet and the extended-release form as Ultram-ER (Ortho- food intake, although increased, does not seem to be clinically rel-
McNeil). evant. The time to peak plasma concentration after an oral dose of
the immediate-release tramadol is 1.6 to 1.9 hours. The time to peak
plasma concentrations for the extended-release tramadol Ultram-
PHARMACOLOGY ER is 12 hours.
Tramadol is rapidly distributed after oral intake with peak brain
Tramadol is a racemic mixture of two enantiomers with different concentrations occurring at 10 minutes and at 20 to 60 minutes for
pharmacologic properties composed of 50% (–)-tramadol and 50% its major active metabolite, O-desmethyl-tramadol (M1). The bind-
(+)-tramadol. Each enantiomer displays differing affinities for varying of tramadol to human plasma proteins is approximately 20%.
ing receptors. The (+) enantiomer shows a greater affinity for the After absorption and distribution, tramadol is extensively metabo-
m-receptor and increases serotonin levels. The (–) enantiomer pre- lized by the liver primarily via N- and O-demthylation and conju-
ferentially stimulates a2-receptors, resulting in higher levels of gation of O-demethylated compounds. The cytochrome P-450
norepinephrine. (CYP450) system (CYP2D6 and CYP3A4 enzymes) appears to be
much involved in the metabolism of tramadol, with alteration of
tramadol pharmacokinetics seen in populations with varied
Mechanism of Action amounts of CYP2D6 activity.
In total, 23 metabolites have been identified in humans
Tramadol is a synthetic medication that is structurally related to (11 phase I metabolites and 12 conjugates). The major active me-
codeine and morphine, with an incompletely understood mecha- tabolite is M1, which displays a m-opioid receptor affinity 300 times
nism of action (Fig. 69–1). It is believed to work primarily in the greater than that of the parent drug, tramadol (see Table 69–1). The
central nervous system via two distinct mechanisms. Tramadol pharmacologic properties of many of the other metabolites have not
functions as a weak opioid approximately one fourth to one fifth been extensively studied but appear to have similar elimination
as potent as morphine with affinity for the m-receptor but little to half-lives and excretion via the kidneys. Elimination of tramadol
HO OCH3 H3CO
N Me
O O
HO
CH3
N N
H H CH3
H
CH3
A HO B C HO
Figure 69^1. Chemical structures of morphine, tramadol, and codeine.
and its metabolites occurs mostly through the kidneys (90%), treatment of nonmalignant pain in the elderly at a long-term facil-
with a negligible amount excreted in the bile and feces. The elim- ity, found decreases in pain and an improvement in intestinal func-
ination half-life of tramadol is 5 to 6 hours, with that of M1 being tion. In the same study, they also noted a decrease in falls, loss of
slightly longer. weight, behavioral symptoms, depression, and in overall consump-
Elimination and metabolism, processes heavily dependent upon tion of analgesics. These changes were accompanied by an increase
renal and hepatic mechanisms, are expected to be affected by in activity levels. In a 2006 Cochrane Review on the use of tramadol
changes in renal and/or hepatic function. The elimination half-life in osteoarthritis,2 data from 11 randomized, controlled trials invol-
is not excessively prolonged, however, as long as one of the two ving nearly 2000 patients was examined. The authors concluded
excretion organs is virtually intact. In patients with severe cirrhosis that tramadol decreases pain intensity, produces symptom relief,
of the liver, the elimination half-life of tramadol was extended to a and improves function, but that these benefits were small.
mean of 13 hours and a maximum of 22 hours. The manufacturer Tramadol has also been proven to be useful in the notoriously
(Ortho-McNeil) has recommended that its use be avoided in difficult to treat condition of chronic low back pain. A review paper
patients with liver failure. In patients with renal failure (creatinine published in 2005 by Mattia and Coluzzi3 examined specifically the
clearance < 5 ml/min), the mean elimination half-life was pro- usefulness of tramadol in musculoskeletal and neuropathic pain.
longed to about 11 hours, with a maximum of 19 hours. Dialysis Tramadol, in both the immediate- and the controlled-release
does not have a significant effect on the plasma concentrations of forms, was found to be effective in reducing pain and improving
tramadol. The total amount of tramadol and M1 removed after a function in patients with low back pain, while providing a lower
4-hour dialysis period (hemodialysis, intermittent or continuous incidence of side effects. This review also described significant
hemofiltration, or peritoneal dialysis) was less than 7% of the admi- reductions in NSAID requirements for patients who had previously
nistered dose. required high doses of NSAIDs for pain control.3
The 2006 market release of a sustained-release formulation in
the United States is likely to make tramadol a more attractive
INDICATIONS option for both patient and practitioner. A controlled trial invol-
ving over 1000 patients investigating the efficacy and safety of this
The unique combination of m-opioid agonism with norepinephrine extended-release tramadol versus placebo in the treatment of osteo-
and serotonin reuptake inhibition allows tramadol to be a particu- arthritis pain was recently published by Gana and coworkers.4 The
larly effective drug across a wide spectrum of painful conditions. findings showed statistically significant improvements in pain and
It is currently used to alleviate many types of musculoskeletal, neu- physical function. Advantages of the sustaine-release version
ropathic, and cancer pain syndromes. include improved adherence to a treatment regimen, avoidances
of plasma peaks that seem to be associated with increased side
effects, and greater therapeutic options. Reported adverse events
Musculoskeletal Pain were generally mild to moderate in severity and were consistent
with the established safety profile of immediate-release tramadol
A wealth of data supports the use of tramadol in musculoskeletal in the treatment of osteoarthritis pain.
pain. A favorable side effect profile allows this medication to be an Whereas first-line pharmacologic treatments of musculoskeletal
attractive choice for practitioners treating musculoskeletal and pain continue to be acetaminophen and NSAIDs, tramadol offers an
arthritic conditions in particular. As chronic usage of analgesics
becomes more prevalent with an aging population, it is imperative
that physicians find methods of treatment with mild side Table 69^1. Affinities of Opioids with Active
effect profiles, minimal risk for drug interactions, and resistance Metabolites at k-Opioid Receptors,
to tolerance. Tramadol is a viable alternative, or adjuvant, to
Given as Ki Values (Lower Value
NSAIDs, particularly among patients with an increased risk for gas-
trointestinal bleeding or other conditions that limit or prevent Denotes Higher Affinity)
NSAID use. In 2003, Mullins and Wild,1 in an analysis of the
Substance Ki value (kM)
O OH Morphine 0.00049 ± 0.00003
CH3
Codeine 0.59 ± 0.0017
OH OH Tramadol 17
H3C H3C
N N (+)-Tramadol 15.7
O-demethylation
()-Tramadol 28.8
CH3 CH3
O-Desmethyltramadol 3.19
Tramadol O-Desmethyl tramadol
Figure 69^2. O-Demethylation of tramadol to the M1 Adapted from Lotsch J. Opioid metabolites. J Pain Sympton Manage
metabolite. 2005;29:S10–S24.
analgesic alternative with an acceptably small risk of side effects. drug safety data concerning the use of tramadol. Information from
This is especially true for those patients who either fail to achieve phases II to IV clinical studies, postmarketing surveillance studies
adequate analgesia via traditional treatments or have contraindica- (covering safety data from a total of more than 21,000 patients),
tions to traditional therapies. and the spontaneous reporting system was taken into consider-
ation. The most frequent adverse events were nausea (6.1%), diz-
ziness (4.6%), drowsiness (2.4%), tiredness/fatigue (2.3%),
Cancer Pain sweating (1.9%), vomiting (1.7%), and dry mouth (1.6%). These
incidences, however, varied according to administration route,
The use of tramadol in cancer pain has also been well documented. with intravenous doses producing higher incidences of side effects.
A significant amount of the literature investigating tramadol for use Adverse events published in the package insert for the sustained-
in cancer pain involves the comparison of tramadol with morphine release formulation, Ultram-ER, were from two 12-week, placebo-
and other opioids traditionally used for treatment of cancer pain. controlled studies in patients with moderate to moderately severe
Leppert and Luczak5 reviewed data from more than 10 comparative chronic pain. Events occurred more frequently than in the data
and noncomparative studies on the use of tramadol for cancer pain. published by Cossmann and associates,7 and were dose depen-
These studies suggested that tramadol is an effective analgesic for dent. The most common were dizziness (15.9%–28.2%), nausea
mild to moderate pain, with a greatly reduced side effect profile (15.1%–26.2%), constipation (12.2%–29.7%), and somnolence
compared with that of morphine. It has also been consistently noted (8.2%–20.3%). This difference may be due to duration of therapy
that the utility of tramadol is especially apparent when treating or to the more stringent conditions inherent with controlled stu-
those who were particularly sensitive to the side effects of the stron- dies. Respiratory depression, a common and potentially life-threa-
ger opioids, such as sedation, constipation, and fatigue, symptoms tening side effect of other opioids, is very rarely observed with
commonly present in patients with cancer owing to disease. tramadol. The few cases of respiratory depression reported
Morphine and the stronger opioids remain the first-line drugs to occurred after large intravenous doses or in patients with severe
treat cancer pain owing to superior analgesia. However, side effects, renal disease.
often severe with traditional opioids, are usually more frequent and The incidence of adverse effects is believed to be less common
often lead to decreases in dosage and resultant increases in pain. and those effects less severe when dosages are gradually increased. In
Tramadol, with a more attractive side effect profile and proven 2000, Pavelka8 published a schedule for tramadol dosing that he
efficacy, should be considered a first-line approach to cancer pain found effective in decreasing side effects. Patients are given 50 mg/
of mild to moderate severity. day for the first 3 days and then increased every 3 days by 50 mg
until 200 mg/day is reached. Doses of 50 to 100 mg every 4 to 6
hours as needed are allowed up to 400 mg/day. A schedule similar
Neuropathic Pain to this is also recommended by the manufacturer.
Another potentially serious complication concerns the risk of
Neuropathic pain is often the result of injury or damage to neural seizures. Medications such as TCAs, monoamine oxidase inhibitors
structures in the central and/or the peripheral nervous systems. It (MAOIs), selective serotonin uptake inhibitors (SSRIs), neurolep-
has a wide range of symptoms, typically including burning pain, tics, and opioids, which can similarly alter levels of neurotransmit-
tingling, shooting sensations, abnormal sensitivity to painless sti- ters, have been shown to increase the risk of seizure when taken
muli, and increased sensitivity to painful stimuli. It is widely with together with tramadol. A multicenter, prospective case series
believed to be the type of pain that is most refractory to treatment. by Spiller and colleagues9 reviewed reports of tramadol exposure
For reasons that remain unclear, reduction of neuropathic pain has from regional poison control centers. The lowest dose associated
been best achieved with medications such as the antiepileptics and with seizure was 500 mg, with a mean of 3.2 g. In a cohort of 9218
the TCAs. Unfortunately, optimal use of these classes of medica- adult tramadol users, fewer than 1% had a presumed incident sei-
tions is often limited by intolerable side effects, which can include zure. Risk was highest among those aged 25 to 54 years, those with
cardiac dysrhythmias resulting from increased levels of catechola- more than four tramadol prescriptions, and those with history of
mines, antimuscarinic effects, orthostatic hypotension, rapid toler- alcohol abuse, stroke, or head injury. An evaluation of a general
ance (TCAs), and central nervous system depression. Opioids, practice research database in Germany identified 21 cases of idio-
although proven efficacious for neuropathic pain at high doses, pathic seizures in 11383 subjects. Of those cases, 3 patients were
are also limited by an extensive side effect profile. exposed to tramadol, 10 to other opioids, 3 to both tramadol and
Tramadol has become an important medication in the manage- other opioids, 1 to other analgesics, and 4 to no analgesics. The risk
ment of neuropathic pain. A Cochrane Library Review published in of idiopathic seizures in these patients was similarly elevated in each
20046 examined the efficacy of tramadol in neuropathic pain tested analgesic exposure category compared with nonusers, suggesting
against placebo (three trials), clomipramine (a TCA) (one trial), that the risk for patients taking tramadol was not increased com-
and morphine (one trial). The review found that the number pared with other analgesics. In general, tramadol should be avoided
needed to treat with tramadol versus placebo was 3.5 in order to in patients with a history of seizures because increases in occurrence
achieve at least 50% pain relief. Data were insufficient to draw may follow. Caution and risk disclosure is advised when prescribing
conclusions about the effectiveness of tramadol compared with clo- to those patients with a history of substance abuse, stroke, or head
mipramine or morphine. Based on this review, the authors con- injury.
cluded that tramadol is an effective treatment for neuropathic The serotonin syndrome, characterized by clonus, hyperreflexia,
pain.6 The recommendations reflected not only an apparent efficacy hyperthermia, and agitation, is another rare but serious potential
but also a markedly reduced side effect profile compared with other complication associated with the use of tramadol when combined
treatments. with other agents that can increase central nervous system levels of
serotonin such as SSRIs and MAOIs. In a review on serotonin
syndrome, Gillman10 concluded that tramadol, which causes a
ADVERSE EFFECTS weak serotonin reuptake inhibition, may infrequently precipitate
dose-dependant serotonin toxicity (when administered in conjunc-
Much has been made about the side effect profile of tramadol tion with any type of MAOI) but perhaps only in large doses or
compared with other methods of treatment. However, as with susceptible individuals. Treatment of this condition includes med-
any drug, adverse side effects are noted with tramadol usage. In ication cessation, symptom management, and antiserotonergic
1997, Cossman and associates7 produced an extensive summary of drugs such as cyproheptadine or chlorpromazine.
Tramadol is an opioid and, thus, has the potential to be abused. the initial portion of treatment to decrease the incidence of nausea
This potential, however, is exceeding low, with estimations at 1 case and vomiting. It has been demonstrated in several studies that
per 100,000 patients. In those cases, 97% were found to occur in slower titration rates led to improved tolerance. The manufacturer’s
those patients with a prior history of substance abuse. Further evi- recommended maximum daily dose, which is much debated, is 400
dence for the low abuse potential of tramadol is provided from a mg/day. In contrast, doses up to 800 mg/day have been safely and
double-blind, placebo-controlled study in volunteers who were pre- effectively used in the treatment of cancer pain. Outside of the
vious addicts. Patients were given morphine (15 and 30 mg) and United States, tramadol has been successfully and routinely admi-
tramadol in varied doses. Morphine produced typical subjective nistered via intravenous, intramuscular, and rectal routes. It has
effects, opioid identification, and miosis. Tramadol 75 mg and also been administered, to a lesser extent, for epidural anesthesia
150 mg was no different from placebo. Tramadol at 300 mg was and as a component of peripheral regional anesthesia.
identified as an opioid but produced no other opioid-like effects. For patients with renal disease and a creatinine clearance of less
A mild abstinence syndrome similar to that seen with other opioids than 30 ml/min, a 12-hour dosing interval should be used to a
can occur with abrupt cessation, but the rate is reported as only 1 maximum of 200 mg/day, as recommended by the manufacturer.
per month per 100,000 cases and can easily be treated by reinstitu- Owing to the possibility of a prolonged elimination half-life for
tion of tramadol. patients older than 75 years of age, the maximum recommended
daily dose of tramadol in those patients is 300 mg.
Although tramadol is uncommonly used in the pediatric popu-
DRUG INTERACTIONS lation, its pharmacodynamics have been studied. After intravenous
injection of tramadol 2 mg/kg in nine children aged 1 to 7 years
Tramadol is extensively metabolized by the CYP450 system and (median 2.4), the mean plasma concentrations of tramadol and M1
may interact with medications metabolized by that same system were only slightly higher than those in adults, with no significant
(e.g., fluoxetine, sertraline, paroxitene, ranitidine, cimetidine). differences in pharmacokinetics noted from those in healthy adult
Cimetidine, a typical CYP450 enzyme inducer, can increase both volunteers.
plasma concentration and elimination half-life, but the clinical sig- The safety and dosing of tramadol in nursing and pregnant
nificance of this is unclear. Carbamazepine, a CYP3A4 inducer, has mothers have not been fully established. The U.S. Food and Drug
been shown to increase the metabolism and decrease the elimina- Administration (FDA) classifies tramadol as pregnancy risk factor
tion half-life of tramadol, thus potentially requiring dose adjust- C. Several studies, however, have been published using tramadol as
ment with concomitant use. The use of any other medication a labor analgesic that show adequate analgesia with no significant
with the potential to cause central nervous system depression neonatal respiratory depression.
with tramadol may also require dose adjustment.
CONCLUSION
DOSAGE AND ADMINISTRATION
Tramadol is a unique analgesic that has been safely used for nearly
The current recommendations for dosing from the manufacturer 30 years in many parts of the world. The synergistic and comple-
are on a conservatively slow titration schedule. It is begun with mentary mechanisms of action involving opioid receptor antago-
25 mg daily and increased every 3 days by 25 mg until 100 to nism and serotonin and norepinephrine modulation provide a
200 mg daily in divided doses is achieved. Then, tramadol may be therapeutic modality that can be useful in treating pain from a
administered 50 to 100 mg every 6 hours on an as-needed basis up broad variety of conditions. It has been used effectively for pain
to 400 mg per day. This dosing schedule requires 16 days while the relief in a multitude of disorders of both malignant and nonmalig-
schedule published by Pavelka8 requires 10 days. These dose titra- nant origin. The benefits include a much lower risk of physical
tions, although appropriate for chronic pain, may not be desirable dependence and abuse, lower incidences of respiratory depression,
for the treatment of acute pain. In the setting of acute pain, a more constipation, and sedation compared with traditional opioids and a
aggressive schedule may be needed. Oral tramadol is generally nonscheduled status allowing for less-complicated prescribing
regarded to be approximately one fourth the potency of oral practices.
morphine. Potencies compared with other opioids are listed in Despite its benefits for mild to moderate pain, tramadol may be
Table 69–2. Despite being generally well tolerated, the gastrointes- underutilized. This is likely due to undesirable side effects secondary
tinal and nervous system side effects of tramdaol are troublesome to aggressive titration schedules and fear of the severe but rare
enough for 19% to 30% of patients to discontinue therapy. Some adverse reactions such as seizures and the serotonin syndrome.
authors advocate the use of the antiemetic metoclopramide during There is also, unlike other opioids, an analgesic ceiling effect
owing to a dose-related toxicity. With both immediate-release
and sustained-release formulations available, the therapeutic
options for tramadol are more variable and may be suited to indi-
vidual patient needs. Tramadol remains a safe and effective therapy
Table 69^2. Relative Potency of Oral Tramadol
for a multitude of pain types when used in appropriate patient
Compared with Other Common populations.
Opioids
Substance Potency
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VIII
BEHAVIORAL MEDICINE
APPROACHES TO PAIN
MANAGEMENT
Chapter 70 Pain behavior: Verbal or nonverbal actions understood by obser-

vers to indicate that a person may be experiencing pain and
PSYCHOLOGICAL ASPECTS OF suffering, such as audible complaints, facial expressions, abnor-
mal postures or gait, use of prosthetic devices, avoidance of
activities, and verbal complaints of pain.
PAIN Self-efficacy: A personal conviction that one can successfully exe-
cute a course of action (i.e., perform required behaviors) to
Akiko Okifuji and Michelle Skinner produce a desired outcome in a given situation.
Coping: Ways of thinking or acting directed at resolving or miti-
gating a problematic situation.
Operant conditioning: A behavioral principle in which a likelihood
of a specific behavior recurring increases (i.e., is reinforced) if
INTRODUCTION the behavior is followed by a rewarding consequence or avoid-
ance of negative consequence. The likelihood decreases as the
Pain is a common human experience. Most pain we experience is a behavior leads to a negative consequence.
relatively minor event and generally remits without any medical
intervention or with over-the-counter analgesics. Yet, some forms
of pain require much medical attention. Some pain is associated
with specific pathology, such as cancer or tissue damages. Some EPIDEMIOLOGY
pain is persistent, failing to remit over and beyond the expected
healing period. A discussion of epidemiology for most of the psychosocial factors
Historically, the psychological factors were considered impor- does not make much sense, because those factors are not pathology
tant only if the pain was ‘‘functional’’ or ‘‘psychogenic,’’ that is, categories. We thus focus only on the prevalence of psychopathol-
the presence and extent of pain could not be explained by physical ogy in this section. Psychopathology, particularly depression and
findings. However, over the past 3 decades, research has repeatedly anxiety disorders, are quite common in chronic pain, estimated to
and consistently demonstrated that pain is not a mere sensory range from 50% to 87%1,2 with a lifetime prevalence of 32%.3 A
experience but represents a complex biopsychosocial phenomenon. recent large-scale study yielded a 35% prevalence of anxiety disor-
A range of cognitive, behavioral, and affective factors has been ders in chronic pain.4
identified as essential aspects of understanding and treating pain
patients, particularly those with chronic pain. In this chapter, we
briefly review cognitive and behavioral concepts that are known to
be significant contributors of chronic pain experience, provide an
overview of a psychological assessment of chronic pain patients, and CLINICAL FEATURES
discuss psychological treatment approaches to chronic pain.
Affective Features
TAXONOMY (DEFINITIONS) Pain is, by definition, an unpleasant experience, and thus, all
chronic pain patients are bound to experience some affective
Pain: An unpleasant sensory and emotional experience associated distress. Many, as noted previously, do meet the diagnostic criteria
with actual or potential tissue damage or described in terms of for a specific mood/anxiety disorder. Others show significant reduc-
such damage. tion in emotional resources, leading to increased irritability as well
Chronic pain: A state of pain that, in general, extends for a long as dysphoria. Many patients suffer from chronic fatigue and low
period of time and/or represents low levels of underlying pathol- energy. These features tend to lead to a further reduction in life
ogy that explain the presence and extent of pain. activities and enjoyment. Fear of reinjury or pain exacerbation is
513
514 Chapter 70 PSYCHOLOGICAL ASPECTS OF PAIN
also common; such fear often is a significant barrier for activating and disability (Table 70–1). The interview can be divided into
therapy. three parts.
Part I: History of Present Illness

Cognitive Features
Many chronic pain patients are nervous in the unfamiliar, psycho-
Patients’ attitudes, beliefs, and expectancies about various aspects of logical interview process. Starting with pain assessment in the psy-
their plight, their own coping capacity, and the health care system chological evaluation may be helpful because it breaks the ice and
influence the reports of pain, activity, disability, and response to gets them to feel comfortable. The pain assessment consists of a
treatment. Some patients consistently show maladaptive beliefs and history of the pain problem and current pain parameters (intensity,
expectations about pain that compromise their coping resources. quality, duration, aggravating and relieving factors, time course) as
Box 70–1 lists common types of maladaptive cognitions. well as relevant medical and surgical history. The patient’s func-
Maladaptive beliefs are often not based upon facts, but rather are tional levels should be assessed in multiple domains including daily
emotionally driven, leading to a sense of helplessness and low self- chores; social, recreational, and occupational activities; sleep; and
efficacy. As a consequence, many pain patients find that their ability sexual and interpersonal functioning to determine the extent of
to adaptively cope with chronic pain and disability is substantially pain interfering with them. In the process, it is also good to get a
compromised. Some patients may also exhibit a strong belief that sense of how the patient perceives her or his chronic pain and
their pain should be ‘‘cured.’’ This passive approach may be related disability, the underlying causes of pain, whether she or he
expressed as resistance to activating therapies and self-management believes adequate diagnostic work has been done, and the expecta-
skill training. tion of how her or his pain should be treated.
Part II: Psychosocial History

Behavioral Features
In this section, the patient’s background and adjustment history are
One of the common behavioral deficits in chronic pain patients is assessed to evaluate how the patient has historically coped
deactivation. Pervasive limitations in daily chores, recreational and with illness and stress and the current life resources that may
social activities, and work lead to an extremely sedentary lifestyle.
Those patients spend most of their days staying home and resting,
thereby severely restricting the opportunity to derive life enjoyment
and compromising the quality of life (QOL). Another important Table 70^1. Current Diagnosis: Psychosocial and
behavioral issue is pain behaviors. Pain behaviors are often used to Behavioral Factors Relevant to
communicate patients’ pain and distress and may become a deter- Chronic Pain
mining factor for the interpersonal dynamics in the family.
An overly solicitous environment, for example, may actually keep Symptoms/Features
the patient from engaging in tasks that could be therapeutic.
Conversely, a punishing environment in which patients’ pain beha- Affective Aspects
viors meet disapproval tends to make them feel alienated and emo- Depression Dysphoria
tionally distressed. Chronic fatigue, low motivation, lethargy
Anhedonia
Irritability
EVALUATION (HISTORY, PHYSICAL Cognitive decline (concentration, memory)
EXAMINATION, LABORATORY Social withdrawal
TESTING, AND IMAGING) Decline in self-care
Sleep disturbance (insomnia, hypersomnia)
Clinical Interview Suicidal ideation
Appetite change (anorexia, overeating, binge
The interview is critical in understanding the historical and current eating)
psychosocial and behavioral factors relevant to the patient’s pain Anxiety Panic-like symptoms: overwhelming feelings
of wanting to ‘‘get out,’’ hyperventilation,
tachycardia, shakiness, dizziness,
Box 70^1 EXAMPLES OF NEGATIVE COGNITIVE PATTERNS gastrointestinal disturbance, sweatiness
Polarizing pattern: Black-and-white thinking. If a patient’s performance Pervasive edginess
falls short of perfect, he or she sees himself or herself as a total Inability to rest and relax
failure, leading to a high expectation that is often unattainable. Avoidance of activities for fear of ‘‘reinjuring’’
Overgeneralization pattern: A patient generalizes beyond the specific or exacerbating pain
facts of a situation and sees a single negative experience as a never-
ending pattern of defeat. Hypervigilance
Catastrophizing pattern: A patient consistently assumes the worst
Cognitive Aspects
possible outcomes. Her or his understanding of her or his own plight
is extremely negative, and she or he tends to interpret relatively Negative thought patterns (see Box 70–1)
minor problems as major catastrophes. Low self-efficacy
Filtering pattern: A patient focuses upon a single negative detail, rather Passive attitude to pain management
than a whole picture, of the event and lets the single detail character-
ize the entire experience. Behavioral Aspects
Emotional reasoning pattern: A patient assumes that his or her nega-
tive emotions reflect the reality.‘‘I really feel it, therefore, this must Deactivated and sedentary lifestyle
be true.’’ Excessive pain behaviors
VIII BEHAVIOR AL MEDICINE APPROACHES TO PAIN MANAGEMENT 515
influence rehabilitation. This includes a family and personal history most potent exacerbating factors for pain, and (3) the application of
of psychiatric illness, substance abuse (including inappropriate use the specific, tangible technique often leads to a greater sense of self-
of prescribed medications), and abuse and trauma. In addition, efficacy in pain management. A variety of relaxation techniques is
education, marital and occupational history, litigation, and disabil- available, and the therapist and patient should review some techni-
ity issues are discussed. ques to determine what might work best for the particular individ-
ual. No matter which technique they decided to pursue, the main
focus should be for the patient to behaviorally manipulate the
Part III: Psychological Examination
arousal, thereby altering his or her physiological states. It is impor-
In this section, the patient’s current mental status, mood functions, tant that the patient learn to actively engage in relaxation, rather
and other maladaptive behavioral patterns are evaluated. As noted than passively listening to music or watching images. In other
earlier, mood disorders are prevalent in chronic pain patients, and it words, relaxation training should enable the person to actively
is often the case that a psychiatric illness presents a potential con- monitor and alter the physiologic state. The most commonly used
found in the interdisciplinary pain care. It is critical that the psy- physiologic avenue for relaxation includes controlling muscle ten-
chological evaluation provides a clear picture of how these factors sion, body temperature, heart rate, and sense of heaviness.
contribute to the current dysfunction of the person and guide the Another common behavioral approach is attentional training.
treatment plan as to how the process of rehabilitation will incor- Attention plays a major role in pain perception. Some pain patients
porate the relevant psychological issues. may also be attuned to any bodily sensation, leading to the ampli-
fication of pain experience. Because our attentional resource is
limited, increasing one’s attention to nonpainful stimuli should
Testing help reduce excessive attention to pain. Attentional control may
be attained via helping the patient actively engage in pain-noncom-
A wide range of self-report inventories is available to complement the patible activities. These may be overt behaviors (e.g., breathing
clinical assessment. They include questionnaires to assess pain and exercise, hobby) or covert activities such as mental imagery.
related dysfunction (e.g., McGill Pain Questionnaires,5 Multidimen- Guided imagery is not necessarily helpful to all patients; whether
sional Pain Inventories6), mood (Center for the Epidemiological imagery can successfully alter the attentional process depends upon
Depression Scale7), pain-related disability (Oswestry Disability the patient’s imaginative ability, sensory involvement, and absorp-
Index8), and health-related QOL (Short Form 36-item Medical tion in using imageries.
Outcomes Study questionnaire [SF-36]9). Most have demonstrated Stressful imageries can be used as a part of a covert behavioral
adequate psychometric properties and can be useful in evaluating rehearsal strategy. Such guided imagery requires the therapist and
the patient and monitoring the treatment progress. However, patient to create a hierarchy of stress/pain-related situations that are
it should be noted that the reliability of measures are estimated realistic enough to provoke actual anxiety responses. Then, the
in a large number of people, and the measurement errors are therapist will assist the patient in pairing each of the situations
expected to be much greater when the inventory is used on an indi- with a relaxation exercise, starting from the least difficult one.
vidual basis. Given this, it is best to use the instruments at multiple The premise of this exercise is to psychophysiologically desensitize
time points, rather than just pre- and posttreatment, to monitor the patient to the known stressful situations and to help her or him
the slope of change as an indicator of treatment progress. attain a greater managing ability over her or his anxiety responses.
As a variation, the same imageries can be used to explore various
problem-solving behaviors and help the patient to mentally rehearse
the execution of the adaptive coping.
MANAGEMENT Behavioral strategy can be used to address functional disability
of the patient. Behavioral activation has been found to be helpful in
Cognitive-Behavioral Approach patients who exhibit symptoms of depression such as inertia, social
withdrawal, and reduced activity.10 The premise for behavioral acti-
Cognitive-behavioral therapy (CBT) is widely used to treat chronic vation strategies is a learning model and suggests that people are
pain patients as a part of comprehensive pain care. The rationale actively trying to cope with overwhelming life circumstances, and
behind the approach is that (1) patients’ own appraisal of internal by coping ineffectively (e.g., activity reduction, social withdrawal),
(e.g., physiologic events) and external events significantly contri- people effectively reduce the opportunity for rewards in the envi-
butes to the sense of well-being and (2) acquisition of adequate ronment. The same premise can be applied to chronic pain patients
behavioral skills facilitates adaptive coping. whose lives are often characterized by depressive symptomatology
such as avoidance patterns of reduced social, recreational, and
employment activities. Thus, a functional analysis of behavioral
Patient Education
patterns, activity monitoring, and planned activation is often
Patient education is essential in the cognitive-behavioral approach employed for patients who have come to live sedentary lifestyles.
to pain management. Well-educated and ‘‘pain-literal’’ patients are The therapist may work in conjunction with the physical therapist
likely to become efficient in self-management for their pain. to employ a graded exercise program that includes a psychological
The education program should be developed to increase the component of charting mood and thoughts during exercise.
patient’s understanding of how the psychological and behavioral Planning goals for recreational and enjoyment activities may also
factors interact with the neurophysiology of pain, stress, mood, provide an opportunity for increased rewards in the patient’s
and sleep. In addition, knowledge related to the behavioral princi- environment.
ples, such as conditioning, reinforcement, pain/illness behaviors, A variety of other behavioral skill training can be added to meet
and how those principles interact with pain and disability, can patients’ clinical needs. For example, interpersonal stress is a major
also help patients prepare for the behavioral skill–training phase. contributor for pain flares and stress for some patients. Behavioral
techniques such as communication skill and problem-solving
training can be beneficial for these patients. In communication
Behavioral Skill^Training
skill training, patients learn their own communication style and
Relaxation and controlled breathing exercises are especially useful how it leads to certain consequences. Some patients are not accus-
for chronic pain patients because (1) most patients can readily learn tomed to express themselves effectively, often driven by overly emo-
these skills, (2) these skills are helpful in managing stress, one of the tional expression or inhibited by fear of interpersonal rejection.
516 Chapter 70 PSYCHOLOGICAL ASPECTS OF PAIN
The therapist provides a safe context in which patients can practice that are known to adversely affect the rehabilitation effort.11
adequate communication patterns. Similarly, in problem-solving Some of the common negative cognitions are listed in Box 70–1.
training, the therapist helps patients recognize optional responses, In cognitive training and restructuring, the therapist helps the
other than what they think is the ‘‘natural response’’ to stressors. patient become aware of her or his tendency to think negatively
The therapist guides the patient to define the problem and goal as about situations. The therapist then collaborates with the patient to
well as to delineate reasonable and executable options. A range of explore adaptive alternatives. This often entails examining the
options can be stratified by their desirability and feasibility; the patient’s belief about pain and stress and directly challenging long-
patient can start executing the plan from the most desirable and standing maladaptive beliefs.
feasible. The results are reviewed, and success should be reinforced.
It should be noted that there is no one way to provide behavioral
Coping
skills sets to patients. It is important to remember that behavioral
skill training is not limited to a mere application of specific Effective self-management of pain depends upon the individual’s
behavioral techniques. A wide variety of techniques are available specific ways of dealing with pain, adapting to chronic pain and
for chronic pain patients (Table 70–2). The key aspect of disability, and minimizing pain-related distress through the use of
the behavioral therapy plan is to apply the behavioral concept to coping strategies. Coping strategies can be passive (e.g., withdraw-
the idiosyncratic problems of a specific patient. The therapist must ing from activities, depending upon others for help) or active
work in conjunction with the patient to identify skill sets that work (employing a strategy to help oneself by engaging in activity and
the best for him or her. maintaining a positive frame of mind). Active coping tends to be
associated with adaptive functioning, and passive coping tends to
lead to greater pain-related disability and health care utilization in
Cognitive Skill Training
chronic pain,12 although no one particular strategy seems to work
One of the critical basics for using cognitive training for chronic on all people.13 The extent to which a patient is able to identify and
pain is to understand that one’s cognition modulates physiologic employ effective strategies depends largely on various personal (e.g.,
and emotional responses, both of which serve as impetuses for self-efficacy beliefs), situational (e.g., work, living arrangements),
behaviors. This relationship is reciprocal in that the physiologic and psychosocial factors (e.g., family history of pain, level of sup-
and emotional states can alter the cognitive process as well. port). Interaction between coping strategies and personal
As can be seen in Section VIII, Chapter 72, Cognitive Therapy for and situational factors may be a critical factor in how coping
Chronic Pain, by Dr. Wootton, the cognitive therapy is an inte- strategies are implemented. Clinicians need to understand how
grated part of the psychological approach to pain. patients interpret their world through the use of their cognitive
systems (e.g., self-talk, self-efficacy beliefs, instrumentality).
In coping skill training, self-efficacy beliefs are particularly
Cognitive Restructuring
important in treatment. Pain patients’ self-efficacy beliefs are largely
Typical cognitive training for pain management begins with helping influenced by their own past success/failure at performing tasks to
patients understand their own cognitive response system. Patients manage their pain. In the course of treatment, the patient must be
can learn to identify and monitor their thoughts triggered by pain- engaged in activities that provide experiences of success and mastery
ful or stressful situations and to understand how the thoughts lead through the patient’s effective performance. This task can be
to subsequent emotions, behaviors, and physiologic responses. accomplished by appropriately giving small and relatively easy
Particular attention should be paid to negative thought patterns behavioral tasks to complete that gradually increase in difficulty.
Early success in treatment and provision of tasks that increases
patients’ self-efficacy for pain management can increase treatment
adherence. Further, early success can help the patient to gradually
be able to cope when the demands of the situation no longer exceed
Table 70^2. Current Therapy the patient’s beliefs about his or her ability to effectively manage.
TherapyTarget Approach
FAMILY PERSPECTIVES
Depression Cognitive restructuring
Behavioral activation Chronic pain certainly affects the QOL of those who are afflicted
Anxiety Breathing exercise with persistent pain and disability. It is also common that chronic
Relaxation exercise pain adversely affects their family. Pain and distress are behaviorally
expressed. It is hard for the family to see their loved ones suffer
Imagery-guided behavioral rehearsal/
despite medications and therapies. Often not intentionally, how-
desensitization ever, patients’ communication of pain and pain behaviors is sub-
Attentional control training jected to reinforcement by the behaviors of the family members in
Maladaptive Education response. According to the operant principle, any behaviors that
Thoughts Cognitive restructuring are immediately followed by rewarding behaviors from others are
Self-efficacy Graded behavioral activation likely to recur (i.e., positive reinforcement). Similarly, behaviors
Problem-solving training that lead to avoidance of unpleasant events (i.e., negative reinforce-
Communication skill training ment) also reinforce such behaviors. Pain behaviors are no excep-
tion to this rule.
Attentional control training
Therapeutic efforts can be extended to address how the interac-
Deactivation Education tion between the patient and her or his significant other (SO) affects
Behavioral activation chronic pain. Although often well intended, the SO may reinforce
Motivation enhancement therapy pain behaviors by responding solicitously. Solicitous responses are
Pain behaviors Family education on operant learning associated with perceived support; however, they may not help
Lack of Motivation enhancement therapy patients to become active in life. Thus, it is important for the
compliance patient and SO to understand that solicitous support may present
a double-edged sword that may increase functional disability.
Helping the SO to engage in enabling behaviors requires that is heavily patient-centered. Detailed descriptions of the spe-
the clinician to address the SO’s beliefs about chronic pain, and cific MET approach are beyond the scope of this paper. Interested
the application of the CBT approaches described previously can be readers may find the comprehensive book by Miller and Rollnick15
helpful. It is also helpful to include the SO in setting treatment goals helpful.
and encouraging the SO to participate in behavioral rehearsal of
coping skills. The activation plan may work more effectively if
activities that they can engage in together are included. In addition, COMPLICATIONS/OUTCOMES
the sessions for both the patient and the SO can address effective
communication by helping them increase straightforward language A large volume of studies has been published reporting on the
and requests for support rather than relying on behaviors as cues efficacy of CBT for chronic pain. Typically, CBT is incorporated
and assuming what the patient is trying to communicate. The inclu- into a multidisciplinary pain care program. Outcomes on measures
sion of the SO in these particular aspects of treatment has been of pain reduction, improved mood, medication adjustment, health
shown to increase patient levels of self-efficacy for pain manage- care utilization, increased activity, and return to work—multidisci-
ment and perceived ability to control pain and to decrease plinary programs that include CBT—have been shown to be highly
pain-catastrophizing thinking.14 Further, these benefits appear to effective, yet there is very little, if any, concern for iatrogenic
be maintained for up to a year after treatment. complications.16 Moreover, when the results have been evaluated
to determine the cost-effectiveness, multidisciplinary programs that
incorporate CBT can save a significant amount of money in medical
MOTIVATIONAL INTERVENTION expenditures and indemnity costs.17
Motivation is an essential aspect of self-management therapies,

because adherence to a daily activating regimen is required for suc- CONCLUSIONS
cessful rehabilitation for chronic pain. Historically, noncompliant
patients are considered as failing to respond to treatment. However, In this chapter, we reviewed the psychological approaches to the
as we are faced with greater needs to manage chronic illnesses, the assessment and treatment of chronic pain. Research in the past 3
issue of how motivation can be addressed through the therapeutic decades has delineated a range of psychosocial and behavioral fac-
process has become of great importance. tors relevant to chronic pain and related disability. The application
Motivation enhancement therapy (MET) is a problem-focused, of CBT and MET that targets to those relevant psychological factors
therapist-directed approach aiming to help patients enhance their has been consistently shown to help patients better manage pain,
readiness to commit and engage in activating self-management. mood, and function, particularly as an integrated part of a com-
The basic aims of MET are to help patients (1) identify the discrep- prehensive pain rehabilitation program.
ancy between what they want (goals) and where they are (current Although we focused in this chapter on the role of psychological
status), (2) delineate how the discrepancy can be reduced, factors in chronic pain, we believe that these same factors may play
(3) understand the cost-benefit ratio of engaging (and not enga- a role in acute pain states as well. We believe that medical, psycho-
ging) in adaptive and maladaptive behaviors, and (4) internalize social, and behavioral factors are all important in the experience
motivational thoughts via improved self-efficacy. of pain per se. The relative weight of these factors may vary, however,
In order to achieve MET goals, clinicians engage in empathetic with medical factors making a larger contribution in acute pain states
listening, reflecting patients’ negative emotion in a nonjudgmental than in chronic pain states and psychological factors making a
manner. Rather than telling patients what to do or what not to do, more significant contribution in chronic pain than in acute pain.
clinicians need to ‘‘roll with resistance.’’ One of the easy pitfalls we In each of these instances, however, attention should be given
all fall into is to press on with what we consider as adaptive coping to the range of factors that contribute to the total experience of pain.
and activation while patients resist and present why they should not
engage in those activities. Efforts should be made to form a thera-
peutic alliance by staying on the same side of the argument, which is REFERENCES
critical to increase patients’ motivation to change.
1. Katon W. The epidemiology of depression in medical care. Int
As a part of the MET process, the clinician helps patients to J Psychiatry Med 1987;17:93–112.
identify specific discrepancies between their treatment goals 2. Romano JM, Turner JA. Chronic pain and depression: does the
(e.g., ‘‘I want to play golf’’) and what they actually do (e.g., ‘‘I evidence support a relationship? Psychol Bull 1985;97:18–34.
don’t exercise because I am afraid it may flare my pain’’). By focus- 3. Atkinson JH, Slater MA, Patterson TL, et al. Prevalence, onset, and
ing on the discrepancy, patients gain insight that their maladaptive risk of psychiatric disorders in men with chronic low back pain:
behaviors and attitudes are actually preventing them from obtaining a controlled study. Pain 1991;45:111–121.
their goals. Similarly, patients benefit greatly from engaging in 4. McWilliams LA, Cox BJ, Enns MW. Mood and anxiety disorders
‘‘decisional balance analysis’’ of their own behaviors. For example, associated with chronic pain: an examination in a nationally
patients list a ‘‘benefit’’ for regular exercise as well as for not exer- representative sample. Pain 2003;106:127–133.
5. Melzack R. The McGill Pain Questionnaire: major properties and
cising and a ‘‘cost’’ for exercising as well as for not exercising. These scoring methods. Pain 1975;1:277–299.
can be incorporated into the discussion of the discrepancy between 6. Kerns RD, Turk DC, Rudy TE. The West Haven-Yale
the patient’s goals and actions. The decisional balance analysis helps Multidimensional Pain Inventory (WHYMPI). Pain 1985;23:345–356.
patients gain a better awareness of their own role in maintaining 7. Radloff L. A self-report depression scale for research in the general
maladaptive behaviors as well as identifying strategies to engage in population. Appl Psychol Meas 1977;1:385–392.
more adaptive behaviors. 8. Fairbank JC, Couper J, Davies JB, O’Brien JP. The Oswestry low back
Another essential feature of MET is to provide a supportive pain disability questionnaire. Physiotherapy 1980;66:271–273.
environment to nurture a sense of self-efficacy and, ultimately, 9. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health
a patient’s ability to change her or his behaviors. By understanding survey (SF-36). I. Conceptual framework and item selection. Med
Care 1992;30:473–483.
that change is a process that the patient has control over, she or he 10. Jacobon N, Martell C, Dimidjian S. Behavioral activation for
realizes that change is possible. With increased self-efficacy beliefs depressions: returning to contextual roots. Clin Psychol Res Pract
come a sense of responsibility and an awareness that it is the 2001;8:255–271.
patients themselves who will choose to engage in therapeutic 11. Cook AJ, Degood DE. The cognitive risk profile for pain:
efforts and execute them. MET is a clinician-directed approach development of a self-report inventory for identifying beliefs and
518 Chapter 71 HYPNOTIC ANALGESIA
attitudes that interfere with pain management. Clin J Pain 15. Miller W, Rollnick S. Motivational Interviewing: Preparing People for
2006;22:332–345. Change. New York: Guilford, 1991.
12. Blyth FM, March LM, Nicholas MK, Cousins MJ. Self-management of 16. Flor H, Turk DC, Rudy TE. Relationship of pain impact and
chronic pain: a population-based study. Pain 2005;113:285–292. significant other reinforcement of pain behaviors: the mediating
13. Fernandez E, Turk DC. The utility of cognitive coping strategies for role of gender, marital status and marital satisfaction. Pain 1989;
altering pain perception: a meta-analysis. Pain 1989;38:123–135. 38:45–50.
14. Flor H, Fydrich T, Turk DC. Efficacy of multidisciplinary pain 17. Okifuji A. Interdisciplinary pain management with pain patients:
treatment centers: a meta-analytic review. Pain 1992;49:221–230. evidence for its effectiveness. Semin Pain Med 2003;1:110–119.
Chapter 71 Association agreed with the BMA in a report published in 1958

by the Council on Mental Health,12 which stated that there are
HYPNOTIC ANALGESIA ‘‘definite and proper uses of hypnosis in medical and dental prac-
tice’’ and recommended the establishment of training facilities in
Lisa J. Norelli the United States. In 1961, the American Psychiatric Association
issued a position statement confirming that hypnosis has definite
clinical applications across different medical fields.13 Two years
later, the American Psychological Association endorsed hypnother-
apy as a branch of psychology. In 1996, a National Institutes of
Health panel14 issued a statement indicating that there was strong
evidence for the use of hypnosis in alleviating chronic pain associ-
INTRODUCTION ated with cancer and other chronic pain conditions. Despite grow-
ing evidence, the routine inclusion of hypnosis in the medical
For thousands of years, the significance of the mind-body connec- armamentarium against pain has been sporadic.
tion in health and disease has been recognized by many healing
systems. Hippocrates acknowledged the importance of emotional
and spiritual attitude on health, and central to his medical practice DEFINITIONS
was the notion that the body has the power to heal itself.1 In more
contemporary times, the predominance (and, some would argue, Broadly defined, hypnosis is an induced state of passive, selective
overreliance upon) technological approaches has skewed modern attention often attained through the use of relaxation and imagery
medical practice toward less humanistic treatment methods at the techniques. During the induction phase of a session, patients are
expense of a holistic approach to health and wellness. With the guided into a state of mental (and often physical) ease, along with
recent rediscovery of the importance of the mind-body connection, sustained focus on an object or mental image of attention. Through
alternative and complementary treatments are the subject of the induction process of relaxation and selective focus, the patient
increasing study and integration into medical practice. becomes absorbed in her or his inner experiences and, with practice,
Hypnosis, one example of the mind-body healing approach, has develops a state of passive attention and reduced range of attention
been used successfully in the treatment of many medical conditions to the environment. This state of mind contributes to a decreased
and particularly in the management of acute and chronic pain.2 monitoring of the environment and the blocking out of some per-
Hypnotic analgesia during and after medical procedures has been ceptual experiences. If the induction process is successful, the
shown to result in significant cost savings, decreased pain severity, patient accepts suggestions without censorship and, thus, is more
and a reduction in the required dose and duration of pain medica- receptive to verbal and nonverbal communications (suggestions)
tions.3 Despite demonstrated effectiveness in a wide variety of without reflection. For pain, the hypnotic suggestions would be
clinical pain scenarios and at virtually no risk to the patient, hyp- tailored to alter the person’s perception of or behavioral response
nosis has been used infrequently compared with other behavioral to the painful sensations. For example, one could suggest a lack of
interventions.4 For over a hundred years, hypnosis practice and sensation or that the painful sensation will be experienced as only
training has been endorsed by the medical establishment, yet it is warmth or coolness.15 Participation in a series of hypnosis sessions
not uniformly available in clinical settings. In the United States, can reinforce the suggestions and teach methods for sustaining the
this is partly a reflection of the inconsistent availability of hyp- analgesic effects. If possible, patients are taught to master the tech-
nosis training opportunities in psychology and medical education niques and use self-hypnosis for pain control independent of formal
programs.5,6 sessions. With regular practice, many patients become adept at self-
In the late 18th century, Franz Anton Mesmer proposed the idea hypnosis. Repetition and self-hypnosis have been shown to enhance
that universal fluid energy mediated hypnotic phenomena. analgesic effects and impart a greater sense of self-agency and mas-
Mesmer’s theory was scientifically discredited, and it was not tery over pain management.16
until nearly a century later that the concept of medical hypnosis
was officially accepted.7,8 The practice of medical hypnosis
reemerged in the 1840s, revitalized by the scientific and clinical MECHANISM OF ACTION
observations of Scottish physician James Braid.9 In 1892, a com-
mittee commissioned by the British Medical Association (BMA) Pain is a complex phenomenon incorporating sensory and affective
investigated the science and practice of hypnosis and found it effec- dimensions. The sensory features of pain (e.g., intensity, temporal
tive for, among other things, relieving pain.10 The BMA reiterated pattern, quality) and the affective features (e.g., attention, expecta-
its approval of medical hypnosis in 1955.11 The American Medical tion, emotional response) are interrelated via spinal pathways and
attitudes that interfere with pain management. Clin J Pain 15. Miller W, Rollnick S. Motivational Interviewing: Preparing People for
2006;22:332–345. Change. New York: Guilford, 1991.
12. Blyth FM, March LM, Nicholas MK, Cousins MJ. Self-management of 16. Flor H, Turk DC, Rudy TE. Relationship of pain impact and
chronic pain: a population-based study. Pain 2005;113:285–292. significant other reinforcement of pain behaviors: the mediating
13. Fernandez E, Turk DC. The utility of cognitive coping strategies for role of gender, marital status and marital satisfaction. Pain 1989;
altering pain perception: a meta-analysis. Pain 1989;38:123–135. 38:45–50.
14. Flor H, Fydrich T, Turk DC. Efficacy of multidisciplinary pain 17. Okifuji A. Interdisciplinary pain management with pain patients:
treatment centers: a meta-analytic review. Pain 1992;49:221–230. evidence for its effectiveness. Semin Pain Med 2003;1:110–119.
Chapter 71 Association agreed with the BMA in a report published in 1958

by the Council on Mental Health,12 which stated that there are
HYPNOTIC ANALGESIA ‘‘definite and proper uses of hypnosis in medical and dental prac-
tice’’ and recommended the establishment of training facilities in
Lisa J. Norelli the United States. In 1961, the American Psychiatric Association
issued a position statement confirming that hypnosis has definite
clinical applications across different medical fields.13 Two years
later, the American Psychological Association endorsed hypnother-
apy as a branch of psychology. In 1996, a National Institutes of
Health panel14 issued a statement indicating that there was strong
evidence for the use of hypnosis in alleviating chronic pain associ-
INTRODUCTION ated with cancer and other chronic pain conditions. Despite grow-
ing evidence, the routine inclusion of hypnosis in the medical
For thousands of years, the significance of the mind-body connec- armamentarium against pain has been sporadic.
tion in health and disease has been recognized by many healing
systems. Hippocrates acknowledged the importance of emotional
and spiritual attitude on health, and central to his medical practice DEFINITIONS
was the notion that the body has the power to heal itself.1 In more
contemporary times, the predominance (and, some would argue, Broadly defined, hypnosis is an induced state of passive, selective
overreliance upon) technological approaches has skewed modern attention often attained through the use of relaxation and imagery
medical practice toward less humanistic treatment methods at the techniques. During the induction phase of a session, patients are
expense of a holistic approach to health and wellness. With the guided into a state of mental (and often physical) ease, along with
recent rediscovery of the importance of the mind-body connection, sustained focus on an object or mental image of attention. Through
alternative and complementary treatments are the subject of the induction process of relaxation and selective focus, the patient
increasing study and integration into medical practice. becomes absorbed in her or his inner experiences and, with practice,
Hypnosis, one example of the mind-body healing approach, has develops a state of passive attention and reduced range of attention
been used successfully in the treatment of many medical conditions to the environment. This state of mind contributes to a decreased
and particularly in the management of acute and chronic pain.2 monitoring of the environment and the blocking out of some per-
Hypnotic analgesia during and after medical procedures has been ceptual experiences. If the induction process is successful, the
shown to result in significant cost savings, decreased pain severity, patient accepts suggestions without censorship and, thus, is more
and a reduction in the required dose and duration of pain medica- receptive to verbal and nonverbal communications (suggestions)
tions.3 Despite demonstrated effectiveness in a wide variety of without reflection. For pain, the hypnotic suggestions would be
clinical pain scenarios and at virtually no risk to the patient, hyp- tailored to alter the person’s perception of or behavioral response
nosis has been used infrequently compared with other behavioral to the painful sensations. For example, one could suggest a lack of
interventions.4 For over a hundred years, hypnosis practice and sensation or that the painful sensation will be experienced as only
training has been endorsed by the medical establishment, yet it is warmth or coolness.15 Participation in a series of hypnosis sessions
not uniformly available in clinical settings. In the United States, can reinforce the suggestions and teach methods for sustaining the
this is partly a reflection of the inconsistent availability of hyp- analgesic effects. If possible, patients are taught to master the tech-
nosis training opportunities in psychology and medical education niques and use self-hypnosis for pain control independent of formal
programs.5,6 sessions. With regular practice, many patients become adept at self-
In the late 18th century, Franz Anton Mesmer proposed the idea hypnosis. Repetition and self-hypnosis have been shown to enhance
that universal fluid energy mediated hypnotic phenomena. analgesic effects and impart a greater sense of self-agency and mas-
Mesmer’s theory was scientifically discredited, and it was not tery over pain management.16
until nearly a century later that the concept of medical hypnosis
was officially accepted.7,8 The practice of medical hypnosis
reemerged in the 1840s, revitalized by the scientific and clinical MECHANISM OF ACTION
observations of Scottish physician James Braid.9 In 1892, a com-
mittee commissioned by the British Medical Association (BMA) Pain is a complex phenomenon incorporating sensory and affective
investigated the science and practice of hypnosis and found it effec- dimensions. The sensory features of pain (e.g., intensity, temporal
tive for, among other things, relieving pain.10 The BMA reiterated pattern, quality) and the affective features (e.g., attention, expecta-
its approval of medical hypnosis in 1955.11 The American Medical tion, emotional response) are interrelated via spinal pathways and
central brain regions. Painful stimuli ascend spinal pathways to the had decreased procedural pain and less anxiety compared with
ventral thalamus, somatosensory cortex (SSC) and the corticolimbic women who received treatment as usual or an empathetic interven-
system (anterior cingulate cortex [ACC], insula). These systems are tion.40 In another study, patients undergoing invasive renal and
involved in emotional response and cognitive mediation of pain. vascular procedures who employed self-hypnosis not only had less
Other spinal pathways project to the amygdala, hypothalamus, pain and anxiety but also were more hemodynamically stable than
reticular formation, medial thalamus, and limbic structures. These patients who received standard treatment or more directed atten-
are involved in arousal, autonomic regulation, and affective tion.41 Hypnosis has also shown benefit in the treatment and man-
response to pain. Hypnotic analgesia is associated with changes in agement of chronic pain, for example, pain arising from malignancy
the neural activity in many of these known pain pathways, including or burn wounds.44–46 When offered, hypnosis is usually provided
higher-order central mechanisms that modulate pain through cog- along with cognitive-behavioral or psychotherapeutic techniques to
nitive factors such as anticipation and attention.17,18 First, it has holistically address other issues associated with pain such as depres-
been demonstrated that hypnosis promotes relaxation, known to sion, secondary gain, and social and functional withdrawal.16
decrease anxiety and increase the pain threshold. Second, it alters
the perception of pain, decreasing unpleasantness. Third, it distracts
from pain by reducing the attention paid to the painful sensation COMPLICATIONS
and focusing attention elsewhere.16,19,20
The accumulating data from physiologic, imaging, and psycho- Hypnosis is a safe and well-tolerated intervention that can be used
logical research has illuminated a more comprehensive neuropsy- in a wide variety of clinical pain situations in both children and
chophysiologic picture of hypnotic analgesia. An integrative model adults. Uncommonly, there are negative effects. MacHovec47
asserts that hypnosis is a state of sustained attention that activates defines hypnosis complications as ‘‘unexpected, unwanted
the cortical and subcortical brain dynamics.21 In hypnotic analgesia, thoughts, feelings or behaviors during or after hypnosis which are
research has shown that the process requires sustained effort and inconsistent with the goals of treatment and interfere with the hyp-
activates specific attentional and inhibitory feedback circuits that notic process by impairing optimal mental function.’’ Untoward
modulate thalamic and cortical areas involved in pain.22,23 Kiernan reactions are typically mild and transient such as nausea, dizziness,
and coworkers24 have provided research evidence in support of at and headaches; rarely, there have been reports of panic or difficul-
least three underlying mechanisms responsible for hypnotic analge- ties awakening from hypnosis.48,49 Negative effects have been attrib-
sia: spinal cord nociceptive reflex attenuation, reduction in aware- uted to failure of technique, failure of the hypnotist to adequately
ness (perceived intensity) of pain, and the selective reduction in prepare the patient, and undetected preexisting severe psychopa-
the affective component (unpleasantness) of pain sensation. thology or personality factors. These potential problems can be
Research employing functional testing has helped to localize the minimized by careful patient screening, appropriate hypnotist
effects of hypnotic analgesia in specific brain regions. training, and careful attention to the treatment environment. It is
Electroencephalographic studies have demonstrated enhanced ante- recommended that the hypnotist monitor the patient’s reactions
rior temporal theta activity during hypnotic analgesia.21–23 In addi- during and after the treatment to detect and obviate negative
tion, functional magnetic resonance imaging and positron-emission reactions.50,51
tomography studies have demonstrated that modulation of differ-
ent pain attributes s associated with specific changes in cortical
activity associated with hypnosis. In these studies, modulation of CONCLUSIONS
pain unpleasantness was associated with changes in the ACC,
whereas changes in pain intensity were associated with primary Hypnotic analgesia is an effective, safe, noninvasive intervention for
SSC activity.25–28 the reduction of the sensory and affective components of acute and
chronic pain. The intervention has been used successfully in both
children and adults. It should have a wider, complementary role
CLINICAL APPLICATIONS in the treatment and management of acute and chronic pain within
medical settings. It may be a preferred treatment modality in
Hypnosis has been used successfully as a primary and an adjunc- patients for whom pain medications are poorly tolerated or pose
tive treatment modality for both acute and chronic pain in chil- a high risk of side effects. Those patients at higher risk of untoward
dren and adults.29–31 One meta-analysis of 18 studies confirmed a side effects, such as children and elderly, are particularly likely to
moderate to large hypnoanalgesic effect size.32 Given its demon- benefit from nonpharmacologic approaches to pain. Patients with
strated effectiveness, it can be argued that hypnotic analgesia pain should have access to an integrative medical and psychological
should be routinely available for an integrated biopsychological approach. This strategy would not only include analgesic medica-
approach to clinical pain. When compared with other psycholog- tion but also incorporate psychological interventions such as
ical interventions, hypnosis has been found to be equally or more hypnosis, cognitive-behavioral techniques, psychotherapy, and
effective.33,34 The main factor that influences the effectiveness of relaxation. Hypnosis training programs should be offered routinely
hypnotic analgesia is hypnotizability or hypnotic susceptibility. during the education of physicians, psychologists, and other health
Despite this observation, some clinical studies suggest that even professionals to foster more widespread availability of expertise in
low-hypnotizable patients can achieve some pain relief with hyp- this modality across clinical treatment settings.
nosis. These findings include increased pain threshold with
repeated suggestions of analgesia and increased pain threshold
and pain tolerance with ongoing skills training.16 Several instru-
Key Points
ments have been developed to assess a patient’s hypnotizability,
although in practice, many clinical hypnotists rely instead on indi- n Clinicians should approach the patient with clinical pain holi-
vidual assessment of responsiveness in the context of the treatment stically, integrating both medical and psychological ‘‘mind-
interaction.35–37 body’’ interventions.
Hypnotic analgesia has demonstrated efficacy in ameliorating n Hypnotic analgesia is a safe, well-tolerated intervention for a
acute pain, for example, during dental procedures,38 biopsies, wide array of acute and chronic pain situations.
other invasive medical procedures,39–41 and labor and delivery.42,43 n This modality can be effective for a range of patients, from
A prospective, randomized study of women undergoing large-core children to adults, including those who are less receptive to
breast biopsy showed those patients using self-hypnosis techniques hypnosis.
n Hypnosis has been shown to reduce the severity of anxiety and 24. Kiernan BD, Dane JR, Phillips LH, Price DD. Hypnotic analgesia
suffering associated with pain, increase pain tolerance, and reduced R-III nociceptive reflex: further evidence concerning the
reduce the use of pain medication. multifactorial nature of hypnotic analgesia. Pain 1995;60:39–47.
n Hypnotic analgesia modulates pain via central and peripheral 25. Rainville P. Pain affect encoded in human anterior cingulate but not
pain pathways and decreases the intensity and unpleasantness somatosensory cortex. Science 1997;277:968–971.
26. Hofbauer RK, Rainville P, Duncan GH, Bushnell MC. Cortical
of pain. representation of the sensory dimension of pain. J Neurophysiol
2001;86:402–411.
27. Faymonville ME, Laureys S, Degueldre C, et al. Neural mechanisms of
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Chapter 72 empathic appreciation for the patient’s dilemma but focused, not
on sympathizing with the patient’s feelings, but rather on addres-
COGNITIVE THERAPY FOR sing his thoughts and beliefs:
Jonathan, it has taken you a long time to reach this point of
CHRONIC PAIN frustration and grief, and it will take some time to begin to turn
back from it, but that is exactly what I and your other providers
Joshua Wootton and Chris Warfield here are dedicated to helping you do. I would like you to meet
with our psychologist—not because I believe your pain is in
your head but rather because I see first-hand the terrible toll
your pain has taken and how it has led you to believe there is no
hope for you. We believe that, if we ignore this part of your pain,
we are simply giving in to it.
INTRODUCTION
Reassured that his pain physician would continue to move
Although pain may not be psychological in origin, how we respond ahead with attempts to provide medical treatment, the patient—
to it is. The quality, intensity, and duration of pain are influenced nevertheless, with some apprehension—arranged for a first
by a host of psychosocial factors; and while these may not have appointment with the pain psychologist, a cognitive therapist.
arisen in the context of pain, they are no less consequential than
the actual or potential tissue damage that gave rise to pain in the
first place. By the time pain has become chronic, it represents the THE BASIS OF COGNITIVE THERAPY
product of conflict between the original sensory stimulus and the
whole person. As pain interferes with one’s work and livelihood, It is a natural and understandable human tendency for family mem-
recreational pursuits, relationships with family and friends, and bers, friends, colleagues, and even medical providers to sympathize
even sexual intimacy and spiritual expression, it can come to be a with the patient in chronic pain, echoing his or her feelings and
powerful influence on self-esteem and the ways in which one views allowing themselves to feel, in some measure, the emotional distress
oneself as a man or woman, husband or wife, father or mother, of the patient. Even many approaches to psychotherapy—including
friend, citizen, and spiritual being. psychoanalytic psychotherapy and many other forms of insight-
Chronic pain will always require some level of adaptation and oriented and supportive treatment—concentrate on the primacy of
adjustment from those who experience it, but the intrusion of emotions as the path to healing and adjustment. The principal argu-
chronic pain is frequently accompanied by obstacles to this process ments against taking this tack with patients in chronic pain are that
of adjustment that make the experience a complex, subjective phe- (1) these approaches are typically long-term and may require many
nomenon, uniquely molded by the environment and the indivi- months, if not years, to result in meaningful insight and progress,
dual’s personality, characteristic strategies for coping, and core (2) they may lead the patient to an uncritical acceptance of his or
beliefs about herself or himself and the world. Consider the patient her feelings, further entrenching the negative emotions associated
in the following case study. with his or her maladaptive response to pain, and (3) the principal
obstacles to successful adjustment to chronic pain can usually
be more fairly characterized as cognitions, not emotions.
Case Study In the 1960s, the type of psychotherapy known as cognitive ther-
apy was developed by the psychologist Aaron Beck, who believed
Jonathan, a 40-year-old married man with two adolescent children, there is a quicker path toward achieving results in the treatment of
was referred to the pain-management center, 14 months after a certain psychological problems than the often laborious and pains-
work-related injury to his lower spine. His pain had remained taking examination and interpretation of the largely unconscious
intractable to multiple surgical interventions, medications, and basis of conflicts and drives. Beck based his approach on the obser-
physical therapy and, if anything, had become more severe over vation that how we think (cognition), how we feel (emotion), and
time. His physicians supported his claim to disability, but his how we act (behavior) are all inseparably bound and interrelated
Workman’s Compensation carrier’s independent medical examiner and that it is our thoughts that influence and often determine our
insisted that he could return to work. Imagining his previously feelings and actions. In other words, negative and unrealistic think-
comfortable life and hopes for the future slipping away, he turned ing is behind much of our distress and maladaptive behavior. In
from those whom he believed he was disappointing and began to Jonathan’s case, then, his thoughts, images, and beliefs about his not
seek solace in the abuse of alcohol and prescription medications. being able to provide for his family gave rise to his distress and led
Withdrawn, irritable, and depressed, he described a household to the maladaptive responses—self-medication, defensive outbursts,
dominated by marital discord and complained that his children and social withdrawal—that only further entrenched his pain and
no longer respected him. In the middle of his examination, he the myriad psychosocial stressors now associated with it.
broke down, becoming tearful and sobbing, ‘‘I’m never going to In the cognitive model of chronic pain, negative cognitions aris-
get better . . .. There’s nothing I can do to help myself. . .. I can’t take ing within the context of the unremitting sensory stimulus of pain
care of my family. . .. I’m a complete failure.’’ exert a correspondingly negative influence on emotions, behaviors,
and reciprocally, even the perception of pain. The negative
It is at this point that many pain physicians and other medical thoughts, images, and beliefs developing as a result can, therefore,
providers experience the helplessness and hopelessness of their maintain or even exacerbate the experience of pain by promoting
chronic pain patients most intensely. We ourselves can easily musculoskeletal tension and autonomic arousal. In the face of sus-
feel overwhelmed in the face of such profound despair. In tained or escalating pain, the resulting negative thinking can also
Jonathan’s case, his pain physician showed an appropriately lead to changes in mood states—anxiety and depression—as well as
522 Chapter 72 COGNITIVE THER APY FOR CHRONIC PAIN
self-defeating behaviors often associated with chronic pain and dis- (4) intermittent refresher or booster sessions are sometimes offered
ability. The picture of chronic pain portrayed in Jonathan’s case is at longer intervals—3 to 5 months—to ensure that patients remain
one of agitated and anxious depression in which a patient has on track with their cognitive skills.
turned for consolation to behaviors that, in the end, can only
worsen his problems and make his situation more dire.
When the signal of pain is processed and interpreted in the Intake and the Introduction to
brain, certain thoughts and images become activated in the soma- the Stress-Pain Cycle
tosensory cortex, and certain emotions are cued in the limbic struc-
tures. When Jonathan, for example, rises from his bed in the During the intake, the cognitive therapist attempts to assess the
morning, he experiences a sharp, lancinating sensation in his background of the patient’s chronic pain, along with the range of
lower back and legs. Emotionally, he experiences frustration and associated stressors—personal, family, social, and occupational—
helplessness, while he thinks, ‘‘This is ridiculous. I can’t even get now impinging on the patient’s life. Some of these stressors may
out of bed without hurting myself. How can I ever work or live my be longstanding and premorbid to her or his pain, but others will
life like this?’’ As his experience of pain becomes more generalized, have developed out of the experience of chronic pain. In either case,
he develops persistent images of himself as disabled; and these stress can render pain less tractable to treatment and introduce
thoughts, in turn, begin to modulate his every signal of pain nega- exacerbations and still other complications and sources of stress.
tively, intensifying his frustration and helplessness and leading to For this reason, the discussion during the intake, as well as during
depression and generalized anxiety. Recent functional magnetic res- the first few sessions of therapy, will often focus on the patient’s
onance imaging (fMRI) studies suggest that the maintenance of characteristic strategies, both conscious and unconscious, for
negative cognitions and their emotional burden can even amplify addressing and responding to the stressors in her or his life.
pain signals—in effect, altering the neurologic circuitry associated
with the experience of pain. In this way, maladaptive patterns of
responding to pain can become firmly entrenched over time, unless Case Study
the negative cognitions behind them are addressed. At least one
study suggests that cognitive therapy might be further refined and Ellen, a 32-year-old single woman was referred to the pain-manage-
improved through real-time monitoring of fMRI patterns. ment center, 1 year after the development of chronic daily headache
In cognitive therapy, patients are led to examine whether, in the with migrainous features. Her headaches had become progressively
process of trying to make sense of their pain and what is happening worse, despite multiple trials of medications and physical therapy,
in their lives as a result of pain, they may be making fundamental and once or twice a week, she was forced to spend several hours in a
errors in their thinking and relying upon or developing mistaken quiet, darkened room to manage her pain and nausea. She had
beliefs. Jonathan had concluded that life, for him, was essentially continued to work as an administrative assistant and editor-
over—that he was only a burden to his family and could no longer in-training at a publishing firm but now faced the possibility of
hope for satisfying and meaningful relationships, pursuits, or goals. losing her ‘‘dream job’’ because of absenteeism. Fearing that she
His cognitive therapist’s task is first to help him identify the would soon ‘‘lose everything,’’ the patient began to overuse her
thoughts and beliefs that led him to this conclusion, to examine medication in anticipation of developing a headache, ultimately
critically their value and veracity, and to assist him in restructuring leading her to double and triple her prescribed dosages once she
his thinking to admit and consider all the possibilities and choices inevitably developed headache pain. She arrived at the pain center,
he may actually have within his grasp. desperate for a new medication or new treatment that would allow
Of course, some of the patient’s negative thoughts and beliefs her to function at her workplace and pursue her career.
may be accurate. He may never, for example, be able to resume his
amateur golfing career or even play pick-up basketball on the play- Here, recognizing and learning about the stress-pain cycle
ground with his children. Here, the aim of therapy would be to help become paramount to the success of the treatment. Once the
the patient identify the negative generalization—that he can never patient acknowledges that stress can play a role in the experience
again enjoy sports or time with his children—and offer new solu- of pain—and that pain itself can become a major stressor—the way
tions—that he can still enjoy other recreational endeavors and still is opened to an examination of what can be done to correct and
have fun and satisfying time with his family through other pursuits. ameliorate this cycle.
He may not be able to return to his old job, but he may still remain In the case of Ellen, a number of stressors appeared to trigger her
active and, if he chooses, pursue other professional or occupational headache pain; and chronic headache pain itself became a source of
directions and goals. stress that precipitated further headaches. Just thinking about her
busy schedule would lead the patient to become anxious and ask
herself, ‘‘But what if I get a headache and can’t do everything that
OUTLINE OF TREATMENT IN needs to get done?’’ This anxiety would result in her becoming
COGNITIVE THERAPY overly vigilant to the physical and situational cues of her pain,
often leading her, in turn, to take medication at the first sign of
Cognitive therapy is structurally flexible and can be refined and trouble or even in anticipation of her pain. Her situation progres-
individualized to meet a particular patient’s or group of patients’ sively worsened with the overuse of her medications and the even-
needs. In most cases, however, the approach to treatment in the tual development of rebound headaches.
context of chronic pain will include (1) an individual intake
during which a thorough anamnesis is recorded and the patient’s
history of coping with stress and pain is examined, followed by (2) Identifying AutomaticThoughts and Core Beliefs
typically 8 to 12 sessions or modules of individual or group ther-
apy, progressively building toward (3) a final session or termina- During the 8 to 12 sessions or modules of treatment, the therapist’s
tion, during which the goals are reviewed and the patient’s goal is to assist the patient toward an understanding that situations
progress is consolidated. The therapy sessions are often divided are ordinarily neutral, until we interpret or assign meaning to them.
into an examination phase, during which patients identify and Typically, a portion of each session will be devoted to identifying
learn to self-monitor their negative cognitions, and a cognitive and examining the automatic thoughts and core beliefs that influ-
restructuring phase, during which they learn to restructure ence patients’ interpretation of their experience. We are often una-
their thinking toward more adaptive cognitive coping. In addition, ware of this step of assigning meaning because we do not usually
stop to examine the thoughts and beliefs that give rise to our emo- not bad now, and I can continue working, while I see what hap-
tional responses to certain situations—and, even when we do, we pens.’’ With this simple cognitive restructuring, the patient was able
may not consider the accuracy of these thoughts and beliefs. to remain at work and actually miss far fewer days accommodating
The essence of the cognitive model of treatment suggests that to her pain. Ellen’s anxiety—expressed in the fear, ‘‘What if I get a
much of our emotional distress and self-defeating behavior is headache?’’—became a more rational and adaptive response: ‘‘Well,
simply based upon inaccurate thinking and that, once our attention if I do, I’ll wait and see what happens. If it’s not bad, I can continue
is drawn to the relationship between our distress and these upset- working. If it becomes severe and I have to leave, I’ll take some
ting thoughts and beliefs, we can test their value and veracity to see work home, in case it improves, and shuffle my priorities on tomor-
whether they form an appropriate basis for our emotions and row’s schedule.’’ Within a few weeks, she was reporting that her
actions or reactions. If not, then changing our thinking to corre- pain seemed more manageable; she was using less medication, and
spond more accurately with reality may result in a change in mood she was clearly less distressed and overwhelmed.
and behavior, as well as in the perception of pain itself. Addressing patients’ automatic thoughts is critical to assisting
In the case of Ellen, several automatic thoughts appeared to them with the management of their pain, but their core beliefs are
predominate in her interpretation of her experience. Whenever typically more influential where their motivation, identity, and self-
she felt the first twinge of pain, she would immediately think, esteem are concerned. In Ellen’s case, her idea that she was weak
‘‘Oh, no, here it comes again! The rest of the day is ruined!’’ and undeserving quickly allowed the negative event of the develop-
A variation of this occurred whenever she faced a particularly chal- ment of her headaches to be interpreted and supported by an image
lenging or packed daily schedule. Just looking at her daily calendar of herself that was vulnerable and impaired. All too quickly, it made
would lead her to think, ‘‘What if I get a headache? I’ll never be able sense to her that her pain would become overwhelming and that she
to do my job!’’ All too often, her perception of her pain would would ‘‘lose everything’’—her ‘‘dream job’’ and her hopes for suc-
quickly move from just noticeable all the way to unbearable, leading cess. Patients often face greater difficulty addressing the core beliefs
her to flee her office in tears after only an hour or two in the supporting their pain and disability precisely because these beliefs
morning. Her pattern of overusing her medications would continue are fundamental to their self-image and their view of the world. Not
to escalate, and her mounting dissatisfaction with her physicians’ all core beliefs are negative, but those that are dysfunctional can
solutions would propel her to renew her search for a doctor who quickly become the foundation of a patient’s view of himself or
could ‘‘fix’’ her. herself as impaired or disabled.
Such automatic thinking is associated with escalating pain and In Ellen’s case, once the dysfunctional core belief was identified,
emotional distress, the overuse of medication, and as the pattern her therapist gently encouraged her to examine the evidence for and
spirals out of control, with greater functional impairment and dis- against it. Although she could point to a deteriorating pattern in
ability. In Ellen’s case, however, certain core beliefs tended to com- her life, since the onset of her headaches, she acknowledged that she
plicate her situation even further. These underlying views and had successfully completed school, landed a good job, and subse-
attitudes about herself left her even more vulnerable to the trigger- quently been promoted to her current position, all because of her
ing events of her pain and provided a platform for her maladaptive talent and hard work. In fact, when she examined her situation
automatic thinking. As a child, she had had often endured the anger carefully, she could see that, not only had she worked hard, but
and impatience of a mother who, herself, was overburdened and she had also overcome much adversity in her struggle to succeed—
often overwhelmed with her responsibilities. Ellen grew up with the an achievement that, she agreed, did not sound reminiscent of
idea that she could never be strong enough or competent enough to weakness at all. As her pain became better managed through the
negotiate life successfully and that she was therefore weak and cognitive restructuring of her maladaptive automatic thoughts, she
undeserving. For the patient, her pain and visions of impending began to see herself not as weak and undeserving but as strong and
failure were simply expressions of this deeply held core belief that empowered—a woman who can succeed despite obstacles and
she could never succeed, and her inability to control or manage her setbacks.
pain was further proof of her weakness and the belief that she did
not deserve a challenging, responsible job.
Final Session and Intermittent Refreshers
Cognitive Restructuring: Constructing During the final session, the therapist’s work is to review and rein-
Alternative Responses force what the patient has learned during the course of treatment
and to emphasize that the newly acquired cognitive skills—identify-
Once patients have become mindful of the stress-pain cycle and ing, evaluating, and challenging automatic thoughts and core beliefs
once the automatic thoughts and core beliefs that influence the and constructing more realistic and adaptive alternatives—must
cycle have been identified, then challenging those thoughts and continually be applied, even after the work of formal therapy is
beliefs and constructing alternative responses becomes the focus concluded. Not to do so risks returning to the role of ‘‘chronic
of treatment. Where automatic thoughts are concerned, the thera- pain patient’’ and surrendering to disability. The irony is that
pist often assists patients with the construction of a list of facts patients who accept their pain as chronic—along with the implied
supporting and refuting each thought in order to reveal the distor- limitations—tend to have lower levels of perceived pain, less distress
tion involved and open the door to considering a more realistic and depression, and higher levels of functioning than those who
alternative. In Ellen’s case, her therapist encouraged her to examine remain focused on finding a cure or being rescued by a new medical
the evidence for and against her thinking. Did the first hint of pain approach. ‘‘Chronic pain patients’’ typically find the limitations of
actually mean that her day was ruined where work was concerned? their pain to be intolerable and the emotional burden of their pain,
Her evidence that the thought was true depended upon her percep- unbearable; whereas patients who accept their pain take satisfaction
tion of a consistency that, when she evaluated her situation, turned in negotiating their limitations and pacing their activities, enabling
out not to be true. a higher quality of life.
Her headaches varied considerably—sometimes severe but just Refresher sessions may be offered individually or in small groups
as frequently, quite mild—and she realized that she usually assumed to support the ongoing cognitive work of the patient and to rein-
the worst, leaving her office, when her pain was sometimes still force the self-help perspective of this approach to treatment.
quite manageable. Constructing an alternative to her previously Usually offered at 1-, 3-, and 6-month intervals, refresher sessions
maladaptive automatic thought led the patient to evaluate her sit- are intended to consolidate the gains of the formal therapy, while
uation more realistically. ‘‘I seem to be getting a headache, but it’s providing assistance with the development of ongoing self-help
524 Chapter 72 COGNITIVE THER APY FOR CHRONIC PAIN
plans. In the case of group cognitive therapy, members of the group with the patient can also serve as a useful reminder that, in a multi-
sometimes agree to continue meeting monthly without the therapist disciplinary approach to care, everyone is focused on the goal of
to support each other in their individual efforts at addressing stress recovery. Asking, for example, ‘‘Would you mind if I shared that
and pain. In individual treatment, the therapist must remain avail- with your doctor?’’ can pave the way for an interdisciplinary under-
able for refresher sessions, especially in the first few months after the standing of the patient’s situation that can prove critical to well-
original course of treatment, to ensure that patients’ cognitive skills managed and successful care.
remain sharp and their motivation high.
Individual versus GroupTreatment

MILIEUAND MODE IN COGNITIVE
THERAPY While no significant differences in outcome and effectiveness have
been found between individual and group cognitive therapy, several
There is a broad array of selection criteria that psychotherapists basic impediments may rule out some patients for group cognitive
must consider when evaluating patients for cognitive therapy. therapy and pose certain obstacles even for individual cognitive
These include both the intrinsic impediments and resistances treatment. Because the critical feature of cognitive therapy is psy-
toward this form of treatment and the indications of which choeducational, much depends upon the individual patient’s
milieu and mode of therapy—clinic-based or private, group or background with and attitudes toward this approach. Below-
individual—is likely to promote the greatest chance of success. average intelligence, deficits in education, and lack of facility with
Every psychotherapist who is regularly engaged in offering group spoken or written English may suggest that certain patients can
therapy, for example, has had the experience of particular patients easily feel overwhelmed in a group environment and become
derailing or redirecting the attention and work of the group to quickly discouraged. For these patients, a more tailored approach
address their own idiosyncratic needs or to conform to their own is required to meet their individual needs and to ensure that they
maladaptive defensive strategies. Even highly skilled group thera- are not awash or lost in the group dynamic. Similarly, certain highly
pists have seen how the dynamic of a group can begin to shift to sensitive patients who tend to resist personal disclosure may find
support the pathology its members, rather than to encourage them that a group environment poses too many risks and dangers to their
to progress toward more adaptive and better-adjusted perspectives. sense of privacy and personal integrity.
Many physicians and psychotherapists have also encountered fail- Still others with rigid or primitive personality structures may
ures in treatment that have resulted from poor communication or find a group dynamic too threatening, unless it conforms to their
even lack of communication between providers. In the treatment of own cognitive distortions and meets their extraordinary needs for
chronic pain, the physician’s or psychotherapist’s lament, ‘‘I wish unqualified acceptance. Because one of the characteristic features of
I’d known that sooner,’’ often foreshadows a less than optimal end. the cognitive approach to treatment is to challenge patients’ inter-
pretations of events and question their appraisals, thoughts, and
beliefs about their pain, the sometimes arduous work of treatment
Clinic-based versus Private Milieu is usually best approached in an atmosphere in which they can feel
less threatened and more accommodated and reassured by the psy-
For some patients, dividing their treatment among several provi- chotherapist’s individual attention. Some attention, too, must be
ders—even a highly coordinated multidisciplinary team—can lead given to an assessment of each patient’s readiness for change,
to a confusion of boundaries. Psychotherapists are frequently asked according to the transtheoretical model. Patients who come to
highly technical questions regarding medical and surgical interven- treatment with a passive attitude—‘‘You’re the doctor; you fix
tions; while physicians, nurses, and physical therapists sometimes me!’’—are often unwilling to consider an active role for themselves
become important confidants regarding patients’ personal lives and in their own treatment and recovery. When patients remain uncon-
even their appraisals of their progress in psychotherapy. Generally vinced that anything they can do will make a difference to their
speaking, the greater the geographic distance between providers, the experience of pain, then the remedial step of encouraging a more
greater the challenges become to maintaining an interdisciplinary empowered and collaborative relationship with their medical pro-
understanding of the patient’s individual needs and responses to viders becomes a necessary preliminary intervention.
treatment. A multidisciplinary pain center, in which the providers
remain in close proximity, tends to foster a setting in which patients
and can feel reassured that critical and appropriate information is EFFICACYOF COGNITIVE THERAPY
freely shared and that a comfortably collaborative perspective on
treatment is maintained. There is considerable evidence in the literature of psychological and
This does not mean that, in situations in which outside and medical research that cognitive therapy is an effective approach to
private referrals for particular treatments are necessary or more the management of chronic pain. Many studies of this form of
expedient, patient care need be compromised. However, it does therapy support its supplementary and complementary roles as a
suggest that frequent communication and consultation among all multidisciplinary intervention, when undertaken with pharmaco-
providers may prove essential to quality of care. Patients may be logic and other medical interventions and physical therapies. One
sensitive to sharing some disclosures with all their providers, so difficulty in establishing a more central role for cognitive therapy is
negotiating what to share and how to share it may become critical that it is typically combined in empirical research with behavioral
to the success of the multidisciplinary enterprise. When a patient techniques, such as relaxation skills and behavioral pacing techni-
asks a psychotherapist for specifically medical information or for a ques, and studied as cognitive-behavioral treatment. In a variety of
medical opinion, not only is it important to consider why the psy- settings, cognitive-behavioral therapy and behavioral therapy,
chotherapist is being asked, but it may also prove most helpful to when combined with other treatments in a multidisciplinary
respond, ‘‘That’s a good question. Shall we ask your doctor?’’ or approach, have been shown to be more efficacious than unimodal
even ‘‘Would you ask you doctor and let me know what she says?’’ medical treatment or no treatment. In direct comparisons, cogni-
Similarly, when personal and psychosocial revelations are presented tive-behavioral treatment was shown to be just as effective, and in
to the physician or nurse, responding, ‘‘I didn’t realize that. Are you some studies, more effective than behavioral therapy alone.
and your psychotherapist working on that?’’ reminds the patient of Problems emerge with drawing more generalizable conclusions
the need to be forthcoming in the milieu of psychotherapy. Taking because of variability across studies as to what is considered a
the further step of negotiating consultation between providers specifically cognitive intervention and what is a behavioral
intervention. There is the further difficulty that the term cognitive McCracken LM, Turk DC. Behavioral and cognitive-behavioral treatment
therapy embraces a variety of specific techniques, not all of which for chronic pain. Spine 2002;27:2564–2573.
are utilized or combined in every study. The broadest application of Morley S, Eccleston C, Williams A. Systematic review and meta-analysis
cognitive therapy would include not only cognitive restructuring, or of randomized controlled trials of cognitive behaviour therapy and
behaviour therapy for chronic pain in adults, excluding headache. Pain
the identification and modification of maladaptive cognitions, but
1999;80:1–13.
training in cognitive coping skills as well, which would include Prochaska JO, Norcross JC, DiClemente CC. Changing for Good.
distraction techniques, positive self-statements, and imaging or New York: William Morrow, 1994.
visualization techniques. In the most empirically rigorous research Thorn BE. Cognitive Therapy for Chronic Pain. New York: Guilford,
to date, cognitive restructuring leading to positive changes in cog- 2004.
nitions was demonstrated to occur prior to reductions in emotional Turk DS. Cognitive-behavioral approach to the treatment of chronic pain
distress and the perception of pain, suggesting that cognitive ther- patients. Reg Anesth Pain Med 2003;28:573–579.
apy can lead to improved pain management. Turner-Stokes L, Erkeller-Yuksel F, Miles A, et al. Outpatient cognitive-
behavioral pain management programs: a randomized comparison of a
group-based multidisciplinary versus an individual therapy model. Arch
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Vlaeyen JWS, Morley S. Cognitive behavioral treatments for chronic pain:
Burns JW, Kubilus A, Bruehl S, et al. Do changes in cognitive factors what works for whom? Clin J Pain 2005;21:1–8.
influence outcome following multidisciplinary treatment for chronic Winterowd C, Beck AT, Gruener D. Cognitive Therapy with Chronic Pain
pain? A cross-lagged panel analysis. J Consult Clin Psychol Patients. New York: Springer, 2003.
2003;71:81–91. Wootton RJ, Caudill-Slosberg MA, Frank JB. Psychotherapeutic
Caudill M. Managing Pain Before It Manages You, rev. ed. New York: management of chronic pain. In Warfield CA, Bajwa ZH (eds):
Guilford, 2002. Principles and Practice of Pain Medicine. 2nd ed. New York:
deCharms RC, Maeda F, Glover GH, et al. Control over brain activation McGraw-Hill, 2004; pp 157–169.
and pain learned by using real-time functional MRI. Proc Natl Acad Sci
U S A 2005;102:18626–18631.
IX
PHYSICAL MEDICINE
APPROACHES TO PAIN
MANAGEMENT
Chapter 73 the patient is managed through a patient-centered, multidisciplin-

ary approach in which the specialists of various disciplines (e.g.,
PHYSICAL MEDICINE physician, occupational therapist [OT] and physical therapist
[PT], psychologist, nurse, social worker) contribute their expertise
to an ongoing patient’s care.2
APPROACHES TO PAIN This chapter provides a description of acute and chronic pain
syndromes together with a discussion of the basic framework of
MANAGEMENT approaching pain conditions from a global physiatric standpoint.
The basic concepts of obtaining a functional history and assessing
Steven Stanos, Mila Mogilevsky, Lynn Rader, gait pattern, posture, strength, and balance (as it relates to a painful
condition) are explained. Various assessment techniques and treat-
James McLean, and Allison Baum ment strategies are discussed. Finally, the role of each member of
the interdisciplinary team is highlighted.
PAIN: GENERAL CONSIDERATIONS

INTRODUCTION The International Association for the Study of Pain (IASP)
describes pain as ‘‘an unpleasant sensory and emotional experience
Physical medicine and rehabilitation, also referred as physiatry or associated with actual or potential tissue damage, or described in
rehabilitation medicine, is a discipline concerned with the evalua- terms of such damage.’’
tion, treatment, and coordination of care for persons with multiple
musculoskeletal injuries, pain syndromes, and/or other physical and
cognitive impairment and disabilities. The primary focus is on max- Differences between Acute and Chronic Pain
imal restoration of physical and psychological function and on alle-
viation of pain (adapted from definitions by the American Board of Pain is usually described as acute or chronic. The distinction
Medical Specialties and the American Board of Physical Medicine between the two types of pain has to do with the duration of
and Rehabilitation). symptoms as well as the physiologic response of the person
The physiatric model of care and, in particular, pain manage- (Table 73–1).
ment is based on fundamental understanding of the individuals’
unique conditions as it relates to the concept of impairment, dis-
Acute Pain Syndromes and Their Management
ability and handicap.1
In acute pain syndrome, the experience of pain is often directly
Impairment is the loss or abnormality from psychological, phy-
related to an underlying tissue injury. For example, an acute episode
siologic, and functional perspectives that results from acquir-
of low back pain may be due to a herniated lumbar disk. Receptors
ing a painful condition.
in the annulus fibrosis of the disk and surrounding neural tissue
Disability is a restriction and/or lack of ability to perform activ-
transmit signals to the dorsal horn, where the signal is modulated.3
ities owing to an impairment (e.g., pain).
The signal then ascends to higher brain levels, where the multi-
Handicap is a disadvantage that an individual possesses due to
dimensional experience of pain is perceived.4 In treating such
the impairment and disability that affects his or her role in
patients, the medical rehabilitation team focuses on acute symp-
society.
tomatic improvement, promotion of the healing process, and
Physical medicine and rehabilitation (physiatry) offers a unique patient education. For patients with an acute herniated disk, the
approach to pain management in which the treatment is focused on initial management may include several days of relative rest, ice, and
a whole patient rather than an isolated painful condition. As such, anti-inflammatory medications. Bracing, corticosteroid injections,
527
528 Chapter 73 PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT
Table 73^1. Differences between Acute and Chronic THE ROLE OF THE PHYSICIAN
Pain
The first role of the physician in the management of a patient with
Acute Pain Chronic Pain pain is to establish a complete and accurate diagnostic assessment
and determine and coordinate other specialists involved in the
Elicited by immediate tissue Persists after tissue injury has patient’s case. Arriving at the specific diagnosis involves a complete
injury resolved or healed history, a comprehensive physical assessment, and appropriate use
Serves as a ‘‘warning’’ of tissue Serves no obvious useful of laboratory and diagnostic tests. Once a diagnosis is reached, the
damage or injury; protective function physician will develop a comprehensive plan of care, which will
of further injury include short- and long-term goals, pharmacologic interventions,
Activates nociceptors Involves central sensitization physical and occupational therapy, cognitive and behavioral treat-
ments, vocational rehabilitation, and patient education.
and permanent structural
abnormalities of the central
nervous system
Physiatric Assessment
Activates sympathetic nervous Physiologic adaptation
system The diverse nature of any pain condition requires a comprehensive
Limits duration Prolonged duration assessment in order to design a tailored treatment plan. Identifying
Remits with resolution and Persists long after resolution the onset of pain, understanding the mechanism of injury, and
analyzing pain-related functional changes are the main components
healing of injury and healing of injury
of physiatric assessment. The analysis of function and the goal set-
Directly associated with injury, Remotely associates with ting can vary dramatically based on the patient’s functional expec-
postoperative conditions, and injury, trauma, or surgical tations. For example, a treatment plan for a marathon runner may
disease processes procedures focus entirely on returning the athlete to a previous level of com-
Responds to treatment Resistant to treatment petitive running. Conversely, a 70-year-old sedentary woman with a
thoracic compression fracture might best benefit from the activities
Adapted from Twanddle M, Cooke K. Assessment of pain and common that focus on negotiating basic daily living tasks (e.g., dressing,
pain syndromes. In Van Roenn JH, Price JA, Preodor ME (eds): Currrent hygiene, and meal preparation). Often, a functional assessment
Diagnosis and Treatment of Pain. New York: Lange/McGraw-Hill, 2006. will be performed before and after therapy sessions to determine
the level of patient’s progress. The Functional Independent Measure
and therapeutic modalities such as ultrasound/electrical stimulation (FIM) scores, although commonly used in the acute inpatient reha-
can be used to reduce inflammation and muscle spasm in selected bilitation arena, can be applied to stratify the level of function with
patients. As the patient’s symptoms gradually improve, normaliza- various activities of daily living (Box 73–2).
tion of range of motion and emphasizing postures that will unload A physiatrist musculoskeletal examination comprises a complete
the herniated disk are taught. Finally, common biomechanical examination of the pain area including bony structures, cartilages,
impairments, such as weakness in core musculature (e.g., abdom- joints, ligaments, tendons, bursae, nerves, and skin. Equally impor-
inals, gluteus muscle groups), lower limb contracture (e.g., hip, tant is a more global evaluation of posture, core strength, balance,
hamstring), and poor lifting techniques, will be the focus of physical and gait (Box 73–3). Performing a proficient physical examination
and occupational therapy. At the conclusion of treatment, the is a fundamental part of identifying pain generators, diagnosing and
patient will be given recommendations about exercises and lifestyle identifying potential areas of dysfunction, narrowing the clinical
modifications. differential diagnosis, and establishing a rational treatment plan.
Chronic Pain Syndromes and Their Management Posture and Postural Abnormalities
Multidisciplinary and interdisciplinary functional restoration pro- Posture is defined as the position of the body at one point in time
grams based on cognitive and behavioral principles and active phys- and is influenced by each of the joints of the body. Proper posture is
ical and occupational therapy have been increasingly used in the
treatment of chronic pain. A biopsychosocial focus is an important
part of the assessment and ongoing treatment program. The colla-
borative rehabilitation team typically comprises a physiatrist or pain Box 73^2 LEVELS OF FUNCTIONAL INDEPENDENCE BY THE
medicine specialist; PTs, OTs, and recreation therapists (RTs); pain FUNCTIONAL INDEPENDENCE MEASURE
psychologists; relaxation therapists; social workers; vocational
counselors; and nurse educators (Box 73–1).
Box 73^1 MEMBERS OF A COMPREHENSIVE

MULTIDISCIPLINARY PAIN TREATMENT TEAM
Physiatrist (or pain specialist)
Physical therapist
Occupational therapist
Pain psychologist
Biofeedback and relaxation training specialist
Therapeutic recreation therapist
Social worker
Vocational counselor
Nurse facilitator/educator
From Stanos S. Developing an interdisciplinary multidisciplinary chronic pain management From Ottenbacher KJ,Christiansen C: Occupational performance assessment. In Christiansen C,
program: nuts and bolts. In Schutman M, Campbell A (eds): Chronic Pain Management: Baum C (eds): Occupational Therapy Enabling Function and Well-being, 2nd ed. Thorofare,
Guidelines for Multidisciplinary Program Development. New York: Informa Healthcare, 2007. NJ: Slack,1997.
IX PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT 529
composed predominantly of slow-twitch muscle fibers, which

Box 73^3 COMPONENTS OF PHYSIATRIST ASSESSMENT help control segmental motion and maintain the mechanical stiff-
ness of the spine.
Pain behavior, affect
Posture
Motor strength and muscle firing patterns Balance and Stability
Balance
Range of motion A concept closely related to core strength is balance and stability.
Core assessment Patient with weak core musculature will often demonstrate weak-
Gait assessment ness in that area. These deficits may lead to increased stress in other
parts of the body and an increased risk of injury. Tissue injury may
in turn lead to more core weakness and the vicious circle will be
established. Bermark7 studied patients with low back pain and
achieved when the body is aligned in such a way that the least demonstrated decreased core strength and postural stability com-
amount of stress and muscle activation is possible. In standing, pared with those without low back pain.
normal posture includes a mild cervical and lumbar lordosis and Balance can be assessed and described as static or dynamic. Static
a thoracic kyphosis. Posture should be observed directly (physical balance is assessed in the sitting or standing position without intro-
examination) and indirectly during the patient interview. One may ducing external perturbations. The patient is asked to perform
assess for shoulder height asymmetry (as it relates to a limb dom- simple activities such as sitting or standing without support. If
inance), head position, positioning of the pelvis (resting position of the task is achieved without difficulty, he or she may be asked to
the iliac crests), and positioning of the feet (flat or arched midfoot, stand on one leg. Further assessment involves asking the patient to
internally or externally rotated in relation to the tibia). It is impor- close his or her eyes, reach across the room, or catch a ball while
tant to evaluate the patient in her or his normal sitting position. standing on one leg. The amount of sway and degree of pain during
Poor sitting posture may place excessive strain on multiple struc- the maneuver is noted, as well as the utilization of compensatory
tures including soft tissues; cervical, thoracic, and lumbar spine; movements during the task. Dynamic balance involves maintaining
intervertebral disks; and facet joints.5 the center of mass over the base of support when the base of sup-
port is moving (i.e., sitting on an exercise ball) or external pertuba-
tions are applied.8
Range of Motion, Muscle Strength, and Muscle Imbalances
Active and passive range of motion should be assessed for each joint
Gait Assessment
(painful joints should be assessed last). The examiner should note
general hyper- or hypomobility of the joint, side-to-side differences Normal gait may be described in two phases and seven parameters
in range of motion, and movements that result in pain. The findings (Box 73–5).9 Understanding the normal gait cycle helps the physi-
of range of motion testing combined with manual muscle testing cian to identify gait deviations that are seen in common pathologic
may lead to objective findings of muscle imbalances around the conditions. In normal individuals, the stance phase (foot on the
joint. This concept has been described by Jull and Janda6 as the ground) represents 60% of the gait cycle, whereas the swing phase
upper crossed and pelvic crossed syndromes. An upper crossed represents 40% of the gait cycle. The notion of an antalgic gait
syndrome is characterized by tight upper postural muscles (pector- commonly refers to shortening of one cycle and lengthening of
alis major and upper trapezius) and lengthened phasic muscles the other. On the affected, painful side, less time is spent in
(rhomboids and serratus anterior, middle and lower trapezius). the stance phase and more in the swing phase. The opposite is
Motor strength assessment is based on the Canadian classification true for the contralateral side that tends to compensate for the
system in which the strength of a limb is analyzed on a scale of 0 to involved extremity. Thus, when assessing the painful side, particular
5, where 0 is the absence of any visible muscle activity and 5 is attention should be paid to the ‘‘uninvolved’’ hip, knee, and ankle
normal strength, comparable with the strength of the examiner because these joints may become problematic in the future.
(Box 73–4). Gait can be assessed when the patient first enters the examina-
tion room. This ‘‘quick scan’’ allows the examiner to form a general
impression of the patient’s gait while assessing for pain behaviors.
Core Strength Evaluation
The examiner should note the positions of the head, shoulders, and
The core is often visualized as a box with the abdominal muscles pelvis during the gait. Observation of arm swing, foot strike, and
in the front, the diaphragm as the roof, and the pelvic floor and foot clearance should be done, assessing for inconsistencies. Special
hip muscles at the bottom. It includes more than 20 pairs of mus- attention should be paid to compensatory patterns of movements,
cle groups that stabilize spinal structures and the pelvis and coor-
dinate movements during the functional tasks such as bending,
lifting, and squatting. The outer, more superficial group of muscles
is composed primarily of fast-twitch fibers, which are capable
Box 73^5 PHASES OF GAIT AND GAIT PARAMETERS
of producing large torque forces, greater speed, and larger areas Phases of Gait
of motion. The deeper muscles lay closer to the spine and are Stance: 60% of the walking cycle; shortened on the painful side
Swing: 40% of the walking cycle; lengthened of the painful side
Important Parameters of Gait
Box 73^4 MOTOR STRENGTH: MANUAL MUSCLE TESTING Width of support: Distance between feet; normally 2^ 4 inches; larger
when pathology of the dorsal columns or an ataxic gait is present;
assess for peripheral neuropathic conditions, vitamin B12 deficiency
Stride length: Distance between sequential corresponding points of con-
tact by the same foot, normally 30 inches
Step length: Shortened on the pain-free side
Pelvic and trunk rotation: Helps to elongate the leg, increasing step length
and stride length
Cadence: Number of steps per minute, normally 100 steps/min
Center of gravity: 2 inches anterior to the second sacral vertebra
From Cutter NC, Kevorkian CG. Handbook of Manual MuscleTesting. New York: McGraw-Hill, From Esquenazi A, Talaty M. Gait analysis: technology and clinical applications. In Braddom RL
1999. (ed): Physical Medicine and Rehabilitation, 3rd ed. Philadelphia: Saunders, Elsevier, 2007; pp 93-110.
such as leaning to one side, circumducting a leg, or holding an arm Table 73^2. Rehabilitation Professionals and Their
in a protective manner Areas of Expertise
Kinetic Chain
After the completion of musculoskeletal assessment, having a firm
understanding of the kinetic chain helps the clinician to summarize
all the findings, interpret the patient’s deficits, and develop a com-
prehensive treatment plan. The kinetic chain concept is based on the
fundamental premises that for functional movement in place, each
link of the body must move in a coordinated pattern. The sequence
of the links and the interrelationship of muscle activation and trans-
lation of forces within the body are referred to as a kinetic chain.10
Each link of the system creates a force and energy that is transferred
from the proximal core-stabilizing link to the distal peripheral link.
Distal links, in turn, will compensate for the proximal link, and the
added stresses and loads will result in further injury. For instance, if
the patient develops a painful hip, the knee will have to absorb more
forces during the gait. If the patient also has a tendency to over-
pronate (flat-foot position) the foot, the forces at the knee are fur-
ther increased. This malalignment of the foot may lead to changes at
the knee, such as excessive patellofemoral joint pressures (knee joint
degeneration and narrowing) and abnormal patellar tracking.
Hence, proper rehabilitation of the patellofemoral joint pain must
address factors along the kinetic chain, that is, proximal to the knee
(pain control of the hip and strengthening of the hip abductors,
extensors, and quadriceps muscles) and more distally (correcting
pronated positioning and strengthening intrinsic muscle strength
and balance at the ankle).11
THE ROLE OF THERAPISTS

From Stanos SP, Tyburski M: Rehabilitation issues: Pain control. In Von
PTs and OTs Roenn JH, Paice JA, Preodor ME (eds): Current Diagnosis and Treatment
of Pain. New York: Lange/McGraw Hill, 2006.
PTs and OTs are an important part of the treatment team. PTs and
OTs utilize therapeutic exercise, physical modalities, and manual
techniques to improve pain control and optimize flexibility,
strength, and endurance of the patient. In addition, they are respon-
sible for ongoing reevaluation and modification of the treatment TREATMENT
program set up at the initial evaluation. Whereas there are simila-
rities between these fields, there are also some differences in the Therapeutic Exercise
treatment approach that PTs and OTs use that make their contri-
bution both different and complementary to each other (Table Therapeutic exercise is the systematic implementation of planned
73–2). Traditionally, PTs are trained to focus more on the areas physical movements, postures, or activities designed to (1) remedi-
of impairment (such as weakness, pain, poor balance, and gait ate or prevent impairments; (2) enhance function; and (3) enhance
difficulties), whereas OTs deal more with the disability issues fitness and well-being.12
(e.g., manufacturing a splint, ordering home equipment, designing Therapeutic exercise has traditionally been a cornerstone form
an ergonomically favorable environment, educating a patient). In of therapy utilized by PTs and OTs (Table 73–3). It is prescribed in
the environment of interdisciplinary patient management, however, the treatment of a variety of clinical conditions and in pain manage-
those boundaries are often blurred, and it is not unusual to see ment, in particular. The principle behind the utilization of exercise
either of these disciplines using manual therapy, working on trans- in pain management is based on the fact that dynamic exercise
fers, or educating a patient on proper lifting techniques. promotes acute physiologic adjustments in most bodily systems.13
Collectively, these adjustments increase the availability of oxygen
and nutrients to the active muscle cells and remove metabolic by-
RTs products, such as carbon dioxide, heat, and lactic acid. The optimal
body function is maintained in the appropriate milieu (pH, body
RTs play an invaluable role in managing patients with more com- fluid, temperature), thus facilitating the healing process. The type,
plex rehabilitation and chronic pain syndromes. An RT assessment frequency, and duration of exercise are often based on the pain
examines the patient’s previous interests, hobbies, and leisure pur- etiology, coexisting medical conditions, and the degree of antici-
suits. It helps the patient to identify barriers to returning to these pated physical stress. For example, a patient suffering from an
activities and, ultimately, aids her or him to reincorporate enjoyable acute rheumatoid arthritis exacerbation may be started on non–
activities into her or his life. RTs help to establish and incorporate weight-bearing, low-impact, and short-duration activities designed
strategies learned from various disciplines of multidisciplinary to optimize movement and flexibility and minimize joint stress.
treatment into social and community functions. Conversely, an athlete presenting with a limited painful knee
Table 73^3. General Components of Therapeutic such as central pain, cancer pain, and human immunodeficiency
Exercise virus/acquired immunodeficiency syndrome (HIV/AIDS) pain
symptoms is promising.
In addition to offering pain relief, therapeutic exercise affects
Active range of Patient moves extremity through arc of
other areas of physiologic adaptation such as
motion motion
Designed to promote joint flexibility and n Blood pressure.
strength. n Muscle strength.
n Aerobic capacity.
Passive range of Therapist moves patient’s extremity
n Hormonal adaptation.
motion through arc of motion n Pain threshold.
Designed to maintain/improve joint
flexibility
Stretching Done actively and passively; designed to Blood Pressure Regulation
improve range of motion A meta-analysis of aerobic exercise training studies demonstrated
Isometric exercises Muscle is contracted without change in an average decrease in systolic and diastolic blood pressures of
length 7 and 6 mm Hg, respectively, in those patients with hypertension
Designed to maintain/improve muscle and 3 and 2 mm Hg in systolic and diastolic pressures, respectively,
strength in acute pain states and in those with normal blood pressure with aerobic training.17
inflammation
Isotonic exercises Muscle is contracted through the Muscle Strength
available range while the load remains
Therapeutic exercises involving resistance training have been shown
the same; designed to improve muscle to cause muscle enlargement leading to an increase in muscle
strength within an available range strength. Muscle fiber hypertrophy is believed to occur through
Isokinetic Muscle is contracted through a constant remodeling of the muscle fiber protein and an increase in the size
exercises angular velocity; designed to improve and number of myofibrils.18
muscle power; essential for fast In addition, muscle hyperplasia has been speculated to be a
repetitive activities possible adaptive strategy in resistance training. However, the
Endurance Performance of repetitive contractions extent of hyperplasia and the exact mechanism of its development
remain the subjects of an ongoing debate.19
training with incremental increases of duration
of exercise; designed to improve
aerobic capacity and long-term Aerobic Capacity
performance Therapeutic exercise is known to have a direct impact on the
Motor Introduced and utilized in conjunction increase in aerobic capacity. Among other factors that affect max-
reeducation with other forms of exercise; designed imum oxygen consumption (VO2max [an index of aerobic capa-
for postural retraining and changing city]), are maximal heart rate, gender, and stroke volume. Body
maladaptive patterns developed as a composition changes associated with loss of physical activity are
result of painful condition found to be detrimental in worsening of aerobic capacity. A sys-
tematic review of six randomized clinical trials using aerobic con-
ditioning exercises, such as stationary bicycling, walking, or aquatic
exercise, in deconditioned patients with rheumatoid arthritis con-
ducted by the Cochrane Group concluded that therapeutic condi-
movement due to recent knee arthroscopy will be offered aggressive tioning exercises were effective in improving aerobic capacity,
active stretching exercises with dynamic strengthening activities and muscle strength, and joint mobility. An estimated average increase
balance training. In each case, the exercise regimen will be adjusted of VO2max with traditional aerobic training program is known to be
and modified as the patient progresses through the different stages 15% to 20%.20
of healing.
In addition to its direct impact on pain management, therapeu-
Hormonal Adaptation
tic rehabilitation is unique in its ability to provide a patient with
tools to be used outside of a therapy office. As part of therapeutic It has been speculated that the endocrine system plays a major role
management, the patient is frequently given a home exercise pro- in the adaptational responses of skeletal muscle to exercise (resis-
gram that he or she is expected to perform. This form of therapy is tance training). Staron and colleagues21 found elevated levels of
designed to give the individual a sense of responsibility, thus testosterone concentration within 6 weeks of heavy-resistance train-
enabling him or her to take an active role in management of his ing among men and women. Testosterone has been found to be
or her own disease. directly involved in stimulating protein synthesis (via alternation of
Besides its physiologic effects on actively contracting muscles, myosin adenosine triphosphatase [ATPase] activity), which leads to
therapeutic exercise offers additional mechanisms for controlling muscle enlargement and hypertrophy with a concomitant increase
pain symptoms via increasing the levels of endogenous endorphins in muscle strength and exercise performance.21
and enkephalins.14,15
Similarly to many psychostimulant agents, an acute bout of
PainThreshold
active aerobic exercise and chronic aerobic exercise training has
been found to increase the dopamine brain concentration in rats The nociceptive nerve endings that are found in skin, joints, mus-
by as much as 80%.16 cles, bone make up an intricate network of pain perception con-
Although the research in humans is currently at its initial stages, trolled by the human central nervous system. Because muscle
the prospect of therapeutic exercise finding its place in the treat- afferent nerve pathways and pain afferent nerve pathways both con-
ment of not only musculoskeletal pain but also chronic conditions verge on the dorsal horn of the spinal cord, it has been proposed
that pain afferents may be susceptible to some form of selective relaxation. Patients attended 30-minute sessions twice weekly for
inhibition as a result of physical activity and exercise training.22 4 weeks. Physical and psychological measures were completed
Another hypothesis is that endogenous opioid release may be before and after intervention and again at a 3-month follow-up.
involved in exercise-induced hypoalgesia. Most likely, exercised- The data revealed conclusively that the hydrotherapy patients
induced hypoalgesia is caused by a host of interrelated factors showed significantly greater improvement in joint tenderness and
that may be partially controlled by the mode and intensity of exer- in knee range of movement (women only) than the other patients.
cise. Koltyn and coworkers’ study23 demonstrated significant hypo- In addition, at the follow-up measurement, the hydrotherapy
algesia after maximal isometric gripping exercise in both men and patients maintained the improvement in emotional and psycholog-
women. These researchers tested 15 males and 16 females under two ical state.
isometric exercise conditions. Subjects squeezed a hand dynamom-
eter for 2 minutes at two different intensities (40%–50% and 100%
of maximal handgrip contractions [MVC]). Passive Physical Modalities
Physical modalities are an integral part of the management of acute
Hydrotherapy and chronic pain conditions in a rehabilitation setting. A modality
describes any physical agent utilized to produce a physiologic
Hydrotherapy entails the heating via submersion of small or large response to a targeted tissue. Commonly prescribed modalities
body surface areas, usually in a small tank or tub. The water tem- include ice, heat, electrical stimulation, ultrasound, transcutaneous
perature usually does not exceed 408C for large body surfaces and electrical nerve stimulation (TENS), interferential current therapy
438C when a limb is submerged. The temperature may be adjusted (ICT), iontophoresis, and phonophoresis. Occasionally, other mod-
depending on the conditions treated and the effects desired (Table alities such as paraffin baths, short-wave diathermy, and laser ther-
73–4). Hydrotherapy provides a gravity-eliminated environment apy are incorporated.
that facilitates joint range of motion. The addition of agitation This section gives a brief overview of each of these modalities.
provided by water flow provides sensory input.
Traditionally utilized mainly as an adjunct to exercise, hydro-
therapy has found a wide use in treatment for acute painful condi- Cryotherapy
tions such as rheumatoid arthritis, complex regional pain
syndrome, and postoperative pain conditions. The benefits of Physiology
water exercises include elimination of gravity, positive effect of Most forms of cryotherapy (ice, cold packs, vapocoolant spray,
buoyancy,24 increased muscle relaxation, and decreased joint com- cryotherapy-compression units) provide transfer of thermal
pression. Hydrostatic forces have been shown to increase venous energy by conduction, with the exception of vapocoolant sprays
return, improve stroke volume and cardiac output, and promote a and whirlpool baths. Common application techniques include use
reflexive bradycardia.25,26 With the buoyancy of water, the effective of ice packs, ice massage, or cold-water immersion.
weight of the patient is proportionally decreased as the depth The physiologic effect of cold application includes immediate
increases. Weight-bearing loads are reduced to 40% of the total vasoconstriction and reflexive vasodilatation that occurs when
body weight when the patient is standing in chest deep water. cold paralyzed vascular smooth muscle relaxes at about 158C.29
With floating, the effects of gravity are eliminated. Exercises in This process ultimately leads to decreased local metabolism and
water may introduce increased loads to tissue by gradually decreas- enzymatic activity, decreased nerve conduction, and analgesia.30
ing the depth at which therapy is performed. Water viscosity pro- Cryotherapy has shown efficacy with acute musculoskeletal pain
vides resistance to movement equal to that of the force exerted by syndromes, soft tissue pain/inflammation, and muscle pain related
the patient. Resistance varies with the speed of the movement to eccentrically activated exercises, a condition known as delayed-
performed.27 onset muscle soreness (DOMS), which normally peaks 1 to 2 days
Clinically, patients experience reduced levels of pain while per- after activity, with symptoms continuing for up to 10 days31,32 (Box
forming passive and active range of motion as well as strengthening 73–6). Ice application may help decrease the time to return to par-
exercises in water. Patients may perform closed kinetic chain activ- ticipation and sport activity.33,34
ities when pain or weight-bearing precautions prohibit land-based
therapy. Water exercise is often perceived as easier than the same
Patient selection
exercise performed on land.
Studies have also demonstrated a reduction of pain and an Indications
improvement of function in patients participating in hydrotherapy Because connective tissue stiffness and muscle viscosity are
as long as 3 months after initiation of therapy. Hall and associates28 increased with cold application, in general, cryotherapy should be
randomly assigned 139 patients with rheumatoid arthritis to receive
hydrotherapy, seated immersion, land exercise, or progressive
Box 73^6 INDICATIONS FOR CRYOTHERAPY

Table 73^4. AquaticTherapy
Acute trauma
Edema
Very hot (1118F) Pain reduction Hemorrhage
Hot (1008F) Arthritis, increase range of motion Pain
Muscle spasm
Warm (948F) Open wounds, débridements Spasticity
Neutral (928F) Circulatory disorders, manual techniques Reduction of metabolic activity
for relaxation Osteoarthritis
Tepid (808F) Therapeutic exercise Minor burns
Acute/chronic pain
Cool (678F) Decrease spasticity Myofascial pain
Cold (508F) Inflammation, acute tissue changes Contusion inflammation
Adapted from Weber DC, Hoppe KM. Physical agent modalities. In Braddom RL (ed): Physical
Adapted from Konlian C. Aquatic therapy: making a wave in the treatment Medicine and Rehabilitation, 3rd ed. Philadelphia: Saunders Elsevier, 2007; pp 459- 478.
of low back injuries. Orthop Nurs 1999;18:11–18.
used during the first 48 hours after musculoskeletal injury.35 Some

studies have suggested that the efficacy of cryotherapy may be Box 73 -7 INDICATIONS FOR HEAT THERAPY
greater for limiting swelling and decreasing pain after acute injury
or surgery, with less vigorous evidence to support its use for chronic Chronic inflammation
Arthritis
pain conditions.36,37 Myofascial pain
Collagen vascular disease
Contraindications Sprains
The main contraindications to cryotherapy are cryoglobulinemia, Strains
cold hemoglobulinemia, cold hypersensitivity, urticaria, Raynaud’s Contracture thrombophlebitis
disease, impaired sensation, paroxysmal cold hemoglobinuria, and
ischemia.
Contraindications
Heat Heat therapy should be avoided in acute trauma, inflammation,
bleeding disorders, edema, scars, impaired sensation, malignancy,
Physiology and multiple sclerosis.
The three commonly used mechanisms of heat transfer are
n Conduction: transferring of heat from one surface to another. Different types of heat applications
n Convection: transfer of heat due to movement of air or water
The heat modalities are generally classified as superficial or deep.
across the surfaces.
n Conversion: transformation of energy to heat, which is
Superficial heat
involved in various forms of cryotherapy/heat (Table 73–5).
The most commonly used forms of superficial heat are hydrocolla-
Heating of the tissues results in increased blood flow to the tor packs, paraffin baths, hydrotherapy, and heat wraps.
surface, vasodilatation, increased oxygenation and leukocytes, indi-
n Hydrocollator packs are available in various sizes for cervical,
rect muscle relaxation, increased metabolism, increased capillary
thoracic, and lumbar areas. They are generally heated in
permeability, and collagen extensibility.
stainless steel containers in water temperatures close to
958C. The common duration of heat treatment is between
Indications 15 and 30 minutes. Hot packs are the most commonly used
heating modality.38
Heat therapy is used to treat pain, contracture, hematoma, chronic
n Hydrotherapy is used for submerging a body part in heated
inflammation, muscle spasm, and arthritis (Box 73–7).
water. Heat treatment also increases active and passive range
of motion of the joint and promotes muscle flexibility.
Hydrotherapy is also a common adjunct to the treatment of
rheumatoid arthritis, diffuse muscle tension, and spasm. The
most commonly used forms of hydrotherapy are whirlpool
Table 73^5. Mechanisms of Cryotherapy
baths and Hubbard tanks.
and Heat Therapy n Paraffin baths are thermostatically controlled tanks filled with
a mixture of mineral oil and paraffin. They are predominantly
Mechanism Cold/Cryotherapy Heat used in treatment of smaller joints, such as hands, fingers,
Conduction: by Cold packs, ice Hot packs, and feet. The mixture of heat and paraffin oil provides
direct contact massage, cold water paraffin baths increased thermal release over that of water. Temperatures
immersion, (1268F–1308F) range from 458C to 528C degrees for lower extremities and
528C to 588C degrees for upper extremities. Care must be
cryocompression
taken with patients with peripheral neuropathies and vas-
Convection: Whirlpool Fluidotherapy culo-occlusive diseases.39
movement of a (1188F/47.88C) n Heat wraps are disposable clothlike patches that, when
medium Whirlpool baths exposed to the air, heat up to approximately 1048F within
Conversion: Ultrasound 30 minutes and last for at least 8 hours (ThermaCare, Proctor
transformation Short-wave diathermy and Gamble Co., Cincinnati, OH).
of energy Microwave
Radiation: emitted IR Deep heat
from surface Near IR The most commonly used forms of deep heat are diathermy (ultra-
temperature (wl-770-1500 nm) sound, short-wave diathermy, and microwave diathermy), phono-
Far IR (wl-1500- phoresis, and iontophoresis.
12,500 nm)
DIATHERMY
Evaporation: Vapocoolant spray The three diathermy agents are ultrasound, short-wave diathermy,
transforms and microwave diathermy.
liquid to gas
Requires thermal n Ultrasound. Ultrasound is commonly used in the treatment
of decreased range of motion, contractures, subacute trauma,
energy
and chronic degenerative osteoarthritis. Ultrasound is often
IR, infrared; wl, wavelength. used as an adjunct to stretching exercises prior to aggressive
Adapted from Weber DC, Brown AW. Physical agent modalities. joint manipulation (Box 73–8). Ultrasound is defined as an
In Braddom RL (ed): Physical Medicine and Rehabilitation, 2nd ed. acoustic vibration with an audible range of 20,000 Hz. The
Philadelphia: WB Saunders, 2000; pp 440–458. heat is produced as a result of the conversion of electrical
Iontophoresis uses electromigration and electroosmosis to increase

Box 73^8 INDICATIONS AND PRECAUTIONS the permeation of charged and neutral compounds. It is noninvasive
FOR ULTRASOUND THERAPY and painless and avoids potential side effects and adverse reactions
of oral medications or injection therapies (e.g., increased risk for
bleeding, intravenous catheter infiltration, and pump malfunction).
Penetration may be particularly intense at sweat glands and areas of
skin breakdown. Iontophoresis therapy has been applied transder-
mally in the postoperative pain-management setting. The U.S. Food
and Drug Administation (FDA) has recently approved an iontopho-
retic transdermal fentanyl system.45 The first needle-free, patient-
activated analgesic system for acute postoperative pain is a potential
alternative to patient-controlled analgesia (PCA). The fentanyl HCl
patient-controlled iontophoretic transdermal system (PCITS) uses
an imperceptible, low-intensity direct current to deliver fentanyl on
demand across the skin and subsequently into the systemic circula-
tion. The quantity of fentanyl delivered is directly proportional to
the magnitude of current applied by the device.46 Studies have
shown the efficacy of iontophoretic fentanyl over PCA morphine
From Stanos SP,Tyburski M: Rehabilitation issues: Pain control.InVon Roenn JH,Price JA,Preodor ME, in a number of postoperative pain states.47,48
et al (eds): Current Diagnosis and Treatment of Pain.NewYork: Lange/McGraw Hill, 2006.
Indication. Iontophoresis is widely used in the treatment of
overuse conditions such as epicondylitis and plantar fasciitis.49,50
current into ultrasound energy through the use of a quartz Yarrobino and coworkers49 investigated lidocaine iontophoresis
crystal, which is subsequently converted into heat. Depth of (LI) in patients with subacute to chronic epicondylitis using 80
heating may be up to 5 cm below the skin surface, providing a mA/min, low-current, long-duration LI over a 24-hour period.
therapeutic benefit to superficial bone, joint capsule, liga- Patients were treated every other day for three treatment sessions
ment, and scar tissue. The ultrasound dosage is measured and demonstrated improved pain and function.49 Osborne and
in Watts per square centimeter. Intensities of 0.8 to 3.0 W/ Allison51 compared 0.4% dexamethasone to placebo and 5%
cm2 are commonly used.40 The dosage is varied depending on acetic acid along with taping in patients with plantar fasciitis. Six
the condition. In subacute painful conditions such as tendi- treatments of acetic acid iontophoresis combined with taping pro-
nitis and adhesive capsulitis, lower intensities and higher fre- vided greater relief from stiffness and greater improvement in
quencies are used. In more chronic conditions, such as morning pain compared with dexamethasone.51 There have been
contractures due to scar formations, intensities as high as case reports of iontophoretic treatment in postherpetic neuralgia.52
3.0 W/cm2 are utilized. Ultrasound may decrease pain and Dowd and associates53 performed a prospective, double-blind,
improve range of motion in acute pain disorders and osteo- placebo-controlled trial of patients with postherpetic neuralgia.
arthritis compared with chronic pain conditions.41 Other stu- The goal of the study was to determine the effect of iontophoretic
dies have found any benefit to be based on empirical administration of vincristine versus saline in patients unresponsive
experience, lacking support from controlled studies.42 to conservative treatment for postherpetic neuralgia. The patients
n Short-wave diathermy. Short-wave diathermy uses an oscil-
were randomly divided in two groups; each group received 20 days
lating electromagnetic field of high frequency to heat body of vincristine (0.01%) or saline for 1 hour a day for 20 days via
surface areas. It heats to a tissue depth of 2 to 3 cm. Despite iontophoresis. Whereas the response was similar in the vincristine
gradual decline in its use, short-wave diathermy still finds its and the saline groups (40% and 55%, respectively, reported mod-
place in treatment of large-surface body areas, such as lower erate to greater improvement after 20 days), the authors concluded
extremities, upper extremities, and back. A study by Garrett that a maintained improvement in both groups (30% with vincris-
and colleagues43 concluded that pulsed short-wave diathermy tine and 33% with saline) at 3 months follow-up could be attributed
was more effective than 1-MHz ultrasound in heating a large to a beneficial effect of iontophoresis.
muscle mass and resulted in the muscles’ retaining heat longer.
n Microwave diathermy. Microwave diathermy uses electro- Electrical Stimulation
magnetic radiation by microwaves and heats to a lesser
tissue depth than short-wave diathermy. It is primarily used The most commonly applied electrical modalities in the treatment
to heat superficial muscles and joints such as the shoulder. of pain include TENS and ICT. TENS and ICT involve the trans-
Besides its use in musculoskeletal conditions, this modality mission of electrical energy to the peripheral nervous system via an
has been employed to reduce the potential effects of cancer external stimulator.
chemotherapy and radiation treatment.44
Physiology
PHONOPHORESIS TENS is based theoretically on the gate-control theory originally
Phonophoresis allows delivery of topically applied medications proposed by Melzack and Wall.54 The theory is based on the con-
(analgesics, anti-inflammatory agents) into the deeper areas of cept of blocking and/or modulating nociceptive transmission at the
skin using ultrasound. Phonophoresis is frequently used in the level of the spinothalamic tract via stimulation of inhibitory inter-
treatment of postinjury conditions (dislocations, joint distortions), neurons. Activity in large myelinated afferent fibers theoretically
rheumatologic and musculoskeletal pain disorders, and spine- activates dorsal horn interneurons that inhibit cephalad transmis-
related conditions (nerve root pain, and disk-related pain). sion in small unmyelinated primary afferent nociceptive fibers
and the secondary transmission cells in the lateral spinothalamic
IONTOPHORESIS tracts. Somatic afferents activate convergent wide-dynamic-range
Iontophoresis is the process by which various drugs (e.g., dexa- cells deep in the dorsal horn (lamina V), which project in the
methasone, fentanyl, insulin, or lidocaine) are introduced into a spinothalamic tract to higher somatosensory processing in the thal-
joint or small body area superficially via electrical current. amus and cortex.
Techniques
Box 73^9 CONTRAINDICATIONS AND PRECAUTIONS FOR n TENS. This treatment is typically applied in two formats: low-
ELECTRICAL STIMULATION THERAPY intensity, high-frequency ‘‘conventional’’ TENS (1–2 mA, 50–
100 Hz) and high-intensity, low-frequency ‘‘dense-disperse’’
TENS (15–20 mA, 1–5 Hz). High-frequency TENS is used to
achieve a faster onset of analgesia for acute pain states and
low-frequency TENS is used for chronic pain conditions.
Treatment times range from 30 minutes for slower analgesia
affects to 2 to 6 hrs for long-duration analgesia.55
n ICT. A variant of TENS, ICT involves mixing of two sine waves
with different frequencies, allowing for summated waveforms
and stimulation of deeper tissues with less patient discomfort.
The proposed mechanism of action involves direct stimulation of
muscle fibers, as opposed to nerve fibers, to achieve increased
vasodilatation and improve healing.
Massage
Therapeutic massage involves certain manipulations of soft tissue of
the body, mostly applied by a practitioner, and can include hold-
ing, causing movement, and/or applying pressure to the body.
Massage therapy has been difficult to assess with regards to clinical
ICT, interferential current therapy; TB, tuberculosis; TENS, transcutaneous electrical nerve
outcomes owing to the variability in techniques, styles, and names.
stimulation. The American Massage Therapy Association publishes a glossary of
From Stanos SP,Tyburski M: Rehabilitation issues: Pain control.InVon Roenn JH,Price JA,Preodor ME,
et al (eds): Current Diagnosis and Treatment of Pain.NewYork: Lange/McGraw Hill, 2006.
terms that help to clarify some of these issues. Four basic massage
strokes are effleurage, petrissage, friction massage, and tapotement.
A proposed taxonomy of massage practice divides therapeutic mes-
sage into four separate groups: (1) relaxation massage, (2) clinical
massage, (3) movement reeducation, and (4) energy work56 (Table
The three routes of neuromodulation include presynaptic inhi- 73–6). Relaxation massage focuses on moving body fluids, such as
bition of the spinal cord, direct inhibition of abnormally firing lymph and blood, nourishing cells, removing waste from local
nerves, and facilitation of afferent input. Other mechanisms of anal- tissue, relaxing muscles, and decreasing pain. Swedish message is
gesia include direct peripheral effects of stimulation as well as the most commonly practiced type of relaxation massage and
increased release of endogenous opioids within the central nervous employs five basic strokes (effleurage, petrissage, friction, vibration,
system. The indications for the use of TENS and ICT are similar, and percussion). Clinical massage involves more focused manipu-
and the decision to use one form over the other is largely based on lation of muscle and/or surrounding soft tissue or fascia and may
clinical preference. Contraindications and precautions for electrical incorporate other effected organs including the lymphatic, cir-
stimulation therapy are similar as well (Box 73–9). culatory, and nervous system as a means of relieving pain and
Table 73^6. Proposed Taxonomy of Massage Practice
From Sherman KJ, Dixon MW, Thompson D, Cherkin DC. Development of a taxonomy to describe massage treatments for musculoskeletal pain.
BMC Compl Alternative Med 2006;6:24.
decreasing restricted movement.57 Common types include myofas- nerves and improvement of central and peripheral nervous system
cial trigger point therapy and release and neuromuscular therapy. functioning.
Movement reeducation focuses on enhancing posture, body aware- The FDA has classified LLLT as class III, nonsignificant risk, and
ness, and movement. Energy work is believed to ‘‘assist the flow of medical device for investigation use only.61
energy in the body’’ with light touch or by holding the hands above
the skin (e.g., Reiki, Therapeutic Touch).58 A meta-analysis of mas-
sage therapy found that a single application of treatment reduced CLINICAL CONDITIONS
anxiety, blood pressure, and heart rate; it reduced pain only after
multiple treatments.59 This section reviews theoretical issues related to underlying mech-
anism of common pain conditions (osteoarthritis, low back pain,
Massage terminology and techniques: american massage and myofascial pain syndrome) and principles guiding active phys-
ical medicine approaches. In many cases, these same principles can
therapy association60 be applied to the other acute and chronic pain conditions.
Massage therapy is a profession in which the practitioner applies
manual techniques, and may apply adjunctive therapies, with the
intention of positively affecting the health and well-being of the Osteoarthritis
client.
Massage is a manual soft tissue manipulation and includes holding, As the population ages, the treatment of osteoarthritis and the
causing movement, and/or applying pressure to the body. symptoms associated with it have become a major part of the reha-
Deep Tissue releases the chronic patterns of tension in the body bilitation medicine. Osteoarthritis is a multifactorial disorder
through slow strokes and deep finger pressure on the contracted resulting from various causes, such as joint degenerative changes,
areas, either following or going across the grain of muscles, genetic predisposition, obesity, and environmental factors. As the
tendons, and fascia. It is called deep tissue because it also focuses patient progresses through the continuum of the disease, she or he
on the deeper layers of muscle tissue. acquires compensatory patterns that often bring her or him to a
Effleurage is a stroke generally used in a Swedish massage treat- physiatric’s attention in the first place. Decreased range of motion,
ment. This smooth, gliding stroke is used to relax soft tissue and muscle imbalance, joint deformities, poor postural adaptation, and
is applied using both hands. pain are some of the presenting signs and symptoms that are man-
Friction is the deepest of Swedish massage strokes. This stroke aged in the rehabilitation setting. As a rule, a rehabilitation program
encompasses deep, circular movements applied to soft tissue, starts with patient education about the disease and behavior mod-
causing the underlying layers of tissue to rub against each ification techniques. The treatment is then initiated with gentle
other. The result is an increase in blood flow to the massaged area. passive and active range of motion exercises of the involved
Myofascial release is a form of bodywork that is manipulative in joints. Active therapy is aimed at restoring range of motion and
nature and seeks to rebalance the body by releasing tension in optimizing joint stability through muscle contraction. A muscular
the fascia. Long, stretching strokes are utilized to release mus- reeducation technique is often used to ‘‘unload ‘‘and protect the
cular tension. joint. Activities, such as active isometric contraction of the quadri-
Petrissage (also called kneading) involves squeezing, rolling, and ceps muscle and reflexive relaxation of the hamstring muscle, have
kneading the muscles; it usually follows effleurage during been shown to improve joint position sense and reduce pain and
Swedish massage. inflammation.62 During acute stages of pain, therapeutic modalities
Reflexology is massage based around a system of points in the such as TENS, ICT, and low-intensity ultrasound are often utilized.
hands and feet thought to correspond, or ‘‘reflex,’’ to all areas Ultrasound is commonly used prior to exercise performance.
of the body. Besides acting as an analgesic anti-inflammatory agent, it also
Shiatsu and acupressure are Oriental-based systems of finger-pres- serves as a deep-heating modality, thus promoting better stretching
sure that treat special points along acupuncture ‘‘meridians’’ and passive movement of the joint. ICT is often used in the middle
(the invisible channels of energy flow in the body). or toward the end of the therapy session, sometimes in combination
Swedish massage is a system of long strokes, kneading, and friction with ice, for optimal pain reduction.
techniques on the more superficial layers of the muscles, com- Occasionally, an external device will be used in conjunction with
bined with active and passive movements of the joints. an active therapy. Joint taping, orthotics, and braces are often
Tapotement is executed with cupped hands, fingers, or the edge of utilized in the acute stages of osteoarthritis when pain and joint
the hand with short, alternating taps to the client. instability are major limiting factors of the daily activity perfor-
mance. Braces and taping may also serve as part of proprioceptive
training,63 helping to improve the patient’s awareness of his or her
joint in space. In addition, foot orthotics such as lateral wedge
LaserTherapy insoles and shock-absorbing devices are often used for improve-
ment of the biomechanics of gait and cosmetic appearance of the
Low-level laser therapy (LLLT) has been investigated and used clin- patient’s limbs. General principles for bracing include supporting
ically for over 30 years in Eastern Europe and Asia. It is beginning to moving body parts, correcting alignment, limiting excessive motion,
gain popularity in Canada. Its use is based on its ability to non- and facilitating motion (Box 73–10).
thermaly and nondestructively alter cellular function. This phenom-
enon, known as laser biostimulation, is the basis for its use in
treatment of many rheumatologic, neural, and soft tissue condi- Box 73^10 GENERAL PRINCIPLES OF BRACING
tions. LLLT uses low outputs levels (15,100 mW), short treatment
times (10–240 sec), and low energy levels (1–4 J/cm2). Support or reorient moving body parts (e.g., joints, tendons)
Control or guide direction of movement
The mechanism and effectiveness of LLLT have been compared Align into more stable or less painful position
with ultrasound therapy and could potentially be used as an Limit or stop excessive motion
extension to the accepted physiotherapy modalities that currently Facilitate or correct motion
utilize parts of the electromagnetic spectrum, such as short waves,
From Rakel B, Barr JO. Physical modalities in chronic pain management. Nurs Clin North Am
microwaves, infrared, and ultraviolet therapy. The proposed 2003;38:477^ 494.
mechanism of action includes repairing of crushed or damaged
Aerobic exercises such as walking, swimming, and cycling have a her or his pain is described as less bothersome, more loca-
special role in the treatment of osteoarthritis.64 Inability to walk is lized, and proximal. Positions of centralization usually
often the very complaint that brings a patient to the attention of a include extension (standing or supine) followed by lumbar
physiatrist. The well-rounded rehabilitation program, which flexion.70 Reducible direction of pain improvement then
includes active strengthening, passive analgesic techniques, and becomes a guide to patient’s treatment. For example, a
appropriate gait-assistive devices, such as canes, crutches, and patient who finds low back pain relief after repetitive exten-
braces, will often enable the patient to ambulate as early as sion movements during the evaluation will most likely benefit
1 week after the beginning of rehabilitation treatment. Swimming from therapeutic exercises focusing on spine extension. The
serves as both an excellent alternative and an adjunct to ambulation. exercises involving this movement are offered in a clinic and
As described previously, water can act as an anti-inflammatory as a part of a home exercise program. The successes in treat-
modality and soothing device for the patient with acute pain. It ing a patient with this approach rests on the fact that the
also provides an adequate resistance to joint movement without patient will eventually be able to independently modify her
the stress of weight-bearing. Stationary cycling can often be started or his symptoms and prevent further spine damage.
on the first day of treatment. The stationary bicycle can be used as 4. The fourth category, referred to as ‘‘other,’’ describes those
an active and a passive stretching/range of motion device as well as a patients who do not meet criteria for a mechanical syn-
dynamic strengthening tool.65 The different degrees of seat elevation drome) as discussed previously and include conditions
and gauge resistance can allow a therapist to train a patient at related to sacroiliac joint disorders, spinal stenosis, spondy-
multiple joint angles while increasing a muscle load. losis, spondylolisthesis, hip pathology, zygapophyseal joint
disorders, or postsurgical conditions.71
Low Back Pain: Physical and Occupational The Philadelphia Panel72 was one of the largest systematic
Therapy Perspective reviews of randomized, controlled trials focusing on the treatment
of low back pain. It looked at specific outcomes including pain,
Back pain is the most common cause of chronic pain in the United quality of life, return to work, patient global assessment, and func-
States. A number of active physical therapy treatments of spine- tion. Interventions for low back pain that were reviewed include
related conditions have demonstrated efficacy in decreasing pain therapeutic massage, therapeutic exercises, biofeedback, ultrasound,
and improving function.66 The possible explanation behind some thermotherapy, TENS, mechanical traction, electrical stimulation,
of the success of physical therapy treatment is an understanding of and combined interventions. Specific to chronic low back pain, the
the heterogeneous nature of spinal conditions and tailoring a treat- Panel recommended extension, flexion, and strengthening thera-
ment plan accordingly. For example, management of low back pain peutic exercises and therapeutic ultrasound for pain relief due to
resulting from a sprain/strain is very different from the one of dis- spasms. Other modalities and treatments could not be recom-
cogenic origin. In addition, owing to the fact that a physical therapy mended for treatment of chronic low back pain secondary to lack
treatment lasts over several sessions, there is often room for an of sufficient evidence and availability of comparative studies based
adjustment, reassessment, and trial-and-error approach not often on the criteria of strict randomized, controlled trials used by the
seen in other specialties. Philadelphia Panel for the systematic review.
Riddle67 cited classification systems that have been used for low
back pain. Four main classification systems were determined to be
General TherapyTreatment Approach
the most appropriate and commonly used by physical therapists
and, therefore, were reviewed systematically. Mechanical classifica- Short- and long-term therapy plans incorporate graded strengthen-
tion in the McKenzie68 mechanical diagnosis and therapy (MDT) ing and stretching exercises as well as postural correction and
system is based on three different ‘‘syndromes’’ or as ‘‘other.’’ retraining. As with any acute or chronic condition, success in man-
agement of spine-related conditions is dependent on successive
1. Posture syndrome involves pain arising from abnormal pos- advancement through four specific phases including
tures and related deformation of normal soft tissues in which
the treatment is focused on posture correction. 1. Pain control.
2. Dysfunction syndrome is the result of end-range stresses of 2. Flexibility and strengthening.
structures that have been shortened, scarred, or adhered. 3. Aerobic conditioning.
Treatment focuses on exercises in the direction of the dys- 4. Retraining in sport-specific or activity-related functioning.
function and the goal of ‘‘remodelling,’’ tissue. Four sub-
groups of the syndrome include flexion dysfunction, Rehabilitation Progression
extension dysfunction, side-gliding dysfunction, and adher-
ent nerve root dysfunction. Pain control
3. Derangement syndrome represents pain occurring as a result Whether acute or chronic in origin, pain remains a major limiting
of a disturbance in the normal resting position of joint sur- factor in a patient’s recovery. If severe, it can compromise not only
faces (e.g., intervertebral disk in lumbar pain syndromes). the physical but also the psychological state of the patient, a factor
This syndrome is classified as either reducible or irreducible invaluable in a successful rehabilitation. Thus, aggressive pain man-
based on the patient’s symptomatic and mechanical response agement should be started as soon as the first visit (the management
to repeated movements or positions as assessed by the ther- of low back pain has been discussed elsewhere in this chapter), the
apist or physician. Hence, directional preference rests on the patient should be frequently reassessed, and end goals should be
‘‘patient’s response’’ to the direction of movement. The clearly established.
patient is asked to move through range of motion while the
therapist assesses the degree of discomfort. The concept of
centralization, recognized by McKenzie,68 is based on the Flexibility and strength
theory by which pain radiating from the cervical, thoracic, Lack of flexibility, imbalance, and weakness of core musculature are
and lumbar spine is sequentially abolished, neurologic symp- commonly seen in patients with low back pain. A basic physical
toms are decreased,69 or reduction of discomfort is noted. therapy treatment should include stretching of tight or contracted
The direction of movement can vary from extension, flexion, muscles, activating inhibiting muscles, and improving core strength.
or side-bending. As the patient moves away from discomfort, Exercises are commonly targeted on retraining multifidus and
erector spinae (back muscles) and rectus and transverse abdominus for myofascial trigger points include postural muscles in the neck,
(deep abdominal muscles) along with additional exercises for the shoulders, pelvic girdle and the upper trapezius, scalene, levator
pelvic floor and breathing control.73 scapulae, quadratus lumborum, and the lumbosacral muscles.
The therapist will train the patient to contract these (core) mus- Myofascial pain syndrome can be aggravated by multiple causes:
cles independently from the more superficial muscles. As a rule, acute tissue trauma, repetitive microtrauma, muscle decondition-
tight, antagonist muscles commonly seen in patients with low ing, postural abnormalities (in the workplace, home, or during rec-
back pain will be addressed simultaneously. Hip flexors, upper reational activities), poor sleeping habits, and metabolic issues
paraspinals, and pectoral muscles will be passively (performed by (including vitamin deficiencies and hypothyroidism).
the therapist) and actively (closed kinetic chain exercises, performed During an evaluation focusing on myofascial pain syndrome, the
by the patient) stretched as the patient progresses through the reha- physiatrist as well as the therapist will focus on posture, body
bilitation program. The anticipated result is that the patient will not mechanics, dynamic joint function, and location and assessment
only have a corrected muscle imbalance but also have acquired a of myofascial trigger points. When assessing trigger points, the cli-
proper posture and biomechanics that will prevent him or her from nician palpates for a rigid, fibrous nodule that is associated with the
further injuries. symptoms mentioned previously. At times, instead of a nodule, the
clinician will palpate a defined hypersensitive collection of muscle
associated with these symptoms.76 The pain associated with the
Balance and aerobic conditioning
trigger point will usually travel in a proximal to distal pattern.
As the patient progresses through the rehabilitation program, bal- Localized muscle groups may refer pain in distinct patterns.
ance and aerobic conditioning become incorporated into the train- Common areas of presentation include the cervical and lumbar
ing repertoire. Balance training is achieved through use of Swiss paraspinals, trapezius, gluteus medius and maximus, and piriformis
(medicine) balls, balance boards, and TheraBand elastic strips. muscle groups (Table 73–7).
The patient will generally start with static balance exercises (such Active physical therapy and passive modalities may be combined
as standing with feet together or standing on one leg) and then as part of a comprehensive treatment plan. Physical therapy focuses
progress to dynamic balance exercises (such as catching a ball on improving posture and body mechanics with functional tasks
while standing on one leg or raising an arm while sitting on a that may be contributing to pain and dysfunction. Therapy is
Swiss ball). Aerobic conditioning training involving walking on a focused on improving function of postural slow-twitch and
treadmill, swimming, or bicycling is generally offered at the begin- phasic fast-twitch peripherally located muscles. Postural (type I)
ning and at the end of therapy sessions. The goal of this type of muscles are slow-twitch fibers with relatively low stores of glycogen
exercise is to optimize the patient’s cardiovascular and respiratory and high myoglobulin and mitochondria, and they characteristically
state as well as to prepare her or himr for anticipated return to her fatigue slowly. Under long-term stress, these muscles shorten,
or his previous employment and/or sports-related activities. Some tighten, and demonstrate reasonable endurance. Phasic (type II)
studies suggest that activity in general may itself be therapeutic in or fast-twitch muscles contain relatively high stores of glycogen
reducing pain and improving psychological functioning.74 and low myoglobulin and, under long-term stress, are prone to
weaken.
Passive modalities may be provided by the therapist as a means
Sports-specific
of decreasing pain and facilitating therapy. Modalities targeted at
The sports- and/or task-specific exercise routine has been a subject deactivating symptomatic trigger points include massage, ultra-
of increased interest in medical rehabilitation. The idea of preparing sound, acupressure, spray and stretch therapy, and TENS (Box
a patient to return to sports that often caused or predisposed him or 73–11).76 (See the section on ‘‘Passive Physical Modalities,’’ earlier.)
her to injury in the first place has always posed a challenge for Spray-and-stretch therapy is a technique performed by the ther-
physicians and therapists. The concept of Specificity Principle apist in which a passive stretch to the affected muscle is applied
states that training must go from highly general training to highly while concurrently spraying a local soft tissue coolant. This cool-
specific training. The principle of Specificity also implies that in ant spray contains dichlorodifuoromethane-trichloromonofluoro-
order to become better at a particular exercise or skill, a patient methane or ethyl chloride with the ability to decrease the
must perform that exercise or skill repeatedly. For example, for a temperature of the skin and provide an analgesic effect by blocking
patient who has injured his or her low back while playing golf, the the spinal stretch reflex and central sensation of pain. With acu-
training will be focused on simultaneous activation of rectus abdo- pressure, clinicians apply gentle manual pressure over areas based
mini, erector spinae, and transverse abdominal muscles during a on meridian and acupuncture pressure points.77
swing phase. The number of swing phases will be gradually
increased until the patient will be allowed to play a full round.
While preparing a patient to return to a specific sport and/or occu- Table 73^7. Common Referral Patterns for
pational task, a physician needs to understand the athletic profile of
the individual. In general, it is recommended that the patients
should refrain from competitive activity until near-normal back
strength and range of motion as well as pain-free activity have
been achieved.75
Myofascial Pain Syndrome

Myofascial pain syndrome is distinguished from other chronic pain
syndromes by localized muscle tenderness, referred pain patterns,
trigger points, local twitch response, pain in a taut band of muscle,
withdrawal to pain when pressure is applied to a myofascial trigger
point, and restriction of motion. It can occur in any muscle, asym-
metrically, and may be due to one or all of these factors: acute tissue Adapted from Simons DG, Travell JG, Simons LS (eds): Travell and
trauma, muscle deconditioning, sensitized nerve foci, postural Simons Myofascial Pain and Dysfunction, The Trigger Point Manual,
abnormalities, and repetitive microtrauma. The main locations Vol.1, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1999.
14. Farrell PA, Gates WK, Maskud MG, et al. Increases in plasma beta-
Box 73^11 TRIGGER POINT DEACTIVATION endorphin/betalipotropin immunoreactivity after treadmill training in
humans. J Appl Physiol 1982;52:1245–1249.
15. Grossman A, Sutton JR. Endorphins: what are they? How are they
measured? What is their role in exercise? Med Sci Sports Exerc
1985;17:74–81.
16. Wilson WM, Marsden CA. Extracellular dopamine in the nucleus
accumbens of the rat during treadmill running. Acta Physiol Scand
1995;155:465–466.
From Alvarez PJ, Rockwell PG: Trigger point diagnosis and management. Am Fam Physician
17. Fagard RH. Exercise characteristics and blood pressure response to
2002;65:653- 660. dynamic physical training. Med Sci Sports Exerc
2001;33(suppl):S484–S492.
18. McDougal JD. Hypertrophy or hyperplasia. In Komi PV (ed):
Strength and Power in Sports. The Encyclopedia in Sports Medicine.
Oxford: Blackwell, 1992; pp 230–238.
SUMMARY 19. Follard JP, Williams AG. The adaptations to strength training.
Morphological and neurological contributions to increased strength.
As with any comprehensive treatment plan for acute or chronic Sports Med 2007;37:145–168.
pain, a physical medicine approach is based on identifying under- 20. Hoffman MD, Sheldahl LM,. Kramer WJ. Therapeutic exercise. In
lying causes of pain, physical impairments, and related disability. DeLisa JA, Gans BM (eds): Physical Medicine and Rehabilitation.
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X
NEUROMODULATION
APPROACHES TO PAIN
MANAGEMENT
Chapter 74 which it reduces pain are still under investigation. In addition to the
pain gate theory described previously, recent animal research find-
TRANSCUTANEOUS ELECTRICAL ings have indicated that low- and high-frequency TENS analgesia is
mediated through the activation of specific opioid receptors, thus
suggesting an alternate mechanism of neuromodulation. Although
NERVE STIMULATION some controversy continues over the effectiveness of TENS, this
modality is widely used to treat a variety of painful conditions.
Deirdre M. Walsh and Jeffrey R. Basford Technological advances have resulted in the development of
more sophisticated TENS units with an overwhelming range of
stimulation parameter choice. Fundamentally, however, little has
changed: all essentially consist of a unit powered by a small battery
that delivers a specified waveform to the skin via superficial elec-
trodes (Figs. 74–1 and 74–2).
INTRODUCTION
Transcutaneous electrical nerve stimulation (TENS) involves the STIMULATION PARAMETERS
application of low-voltage electrical currents to the skin.
Technically, the term TENS can be used to cover a range of stim- Stimulation parameter choice is fundamental to the effective use of
ulation currents such as interferential currents and functional elec- TENS and depends on a basic understanding of human physiology,
trical stimulation. For the purposes of this chapter, the term is used nerve transmission, and electricity itself. However, in practice, trial
to describe the application of a specific type of low-voltage current and error and intuition remain important also. Stimulation para-
to the skin for the purposes of pain relief. meters of TENS are described below.
Natural forms of electricity (such as those produced by electric
Current: TENS devices typically use a pulsed current with a
rays) have been used as a method of pain relief since the Egyptian
rectangular-shaped waveform (Fig. 74–3). The waveform
era. The subsequent development of the battery and the induction
itself may be symmetrical or asymmetrical.
coil resulted in early prototypes of TENS units being available by
Frequency: The number of pulses per second (measured in Hertz).
the late 1800s. However, electroanalgesia was poorly accepted until
Pulse duration: The time the pulse is delivered (usually mea-
1965, when Melzack and Wall laid a theoretical foundation for it
sured in milliseconds or microseconds).
with their gate theory of pain. This theory proposed that a ‘‘gate’’
Pulse amplitude/intensity: The voltage or current output is mea-
existed in the dorsal horn of the spinal cord that could regulate the
sured in millivolts or milliamperes (depending on whether the
intensity of nociceptive small-diameter afferent nerve fiber signals
device is designed to deliver a constant current or a constant
that could reach the brain. This gate could effectively be closed by a
voltage).
variety of stimuli (e.g., touch, pressure, and electrical currents) that
Output: The pattern in which the pulses are delivered; it can be
activated the large-diameter afferent fibers.
continuous, burst, or modulated (Fig. 74–4). The continuous
A number of studies appeared shortly after the theory was pub-
and burst outputs are self-explanatory. A modulated output is
lished that supported the effective use of percutaneous electrical stim-
produced by varying pulse duration, frequency, and/or ampli-
ulation for the treatment of chronic neurogenic pain. However,
tude in a regular and cyclical manner. If the output is set for
widespread acceptance of transcutaneous electrical stimulation did
amplitude modulation, a cyclical modulation in amplitude is
not occur until Norman Shealy, MD, reported that pain relief with
produced that increases from 0 to a preset level, then back to
an early version of a TENS unit was an effective means of screening
0 again. Modulated outputs are provided by manufacturers in
patients being considered for a then-new technique for pain relief,
the hope of improving treatment effectiveness by avoiding the
dorsal column stimulation, that involved the surgical implantation
accommodation of nerve fibers to a constant stimulus; the
of electrodes in the dorsal column of the spinal cord. Despite TENS
reality of its benefits remains debatable.
being used by health professionals for decades, the mechanisms by
541
542 Chapter 74 TR ANSCUTANEOUS ELECTRICAL NERVE STIMULATION
Acupuncture-like
Acupuncture-like TENS uses stimulation at a low-frequency
(usually 1–4 Hz), long-pulse duration (200 msec), and high inten-
sity. With acupuncture-like TENS, the intensity is increased to pro-
duce visible nonpainful muscle contractions. Pain relief is believed
to be produced by descending pain inhibitory pathways through the
release of endogenous opioids. The electrodes should be positioned
to produce visible muscle contractions (e.g., over a myotome
related to the painful area). The patient will experience paresthesia
and muscle contraction (twitching type) with this mode. As muscle
contractions occur, additional sensory information is carried from
the muscle spindle via muscle afferents (Ad). It is desirable that the
patient experiences motor contraction; therefore, the intensity
should be increased until the patient feels this.
Traditionally, conventional TENS analgesia was associated with
gating effects and acupuncture-like TENS analgesia with the release
of opioids through descending inhibitory pathways. However,
recent animal studies have demonstrated that low- and high-
frequency TENS-induced antihyperalgesia is mediated by activation
of serotonin, m and d opioid receptors, thus providing an additional
mechanism of action for this modality.
Burst
Burst TENS is an amalgamation of conventional and acupuncture-
like TENS and consists of a combination of a baseline low-
Figure 74^1. NeuroTrac 3 TENS device. (Courtesy of Verity frequency current together with high-frequency trains (see Fig.
Medical Ltd., UK.) 74–4). Some texts also refer to this mode of TENS as acupunc-
ture-like TENS. The main difference between burst TENS and
acupuncture-like TENS is that the burst mode has high frequency
trains of pulses delivered at a low frequency, whereas acupuncture-
MODES OF TENS like TENS has single pulses delivered at a low frequency. Typically,
the frequency of the individual pulse bursts (trains) is 1 to 4 Hz,
Commercially available TENS units provide the necessary parame- with the internal frequency of the trains around 100 Hz. Some
ter ranges (frequency, pulse duration, intensity settings, and burst patients prefer this mode to acupuncture-like TENS because the
versus continuous output) for four modes of stimulation. pulse trains produce a more comfortable muscle contraction.
Conventional Brief IntenseTENS

Conventional TENS involves stimulation at a high-frequency Brief intense (‘‘counterirritant’’) TENS uses high-frequency
(typically > 100 Hz), short-pulse duration (50–80 msec), and low (100–150 Hz) and long-duration (150–250 msec) pulses delivered
intensity. Large-diameter afferents (Ab-fibers) are stimulated, thus at the patient’s highest tolerable intensity for short periods of time
producing paresthesia under the electrodes. Pain relief is believed to (<15 min). Some authors recommend the use of this mode for
be produced primarily by segmental inhibition (i.e., gating effects). painful procedures such as skin débridement.
Figure 74^2 Please check and provide sequence idFont not provided 6,2TENS self-
adhesive electrodes.Courtesy of Verity Medical Ltd., UK.
X NEUROMODULATION APPROACHES TO PAIN MANAGEMENT 543
CONTRAINDICATIONS AND
PRECAUTIONS WITH TENS
As with any therapeutic procedure, screening for contraindications
is necessary prior to the initial application. Precautions and contra-
indications are largely empirical and, for the most part, reflect
‘‘common sense.’’
1. Impaired sensation. A simple sharp/blunt test will determine
whether cutaneous innervation is intact. If an area of skin has a
deficient sensation, treatment is likely to be ineffective. More
importantly, a greater stimulus intensity will have to be
employed that may cause skin irritation and even a burn. If
sensation is impaired in a specific area, electrodes may be
placed at an alternate site (e.g., in a proximal location that
has intact sensation).
2. Impaired alertness or cognitive function. Patients who are
Figure 74^3. Typical TENS waveform. incompetent or who cannot comprehend the clinician’s
instructions should not be treated. A patient’s ability to operate
a TENS unit at home may have to be considered.
3. Anterior neck. Electrodes should never be placed in the vicinity
of the carotid sinuses because they contain baroreceptors and
INDICATIONS stimulation in this area may alter blood pressure. Electrodes
should also not be placed over the eyes, which common sense
TENS is typically used in the treatment of chronic pain arising from
would indicate.
conditions such as arthritis and low back pain. However, it can also
4. Pregnancy. TENS should not be delivered over the pregnant
be utilized for a range of acute pain conditions, with research, for
uterus because this might conceivably induce labor. It is pru-
example, showing varying benefits for pain associated with acute
dent to avoid using TENS during the first trimester because its
fractures, labor pain, and surgery. Trial and error is always associ-
effects on fetal development are unknown. Some authors have
ated with the application of TENS. However, a systematic approach
documented using TENS after the first trimester for low back
is essential, and the following sections outline the approach that
pain associated with pregnancy, although definitive research on
should be taken in its application.
this application is not available. During labor, TENS can be
used as a method of analgesia, with two pairs of electrodes
positioned over the T10–L1 and S2–4 spinal nerve roots.
5. Implanted pumps and pacemakers. These devices are also usu-
Continuous output (single pulses delivered over time) ally listed as a contraindication to TENS, and most people
avoid its use in these situations. TENS has been shown to inter-
fere with certain types of pacemakers. If a trial of TENS is
justified on a patient with a pacemaker, discussion with the
patient’s primary physician or cardiologist and concomitant
electrocardiographic/Holter monitoring is strongly advised to
determine any adverse effects.
6. Contact allergy. A history of a contact allergy to the electrode
gel or tape can usually be ascertained from the patient’s history
or during the first treatment. A few cases of contact dermatitis
Burst output (pulses delivered in groups/trains over time) have been reported owing to propylene glycol, a common
ingredient in TENS gel.
7. Epilepsy. The risk seems remote, particularly for use at a distal
site. However, the potential should be reviewed with the
patient.
8. Driving or operating machinery. Patients should be advised
not to wear TENS while driving or operating machinery
because an abrupt change in stimulation intensity could con-
ceivably provide a distraction.
9. Active epiphyseal regions in children.
10. Broken and irritated skin.
Modulated amplitude output (pulses delivered in a
cyclical fashion over time)
APPLICATION TECHNIQUE
Using TENS on a Patient for the First Time

Box 74–1 summarizes the principles necessary to ensure the safe
application of TENS. The patient should be positioned comfortably
with the treated limb/body part suitably supported. The clinician
should take the patient’s assessment details, possible precautions
Figure 74^4. Types of output. and contraindications, and medical history into consideration
Treatment Time
Box 74^1 PRINCIPLES FOR SAFE APPLICATION OF TENS
The first TENS trial should be less than 30 minutes in duration to
Perform routine safety checks of equipment and ensure device is cali- allow the patient to get used to the sensation and the clinician to
brated on regular basis.
Explain goals and nature of treatment. monitor adverse reactions, such as allergies to electrode tape/gel,
Position patient comfortably. and the patient’s tolerance. After the initial trial, treatment sessions
Assess patient and screen for contraindications. can be increased to 1 hour at a time at subsequent visits. Skin
Collect equipment and test it on yourself. irritation with prolonged use is an issue, and personal experience
Demonstrate treatment to patient. has led the authors to advise a maximum treatment period of 1
Clean skin and attach electrodes. Check that leads are attached cor- hour with breaks of 30 or more minutes to lessen its risk.
rectly between device and electrodes. Acupuncture-like TENS produces muscle contractions, and pro-
Select appropriate stimulation parameters. longed stimulation may produce muscle fatigue—another good
Inform patient with regard to what they should and should not expect reason for limiting treatment time to less than 1 hour at a time.
to feel.
Increase intensity slowly and monitor treatment. During treatment, It is important that the clinician explains to the patient that TENS
increase intensity as required to overcome perceived accommodation should not be used to mask pain so that painful activities can be
of the nerve fibers. performed that would otherwise be impossible (e.g., throwing and
Terminate treatment by slowly decreasing intensity and remove shoulder pain). Finally, home use of TENS is advocated provided
electrodes. appropriate instruction is given to the patient.
Check skin for any adverse effects.
Document treatment.
TENS, transcutaneous electrical nerve stimulation.
Electrodes and Their Placement
Electrodes
before proceeding. Trials should be performed when the analgesic
effects of any medication are at their nadir to avoid confusing TENS TENS devices are typically provided with a supply of self-adhesive
and medication effects. The treatment should be carefully explained electrodes, available in a variety of shapes and sizes (see Fig. 74–2).
and demonstrated by attaching the electrodes over a visible body Reusable carbon rubber electrodes may also be used, despite the
area (e.g., the arm/forearm) and allowing the patient to experience need for increased application time associated with taping them
the sensation. The patient should be instructed not to move nor in place and the application of a conductive gel. However, if gel
touch the electrodes during the treatment. Finally, the skin at the is used, it is imperative that it covers the entire electrode and that
treatment sites should be cleansed to remove surface lipids before the securing tape is firmly in place to ensure that the conduction
attaching the electrodes. pathway is as uniform as possible (Fig. 74–5).
Ineffective electrode placement is a primary cause for a poor
response to TENS treatment. Optimal electrode placement involves
Selection of TENS Parameters a degree of trial and error, and it is essential that several sites
are assessed before deciding that a patient will not benefit from
These points should be considered before the selection of stimula- TENS. Consequently, patients should be told that a few treat-
tion parameters: ments are likely to be required to locate an optimal electrode site
and parameter choice. There are four choices of TENS electrode
1. Has the patient been treated with TENS previously? If so,
placement: directly over the painful area; over the peripheral nerve;
what were the parameters and how beneficial was the treat-
at spinal nerve roots; and at specific sites such as those associated
ment? There is no point in reinventing the wheel if a patient
with acupuncture and trigger points.
has or has not responded favorably previously.
2. What is the nature of the pain? For example, if a patient has
sustained an acute soft tissue injury of the shoulder, she or he
may not respond favorably to a high-intensity, low-frequency
current that would cause pulsing contractions in already-
traumatized muscle.
3. It is advisable to commence treatment using conventional
TENS because most patients find its ‘‘tingling, buzzing’’ sen- χ
sation more comfortable than the sensation and muscle con-
tractions associated with acupuncture-like TENS. Even if
pain relief is achieved with conventional TENS, acupunc-
ture-like TENS should also be tried for at least one treatment
to establish whether additional benefits can be obtained.
Stimulation intensity should be increased slowly and the patient
asked to report the onset of any sensation under the electrodes.
Once this is reported, ask the patient to describe the sensation χ
because it is helpful to use the patient’s own description (typically
words like ‘‘tingling,’’ ‘‘buzzing,’’ ‘‘pricking,’’ ‘‘vibration,’’ or
‘‘tapping’’) when explaining that the intensity will be increased
slowly until this sensation is ‘‘strong but comfortable.’’ The patient
should be warned that a painful stimulation is not beneficial. Even
in the application of acupuncture-like TENS, in which the produc-
tion of muscle contractions is desirable, the patient should be able
to tolerate the intensity. Owing to perceived accommodation, the
intensity can be increased during the treatment to maintain a sub-
jective sensation of ‘‘strong but comfortable.’’ Figure 74^5. Application of tape over electrode.
Table 74^1. Summary of Cochrane Systematic Reviews onTENS for Pain Relief
Reference Condition Studied Inclusion Criteria Participants Conclusion

Nnoaham Chronic pain Full journal publications of one Adults with chronic pain of Evidence is inconclusive.
and or more RCTs which examined > 3 months. Chronic pain
Kumbang, the analgesic effects of repeated conditions associated with
2008 or continuous use of TENS in acute episodes, such as angina,
people with chronic pain. tension-type headache,
24 studies met the inclusion migraine and dysmenorrhea
criteria. were not considered.
Robb et al, Cancer pain in RCTs where the control 18 years or older who had Evidence is inconclusive.
2008 adults (placebo) group was clearly experienced cancer-related pain,
defined and was either no unspecified or persistent cancer
active stimulation or no treatment-related pain, or both,
treatment. for a minimum of three months
2 studies met the inclusion after any anti-cancer treatment
criteria. had been completed.
Khadilkar Chronic LBP RCTs with >5 patients per 18 yr with chronic mechanical Available evidence supporting
et al, 2005 treatment group. LBP use of TENS as isolated
2 studies met inclusion criteria. treatment of LBP is limited
and conflicting.
Brosseau RA of the hand RCTs and controlled clinical 18 yr, with clinical and/or Acupuncture-like TENS helps
et al, trials. radiologic confirmation of RA decrease hand pain in people
2003. 3 studies met inclusion criteria. of the hand. with RA.
Proctor TENS and RCTs comparing TENS or Inclusion criteria: High-frequency nerve
et al, 2002 acupuncture for acupuncture to each other, Women of reproductive age stimulation may help relieve
primary placebo, no treatment, or Women with moderate to painful menstrual cramps.
dysmenorrhea medical treatment. severe primary
9 studies met inclusion criteria. dysmenorrhea (severe/
incapacitating pain for at
least 1 day of menses).
Women affected by
dysmenorrhea in >50% of
their menstrual cycles.
Exclusion criteria:
Dysmenorrhea associated
with pelvic pathology, an
IUD.
Mild or infrequent
dysmenorrhea.
Osiri et al, Knee RCTs and controlled clinical 18 years or older, with clinical TENS and AL-TENS are shown
2000 osteoarthritis trials that were eligible and/or radiological to be effective in pain control
according to an a priori confirmation of OA of the over placebo.
protocol. knee and no history of surgery
7 studies met the inclusion of the affected knee.
criteria.
IUD, intrauterine device; LBP, low back pain; RA, rheumatoid arthritis; RCT, randomized, controlled trials; TENS, transcutaneous electrical nerve
stimulation.
Placement more appropriate to place the electrodes proximal to the area of

hypersensitivity.
Painful area
Placement over a painful area is the most common starting point Peripheral nerves
because it is desirable, with conventional TENS, to achieve a sen-
sation of paresthesia over the painful area. As previously outlined, The electrodes may also be placed over a peripheral nerve that has
skin sensation must be assessed to ensure normal innervation of the a cutaneous distribution in the painful area. A sound knowledge of
affected area. Patients with impaired sensation in the affected area surface marking and neuroanatomy is required to determine where
may be treated by placing the electrodes over normally innervated the peripheral nerves are most superficial and, therefore, most
skin just proximal to the painful area in order to stimulate the easily accessible for stimulation. For example, pain experienced
afferent sensory nerves traveling to the spinal cord. There are also on the dorsum of the lateral aspect of the hand and the first and
occasions when application of electrodes at the painful site would second digits can be treated with electrodes placed over the course
be uncomfortable for the patient, and here again, it may also be of the superficial radial nerve as it traverses the lateral aspect of the
distal forearm. Other examples of superficial points of peripheral EVIDENCE BASE

nerves are the ulnar groove for the ulnar nerve and the head of the
fibula for the common peroneal nerve. Although the evidence base for TENS effectiveness has
expanded over recent years, it remains surprisingly equivocal.
Evaluations range in quality from well-designed randomized, con-
Spinal nerve roots
trolled trials to single case studies. A number of systematic reviews
The spinal nerve roots emerge through the intervertebral foramina have been published addressing the effectiveness of TENS analgesia
that lie between the nonpalpable transverse processes of the verte- for different pain conditions. In particular, the Cochrane
bral column. Placing the electrodes parallel to the vertebral column Collaboration has produced systematic reviews on primarily
(paraspinal application) and over the intervertebral foramina will chronic pain conditions (Table 74–1). It is obvious that definitive
allow for stimulation of the appropriate roots of spinal nerves that evidence is lacking and that this deficiency is due to a combination
supply the affected dermatome or myotome. Acupuncture-like of poor trial quality and study heterogeneity. Although the number
TENS is commonly applied to myotomes segmentally related to of randomized, controlled clinical trials on TENS has increased
the area of pain to produce the desirable muscle contractions asso- since the late 1990s, further high-quality randomized, controlled
ciated with this mode of TENS. There is considerable overlap trials are necessary in order to provide an evidence base for this
between adjacent dermatomes in a specified body part and, there- pain-management modality.
fore, knowledge of the spinal nerve responsible for the dermatome
in question is required in order to accurately select the correct
spinal segment for stimulation. SUGGESTED READINGS
A knowledge of the relationship between spinal cord segments, Brosseau L, Yonge KA, Robinson V, et al. Transcutaneous electrical nerve
their corresponding spinal nerves, and the spinal vertebral processes stimulation (TENS) for the treatment of rheumatoid arthritis in the
is particularly important. For example, there are eight cervical hand. Cochrane Database Syst Rev 2003;(2):CD004377.
spinal nerves and only seven cervical vertebrae, so the seventh cer- Johnson MI. Transcutaneous electrical nerve stimulation (TENS). In
vical nerve will emerge between the last cervical and the first tho- Watson I (ed): Electrotherapy, Evidence-Based Practice, 12th ed.
racic vertebrae. It is important to remember that angulation of the Edinburgh: Churchill Livingstone, 2008; pp 253–296.
posterior spinous processes changes with their position in the ver- Kalra A, Urban MO, Sluka KA. Blockade of opioid receptors in rostral
ventral medulla prevents antihyperalgesia produced by transcutaneous
tebral column, and palpation of a specific spinous process does not electrical nerve stimulation (TENS). J Pharmacol Exp Ther
necessarily result in localization of the corresponding cervical nerve 2001;298:257–263.
(e.g., the C5 spinous process is palpable at the level of the C6 nerve Khadilkar A, Milne S, Brosseau L, et al. Transcutaneous electrical nerve
root). Thus, localization is important. However, the need for stimulation (TENS) for chronic low-back pain. Cochrane Database Syst
extreme accuracy is limited by the fact that areas are frequently Rev 2005;3:CD003008.
innervated by more than one nerve root and the length of standard Nnoaham KE, Kumbang J. Transcutaneous electrical nerve stimulation
electrodes (5 cm) allows at least two adjacent roots to be stimu- (TENS) for chronic pain. Cochrane Database Syst Rev
lated simultaneously. It is also important that the electrodes are 2008;3:CD003222.
placed parallel to the spinal column to ensure stimulation of a Osiri M, Welch V, Brosseau L, et al. Transcutaneous electrical nerve
stimulation for knee osteoarthritis. Cochrane Database Syst Rev
maximum number of roots. 2000;4:CD002823.
Proctor ML, Smith CA, Farquhar CM, Stones RW. Transcutaneous
Acupuncture, motor, and trigger points electrical nerve stimulation and acupuncture for primary
dysmenorrhoea. Cochrane Database Syst Rev 2002;1:CD002123.
Electrode placement in these categories was directed by the location Radhakrishnan R, King EW, Dickman JK, et al. Spinal 5-HT(2) and
of pathology or nervous tissue. TENS treatment may also be applied 5-HT(3) receptors mediate low, but not high, frequency TENS-induced
to a number of specific sites: typically acupuncture, motor, and antihyperalgesia in rats. Pain 2003;105:205–213.
trigger points. Treatment over acupuncture points has an obvious Robb KA, Bennett MI, Johnson MI, et al. Transcutaneous electric nerve
rationale, given the importance of their stimulation in the treatment stimulation (TENS) for cancer pain in adults. Cochrane Database Syst
Rev 2008;3:CD006276.
of disease in traditional Chinese medicine. Treatment at the other Sluka KA, Deacon M, Stibal A, et al. Spinal blockade of opioid receptors
sites is more empirical, but it should be noted, for example, that a prevents the analgesia produced by TENS in arthritic rats. J Pharmacol
motor point, defined as the point at which a motor nerve synapses Exp Ther 1999;289:840–846.
with the fibers of a muscle and is characterized by low skin resis- Sluka KA, Walsh D. TENS: basic science mechanisms and clinical
tance, should be an optimal location for treatment when the gentle effectiveness. J Pain 2003;4:109–121.
muscle contractions associated with acupuncture-like TENS are Walsh DM. TENS: Clinical Applications and Related Theory. New York:
desired. Trigger points, conversely, are areas characterized by ten- Churchill Livingstone, 1997.
derness on palpation and the production of referred pain; a choice
of their treatment also seems intuitively strong.
Chapter 75 whereas factors that activate the small fiber system keep the gate
‘‘open’’ and allow transmission of noxious information. In addi-
SPINAL CORD STIMULATION tion, a descending modulatory system exists that also influences the
spinal gating mechanism.
FOR THE TREATMENT OF Because spinal cord stimulation (SCS) is known to activate the
large fiber system of the dorsal column (DC), it seemed rather
logical to hypothesize that electrical stimulation applied to the
CHRONIC INTRACTABLE PAIN DC would result in a closing of the gate and inhibition of pain
transmission. In 1967, Shealy and associates3 first tested this
Richard K.Osenbach and Emily A. Davis theory clinically by implanting electrodes directly on the dorsal
surface of the spinal cord; the technique became known as DC
stimulation. This was a fairly simplistic if not elegant explanation
of the therapeutic effect of SCS. As research on pain transmission
and processing and SCS has evolved and knowledge has accumu-
lated, a substantial body of evidence gained since the late 1970s
has shown that multiple mechanisms are likely responsible for the
INTRODUCTION analgesic effects of SCS. Notwithstanding the criticisms of the gate
theory, its relative simplicity has previously and continues to pro-
The use of electrical stimulation as a treatment modality for pain vide a useful framework for the development of various techniques
is not a new concept. Indeed, the application of electricity for the of electrical stimulation as new treatment modalities.
treatment of illness dates back at least several hundred years. John It is readily apparent that SCS has improved considerably since
Wesley, founder of the Methodist Movement, championed the use its inception 40 years ago. This evolution can be linked to a number
of electricity as early as the 1700s to treat a variety of pain condi- of factors including a better understanding of the mechanisms of
tions such as angina, headache, and sciatica. This was obviously SCS, an improved understanding of the concepts and mechanisms
long before there was any sort of clear understanding of the phys- underlying neuropathic pain, improvements in equipment and
iology of pain transmission and processing. Clearly, the utilization technology, the use of novel electrode placements, and a greater
of electricity as a therapeutic ‘‘drug’’ has indeed come a long way. appreciation of the indications and efficacy of SCS. All of these
It is also somewhat ironic that the conditions for which Wesley advo- factors have contributed to improved patient selection and, as a
cated electrical stimulation include some of the more common result, a direct improvement in outcomes associated with SCS.
pain conditions that electrical stimulation is currently employed for.
Despite early clinical observations of the beneficial effects of
electrical stimulation on pain, it was not until Melzack and MECHANISMS OF SCS
Wall1 published the gate control theory of pain transmission in
1965 that the concept of electrical stimulation for the treatment of Despite the fact the SCS has been employed for over 40 years, our
pain really began to emerge and be better understood. However, understanding of the exact mechanisms through which this modal-
the first modern applications of electrical stimulation actually did ity produces beneficial effects is still fragmentary and unclear.
not originate from the gate control theory. Five years earlier, Mazar Experimental animal studies have been performed by relatively
and coworkers2 had begun to investigate thalamic sensory stimu- few investigators and studies in humans are even more uncommon.
lation using implanted electrodes as a treatment for chronic neu- A major drawback of animal studies is that the results may not
ropathic pain. Mazar and coworkers’ work was based largely on the necessarily be directly applicable in humans, particularly when
older theory of Henry Head and Gordon Holmes that chronic pain studying pain behavior. Most experimental animal models of pain
occurs secondary to an imbalance between the epicritic and the involve acute, noxious stimuli (e.g., heat, pressure, pinch, and
protopathic components of pain. Head and Holmes had postulated application of algogenic substances), whereas in humans, SCS is
the explicit existence of modulatory influences on pain. They sug- utilized clinically for chronic pain. It is also conceivable that the
gested that the thalamus is the center for pain perception and that mechanisms of analgesia may be different for neuropathic pain than
the neocortex exerts a continuous influence on the response of the for ischemic pain. The experimental work in this area is indeed
thalamus to nociceptive input. Mazar and coworkers2 believed that fascinating. Unfortunately, an in-depth discussion of this topic is
stimulation of the sensory thalamus might compensate for this well beyond the scope of this chapter. The interested reader should
imbalance by enhancing the epicritic difference. Their work not consult any number of excellent reviews on this subject.4–8
only preceded the description of the gate control theory but also As discussed previously, one of the original concepts was that
came long ahead of our current understanding of the concept of SCS produced much of its effect based on the gate control theory.
neuropathic pain. Basically, this theory suggested that nociceptive transmission could
The gate control theory was the first to incorporate the concept be interrupted at the first dorsal horn relay by stimulation of large
of a descending modulatory control process with local spinal Ab-fibers in the DC through both orthodromic and antidromic
mechanisms of pain processing. In simple terms, the gate control activation of collaterals that project to the corresponding spinal
theory postulates that within the dorsal horn of the spinal cord, segment. These effects are actually very short lasting when studied
there exists an action or output system, namely thalamic projection in animals, and perhaps even more important, the inhibitory effects
neurons (TPN), that transmits noxious information rostrally to the were exerted on afferent discharges from Ad- and C-fibers in
thalamus. These TPN are locally modulated or ‘‘gated’’ by the rel- response to noxious input.5 This observation is actually contrary
ative amount of input from both large myelinated Ab-fibers and the to many of the clinical observations of SCS. Notwithstanding, the
small diameter Ad- and C-fibers. A preponderance of activity in general mechanism of SCS is still understood to some extent in
large fibers serves to ‘‘close the gate’’ and inhibit pain transmission, terms of these gating mechanisms in the spinal cord.
548 Chapter 75 SPINAL CORD STIMULATION FOR THE TREAT MENT OF CHRONIC INTR ACTABLE PAIN
Spinal and supraspinal mechanisms for SCS have also been sug- Cerebrospinal fluid (CSF) is the most conductive of all the
gested. Single-cell activity recorded from the dorsal horn (laminae intraspinal elements, followed in decreasing order by longitudinally
IV and V) evoked by various noxious stimuli has been shown to be oriented white matter, gray matter, epidural fat, dura mater, and
inhibited by SCS applied to the DC. This inhibitory effect is pre- bone. Understanding these differences has practical applications for
served even when the DC has been transected rostral to the level at SCS in terms of the neural elements recruited and the power con-
which SCS has been applied, suggesting that the inhibitory effect is sumption. Because CSF has the highest conductivity, it stands to
mediated through spinal mechanisms alone.5 Studies of the effects reason that the depth or thickness of the CSF space will have an
of SCS on spinothalamic tract cells excited by peripheral stimula- influence on the specific structures that may be recruited and the
tion using bradykinin or noxious pinch in their respective receptive threshold of activation. The larger the width of the dorsal CSF
fields have shown that SCS applied to the ipsilateral DC suppressed space, the higher the stimulation threshold for both DC and
their discharge activity, suggesting that SCS may preferentially inhi- dorsal root (DR) fibers.8,9 Furthermore, the difference between
bit high-threshold nociceptive specific cells. Inhibition occurred as stimulation thresholds of DR and DC fibers becomes greater with
an immediate effect of SCS applied with high amplitude and con- increasing CSF width. It has also been shown that DR and DC fibers
comitant with the noxious stimulus. Moreover, the inhibitory possess different electrical properties. DR fibers have a stimulation
effects of SCS did not outlast the duration of SCS. Clinically, it is threshold that in some cases is less than 50% of that of DC fibers.
well known that the effects of SCS often persist well beyond the This discrepancy is due to several factors.8 First, DR and DC fibers
duration of stimulation, and it has been suggested that this pro- have a different orientation with respect to the spinal electrode and
longed effect may be related to supraspinal influence. Indeed, spinal the electrical field that is produced. DR fibers are curved and
transaction rostral to the applied stimulation site has been shown to oriented somewhat differently with respect to the electrode; this
abolish this poststimulatory suppression of wide dynamic range has an impact on activation threshold. In general, as the angle
(WDR) neurons in the deep dorsal horns activated by noxious between the fiber and the transverse plane increases, the threshold
stimuli in intact awake animals.5 becomes higher. Also, when DR fibers enter the spinal cord, they
Peripheral nerve lesions in animals result in hyperexcitability of do so by crossing between a high-conductivity (CSF) and a low-
WDR neurons in the dorsal horn in animals rendered allodynic conductivity (spinal cord) interface.10–12 These data correlate well
compared with those that are nonallodynic. Application of SCS with the observation that initial paresthesias that are perceived with
using current ‘‘clinical parameters’’ can induce significant depres- SCS are usually felt at the segmental level of stimulation and then
sion of these exaggerated responses in allodynic animals, suggesting spread to encompass more caudal segments. These differences also
that this suppressive action on WDR neurons corresponds to the explain the clinical observation as to why an electrode placed too far
observed clinical benefit of reduction in tactile allodynia as well as laterally often produces purely segmental stimulation. In addition,
spontaneous neuropathic pain.5 the width of the epidural space will have an impact on activation
Other mechanisms of SCS for neuropathic pain have been sug- thresholds. The greater the distance between the electrode and the
gested based on animal studies, and entirely different mechanisms DC, the higher the activation threshold. It can now be easily under-
have been proposed for ischemic pain. Suffice it to say that SCS stood why paresthesia perception thresholds are generally higher in
likely produces its beneficial effects through multiple mechanisms. the midthoracic region than in the cervical region where the epi-
Whereas the gate control theory may not fully explain these effects, dural space is narrowest.
it does seem clear that, at least based on the experimental data and An important anatomic concept is the somatotopic organiza-
the clinical importance of paresthesia perception, that the DC does tion of the DC. Primary afferent fibers in the DR become
indeed play a central role in the mechanistic effects of SCS. segregated as they enter the dorsal horn of the spinal cord. The
large-diameter Ab-fibers carrying touch and proprioception
destined to enter the DC become segregated more medially at
ELECTROPHYSIOLOGYAND APPLIED the dorsal root entry zone (DREZ), whereas the smaller nocicep-
ANATOMYOF SCS tive Ad- and C-fibers are situated more laterally. The large myeli-
nated fibers continue to be displaced medially, and consequently,
A general understanding of the basic electrophysiology of SCS is sacral fibers are located most medially, with lumbar fibers more
important if not essential for the successful application of this laterally, and so on. Again, this can sometimes have important
modality. SCS is applied clinically through epidural electrodes practical implications in terms of electrode location and paresthe-
that are generally placed over the DC of the spinal cord. When a sia production.
neuron or axon is made more positive or depolarized, the end result The stimulation-induced paresthesias produced by SCS reflect
is production of an action potential that is then propagated along activation of the various spinal structures including the DC, DR,
the nerve fiber. Clinically, SCS is typically produced by choosing dorsal horn, and DREZ.8 Distinguishing DR from DC activation is
two electrodes that are close together; one electrode functions as a sometimes feasible, especially if the patient initially perceives uni-
cathode (negative) and the other as an anode (positive). The elec- lateral segmental paresthesias at a very low perception threshold or
trode that effectively produces depolarization is the cathode and. if early motor recruitment occurs. More diffuse bilateral distribu-
therefore. this is termed a cathodal effect. When the neuron or axon tion of paresthesias at a slightly higher threshold below the spinal
becomes more negatively charged or hyperpolarized, the threshold level being stimulated is more indicative of DC activation. It should
for activation is increased and the ability to conduct an action be understood that with current electrode designs, it is likely that
potential is reduced. A positively charged electrode or anode pro- several structures are being stimulated simultaneously.
duces this type of anodal effect. Practically, with SCS, the active The most effective stimulation for the extremities is generally
electrode for stimulation is the cathode; in other words, stimulation achieved with an electrode positioned within 3 mm of the physio-
occurs at the cathode. Although the electrical field may be drawn in logic midline. In order to stimulate more midline structures (e.g.,
the direction of the anode, the anode will practically function to axial lower back), the electrode must be positioned in the physio-
‘‘shield’’ neuronal structures from stimulation, a concept termed logic midline.8,12 Recalling the somatotopic organization of the DC
anodal shielding. This is an important concept to understand in in the lower thoracic spine, the posterior leg will generally be more
order to stimulate certain structures that one desires to stimulate easily and consistently stimulated by an electrode directly in the
while avoiding producing unwanted stimulation in other structures. midline, whereas the anterior leg (supplied by more rostral derma-
The closer the proximity of the anode in relation to the cathode, the tomes) will be covered by slightly more laterally placed electrodes.8
more influence it will have over the shape and distribution of the In order to stimulate bilaterally, the electrode must be perfectly
electrical field. positioned in the physiologic midline. The chest and abdominal
wall will be stimulated by more laterally placed electrodes. to surgery because nearly all patients with chronic pain have some
The upper extremity can be relatively easily stimulated by either psychological factors that contribute to their overall pain and suf-
midline or lateral electrodes. As a general rule, the stimulation- fering.13 Virtually all patients with chronic pain suffer at least some
induced paresthesias will spread caudal to the level of the electrode element of depression that often improves with better pain control.
and occasionally rostrally. Indeed, some patients may report par- However, patients with major depression accompanied by suicidal
esthesias in the upper extremities from a midthoracic electrode, thoughts or gestures require intense psychiatric intervention and are
although this is very inconsistent and unpredictable. It is important not appropriate candidates for any invasive intervention until these
to remember that the spinal cord may not be perfectly centered issues have been addressed and brought under control. Other psy-
within the spinal canal in many patients. Consequently, the physi- chosocial stressors such as job dissatisfaction and marital problems
ologic midline may not correspond to the anatomic midline. For should also be addressed because surgery is not going to fundamen-
example, some patients may report paresthesias in the left leg with tally alter those issues. Patients with major personality disorders
an electrode that clearly is positioned anatomically to the right of often do not have favorable outcomes from procedures to treat
the midline. It is important to not dismiss the patient’s response as chronic pain, and one should use caution in selecting these patients
aberrant but rather to make the proper adjustments in electrode for procedures such as SCS. Finally, careful judgment and caution
position to overcome the problem. should be exercised in considering implantable pain therapy for
patients in whom problems such as alcoholism or drug addiction
have been identified as ongoing issues. The presence of these beha-
GENERAL PRINCIPLES OF SURGICAL viors often portends a poor prognosis with any type of implantable
TREATMENTOF CHRONIC PAIN pain therapy.13
Assessing the role of psychological factors can be somewhat
Management of the patient with a chronic pain condition is often a complicated. First, there is the need to identify their presence or
complex and difficult challenge, for both the patient and the health absence. Most patients show a mixture of depression, somatic focus
care provider. Successful management of these patients requires a (e.g., hypocondriasis), anxiety, and/or emotional reactivity (e.g.,
thorough understanding of the pain problem along with a careful hysteria). The degree of sensitivity and specificity among various
and contemplative approach in developing an effective treatment psychological tests to detect these and other psychological states
algorithm. Failure to obtain a complete and meticulous history varies.13 Second, the magnitude of psychological factors appears
regarding the details of the patient’s pain and previous treatment to vary with the complexity of the disorder. It has been shown
not uncommonly leads to poor patient selection and failure of the that patients with multiple areas of pain demonstrate increased
treatment employed. It simply cannot be overemphasized that care- levels of psychological distress compared with patients with a
ful patient selection represents the cornerstone of successful surgical single pain complaint. Third, psychological factors may be media-
management of chronic pain. This is especially true for patients tors, modulators, or maintainers of pain. For example, in some
being considered for SCS or, for that matter, any type of implan- patients with a clear-cut pain generator, the degree of psychological
table pain therapy. One needs to also recognize and accept that distress as measured by the Symptom Checklist 90 (SCL-90) was
chronic pain is a multidimensional biopsychosocial problem and, either reduced or resolved along with the pain, suggesting that the
in a sense, a chronic disease. Consequently, it must be understood psychological distress was secondary to the pain.13 In contrast, in
that effective management of most patients with longstanding pain patients with more generalized diffuse pain of unclear cause, the
requires a multidisciplinary approach, utilizing all modalities and correlation is not so clear. Patients with histories of physical/sexual
specialists at one’s disposal. Indeed, the belief on the part of the abuse were found more likely to develop chronic pain after injury
patient and/or the physician that a surgical procedure alone, such as and more recalcitrant to treatment, implying some type of predis-
implantation of a spinal cord stimulator, will provide a ‘‘cure’’ is a position to pain. Such patients may manifest a differential response
foolish thought and will nearly always result in treatment failure to an ‘‘acute’’ procedure such as a brief trial of SCS rather than
and a dissatisfied patient. The successful treatment of chronic pain chronic treatment (e.g., long-term SCS therapy), perhaps explaining
should follow a logical algorithm, beginning with the most simple the reduced effectiveness after a permanent implant that occurs in
and least interventional therapies and progressing to more complex some patients.
invasive modalities. Unfortunately, and perhaps all too commonly, some chronic
pain patients and even some physicians harbor the belief that ‘‘if
the pain is relieved everything else will be fine.’’ Clearly, it is overly
PSYCHOLOGICAL SCREENING simplistic and frankly foolish for the patient and especially for the
treating physician to believe that any surgical procedure is going to
Because nearly all patients with chronic pain demonstrate at least correct everything that is wrong in a patient’s life. Application of
some degree of psychosocial stress, a baseline neuropsychological therapies such as SCS under these circumstances will more often
evaluation should be completed in every patient as part of the screen- than not result in treatment failures as well as a variety of other
ing process prior to proceeding with a trial of SCS. Evaluation by a problems. It is important to remember that, even under ideal cir-
skilled pain psychologist is invaluable for identifying factors, such as cumstances, not everyone can be helped with an implanted device
significant depression and external psychosocial stressors, that and the decision not to proceed with a pain procedure—rather than
might influence the effectiveness of treatment. An experienced going ahead with an operation in which the risks significantly out-
pain psychologist is also helpful in reinforcing reasonable expecta- weigh the potential benefits—is sometimes in the patient’s best
tions regarding effectiveness of a particular treatment and assisting interest.
the patient in coping with residual pain not alleviated by procedure.
This is extremely important because SCS, or any other pain proce-
dure for that matter, is unlikely to completely eliminate or ‘‘cure’’ CLINICAL INDICATIONS, PATIENT
the condition(s) for which this therapy is applied. In fact, we have SELECTION, AND RESULTS
anecdotally noted improved results in patients treated with SCS
who participate in various behavioral therapies such as biofeedback, All patients considered for SCS or any implantable pain device
stress relaxation training, and coping skills in addition to receiving should undergo a comprehensive preoperative evaluation and
their SCS implant. screening including a detailed history of their pain problem and
Identification of psychological factors believed to affect the all prior treatments along with a thorough neurologic examination.
patient’s pain should not necessarily be viewed as a contraindication Imaging studies appropriate to the particular problem should be
reviewed to clarify the underlying pathologic process if possible and Approximately 30% of these patients continue to report persistent
exclude a potentially correctable primary surgical problem. pain in spite of surgical intervention; many of these subsequently
Evaluation tools such as the McGill Pain Questionnaire (MPQ) undergo repeat surgery that is often similarly unsuccessful. There
and visual analog scale (VAS) are useful in characterizing the type are multiple reasons for FBSS including failure to correct the orig-
and intensity of pain and should be completed prior to surgery and inal pathology, complications of the surgical procedure such as
at fixed postoperative intervals to monitor effectiveness of therapy. inadvertent nerve root injury or arachnoiditis, lack of a good indi-
Unfortunately, changes in VAS scores alone often do not reflect the cation for the original surgery, and the existence of a condition for
true effectiveness of a particular therapy and clearly are inadequate which surgery is known to be ineffective.
for determining the benefit of a particular therapy on functional Most patients with FBSS probably suffer from a mixture of both
capacity, quality of life, and other factors. Indeed, many patients neuropathic and nociceptive pain. Most authors have maintained
show a significant discrepancy in their reported degree of subjective and continue to maintain that SCS is most effective for neuropathic
pain relief (as a percentage of their baseline pain) compared with pain that is predominantly radicular in nature.15 Predominantly
the absolute reduction in their VAS score postimplant. The use of axial pain in the lower back or pain that involves other midline
standardized validated questionnaires such as the Health Status regions (e.g., perineum) can be very difficult, although perhaps not
Questionnaire 2.0 (HSQ 2.0) and Quality of Life Inventory impossible, to treat effectively with SCS.
(QOLI) (NCS Pearson, Inc.) for assessing the impact of SCS as Early success rates as high as 90% have been reported in patients
well as other implantable pain therapies can be very helpful in with FBSS. Unfortunately, the long-term analgesia has not been as
assessing the impact of a particular treatment on function and qual- durable as one would desire. Indeed, a gradual decline in efficacy
ity of life. tends to occur over time such that long-term outcomes are consid-
Although numerous published series in the literature detail the erably less. Kumar and colleagues31 summarized the overall results
results of SCS, most are retrospective and vary significantly in their of 16 series of SCS reported in the literature. Pooled data from 8 of
methods of data collection and reliability. Indeed, prospective series these series that included all types of pain syndromes indicated that
in general and randomized trials in particular are lacking. One of of 1261 patients who were screened, 894 (71%) received a perma-
the major problems in assessing the efficacy of SCS based on the nent implant. Long-term pain relief (i.e., >50%) was achieved in
available literature is a lack of uniformity of the definition of a 530 (59%) patients. However, the results for the group of patients
successful outcome and the manner in which outcomes are reported with FBSS were less impressive. Collated data from 10 different
in general. The overall long-term results of SCS vary considerably. series showed that the implantation rate was higher in the group
The percentage of patients who continue to maintain more than with FBSS; 860 (88%) patients were implanted out of 972 who were
50% reduction in pain ranges from less than 20% to as high as 75% initially screened. However, in examining the long-term efficacy,
depending on the clinical series, underlying pain conditions, and only 42% of patients continued to maintain more than a 50%
length of follow-up.14 reduction in pain.
Overall, the outcomes for SCS in patients with FBSS have been
fairly consistent. In looking at multiple clinical series, it can be
Failed Back Surgery Syndrome concluded that about 50% to 60% of patients will derive at least
50% reduction in pain with SCS. Approximately 60% of patients
SCS is currently used for a wide variety of painful conditions experience improvement in activities of daily living as the result of
(Box 75–1).15–30 In the United States, by far the most common SCS. Although the effect on medication intake is more variable,
indication for SCS is in patients with so-called failed back surgery some studies report in excess of 80% to 90% of patients who
syndrome (FBSS). Patients with FBSS represent a heterogeneous were able to discontinue the use of pain medications.
group of patients who continue to experience persistent axial Recently, North and coworkers17 demonstrated a statistically
back and/or radicular pain after one or more surgical procedures significant benefit of SCS over reoperation for patients with FBSS.
on the spine. Of the more than 600,000 patients who undergo spinal Sixty patients judged to be candidates for reoperation were ran-
surgery annually, more than 50% involve the lumbosacral spine. domly assigned to either a trial of SCS or reoperation. Fifty patients
ultimately proceeded to treatment. Six months after the initial treat-
ment, patients were given the option to cross over to other treat-
Box 75^1 CURRENT APPLICATIONS OF SCS ment arm. An additional 39 patients who did not consent to
randomization underwent reoperation.
Postlaminectomy pain syndrome (i.e., FBSS) Fourteen of 26 patients initially assigned to reoperation eventu-
Persistent radiculopathy ally crossed over to SCS (54%) whereas only 5 of 24 patients who
Axial low back pain were treated with SCS crossed over to reoperation (21%) (P = .02).
Adhesive arachnoiditis Out of 38 nonrandomized patients who underwent reoperation,
Brachial plexitis 14 (37%) ultimately chose to undergo SCS. Among patients avail-
Neurogenic thoracic outlet syndrome
able for long-term follow-up, SCS proved significantly more suc-
CRPS
Type I (i.e., reflex sympathetic dystrophy)
cessful than reoperation. Nine of 19 (47%) of patients randomized
Type II (i.e., causalgia) to SCS achieved at least 50% pain relief and were satisfied with the
Peripheral nerve injury pain treatment compared with only 3 of 26 patients (12%) randomized
Painful peripheral neuropathy (e.g., diabetic neuropathy) to reoperation (P < .01). When the authors analyzed the results
Ischemic limb pain secondary to peripheral vascular disease based on the latest treatment (including cross-over), 52% (15 of 29)
Intractable angina pectoris of patients treated with SCS were considered long-term success
Post-thoracotomy pain or intercostal neuralgia whereas the success rate for those whose final treatment was
Ilioinguinal neuralgia reoperation was 19% (3 of 16). The authors also looked at opioid
Postherpetic neuralgia usage as a secondary outcome measure and found that opioid usage
Interstitial cystitis
Visceral pain syndromes
either remained stable or was reduced in 87% of patients treated
Coccydinia with SCS compared with 58% who underwent reoperation.
Vulvodynia Therefore, in the absence of spinal instability or neurologic deficit
referable to a compressive lesion, it would appear that the results
CRPS, complex regional pain syndrome; FBSS, failed back surgery syndrome; SCS, spinal cord
stimulation.
obtained with SCS are superior to those for patients who undergo
further surgery.
Complex Regional Pain Syndromes and this effect has been shown to be durable over time.34
Consumption of short-acting nitrates is significantly reduced with
Complex regional pain syndrome (CRPS) type I (reflex sympathetic SCS, sometimes as much as 80%. SCS also results in improved
dystrophy) and type II (causalgia) represents another excellent indi- exercise tolerance along with ischemia-induced electrocardio-
cation for SCS. Unfortunately, the variable nature of the sympto- graphic changes (i.e., ST depression).5 Additional benefits of SCS
matology in patients with CRPS makes comparison of clinical series on angina are highlighted in Box 75–2.
somewhat difficult. Kumar and associates32 performed SCS in 12 In 1998, Mannheimer and associates35 published the results of
patients with CRPS type I. Two thirds had undergone a previous the ESBY Study, a prospective, randomized, controlled trial of SCS
sympathectomy without benefit. All patients experienced sufficient versus coronary artery bypass grafting (CABG) to determine
pain reduction during a trial of stimulation to justify a permanent whether SCS might be an alternative to CABG in high-risk patients.
implant. All patients experienced either good (50%–75%) or excel- The results in 51 patients who underwent CABG and 53 patients
lent (75%–100%) relief of pain with an average follow-up of 41 treated with SCS were very similar in regard to reduction in angina
months. Kemler and colleagues19 reported the results of a retro- frequency (67.9% vs. 69.9%, respectively), reduction in nitrate
spective analysis of SCS in 23 patients with CRPS I. Eighteen (78%) intake (77.4% vs. 73%, respectively), self-reported symptom relief
patients had a successful trial and underwent placement of a per- (79.5% vs. 83.7%, respectively), and overall morbidity. The CABG
manent system. Three patients had the system removed after group did demonstrate a greater reduction in myocardial ischemia
implantation. Of the remaining patients, mean pain scores at 6 months, although exercise testing was conducted with SCS
decreased from 7.9 to 5.4 with a mean follow-up of 32 months. turned off. However, patients who underwent SCS had a signifi-
The same authors have since published their results of a rando- cantly lower mortality (1.9%) compared with those who underwent
mized, controlled trial of SCS plus physical therapy (PT) compared CABG (13.7%) and only one fourth of the cerebrovascular mor-
with PT alone.20 Patients were randomized 2:1 to receive SCS plus bidity experienced in the CABG patients. A more recent study with
PT versus PT alone. Twenty-four of 36 patients who underwent test an average follow-up of nearly 5 years after implant showed
stimulation received a permanent implant. Nineteen of 24 patients Kaplan-Meier curves that paralleled each other, indicating similar
had a reduction of at least 50% in their baseline VAS score. All survival figures for both groups. Moreover, late quality of life data
patients reported that they were ‘‘much improved’’ using a global demonstrated equal benefits in both the SCS and the CABG
perceived-effect score. Based on an intention-to-treat analysis, VAS groups.36
scores were reduced in the SCS group by an average of 2.4 versus an Currently, SCS is indicated for patients with severe chronic
increase of 0.2 in the group that received PT only (P < .001) after intractable angina (New York Heart Association classes III–IV)
6 months of follow-up. Of the 24 patients who actually received who have received maximal medical therapy and are not candidates
an implant, the VAS score was reduced by an average of 3.6. Of the for further coronary revascularization procedures. Comprehensive
36 patients assigned to the SCS group, 14 (39%) had a global inclusion and exclusion criteria are outlined in Box 75–3.
perceived-effect score of 6 (6 = much improved) compared with
only a single patient (6%) in the group assigned to PT alone.
Similar results have been reported with 2-year follow-up.28 Peripheral Vascular Disease
Unfortunately, SCS did not appear to result in any functional
improvement. SCS has been used for the treatment of tissue ischemia since the
mid-1970s. SCS has been shown to produce arterial vasodilatation
as measured by plethysmography, Doppler flow studies, and xenon
Angina clearance.5,37 Increases in capillary blood flow, limb temperature,
and cutaneous oxygen tension, which may be a requirement for
Mannheimer and coworkers33 using transcutaneous electrical stim-
ulation (TENS) were the first to demonstrate that angina responds
favorably to electrical stimulation. SCS has been used to relieve Box 75^3 INCLUSION AND EXCLUSION CRITERIA FOR SCS
intractable angina pectoris since the late 1980s, primarily in IN PATIENTS WITH INTRACTABLE ANGINA
Europe. Indeed, long-term studies of SCS for intractable angina
have demonstrated that SCS is effective in more than 80% of Inclusion Criteria
patients. However, only recently has SCS been approved by the Chronic intractable angina
U.S. Food and Drug Administration (FDA) for clinical trials in Maximal medical management
b-Blockers, calcium channel agents, nitrates, ASA
the United States. SCS has been shown have a number of benefits Objective reversible myocardial ischemia
in this population of patients (Box 75–2). Significant coronary artery disease
SCS has clearly been shown to reduce the frequency and severity 70% reduction in major vessel with poor run-off
of anginal attacks and, in some patients, can actually eliminate Unsuitable for coronary revascularization
angina. Angina frequency is reduced at least by 50% on average, PTCA or CABG
Able to provide informed consent
Exclusion Criteria
Box 75^2 BENEFITS OF SCS FOR INTRACTABLE ANGINA Inability to accurately describe angina
Myocardial infarction during prior 3 mo
PECTORIS Inability to perform exercise test
Conduction disturbances precluding recognition of ischemia
Reduction in number and severity of angina attacks Patient with ‘‘on-demand’’ pacemaker (relative contraindication)
Reduction in short-acting nitrate consumption Inadequate medical therapy
Reduction in exercise-induced ischemia and (severity, duration, MRI with body coil planned in near future
latency) Spinal pathology precluding SCS placement
Increased latency to onset of exercise-induced angina Coagulopathy
Improvement in exercise tolerance Dementia
Reduction in number of emergency room visits and admissions for Unwilling or unable to comply with follow-up
uncontrolled angina
Improved quality of life ASA, acetylsalicylic acid; CABG, coronary artery bypass graft; MRI, magnetic resonance imaging;
Reduction in overall cost of care PTCA, percutaneous transluminal coronary angioplasty.
analgesia, have all been shown to occur with SCS. As early as 1976, Overall, they reported more than a 75% reduction in pain in 78% of
it had been shown that SCS performed in patients with multiple patients including 102 (89%) with stage III disease and 36 (57%)
sclerosis resulted in improvement of lower extremity blood flow.5 with stage IV involvement. This initial improvement persisted for at
It was further postulated that analgesia in patients with peripheral least 6 months in nearly two thirds of the patients. Clearly, patients
vascular disease (PVD) could be directly correlated with augmen- with stage III disease have better outcomes. However, even a success
tation of limb circulation. It was believed that SCS resulted rate of 57% in stage IV patients is comparable with that achieved in
in improvement in blood flow by suppression of sympathetic vaso- the average patient with FBSS. Kumar and coworkers41 evaluated 46
motor control and, therefore, might even be more effective in patients with unilateral ischemic pain for implantation of a SCS.
patients with a significant component of vasospastic disease. The authors defined their criteria for a successful outcome as
Based on encouraging reports from several initial studies, the use greater than a 50% reduction in VAS pain score, doubling of base-
of SCS for peripheral limb ischemia spread rapidly in Europe. line claudication distance, a 50% or greater increase in tcPO2, a 25%
Similar to the results seen in patients with angina, satisfactory or greater increase of peak flow velocity, and a 25% or greater
pain relief has been reported in 67% to 93% of patients with ische- increase in pulse volume recording in calf/foot. Failure was defined
mic pain related to PVD.8 In addition, a limb salvage effect has also by an unsuccessful SCS trial, amputation, or removal of the device
been suggested in this group of patients. However, much like after implantation. Thirty-nine of 46 (85%) patients received an
angina, this application of SCS has not been widely adopted in implant, and 30 (77%) were determined to be long-term successes
the United States despite the seemingly excellent results that have with an average follow-up of 21 months. Pain relief was shown to
been reported. correlate with changes in tcPO2 (P = .016) as well as in peak flow
Peripheral arterial disease may produce several different pain velocity (P = .031).41
components including a deep aching ischemic pain caused by As discussed previously, it was originally believed that SCS
ischemic ulcers and pain from the border of gangrenous tissue might have a significant limb salvage effect or, more accurately, a
zones. Both are primarily nociceptive and generally respond to reduction in amputation rates. Whereas this may be true to some
opiates. However, with advanced disease, many patients also extent, the original enthusiasm for this claim probably needs to be
develop a significant neuropathic pain component that is more tempered. There have been three relatively recent randomized, con-
opiate-resistant. Despite the fact that ischemic pain has a significant trolled studies that have failed to show any statistically significant
nociceptive component, it still seems to respond quite well to SCS. difference in amputation rates with SCS at 12 and 18 months
Indeed, good evidence indicates that one of the primary mechan- follow-up. However, an ‘‘almost significant’’ limb salvage has
isms by which SCS alleviates pain in PVD is through resolution been shown in a subgroup of patients with baseline tcPO2 values
of tissue ischemia. between 10 and 30 mm Hg measured over the dorsum of the foot.
SCS is potentially indicated for patients with primary vasospas- Furthermore, even more recently, Amman and coworkers27
tic diseases such as Raynaud’s, limb ischemia in patients with reported a highly significant difference in limb survival in patients
collagen vascular diseases, degenerative atherosclerotic disease, with inoperable, stable, critical limb ischemia for those treated with
and diabetic arteriopathy. The largest group of patients with SCS compared with controls.
PVD for which SCS is indicated includes those with claudication The outcome of SCS in patients with vasospastic disease is gen-
plus rest and/or night pain who have a life expectancy of at least erally more promising and Augusstinsson29,37 has even maintained
3 to 6 months and who lack significant tissue involvement. These that vasospastic disease may be the best indication for SCS. In addi-
patients have exhausted conservative therapy and are not candi- tion to Raynaud’s, SCS may also improve outcome in patients with
dates for further revascularization procedures. It has been shown frostbite, Buerger’s disease, and scleroderma. It is therefore some-
that SCS can in fact result in frank healing of ulcers or at least what surprising that the number of published cases of this applica-
arrest the progression of tissue loss in an extremity. It has also tion remains relatively small.
been suggested by some studies that SCS may reduce the need for
or prolong the time to amputation in this population of patients,
although whether SCS actually has a significant limb salvage effect OTHER INDICATIONS
is still debatable.
Transcutaneous tissue oxygen levels (tcPO2) have been shown There are a number of other indications for SCS. There is probably
to be of prognostic value in determining those who will respond a well-defined role in patients with painful diabetic peripheral
best to SCS.38,39 Patients with baseline preoperative tcPO2 between neuropathy who have otherwise exhausted pharmacologic ther-
10 and 30 mm Hg have been shown to have the best outcomes apy.41,42 The success of SCS in this group of patients may be
with SCS. Moreover, within this group of patients, those with related to the severity of neuropathy and the degree of large
successful outcomes had a mean change in tcPO2 of around fiber sensory impairment. SCS has been successfully employed in
45 mm Hg with SCS versus a mean change of 15 mm Hg in patients with postamputation pain syndromes including both
those who were failures. It has been further suggested that a com- stump pain and phantom pain. Stump pain is the result of a
parative evaluation between tcPO2 levels in the supine and sitting painful neuroma and really represents a peripheral nerve injury.
positions may provide additional evidence of success.38 A gradient Logic would suggest that this type of pain should in fact respond
exceeding 15 mm Hg was shown to predict a successful outcome relatively well to SCS. Conversely, it is curious that phantom pain
in 88% of patients. does in fact respond to SCS in some patients. Interestingly, in
SCS has been shown to result in satisfactory pain relief in 68% to patients with phantom pain who are successfully treated with
93% of patients. Indeed, the effectiveness of SCS in PVD has been SCS, ‘‘phantom paresthesias’’ are generally perceived overlapping
confirmed in a Cochrane meta-analysis of 450 patients.25 In the the region of phantom pain. Although the success rate is probably
earliest published series, 102 out of 115 (89%) of patients who much lower than for other types of neuropathic pain, SCS is
underwent a trial of SCS received a permanent implant. Of worth considering because the other alternatives such as motor
these patients, good or excellent pain relief was reported in cortex stimulation or DREZ lesions are more invasive and have
around 80%.24,29,30 Augustinsson and colleagues22 treated 34 higher morbidity. Finally, SCS has also been suggested for the
patients with SCS and reported significant pain relief in 94%, a treatment of conditions such as postherpetic neuralgia and post-
50% ulcer healing rate, and an amputation rate of 38% compared thoracotomy pain. In the author’s experience (RKO), postherpetic
with 90% in a control group followed over 16 months. Horsch and neuralgia responds quite poorly to SCS. The inconsistent results in
Claeys40 performed SCS in 177 patients with ischemic limb pain the literature may be related to the degree of deafferentation that
including 114 with Fontaine stage III and 63 with stage IV disease. occurs in this condition.
SCREENING TRIAL FOR SCS extension is removed, and the original electrode is connected to a
permanent power source. However, if the trial is unsuccessful, the
One of the major advantages of SCS is that a screening trial can be patient must be returned to the operating room to remove the
performed to determine effectiveness prior to proceeding with a electrode. The main advantage of this technique is that it obviates
permanent implant. The primary purpose of a trial is to identify the need to place new electrodes for the permanent implant. This
and accurately select patients who will achieve long-term success method can be very useful in situations in which placement of the
after implantation of a SCS system. Without exception, every trial electrode was very difficult or it was difficult to position the
patient who is believed to be a candidate for SCS should have a electrode in a location to obtain adequate paresthesias overlap of
screening trial performed before implantation of a permanent the pain pattern. Although many implanters might argue that this
system. It should be understood that the goals of the trial and cri- method is associated with a higher risk of infection, it has not been
teria for success may not be uniform for all patients; these need to the experience of the author (RKO).
be defined on a case-by-case basis. It is important that the specific The third method of screening involves implantation of a sur-
goals and criteria for success be discussed and defined by both the gical lead. Surgical leads can be particularly useful in patients who
physician and the patient before proceeding with the trial. have undergone extensive multilevel laminectomies, which can
The most obvious, and probably the outcome on which patients make accessing the epidural space with a needle and placement of
are most focused, but sometimes the most overrated goal of any a percutaneous electrode difficult and, in some cases, impossible. If
treatment for chronic pain is absolute pain reduction. The ‘‘gold a surgical lead trial is considered, the process is then identical to
standard’’ that generally has been accepted as the criteria for suc- that described previously for the tunneled percutaneous trial.
cessful treatment is a 50% reduction in baseline pain. There is no general consensus as to the ideal duration for a trial,
Unfortunately, pain reduction alone does not always translate which can last anywhere from 24 hours to several weeks. Regardless
into a significant or acceptable improvement in a given patient’s of the method used, the author’s (RKO) personal preference is usually
condition. This can be described by the concept that ‘‘one man’s to perform a 10- to 14-day trial. However, in the author’s opinion
junk is another man’s treasure.’’ Some patients may be quite satis- (RKO), the trial should be no less than 3 days and preferably at least 1
fied with a lesser degree of pain reduction and positively translate week. Longer trials allow for better assessment of function, give the
this into their daily life with increased activity, and the like. patient ample opportunity to assess the effects of the stimulation, and
Conversely, there are some patients who may not ultimately be provide the opportunity to adjust programming and stimulation
satisfied with a pain reduction of 90%. This discrepancy in large parameters to obtain the ideal paresthesia coverage. Moreover, a
measure is a reflection of the psychosocial factors that influence longer trial allows for dissipation of any potential placebo response
pain and suffering for a given patient. Although pain reduction is that may occur in a given patient. In the author’s opinion (RKO),
certainly important, just as important is a demonstration of func- trialing for analgesia in the operating room with immediate implan-
tional improvement with treatment. Unfortunately, there are no tation of the permanent system should be discouraged.
good standardized tools to measure functional improvement that There are several additional principles of screening central to
have been applied to patients undergoing implantable pain thera- obtaining accurate information that will eventually lead to a suc-
pies. Level of function varies considerably among patients, and what cessful permanent implant. With few exceptions, one should gen-
is significant for one may not be significant for another. Other erally select the type of electrode configuration for the screening
measures of success may include improvements in mood and trial that one anticipates will be required for an effective permanent
sleep pattern as well as reductions in medication consumption. implant. For example, if a dual-electrode system is considered nec-
Many patients incorrectly assume that an SCS or other implantable essary to achieve optimal paresthesia coverage, then dual electrodes
device may allow them to discontinue medications. Whereas this should be considered for the trial. It is crucial that an optimal
is certainly a potential benefit of SCS, in the author’s experience stimulation pattern, that is, 100% coverage of the pain topography,
(RKO), most patients continue to require some medications even be achieved and consistently maintained with the trial in order
after what is considered a successful implant. to make an accurate judgment as to the therapeutic benefit.
Several methods are available for screening: the temporary Remember, with rare exceptions, for SCS to be effective, the patient
percutaneous trial, a percutaneous tunneled trial, or a trial with a must be able to perceive paresthesias that overlap the pain topog-
surgical or paddle electrode. Each method has advantages and draw- raphy. Lastly, one should avoid overstimulation of one area in order
backs, and there is no consensus as to the best method. A pure to get stimulation into a different area. For example, if a patient has
temporary trial is performed using a percutaneous electrode that pain restricted to the foot and first perceives stimulation in the
is externalized with the intention of removing it at the conclusion of thigh, one should avoid simply ramping up the amplitude in
the trial. This is a very simple and straightforward procedure that in order to drive the stimulation more caudally. This may produce
many cases can be performed in the outpatient clinic setting. painful stimulation in an area that is not part of the pain topogra-
Because the electrode is always removed at the end of the trial, it phy and may cause the patient to dislike the sensation and effec-
does not commit the patient to any additional procedures in the tively produce a false-negative trial.
event the trial is unsuccessful. This is an ideal technique, particu- Lastly, it is critical for the clinician to remember that a successful
larly in situations in which the clinician may have some doubts as to trial in no way guarantees long-term success of a permanent
whether trial will be successful. Furthermore, because the patient implant. This is supported by the observation that as many as
also understands that the trial electrode will be removed and there is 50% of patients who experience battery failure never have their
no anticipation of a staged procedure for a permanent implant, she internal pulse generator replaced. The key to long-term success
or he may be less likely to embellish the result and thereby lessen the with SCS, as with any other pain procedure, is careful patient selec-
chances of a false-positive trial. The most significant downside to tion, education of the patient as to the realistic expectations, and a
this method is that occasionally ideal placement of a permanent thorough understanding by the implanting physician of the benefits
electrode cannot be replicated during the permanent procedure, and limitations of the device.
although for the experienced implanter this is relatively uncommon.
A second method of screening is the percutaneous tunneled trial.
With this method, after the electrode(s) is inserted and properly PERMANENT SCS IMPLANT
positioned, an incision is made incorporating the wire and the elec-
trode is anchored to the fascia. This is then connected to a tempo- Following a successful trial by whatever criteria have been set by the
rary extension wire that is brought out through the skin, remote patient and implanting physician, a permanent SCS system is
from the surgical incision. If the trial is successful, the temporary implanted. Assuming the trial was performed with a temporary
percutaneous electrode, one needs to decide whether to use a per- rechargeable IPGs. The choice of the power source depends on a
cutaneous electrode or a surgical lead for the permanent implant. number of factors including the total number of contacts to be con-
Some of the considerations for using percutaneous as opposed to nected, the anticipated power requirements, frequency needs, and
surgical leads have been discussed previously. Because most physi- patient compliance and competence (Table 75–1). For pure conve-
cians who implant SCS systems are nonsurgeons and lack formal nience, most patients prefer a fully implantable IPG as opposed to an
surgical training, they will naturally choose percutaneous electrodes RF system that requires the patient to wear an antenna over the
unless they enlist the services of a spine surgeon. Conversely, many receiver in order to use the stimulator. For the most part, RF systems
surgeons will naturally choose surgical leads because they may not have been supplanted by primary cell or rechargeable IPGs. However,
be comfortable with the percutaneous needle techniques required to there are selected circumstances in which an RF system may be
place percutaneous electrodes. Again, there are both advantages and useful. Some patients, particularly those with CRPS, sometimes
drawbacks to each type of lead. require very high frequency stimulation for analgesic benefit. In
Percutaneous electrodes are usually fairly easy to place and such cases, an RF system may be the best option. Unlike IPGs, an
require only a fairly superficial soft tissue dissection for anchoring. RF receiver is merely a passive device and, therefore, never requires
Percutaneous electrodes also provide more flexibility than surgical replacement unless there is a physical problem with the device.
leads and may be advantageous in patients with complicated pain It is worthwhile to mention something regarding anesthetic
patterns. Percutaneous leads come in either 1 x 4 or 1 x 8 config- technique for implantation of a SCS system. In order to achieve
urations with a variety of interelectrode distances. It is possible to optimum electrode position and ensure a successful outcome to the
design a ‘‘custom’’ stimulation system utilizing multiple percuta- greatest extent possible, it is necessary for the patient to provide
neous leads. Percutaneous leads are steerable to some degree and accurate feedback during placement of the electrodes. Therefore,
allow one to explore a much larger area of the spinal cord in a with a few specific exceptions, implantation of an SCS system
rostral-caudal direction in order to identify the ‘‘sweet spot’’ for must be performed with the patient awake. This is true whether
stimulation that will produce the optimum paresthesia coverage. one is using percutaneous electrodes or a surgical lead. Most
The major downside to percutaneous leads is their propensity to implants can be accomplished using local anesthesia combined
migrate, especially in a rostral-caudal direction. This can be pre- with light intravenous sedation. Indeed, percutaneous electrodes
vented, for the most part, by employing sound anchoring techni- can usually be placed with relatively little, if any, sedation by liber-
ques including multiple anchoring points and the use of generous ally employing local anesthetics. It is important to anesthetize not
strain relief loops in the electrode. In contrast, placement of sur- only the superficial tissues but also the deeper tissues including the
gical leads is generally restricted to the areas immediately rostral or periosteum. If additional sedation is required, a short-acting, read-
caudal to the level of spinal exposure. Surgical leads do have some ily reversible agent such as propofol supplemented by a modest dose
advantages. Because of their shape, they are less prone to migra- of intravenous opiate works quite well. The author’s preference
tion, particularly in the cervical spine where there is significant (RKO) is to completely avoid giving any benzodiazepines, especially
movement. Indeed, once a surgical lead becomes scarred in in older patients. These drugs tend to produce more cognitive
place, it will virtually never move with normal activity. Also, impairment that sometimes completely prevents the patient from
because surgical leads are insulated except at the contact, the providing an adequate description of the paresthesia coverage. Once
entire electrical field is directed ventrally at the target, and this the electrode has been properly positioned and securely anchored to
may result in better performance in terms of power requirements prevent migration and intraoperative testing has been completed,
than percutaneous leads in which the contacts are circumferential. the patient can be deeply sedated for tunneling of the wires and
The latter is probably somewhat less important now that the use creation of the subcutaneous pocket to house the IPG.
of rechargeable impedance plethysmographs (IPGs) has become Another technique that has proved very helpful is the use of
more common. Regardless of what type of electrode is employed, spinal anesthesia. One might wonder how the patient can perceive
it cannot be overemphasized that the most important aspect of paresthesias in the presence of a complete spinal block. Remember
electrode placement is complete capture of the pain area with that local anesthetics primarily block root fibers. Activation of the
stimulation-induced paresthesias. DC is unaffected. Since 2007, the author (RKO) has utilized this
Once the electrode has been implanted, it is connected to an technique in approximately 20 patients for implantation of surgical
internal power source. There are three types of power sources: ra- lead SCS systems. In no case was the patient unable to perceive
diofrequency (RF) receivers, primary cell IPGs, and more recently, paresthesias. The only difference noted between patients operated
Table 75^1. Power Source Device Selection Matrix
Primary Cell IPG Rechargeable IPG RF System

Power needs Low to moderate Moderate to high Very high
Frequency needs Low Moderate to high Very high
Pain targets Single Multiple Multiple
Disease state Stable Stable or likely to progress Stable or likely to progress to
multiple extremities
Coverage needs 1 or 2 leads 1, 2, 3, or 4 leads 1, 2, 3, or 4 leads
Compliance requirements Easiest to use Requires following specific battery- Requires daily effort
management procedures
Competence (physical or Appropriate for all Moderate level required Moderate to high level
mental limitations) levels required
Programming needs (programs Simple, <2 Moderate, <3 Complex, >3
running in parallel)
Skin sensitivity N/A Moderate to low sensitivity Low to no sensitivity
IPG, impedance plethysmograph; N/A, not applicable; RF, radiofrequency.
upon under spinal anesthesia and those receiving local anesthesia stimulation can be intentionally attempted in patients with condi-
with intravenous sedation was the observation of slightly higher tions such as postherpetic neuralgia and post-thoracotomy pain.
perception thresholds in those who received a spinal anesthetic. However, in most cases, this is seen as an undesirable side effect.
However, these differences were minimal and inconsistent and Patients more often than not complain that trunk stimulation is
did not have any bearing on the outcome of the procedure in painful or uncomfortable and will describe the sensation as a con-
terms of accurate placement of the electrode. strictive band. Moreover, for the reasons noted earlier, sensory and
In selected cases, an SCS system can be placed under general motor activation are often achieved at the same threshold, preclud-
anesthesia. This includes placement of surgical leads in the cervical ing any therapeutic benefit.
spine, implantation of surgical leads for sacral nerve root stimula- Stimulation of the axial low back is a special consideration.
tion, and implantation of small surgical leads for spinal nerve root Many patients, particularly those with FBSS, have a significant com-
stimulation. Since 2000, for nearly all patients requiring upper ponent of lower back pain. The ability to cover the lower back with
extremity coverage, the author (RKO) has employed surgical leads paresthesias in some ways has been like a search for the Holy Grail.
placed retrograde at C1–2. This technique was originally described At best, the ability to capture the lower back has been sporadic.
by Barolat8 and has proved very effective in producing upper Many anatomic and physiologic reasons have been proposed as to
extremity coverage. We have found that placement of a 2 x 4 elec- why this has been so difficult.
trode array just off the midline consistently produces paresthesias The reasons the why the lower back may be more difficult to
coverage of the entire upper extremity with the exception of the effectively stimulate is perhaps best understood by examining the
medial arm between the elbow and axilla. Out of nearly 40 cases of sensory representations of various body areas in the brain. There are
C1–2 electrodes, we have failed to achieve adequate paresthesia several hypothetical reasons why the low back is a challenging
overlap in only a single patient. Unlike percutaneous cervical target. The first is related to the sensory homunculus, which repre-
leads, which have a relatively high incidence of migration, C1–2 sents the amount of nervous tissue dedicated to processing sensory
surgical leads almost never migrate. Conversely, these electrodes information from that particular body part or region. Because the
still have a relatively high rate of revision secondary to fracture low back is not particularly important from a functional standpoint,
from the motion of the cervical spine. it has an extremely small representation in the brain compared, for
Some surgeons will implant surgical leads under general anes- example, with the hand or face. Second, the lower back is primarily
thesia based on the location of a trial electrode. The assumption is represented by the L2–5 dermatomes. However, the area of the
that if the surgical lead is placed at the same rostral-caudal level as lower back represented by these dermatomes is only 25% of that
the trial, the stimulation pattern will be the same. Unfortunately, represented in the lower extremities by the same dermatomes.
this is not uniformly the case, and it is not uncommon to have to Therefore, if one assumes that the ‘‘receptive fields’’ per nerve are
revise electrodes placed under general anesthesia. There is nothing equal, there would be at least four times fewer fibers for back cov-
more frustrating than to implant an electrode only to have the erage than for leg coverage in the DC. Finally, there is no reason to
patient wake up, have the stimulator turned on, and realize that believe that the leg and back fibers are not distributed evenly in the
adequate paresthesia overlap cannot be achieved. What is even more DC. In other words, a low back fiber is just as likely to be located
frustrating is the refusal of the implanting physician to revise the superficially as at a deeper level.
system. More recently, some surgeons have been employing intra- So, how can one achieve low back coverage? Currently, it is
operative electrophysiologic monitoring primarily for side-to-side generally accepted that the electrode should be placed around T8–
localization. Anecdotally, some surgeons report good success with 9. Although some implanters have advocated the use of dual elec-
this technique, but this is certainly not considered a standard. trodes placed side-by-side, there is now evidence to suggest that a
single perfectly midline column will provide a better chance of low
back coverage.42 Furthermore, it has also been shown that a surgical
Implant Strategy Based on PainTopography lead may perform better than a percutaneous wire in this regard.
North and coworkers17 have in fact shown that the lower back can
Successful application of an SCS system requires that the patient be stimulated in about 70% of patients and that the stimulation can
perceive paresthesias in the distribution of the pain. It is relatively be maintained over at least a 2-year follow-up. Moreover, up to
easy to produce paresthesias in both the upper and the lower 50% of the patients who achieve back coverage also experience
extremity but more difficult to effectively stimulate axial regions. sustained reduction in pain.
Stimulation of the lower extremity is relatively easy with an elec-
trode positioned somewhere between T9 and T12. An electrode
positioned in the lower thoracic–upper lumbar region has greater COMPLICATIONS
than a 70% chance of producing stimulation that will be felt in the
foot. For patients with isolated foot pain (e.g., CRPS I), selective Minor complications are not uncommon after SCS. In a systematic
stimulation of the foot is more difficult. The chances of stimulation review of 13 case studies of SCS for chronic low back pain, Turner
of the foot with a midline or laterally placed electrode positioned at and associates16 reported a complication rate of 42% (20%–75%).
T9–12 at the perception threshold are 22% and 13%, respectively.8 Although a complication implies some degree of adverse outcome,
Conversely, if the electrode is positioned over L1–2, the chance of it does not, in and of itself, suggest negligence. Complications can
foot stimulation at the perception threshold increases to around generally be divided into surgical, device-related, and stimulation-
50%. Alternatively, the foot can be stimulated by selective L5 and related complications.
S1 nerve root stimulation with thin surgical leads placed over the The most common surgical complication is perioperative infec-
nerve roots into the neural foramen. Stimulation of the rectum and/ tion, reported on average in 5% (0%–12%) of cases. Most infections
or perineum is extremely difficult. It can rarely be accomplished by involve the IPG site, with intraspinal infection being very uncommon.
an electrode at T11–L1; alternatively, one can utilize electrodes Other surgical complications include wound hematoma/seroma,
placed through the sacral foramina. CSF leak/spinal headache, and neurologic injury. Neurologic injury
In the cervical region, it has already been pointed out that C1–2 is quite rare. It is probably more commonly associated with place-
electrodes are capable of producing coverage of most of the upper ment of a surgical lead. Neurologic injury can be avoided by always
extremity. Complete coverage of the hand can also be obtained with obtaining an imaging study of the proposed electrode site, especially
an electrode at C4–5, although subaxial surgical leads are more if a surgical lead is contemplated. Most wound complications such
difficult to place. Selective coverage of the ulnar aspect of the as infection can be avoided by strict attention to aseptic technique,
hand is best accomplished at C7–T1. Chest and abdominal wall meticulous hemostasis, and gentle handling of tissues.
Device-related complications include things such as electrode 19. Kemler MA, Gerard AM, Van Kleefe M, et al. Electrical spinal cord
migration or fracture and IPG-related problems. Device complica- stimulation in reflex sympathetic dystrophy: retrospective analysis in
tions were reported in 30% of the cases reviewed by Turner and 23 patients. J Neurosurg 1999;90:79–83.
associates.16 Migration is generally more problematic with percuta- 20. Kemler MA, Gerard AM, Van Kleefe M, et al. Spinal cord stimulation
neous than with surgical electrodes, especially cervical electrodes. in patients with chronic reflex sympathetic dystrophy. N Engl J Med
2000;343:618–624.
Migration most often results in loss of stimulation coverage. This 21. Claeys LG, Horsch S. Treatment of chronic phantom limb pain by
can be overcome to some extent by using multiple electrodes with a epidureal spinal cord stimulation. Pain Dig 1997;7:4–6.
higher number of contacts, in which case a small degree of migra- 22. Augustinsson LE, Carlsson CA, Holm J, et al. Epidural electrical
tion may be overcome by reprogramming the system. stimulation in severe limb ischaemia. Pain relief, increased blood flow
Finally, some patients report that the stimulation-induced par- and a possible limb-saving effect. Ann Surg 1985;202:104–110.
esthesias are uncomfortable or may aggravate their baseline pain. 23. Jivegard L, Augustinsson LE, Carlsson CA, et al. Long-term results by
The true incidence is difficult to ascertain from the literature. spinal electrical stimulation (ESES) in patients with inoperable severe
Burchiel and colleagues15 reported the incidence of these patient- lower limb ischaemia. Eur J Vasc Surg 1987;1:345–349.
related complications to be around 3% (5 of 219 patients).15 The 24. Broseta J, Barbera J, De Vera JA, et al. Spinal cord stimulation in
peripheral arterial disease. A cooperative study. J Neurosurg
fact is these problems should be rare in patients with a permanent 1986;64:71–80.
implant if the screening trial was conducted properly. 25. Ubbink DT, Vermeulen H. Spinal cord stimulation for non-
reconstructable chronic critical leg ischaemia (Cochrane Review).
Cochrane Library 2003;3.
26. Jivegard L, Augustinsson LE, Holm J, et al. Effects of spinal cord
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1965;150:971–979. 27. Amann W, Berg P, Gersbach P, et al. Spinal cord stimulation in the
2. Mazars GJ, Roge R, Masars Y. Stimulation of the spinothalmic treatment of non-reconstructable stable critical leg ischemia: results of
fasciculus and their bearing on the physiology of pain. Rev Neurol the European Peripheral Vascular Disease Outcome Study
(Paris) 1960;103:36–138. (SCS-EPOS). Eur J Vasc Endovasc Surg 2003;26:280–286.
3. Shealy CN, Mortimer JT, Reswick JB. Electrical inhibition of pain by 28. Kemler MA, De Vet HCW, Barendse LG, et al. The effect of spinal
stimulation of the dorsal columns: preliminary clinical report. Anesth cord stimulation in patients with chronic reflex sympathetic
Analg 1967;46:489–491. dystrophy: two years’ follow-up of the randomized controlled trial.
4. Linderoth B, Meyerson BA. Spinal cord stimulation. Mechanisms of Ann Neurol 2004;55:13–18.
action. In Burchiel K (ed): Pain Surgery. New York: Thieme, 2000; 29. Augustinsson LE, Linderoth B, Mannheimer C, et al. Spinal cord
pp 505–526. stimulation in cardiovascular disease. Neurosurg Clin North Am
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stimulation. In Melzack R, Wall P (eds): Textbook of Pain, 5th ed. 30. Broggi G, Servello D, Franzini A, et al. Spinal cord stimulation for
London: Elsevier Churchill Livingstone, 2006; pp 563–582. treatment of peripheral vascular disease. Appl Neurophysiol
6. Linderoth B, Foreman RD. Physiology of spinal cord stimulation: 1987;50:439–441.
review and update. Neuromodulation 1999;2:150–164. 31. Kumar K, Nath R, Wyant G. Treatment of chronic pain by epidural
7. Oakley J, Prager J. Spinal cord stimulation. Spine 2002;27:2574–2583. spinal cord stimulation: a 10-year experience. J Neurosurg
8. Barolat G. Spinal cord stimulation for persistent pain management. In 1991;75:402–407.
Gildenberg PL, Tasker RR (eds): Textbook of Stereotactic and Functional 32. Kumar K, Nath R, Toth C. Spinal cord stimulation is effective in the
Neurosurgery. New York: McGraw-Hill, 1998; pp 1519–1538. management of reflex sympathetic dystrophy. Neurosurgery
9. Holsheimer J. Principles of neurostimulation. In Simpson BA (ed): 1997;40:736–747.
Electrical Stimulation and the Relief of Pain. Pain Research and 33. Mannheimer C, Carlsson CA, Ericsson K, et al. Transcutaneous
Clinical Management. Amsterdam: Elsevier, 2003; pp 17–36. electrical nerve stimulation in severe angina pectoris. Eur Heart
10. Struijk JJ, Holsheimer J, Van der Heide GG, et al. Recruitment of J 1982;3:297–302.
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1992;39:903–912. systems in patients with refractory angina; a prospective feasibility
11. Struijk JJ, Holsheimer J, Barolat G, et al. Paraesthesia thresholds in study. Pacing Clin Electrophysiol 1994;17:1751–1760.
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clinical data. IEEE Trans Biomed Eng 1993;1:101–108. stimulation versus coronary artery bypass surgery in severe angina
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epidural stimulation of the intraspinal neural structures in man. 36. Eliasson T, De Jongste MJL, Mannheimer C. Neuromodulation for
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16. Turner JA, Loeser JD, Deyo RA, et al. Spinal cord stimulation for predict the efficacy of spinal cord stimulation to improve limb salvage
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18. Bennett DS, Cameron TL. Spinal cord stimulation for complex in peripheral neuropathy. Surg Neurol 1996;46:363–369.
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and the Relief of Pain. Pain Research and Clinical Management. for painful diabetic peripheral neuropathy. Lancet
Amsterdam: Elsevier, 2003; pp 111–130. 1996;348:1698–1701.
XI
COMPLEMENTARY AND
ALTERNATIVE MEDICINE
APPROACHES TO PAIN
MANAGEMENT
Chapter 76 and helps move the patient from passive therapies to a more
active role in her or his self-care.
COMPLEMENTARY AND The National Center for Complementary and Alternative
Medicine (NCCAM) is a U.S. government agency dedicated to
exploring complementary and alternative healing practices in the
ALTERNATIVE MEDICINE FOR context of rigorous science, training CAM researchers, and disse-
minating authoritative information to the public and professionals.
NONCANCER PAIN NCCAM defines complementary and alternative medicine as ‘‘a
group of diverse medical and health care systems, practices, and
Gira Patel, David Euler, and Joseph F. Audette products that are not presently considered to be part of conven-
tional medicine.’’1 It also defines integrative medicine as ‘‘[com-
bining] mainstream medical therapies and CAM therapies for
which there is some high-quality scientific evidence of safety and
effectiveness.’’1
The various modalities of CAM are well positioned to create a
more healthy bridge between the patients’ needs and the Western
INTRODUCTION allopathic approaches. On the one hand, CAM approaches try to
enhance and simplify the allopathic treatments as well as making
In most modern, allopathic Western pain clinics, patients are being them less toxic to the patient. On the other hand, CAM practi-
treated with a multitude of medications and procedures that may tioners try to engage the patients in their own healing process.
create a viscous circle of pain and adverse side effects. Symptomatic This chapter provides an insight into the use of acupuncture as
treatment with medications that can be addictive in nature, and well as some Chinese and Western herbal treatment strategies for
procedures that are not proved to be effective can cause a barrage pain management.
of unwanted side effects. It is not uncommon that patients find
themselves with a growing list of medications to take on a daily
basis without experiencing true relief of pain and/or a return to a ACUPUNCTURE
normal lifestyle. The problem has more than one side because many
patients who come to pain clinics are seeking (and often demand- Acupuncture is one the most widely used of the CAM modalities for
ing) quick fixes without the motivation or interest to devote any pain management. A growing number of hospitals offer acupunc-
time or effort toward a change in lifestyle and behavior that could ture through their pain clinics. There is also a growing number of
have a more profound effect on pain than what the clinician can physician and nonphysician acupuncturists. In 2002, the National
provide. These patients expect (often unrealistically) the physician Health Institute showed that an estimated 8.2 million adults had
to diagnose and prescribe a medication or perform a procedure that used acupuncture as opposed to an estimated 2.1 million who had
eliminates the pain quickly, even in a chronic condition, and used it in 2001. Not only is the usage of this modality growing, but
thereby absolves the patient of any responsibility to change. there is a growing body of research to support its efficacy as well.
Unfortunately, the physician is often all too ready to make such Acupuncture can be used in a clinical setting for a wide array of
heroic attempts, even when he or she knows it is unlikely to suc- pain conditions (Table 76–1).
ceed, at the expense of patient wellness. In this pain-management In order to understand how acupuncture can be used for the
quagmire, complementary and alternative medicine (CAM) can management of pain, one has to understand its origins and purpose.
provide a perfect counterbalance to conventional approaches to Different from Western allopathic medicine in which the symptom-
help reintroduce a model of care that is more process oriented atic presentation of pain is often treated via a medication or a
557
558 Chapter 76 COMPLEMENTARY AND ALTERNATIVE MEDICINE FOR NONCANCER PAIN
Table 76^1. Short List of Common Pain Conditions The manifestation of this disorder varies from patient to patient,
Treated by Acupuncture making it difficult to treat. Often, patients suffering from fibromy-
algia are highly sensitive and do not do well with current allopathic
Area of Body Pain Conditions Western treatment strategies. A growing number of these patients
turn to CAM therapies, of which acupuncture is one of the more
Low back and Degenerative disk disease, osteoarthritis, popular choices. Berman and coworkers4 reviewed seven studies,
neck pain herniated or bulging disk, spinal stenosis, including three randomized, controlled trials (RCTs) and four
postlaminectomy syndrome, sacroiliac cohort studies; only one was of high methodological quality. The
pain, myofascial pain results of the high-quality study suggest that acupuncture is effec-
Shoulder Rotator cuff problem, tendinitis/bursitis, tive for relieving pain, increasing pain thresholds, improving global
adhesive capsulitis, osteoarthritis, ratings, and reducing the morning stiffness of fibromyalgia; unfor-
postoperative pain after breast surgery, tunately, the duration of benefit after the acupuncture treatment
series is not known. The three lower-quality studies showed results
myofascial pain
consistent with these findings.
Elbow Lateral and medial epicondylitis, bursitis,
repetitive strain, osteoarthritis
Shoulder Pain
Wrist/fingers Osteoarthritis, tendinitis, sprain, trigger
finger, gout One high-quality study showed that acupuncture is an effective
Hip pain Trochanteric bursitis, tendinitis, treatment for soft tissue lesions of the shoulder, including rotator
osteoarthritis. postoperative pain cuff tendinitis, capsulitis, bicipital tendinitis, and/or bursitis.5 This
RCT included 130 patients divided into an acupuncture group
Knee pain Osteoarthritis, tendinitis, strain/sprain, and a placebo acupuncture group. Both groups were assessed
Baker’s cyst before, during, and after procedure at 3 months and 6 months.
Ankle/foot pain Sprain/strain, fracture, osteoarthritis, gout After 6 months, the true acupuncture group demonstrated statis-
tically significant improvement over the placebo acupuncture
group in the pain intensity score as well as range of motion,
functionality, quality of life, and use of anti-inflammatory
medication.
procedure, traditional Chinese medicine (acupuncture and Chinese
herbal formulas) treats the individual by focusing on the root cause
Epicondylitis
of why the patient cannot heal. Traditional Chinese medicine is
tailored to the individual and not necessarily the ‘‘disease.’’ Trinh and associates6 performed a systematic review of 53 studies
Acupuncture is a medical procedure in which fine, filiform nee- demonstrating that acupuncture was effective for short-term relief
dles are inserted into specific areas in the body (acupuncture of lateral epicondyle pain. They identified 6 high-quality rando-
points) to achieve clinical results either by modulating the course mized or quasirandomized trials that utilized needle acupuncture.
of a disease or by symptomatically reducing objective and subjective The studies evaluated patients with any pain originating from the
findings. Acupuncture is commonly practiced in conjunction with a common extensor tendon at the lateral epicondyle. The acupunc-
technique called moxibustion. Moxibustion is a thermal therapy in ture group in all 6 studies showed a significant relief in pain com-
which a dried herb, Artemisia vulgaris, is burned at or above the pared with the control group.
skin to deliver a heat stimulus to an area or acupuncture point.
Since the late 1970s, a great deal of scientific evidence has
Headache
accumulated to verify that both acupuncture stimulation and elec-
troacupuncture stimulation have reproducible physiologic effects. A In recent years, well-designed studies have provided positive results
large body of evidence has developed to show that both acupunc- for the treatment of chronic headaches and migraines. In an RCT of
ture stimulation and electroacupuncture stimulation lead to the 270 patients, Melchart and colleagues7 concluded that acupuncture
release of endorphins and enkephalins into the cerebrospinal had an effect comparable with that of other types of Western allo-
fluid. Furthermore, the release of these neuropeptides have been pathic headache treatments. In another RCT of 302 patients suffer-
demonstrated to play a role in the analgesic effect of acupuncture ing from migraines, the patients were divided into three groups:
as evidenced by the fact that opioid receptor antagonism can abol- true or verum acupuncture, sham acupuncture, and waiting list
ish the analgesia obtained with acupuncture in both human and control.8 Sham acupuncture was defined as superficial needling at
animal models of acute pain.2 distant nonacupuncture points. The result of this study was similar
The second line of evidence depends on recent technologic to that of Melchart and colleagues7 in that the number of days with
advances in mapping brain activity using functional magnetic res- headache was significantly reduced in the acupuncture and sham
onance scanning (fMRI) that have begun to be applied to acupunc- acupuncture group compared with that of the waiting list group.
ture to demonstrate the neuromodulatory effect of acupuncture However, the sham treatment was as effective as the true acupunc-
stimulation.3 ture treatment.
Another long-term RCT studied patients with chronic
headaches (the majority had migraines) at baseline, 3 months,
Clinical Data and 12 months.9 At the end of a year, the study showed that the
patients who received acupuncture had significantly lower headache
The following is a summary of favorable, high-quality research scores than the control group. In addition, the acupuncture group
papers on acupuncture and the treatment of common pain condi- missed fewer days at work, used less medication, and had fewer
tions (Tables 76–2 and 76–3). visits to the general practitioner than did patients in the control
group. A smaller study was performed to study the change in cer-
ebrovascular blood flow in patients suffering from migraine head-
Fibromyalgia
aches.10 This study showed that 60% of migraineurs in the trial who
Signs and symptoms of fibromyalgia can vary, depending on benefited from the acupuncture had less abnormality in cerebrovas-
the weather, stress, physical activity, or even the time of day. cular response to visual stimulation.
XI COMPLEMENTARY AND ALTERNATIVE MEDICINE APPROACHES TO PAIN MANAGEMENT 559
Table 76^2. Summary of Clinical Efficacy for AcupunctureTreatment of Painful Conditions
Condition Overall Efficacy Comments

Fibromyalgia Acupuncture relieves pain, improves global ratings. Based on 1 study identified from a systematic
review of 7 studies; duration of relief is not
known.
Myofascial pain Nonlocal may provide greater initial improvement Only a few low-powered studies have been
in pain and ROM compared with local DDN for published; more information is needed about
neck pain. DDN, however, is superior to SDN for technique of needling.
LBP and shoulder pain at long-term follow-up.
RA Electroacupuncture may reduce knee pain in RA. A Based on 2 studies identified from a systematic
brief single-needle technique of acupuncture has review, both of which were criticized for
no significant effect on numerous clinical and unacceptably brief treatment periods.
laboratory measures.
Headache (tension-type True acupuncture is more effective than no Sham acupuncture used in these high-quality
and migraine) treatment, but not more effective than sham studies may not have been an inert placebo.
acupuncture.
Neck pain Studies suggest that true acupuncture is more Effectiveness seems dose-dependent—studies
effective than both sham acupuncture and no with a greater total number of treatments
treatment, but data are inconclusive. yielded more positive results.
Chronic LBP Short-term: Acupuncture is significantly more Based on comprehensive meta-analysis of 35
effective than sham acupuncture, sham TENS, studies, including 22 RCTs.
and no-additional-treatment controls.
Long-term: Acupuncture is significantly more
effective than sham TENS and no-additional-
treatment controls.
Shoulder pain Acupuncture is more effective than placebo needle Based on RCT in which assessment was done
for improving pain, ROM, and function. at 3 and 6 mo postprocedure
Lateral epicondylitis Effective in the short-term relief of lateral Based on a systematic review of 6 high-quality
epicondyle pain. RCTs.
Knee osteoarthritis True acupuncture is effective in decreasing pain Based on several studies of varying quality. Few
and improving function. data are available on long-term outcomes.
DDN, deep dry needling; LBP, low back pain; RA, rheumatoid arthritis; RCT, randomized, controlled trial; ROM, range of motion; SDN, superficial dry
needling; TENS, transcutaneous electrical nerve stimulation.
See Patel G, Euler D, Audette JF. Complementary and alternative medicine for noncancer pain. Med Clin North Am 2007;91:141–167, for a more detailed
review of the literature to support these findings.
Neck Pain
allowed to receive usual medical care. At 3 months, patients in
Neck pain (as well as low back pain) is one of the most common the acupuncture group had significant improvement in neck pain
symptoms for which patients seek CAM therapies. Irnich and co- and disability over the control group. This study also demon-
workers11 published a randomized, double-blinded, sham-con- strated that acupuncture can be a valuable adjunct to usual med-
trolled, cross-over trial investigating the effect of acupuncture on ical care.
patients with chronic neck pain. The patients included in this
study presented with at least a 2-month history of neck pain.
Pain during Pregnancy
The patients were divided into three groups: nonlocal acupuncture
(acupuncture given in points distal to the presenting complaint of Elden and associates13 conducted a randomized, single-blinded,
neck pain), dry needling (local dry needling of the active trigger controlled trial with 386 pregnant women suffering from pelvic
points in the neck), and sham laser acupuncture. Each patient was girdle pain. The women were randomized into three groups: stan-
given one 30-minute session and then assessed. The study con- dard treatment, standard treatment with acupuncture, and standard
cluded that a single session of nonlocal acupuncture was superior treatment with stabilization exercises. The patients receiving acu-
to dry needling and sham laser in immediate improvement of puncture showed significantly lower pain scores when compared
motion-related cervical pain and range of motion. The results of with patients receiving standard care alone or standard care with
this study suggest that stimulation of distal points on the body can stabilization exercises. This study also demonstrated that using
be more effective than local needling for short-term pain relief, acupuncture in conjunction with standard Western allopathic care
supporting the concept that nonsegmental antinociceptive systems is more beneficial to a patient in a clinical setting. Another RCT
may play a major role in acupuncture analgesia. In another very showed acupuncture to be effective in decreasing visual analog scale
large study done in Germany with 14,161 patients, subjects with (VAS) pain scores in pregnant women suffering from low back pain
chronic neck pain were randomized to acupuncture or a control and pelvic pain.14 The study also reported decreases in pain dur-
group with no acupuncture.12 In addition, all patients were ing physical activity in the subjects who received acupuncture.
Table 76^3. General Guidelines for AcupunctureTreatment Frequency and Duration for
Various Pain Conditions
Pain Presentation Examples Treatment Frequency Duration*

Acute musculoskeletal injury Sprain/strain, sports injuries, whiplash 2–3 times/wk 5 treatments
Acute visceral pain Hepatitis, cholecystitis, kidney stones, Twice/wk 5–7 treatments
conjunctivitis, gastritis
Chronic musculoskeletal pain Myofascial pain, low back pain, shoulder Once/wk 5–10 treatments
tendinopathy, tension-type headaches
Chronic visceral pain Cholitis, irritable bowel syndrome, crohn’s, Once/wk 8–15 treatments
pancreatitis, hepatitis, pelvic pain
Acute neuropathic pain Sciatica, Bell’s palsy, trigeminal neuralgia, herpes 2–3 times/wk 5 treatments
zoster
Chronic neuropathic pain Carpal tunnel syndrome; diabetic, chemical, and Once/wk 8–15 treatments
idiopathic neuropathies
Acute headache 3 times/wk 3 times
Chronic migraine 1–2 times/wk 5–10 treatments
*Duration reflects the number of visits at which the patient should start to see a noticeable change in symptoms. This number depends a great deal on
patient willingness to follow through on recommended lifestyle changes.
These studies should help the physician practicing Western allo- HERBAL MEDICINE
pathic medicine to feel comfortable prescribing acupuncture for
pregnant patients who suffer from pain. Herbal medicine is the use of various parts of plants for medicinal
purposes. Since the beginning of history, all indigenous cultures in
the world have used natural substances (especially plants and
Low Back Pain
animal parts) to promote healing and alleviate pain. In the
A study published by the Cochrane Review including 35 RCTs modern Western clinic, the most common approaches in herbal
concluded that acupuncture is an effective treatment for chronic medicine include Western herbal approaches, traditional Chinese
low back pain.15 A recent meta-analysis had similar conclusions, herbal formulas, and Ayurvedic medicine (traditional Indian med-
finding that acupuncture was effective in the relief of low back icine). This section emphasizes the Western and traditional Chinese
pain.16 This review not only supported the analgesic effect of acu- approaches.
puncture for low back pain but also suggested that acupuncture can The main difference in the various approaches to herbal medi-
improve functionality and leads to decreased use of analgesic med- cine lies in the differential diagnosis and the clinical strategies for
ications in this population. These data are very encouraging and prescribing specific herbs. Whereas in the Western approach the
should lead to at least the consideration of utilizing acupuncture strategy for prescribing herbs is more symptom-oriented and
rather than opioids to manage chronic low back pain. Another leans toward single herbs for specific ailments, the Ayurvedic and
study published in the Archives of Internal Medicine showed that traditional Chinese approaches rely on prescribing herbal combina-
patients who received acupuncture over an 8-week period had a tions (formulas) for syndromes as they appear in different types of
greater reduction in low back pain than those on a waiting list patients (e.g., a ‘‘hot patient’’ who presents with a red face, feels
control.17 Molsberger and colleagues18 demonstrated that acupunc- warm, and might run a higher blood pressure as opposed to a ‘‘cold
ture coupled with conventional orthopedic treatment was much patient’’ who might present with a pale face and body, feeling cold,
more effective than conventional orthopedic treatment alone or and having a lower blood pressure). This unique difference between
sham acupuncture with conventional orthopedic treatment in approaches can be bridged in clinical practice by using the best of
relieving chronic low back pain. both worlds. For example, if a patient is suffering from chronic low
back pain, one can prescribe an external rub of the essential oils
from lavender (warming and analgesic) and rosemary (stimulating
Knee Pain
circulation) as well as a traditional Chinese herbal formula, Te Xiao
In recent years, a number of well-designed studies have been pub- Yao Tong Pian (treating weak kidney qi with cold back and frequent
lished, demonstrating the positive effect of acupuncture on knee urination as well as knee pain and impotence), taken internally as
osteoarthritis. A large RCT published by Berman and coworkers19 herbal pills.22
showed that acupuncture provided significantly more pain relief As one can see, the differential diagnosis for the traditional
and improvement of function in patients suffering from osteoar- Chinese herbal formula is more complex and requires an under-
thritis of the knee. Another study by Linde and associates20 showed standing of whether certain conditions are present in the patient in
that patients with various types of osteoarthritis demonstrated a addition to the symptom of low back pain in order to make the
decrease in pain for up to 6 months after acupuncture treatments. prescription of this specific formula. Often, one can find a multi-
Acupuncture has also been shown to be a complementary therapy tude of traditional Chinese herbal formulas for one specific symp-
to pharmacologic treatment. Vas and colleagues21 showed that tom. This depends on the constitution of the patient, the etiology of
patients who received acupuncture and diclofenac versus dicofenac disease, and the coexistence of other symptomatic presentations
and placebo acupuncture had a greater decrease in pain and stiff- such as heat or cold, dampness or dryness, or symptoms located
ness. In addition, the group receiving true acupuncture had a sig- mainly in the upper body or lower body. Also apparent, when one
nificant increase in physical function. reads the indications of the Chinese herbal formulas, is that the
XI COMPLEMENTARY AND ALTERNATIVE MEDICINE APPROACHES TO PAIN MANAGEMENT 561
Table 76^4. Summary of Botanicals
Botanical Substance Therapeutic Indications Common Dose Ranges Safety Issues of Concern
Capsicum (Capsicum Relief of neuropathic and Capsaicin creams: 0.025% and Burning and worsening of pain
frutescens [L.], musculoskeletal pain 0.075% strengths, applied common initially when applying
C. annuum) 3–4 times/day. topical cream. Patients should be
Fruit powder: 30–120 mg instructed to wash their hands
Tincture: 1.20 g/ml, 60% thoroughly with soap and water
ethanol: 0.3-1.0 ml after applying to avoid contact with
sensitive mucous membranes.
Cat’s claw (Uncaria Osteoarthritis, rheumatoid Extract U. tomentosa: 60 mg/day Low potential for toxicity. Safety in
tomentosa [wild] DC) arthritis, gastrointestinal pain extract (20 mg root extract/capsule pregnancy and lactation is not
standardized to 1.3% pentacyclic known.
oxindole alkaloids and free of Contraindicated pre- and postsurgery
tetracyclic oxindole alkaloids). or existence of blood clotting
Tincture: 2–4 ml disorder. Large dosage may cause
Decoction: 1 cup twice/day stomach pain, diarrhea.
Devil’s claw Acute back pain, osteoarthritis, Aqueous extracts of devil’s claw Contraindicated in gastric and
(Harpagophytum mixed pain conditions providing 50 mg or more duodenal ulcers. May potentiate
procumbens) harpagoside per day. activity of warfarin. Safety in
Tincture: 30 drops 2 times/day pregnancy and lactation is not
known.
Feverfew (Tanacetum Migraine 50–250 mg of a dried leaf preparation Withdrawal syndrome can occur after
parthenium [L.] Osteoarthritis taken daily, standardized to 0.2% abrupt discontinuation by long-
Schultz-Bip.) parthenolide (a common dose is term users. Mouth ulceration and
125 mg/day). Doses of 70–86 mg of gastric disturbance can occur in a
dried chopped feverfew leaves in small percentage of patients.
capsules, taken once/day, can be also Allergic reactions theoretically
used. possible in those sensitive to
Treatment of migraine headaches: members of the Asteraceae family
1–2 g parthenolide daily. (e.g., ragweed, marigolds, daisies).
Other conditions (such as arthritis): There is a potential interaction with
20–60 drops twice/day of 1:1 fluid warfarin and other anticoagulant
extract; or 60–120 drops twice/day therapies. Feverfew is
of 1:5 tincture (solution made from contraindicated during pregnancy.
herb and alcohol, or herb, alcohol,
and water).
Curcumin (Rhizoma Rheumatoid arthritis, 1 g 1–3 times/day Heartburn with higher doses not
curcumae, Curcuma osteoarthritis, inflammatory uncommon.
longa) pain syndromes
Ginger (Zingiber Osteoarthritis, toothache Maximum dosages: Heartburn with higher doses not
officinale) (external use) Powdered herb is 2 g. uncommon. Contraindicated in
Essential oil: 9 drops distributed in those with active gallstone disease.
3 takings. Possibly an increased risk of
Dry extract: 400 mg distributed in hemorrhage in those using
3 takings > 4 g/day dried ginger and taking
anticoagulants.
St. John’s wort Mild to moderate depression 900–1800 mg/day extract generally Generally well-tolerated in clinical
(Hypericum perforatum aids in chronic pain standardized to 0.3% hypericin, trials. Rare cases of phototoxicity.
[L.]) treatment. 2%–5% hyperforin or both. Herb-drug interactions due to
induction of CYP3A4 and
P glycoprotein drug transporter.
Willow (Salix spp.) Acute back pain, osteoarthritis, Willow bark extract providing Theoretically, the risks are similar to
rheumatoid arthritis 240 mg/day salicin those of aspirin, although this is
not well-supported by clinical trial
data.
See Patel G, Euler D, Audette JF. Complementary and alternative medicine for noncancer pain. Med Clin North Am 2007;91:141–167, for a more detailed
review of the literature to support these findings.
language used for the differential diagnosis differs from that used in REFERENCES
Western allopathic medicine.22 1. National Institutes of Health/National Center for Complementary and
The Western approach to herbs for treating pain syndromes is Alternative Medicine (NIH/NCCAM). Meditation for health purposes.
more symptom-oriented and restricted to single-herb functions. Available at http://nccam.nih.gov/health/
Single herbs are often combined to treat one or several symptoms. 2. Han JS. Acupuncture and endorphins. Neurosci Lett 2004;361:258–261.
The single-herb approach is simpler to research and control, but the 3. Hui KK, Liu J, Makris N, et al. Acupuncture modulates the limbic
effects may not be as comprehensive and satisfactory or well-fitted system and subcortical gray structures of the human brain: evidence
to the individual patient as Chinese herbal formulas. Several herbs from fMRI studies in normal subjects. Hum Brain Mapp 2000;9:
were found to have satisfactory analgesic effects, among them 13–25.
Rhizoma curcumae (three species of Curcuma rhizomes are being 4. Berman BM, Ezzo J, Hadhazy V, Sawyers JP. Is acupuncture effective
in the treatment of fibromyalgia? J Fam Pract 1999;48:213–218.
used, which include C. wenyujin, C. phaeocaulis, and C. kwangsien- 5. Guerra de Hoyas JA, Andrés Martin Mdel C, Bassas Y Baena de Leon
sis), ginger extract, willow bark, capsaicin, Devil’s claw, boswellia, E, et al. Randomised trial of long-term effect of acupuncture for
lavender, and feverfew. Most commonly, these herbal remedies are shoulder pain. Pain 2004;112:289–298.
ingested in capsules that contain concentrated extracts of the herb. 6. Trinh KV, Phillips SD, Ho E, et al. Acupuncture for the alleviation of
The essential oil of these herbs can be ingested, inhaled, and/or lateral epicondyle pain: a systematic review. Rheumatology
rubbed onto the painful area. For a milder effect, one can drink 2004;43:1085–1090.
the tea or infusion of these herbs22 (Table 76–4). 7. Melchart D, Streng A, Hoppe A, et al. Acupuncture for patients
with tension-type headache: randomized control trial. BMJ
2005;331:376–382.
8. Linde K, Streng A, Jurgens S, et al. Acupuncture for patients with
CONCLUSIONS migraine: a randomized control trial. JAMA 2005;293:2118–2125.
9. Vickers A, Zollman C, McCarney R, et al. Acupuncture for
In summary, the past several years have shown an increase in the chronic headache in primary care: large randomized trial. BMJ 2004;
quality of trials examining the clinical efficacy of various CAM 328:744.
modalities for pain conditions. There is still need to raise the quality 10. Backer M, Hammes M, Dander D, et al. Changes of cerebrovascular
of the studies from a scientific and methodological point of view in response to visual stimulation in migraineurs after repetitive session
many areas of CAM research by randomizing, choosing the appro- of somatosensory stimulation (acupuncture): a pilot study, headache.
priate sample size, blinding, and developing more sophisticated J Head Face Pain 2004;44:95.
sham procedures. However, much work still has to be done to 11. Irnich D, Behrens N, Gleditsh JM, et al. Immediate effects of dry
needling and acupuncture at distant points in chronic neck pain:
find ways to preserve the clinical authenticity of CAM treatment results of a randomized, double-blinded, sham-controlled crossover
methods when they are brought into the light of a research proto- trial. Pain 2002;99:83–89.
col. Recent attempts have been made to find a method of main- 12. Witt C, Jena S, Brinkhaus B, et al. Acupuncture for patients with
taining the standardization and reproducibility of a research chronic neck pain. Pain 2006;125:98–106.
protocols while allowing the kind of flexible treatment that would 13. Elden H, Ladfors L, Fagevik O, et al. Effects of acupuncture and
normally be applied in a clinical setting. Other questions that stabilising exercises as adjunct to standard treatment in pregnant
should be answered with future studies include understanding women with pelvic girdle pain: randomised single-blind controlled
how treatment length influences outcome, whether maintenance trial. BMJ 2005;330:761.
treatments are needed for chronic conditions, and cost and risk 14. Kvorning N, Holmberg C, Greenert L, et al. Acupuncture relieves
pelvic and low back pain in late pregnancy. Acta Obstet Gynecol
comparisons with standard pharmacologic treatment. Providing Scand 2004;83:246–250.
this kind of detail will both assist with reproducibility and help 15. Furlan AD, van Tulder MW, Cherkin DC, et al. Acupuncture and dry
us gain a better understanding about whether certain treatment needling for low back pain. Cochrane Database Syst Rev
paradigms are superior to others for specific clinical conditions. 2005;(1):CD001351.
Finally, physicians who have an interest in pursuing CAM research 16. Manhelmer E, White A, Berman B, et al. Meta-analysis: acupuncture
should educate themselves both about the methodological issues for low back pain. Ann Intern Med 2005;142:651–663.
inherent with the particular area of interest as well as about ways 17. Brinkhaus B, Witt C, Jena S, et al. Acupuncture in patients with
to maintain the authenticity of the CAM treatment protocols so chronic low back pain. Arch Intern Med 2006;166:450–457.
that the literature is not populated with more poorly designed 18. Molsberger A, Mau J, Pawelec D, Winkler J. Does acupuncture
improve the orthopedic management of chronic low back pain?—a
studies. For example, physicians can trial the three species of randomized, blinded, controlled trial with 3 months follow-up. Pain
C. rhizomes being used (which include C. wenyujin, C. phaeocaulis, 2002;99:579–587.
and C. kwangsiensis) as well as acupuncture at the Harvard 19. Berman BM, Lao L, Langenberg P, et al. Effectiveness of acupuncture
Continuing Medical Education course, ‘‘Structural Acupuncture as adjunctive therapy in osteoarthritis of the knee. Ann Intern Med
for Physicians.’’ With the emerging interest in integrative medicine 2005;141:901–910.
comes a growing interest in collaboration, and a greater number of 20. Linde K, Weidenhammer W, Streng A, et al. Acupuncture for
physicians are interested in obtaining training in CAM modalities to osteoarthritic pain: an observational study in routine care.
help bridge this gap between CAM and conventional clinicians. For Rheumatology 2006;45:222–227.
example, the American Academy of Medical Acupuncturists has 21. Vas J, Mendez C, Perea-Milla E, et al. Acupuncture as a
complementary therapy to the pharmacological treatment of
been formed to help as both an educational and a research forum osteoarthritis of the knee: randomized controlled trial. BMJ
for physician acupuncturists, and the American Holistic Medical 2004;329:1216 doi:10.1136/bmj.38238.601447.3A.
Association provides educational exposure to a broader range of 22. Patel G, Euler D, Audette JF. Complementary and alternative
integrative and CAM modalities. The future of medicine will medicine for noncancer pain. Med Clin North Am 2007;91:141–167.
likely be integrative, and the more that health care providers can
educate themselves about this area of medicine, the better they will
be able to provide the highest quality of care to their patients.
XII
NEUROSURGICAL
APPROACHES TO
PAIN MANAGEMENT
Chapter 77
SURGICAL PROCEDURES
NEUROSURGICAL TREATMENT Surgical procedures for the treatment of chronic pain can be
divided into two general categories: neuromodulation and neuro-
OF PAIN ablation (Box 77–2).1,2 The field of neuromodulation primarily
encompasses procedures that utilize techniques of electrical stimu-
Daniel Clayton, Emily A. Davis, and Richard K.Osenbach lation applied to neural structures and neuraxial drug delivery.
Indeed, neuromodulation is currently performed not only for the
treatment of pain but also for numerous other medical conditions
including movement disorders, epilepsy, psychiatric disorders, gas-
tric motility problems, and urinary incontinence. For patients with
nonmalignant pain, taking into consideration the clinical problem,
INTRODUCTION pain topography, and type of pain (nociceptive vs. neuropathic),
neuromodulation or some type of nonablative procedure should
Patients with chronic intractable pain not uncommonly present generally be considered before moving on to an irreversible destruc-
complex and difficult challenges for the treating physician. tive procedure. Neuromodulation procedures are particularly
Successful management of these complicated patients requires a attractive because they are nondestructive and reversible and can
thorough understanding of the underlying pain condition along be tested with some degree of certainty as to their potential for
with a careful and thoughtful approach to developing an effective effective long-term pain relief.
treatment algorithm. When considering any surgical intervention
for chronic pain, the central importance of careful patient selection
to a successful outcome cannot be overemphasized. Remember that NEUROABLATIVE PROCEDURES
chronic pain is a multidimensional biopsychosocial problem; it is
truly a chronic disease for which there is generally no cure; and it Up until the late 1960s, the management of severe intractable pain
must necessarily be approached much as would a chronic disease primarily involved neurosurgical treatments. Early treatments were
such as diabetes or cancer. Indeed, effective management of most nearly all ablative in nature and served as a way of interrupting
patients with chronic pain requires a multidisciplinary approach, either the transmission of pain to the central nervous system
utilizing all modalities and specialists at one’s disposal. The belief (CNS) or the perception of pain within the CNS. Indeed, a signif-
on the part of the patient and/or physician that a surgical procedure icant body of knowledge regarding functional neuroanatomy was
alone (e.g., spinal cord stimulator implant) will provide a ‘‘cure’’ for discovered as a result of applying ablative procedures, and even
the pain is a foolish thought and will nearly always result in treat- today, some of these earlier treatments such as cordotomy continue
ment failure and a dissatisfied patient. The successful treatment of to have contemporary indications.
chronic pain should follow a logical algorithm, beginning with the Prior to the introduction of spinal drug delivery, ablative pro-
most simple and least interventional therapies and progressing to cedures formed the cornerstone of treatment for patients with pain
more complex invasive modalities. related to cancer and, to a lesser extent, nonmalignant pain syn-
The purpose of this chapter is to present a relatively brief yet dromes. However, the development and evolution of intrathecal
comprehensive review of the various neurosurgical treatments cur- (IT) opiates in the 1980s significantly altered the landscape for
rently available for the management of chronic intractable pain in the treatment of cancer pain. There is a fairly clear correlation in
both cancer and noncancer patients. A discussion of spinal cord the decline of ablative procedures with the development of intra-
stimulation (SCS; Box 77–1) has been deliberately omitted because thecal drug delivery (ITDD) systems, and certainly since the mid to
this topic is covered in Section X, Chapter 75. Also, the treatment of late 1990s, there has been a radical trend away from the use of
trigeminal neuralgia is not addressed because this topic is complete ablative procedures. This is rather unfortunate because some
unto itself and cannot be adequately covered in this review. of these techniques such as percutaneous cordotomy are highly
563
564 Chapter 77 NEUROSURGICAL TREAT MENT OF PAIN
procedures are obviously irreversible and carry the risk of neuro-

Box 77^1 CURRENT APPLICATIONS OF SPINAL CORD logic morbidity. Also, the analgesic efficacy of most destructive
STIMULATION procedures cannot be tested with any degree of certainty, as is the
case with neuromodulation procedures. On the positive side, abla-
Postlaminectomy pain syndrome (i.e., failed back surgery syndrome) tive techniques can be performed in a single stage and can result in
Complex regional pain syndromes immediate and complete pain relief. An effective ablative procedure
* Type I (i.e., reflex sympathetic dystrophy)
allows the patient more freedom by eliminating the requirement of
* Type II (i.e., causalgia)
Peripheral nerve injury pain continuous interactions with health care providers that is necessary
Post-thoracotomy pain or intercostal neuralgia in the case of spinal drug pumps that require periodic refilling and
Ilioinguinal neuralgia sometimes frequent reprogramming in order to achieve effective
Ischemic limb pain secondary to peripheral vascular disease pain control. Moreover, the overall cost of ablative procedures is
Intractable angina pectoris probably lower because the initial high costs of an implant are
Interstitial cystitis avoided. Consequently, the senior author (RKO), as well as other
Coccydynia neurosurgeons familiar with these techniques, firmly believes they
Vulvodynia should continue to play an important role in the management of
patients with cancer-related pain. For patients with nonmalignant
pain syndromes (albeit with some exceptions [e.g., trigeminal neur-
effective in patients with cancer pain. Indeed, improvements in algia]), whenever feasible, a neuroaugmentative approach should
imaging, stereotactic localization, electrode design, and lesioning generally be attempted because this is more likely to result in
techniques have created the potential to make these techniques long-term success than destructive procedures for which the anal-
even safer and more effective than ever before. gesic effects often fade with time.
There are certainly both advantages and disadvantages to
destructive pain procedures. On the negative side, destructive
Peripheral Neurectomy
Pain is a common symptom after peripheral nerve injury as well as
Box 77^2 NEUROMODULATION AND ABLATIVE some diseases of the peripheral nerve, such as diabetic neuropathy.
PROCEDURES FOR CHRONIC PAIN Injury to a major nerve trunk may result in a devastating pain
syndrome known as complex regional pain syndrome (CRPS)
Neuromodulation type II, also known as causalgia. Painful nerve injuries are often
Spinal cord stimulation (i.e., dorsal column stimulation) complex problems that necessitate commitment and perseverance
Peripheral nerve stimulation from both the patient and the physician. Multiple pathophysiologic
* Major extremity nerves (median, ulnar, radial, sciatic, peroneal, tibial) mechanisms for nerve injury pain have been proposed including
* Occipital nerve stimulation
sensitization of peripheral nerve terminals, abnormalities in pri-
* Spinal nerve root stimulation
mary afferent fibers, abnormal electrical communication between
* Trigeminal nerve stimulation (peripheral)
Spinal drug infusion

adjacent axons, and alterations in the circuitry and neurochemistry
Intraventricular opiates of the dorsal horn. Much work has been focused on the pathophys-
Deep brain stimulation iology of neuromas, which have been shown to produce abnormal
* Endogenous opiate system (periaqueductalgray, periventricular gray) single-unit electrical discharges, although neuroma formation per se
* Lemnisal system (medial lemniscus, sensory thalamus, internal is not necessary to produce abnormal electrical activity within a
capsule) nerve.3
Motor cortex stimulation Peripheral neurectomy (i.e., cutting the nerve) is sometimes
Ablative Procedures beneficial in carefully selected patients with peripheral nerve
Peripheral procedures pain.4 The pain may be related to a traumatic injury (e.g., painful
* Peripheral neurectomy neuroma), a compressive neuropathy (e.g., meralgia paresthetica or
* Excision of painful neuromas tumor invasion of the brachial plexus), or an idiopathic condition
* Sympathetic ganglionectomy
(e.g., occipital neuralgia). Peripheral neurectomy has also proved
* Trigeminal system procedures
beneficial for a small group of patients with refractory trigeminal
n Retrogasserian radiofrequency thermal rhizotomy
neuralgia who, because of significant comorbidity, may not be can-
n Percutaneous glycerol rhizolysis
n Balloon microcompression didates for more standard therapies such as microvascular decom-
Spinal procedures pression or even any of the percutaneous retrogasserian procedures.
* Dorsal root ganglionectomy Supraorbital and infraorbital neurectomy can also be considered in
* Dorsal rhizotomy patients with neuropathic pain after traumatic injury to these
* Anterolateral cordotomy nerves. Neurectomy of the supra- and infraorbital nerves for first-
* Midline (commissural) myelotomy and second-division pain, respectively, can be performed relatively
* Percutaneous high-cervical cordotomy (C1^2)
easily under local anesthesia. Even inferior alveolar neurectomy for
* Dorsal root entry zone (DREZ) lesion
third-division pain is feasible, although it is necessary to expose this
Brainstem and thalamic procedures
nerve through a small opening in the mandible. The current indica-
* Caudalis DREZ
* Medullary tractotomy
tions for peripheral trigeminal branch neurectomy are admittedly
* Pontine tractotomy
few, especially now that stereotactic radiosurgery is accepted as
* Mesencephalic tractotomy a completely noninvasive treatment for trigeminal neuralgia.
* Medial thalamotomy Although peripheral trigeminal neurectomy is infrequently indi-
* Pulvinotomy cated, it should be remembered as a viable alternative in selected
Other procedures patients.5
* Cingulotomy
Obviously, peripheral neurectomy is limited to pure sensory
* Pituitary ablation
nerves or mixed nerves in which there has been complete loss of
* Hypothalamotomy
function (e.g., painful amputation neuroma) without the hope of any
* Stereotactic radiosurgery
return. Neuromas that involve pure sensory nerves including the
XII NEUROSURGICAL APPROACHES TO PAIN MANAGEMENT 565
dorsal cutaneous ulnar branch, superficial sensory radial branch, which the tumor has not spread into an extensive area.7–9 Pain from
antebrachial cutaneous nerves, and the sural and saphenous deep and extensive invasive facial cancer can sometimes be effec-
nerves are usually best managed with excision without consider- tively treated by rhizotomy. In such cases, it is necessary to cut the
ation of repair. The sensory territories supplied by these nerves trigeminal nerve, nervus intermedius, glossopharyngeal nerve, and
are of low functional importance, and numbness in their distribu- upper third of the vagus, combined with dorsal rhizotomy from
tion is usually preferable to pain, dysesthesias, hyperalgesia, and C1 (if present) through C4. Rhizotomy from C8 to T4 may be
allodynia. Because recurrent pain and paresthesias may occur with utilized for pain produced by tumors in the upper thoracic and
nerve regeneration, the proximal nerve stump should be implanted lower cervical region that are limited in size (e.g., Pancoast’s
into either underlying muscle or bone. This technique minimizes tumor) and that involve the brachial plexus to such an extent
the chances of a recurrent superficial mechanically sensitive neuro- that there is irreversible loss of function in the upper extremity.
ma in the event there is significant regeneration. For more extensive tumors in which rhizotomy is required at
Meralgia paresthetica, for example, is a condition that can be more rostral levels, a useless, nonfunctional extremity is an absolute
successfully treated by sectioning of the lateral femoral cutaneous prerequisite. Bilateral dorsal rhizotomy has proved effective for pain
nerve. A recent operative series showed complete symptomatic relief related to pelvic cancer when the tumor involves the more caudal
in 73% and partial relief in 20% of cases.6 Neurectomy has also been sacral levels (S2 or S3 and below). Sacrococcygeal rhizotomy may
advocated for chronic ilioinguinal pain. Some authors have also be useful for perineal pain related to cancer. However, bilateral
reported success rates exceeding 85% in patients with intractable sacral rhizotomy is contraindicated in patients with normal bladder
ilioinguinal neuralgia after hernia repair. However, based on the and bowel control.
senior author’s (RKO) personal experience, this seems to be Not unlike other destructive pain procedures, the application of
overly optimistic. Occipital neuralgia is another condition that tra- dorsal rhizotomy in patients with nonmalignant pain is more prob-
ditionally has been managed with peripheral neurectomy. lematic and demands even more prudent judgment.7–9 Rhizotomy
Unfortunately, recurrence of pain is often the rule, and long-term has no role in spontaneous steady neuropathic pain of nonmalig-
success rates have not been encouraging. nant origin and, in fact, leads to further deafferentation. However,
One of the most important prerequisites of peripheral neurec- rhizotomy may have a role in relieving hyperpathia limited to a
tomy is complete relief of pain after repetitive local anesthetic nerve radicular distribution, particularly if the pain is relieved by local
blocks. It is important that these blocks be performed without epi- anesthetic block, as described previously.
nephrine because injured peripheral nerves and neuromas abnor- In animal studies, it has been shown that removal of the dorsal
mally express adrenergic receptors, which are algogenic when root ganglion (DRG) leads to degeneration of most of the small
activated and can, therefore, produce a false-negative response to unmyelinated high-threshold nociceptive-specific fibers that enter
blockade. Several other factors also seem to have prognostic value in through the ventral root, and horseradish peroxidase–labeling stu-
predicting a successful result with peripheral neurectomy. Ideally, dies have confirmed the origin of these fibers to be the DRG. Based
the pain should be related to a traumatic injury; it should be on these observations and the large number of failures with dorsal
restricted to the territory of a single peripheral nerve; and Tinel’s rhizotomy, dorsal root ganglionectomy is now generally the
sign should be present with percussion over the neuroma. preferred technique that is expected to produce the best results.7
Notwithstanding all of the these criteria, the overall success rate Aside from improved efficacy, dorsal root ganglionectomy offers
for excision of painful neuromas is probably no higher than 60%.4 several other advantages over intradural dorsal rhizotomy.7,8,10
Ganglionectomy obviates the need for a laminectomy and an intra-
dural exposure and, therefore, reduces the anesthetic time to which
a debilitated patient must be exposed. It also significantly reduces
Spinal and Paraspinal Procedures the risk of cerebrospinal leak. In addition, each DRG is associated
Dorsal Rhizotomy and Dorsal Root Ganglionectomy with its corresponding neural foramen, making localization some-
what easier.
Dorsal rhizotomy has been performed since the late 1890s. Dorsal root ganglionectomy may be indicated for pain in the
Application of dorsal rhizotomy for the relief of pain is based on neck, trunk, or abdomen. It is contraindicated for extremity pain
the law of Bell and Magendie, which states that the dorsal roots because the extent of denervation required to produce the desired
subserve afferent and ventral roots efferent function, respectively. effect would result in near-complete loss of tactile and propriocep-
Intuitively, destruction of the dorsal roots should eliminate the tive function, thereby rendering the extremity useless. Therefore,
entry of segmental nociceptive information that normally would the procedure can be applied to the following roots: C1–4, T1–12,
enter the spinal dorsal horn at these levels. Unfortunately, the and L1–2.7,8,10 Prior to surgery, selective nerve root blocks that
results of dorsal rhizotomy have been variable at best and often result in 100% pain relief may suggest but not unequivocally
unrewarding. Two factors likely contribute to the poor outcomes prove that ganglionectomy might be effective. Conversely, failure
associated with dorsal rhizotomy. First, dorsal rhizotomy depends to derive any pain relief from local anesthetic blockade may indicate
on denervation of the area from which the pain is believed to be that there is a central component to the pain that will not be helped
generated, for example, from an intercostal nerve damaged by a rib by ganglionectomy.
fracture or injured during thoracotomy. However, the ability to Although dorsal root ganglionectomy is infrequently performed,
completely denervate a particular region with this procedure is limit may be effective in a selected number of pain conditions including
ited by the high degree of sensory overlap between adjacent derma- intractable occipital neuralgia that has not responded to electrical
tomes, especially on the trunk. Indeed, complete denervation of a stimulation (either occipital nerve stimulation or high-cervical
single thoracic dermatome requires interruption of the segmental [C1–2] SCS) or peripheral neurectomy,11 post-thoracotomy or
afferent input at least two dermatomal levels above and below the postlaparotomy pain, chest wall pain related to pleural-based malig-
segmental level of pain. Second, a substantial body of literature now nant tumor invasion, and perineal pain secondary to pelvic malig-
exists demonstrating that as many as 30% of nociceptive afferent nancy.7,8,10 Previous studies of dorsal root ganglionectomy
fibers enter the spinal cord through the ventral root, the so-called have failed to show any significant efficacy for persistent radicular
ventral root afferents. Consequently, intradural dorsal rhizotomy, pain after failed back surgery syndrome.12 In patients with perineal
which is a preganglionic procedure, will fail to interrupt the noci- pain, bilateral interruption of the sacral roots is necessary. Because
ceptive input carried by these ventral root nociceptive afferent fibers this may produce a sensory neurogenic bladder, this procedure
Notwithstanding the drawbacks, dorsal rhizotomy may have should be limited to patients who have either already lost control
limited applicability, especially in the treatment of cancer pain in of urinary and rectal sphincter function or who have undergone
colostomy and urinary diversion. For patients with preserved cell column. The second-order sympathetic efferent fibers exit the
sphincter function, midline myelotomy (see later) may be a reason- spinal cord in the ventral roots of T2–10, enter the sympathetic
able alternative. chain via the white rami, and synapse in the paravertebral sympa-
thetic ganglia. Postganglionic sympathetic efferent fibers leave stel-
late and middle cervical ganglia and join the C5–T1 roots, although
Sympathectomy
the majority of the fibers travel with the C7–T1 roots. According to
Sympathectomy has been in use since the late 1800s for a variety of this schema, resection of the T2 ganglia is usually sufficient to pro-
conditions including hyperhidrosis, epilepsy, spasticity, angina, and duce near-complete sympathetic denervation of the upper extrem-
various pain conditions, most notably complex CRPS type I, for- ity.14 Pupillary fibers originate from T1 and pass through the stellate
merly known as reflex sympathetic dystrophy.13,14 At present, the ganglion to synapse in superior cervical ganglion. If stellate resec-
most common indication for sympathectomy is symptomatic hy- tion is required, Horner’s syndrome is likely to occur. This can
perhidrosis. As a primary treatment for pain, the major indication sometimes be avoided by resecting only the lower one half of the
for sympathectomy is for the treatment of sympathetically mediated stellate ganglion.
pain (SMP), most commonly associated with the group of painful Various alternative efferent pathways have also been described
disorders known as CRPS I and II. However, not all patients with including extraganglionic sympathetic pathways, origin of fibers
CRPS display SMP. Wheeas many patients with CRPS I or II may from the C8 and T1 roots, and intermediate ganglia in the spinal
have a component of SMP, there is usually also one or more com- roots of C8–T2. In most cases, it would appear that these pathways
ponents of sympathetically independent pain (SIP) that will clearly are probably not clinically significant, and resection of the T2 gan-
not respond to sympatholysis. It should be kept in mind that many, glion is adequate for near-complete sympatholysis to the arm. It
if not the majority of, patients with longstanding CRPS I do not in should be noted that, previously, preganglionic sympathectomy
fact have a large component of SMP, and this probably explains the (resection of ventral roots, white rami, and sympathetic chain
general lack of effectiveness of sympathectomy in patients with with preservation of the ganglia) was considered preferable to a
chronic CRPS. postganglionic sympathectomy. The rationale for this was that pres-
Generally, sympathectomy may be indicated for patients with a ervation of the ganglia might prevent ‘‘hypersensitivity’’ of target
component of SMP who respond favorably to temporary chemical organs to circulating catecholamines. It is now believed that this
sympathetic blockade.15 It is generally best suited for SMP involving phenomenon either does not occur at all or has minimal clinical
the upper extremity. Customarily, at least in the senior author’s significance.
(RKO) opinion, several successful sympathetic blocks should be T2 sympathetic ganglionectomy can be performed with a variety
performed in which the patient obtains either complete or nearly of surgical techniques including open procedures (dorsal interscap-
complete pain relief before considering a surgical sympathectomy. ular transaxillary and supraclavicular),13,14 percutaneous RF tech-
Selective sympathetic ganglion block can be accomplished niques,16 and most recently, minimally invasive thoracic endoscopic
through local anesthetic injection of the stellate ganglion (head, techniques.17,18
neck, and upper extremity), lumbar sympathetic chain (lower extre- Percutaneous radiofrequency (RF) sympathectomy is a quick
mity), or celiac plexus (abdomen).15 The diagnostic utility of chem- and easy method for sympathetic denervation of the upper
ical sympathetic blockade depends on the ability to selectively extremity. Several modifications of the technique since the late
interrupt sympathetic activity while leaving somatic pathways 1980s have resulted in improved immediate as well as long-term
undisturbed. Therefore, it is necessary to perform careful sensory results.16 The indications are identical to those for both open and
testing in order to conclude that pain relief is not in part related to a endoscopic procedures. The operation can be preformed on an
subtle somatosensory block, thereby producing a false-positive outpatient basis under neuroleptic analgesia. The operation has
result. Few accepted standards exist to judge the adequacy of sym- been described in detail by Wilkinson, who developed the proce-
pathetic blockade. Observation of Horner’s syndrome indicates dure. The advantages of the percutaneous RF technique include
interruption of the sympathetic fibers to the head but does not avoidance of general anesthesia, the ease of performing bilateral
ensure blockade of sympathetic efferents to the upper extremity. procedures, and the ability to tailor the procedure based on phys-
Generally, effective upper extremity blockade is indicated by a tem- iologic monitoring. Moreover, the procedure can be easily
perature increase of 1.08C to 3.08C, although this may be unreliable repeated with good results. The most common complications
if the initial skin temperature is warm.15 Other techniques include include pneumothorax and intercostal neuralgia, which is usually
microneurography, which is invasive and requires sophisticated transient.
equipment, and measurement of skin blood flow using laser The transthoracic endoscopic approach was initially described in
Doppler flowmetry. the mid-1950s and then reintroduced nearly a quarter century later.
There are a number of problems in interpreting efficacy studies The evolution of contemporary video-assisted endoscopic techni-
of regional sympathetic blockade for CRPS.15 First, the success ques and refinement of endoscopic instrumentation has made
rate of actually achieving a complete selective sympathetic block video-assisted thoracoscopic sympathectomy (VATS) a relatively
is not known. Second, no randomized, placebo-controlled trials easy and safe procedure. VATS is performed through an intercostal
have been published. Finally, the specificity of sympathetic block- approach with deflation of the ipsilateral lung. The lung is manually
ade is not known. In other words, inadvertent blockade of somatic retracted and the appropriate anatomic landmarks are identified.
nerve fibers from diffusion of local anesthetic may produce The sympathetic chain is identified beneath the pleura lying along-
pain relief and lead to a false-positive result. Unfortunately, the side the lateral portion of the vertebral body coursing over the head
specificity of chemical sympathetic blockade and its ability to pre- of each rib. A segment of the sympathetic chain and the associated
dict the response to permanent surgical sympathectomy are less ganglia are excised. At a minimum, the T2 ganglion is resected, but
than ideal. However, in spite of its limitations, sympathetic block- for a complete denervation of the upper extremity, the sympathetic
ade is still an important adjunct in the treatment of CRPS, especially chain extending from just below the stellate ganglion to T4 should
prior to pursuing surgical sympathectomy as a viable treatment be excised. At the conclusion of the procedure, the lung is reinflated
option. and a chest tube placed. A postoperative x-ray should be obtained
to ensure proper inflation of the lung. The most common compli-
cation of VATS is persistent pneumothorax. Some patients will
Upper thoracic sympathectomy
complain of local pain at the portal sites, but this is usually
The sympathetic innervation of the upper extremity is supplied rather self-limited and customarily resolves without any specific
by preganglionic fibers that originate from the intermediolateral treatment.
Splanchnicectomy
same success. Conversely, some studies concluded that timing of
Visceral afferent fibers have been described that carry nociceptive surgery has no effect on outcome. Unfortunately, the author’s
information from internal organs such as the heart, pancreas, kid- (RKO) experience with surgical sympathectomy has been less pos-
neys, and other organs. Pathologic processes that involve the pan- itive than some of the outstanding results reported in the literature.
creas such as carcinoma and chronic pancreatitis can be a source of In spite of preoperative positive responses to chemical sympathetic
intractable pain. Visceral afferents from the pancreas travel exclu- blockade, pain relief exceeding 1 year has been the exception rather
sively through splanchnic chain and enter the spinal cord primarily than the rule.
through the greater splanchnic nerve (GSN) via the celiac ganglion. There are several explanations for failed surgical sympathec-
In addition to bilateral innervation through the GSN (T4–9), vis- tomy. First, the diagnosis may have been incorrect, leading to
ceral nociceptive afferents may also travel with the lesser splanchnic poor patient selection. The difficulty with patient selection based
nerves (LSN) the least splanchnic nerves, and perhaps even from on the response to sympathetic blockade has already been men-
lower portions of the thoracic ganglia and upper lumbar chains. tioned. There is a high placebo-response rate among patients with
The deep, diffuse, aching pain associated with pancreatic carcinoma chronic pain in general and CRPS in particular. Therefore, multiple
or chronic pancreatitis in particular suggests involvement of visceral blocks that produce unequivocal pain relief for the duration of the
afferents, whereas radicular pain implies involvement of somatic anesthetic block are essential. Another reason for failure is inade-
afferents. The source of pain can often be determined through the quate resection of the sympathetic chain. Consequently, to maxi-
use of temporary splanchnic block. In the event that temporary mize the chance for success, it is imperative to completely interrupt
splanchnic blockade produces significant pain relief, splanchnicec- all sympathetic outflow to the involved extremity. Recurrent pain
tomy can be considered. A bilateral operation is usually required to after an initial successful result may result from regeneration of the
achieve adequate pain relief and involves removal of the T9–12 sympathetic chain, which is well known to occur. Lastly, there are
thoracic ganglia along with the GSN, LSN, and least splanchnic reports of cross-communication of the sympathetic system, more
nerves.13 common in the lumbar region, in which anatomic studies have
shown cross-over fibers in nearly 30% of specimens. As a result,
some patients may develop recurrent pain owing to contralateral
Lumbar sympathectomy
sympathetic reinnervation of the affected extremity after an ipsilat-
The sympathetic efferent outflow to the lower extremity originates eral sympathectomy.
from the lower thoracic cord and then passes through the lumbar
ganglia, whose efferents leave the spinal canal with the ventral roots
Dorsal Root Entry Zone Lesions
of L1 and L2. Customarily, resection of the L2 and L3 sympathetic
ganglia should be sufficient to produce relatively complete sympa- Lesions of the dorsal root entry zone (DREZ) were first described by
tholysis in the lower extremity. Some sympathetic efferents may Sindou and associates21 in 1974 using small microincisions to inter-
originate in L2 or L3 and then course caudally through the sympa- rupt incoming nociceptive afferent fibers. This work was further
thetic chain and exit with postganglionic rami of the L4 and extended by Nashold and Ostdahl22 (who coined the term DREZ)
L5 roots. Consequently, some authors have advocated additional in 1979 using an RF technique. The most common indication for
resection of L4 and L5 to improve long-term results. DREZ lesioning has been in patients with deafferentation pain
Lumbar sympathectomy is performed through a muscle-split- related to brachial plexus avulsion injuries. It is believed that deaf-
ting transverse flank incision extending from beneath the costal ferentation pain develops and is sustained owing to lesions that
margin to the lower quadrant.13 Although lumbar sympathectomy isolate afferent input from the second-order neurons whose cell
is a relatively straightforward operation, a number of pitfalls must bodies reside within the dorsal horn, brachial plexus avulsion
be avoided. The ureter must be identified and retracted medially being the classic example. Isolation or deafferentation of these
with the kidney, and the vena cava or aorta must be carefully pre- second-order neurons is believed to result in abnormal electro-
served at the extremes of the dissection. Also, care must be exercised chemical signals, thus producing pain. Consequently, it was pro-
not to injure somatic nerves passing through the psoas and posed that destruction of this abnormal neuronal pool in the dorsal
quadratus lumborum muscles. It must also be recognized that in horn might produce pain relief, which indeed seems to be the case
males, bilateral sympathectomy is often accompanied by sexual for certain conditions.
dysfunction. Several techniques can be used for performing DREZ lesions, the
details of which have been extensively published. Suffice it to say
that central to all of these techniques is surgical exposure of the
Results of sympathectomy for pain
DREZ and destruction of the superficial five layers of Rexed’s lam-
A survey of the more recent literature regarding the effectiveness of inae. The DREZ operation has been employed and the results eval-
surgical sympathectomy for CRPS indicates variable rates of success uated for a number of deafferentation pain conditions. Without
ranging from 65% to 100%. For the most part, this is consistent question, the best single indication for DREZ lesioning is pain
with the older literature. On average, ‘‘long-term’’ successful out- that follows brachial plexus avulsion. Pain relief is usually immedi-
comes have been reported in 70% to 85% of cases.17 In general, ate, although some patients may occasionally be worse for a short
upper thoracic sympathectomy is more effective in alleviating upper time after surgery. Long-term pain relief in excess of 5 years has
extremity pain than is lumbar sympathectomy in relieving lower been reported in approximately 70% of patients who have under-
extremity pain. There does not appear to be any major difference gone the DREZ procedure for brachial plexus avulsion.23
in outcomes based on the particular surgical approach. Indeed, Interestingly, DREZ lesioning is ineffective for neuropathic pain
although less invasive, the results of VATS are similar to those of that develops after stretch injures of the brachial plexus.
open procedures. It has been suggested that an important factor in Therefore, it is important to be certain that the pain is due to
determining the success of surgical sympathectomy is the duration avulsion rather than stretch injury. Although sometimes difficult,
of symptoms prior to the procedure. In a study of 21 patients with there are several ways to differentiate avulsion from a stretch injury.
CRPS I followed from 4 months to 12 years, 95% of patients who Patients with avulsion of the entire plexus will present with a flail
underwent sympathectomy within 1 year of diagnosis achieved a extremity that is completely anesthetic. In patients with avulsion
good result.19 Similarly, Schwartzmann and coworkers20 reported injuries, the onset of pain is almost immediate. It can involve any
long-term pain relief (follow-up 36–68 mo) for patients with CRPS portion of the extremity, although most patients will relate that the
I who underwent sympathectomy within 12 months. In contrast, most severe pain is felt in the hand, which is anesthetic. These
only 44% of patients operated on after 12 months had the patients commonly described the pain as though the hand is
being crushed in a vice. Other clinical clues to the presence of In considering a patient for cordotomy, or midline myelotomy
avulsion include weakness of the rhomboid muscles (supplied by for that matter, the severity of the pain should be sufficient to justify
the dorsal scapular nerve, which originates very proximally from the the procedure and the attendant risks. In this sense, it is important
C5 nerve root), winging of the scapula, and the presence of to attempt to segregate physical pain (biologic) due to the under-
Horner’s syndrome. Because root avulsion is a preganglionic (i.e., lying cancer and the emotional suffering related to depression and
DRG) injury, the evoked sensory nerve action potential (SNAP) is other socioeconomic and secondary gain issues (psychosocial).
still present as opposed to a postganglionic stretch injury in which Also, as with any destructive procedure, all reasonable noninvasive
the SNAP will be lost. Avulsion can also be demonstrated radio- methods for pain control should have been attempted and failed to
graphically using either magnetic resonance imaging (MRI) or com- provide adequate pain relief.
puted tomography (CT)–myelography. The observation of a The most common indication for percutaneous cordotomy is in
pseudomeningocele may suggest an avulsion, although this finding the patient with opiate-resistant or opiate-tolerant cancer pain.
may also be seen in the absence of root avulsion. Moreover, root Indeed, most candidates for cordotomy have failed to respond ade-
avulsion is not always associated with a pseudomeningocele. The quately to high doses of long-acting oral opiates and/or intraspinal
most accurate finding is the demonstration of the absence of the opiates. In some patients, for a variety of reasons, intraspinal opi-
dorsal roots. In the author’s (RKO) opinion, CT-myelography ates may not be a practical or viable option for pain management,
remains superior to MRI in demonstrating this finding. in which case percutaneous cordotomy remains an excellent alter-
The procedure is performed with the patient under under gen- native. Percutaneous cordotomy has also been utilized in other
eral anesthesia. A bilateral cervical laminectomy is performed and pathologic conditions such as spinal cord injury pain, radiation
the dura opened to expose the spinal cord. Although DREZ can be plexitis, postamputation stump pain (phantom pain does not
performed through a hemilaminectomy, the senior author (RKO) respond to cordotomy), pain from tabes dorsalis, and even in
prefers a bilateral exposure in order to clearly visualize the contra- intractable pain from failed back surgery.24
lateral normal side. This can be very helpful for orientation because Another important consideration in patient selection is the
some patients will develop significant arachnoid scarring and/or pathophysiology of the pain. In general, cordotomy is more effec-
rotation of the cord, which can sometimes make clear identification tive for nociceptive than for neuropathic pain syndromes. Pain
of the affected DREZ difficult. Once the location of the dorsolateral generated from continuous activation of peripheral nociceptors
sulcus has been confirmed, DREZ lesions are created from the last such as that produced by involvement of a long bone by cancer
intact root caudally to the most rostral intact root. Lesions are and pain from direct compression or infiltration of nerve plexuses
created at 1- to 2-mm intervals using a thermocouple tempera- represent the two conditions that respond best to percutaneous
ture-monitoring electrode inserted into the DREZ at a 208 to 308 cordotomy. Central pain and evoked pain with hyperpathia or
angle from the vertical. The electrode is designed such that a allodynia may respond to cordotomy but less predictably than the
15-second lesion made at 758C will produce thermal coagulation conditions listed previously. Location of the pain is another impor-
of the superficial five layers of the dorsal horn.22 The most signif- tant consideration. A properly performed C1–2 percutaneous cor-
icant complications of DREZ lesioning include inadvertent injury to dotomy will reliably produce analgesia up to and including the C5
the ipsilateral dorsal columns or corticospinal pathways, which may dermatome.24 Pain that is consistently rostral to C5 as well as pain
produce proprioceptive sensory loss and/or lower motor neuron in the head is not effectively treated by cordotomy. Also, unilateral
weakness of the ipsilateral lower extremity. localized pain is much more effectively treated than is bilateral or
The single best indication for DREZ is brachial plexus avulsion. midline pain, which require a bilateral procedure. Unilateral cor-
It can also be performed after avulsion injuries of the lower lum- dotomy is a relatively low-risk procedure whereas a bilateral C1–2
bosacral nerve roots, although this injury is far less common cordotomy carries a significantly higher rate of complications.24,26
than brachial plexus avulsion. Pain relief is similar to that achieved Patients considered for cordotomy should have a limited life
with brachial plexus avulsion. Another good indication for the expectancy, generally less than 12 months, because the analgesic
DREZ procedure is in patients with spinal cord injury who suffer effects of cordotomy are often not permanent. Indeed, the analgesia
from ‘‘end zone’’ pain. These patients complain of severe bandlike produced by cordotomy tends to fade with time, and pain conco-
constricting pain at the area of transition from anesthesia to rela- mitantly recurs. Some patients may also develop mirror pain (con-
tively normal sensation. However, DREZ lesioning is ineffective tralateral pain involving the identical body area as the original
for the diffuse constant burning pain that occurs below the level pain), which may be difficult to manage. Finally, there should be
the injury. DREZ has been used, albeit less successfully, for condi- no medical contraindications to the procedure. Assessment of base-
tions such as phantom limb pain, postherpetic neuralgia, and line pulmonary function is important in this regard because percu-
peripheral nerve injury pain.22 It is neither indicated nor effective taneous cordotomy at C1–2 may damage the ipsilateral
for CRPS I. reticulospinal pathway that lies adjacent to the cervical fibers in
the spinothalamic tract. This pathway originates in the respiratory
center of the medulla and mediates unconscious or automatic res-
Anterolateral Cordotomy
piration. If both lungs are normal, unilateral damage to this path-
The lateral spinothalamic tract, located in the lateral funiculus of way is not clinically significant. However, if there is underlying
the spinal cord, is a crossed pathway that transmits the majority of pulmonary insufficiency, especially of the lung on the side contra-
pain and temperature input in the CNS, and a number of proce- lateral to the cordotomy, or loss of unconscious respiration from
dures have been described to interrupt this pathway including open underlying disease such as a Pancoast tumor, then loss of the retic-
or percutaneous cordotomy and commissural or midline myeloto- ulospinal pathway may lead to life-threatening respiratory compro-
my. Open cordotomy, as first described in 1912 by William Gibson mise and even fatal sleep apnea (Ondine’s curse).
Spiller and Edward Martin, is performed with the patient under Cordotomy is carried out with the patient supine using local
general anesthesia through a laminectomy. However, the open pro- anesthesia with light intravenous sedation in order to obtain feed-
cedure has largely been supplanted by percutaneous techniques that back from the patient.24 Lateral fluoroscopy is used to image the
are less invasive, generally associated with less morbidity, and con- C1–2 level, and a subarachnoid puncture is performed. After con-
sequently usually better tolerated by patients with advanced cancer firming flow of CSF, several milliliters of preservative-free contrast
who may be ill and debilitated.24–28 Mullan and colleagues28 initially are injected to identify the dentate ligament, which defines the hor-
described percutaneous C1–2 cordotomy. Although the procedure izontal equator of the spinal cord. The spinothalamic pathway is
has evolved considerably since the initial description, it remains an located just ventral to the dentate ligament. A temperature-mon-
excellent option for the treatment of refractory cancer pain. itoring cordotomy electrode (similar to the DREZ electrode) is then
inserted into the spinal cord just ventral to the dentate ligament. of a new neuropathic pain syndrome. The third cause of new pain is
Intraoperative stimulation is performed for physiologic localization the development of postcordotomy dysesthesias. The development
of the electrode. Keep in mind that the spinothalamic tract is soma- of pain on the side of the body opposite the original pain may also
totopically organized such that the sacral and lumbar fibers are signal progression of disease or the development of mirror pain.
located more dorsal and laterally whereas the cervical fibers are
somewhat more ventral and medial. In general, with the electrode
Midline (Commissural) Myelotomy
properly positioned, the patient will describe either a painful or a
warm sensation in the distribution of the pain. Once the target is Midline or commissural myelotomy is a procedure in which the
confirmed, an RF lesion is made usually for about 60 seconds at decussating fibers of the spinothalamic tract are interrupted as they
758C to 808C. The end-point is reduction or elimination of pain cross in the anterior white commissure of the spinal cord. The
and temperature sensation overlapping the area of pain and extend- lesion is usually created over several spinal cord segments at the
ing several dermatomes rostrally. The most significant complication lower thoracic level, although lesions at C1 have also been reported.
of unilateral cordotomy is ipsilateral leg weakness due to damage of Midline myelotomy is most effective for pain in the lower portion
nearby corticospinal fibers. Other complications include meningitis of the body, especially midline or bilateral pain for which cordot-
and postcordotomy dysesthesias (10%–15%). omy or other ablative procedures may not be as applicable. The
It is difficult, if not impossible, to correlate and compare the overall efficacy of midline myelotomy has been reported to be on
results of different authors owing to variability in selection criteria the order of about 70%.
and definitions of outcome in terms of pain relief. Tasker24 Broager29 reported his results of midline myelotomy in
reviewed and collated data from 21 published series of unilateral 44 patients, of whom 33 had adequate follow-up information avail-
percutaneous cordotomy including his own personal series. able. Forty-one (93%) patients suffered from malignant pain. An
Complete pain relief was reported in 63% to 90% of patients, excellent result (pain eliminated, no side effects) was initially
with ‘‘significant’’ pain relief in 59% to 96% of patients. In a achieved in 25 patients. Pain recurrence occurred between 1 and
series of 136 patients, 72% and 84% of patients had either com- 6 months in 9 of these patients. Cook and Kawakami30 summarized
plete or significant relief of their target pain, respectively. Thus, their results of midline myelotomy in 24 patients. Most patients
28% of patients in Tasker’s personal series had persistent pain in achieved initial pain relief. However, in the group of patients with
the target area. nonmalignant pain related to lumbar arachnoiditis, the procedure
Ischia and coworkers25 reviewed 69 patients who underwent was ultimately a total failure because pain uniformly returned.
cordotomy for neoplastic vertebral bone pain. Seventy-one percent These authors also concluded that pain from pelvic metastases
of the patients were believed to have benefited from the surgery, does not respond particularly favorably to myelotomy.
obtaining either complete pain relief or a significant reduction in Several authors have introduced the concept of a more limited
pain amenable to control by analgesics. Ischia and coworkers25 later punctuate midline myelotomy, particularly for patients whose pain
reported the results of unilateral percutaneous cordotomy in a may be more visceral than somatic in nature.31,32 It is believed that
group of 119 patients with cervicothoracic and thoracic pain a rather large component of visceral pain is carried in the medial
secondary to lung cancer who were followed up until death. aspect of the dorsal columns in the dorsal column polysynaptic
Approximately one third of the patients enjoyed complete pain pathway. Therefore, in a limited myelotomy, rather than dividing
relief up to the time of death. However, 81% of patients achieved the crossing fibers of the spinothalamic tract in the anterior white
complete pain control with cordotomy and the addition of analgesic commissure, this procedure is designed to interrupt visceral noci-
medications. Amano and associates26 compared the results of uni- ceptive pathways that lie in the deep aspects of the medial dorsal
lateral with those of bilateral cordotomy in a series of 221 patients.26 columns. Kim and coworkers32 performed limited high-thoracic
Unilateral high-cervical cordotomy was performed in 161 patients (T1–2) myelotomy on eight patients with gastric cancer who suf-
with bilateral procedures in 60. Complete or nearly complete pain fered from intractable visceral pain. Five of these patients either
relief was reported in 95% and 82% of patients who underwent were pain-free or had residual pain that was adequately managed
bilateral or unilateral procedures, respectively. Overall, percutane- with either a weak opiate (e.g., codeine) or even nonopiate analge-
ous cordotomy failed to produce even tolerable pain relief in only sics. Limited myelotomy has been reported to have a number of
5% of all patients. Finally, Kanpolat and colleagues27 performed advantages over the more classic midline myelotomy. There is a
CT-guided percutaneous cordotomy in 67 patients with pain due better chance of alleviating visceral pain, the risk of bothersome
to malignancy. Complete pain control was achieved in 97% of dysesthesias seems to be less, and the risk of neurologic dysfunction
patients. In just over two thirds of the patients, the authors were such as loss of proprioception or transient motor weakness, albeit
able to perform a selective cordotomy, meaning that analgesia was relatively small, is less. Because neither classical nor limited myelot-
produced in an area limited to the distribution of pain. omy is performed with any frequency, more studies are needed to
There are a number of explanations for persistent pain after determine the role, particularly of limited myelotomy.
unilateral cordotomy. In general, postcordotomy pain can be clas-
sified into three different categories: (1) original pain that is not
relieved, (2) original pain that disappears only to recur, and (3) new
pain.24 Cordotomy has been shown to consistently reduce nocicep-
Brainstem and Diencephalic Procedures
tive pain. Therefore, failure to relieve pain may indicate that the Caudalis DREZ
pain for which the procedure was done had a significant neuro-
pathic component that is not consistently relieved by cordotomy. The nucleus caudalis DREZ operation is an off-shoot of the spinal
Alternatively, the original pain may have been bilateral or had a procedure.33 The nucleus caudalis represents the origin of the
significant midline component, in which case a bilateral procedure second-order afferent neurons that carry nociceptive information
must be considered. Often, the original pain will be relieved only to from structures of the head and face. It receives afferent nociceptive
recur anywhere from several days to several months after cordoto- input from not only the trigeminal but also the facial, glossophar-
my. In many cases, this is due to regression of the level of analgesia, yngeal, and vagus nerves. This structure corresponds to and is con-
in which case, the procedure may need to be repeated. Some tiguous with lamina II or the substantia gelatinosa in the upper
patients will also develop new pain after cordotomy. For new cervical spinal cord. The procedure is performed through a small
pain located on the same side above the level of analgesia produced suboccipital craniotomy and C1 laminectomy. A series of RF lesions
by cordotomy, one must be suspicious of progression of the under- is made from the level of the C2 dorsal root to the obex in order to
lying disease. Progression of disease may also lead to development destroy the second-order neurons originating in the nucleus
caudalis and ascending rostrally to connect with the thalamus and nucleus (VCpc) has also been identified at the most caudal margin
reticular formation. The operation is in some respects similar to the of the Vc nucleus.36
trigeminal tractotomy described by Sjoquist, except that the latter is Although Vc thalamotomy has been performed in the past, it is
designed to interrupt the descending spinal trigeminal fibers. The not currently recommended because it is accompanied by a high
major complication associated with caudalis DREZ lesioning is ip- complication rate such as loss of contralateral sensory modalities
silateral ataxia owing to injury to the spinocerebellar tract, which and pseudoparesis. Indeed, lesions in the Vc nucleus are associated
overlies the entire length of the nucleus caudalis. A caudalis DREZ with a high incidence of dysesthesias and may even produce a full-
operation can be considered in patients with intractable recurrent blown thalamic pain syndrome. It has been reported that selective
trigeminal neuralgia who have failed multiple previous operations, lesions of the VCpc may offer pain relief by producing a dissociative
postherpetic trigeminal facial pain, and trigeminal neuropathic and sensory loss (i.e., interruption of nociceptive information with pres-
deafferentation pain.33 It has also been recommended for selected ervation of lemniscal input). However, the results of selective
patients with refractory atypical facial pain, although in the author’s lesions of this nucleus have produced wide discrepancies in success.
(RKO) opinion, destructive procedures in general should be There is no consensus as to which nuclei are included in medial
avoided in this particular condition. thalamotomy.37 Although specific nuclear targets have been
described (see earlier), it is somewhat difficult to conceive that,
with the current technology, lesions can be produced that respect
MidbrainTractotomy
the physiologic borders of these individual nuclei. In general,
Mesencephalic or midbrain tractotomy (i.e., mesencephalotomy) is medial thalamotomy is generally centered around the CM-PF-intra-
not commonly used in the United States. The procedure depends laminar nuclei, an area in which a lesion produces no detectable
on destruction of the spinothalamic and/or trigeminothalamic neurologic deficit. Intraoperative stimulation in this area likewise
fibers that ascend in the brainstem. The primary indication for produces no characteristic response except at very high intensities at
midbrain tractotomy is pain in the head, face, neck, or arm that which stimulation may produce paresthesias. The degree of pain
is refractory to pharmacologic management including intraspinal relief afforded by medial thalamotomy appears to be superior to
narcotics.34,35 Although C1–2 percutaneous cordotomy may be that achieved with either Vc or VCpc thalamotomy. Nociceptive
effective for upper extremity pain, effective analgesia is difficult in pain seems to be treated more effectively than neuropathic or de-
patients whose pain is in the shoulder and neck region and cordot- afferentation pain, and pain in the upper body appears to respond
omy is ineffective for pain in the head and face. better than that in the lower body and legs.
Midbrain tractotomy was first performed as an open procedure The results of medial thalamotomy vary widely.37,38 However,
in the late 1930s, and about a decade later, stereotactic midbrain comparison of results is difficult because of the heterogeneous
tractotomy was introduced by Spiegel and Wycis. At present, nature of the clinical series, the nonuniformity of how the procedure
improvements in imaging techniques, stereotactic localization, is performed (exact target, unilateral vs. bilateral lesions), and the
and electrode design have made this procedure much easier and variable methods by which results are conveyed. Young and Rinaldi39
probably safer. Following imaging and target selection, stereotactic suggested that 65% to 85% of patients with cancer pain whose
midbrain tractotomy is performed with the patient under local life expectancy is less than 1 year should obtain lasting pain relief
anesthesia. The midbrain target, namely the spinothalamic and/or with medial thalamotomy. The authors suggested that for nonma-
quintothalamic pathway, cannot be directly visualized from the lignant pain, medial thalamotomy carries a 20% immediate failure
MRI but is calculated based on standard landmarks used for func- rate and that pain relief occurs in only 50% to 60% of patients for
tional neurosurgery. The customary target is located 5 mm behind more than 1 year. More recently with the evolution of stereotactic
and 5 mm below the posterior commissure and 5 to 10 mm lateral radiosurgical techniques, there has been a renewed interest in
to the midline.34 The target is roughly in line with the inferior medial thalamotomy. Several groups have reported pain relief in
border of the superior colliculus. The target is confirmed with in- 40% to 50% of patients with cancer-related pain, although there
traoperative physiologic testing (i.e., macrostimulation) before the was a latency of 1 to 6 weeks before a positive benefit was achieved.
lesion is made. A lesion or series of lesions is then made, the lesion
parameters depending to some extent on the electrode design. The
major complications associated with midbrain tractotomy include
ocular disturbances and injury to the lemniscal tract, which can
Other Procedures
produce bothersome dysesthesias. Midbrain tractotomy appears to Cingulotomy for Intractable Pain
be of significant benefit in the treatment of patients with cancer
pain, in whom 75% pain relief has been reported on both a short- Surgical interruption of limbic pathways has traditionally been
and a long-term basis.34 Based on the available literature, it is dif- employed in patients with intractable psychiatric illness such as
ficult to assess the efficacy of midbrain tractotomy for pain related obsessive-compulsive disorder, major refractory depression, bipolar
to nonmalignant conditions. disorder, and even Gilles de la Tourette syndrome. However, in
patients with intractable pain due to widespread cancer, especially
those with an intolerable component of anxiety, bilateral cingulot-
Thalamotomy
omy can provide effective relief of pain and suffering for those with
The multiple connections between the sensory pathways that ter- relatively limited life expectancy.40 Indeed, cingulotomy can some-
minate in the thalamus have made this structure a natural target for times provide impressive results in patients for whom more tradi-
the treatment of pain. Discriminative somatotopically arranged sen- tional therapies have been ineffective.
sory information carried by spinothalamic fibers along with the Cingulotomy is indicated and is most effective for nociceptive
sensory input of the lemniscal pathways projects to and terminates pain related to diffuse musculoskeletal metastases, in patients whose
in the ventral caudal (Vc) nucleus, which is the main sensory relay life expectancy is less than 6 to 9 months. These patients usually
nucleus of the thalamus. Nociceptive information that terminates in have exhausted all other forms of conventional therapy including
the Vc nucleus is considered to be part of the neospinothalamic surgical resection, radiation, chemotherapy, systemic and/or spinal
pathway. Nociceptive information is also projected from the retic- narcotics, as well as other interventions such as nerve blocks. The
ular formation through a more medial paleospinothalamic system cingulum is an integral part of the medial limbic loop or Papez
that has more diffuse projections to nonspecific nuclei (centrum circuit and is believed to play an integral role in pain perception.
medianum [CM], parafascicular [PF], intralaminar, centrolateral, The procedure is performed stereotactically with the patient under
nucleus submedius). A nociceptive relay, the ventral parvocellular local anesthesia and is usually well-tolerated, even by very
debilitated patients. The center of the cingulate gyrus can be located pain relief may be delayed as it commonly is when radiosurgery is
stereotactically 24 mm posterior to tip of the frontal horn of the used for the treatment of trigeminal neuralgia. This is a significant
lateral ventricle, 1.5 mm lateral to the midline, and 15 mm above limitation in this population of patients who are suffering or have a
the roof of the lateral ventricles. The object of the procedure is to limited life expectancy and for whom immediate pain relief is highly
produce a lesion, usually by RF thermocoagulation, in as large an desirable.
area of the cingulate gyri as possible without impinging on sur- Perhaps the most useful technique for pituitary ablation is trans-
rounding structures. Cingulotomy is contraindicated in patients sphenoidal injection of absolute alcohol into the pituitary fossa. The
with intracranial vascular anomalies that would be in the path of procedure can be performed with the patient under light general
the electrode trajectory and in patients with an active calvarial or anesthesia using an intravenous neuroleptic and/or inhalation
intracranial infection. agent. The procedure is performed using C-arm fluoroscopy and
The pain relief from cingulotomy is usually immediate and involves placing a special cannula with a sharp obturator through
can be dramatic. However, pain relief is not generally durable the anterior wall of the sella and into the pituitary gland. After
over a long period, and therefore, patients with a life expectancy confirming that the tip is within the pituitary gland by injection
much more than 9 months are probably not good candidates. of a small amount contrast agent (0.1–0.2 ml), absolute alcohol is
Most patients are able to significantly reduce their intake of injected at a rate of 0.1 ml/min. During the injection period, one is
oral narcotics and increase activity levels. Several clinical studies able to track the ascent of the contrast up the pituitary stalk into the
of MRI-guided cingulotomy have reported that at least 50% of hypothalamus and third ventricle. Customarily, a total of 1 to 2 ml
patients have moderate to complete pain relief 3 months after the of alcohol is injected. During injection, pupillary size and reaction
procedure.40 Notwithstanding any ethical or technical concerns, are carefully observed because there is a risk of damage to the optic
for this reason alone, cingulotomy is probably not indicated for pathways. In the event that pupillary changes are observed, Miles41
the treatment of benign pain conditions. Although repeat lesion- advocated immediate subarachnoid injection of corticosteroids via
ing is possible and has been performed for psychiatric applica- a C1–2 puncture. Since the degree of hypopituitarism is unpredict-
tions, there are little data to support the use of repeat able, all patients should routinely receive pituitary replacement
cingulotomy for pain. Interestingly, some patients report only therapy.
modest pain reduction in spite of dramatic reduction in narcotic The pain relief achieved with pituitary destruction is variable,
usage and increased levels of activity. Moreover, these patients most authors reporting pain relief on the order of 70% to 90%,
respond appropriately to new sources of pain, indicating that with nearly two thirds of patients having complete pain relief.41
there may be a discrepancy in discriminative pain sensation and Patients with hormonally independent tumors achieve pain relief
pain perception at the lower end of the spectrum whereas those with breast or
prostate cancer enjoy pain relief nearer to 90%. The duration of
pain relief is somewhat variable but tends to fade rather quickly.
Pituitary Destruction for Cancer Pain
Around 65% of patients will experience pain relief for 3 months
Destruction of the pituitary gland for the relief of pain is not new. or less, although long-term relief in excess of a year has certainly
In fact, pituitary ablation has been employed for several dec- been reported. Notwithstanding the more successful cases, it
ades.41,42 There appears to be a clear association between the pitu- would seem that pituitary destruction is, therefore, primarily indi-
itary gland, pain, and analgesia. However, the exact mechanism(s) cated for patients with a life expectancy of perhaps 3 to 6 months.
by which hypophysectomy produces analgesia remains unclear. The Aside from damage to the visual system, other complications
initial and most obvious logic was that there was some type of include diabetes insipidus (as high as 50% with large volumes of
endocrine effect because the treatment is primarily effective for alcohol), ocular palsies, cerebrospinal fluid leakage, and
patients with breast or prostate carcinoma. It was believed that meningitis.
the degree of pain relief should correlate with the extent of hor-
monal depletion. However, there is a well-recognized discrepancy
between pain relief, the hypopituitarism produced by the proce-
dure, and tumor regression, and in fact, some authors report a NEUROMODULATION
complete absence of correlation between hormonal depletion and
analgesia.43 Consequently, other mechanisms have been proposed, Spinal and Intraventricular Drug Delivery
including a stress analgesic effect as well as a neurolytic effect
because there are connections between the pituitary gland and Since the 1980s, intraspinal drug delivery has assumed an increas-
regions of the hypothalamus that are known to be involved in ingly important role in the management of intractable pain.
pain processing. Indeed, there have been reports of stimulation- Although the initial application of this therapy was restricted to
produced analgesia when electrical stimulation has been applied patients with refractory cancer pain, the use of spinal opiates for
to the pituitary gland. nonmalignant pain has now become the primary indication for this
Whatever the mechanism, pituitary ablation is indicated for therapy. Chronic IT drug infusion has been shown to be effective
patients with very advanced malignancy with intractable pain sec- and has clearly been accepted in patients with cancer pain who
ondary to widespread metastases. Pituitary destruction can be per- cannot gain effective analgesia with systemic opioids without sig-
formed in a variety of ways: (1) transcranial hypophysectomy, (2) nificant side effects. In this group of patients, the treatment has a
transsphenoidal hypophysectomy, (3) radiation-induced hypophy- defined end-point and can produce substantial improvements in
sectomy, (4) RF thermal coagulation, (5) cryogenic hypophysect- quality of life. Even though chronic spinal drug infusion is now
omy, and (6) chemical hypophysectomy using alcohol. Open well accepted for noncancer pain, there continues to be an element
procedures such as transcranial or transsphenoidal hypophysecto- of controversy surrounding its long-term use in this particular
my are major surgical procedures and would now be rarely indi- patient population.
cated given the other options available. Radiation-induced pituitary IT opiates should be considered only after less invasive and
destruction was previously performed by either transsphenoidal complex modalities have been attempted and have failed. Again,
implantation of an yttrium screw or external radiation. Although patient selection, particularly with nonmalignant pain, plays a cen-
there are little if any data, it might be feasible to now consider tral role in the success of this therapy. It must be appreciated by the
stereotactic radiosurgery for this purpose. High doses of radiation treating physician, other members of the pain treatment team, and
can be focused in the pituitary fossa without injuring surrounding the patient that the decision to implant a drug pump represents a
structures. The one potential problem with this technique is that huge commitment on the part of all parties. Indeed, for patients
with nonmalignant pain, chronic spinal drug infusion is a labor- drug delivery. The panel, consisting of 17 internationally recognized
intensive therapy that has no definitive end-point. experts in the field of spinal drug delivery, critically reviewed the
Several factors should influence the clinician in considering literature on the use of opioids, local anesthetics, adrenergic agents,
spinal drug infusion including pain topography, type of pain N-methyl-D-aspartate (NMDA) antagonists, somatostatin analo-
(nociceptive vs. neuropathic), pain response to long-acting oral gues, calcium channel blockers, and various other agents36; devel-
opiates, prior history of drug abuse, psychological screening, oped standardized clinical guidelines for spinal analgesia44; and
response to a screening trial, and patient access to care. In general, suggested future directions for research and development of alter-
spinal drug infusion, particularly using opioids, is most ideally native agents for IT analgesia.45
suited to patients with nociceptive pain that has a more diffuse Intraventricular drug administration may occasionally be indi-
pattern (e.g., patient with failed back surgery syndrome with pri- cated in patients with craniocervical pain due to head and neck
marily diffuse axial lower back pain). Classically, it has been cancer with limited survival (usually <3 mo) who either fail to
taught that neuropathic pain does not respond to opiates, but respond to intraspinal opioids or who had an initial favorable
this is not true in many instances. Clearly, there are patients response but subsequently developed tolerance to the intraspinal
with pure neuropathic pain who do, in fact, respond to opiates, infusion.46 The drug may be administered using an implanted infu-
albeit perhaps at higher does than might be required for nocicep- sion pump or by intermittent injection through an Ommaya reser-
tive pain. This is actually true for both oral and IT opiates. voir. The usual daily dose of morphine for intraventricular delivery
Although spinal infusion may be effective for head and neck is between 50 and 700 mcg/day. Intraventricular administration of
pain in selected patients, because of drug properties and factors morphine produces a potent analgesia in excess of that provided by
related to drug distribution in the cerebrospinal fluid, this therapy intraspinal infusion (epidural or IT) that appears to be mediated
is best suited to pain that occurs below the upper thoracic derma- through supraspinal pathways. The side effect profile of intraven-
tomes. In general, the pain should be opiate-responsive, although tricular morphine appears similar to that of intraspinal delivery
again, patients whose pain has a significant neuropathic compo- except that the risk of respiratory depression appears to be minimal
nent may show a relative resistance to opiates even at reasonable after the first several days of therapy.
dose levels that are devoid of systemic side effects. Lazorthes and associates,46 over a 10-year period, treated
Prior to implantation of a permanent pump for chronic ther- 82 patients with terminal cancer, all of whom were opiate tolerant,
apy, all patients being considered should undergo a screening trial. using intraventricular opiates. The authors employed a subcutane-
Screening can be performed in a variety of ways: single or multiple ous access port attached to a ventricular catheter. The initial dose to
IT boluses or continuous epidural or IT infusion. Screening can be determine efficacy and minimize the occurrence of side effects was
performed either with or without placebo control. There are around 0.1 mg of morphine. Depending on the degree of analgesia,
advantages and disadvantages of each technique and currently the dosage was later increased. The average follow-up for these
no consensus as to which method best predicts long-term patients was 65 days (range 12–443 days). The mean initial daily
response to therapy. The author’s (RKO) preference is to perform intraventricular morphine dose required for analgesia was 0.3 mg
a continuous IT over 3 to 4 days using a tunneled IT catheter. For (0.1–2.0 mg); the final mean dose was 2.5 mg (0.1–60 mg). Overall,
patients who are opiate tolerant, the daily opiate dose is reduced during a mean follow-up period of around 2.5 months, 66 (80%)
by half at the beginning of the trial and a short-acting oral agent is patients achieved good or excellent pain relief, 14 (17%) patients
prescribed as needed for breakthrough pain. This method most had moderate relief, and 2 (3%) patients failed. Relatively minor
closely replicates the effect that will be derived from a pump and morphine side effects such as nausea, vomiting, drowsiness, urinary
may, in theory, at least partially eliminate the potential placebo retention, and constipation were common during the trial and titra-
response that can occur with a single IT bolus. Moreover, this tion phase but were almost always transient. In fact, only 6 (7%)
method allows dose escalation during the trial, which may be patients experienced chronic side effects (nausea and vomiting 5,
important in opiate-tolerant patients who have been receiving drowsiness 1). Only 3 (3.5%) patients experienced major central
exceedingly high doses of oral narcotics. The trial should be con- side effects: 2 patients developed drowsiness and respiratory depres-
ducted using the drug one plans to deliver with the implanted sion, and a single patient experienced visual hallucinations and
pump. For example, it is not rational to screen a patient with a behavioral problems. All of the central side effects were immediately
combination of morphine and clonidine and then begin chronic reversed by systemic naloxone administration with minimal effects
therapy with morphine alone. Also, catheter position is important, on analgesia.
depending on the drug chosen. With hydrophilic drugs such as Although IT opiates delivered chronically with an implanted
morphine, catheter position is not critical because the drug will pump has proved highly effective, this therapy does in fact have
distribute over the entire spinal axis. However, when using drugs its drawbacks including cost, requirements for ongoing refills and
such as clonidine or fentanyl, which are more lipophilic, the cath- pump maintenance, and the risk of bacterial contamination with
eter tip must be positioned within several segments of the derma- refills. Consequently, a number of preclinical studies have been
tomal level of the pain. conducted to determine the feasibility and efficacy of IT adrenal
In the past, IT drug infusion was synonymous with IT opiates. medullary transplants for the management of chronic pain. The
Even at present, morphine is still the only opiate approved by the theory is that chromaffin cells that are grafted into the cerebrospinal
U.S. Food and Drug Administration (FDA) for ITDD using a pro- fluid will produce analgesic substances such as catecholamines
grammable pump. Notwithstanding, other opiates (hydromor- (which are known to be involved in the descending inhibitory
phone, fentanyl, sufentanyl, meperidine, methadone) as well as a system) and opioid peptides (which reduce pain in a synergistic
number of nonopiate agents such as bupivicaine and clonidine are manner). Along those lines, Lazorthes and colleagues47 published
currently being used. Indeed, the concept of polyanalgesia has their results of a phase II trial of IT chromaffin cell grafts in
become quite popular insofar as ITDD is concerned. A substantial 15 patients with cancer pain. Pain had previously been controlled
body of literature details the efficacy of many of these alternative in all patients with IT morphine. Twelve patients with an average
agents and drug combinations, and it would appear based on clin- follow-up of 4.5 months were judged to benefit from enhanced
ical series that many of these agents and combinations are in fact analgesia. Seven patients were able to either eliminate (n = 5) or
safe for long-term use.36,44,45 However, one should be cautious significantly decrease (n = 2) their requirements for IT morphine.
about utilizing agents for which animal toxicity data are lacking Five patients were able to remain at a stable IT morphine dose
and/or that have not been shown at least over time to be safe. without the need for dose escalation. In most of the patients, a
In 1999, the PolyAnalgesic Consensus Conference was convened relationship was noted between analgesic response and cerebrospi-
in an effort to address some of the crucial issues in the field of spinal nal fluid met-enkephalin levels. Although this represents a small
series of patients, the results suggest that this therapy may be ben- In patients with primarily nociceptive pain that is opiate
eficial and it should perhaps be tested and confirmed in a larger, responsive, the preferred target is the PVG. The specific target
controlled group of patients. coordinates vary between authors. Richardson49 selects his PVG
target 8 to 10 mm behind the midcommissural point, approxi-
mately 5 mm from the midline, and places the tip of the electrode
Deep Brain Stimulation on the commissural plane. Stimulation is again performed,
although the responses obtained from PVG and/or PAG stimula-
Nearly 50 years ago, during the course of performing various intra- tion are not as discreet as those from stimulation in the Vc. At
cranial neurosurgical procedures, a serendipitous observation was this target location, a good indicator of correct electrode place-
made: that electrical stimulation of various anatomic structures ment is a sensation of either heat or cold in the contralateral face.
within the brain could produce analgesia. Beginning in the 1960s Other sensations that have been reported include a sensation of
and continuing into the 1970s, several authors reported that stim- bodily warmth, floating, dizziness, or general well-being. Again,
ulation of the lemniscal pathways including the Vc thalamic sensory once the target is confirmed, permanent electrodes are introduced
relay nucleus (i.e., ventral posterolateral [VPL] and ventral postero- and connected to temporary extensions that are externalized for a
medial [VPM] nuclei) and internal capsule could effectively relieve trial period of stimulation. Although PVG or Vc stimulation is
neuropathic pain. In 1969, Reynolds48 discovered that stimulation preferred for pure nociceptive or neuropathic pain, respectively, in
of the periaqueductal gray (PAG) area in rats produced such a fact many patients have mixed nociceptive and neuropathic pain.
profound analgesia that surgical procedures could be performed In these patients, it has become a common practice to place
without any evidence of pain. This resulted in a large number of electrodes at both targets and permanently implant the electrode
animal studies further investigating stimulation-produced analgesia that produces the best analgesia. In some cases, both electrodes are
(SPA). Subsequently, deep brain stimulation (DBS) was carried out implanted for chronic stimulation.43 More than 1000 patients have
using a variety of targets including PAG, periventricular gray been treated using DBS. Various measures of long-term efficacy
(PVG), VPL, and VPM. have been employed including greater than 50% reduction in
DBS has been performed for a variety of pain conditions includ- baseline pain, continued use of the stimulator, and pain relief
ing failed back surgery syndrome, brachial plexus avulsion, painful reported using descriptive terms such as ‘‘excellent,’’ ‘‘good,’’
peripheral neuropathy, refractory trigeminal neuropathic pain, ‘‘fair,’’ and ‘‘poor.’’ The overall long-term success rate for DBS
spinal cord injury pain, and thalamic pain syndromes.43,49 DBS has been reported to average around 60% (range 19%–79%).
should be considered a procedure of last resort for patients with Bendok and Levy43 performed a meta-analysis of DBS for chronic
intractable pain in whom multiple, more conventional therapeutic pain that encompassed all studies that included more than 15
modalities have failed. patients. Thirteen series were identified with 1114 patients for
There are several major considerations in patient selection for which long-term outcome data were available. Long-term
DBS. First, one should seek a clear organic basis for the pain. successful pain relief was reported in 561 (50%) patients. Nearly
Patients with vague diffuse pain complaints without a clear under- 700 patients underwent DBS for neuropathic pain, with an average
lying cause should be excluded from consideration. As with most long-term success rate of 42%. Both initial and long-term success
other types of ‘‘pain surgery,’’ patients should be evaluated by a rates were quite variable, ranging from 29% to 78% and 26% to
multidisciplinary team. Preoperative psychological evaluation 84%, respectively. For patients who underwent DBS for nocicep-
should be routinely performed although many of these patients tive pain, the long-term efficacy was somewhat better, averaging
will have already undergone such an evaluation prior to other 61% (272 out of 443 patients). Again, initial and long-term suc-
treatment modalities. Most, if not all, patients with chronic pain cess rates were variable, ranging from 0% to 98% and 0% to 81%,
of such severity in whom DBS is being given serious consideration respectively.
harbor mild psychological disturbances such as depression and A relatively clear relationship appears to exist between efficacy,
anxiety that influence their pain but are not so significant as to type of pain (nociceptive vs. neuropathic), and target selection
exclude them from surgical consideration. A second major con- (VPL/VPM or PVG/PAG). Treatment of nociceptive pain with sen-
sideration is the location of the pain. Patients with pain in the sory thalamic stimulation (i.e.,VPL/VPM) is uniformly unsuccess-
upper half of the body and pain in the head and face may be good ful. Indeed, not a single patient (n = 51) with nociceptive pain in
candidates for DBS. Patients with poorly defined diffuse pain in whom VPL/VPM stimulation was used achieved long-term pain
the pelvis, rectum, and perineum of unclear etiology should not be relief. Conversely, PAG/PVG stimulation produced long-term suc-
considered for DBS. Because there are multiple target sites that cess in 59% of patients with nociceptive pain. In contrast, VPL/
may be selected, it is important to determine whether the pain is VPM stimulation for patients with deafferentation pain was suc-
primarily nociceptive or neuropathic because this will influence cessful in 56%. For patients with nociceptive pain, VPL/VPM stim-
target selection. In general, nociceptive pain that is opiate- ulation was successful in only 23% of patients.
responsive generally responds best to PAG or PVG stimulation Since the late 1990s, the FDA reclassified DBS (previously an
whereas neuropathic pain responds most favorably to stimulation approved procedure) as experimental, citing a lack of safety and
of VPL/VPM.43 efficacy data. There are certainly sufficient safety data from the lit-
DBS is performed using stereotactic guidance with the patient erature on thalamic stimulation for tremor. However, the device
under local anesthesia. For unilateral pain that is purely neuro- used is not approved for pain applications. At present, DBS is
pathic, an electrode is stereotactically placed in the contralateral performed under the auspices of a physician investigational device
Vc (VPL or VPM). If the pain is bilateral, bilateral electrode place- exemption or at the discretion of the physician with the consent of a
ment is obviously necessary. The location of the Vc is initially deter- well-informed patient for whom no other viable treatment options
mined with stereotactic anatomic coordinates and then confirmed exist. However, on the basis of the available data, it would appear
using physiologic mapping. The goal is to identify the area where that DBS is indeed a safe and effective treatment option for carefully
stimulation-induced paresthesias are perceived in the area of pain. selected patients.
Once the optimal target has been localized, a permanent electrode is
placed and connected to a temporary extension for a trial period
that may last anywhere from a few days up to a week. Generally, at Motor Cortex Stimulation
least a 50% reduction in baseline pain is required to justify implan-
tation of the permanent system, which is then implanted as a Motor cortex stimulation (MCX) represents a novel approach to
second stage under general anesthesia. the treatment of patients with deafferentation pain.50–53
Deafferentation pain develops when sensory information is either tunneled and connected to a temporary extension, and a trial
partially or completed interrupted at any point within the neospi- period of stimulation is conducted. Stimulation is performed
nothalamic system. The presence of deafferentation pain necessarily and analgesia obtained at stimulation amplitudes that are well
implies the presence of either partial or complete sensory loss, most below the motor threshold, implying that the mechanism of
notably related to pain and temperature. Common examples of this action is unrelated to activation of primary motor neurons. If at
type of pain include pain after brachial plexus root avulsion, pain least a 50% reduction in baseline pain is achieved, the electrode is
after either bulbar or thalamic infarction, phantom limb pain after then connected to a permanently implanted pulse generator during
amputation, and pain after spinal cord injury. Deafferentation pain a second stage. Stimulation is intermittent and is usually cycled in
may also be iatrogenic and may occur after destructive pain proce- an ‘‘on-off’’ pattern for periods of anywhere from 30 minutes to
dures that target the spinothalamic system such as cordotomy or several hours. Some patients, however, actually require nearly con-
peripheral destructive procedures of the trigeminal system such as tinuous stimulation for adequate pain relief. MCX using the
retrogasserian RF rhizotomy that may occasionally result in anes- devices described previously is not FDA approved, and therefore,
thesia dolorosa. the application of this technique should be dictated by the same
Physiologic evidence suggests that at multiple levels of the CNS, principles outlined previously for DBS.
nociceptive neurons are subject to inhibitory influences exerted by Even though there are relatively little long-term data for large
the somatosensory system, which mediates nonnoxious sensation numbers of patients, MCX has emerged as an accepted and prom-
such as light touch.50,51 This concept is supported by the observa- ising tool for the treatment of deafferentation pain. Yamamoto and
tion that peripheral nerve stimulation, SCS, and thalamic sensory coworkers52 performed chronic MCX on 28 patients with central
stimulation can attenuate nociceptive responses. However, in many pain and reported the results after 1 year of therapy. Overall, MCX
patients with partial sensory preservation, peripheral nonnoxious was judged to be effective in 13 of 28 (46%) patients. However,
stimulation within the area of sensory loss may actually evoke pain when the results were analyzed based on the preoperative response
that can spread over the entire area of sensory loss, implying dys- to intravenous infusion, the results were quite interesting. Of the 18
function of the pain inhibitory function of the sensory system med- patients who responded to either barbiturate or ketamine, 12 (67%)
iating nonnoxious sensation. It has been observed that stimulation were considered successful. In contrast, out of 10 patients whose
at a site rostral to the level of deafferentation may provide better pain was not responsive to barbiturate or ketamine infusion, only 1
pain relief, implying a functional somatosensory pain inhibitory (10%) had a successful result. Nguyen and associates53 reported the
system rostral to the site of deafferentation. Based on these con- results of chronic MCX in 32 patients with refractory neuropathic
siderations and their own observation that stimulation of the pre- pain of either central or peripheral origin. Long-term mean visual
central rather than postcentral gyrus sometimes produced profound analog scale (VAS) scores fell from 86 to 40 (P = .001) and med-
pain inhibition, Tsubokawa and colleagues pioneered the concept of ication intake as measured by the medication quantification scale
MCX for deafferentation pain.50,51 The exact mechanism(s) through (MQS) was reduced (17.9 preoperative to 12.3 postoperative;
which MCX produces analgesia is not clear. However, there are P = .001). Overall, 24 of 32 (75%) experienced either a ‘‘good’’
known to be reciprocal connections between the primary motor (pain reduced by 70%–100%) or a ‘‘satisfactory’’ (pain reduced
and the primary sensory areas. Based upon the proposed mecha- by 40%–69%) result in terms of pain reduction. Ten of 13 (77%)
nism of deafferentation pain described previously, it is believed that patients with central pain had pain reduction; 9 out of 12 (75%)
MCX produces its effect by restoring inhibitory fields that would patients with trigeminal neuropathic pain also enjoyed a definite
normally surround primary sensory neurons but that have been lost benefit. Interestingly, 1 patient with postherpetic neuralgia had a
as a result of deafferentation. positive response; and this may represent at least one alternative for
MCX has been most effectively utilized in patients with deaffer- the treatment of this dreadful condition for which few treatments
entation pain after thalamic or bulbar stroke and in those with are effective. Several patients experienced loss of effect over the first
refractory trigeminal neuropathic pain. It has been suggested that few months of therapy. In some cases, this was related to migration
the response of the patient’s pain to intravenous opiates, barbitu- of the electrode, which when repositioned correctly, resulted in
rates, or ketamine may provide prognostic information regarding restoration of analgesia.
the potential response to MCX. Yamamoto and coworkers52 per-
formed intravenous infusions of morphine, thiamylal (barbiturate),
and ketamine in 39 patients with central poststroke pain (hemibody SUMMARY
pain with dysesthesias). Definite pain reduction occurred in 22 of
39 (56%) patients with barbiturate infusion, 11 of 23 (48%) patients From the preceding discussion, it should be clear that we now have
with ketamine infusion, and only 8 of 39 (21%) patients with mor- at our disposal more options for the surgical treatment of pain than
phine infusion. Comparison of long-term results demonstrated that have ever been available. Indeed, in qualified hands, any of these
patients whose pain responded favorably to barbiturates or keta- may be highly effective depending on the clinical situation.
mine and was resistant to morphine displayed long-lasting pain However, along with the opportunities provided comes a responsi-
reduction with MCX. bility to utilize these techniques in a careful, thoughtful, and ratio-
MCX is performed through a small craniotomy that exposes the nal manner. This begins with a thorough assessment of the biologic,
dura overlying the motor cortex contralateral to the side of pain. psychological, and social aspects of each patient’s pain and knowl-
The motor cortex can be localized using a variety of methods edge of the indications for and advantages and limitations of the
including framed-based as well as frameless stereotactic techniques, various surgical approaches. It is the firm belief of the author
somatosensory evoked potentials, direct cortical stimulation map- (RKO) that when it comes to the surgical treatment of pain, one
ping, and functionally using either functional magnetic resonance should take very seriously the philosophy of Hippocrates to ‘‘do no
imaging (MRI) or magnetoencephalography. Functional MRI and harm.’’ Unfortunately, not every patient with pain can be helped
magnetoencephalography are particularly exciting and intriguing with surgery, in which case alternative or complementary nono-
because the possibility now exists for the ‘‘functional’’ images to perative approaches must be recommended. Indeed, the philosophy
be imported into a variety of frameless intraoperative stereotactic that one ‘‘just has to do something’’ for the desperate patient with
navigation systems that can then be used for precise localization of intractable pain is at its best misguided and at its worst potentially
the primary motor cortex. harmful. However, on a more optimistic note, it should be clear
Two 1 x 4 contact insulated plate electrodes are placed epidu- that surgical treatment of pain can be highly effective and, when
rally over the area of the motor strip from which motor contrac- used in a thoughtful way, can dramatically change the lives of many
tions can be elicited in the painful area. The electrodes are then patients for the better.
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XIII
INTERVENTIONAL
APPROACHES TO PAIN
MANAGEMENT
Chapter 78 temperature, sweating, piloerection, proprioceptive disturbances,

and erythema of the overlying skin are autonomic manifestations
MYOFASCIAL TRIGGER POINTS of myofascial pain.
Elizabeth Demers Lavelle and William F. Lavelle

ETIOLOGY
Trigger points, small contraction knots in the muscle tissue, may
develop after an initial injury to muscle fibers. This injury may
include a noticeable traumatic event or repetitive microtrauma to
the muscles. The trigger point causes pain and stress in the muscle
INTRODUCTION or muscle fiber, maintaining a hard contraction on the muscle. The
constant tension caused by these taut bands also stresses the joints
Myofascial pain syndrome is a common but poorly understood and muscle insertions. As the stress increases, the muscles become
cause of chronic musculoskeletal pain. A myofascial trigger point is fatigued and more susceptible to activation of additional trigger
a hyperirritable point in skeletal muscle that is associated with a points. The stressed muscle itself is also susceptible to injury.
hypersensitive palpable nodule. Approximately 10% of the U.S. When predisposing factors combine with a triggering stress event,
population have chronic disorders of the musculoskeletal system. activation of a trigger point occurs. This theory has been termed the
In patients presenting with pain complaints, at least 30% had acute injury pool theory.
trigger points. Painful conditions of the musculoskeletal system,
including myofascial pain syndrome, constitute some of the most
important and difficult to treat problems encountered in clinical PATHOPHYSIOLOGY
practice.
No pathologic or laboratory tests for identifying trigger points exist
at this time. Therefore, much of the pathophysiologic research on
DEFINITIONS trigger points has been directed toward verifying common theories
of their formation. There are currently three hypotheses about the
Travell and Simons1 defined the myofascial trigger point as formation of a trigger point: the energy crisis theory, the muscle
‘‘a hyperirritable spot, usually within a taut band of skeletal spindle theory, and the motor endplate theory.
muscle or in the muscle fascia which is painful on compression
The energy crisis theory. The energy crisis theory was initially devel-
and can give rise to characteristic referred pain, motor dysfunction,
oped to explain the taut band of muscle. This theory postulates
and autonomic phenomena.’’ Put simply, when a trigger point is
an initial release of calcium, either from the sarcoplasmic retic-
pressed, pain is caused and produces effects at a target, the zone of
ulum or from the extracellular fluid through the injured sarco-
reference or referral zone. This area of referred pain is the distin-
lemma. The ionic calcium release causes sustained sarcomere
guishing feature that differentiates myofascial pain syndrome from
shortening and increased metabolism. The sustained shortening
fibromyalgia. This pain is reliably reproduced on palpation of the
also could compromise local circulation, leading to decreased
trigger point despite the fact that it is remote from its source of
oxygen and nutrient supply with an increased metabolic
origin. This referred pain does not necessarily coincide with derma-
demand. Hence, an energy crisis is formed. The lack of energy
tologic or neuronal distributions, but it follows a consistent and
could compromise recovery of the calcium by the sarcoplasmic
reproducible pattern.
reticulum, which would perpetuate the cycle.
A myofascial pain syndrome is defined as sensory, motor, and
The muscle spindle theory. The muscle spindle theory was developed
autonomic symptoms caused by myofascial trigger points. The sen-
by Hubbard and Berkoff,2 who proposed that the muscle spindle
sory disturbances that are produced are dysesthesias, hyperalgesia,
was the generator of a highly localized area of electrical activity
and referred pain. Coryza, lacrimation, salivation, changes in skin
577
578 Chapter 78 MYOFASCIAL TRIGGER POINTS
characteristic of myofascial trigger points. At the time, those be projected in a peripheral referral pattern, a central referral pat-
authors dismissed the possibility that these potentials could tern, or a local pain pattern (Fig. 78–1). When a hyperintense area
arise from motor endplates because the activity was not localized of pain is identified, its area of referred pain should then be
enough to be generated in the endplate and that the activity did identified.
not have the expected location or waveform morphology. Since The palpable band is considered to be critical in the identifica-
that time, there have been multiple studies supporting the tion of the trigger point. The patient should be in a relaxed position
notion that the motor endplate (not the muscle spindle) appears during evaluation and location of a trigger point. Trigger points will
to be the area that generates electrical activity characteristic of consist of tender, hard knots or nodules surrounded by what feels
myofascial trigger points. like normal muscle tissue. Three methods have been identified for
The motor endplate theory: The motor endplate hypothesis identifies trigger point palpation: flat palpation, pincer palpation, and deep
dysfunction in the region of extrafusal motor endplates, or neu- palpation. Flat palpation refers to sliding a fingertip across the
romuscular junction, as the cause of myofascial trigger points. muscle fibers of the affected muscle group. The skin is pushed to
This theory has been supported by studies demonstrating elec- one side and the finger is drawn across the muscle fibers. This
tromyographic (EMG) evidence for this area as the source of the process is repeated with the skin pushed to the other side. A taut
trigger point. This theory incorporates the energy crisis theory in band may be felt passing under the physician’s finger. Snapping
its ideas of the origins of trigger point formation. palpation, like the plucking of a violin, is employed to identify
the specific trigger point. Pincer palpation is a method that employs
firmly grasping the muscle between the thumb and the forefin-
ger(s). The fibers are pressed between the fingers in a rolling
DIAGNOSIS manner while the examiner attempts to locate a taut band. Deep
palpation may be used to find the trigger point that is obscured by
A diagnosis of myofascial pain is often made after other types of superficial tissue. The fingertip is placed over the muscle attachment
acute musculoskeletal injury have been excluded. The diagnosis is of the area suspected of housing the trigger point. When the
best made through a careful analysis of the history of pain along patient’s symptoms are reproduced by pressing in one specific
with a consistent physical examination. The physical examination direction, a trigger point may be presumed to be located.
should include an evaluation of the patient’s posture and range of Several devices have been developed to assist in the location of a
motion. Strength testing and neurologic assessments should also be myofascial trigger point. Fischer3 developed a pressure threshold–
completed. The diagnosis of myofascial pain syndrome, as defined measuring gauge to assist in the diagnosis and location of the myo-
by Simons and Travell,1 relies on eight clinical characteristics, fascial trigger point. It is a hand-held device calibrated in kilograms
including per centimeter2. Pressure is gradually increased evenly until the
patient verbally reports discomfort. This pressure measurement is
n The onset description and immediate cause of the pain.
then recorded. Contralateral pressure measurements are taken to
n The pain distribution pattern.
establish relative sensitivity of the point in question, with a differ-
n A restricted range of motion with sensitivity to stretch.
ence of 2 kg/cm2 considered an abnormal reading. An EMG mon-
n Pain causing muscle weakness with no atrophy.
itor may also assist in the diagnosis of the trigger point. When the
n Pain similar to the patient’s chief complaint caused with
active locus is entered, the peak amplitudes will often be off the
compression.
scale of the EMG monitor. This method, although it may appear
n A taut band of muscle.
scientifically useful, has not been found to have significant clinical
n Snapping palpation or rapid needle insertion causing a local
results.
twitch response.
n Mechanical stimulation of the trigger point reproducing
referred pain.
The identification of the pain distribution is one of the most
critical elements in diagnosing and treating myofascial pain. The TECHNIQUES FOR MANAGEMENT
physician should ask the patient to identify the most intense area of
pain using a single finger. There is also an associated consistent and NoninvasiveTechniques
characteristic referred pain pattern on palpation of this trigger
point. This referred pain is often not located in the immediate A significant component of the treatment of myofascial trigger
vicinity of the trigger point, but it is commonly found in predictable points is the identification of an underlying cause for the injury.
patterns. These patterns are clearly described in Travell and Simons’ The physician should review contributing factors including exercise
Myofascial Pain and Dysfunction: The Trigger Point Manual.1 Several habits, body posture and mechanics, work ergonomics, and stress.
common patterns and locations are shown in Table 78–1. Pain can Dietary causes should be addressed because Travell and Simons1
Table 78^1. CommonTrigger Points
Muscle Involved Radiation of Pain Common Symptoms

Trapezius Back of neck, temporal region Headache
Temporalis Teeth, jaw Headache, jaw pain
Anterior serratus Side of chest to border of scapula Shortness of breath
Infraspinatus or supraspinatus Shoulder and down into arm May mimic rotator cuff tear or cervical radiculopathies
Quadratus lumborum Low back pain
Gluteus maximus Buttock pain May mimic lumbar radiculopathies
Quadriceps Thigh pain or knee pain May mimic lumbar radiculopathies
Gastrocnemius, soleus Calf pain May radiate into the foot
XIII INTERVENTIONAL APPROACHES TO PAIN MANAGEMENT 579
A B
C
Figure 78^1. Trigger points and their reference zones. A, Peripheral projection of pain. B, Central projection of pain. C, Local pain.
have cited deficiencies of vitamins B1, B6, B12, folic acid, and vita- one end of the muscle with the trigger point zone securely
min C as contributory to trigger point pain. Anxiety and depression anchored. The patient should be marked after careful diagnosis of
are common comorbidities and should be considered. the trigger point region, and the reference zone should be noted.
The skin overlying the trigger point should be anesthetized by use of
Spray (freeze) and stretch. Travell and Simons1 advocate pas- a vapocoolant spray (ethyl chloride or trichloromonofluoro-
sive stretching of the affected muscle after application of sprayed methane-dichlorofluoromethane [Fluori-Methane]) over the
vapocoolant to be the ‘‘single most effective treatment’’ for trigger entire length of the muscle. This spray should be applied from
point pain. The proper technique depends on patient education, the trigger point toward the reference zone until the entire length
cooperation, compliance, and preparation. The patient should be of the muscle has been covered. Immediately after the first vapo-
positioned comfortably, ensuring that the trigger point area is well coolant spray pass, passive pressure should be applied to the other
supported and under minimal tension. The position should place end of the muscle, resulting in a stretch. Multiple slow passes of
580 Chapter 78 MYOFASCIAL TRIGGER POINTS
spray over the entire width of the muscle should also be performed be reached utilizing a 21-gauge, 2-inch or 2.5-inch needle. The
while the passive muscle stretch is maintained. This procedure is needle should never be inserted to the hub because this is the
repeated until full range of motion of the muscle group is reached, weakest point on the needle.
to a maximum of three repetitions before rewarming the area with Once the skin is prepared and the trigger point identified, the
moist heat. Care must be taken to avoid prolonged exposure to the overlying skin is grasped between the thumb and the index finger or
vapocoolant spray, assuring that each spray pass lasts less than 6 the thumb and the middle finger. The needle is inserted approxi-
seconds. Patients must be warned not to overstretch muscles after a mately 1 to 1.5 cm away from the trigger point to facilitate the
therapy session. advancement of the needle into the trigger point at a 308 angle.
The grasping fingers isolate the taut band and prevent it from roll-
Physical therapy. Some of the best measures to relieve cyclic ing out of the trajectory of the needle. A ‘‘fast-in, fast-out’’ tech-
myofascial pain involve the identification of perpetuating factors. nique should be used in order to elicit a local twitch response. This
Physical therapists assist patients in the determination of predispos- local twitch has been shown to predict the effectiveness of the trig-
ing activities and are often able to correct elements of poor posture ger point injection. After the trigger point is entered, the needle
and body mechanics. should be aspirated to ensure that the lumen of a local blood vessel
has not been violated. If the physician chooses to inject an agent, a
Transcutaneous electrical stimulation. Transcutaneous electri- small volume should be injected at this time. The needle may be
cal stimulation (TENS) is used as common adjuvant therapy in withdrawn to the level of the skin without exiting, and it should be
chronic and acute pain management. It is noted that the placement redirected to the trigger point, repeating the process. The process of
of the TENS electrode is an empirical process and may involve entering the trigger point and eliciting local twitch responses should
placement at trigger point sites or along zones of referred pain. proceed, attempting to contact as many sensitive loci as possible
(Fig. 78–2).
Ultrasound. Ultrasound may be employed as an adjunctive An integral part of trigger point therapy is postprocedure
means of treatment. Ultrasound transmits vibration energy at the stretching. After trigger point injection, the muscle group that
molecular level; approximately 50% reaches a depth of 5 mm. was injected should undergo a full active stretch.
Massage. Massage is advocated by Simons and coworkers.4 Their Complications of trigger point injections. As with the introduc-
technique is described as a ‘‘deep stroking’’ or ‘‘stripping’’ massage. tion of any foreign body through the skin, the risk of skin or soft
The patient is positioned comfortably to allow the muscle group tissue infection is a possibility. Injection over an area of infected
being treated to be lengthened and relaxed as much as possible. skin is contraindicated. The physician should never aim the needle
at an intercostal space in order to avoid the complication of a
Ischemic compression therapy. The term ischemic compression pneumothorax. Hematoma formation after a trigger point injection
therapy refers to the belief that the application of pressure to a can be minimized with proper injection technique and holding
trigger point produces ischemia that will ablate the trigger point. pressure over the surrounding soft tissue after withdrawal of the
Pressure is applied to the point of increasing resistance and then needle.
maintained until the physician feels a relief of tension. The patient
may feel mild discomfort, but should not experience profound pain.
The process is repeated for each band of taut muscle encountered.
Medications for Injection
Local anesthetics. Local anesthetics are the substances that have
InvasiveTechniques been most frequently investigated for the treatment of myofascial
Trigger point injection remains the treatment with the most scien-
tific evidence and investigation for support. It is also the most
common method employed by clinicians. It is typically advocated
for trigger points that have failed noninvasive means for treatment.
Injections are highly dependent on the clinician’s skill to localize the
active trigger point with a small needle.
Various injected substances and techniques have been investi-
gated, including local anesthetics, corticosteroids, botulinum toxin,
sterile water, sterile saline, and dry needling. One common finding
with these techniques is that, at least anecdotally, the duration of
pain relief after the procedure outlasts the duration of action of the
injected medication or technique.
The Universal Technique for Injection

The patient should be positioned in a recumbent position to pre-
vent syncope, assist in patient relaxation, and decrease muscle ten-
sion. The trigger point must then be identified correctly. The
palpable band is considered to be critical to the identification of
the trigger point. This can be done with any of the three methods
described previously. The trigger point should be clearly marked.
Then, the skin is prepared in a sterile fashion. Various physicians
use different skin preparations for their local procedures. One
common skin preparation technique is to first cleanse the skin Figure 78^2. Injection technique. The trigger point is positioned
with a topical alcohol solution followed by preparation with povi- between two fingers to prevent the sliding of the trigger point during
done-iodine (Betadine). A 22-gauge 1.5-inch needle is recom- injection.The fingers are pressed downward and apart to maintain
mended for most superficial trigger points. Deeper muscles may pressure and ensure hemostasis.
trigger points. Local anesthetic injections have been shown to REFERENCES

improve measures on a pain scale, range of motion, and algometry 1. Travell JG, Simons DG. Myofascial Pain and Dysfunction: The Trigger
pressure thresholds. The volume of local anesthetic injected has also Point Manual. Baltimore: Williams & Wilkins, 1983.
been investigated, and small volumes are considered the most effec- 2. Hubbard D, Berkhoff G. Myofascial trigger points show spontaneous
tive. Typically less than 1 ml of local agent should be injected in a needle EMG activity. Spine 1993;18:1803–1807.
highly controlled manner. The primary use for a local anesthetic is 3. Fischer AA. Pressure threshold meter: its use for quantification of
to prevent local soreness. Procaine is often chosen because it is tender points. Arch Phys Med Rehabil 1986;67:836–838.
selective for small, unmyelinated fibers that control pain perception 4. Simons DG, Travell JG, Simons LS. Travell and Simon’s Myofascial
rather than motor control. Lidocaine is a common substitute for Pain and Dysfunction: The Trigger Point Manual, 2nd ed. Baltimore:
procaine, but no experimental comparisons are available in the Williams & Wilkins, 1998.
literature.
SUGGESTED READINGS
Corticosteroids. Local steroid injections offer the potential
advantage of control of a local inflammatory response. However, Acquandro MA, Borodic GE. Treatment of myofascial pain with botulism
the theory that a trigger point is due to a local energy crisis does not toxin A. Anesthesiology 1994;80:705–706.
Chen J, Chung K, Hou C, et al. Inhibitory effect of dry needling on the
support its clinical use. Steroids are a common tool used by the
spontaneous electrical activity recorded from myofascial trigger points
orthopedic surgeon and rheumatologist to treat local conditions of rabbit skeletal muscle. Am J Phys Med Rehabil 2001;80:729–735.
such as trigger finger and tennis elbow. They impose the added Cheshire WP, Abashian SW, Mann JD. Botulism toxin in the treatment of
dangers of local myotoxicity, subcutaneous tissue damage, and myofascial pain syndrome. Pain 1994;59:65–69.
skin discoloration. Although a number of physicians support the Graff-Radford S. Myofascial pain: diagnosis and management. Curr Pain
use of injection of steroids for treatment of a trigger point, we Headache Rep 2004;8:463–467.
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electrical nerve stimulation on myofascial pain and trigger point
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Hong C-Z. Trigger point injection: dry needling vs. lidocaine injection.
commercially prepared botulinum toxin A relaxes an overactive
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lished. When injecting botulinum toxin, the physician should J Musculoskel Pain 1996;4:61–79.
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points and normal motor endplates. The physician should be care- mechanisms of myofascial trigger points. Arch Phys Med Rehabil
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prior to injection. EMG assistance may be utilized with this method. Hubbard D. Chronic and recurrent muscle pain: pathophysiology and
Extinction of a hyperactive motor signal would imply proper place- treatment, and review of pharmacologic studies. J Musculoskel Pain
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ment of the injection.
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any injection technique, the physician should aim to (1) elicit a Sports Med 2001;29:49–53.
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582 Chapter 79 EPIDUR AL STEROID INJECTIONS
Chapter 79 ANATOMYOF THE SPINE AND

EPIDURAL SPACE
EPIDURAL STEROID INJECTIONS The epidural space extends from the foramen magnum to the sacral
Alane B. Costanza and Salahadin Abdi hiatus and is located within the vertebral column. The column is
made of 33 vertebrae organized into five areas, and only 24 are
movable. There are 7 cervical, 12 thoracic, and 5 lumbar vertebrae.
The 5 sacral bones and an additional 4 coccygeal vertebrae are fused
together to form the sacrum and coccyx, respectively, in adults. The
lumbar and sacral bones bear more weight than the cervical and
thoracic counterparts, accounting for the larger size of these struc-
tures. Intervertebral joints are found in the 24 cervical, thoracic, and
INTRODUCTION lumbar vertebrae and afford the spine flexibility. Three quarters of
the spine’s height is attributable to vertebral bodies, whereas one
Epidural steroid injections (ESIs) have been used extensively in the quarter is attributable to the intervertebral disks. Whereas the
United States to treat chronic pain. It is estimated that as many as number of cervical vertebrae remains fixed, the number of thoracic,
80% of Americans will suffer from back pain at least once in their lumbar, and sacral vertebrae can vary in up to 5% of the popula-
lifetime. Fortunately, 90% of people recover within weeks with little tion. As a result, counting vertebrae should begin at the base of the
or no treatment, and only 5% go on to have pain for greater than neck.
3 months. The patients with unrelenting pain are often seen in pain The spine has four curvatures in adults, two anterior and two
clinics after trying various treatments with minimal success. posterior. The thoracic and sacrococcygeal curvatures are kyphotic
Currently, no treatment options offer complete and lasting relief and also known as ‘‘primary’’ curvatures because they develop first.
conservatively or surgically. It is well known that pain may be per- The cervical and lumbar curvatures, also known as ‘‘secondary’’
sistent and even worse after surgical interventions. curvatures, are not obvious until infancy. Once a child begins to
Even though many important studies have been published on hold her or his head up, the cervical curvature becomes more pro-
the topic of ESIs in recent years, debate remains strong over the nounced. Thoracic vertebrae are somewhat wedge-shaped, and this
efficacy of ESIs. Thus, the purpose of this chapter is to update the accounts for their anterior curvature. The lumbar curvature
status of ESIs with regards to current practice guidelines. becomes noticeable once an infant begins to walk and is more pro-
nounced in females.
Vertebrae structure varies greatly throughout the spine and is
HISTORYOF ESIS made of a vertebral body and arch. The anterior portion, or verte-
bral body, functions as the main support for the vertebral column
The first known epidural injection was described in 1901 by French and progressively enlarges down the vertebral column. The larger
physicians Sicard and Cathelin. It was a caudal approach using bodies found in the thoracic and lumbar area account for the
cocaine as a treatment for low back pain and sciatica. In 1925, spine’s ability to bear weight. The anterior longitudinal ligament
Viner also described the caudal route for epidural injections using envelops the anterior vertebral bodies and the corresponding inter-
procaine in normal saline. Injections of this nature continued to be vertebral disks. Its strength preserves vertebral column joint stability
described through the 1930s by Evans. Interestingly, even back then, and aids in prevention of hyperextension. The posterior longitudi-
it was found that the volume of solution, with or without local nal ligament is thinner and relatively less strong than the anterior
anesthetic, was the most important factor in relieving pain. In ligament. It runs from the posterior edge of the vertebral bodies
1934, Mixter and Barr1 reviewed several cases of low back pain connecting to the intervertebral disks and aids in prevention of
believed to be caused by cartilaginous tumor. Their investigation hyperflexion as well as posterior disk protrusion.
revealed herniation of the nucleus pulposus to be the cause of the The posterior aspect of the vertebrae is made of lamina and
majority of lumbago by a ratio of 3:1. pedicles, which form the vertebral arch. The pedicles attach directly
Later in that decade, cortisone was discovered by E. C. Kendall2 to the posterior portion of the vertebral body and have superior and
and was found to improve inflammatory diseases such as rheuma- inferior notches, which form the intervertebral foramina. The
toid arthritis. By the 1950s, the longer-acting steroids, such as lamina extends posteriorly as two bony plates. Superior and inferior
hydrocortisone, were also found to have the same benefit. The articular processes originate at the union between the pedicle and
steroids were injected into joints, and inflammation reduction the laminae. Bilateral transverse processes also arise from the junc-
could be confirmed histologically. Steroid injections quickly tion between the pedicle and the laminae. Lastly, the spinous pro-
became a sought-after treatment for many inflammatory and debil- cess extends from the posterior union of the laminae and partially
itating diseases. overlaps the underlying vertebrae. These spinous processes are con-
Soon thereafter, the first ESI was reported because it was nected via a strong supraspinous ligament dorsally, followed by
believed that the patient’s low back pain and sciatica were caused interspinous ligaments. The ligamentum flavum is a strong elastic
by ‘‘inflammation.’’ Controversy remains as to whether the first ESI band that attaches the lamina vertically and maintains the normal
with hydrocortisone occurred in 1951 or 1953, but the first ESI curvature of the spine.
placed in the United States was published in 1961 by Goebert. The epidural space is located within the vertebral column and
His technique used procaine and hydrocortisone. Many subsequent extends from the foramen magnum to the sacral hiatus. Its main
studies, through the late 1960s, found ESIs to drastically improve anatomic delineations are the tough dura mater, which is the out-
lumbago and sciatica when compared with high-volume and local ermost covering of the spinal cord, and the vertebral periosteum. At
anesthetics. Today, ESIs have become a mainstay of treatment for the skull base, the endosteal and cranial dura separate to allow for
chronic low back pain. the venous sinuses. The cranial dura becomes the spinal dura, and
the endosteal dura forms the periosteum of the spinal canal. The Exposure to a greater vascular surface area also potentially increases
epidural space is the space created between the spinal dura and the the risk for local anesthetic toxicity owing to absorption from the
periosteum of the spinal canal. It surrounds the dural sac and is epidural space.
bounded anteriorly by the posterior longitudinal ligament, poster- The anterior epidural space in which these large venous plexuses
iorly by the ligamentum flavum and the periosteum of the lamina, are found is formed between the posterior longitudinal ligament
and laterally by the vertebral pedicles and intervertebral foramina. and the periosteum of the vertebral body. Here, the anterior dura
The epidural space communicates freely with the paravertebral sticks securely to the posterior longitudinal ligament, which
space through the intervertebral foramina. Communication is indi- stretches across the intervertebral disks. Directly next to the inter-
rect with the cerebrospinal fluid (CSF). vertebral disks, connective tissue bands extend superiorly and infer-
Varying methods have been used to identify the anatomy of iorly, further dividing the anterior epidural space into lateral
theepidural space, especially in the lumbar region. In 1988, halves. This lateral epidural space communicates freely with the
Groen and Drukker3 reviewed the innervation of the dura mater paravertebral space through the intervertebral foramina. The lateral
in human fetuses stained with acetylcholinesterase and found sig- epidural space is divided from the posterior epidural compartment
nificant differences between the ventral and dorsal areas. A thick, by the vertebral arch pedicle that comes in contact with the nearby
longitudinally arranged nerve plexus was found in the ventral dura and is filled with fat, spinal nerve roots, and blood vessels.
spinal dura involving the nerve plexuses from the posterior longi- Again, it is here that the open intervertebral foramina can transmit
tudinal ligament, radicular branches of segmental arteries and sinu- intra-abdominal pressure directly to the epidural space. These fo-
vertebral nerves. The nerves of the dorsal dura arise from the ramina can narrow as a result of osteoarthritis and prevent the
ventral dural plexus but do not form a nerve plexus and do not spread of local anesthetic through the foramina, causing an
extend into the medial dorsal area. The authors3 also found ventral increased distribution of local anesthetics through the length of
dural nerves to extend up to eight vertebral levels, overlapping the epidural space.
throughout those levels. Dural innervation is of importance In addition to identifying structures within the epidural space,
because it has been thought to be one of the tissues responsible cryomicrotome sectioning has been used to examine the dura
for low back pain. mater. In 1991, using this technique, Hogan4 found no evidence
Cryomicrotome sections, in addition to computed tomography of a midline dorsal connective tissue band or any septation of the
and magnetic resonance imaging, have revealed the epidural space posterior epidural space. However, several studies support the
to be filled with loose connective tissue, fat, lymphatics, arteries, existence of a dorsomedian dural fold, the plica mediana dorsalis.
internal venous plexuses, and spinal nerve roots. Most of the In 1988, Savolaine5 demonstrated the connective tissue band using
epidural space is filled with fat. The fat is semifluid and lobulated, computed tomographic epidurography that divided the posterior
occupying more posterior space. Its content decreases as it nears epidural space in the midline. With this type of imaging, the plica
the vertebral articular process and becomes more abundant in the seems to attach the dura mater closely to the ligamentum flavum,
lateral epidural space near the spinal nerve roots. Here, it becomes causing tenting of the dura and a narrowing of the epidural space
continuous with the fat encompassing the spinal nerve roots in in the midline. Anatomically, the plica is described as separating
the foramina and the fat in the paravertebral space. The least the posterior epidural space into lateral compartments and nar-
amount of fat is found in the anterior vertebral space, and as a rowing the space in the midline. It has been proposed that this
result, the dura lies in close proximity to the posterior longitudi- division of the epidural space may obstruct epidural catheter
nal ligament. For the most part, epidural fat lies freely within the placement or cause unequal distribution of local anesthetics. In
epidural space, with the exception of fat located in the interver- 1997, Beaujeux6 proposed that the appearance of the connective
tebral foramina. Here, it is attached to surrounding structures via tissue band may be due to the presence of an epidural fat pad that
connective tissue. Examinations have revealed that the amount of slides away from the dural sac and periosteal lining of the spinal
fat located within the epidural space is directly related to the canal.
amount of fat throughout the rest of one’s body; therefore,
obese patients have more fat within their epidural space than
their leaner counterparts. Highly lipid-soluble drugs are taken RATIONALE FOR ESIS
up extensively by epidural fat and can take long periods of time
to be released. The many capillaries of the epidural fat also take ESIs are a low-risk alternative to surgical intervention in the treat-
up a great deal of local anesthesia and form a large vascular ment of spine pain. The mechanism by which epidural steroids
system within the epidural space. work is not fully understood, but it is believed to act through var-
The vascularity within the epidural space is not limited to the ious methods including decreased activity of the inflammatory
epidural fat, but encompasses the many epidural veins that lie pri- mediator phospholipase A2, interruption of nociceptive C-fiber
marily within and fill the anterior epidural space. The many veins transmission, and the pain-spasm cycle to name a few.
make up a large venous plexus, and their location is conveniently Phospholipase A2 has long been thought to be the cause of nerve
away from a correctly placed epidural needle. The rich venous root inflammation, and ESIs have been evaluated on their ability to
plexus has several vascular links within the epidural space, vertebral inhibit the action of this enzyme. Further, inflammation is known
bodies, and foramina. Cephalad, the epidural space connects with to induce increased capillary permeability and edema. Thus, the
the venous sinuses of the skull, namely the basilar, occipital, and ability of steroids to decrease inflammation results in less nerve
sigmoid sinuses. Caudad, the vertebral venous plexuses are con- root inflammation and compression by reducing edema and con-
nected to the sacral venous plexus, creating a link to the uterine sequently resulting in less pain. In 1998, Lee and coworkers7 studied
and iliac veins. The thoracic and abdominal veins are connected to the effects of epidural betamethasone injections on phospholipase
the vertebral plexus through the intervertebral foramina, and pres- A2 in a rat model of spinal nerve ligation. The authors reported that
sure changes within these cavities are spread to the epidural veins. rats treated with epidural steroid showed less thermal hyperalgesia
As a result, compression of the inferior vena cava because of preg- compared with their control groups. Furthermore, they reported
nancy or an intra-abdominal mass may result in distention of the that the phospholipase A2 level, which was high postinjury, was
epidural veins and hasten blood flow cephlad to the vertebrobasilar reduced in rats that were treated with epidural steroid.
plexus via the azygos vein. The risk of intravascular cannulation is In addition to phospholipase A2, stimulation of nociceptive
increased in this circumstance with an epidural catheter or needle. C-fibers has been implicated in pain mediation, specifically with
In addition, the epidural space is decreased and local anesthetics can reference to the dorsal root ganglion (DRG). Studies analyzing
migrate more extensively with resulting greater degrees of block. repetitive stimulation of C-fibers showed amplified reactions of
neurotransmitters yielding central sensitization and causing con-

stant pain without peripheral stimulation. In 1977, Howe and
associates8 demonstrated that repetitive stimulation of C-fibers
was not necessarily directly related to repetitive stimulation of
peripheral nociceptors. These authors found that after a neuronal
lesion occurred and axonal regeneration took place, there was
extreme sensitivity to mechanical stimulation associated with spon-
taneous activity. As a result, when peripheral neuronal lesions
occur, the damaged ganglion produces ectopic neuronal activity
from increased mechanosensitivity, leading to continuous pain.
Interruption of this pain cycle can be accomplished by blocking
sensory afferent C-fibers. Devor and colleagues in 19859 and
Johansson and coworkers in 199010 showed corticosteroids to be
effective in blocking C-fiber transmission, contributing to the ratio-
nale for steroid injection for chronic pain. Furthermore, Devor and
associates in 199211 showed that systemic lidocaine suppressed ec-
topic discharge originating from the DRG and peripheral injured
nerve without blocking nerve conduction.
It has been considered for some time that root injury may be
related not just to deformation of a nerve root but also by the
presence of herniated nucleus pulposus cells in the epidural
space. Many investigations have demonstrated the effect of au-
tologous nucleus pulposus cells causing axonal injury, myelin
sheath damage, intravascular coagulation, increased vascular per-
meability, decreased intranueral blood flow, and leukotaxis
when applied locally. It has also been shown that the effects of Figure 79^1. Anteroposterior (AP) fluoroscopic view of interlaminar
nucleus pulposus cells can be markedly inhibited by methylpred- epidural contrast dye injection.
nisolone and cyclosporine and somewhat less by indomethacin
and lidocaine.
Knowing the effects of nucleus pulposus cells on nerve injury,
investigators have examined which cytokines in the nucleus pulpo- n Finally, inject 2 ml of 40 mg/ml triamcinolone with 1 to 3 ml of
sus may be responsible for nerve damage. Olmarker and Larsson12 0.25% bupivacaine into the epidural space after negative aspira-
examined pig nucleus pulposus cells and found that tumor necrosis tion for blood and CSF.
factor-a (TNF-a) may be contained inside. When this data were n Then, replace the stylet in the needle (to avoid tracking steroid
further analyzed, it was thought that TNF-a may be the cytokine through skin) and withdraw the needle, clean the area, and apply
responsible for nerve injury, mainly regarded as a characteristic a sterile dressing.
myelin injury induced by nucleus pulposus cells. Interestingly,
TNF-a has also been associated with increased vascular permeability
and the initiation of coagulation and may be inhibited by steroids Transforaminal Approach (Fig. 79^2)
and cyclosporine. Furthermore, nonsteroidal anti-inflammatory
drugs have a reduced blocking effect on TNF-a, and lidocaine has This approach is useful especially if symptoms are mainly radicular
an extremely low or opposite effect. and previous midline injections have not helped.
n Under AP fluoroscopic guidance, locate the correct level and
mark it on the skin.
TECHNIQUES OF ESI n Then, clean the skin with povidone-iodine (Betadine)/chlor-
hexidine and drape using sterile technique.
In order to be able to perform a successful ESI, the techniques we
n Infiltrate the skin and subcutaneous tissues with 1% lidocaine
commonly use are as follows:
using a 25-gauge, 1.5-inch needle.
n Using a 3.5-inch, 22- or 25-gauge spinal needle, under obli-
que fluoroscopic guidance, advance the needle just below the
Interlaminar Approach (Fig. 79^1) pedicle (at the 6 o’clock position) toward the posterior
border of the foramina.
n Under anteroposterior (AP) fluoroscopic guidance, locate the n Verify the needle depth with lateral cross-table fluoroscopy.
correct level and mark it on the skin. n Inject 0.5 to 1 ml of dye (Omnipaque 240) to confirm the
n Then, clean the skin with povidone-iodine (Betadine)/chlorhex- final position of the needle.
idine and drape using sterile technique. n Finally, inject 0.5 ml of 40 mg/ml triamcinolone with 1 to 2
n Infiltrate the skin and subcutaneous tissues with 1% lidocaine ml of 0.25% bupivacaine after negative aspiration for blood
using a 25-gauge 1.5-inch needle. and CSF.
n Using a 3.5-inch, 22-gauge spinal needle, under AP fluoroscopic n Then, replace the stylet in the needle (to avoid tracking ster-
guidance, advance the needle between the lamina until the liga- oid through skin) and withdraw the needle, clean the area,
mentum flavum is reached. Then, using a loss of resistance and apply a sterile dressing.
(LOR) to saline or air technique, carefully advance the needle
into the epidural space, which is reached as soon as resistance is
lost.
n Verify the needle depth with lateral cross-table fluoroscopy. Caudal Approach (Fig. 79^3)
n Inject 1 to 2 ml of dye (Omnipaque 240) to confirm the final
Caudal entry is easily achieved with minimal risk of inadvertent
position of the needle within the epidural space.
dural puncture, but it requires injection of a relatively high
B
Figure 79^2. A, AP fluoroscopic view of transforaminal epidural
contrast dye injection. B, Lateral fluoroscopic view of transforaminal B
epidural contrast dye injection.
Figure 79^3. A, AP fluoroscopic view of caudal epidural contrast
dye injection. B, Lateral fluoroscopic view of caudal epidural contrast
dye injection.
volume to arrive at the affected site. Caudal ESIs are often per-
formed when blockade of sacral and lumbar nerves is needed.
This route can be used for lysis of adhesions in patients who have It has been shown in randomized trials and nonrandomized
had previous surgical interventions and continue to have back pain. reports that caudal ESIs gave a strong level of evidence for short-
The patient is placed in either a prone or a lateral position. If the term relief and a moderate level of evidence for long-term relief in
patient is positioned prone, a pillow is placed under the pelvis. The managing chronic lumbar pain from radiculopathy and postlumbar
skin over the sacrococcygeal area is then prepared with antiseptic laminectomy syndrome.
solution and draped in a sterile fashion. Under fluoroscopic gui-
dance, the 25-gauge, 1.5-inch needle is used to inject 1% lidocaine
and create a skin wheal over the intended needle insertion site. Role of Fluoroscopy
Then, using a 22-gauge, 3.5-inch spinal needle, the caudal epidural
space is accessed under fluoroscopic guidance and the final needle The use of fluoroscopy and injection of radiologic contrast material
position is verified by injecting contrast dye. It is important that the provides confirmation of accurate needle placement within the epi-
needle is not advanced more than 1.5 cm because the dural sac ends dural space. In 1983, White13 found that the LOR technique alone
at the S2 level. At this point, the intended epidural medications may has been proved to result in incorrect epidural needle placement
be administered after negative aspiration for CSF or blood. in up to 30% of lumbar ESIs. In 1999, Johnson and associates14
reviewed 5334 injections before and after epidurography. There Corticosteroid Use Caution Advised
were four complications (0.07%) that required the patient be
n Patients with poorly controlled diabetes
taken to an emergency room or be hospitalized. No patients in
n Patients with a history of congestive heart failure
the study required surgical intervention, and all symptoms were
found to be self-limiting. They concluded that epidurography in
conjunction with ESIs provides for safe and accurate therapeutic
injection and is associated with an exceedingly low frequency of COMPLICATIONS
untoward sequelae.
In 2002, Stojanovic15 found a 53% inaccurate cervical epidural The most common complications of ESIs can be divided into two
needle placement using LOR. In addition, the ligamentum flavum, categories: those related to needle placement and those related to
which is the most important gauge for the LOR technique, has been drug administration. Complications include inadvertent dural
implicated in inaccurate epidural needle placement. The lateral puncture (with or without total spinal blockade), spinal cord
halves of the ligamenta flavum have been shown to meet unpredict- trauma, bladder dysfunction, anterior spinal artery syndrome,
ably in the midline at an angle less than 908 and to form a steeply caudal equine syndrome, infection (including meningitis and
arched roof over the lumbar posterior epidural space. A midsagittal abscess formation), epidural hematoma, subdural injection of med-
gap between the ligamenta flavum in the midline is common in the ications, injection of air (pneumocephalus), epidural lipomatosis,
cervical and thoracic regions. This midsagittal gap may contribute pneumothorax, nerve injury, headache, brain damage, death,
to an unpredictable LOR when the midline approach is used to increased intracranial pressure, intravascular injection, vascular
enter the epidural space. Lirk and associates16–18 reported their injury, cerebrovascular or pulmonary embolism, and adverse effects
findings using cadavers that the ligamentum flavum frequently of steroids. Although spinal cord trauma and the formation of
fails to fuse in the midline over the cervical, thoracic, and lumbar spinal cord or epidural hematoma formation are devastating com-
vertebral interspaces and that midline gaps were observed more plications, fortunately, they are rare.
frequently in cervical and high thoracic vertebral regions. As a In 2000, Botwin and colleagues19 examined complications of
result, the LOR technique might lead to increased difficulty in fluoroscopically guided interlaminar ESIs and found an overall inci-
localizing the epidural space. dence of minor complications to be 9.6% per injection with no
major complications. They reported complications in 207 patients
receiving 322 transforaminal lumbar epidural injections.
INDICATIONS Complications included transient headaches (3.1%), increased
back pain (2.4%), increased leg pain (0.6%), facial flushing
Although a variety of indications for ESI have been proposed, the (1.2%), vasovagal reaction (0.3%), hyperglycemia (0.3%), and
most common indication remains to be a herniated nucleus pulpo- high blood pressure (0.3%).
sus causing radicular pain. Some of the indications are In 2001, the same group20 investigated complications of 257
fluoroscopically guided caudal epidural injections and found the
n Disk herniation and radiculopathy.
incidence of minor complications to be 15.6% per injection.
n Degenerative disk disease.
Complications included insomnia, transient headaches, worsening
n Postlaminectomy syndrome.
of back pain, facial flushing, vasovagal reactions, nausea, and leg
n Postherpetic neuralgia.
pain.
n Spondylolysis/spondylolisthesis.
The work of Botwin and coworkers21 continued in 2003 when they
n Spinal stenosis.
evaluated complications related to fluoroscopically guided interla-
minar cervical epidural injections. The overall incidence of compli-
cations per injection was found to be 16.8%. In this study, 157
CONTRAINDICATIONS patients receiving 345 injections were evaluated and complications
were reported. Complications included increased neck pain (6.7%),
nonpositional headaches (4.6%), insomnia the night of injection
Absolute Contraindications for ESIs (1.7%), vasovagal reactions (1.7%), facial flushing (1.5%), fever
n Sepsis the night of the procedure (0.3%), and dural puncture (0.3%).
n Infection at the site of planned injection Further, in 2006, the same group22 examined fluoroscopically
n Bleeding disorder guided interlaminar thoracic ESIs performed in 21 patients who
n Therapeutic anticoagulation received 39 injections. No major complications were reported,
n Allergy to medications that would be injected (e.g., contrast, and adverse effects were reported to occur at a rate of 20.5%.
local anesthetic, corticosteroid) Intravascular penetration is a known complication of ESIs.
n Increased intracranial pressure Several authors have evaluated its occurrence. In 2000, Furman
n Thrombocytopenia and associates23 examined the incidence of intravascular penetra-
n Hypovolemia tion during transforaminal lumbosacral ESIs. The study examined
n Patient refusal 761 injections and found an overall incidence of intravascular pen-
etration to be 11.2%. Interestingly, this examination demonstrated
an increased rate (21.3%) of intravascular injections at the sacral
level rather than at the lumbar level (8.1%). In 2003, Furman and
Relative Contraindications for ESIs colleagues studied the rate of intravascular penetration of transfo-
n Uncooperative patients
raminal cervical ESIs. This time the rate was found to be 19.4%.
n Preexisting neurologic disorders (e.g., multiple sclerosis—this is
In 2004, Manchikanti24 found a 22% rate of intravascular pen-
controversial) etration in 100 consecutive patients using contrast flow patterns. In
n Fixed cardiac output states (e.g., aortic stenosis, hypertrophic
the same study, complications associated with caudal epidurals were
obstructive cardiomyopathy, mitral stenosis, and complete examined. On injection, back pain was found in 43% of patients
heart block) and leg pain was found in 22% of the patients in the group. The
n Vertebral column abnormalities
postprocedure complication rate was calculated to be 34%. Eighteen
n Prophylactic low-dose heparin
percent experienced soreness at the injection site, 5% experienced
increased pain, 4% had muscle spasms, 4% had swelling,
3% experienced headache, and 2% had minor bleeding. Dizziness, 14. Johnson BA, Schellhas KP, Pollei SR. Epidurography and therapeutic
nausea and vomiting, fever, numbness, and voiding difficulties each epidural injections: technical considerations and experience with 5334
occurred in 1%. cases. AJNR Am J Neuroradiol 1999;20:697–705.
15. Stojanovic MP, Vu TN, Caneris O, et al. The role of fluoroscopy in
cervical epidural steroid injections: an analysis of contrast dispersal
patterns. Spine 2002;27:509–514.
EVIDENCE 16. Lirk P, Colvin J, Stefer B, et al. Incidence of lower thoracic
ligamentum flavum midline gaps. Br J Anaesth 2005;94:852–855.
In 2007, Abdi and coworkers25 published an extensive systematic 17. Lirk P, Kolbitsch C, Putz G, et al. Cervical and high thoracic
review about the evidence for ESIs. The authors report that in ligamentum flavum frequently fails to fuse in the midline.
managing lumbar radicular pain with interlaminar lumbar ESIs, Anesthesiology 2003;99:1387–1390.
the evidence is strong for short-term relief up to 6 weeks and lim- 18. Lirk P, Moriggl B, Colvin J, et al. The incidence of lumbar
ited for long-term relief beyond 6 weeks. In managing cervical ra- ligamentum flavum midline gaps. Anesth Analg 2004;98:1178–1180.
dicular pain with cervical interlaminar ESIs, the evidence is 19. Botwin KP, Gruber RD, Bouchlas CG, et al. Complications of
moderate. The evidence for lumbar transforaminal ESIs in mana- fluoroscopically guided transforaminal lumbar epidural injections.
Arch Phys Med Rehabil 2000;81:1045–1050.
ging lumbar radicular pain is strong for short-term and moderate 20. Botwin KP, Gruber RD, Bouchlas CG, et al. Complications of
for long-term relief. The evidence for cervical transforaminal ESIs in fluoroscopically guided caudal epidural injections. Arch Phys Med
managing cervical nerve root pain is moderate. The evidence is Rehabil 2001;80:416–424.
moderate in managing lumbar radicular pain in postlumbar lami- 21. Botwin KP, Castellanos R, Rao S, et al. Complications of
nectomy syndrome. The evidence for caudal ESIs is strong for fluoroscopically guided interlaminar cervical epidural injections. Arch
short-term relief and moderate for long-term relief in managing Phys Med Rehabil 2003;84:627–633.
chronic pain of lumbar radicular pain and postlumbar laminectomy 22. Botwin KP, Baskin M, Rao S. adverse effects of fluoroscopically
syndrome. guided interlaminar thoracic epidural steroid injections. Am J Phys
Med Rehabil 2006;85:14–23.
23. Furman MB, O0 Brien EM, Zeleszewski TM. Incidence of intravascular
penetration in transforaminal lumbosacral epidural steroid injections.
SUMMARY Spine 2000;25:2628–2632.
24. Manchikanti L, Cash KA, Pampati V, et al. Evaluation of lumbar
ESIs (with or without local anesthetics) is a very useful interven- transforaminal epidural injections with needle placement and contrast
tional procedure that could be offered to our spine pain patients in flow patterns: a prospective, descriptive report. Pain Physician
combination with other systemic pharmacologic agents and physi- 2004;7:217–224.
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efficacy, we think that it is very beneficial if patients are appropri- chronic spinal pain: a systematic review. Pain Physician 2007;10:185–212.
ately selected. Currently, there is no consensus about the type and
the dose of steroids and/or local anesthetics used, the frequency of SUGGESTED READINGS
injections, and the interval between the injections.
Bogduk N, Christophidis N, Cherry D. Epidural Use of Steroids in
Management of Low Back Pain. Report of Working Party on Epidural
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10. Johansson A, Hao J, Sjölund B. Local corticosteroid application Rydevik B, Brown MD, Lundborg G. Pathoanatomy and pathophysiology
blocks transmission in normal nociceptive C-fibres. Acta Anesthesiol of nerve root compression. Spine 1984;9:7–17.
Scand 1990;34:335–338. Saal JS, Franson RC, Dobrow R, et al. High levels of inflammatory phospholipase
11. Devor M, Wall PD, Catalan N. Systemic lidocaine silences ectopic A2 activity in lumbar spine herniations. Spine 1990;15:674–678.
neuroma and DRG discharge without blocking nerve conduction. Wall PD, Devor M. Sensory afferent impulses originate from dorsal root
Pain 1992;48:261–268. ganglia as well as from the periphery in normal and nerve injured rats.
12. Olmarker K, Larsson K. Tumor necrosis factor (alpha) and nucleus- Pain 1983;17:321–339.
pulposus–induced nerve root injury. Spine 1998;23:2538–2544. Wall PD, Gutnick M. Ongoing activity in peripheral nerves: the
13. White AH. Injections techniques through the diagnosis and treatment physiology and pharmacology of impulses originating from a neuroma.
of low back pain. Orthop Clin North Am 1983;14:553–567. Exp Neurol 1974;43:580–593.
588 Chapter 80 DIAGNOSIS AND TREAT MENT OF FACET-MEDIATED CHRONIC LOW BACK PAIN
Chapter 80 highlighting the role of the intervertebral disk. Their work

emphasized protrusion of the nucleus pulposus and resultant
DIAGNOSIS AND TREATMENT compression of the nerve root as the principal cause of radicular
low back pain. The influence of this paper overshadowed
Ghormley’s ‘‘facet syndrome’’ until 1963 when Hirsch and co-
OF FACET-MEDIATED CHRONIC workers9 observed that pain in the back and upper thigh could be
produced by injecting 11% hypertonic saline in the region of the
LOW BACK PAIN human facet joint. Hirsch and coworkers9 noted that the resultant
pain in the gluteal region radiated into the lateral hip. In subse-
John D. Markman, Payam Hadian, and Annie Philip quent studies, Mooney and Robertson performed saline intra-
articular facet joint injection that reproduced a similar pattern of
referred pain. With these lines of evidence implicating the facet
joint as a source of pain, research began to focus on reducing
nociceptive input through the disruption of the joints’ nerve
supply.
In 1972, Rees described a denervation technique accomplished
INTRODUCTION through transection of the sensory nerve supply to the joint. He
claimed an improbably high success rate of 99.8% in relieving low
Pain of spinal origin is the most prevalent chronic noncancer pain back and radicular pain in over 1000 patients, although hemor-
syndrome. Nearly two thirds of all adults will experience acute low rhagic complications were a frequent complication of the proce-
back pain at some point during their lifetime.1 Episodes of acute dure. Shealy attempted to reproduce these results with less
low back pain have a favorable prognosis in the vast majority of success; in the process, he refined Rees’ technique by employing
patients; however, a sizeable subpopulation develops persistent radiofrequency electrocoagulation. He would later go on to use
pain. Consequently, chronic low back pain is a leading of cause 0.4% phenol in the same location. Beginning in 1979, Bogduk
of disability in industrialized nations. Degeneration of the lumbar and Long10,11 published the definitive neuroanatomic studies in
zygapophyseal (facet) joints has long been proposed as an impor- human cadavers that clearly established the anatomy of the
tant anatomic correlate of chronic low back pain, but the extent of medial branch. They clarified that the target of Rees’ and Shealy’s
this localized problem remains unknown.2 procedures were not the articular branches of the facet joint but the
Parsing chronic low back pain syndromes based on clinical fea- medial branch of the dorsal ramus.
tures is notoriously difficult. The resulting lack of agreement among
practitioners as to underlying causes contributes to wide variation
in spine treatments within and across specialties.3 Propelled by the ANATOMYOF THE FACET JOINT
widespread adoption of axial imaging techniques such as magnetic
resonance imaging (MRI) and computed tomography (CT) The facet joints are paired synovial joints formed by the inferior
scanning, interventional treatments targeting specific anatomic articular process of one vertebra and the superior articular pro-
structures are currently among the most common analgesic cess of the vertebra below. A tough fibrous capsule is present on
approaches for the treatment of chronic low back pain.4 There is the posterolateral aspect of the joint. Adjacent vertebrae are con-
still great uncertainty about the pathophysiology of diverse group of nected by a compound joint composed of an intervertebral disk
syndromes encompassed by the term chronic low back pain.5 Several anteriorly and two zygapophyseal (facet) joints posteriorly. The
lines of evidence in recent years suggest that chemical factors facet joints are true joints encapsulated and lined with synovial
released from the nucleus pulposus and facet joint synovium membrane. Along the superomedial aspect, the ligamentum
rather than mechanical compression of nerve roots are common flavum blends into the capsule. The synovial membrane of the
causes of both axial and radicular low back pain syndromes.6 facet joints is made up of synovial villi, which vary in size, shape,
Increasingly, the facet joint is the anatomic target of interventional and appearance and contain a rich supply of blood vessels and
treatment through either local deposition of anti-inflammatory nociceptors.12 The nerve supply of each joint derives from the
medication, denervation with local anesthetic or radiofrequency posterior primary rami of the same level and the level above. The
techniques, or instrumented stabilization.7 This chapter examines medial branch of the dorsal ramus passes through a small fora-
the significance of the facet joint as a cause of chronic spine pain men in the intertransverse ligament in an anteroposterior direc-
and the conflicting evidence for one type of interventional treat- tion and then lies against the bone, bound by connective tissue
ment targeting this structure. to the periosteum, in a small groove formed where the superior
articular process joins the base of the transverse process. Slightly
more inferiorly, at the level of the caudal margin of the facet
HISTORICAL PERSPECTIVE joint, the medial branch turns medially and passes through a tiny
notch formed between the mamillary and the accessory processes,
In an early description dating to 1933, Ghormley8 identified the where the nerve is secured within the notch by a tiny ligament.
facet joint (or zygapophyseal joint) as a possible anatomic source Beyond the ligament, the medial branch sends branches to inner-
of low back pain. ‘‘The facet syndrome,’’ as he described it, was a vate the facet joint, multifidus muscle, interspinal muscles, and
‘‘lumbosacral pain with or without radiculopathy, occurring most interspinous ligaments. There are three branches of the medial
often after a sudden twisting or rotary strain of the lumbosacral branch: the proximal branch, which hooks around the articular
region.’’ The notion that the facet joint was the culprit structure process to supply the facet above; the medial descending branch,
causing chronic low back pain gained increasing prominence which courses inferomedially to innervate the superior and
until the publication of Mixter and Barr’s landmark study medial portions of the facet capsule below, in addition to
muscle and skin; and the ascending branch, which supplies the evaluation is relief of symptoms with provocative maneuvers
facet above. The lateral branch of the dorsal primary ramus during the anesthetic phase after administration of local anes-
supplies the erector spinae muscle. The innervation of the facet thetic. Documentation of patient’s self-report of symptom
joint capsule with low-threshold, rapidly adapting mechanosensi- change (or lack thereof) with a time-stamped diary is essential
tive neurons supports their role in proprioception.13 The three- to minimize recall bias at follow-up evaluation. The duration of
joint complex composed of the paired zygapophyseal joints and effect should be well correlated with the temporal profile of the
the intervertebral disk functions as a unit to prevent injury local anesthetic. Intra-articular injections with local anesthetic
through multiplanar limitation of movement. and steroid have proved to be of little value diagnostically or
therapeutically for the treatment of chronic low back pain.23,24
The value of imaging studies including radiographs, CT scans,
PATHOANATOMY and MRI imaging and with respect to the localization of chronic
low back pain is very limited in the absence of clinical correlation.
The enlargement of the facet joint due to bony overgrowth For the detection of malignancy and acute infection, these technol-
characteristic of lumbar spondylosis results from a proliferative, ogies are highly sensitive and specific. In the assessment of chronic
inflammatory process.14 With aging, the orientation of the facet inflammation, the changes identified by these studies such as for-
joints along the sagittal plane changes. Such a change, known as aminal narrowing and stenosis as well as facet joint hypertrophy are
tropism, has been linked to disk degeneration and herniation.15 not sensitive or specific to the experience of pain. These imaging
Inflammation induced in abnormally loaded and stressed facet modalities can also detect changes in facet joint morphology prior
joints is likely an important source of pain in older patients to low back pain symptoms. In summary, imaging studies, includ-
subject to repetitive stress and in patients with segmental insta- ing radiography, MRI, and CT, are unreliable indicators in facet-
bility in conditions such as lumbar spondylolisthesis. Pathogenic mediated pain.25 Facet syndrome remains a clinical diagnosis. The
loading patterns also occur with segmental instability in lumbar diagnosis is made through assessment of anatomic distribution of
spondylolisthesis and in an iatrogenic form in the spinal seg- pain, provoking factors on physical examination, and the absence of
ments adjacent to instrumented lumbar fusion. Synovial inflam- findings supportive of alternative localizations such as nerve root
mation represents a source of inflammatory cytokines that cause compression.
chronic radicular pain as well as axial low back symptoms.16 The Differential diagnosis includes both vertebral and paravertebral
medial branch of the dorsal primary ramus (the sensory nerve causes for low back pain such as disk prolapse, annular tears, spinal
endings innervating the facets) and the surrounding tissues stenosis, arachnoiditis, musculoskeletal disorder, neoplasm, infec-
become sensitized by the release of cytokines. Movements such tious etiology, rheumatic conditions, traumatic injuries, and/or
as lumbar extension that are typically innocuous become pain- idiopathic factors. Referred causes are of vascular, biliary, gastro-
ful.17 Localization of the source of facet pain remains a challenge intestinal, uterine, and/or renal origin.
because of referral patterns to anatomic areas remote from the
joint of origin.
The variability of anatomic distributions of pain referred from TREATMENT
facet joints contributes to the controversy surrounding claims of
these structures as a source of pain. In 1976, Mooney and This section reviews clinical studies of radiofrequency ablation for
Robertson18 showed that injection of 1 to 3 ml of 5% hypertonic facet syndrome. There are myriad approaches from transfacet screw
saline produced a deep, dull, vague discomfort in the injection site fixation to simple bracing that are covered elsewhere, but are likely
in 5 seconds. In approximately 20 seconds, this uncomfortable sen- important in controlling this symptom pattern. The uneven clinical
sation spread to the region of the greater trochanter and then trial results evaluating radiofrequency ablation likely reflects the
radiated down the posterior lateral portion of the thigh. In 2 of difficulty of assessing treatment efficacy in the absence of well-
the 20 patients, the low back pain crossed the midline, and in validated diagnostic criteria.
3 patients, the pain radiated down the entire leg to the foot. The Two prospective, double-blind, randomized, controlled trials of
distance the pain radiates down the leg depends on the amount of percutaneous radiofrequency neurotomy demonstrate lasting
irritation and the period of time the joint was irritated. The relief.26,27 In both of these trials, patients were enrolled based on
L3–4 facet joints usually produce pain down a slightly more lateral response to local anesthetic blockade of the medial branches of the
aspect of the leg. If the L4–5 facet was stimulated after irritation of dorsal rami supplying the putatively symptomatic joints.28 The
the L3–4 joint, the pain pattern from the L4–5 appeared to be more Lord and associates study29 achieved a minimum of 50% reduction
anterior than when it was stimulated after prior stimulation of in pain intensity for 263 days in the active treatment group with
the L5–S1. cervical zygapophyseal joint pain after motor vehicle accident com-
pared with 8 days in the placebo group. This study applied an
uncharacteristically rigorous protocol of three blocks (i.e., two
CLINICAL PRESENTATION active with differing concentrations of local anesthetic and one
sham block) to identify patients with zygapophyseal (i.e., facet)
The diagnostic criteria for facet syndrome remain a matter of joint syndrome.29 Van Kleef and colleagues27 replicated this result
controversy. Older age, relief of back pain with recumbency, in the lumbar spine with patients selected by response to diagnostic
exacerbation of pain upon extension but not flexion, localized nerve block of the posterior primary ramus of the segmental nerves
tenderness with palpation of the region overlying the facet joint, at L3, L4, and L5 versus placebo. The primary end-point of 50%
absence of leg pain, and radiologic characterization of hypertro- reduction in pain or greater than a 2-point reduction on numeric
phied joints have all been proposed as relevant features of ‘‘facet rating scale was achieved in these patients with at least 1 year of
syndrome.’’19–21 The lack of sensitivity and specificity of these chronic low back pain. The patients undergoing radiofrequency
signs and symptoms has complicated attempts to define inclu- ablation reported a reduction in opioid use and improved
sion criteria for treatment trials. Attempts to define facet syn- Oswestry disability index scores. A third, small prospective trial
drome through prospective study of intra-articular facet joint and a large retrospective series (outcome assessed by third party)
injection have not produced consistent, validated criteria.22 To demonstrated prolonged benefit in patients with a positive response
overcome this challenge, blockade of the medial branches of the to diagnostic block compared with nonresponders.30 In addition,
dorsal ramus innervating the joint has emerged as a cornerstone radiofrequency facet denervation has been used by Shealy31,32 to
of diagnostic assessment. A cornerstone of the diagnostic treat low back pain.
590 Chapter 80 DIAGNOSIS AND TREAT MENT OF FACET-MEDIATED CHRONIC LOW BACK PAIN
Since Rees’ reports on subcutaneous rhyzolysis,33 the rationale one case of chemical meningitis37 and in a separate case of epidural
for neurotomy is based on the assumption that cutting the nerve abscess formation.38
supply to a painful structure may alleviate pain and help in the
return of function for 6 months to 1 year. It is theorized that the
radiofrequency damages the axon of the postganglionic nuclei. CONCLUSION
The soma can regenerate the axon and its connection, causing the
return of pain. Radiofrequency neurotomy is performed by placing Pain originating from the lumbar zygapophyseal (facet) joints is a
the patient prone in the fluoroscopy table. For the introduction of potential source of chronic low back pain. With aging in the biped,
the radiofrequency electrode, the C-arm fluoroscope is rotated the joint structure weakens and its orientation changes, making it
some 158 from a conventional posteroanterior orientation and more susceptible to injury and inflammation owing to rotational
angled caudad by approximately 208. This view at an angle from stress. The lack of discrete clinical features and overlapping referral
below shows the transverse process on the edge and demonstrates patterns of pain make facet syndrome a diagnostic challenge.
the groove between the transverse process and the superior articular Careful study of the innervation of these joints by the medial
process along which the target nerve runs. For the cervical antero- branches arising from the posterior rami of the spinal nerves has
posterior pillar view, the target point is located in the center of the provided a rationale for diagnostic blockade with local anesthestic.
articular pillar. Patients are selected if they have more than 50% As with intra-articular lumbar zygapophyseal joint injection, there
pain relief with the diagnostic blocks. The radiofrequency ablation is the potential for false-positive and false-negative responses,
needle is advanced until the target is reached, and sensory testing is but these appear to be predictive of the usefulness of neurolytic
performed at 50 Hz with the range of 0 to 1 V. The voltage is procedures in some series. Neurolytic approaches are considered
gradually increased until pain or pressure is elicited that may be third line after conservative management with anti-inflammatory
concordant with the usual pain. Once sensory stimulation is com- medication and nonpharmacologic intervention such as physical
pleted, the voltage should be turned down and the stimulation mode therapy because long-term efficacy is not well characterized. The
is changed to motor testing. Motor stimulation is performed at 2 Hz risk profile appears to be more favorable compared with more
with a voltage range of 1 to 10 V. The voltage is very gradually invasive procedures such as arthodesis, but further study is needed.
increased to at least twice the intensity required to elicit the initial
sensory symptoms. Muscle contraction observed in the distal lower
extremity muscles or in the face and upper extremity indicates that REFERENCES
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8. Ghormley RK. Low back pain with special reference to the articular
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treatment, there were significantly more improvements in the VAS 1933;101:773.
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that in carefully selected patients with back pain, uncomplicated by 10. Bogduk N, Long DM. Percutaneous lumbar medial branch neurotomy:
comorbidity and psychosocial factors and with the use of meticu- a modification of facet denervation. Spine 1980;5:193–200.
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provide marked relief. and the relationship to the facet denervation in the treatment of low
Leclaire and associates35 performed a double-blind, randomized, back pain. J Neurosurg 1979;51:172–177.
12. Edgar M. The applied anatomy of lumbar facet innervation. Presented
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improvement was noted in the VAS score or functional disability. pain: biomechanics, neuroanatomy, and neurophysiology. J Biomech
The principal difference between the Van Kleef and coworkers34 and 1996;29:117–129.
the Leclaire amd associates35 studies was the difference in the diag- 14. Dory, MA. Arthography of the lumbar facet joints. Radiology
nostic blocks. Van Kleef and coworkers’ study34 used medial branch 1981;140:23–27.
block, and Leclaire and associates’ study35 used intra-articular facet 15. Vanharanta H, Floyd T, Ohnmeiss D, et al. The relationship of facet
joint block. This provides evidence that relief with facet joint block tropism to degenerative disc disease. Spine 1993;18:1000–1005.
16. Tachihara H, Kikuchi S, Konno S, Sekiguchi M. Does facet joint
is not a good indicator for proceeding with radiofrequency ablation. inflammation induce radiculopathy?: an investigation using a rat
Minor complications can occur from radiofrequency ablation, model of lumbar facet joint inflammation. Spine 2007;32:406–412.
1% per lesion site.36 Localized pain at the needle site lasting for 17. Igarashi A, Kikuchi S, Konno S, et al. Inflammatory cytokines released
more than 2 weeks is rare (0.5%), and there were no cases of new from the facet joint tissue in degenerative lumbar spinal disorders.
motor or sensory deficits. Intrathecal injection has been reported in Spine 2004;29:2091–2095.
18. Mooney V, Robertson J. The facet syndrome. Clin Orthop lumbar spine. Part 13: injection therapies, low-back pain, and lumber
1976;140:149–156. fusion. J Neurosurg Spine 2005;2:707–715.
19. Jackson RP. The facet syndrome: Myth or reality? Clin Orthop Relat 29. Lord SM, Barnsley L, Wallis BJ, et al. Percutaneous radio-frequency
Res 1992;279:110–121. neurotomy for chronic cervical zygapophyseal-joint pain. N Engl J
20. Lewinnek GE, Warfield CA. Facet joint degeneration as a cause of low Med 1996;335:1721–1726.
back pain. Clin Orthop Relat Res 1986;213:216–222. 30. Gallagher J, Petriconne di Vadi P, Wedley J, et al. Radiofrequency
21. Schwarzer AC, Wang SC, O’Driscoll D, et al. The ability of computed facet joint denervation in the treatment of low back pain: a
tomography to identify a painful zygapophyseal joint in patients with prospective controlled double-blind study to assess efficacy. Pain Clin
chronic low back pain. Spine 1995;20:907–912. 1994;7:193–198.
22. Schwarzer AC, Aprill CN, Derby R, et al. Clinical features of 31. Shealy CN. Facet denervation in the management of back and sciatic
patients with pain stemming from the lumbar zygapophyseal joints. pain. Clin Othop 1976;115:157–164.
Is the lumbar facet syndrome a clinical entity. Spine 32. Shealy CN. Percutaneous radiofrequency denervation of spinal facets:
1994;19:1132–1137. treatment of chronic back pain and sciatica. J Neurosurg
23. Carette S, Marcoux S, Truchon R, et al. A controlled trial of 1975;43:448–451.
corticosteroid injections into facet joints for chronic low back pain. 33. Rees WES. Multiple bilateral subcutaneous rhizolysis. Med J Aust
N Engl J Med 1991;325:1002–1007. 1974;1:536–537.
24. Jackson RP, Jacobs RR, Montesano PX. Facet joint injection in low 34. Van Kleef M, Barendse G, et al. Randomized trial of radiofrequency
back pain. Spine 1988;13:966–971. lumbar facet denervation for chronic low back pain. Spine
25. Schwarzer AC, Wang SC, et al. The ability of CT to identify a painful 1999;24:1937–1942.
zygapophyseal joint in patients with chronic low back pain. Spine 35. Leclaire R, Fortin L, et al. Radiofrequency facet joint denervation in
1995;20:907–912. the treatment of low back pain: a placebo-controlled clinical trial to
26. Lord SM, Barnsely L, Wallis B, et al. Percutaneous radio-frequency assess efficacy. Spine 2001;26:1411–1416.
neurotomy for chronic cervical zygapophyseal-joint pain. N Engl 36. Kornick C, Kramarich S, et al. Complications of lumbar
J Med 1996;335:1721–1726. radiofrequency facet denervation. Spine 2004;29:1352–1354.
27. van Kleef MV, Barendse GA, Kessels A, et al. Randomized trial of 37. Thomson SJ, Lomax DM, et al. Chemical meningitis after lumbar
radiofrequency lumbar facet denervation for chronic low back pain. facet joint block with local anesthetic and steroids. Anaesthesia
Spine 1999;24:1937–1942. 1991;46:563–564.
28. Resnick DK, Choudhri TF, Dailey AT, et al. Guidelines for the 38. Alcock E, Regaard A, Browne J. Facet joint injection: a rare form
performance of fusion procedures for degenerative disease of the cause of epidural abscess formation. Pain 2003;103:209–210.
Chapter 81 On a cellular level, steroids are believed to work at the cell’s

INTRA-ARTICULAR INJECTIONS nucleus by altering transcription. By acting on the cells that con-
tribute to inflammation such as lymphocytes, macrophages, and
mast cells, steroids reduce phagocytosis, lysosomal activity, and
William F. Lavelle, Elizabeth Demers Lavelle, and the release of inflammatory mediators. It is thought that by redu-
Lori A. Lavelle cing inflammatory pain, symptoms are improved. This theory
applies to the activity of oral steroids; however, intra-articular ster-
oid injections may avoid the majority of systemic effects (or the
degree of such effects), such as skin thinning, resulting in easy
bruising; peptic ulceration; and aggravation of diabetes. Although
INTRODUCTION there are a few reports of the systemic absorption of intra-articular
steroids, in general, a significant portion of the steroid load remains
Intra-articular injections provide clinicians a direct method for the in the joint, thereby providing a high local dose and hopefully
treatment of joint pain. Over 50 years ago, corticosteroids were improvement of the local pain.
introduced into common practice as a means of treatment of Hollander2 reported an 80% success rate in what was the
joint pain.1 Since that time, other agents have been introduced first large-scale trial of steroid injections. Since that time, a multi-
into joints in an attempt to provide analgesia. Local anesthetics, tude of studies have proved the excellent short-term pain relief
opioid (‘‘narcotic’’) medications, and supplemental joint fluid are (1–4 wk) from injected corticosteroids. More enduring results
now areas of current therapy for joint pain. have been reported but are not commonplace for a truly arthritic
joint.3
INJECTIONS FOR CHRONIC JOINT PAIN Choice of Steroid

Classically, the duration of a steroid’s effect should be inversely
Steroid Injections proportional to solubility of the steroid. With this being said,
there are few studies that address the clinical superiority of one
Steroid injection may be an old remedy, but they are still the most agent over another. All other things being reasonably equal, clin-
used current therapy for intra-articular injections. Hydrocortisone icians typically choose medical agents based on familiarity. In a
acetate was injected into more than 1000 knees in the 1950s with survey performed with members of the 1994 American College of
a great deal of success. Modern clinicians routinely utilized corti- Rheumatology, approximately one third favored methylpredniso-
costeroid injections as one element of multimodal joint pain lone, one third favored triamcinolone hexacetide, and one fifth
therapy. favored triamcinolone acetonide.4
18. Mooney V, Robertson J. The facet syndrome. Clin Orthop lumbar spine. Part 13: injection therapies, low-back pain, and lumber
1976;140:149–156. fusion. J Neurosurg Spine 2005;2:707–715.
19. Jackson RP. The facet syndrome: Myth or reality? Clin Orthop Relat 29. Lord SM, Barnsley L, Wallis BJ, et al. Percutaneous radio-frequency
Res 1992;279:110–121. neurotomy for chronic cervical zygapophyseal-joint pain. N Engl J
20. Lewinnek GE, Warfield CA. Facet joint degeneration as a cause of low Med 1996;335:1721–1726.
back pain. Clin Orthop Relat Res 1986;213:216–222. 30. Gallagher J, Petriconne di Vadi P, Wedley J, et al. Radiofrequency
21. Schwarzer AC, Wang SC, O’Driscoll D, et al. The ability of computed facet joint denervation in the treatment of low back pain: a
tomography to identify a painful zygapophyseal joint in patients with prospective controlled double-blind study to assess efficacy. Pain Clin
chronic low back pain. Spine 1995;20:907–912. 1994;7:193–198.
22. Schwarzer AC, Aprill CN, Derby R, et al. Clinical features of 31. Shealy CN. Facet denervation in the management of back and sciatic
patients with pain stemming from the lumbar zygapophyseal joints. pain. Clin Othop 1976;115:157–164.
Is the lumbar facet syndrome a clinical entity. Spine 32. Shealy CN. Percutaneous radiofrequency denervation of spinal facets:
1994;19:1132–1137. treatment of chronic back pain and sciatica. J Neurosurg
23. Carette S, Marcoux S, Truchon R, et al. A controlled trial of 1975;43:448–451.
corticosteroid injections into facet joints for chronic low back pain. 33. Rees WES. Multiple bilateral subcutaneous rhizolysis. Med J Aust
N Engl J Med 1991;325:1002–1007. 1974;1:536–537.
24. Jackson RP, Jacobs RR, Montesano PX. Facet joint injection in low 34. Van Kleef M, Barendse G, et al. Randomized trial of radiofrequency
back pain. Spine 1988;13:966–971. lumbar facet denervation for chronic low back pain. Spine
25. Schwarzer AC, Wang SC, et al. The ability of CT to identify a painful 1999;24:1937–1942.
zygapophyseal joint in patients with chronic low back pain. Spine 35. Leclaire R, Fortin L, et al. Radiofrequency facet joint denervation in
1995;20:907–912. the treatment of low back pain: a placebo-controlled clinical trial to
26. Lord SM, Barnsely L, Wallis B, et al. Percutaneous radio-frequency assess efficacy. Spine 2001;26:1411–1416.
neurotomy for chronic cervical zygapophyseal-joint pain. N Engl 36. Kornick C, Kramarich S, et al. Complications of lumbar
J Med 1996;335:1721–1726. radiofrequency facet denervation. Spine 2004;29:1352–1354.
27. van Kleef MV, Barendse GA, Kessels A, et al. Randomized trial of 37. Thomson SJ, Lomax DM, et al. Chemical meningitis after lumbar
radiofrequency lumbar facet denervation for chronic low back pain. facet joint block with local anesthetic and steroids. Anaesthesia
Spine 1999;24:1937–1942. 1991;46:563–564.
28. Resnick DK, Choudhri TF, Dailey AT, et al. Guidelines for the 38. Alcock E, Regaard A, Browne J. Facet joint injection: a rare form
performance of fusion procedures for degenerative disease of the cause of epidural abscess formation. Pain 2003;103:209–210.
Chapter 81 On a cellular level, steroids are believed to work at the cell’s

INTRA-ARTICULAR INJECTIONS nucleus by altering transcription. By acting on the cells that con-
tribute to inflammation such as lymphocytes, macrophages, and
mast cells, steroids reduce phagocytosis, lysosomal activity, and
William F. Lavelle, Elizabeth Demers Lavelle, and the release of inflammatory mediators. It is thought that by redu-
Lori A. Lavelle cing inflammatory pain, symptoms are improved. This theory
applies to the activity of oral steroids; however, intra-articular ster-
oid injections may avoid the majority of systemic effects (or the
degree of such effects), such as skin thinning, resulting in easy
bruising; peptic ulceration; and aggravation of diabetes. Although
INTRODUCTION there are a few reports of the systemic absorption of intra-articular
steroids, in general, a significant portion of the steroid load remains
Intra-articular injections provide clinicians a direct method for the in the joint, thereby providing a high local dose and hopefully
treatment of joint pain. Over 50 years ago, corticosteroids were improvement of the local pain.
introduced into common practice as a means of treatment of Hollander2 reported an 80% success rate in what was the
joint pain.1 Since that time, other agents have been introduced first large-scale trial of steroid injections. Since that time, a multi-
into joints in an attempt to provide analgesia. Local anesthetics, tude of studies have proved the excellent short-term pain relief
opioid (‘‘narcotic’’) medications, and supplemental joint fluid are (1–4 wk) from injected corticosteroids. More enduring results
now areas of current therapy for joint pain. have been reported but are not commonplace for a truly arthritic
joint.3
INJECTIONS FOR CHRONIC JOINT PAIN Choice of Steroid

Classically, the duration of a steroid’s effect should be inversely
Steroid Injections proportional to solubility of the steroid. With this being said,
there are few studies that address the clinical superiority of one
Steroid injection may be an old remedy, but they are still the most agent over another. All other things being reasonably equal, clin-
used current therapy for intra-articular injections. Hydrocortisone icians typically choose medical agents based on familiarity. In a
acetate was injected into more than 1000 knees in the 1950s with survey performed with members of the 1994 American College of
a great deal of success. Modern clinicians routinely utilized corti- Rheumatology, approximately one third favored methylpredniso-
costeroid injections as one element of multimodal joint pain lone, one third favored triamcinolone hexacetide, and one fifth
therapy. favored triamcinolone acetonide.4
592 Chapter 81 INTR A-ARTICULAR INJECTIONS
Clinicians also disagree on the use of a local agent in conjunc- Most recently, a large meta-analysis of randomized, controlled
tion with a steroid injection. Many believe that the immediate anes- trials looking at the efficacy of hyaluronic acid was completed and
thetic response achieved by a local agent confirms proper published in the Journal of Bone and Joint Surgery.9 Twenty studies
placement, whereas others simply believe that the local agent acts were included in the analysis. Overall, the analysis found significant
to dilute the steroid crystals. In any respect, steroid injections may improvements in pain and functional outcomes with few adverse
be administered either with or without a local agent depending on events, although the power of some of the studies included in the
the preference of the treating clinician. analysis may be drawn into question.
Intra-articular steroid injections are not without risk. Despite The most common and worrisome adverse reaction is iatro-
the fact that few orthopedists and rheumatologists report having genic infection. This has not been reported as being any more
experienced a poststeroid septic arthritis, it is still the most apparent common with hyaluronic acid than with any other agent. A pseu-
concern. Recent reports have found infection rates between 1:3000 doseptic reaction has also been described for intra-articular hya-
and 1:50,000, with the most common infecting organism being luronic acid. Clinical findings include erythema, joint pain,
Staphylococcus aureus.5 Despite the fact that the steroid injection warmth, a large effusion, and stiffness; however, the joint fluid
is given to alleviate pain, 2% to 6% of patients experience worsened will reveal no infectious organisms. A large number of mononu-
symptoms in the first 24 to 48 hours after injection. This is believed clear cells and eosinophils are seen, however. The reaction is more
to be the result of a chemical synovitis induced by the injected common with repeat injections and may represent a sensitization
crystals. Although the steroid is believed to remain intra-articular to the product. The long-term effects of these hypersensitivity
with little systemic absorption, transient increases in blood glucose reactions have not been described. This pseudoseptic reaction
have been reported; however, there is no well-controlled study has been observed in 2% to 8% of patients treated with hylan
directly linking intra-articular steroids to long-term deleterious G-F 20 (Synvisc).7
effects in diabetics.6
A common question among patients and clinicians is the
number of injections a patient can receive in a given period of INTRA-ARTICULAR ANALGESIA FOR
time. Animal studies have been suggestive of damage to articular POSTOPERATIVE PAIN
cartilage as a result of intra-articular steroid injections; however, to
date, there are no human data corroborating this claim. Despite this The analgesic effects of intra-articular agents in the postoperative
lack of evidence, it is commonplace for physicians to recommend a period are controversial; however, the use of these agents is becom-
3-month interval between injections. ing more common and has helped popularize outpatient orthopedic
An adjunct to the success of steroid treatment in the patient with surgery. Poor postoperative pain control defines the difference
an effusion may be the aspiration of that effusion. Eighty-four between a successful outpatient procedure and a procedure that
patients with osteoarthritis were randomized to receive either tri- both the patient and the physician will wish was completed in the
amcinolone hexacetonide or placebo.7 Patients receiving the steroid hospital setting.
reported a statistically significant improvement in pain, distance Because of its long duration of action, most anesthesiologists
walked in 1 minute, and Health Assessment Questionnaire. In and orthopedic surgeons select bupivacaine.10 A systematic review
patients treated with steroids, patients with an effusion that was of double-blind, randomized, controlled trials that compared
aspirated at the time of injection revealed greater improvement in intra-articular local anesthetic injection with either a placebo
their pain. Joint lavage similarly improves pain and function if intra-articular injection or no intervention. A statistically significant
performed at the time of steroid injection. improvement in pain was found in the treatment groups. Pain
scores were significantly lower in the treatment groups, and the
consumption of supplemental analgesics was reduced by 10% to
Hyaluronic Acid 50% in the treatment groups.
The continuous infusion of intra-articular analgesia is also pos-
Hyaluronic acid is a glycosaminoglycan that is naturally occurring sible, but this is more appropriate for the inpatient setting. One of
in human joints. It is principally responsible for the viscosity and the more common regions for this type of anesthesia is the shoul-
normal lubrication of these joints. Fluid studies have revealed that der. Complex shoulder procedures often demand large amounts of
the non-Newtonian properties of hyaluronic acid reduce shear rates analgesia. Anesthesiologists as well as orthopedic surgeons have
and wear of articular cartilage. The concentration and quality of examined both continuous peripheral nerve blocks and continuous
hyaluronic acid have been found to decrease as degenerative arthri- intra-articular anesthesia. Both offer a means of a constant flow of
tis progresses, but the exact mechanism by which joint degeneration an anesthetic; however, intra-articular blocks are often easier to
causes pain is unclear. Rydell and Balazs first proposed what has place.11,12
now been termed viscosupplementation in the 1960s.7 Hyaluronic The intra-articular environment dictates the chemical activity of
acid was first prepared from rooster combs and umbilical cords. a local anesthetic. As illustrated in Figure 81–1, local anesthetics
There are now multiple artificially synthesized forms of hyaluronic exist in two forms as dictated by their tertiary amine. The first is
acid. The exact mechanism of action by which intra-articular injec- an electrically neutral form that is hydrophobic and lipophilic. This
tions of hyaluronic acid relieve pain is unclear. In the destructive form of the drug has better nerve cell membrane and tissue trans-
processes of osteoarthritis, it is conceivable that on a ‘‘low- port, but poor solubility in water. The charged or protonated form
level’’—smoldering chronic basis—leukocytes mediate enzymatic (which is seen when the local agent is exposed to an acidic envir-
and oxidative free radical reactions. Hyaluronic acids have been onment) is more water-soluble, but has a decreased ability to affect
found to inhibit leukocyte migration, chemotaxis, and cellular the cell membrane (see Fig. 81–1). In an inflamed or infected knee,
adhesion. Theoretically, this would slow the degenerative processes the chemical environment is less favorable to the local agent.
and, thus, abate pain. Sodium bicarbonate may be added to the block to improve its
A randomized, placebo-controlled study compared over effect, but the harsh intra-articular environment is often overpow-
100 patients receiving either hyaluronic acid, corticosteroid ering. Other forms of analgesia are best selected in these
(Depo-Medrol), or isotonic saline. Injections were administered at circumstances.
14-day intervals, with each patient receiving three injections. Another factor that may alter the activity of intra-articular
Significant improvement was seen when comparing each treatment local analgesia is the presence of hemarthrosis, which can increase
group with the placebo group. There was, however, no difference in the level of pain and decrease the concentration of local agent.
pain relief between the two treatment groups.8 Intra-articular blood carries with it additional inflammatory
BH+ B + H+
Lipid bilayer Na channel

BH+
A H+ + B BH+
H+ H+ H+
H+ H+
H+
H+
BH+ B + H+
H+
Lipid bilayer Na channel

BH+
B H+ + B BH+
Figure 81^1. The effect of pH on local anesthetics. When exposed to an acid environment, a local anesthetic will form a conjugate acid
that is positively charged, making it more soluble in water but less apt to penetrate the cell membrane. A, Local anesthetic in a base
environment. B, Local anesthetic in an acidic environment.
mediators. The increased volume of the joint is itself painful studies in which intra-articular morphine was utilized. Within
because a distended joint activates stretch receptors that them- these studies, visual analog scores were collected at the early
selves signal pain. phase (0–2 hr), the intermediate phase (2–6 hr), and the late
phase (6–24 hr). This analysis concluded that, although no clear
dose-response effect was seen, a definite but mild analgesic effect
Intra-articular Opiates was present.
The classic thinking was that opioid receptors are found only in the
central nervous system. Fortunately, opioid receptors have been Techniques for Successful Placement
found in the peripheral nervous system as well, particularly intra-
articularly. m-, d-, and k-receptors have been all been found on There is no substitute for experience when introducing intra-
peripheral nerves. It is believed that injured and inflamed tissue articular agents. Joints that are more commonly accessed are
possesses nerves that have disrupted perineurium. These disrupted larger joints like the shoulder (Fig. 81–2) and knee (Fig. 81–3).
nerves allow for easier access of opioids to m-, d-, and k-receptors. For smaller joints like the first carpometacarpal joint (Fig. 81–4),
Furthermore, opioids/opioid receptors may be brought together at a complete understanding of the regional anatomy is necessary.
the site of inflammation via immune cells. The plasma concentra- An easy method that may allow for improved accuracy is the
tion achieved from an intra-articular injection is far too low for a aspiration of synovial fluid prior to injection of a steroid.
systemic effect to be observed; however, within the joint itself, the Advanced imaging techniques have also aided in the placement
relative concentration is quite high.13 of intra-articular injections. Fluoroscopy along with a radiopaque
A number of well-controlled studies have found greater efficacy tracer will allow the clinician to document the delivery of an agent
of intra-articular morphine compared with placebo. Four studies into a joint. A recent article assessed the accuracy of needle place-
compared intra-articular morphine to intravenous or intramuscular ment in the intra-articular space of the knee using three com-
morphine and found greater efficacy for intra-articular morphine monly employed knee joint portals. The authors documented
(at very low doses that would not provide adequate analgesia the location of the injected fluid by fluoroscopic imaging of the
parenterally).14 injected material. The authors found far more success with a lat-
The proper dose for an intra-articular injection of an opiate eral midpatellar injection than any of the other injection portals.
such morphine is debatable. No dose true dose-response effect has Despite this study, clinicians do and should use the technique that
been found in a review of the literature. One study found a dose has provided them with the greatest amount of comfort and
of 0.5 mg had no efficacy, whereas a dose of 1 mg did. No success.
significantly greater effect was found when a dose of 1 mg was
compared with 2 mg. Readers should remember that the proper
dose for intra-articular injection of opiates requires clinical
discretion. SUMMARY
The most thorough analysis on this topic was reported by
Gupta and coworkers.15 A meta-analysis was completed on the Steroids, hyaluronic acid, local anesthetic agents, and opiates
pooled data of 19 prospective, placebo-controlled, randomized are all agents commonly injected into joints as a means of
594 Chapter 81 INTR A-ARTICULAR INJECTIONS
*
A B
C
Figure 81^2. Shoulder injections. The different spaces in the shoulder that may be treated by an intra-articular injection. A, Subacromial
space: frontal view. B, Acromialclavicular joint: frontal view. C, Glenohumeral joint: posterior view.
*
*
A
B
D
C
Figure 81^3. Knee injections. The different portals used to access the knee for an intra-articular injection. A, Medial parapatella portal.
B, Medial parapatella portal. C, Superolateral portal. D, Midpatella portal.
596 Chapter 82 R ADIOFREQUENCY TREAT MENT
5. Charalambous CP, Tryfonidis M, Sadiq S, et al. Septic arthritis

following intra-articular steroid injection of the knee—a survey of
current practice regarding antiseptic technique used during intra-
articular steroid injection of the knee. Clin Rheumatol 2003;22:386–390.
6. Cole BJ, Schumacher HR Jr. Injectable corticosteroids in modern
practice. J Am Acad Orthop Surg 2005;13:37–46.
7. Roberts WN, Babcock EA, Breitbach SA, et al. Corticosteroid
injection in rheumatoid arthritis does not increase rate of total joint
arthroplasty. J Rheumatol 1996;23:1001–1004.
8. Ravaud P, Moulinier L, Giraudeau B, et al. Effects of joint lavage and
steroid injection in patients with osteoarthritis of the knee: results of
a multicenter, randomized, controlled trial. Arthritis Rheum
1999;42:475–482.
9. Reuben SS, Sklar J. Pain management in patients who undergo
outpatient arthroscopic surgery of the knee. J Bone Joint Surg Am
2000;82:1754–1766.
10. Henderson RC, Campion ER, DeMasi RA, Taft TN. Postarthroscopy
analgesia with bupivacaine. A prospective, randomized, blinded
evaluation. Am J Sports Med 1990;18:614–617.
Figure 81^4. First carpometacarpal joint. The thumb is moved 11. Boss AP, Maurer T, Seiler S, et al. Continuous subacromial
while palpating the base of the metacarpal.The needle is placed just bupivacaine infusion for postoperative analgesia after open
proximal to the first metacarpal on the extensor surface. Care must acromioplasty and rotator cuff repair: preliminary results. J Shoulder
be taken to avoid the radial artery and the extensor pollicis tendons. Elbow Surg. 2004;13:630–634.
12. Savoie FH, Field LD, Jenkins RN, et al. The pain control infusion
pump for postoperative pain control in shoulder surgery. Arthroscopy
providing analgesia. Intra-articular steroid injections are most
2000;16:339–342.
often used for management of inflammatory joint diseases, par- 13. Stein C, Millan MJ, Shippenberg TS, et al. Peripheral opioid receptors
ticularly chronic arthritic conditions. Hyaluronic acid is used as mediating antinociception in inflammation. Evidence for involvement
a method of viscosupplementation, with clinical studies showing of mu, delta and kappa receptors. J Pharmacol Exp Ther
an advantage of this agent over placebo. Local anesthetics may 1989;248:1269–1275.
be used in combination with steroids as a technique for provid- 14. Kalso E, Tramer MR, Carroll D, et al. Pain relief from intra-articular
ing immediate pain relief and confirming successful intra- morphine after knee surgery: a qualitative systematic review. Pain
articular placement of both agents. Both local agents aand 1997;71:127–134.
opiates have provided for the success of outpatient arthroscopy. 15. Gupta A, Bodin L, Holmstrom B, Berggren L. A systematic review of
the peripheral analgesic effects of intra-articular morphine. Anesth
Analg 2001;93:761–770.
REFERENCES 16. Jackson DW, Evans NA, Thomas BM. Accuracy of needle placement
into the intra-articular space of the knee. J Bone Joint Surg Am
1. Schumacher HR Jr. Aspiration and injection therapies for joints. 2002;84-A:1522–1527.
Arthritis Rheum 2003;49:413–420.
2. Hollander JL. Hydrocortisone and cortisone injected into arthritic
joints. Comparative effects of and use of hydrocortisone as a local SUGGESTED READINGS
antiarthritic agent. JAMA 1951;147:1629.
3. Ropes MW, Bauer W. Synovial Fluid Changes in Joint Disease. Geutjens G, Hambidge JE. Analgesic effects of intra-articular bupivacaine
Cambridge, MA: Harvard University Press, 1953. after day-case arthroscopy. Arthroscopy 1994;10:299–300.
4. Centeno LM, Moore ME. Preferred intra-articular corticosteroids and Snibbe JC, Gambardella RA. Use of injections for osteoarthritis in joints
associated practice: a survey of members of the American College of and sports activity. Clin Sports Med 2005;24:83–91.
Rheumatology. Arthritis Care Res 1994;7:151–155.
Chapter 82 radiofrequency (RF) for neural lesioning may date back to 1863
RADIOFREQUENCY TREATMENT when Beaunis used direct current to induce a lesion in the animal
brain.4 Shortly thereafter in 1873, Fournie created bipolar lesions in
animal neural tissue.4 This was followed by extensive research
Richard Field, Douglas Keene, and Salahadin Abdi regarding the nature of direct current and its electrolytic lesioning
effect on neural tissue over the next 50 years.2 Golsinger in 1895
used monopolar electrodes for lesioning.1 Horsely and Clarke stud-
ied the effect of electrode material and polarity on the quality of
lesions and established relationships between lesion size, current,
and time parameters.1,2
Harvey Cushing, in the 1920s, investigated the potential use of
HISTORY RF for electrosurgery.5,6 Kirschner in 1931 used RF for thermoco-
agulation of the gasserian ganglion as a treatment for pain in tri-
There was a great deal of experimentation in the 1800s in electricity geminal neuralgia.4,7 Research then centered on increasing the
and its effects on neural tissue,1–3 and one of the earliest uses of predictability and reproducibility of the lesion produced. In 1953,
5. Charalambous CP, Tryfonidis M, Sadiq S, et al. Septic arthritis

following intra-articular steroid injection of the knee—a survey of
current practice regarding antiseptic technique used during intra-
articular steroid injection of the knee. Clin Rheumatol 2003;22:386–390.
6. Cole BJ, Schumacher HR Jr. Injectable corticosteroids in modern
practice. J Am Acad Orthop Surg 2005;13:37–46.
7. Roberts WN, Babcock EA, Breitbach SA, et al. Corticosteroid
injection in rheumatoid arthritis does not increase rate of total joint
arthroplasty. J Rheumatol 1996;23:1001–1004.
8. Ravaud P, Moulinier L, Giraudeau B, et al. Effects of joint lavage and
steroid injection in patients with osteoarthritis of the knee: results of
a multicenter, randomized, controlled trial. Arthritis Rheum
1999;42:475–482.
9. Reuben SS, Sklar J. Pain management in patients who undergo
outpatient arthroscopic surgery of the knee. J Bone Joint Surg Am
2000;82:1754–1766.
10. Henderson RC, Campion ER, DeMasi RA, Taft TN. Postarthroscopy
analgesia with bupivacaine. A prospective, randomized, blinded
evaluation. Am J Sports Med 1990;18:614–617.
Figure 81^4. First carpometacarpal joint. The thumb is moved 11. Boss AP, Maurer T, Seiler S, et al. Continuous subacromial
while palpating the base of the metacarpal.The needle is placed just bupivacaine infusion for postoperative analgesia after open
proximal to the first metacarpal on the extensor surface. Care must acromioplasty and rotator cuff repair: preliminary results. J Shoulder
be taken to avoid the radial artery and the extensor pollicis tendons. Elbow Surg. 2004;13:630–634.
12. Savoie FH, Field LD, Jenkins RN, et al. The pain control infusion
pump for postoperative pain control in shoulder surgery. Arthroscopy
providing analgesia. Intra-articular steroid injections are most
2000;16:339–342.
often used for management of inflammatory joint diseases, par- 13. Stein C, Millan MJ, Shippenberg TS, et al. Peripheral opioid receptors
ticularly chronic arthritic conditions. Hyaluronic acid is used as mediating antinociception in inflammation. Evidence for involvement
a method of viscosupplementation, with clinical studies showing of mu, delta and kappa receptors. J Pharmacol Exp Ther
an advantage of this agent over placebo. Local anesthetics may 1989;248:1269–1275.
be used in combination with steroids as a technique for provid- 14. Kalso E, Tramer MR, Carroll D, et al. Pain relief from intra-articular
ing immediate pain relief and confirming successful intra- morphine after knee surgery: a qualitative systematic review. Pain
articular placement of both agents. Both local agents aand 1997;71:127–134.
opiates have provided for the success of outpatient arthroscopy. 15. Gupta A, Bodin L, Holmstrom B, Berggren L. A systematic review of
the peripheral analgesic effects of intra-articular morphine. Anesth
Analg 2001;93:761–770.
REFERENCES 16. Jackson DW, Evans NA, Thomas BM. Accuracy of needle placement
into the intra-articular space of the knee. J Bone Joint Surg Am
1. Schumacher HR Jr. Aspiration and injection therapies for joints. 2002;84-A:1522–1527.
Arthritis Rheum 2003;49:413–420.
2. Hollander JL. Hydrocortisone and cortisone injected into arthritic
joints. Comparative effects of and use of hydrocortisone as a local SUGGESTED READINGS
antiarthritic agent. JAMA 1951;147:1629.
3. Ropes MW, Bauer W. Synovial Fluid Changes in Joint Disease. Geutjens G, Hambidge JE. Analgesic effects of intra-articular bupivacaine
Cambridge, MA: Harvard University Press, 1953. after day-case arthroscopy. Arthroscopy 1994;10:299–300.
4. Centeno LM, Moore ME. Preferred intra-articular corticosteroids and Snibbe JC, Gambardella RA. Use of injections for osteoarthritis in joints
associated practice: a survey of members of the American College of and sports activity. Clin Sports Med 2005;24:83–91.
Rheumatology. Arthritis Care Res 1994;7:151–155.
Chapter 82 radiofrequency (RF) for neural lesioning may date back to 1863
RADIOFREQUENCY TREATMENT when Beaunis used direct current to induce a lesion in the animal
brain.4 Shortly thereafter in 1873, Fournie created bipolar lesions in
animal neural tissue.4 This was followed by extensive research
Richard Field, Douglas Keene, and Salahadin Abdi regarding the nature of direct current and its electrolytic lesioning
effect on neural tissue over the next 50 years.2 Golsinger in 1895
used monopolar electrodes for lesioning.1 Horsely and Clarke stud-
ied the effect of electrode material and polarity on the quality of
lesions and established relationships between lesion size, current,
and time parameters.1,2
Harvey Cushing, in the 1920s, investigated the potential use of
HISTORY RF for electrosurgery.5,6 Kirschner in 1931 used RF for thermoco-
agulation of the gasserian ganglion as a treatment for pain in tri-
There was a great deal of experimentation in the 1800s in electricity geminal neuralgia.4,7 Research then centered on increasing the
and its effects on neural tissue,1–3 and one of the earliest uses of predictability and reproducibility of the lesion produced. In 1953,
Sweet and Mark demonstrated the disadvantages of direct cur- variability of tissue characteristics. Temperature monitoring, not
rent lesions: irregular borders, variability in size, and difficulty in voltage or current monitoring, assured the creation of a lesion.18
control.2,5 They as well as others8 correctly suggested that high- Since the inception of radiofrequency lesioning, the character-
frequency currents would offer advantages, and this was followed istics of the lesion and parameters to control its formation have
by the first practical RF lesion generators by Aranow and Cosman.2 been studied extensively, as lesioning is used not only in to destroy
Using 1 Mhz as a frequency with adjustable current and power nervous tissue but also in tumor ablation. Early studies using dorsal
parameters, they were able to produce smooth-bordered lesions root entry zones in cats18 with fixed temperatures and variable
without the unwanted side effects inherent with direct current: lesion times suggested that lesion sizes grow asymptotically with
electrolysis, tissue polarization, and gas formation.2 In 1960, time, achieving a significant portion of their final dimensions by
Mundinger and coworkers9 emphasized the importance of moni- 30 seconds, and plateau after 45 seconds, beyond which only mini-
toring electrode temperature to achieve predictable lesion size, a mal increases in growth would occur, and thermal equilibrium is
concept that is still important today. achieved in 60 seconds.18 The shape of the lesion is characteristically
spheroid around the active electrode and tapers at the tip with
minimal lesion formation beyond the tip.19
DEVELOPMENTAND PERFECTION Increased tissue temperature, beyond 458C, leads to irreversible
tissue injury and to cell necrosis and is the therapeutic basis for
Observations of the sequelae of retrogassarian thermal rhizotomy10 radiofrequency lesioning.20 After lesion creation, the tissue has a
in the treatment of trigeminal neuralgia, that touch sensation histological appearance of a local burn, with nerve architecture
remained intact within the lesioned zones that were rendered analge- destroyed.20 Subsequently, neurons undergo Wallerian degenera-
sic, suggested that heavily myelinated Ab-fibers were more resistant tion.20 Unlike cryolesioning, in which the endoneurium, perineur-
to destructive effects of heating.11 They demonstrated that RF heat ium and ectoneurium remain intact,21 the perineurium after
lesions block smaller d- and C-fiber action potentials before those radiofrequency lesioning may also be destroyed, leading to neuroma
of the ab group, and this concept was believed to be the therapeutic formation.20
basis of RF.12,13 In 1977, however, it was found that RF thermoco- Temperature monitoring during lesioning increases lesion con-
agulation causes indiscriminate rather than selective destruction sistency and safety.18,19 Factors that affect temperature near the
of small and large myelinated fibers.13,14 Smith and associates13 con- active electrode include the thermal characteristics and homogene-
cluded in a dog model that RF lesions were not specific for destruc- ity of local tissue, and of surrounding structures such as bone,
tion of unmyelinated C-, small myelinated, or large myelinated which may be insulating, or blood vessels and cerebrospinal fluid,
fibers, nor were 2-minute lesions at specific temperatures of 458C, which may serve as a heat sink.22
558C, 658C, and 758C. Stereotactic placement of the electrode with Impedance monitoring can be used to assess the placement of
precision advanced the technique of RF of trigeminal neuralgia.15 the electrode and the functioning of the equipment and the char-
Radiofrequency lesioning (RFL) for chronic spinal pain was used acteristics of the tissue being lesioned. Electrical conductivity of the
in 1975 for percutaneous denervation of the lumbar facets by tissue changes as structural changes occur secondary to heat
Shealy.4,16 Sluijter refined percutaneous RF techniques for the cer- lesions.23 Real time impedance monitoring can also assess the integ-
vical, lumbar, and thoracic spine,15 and with Mehta, modified the rity of the circuit or the presence of a short circuit.23
RF electrode with the addition of temperature monitoring. Electrode placement near the target nerve is critical for the suc-
cess of a neuroablative procedure. The goal is to achieve maximal
desired complete tissue destruction with minimal zones of reversi-
BASIC PRINCIPLES bility, and minimal destruction of surrounding tissue. This can be
achieved by placing the electrode parallel to the axis of the nerve to
Radiofrequency is a term used to classify a rate of oscillation in the be lesioned.19 Gross placement of the electrode can be achieved via
range of 3 kHz to 300 GHz,17 and is typically applied to electro- biplanar fluoroscopy, and fine adjustment can be achieved the use
magnetic radiation. Application of voltage between electrodes con- of non-ionic contrast dye.24 Electrostimulation at 50Hz is used to
nected by tissue in a closed circuit creates an electric field which elicit sensory patterns used for feedback of electrode placement.24,25
causes current to flow. Oscillating voltage in such a system moves As the electrode approaches nerve tissue, the voltage required to
ions in the tissue electrolytes back and forth which generates fric- evoke sensation decreases. For dorsal root ganglion ablation, repro-
tion and heat which is dissipated in the tissue medium and is duction of concordant pain at voltages from 0.4 to 0.7V suggests
responsible for the resulting lesion.18 The temperature surrounding optimal electrode placement, while voltages below 0.2V suggest
the electrode tip in homogenous tissue is regulated by the thermal intraneural electrode placement, which increases the risk of neur-
conductivity of the tissue, the circulation of heat-dissipating blood itis.24 Electrostimulation at 2Hz and 2V is used to seek motor
through the tissue, the shape of the electrode, and generally function, the presence of which may indicate electrode placement
decreases as a function of distance from the electrode tip.18 The near a ventral nerve root.24
region or isotherm in which tissue achieves a temperature between The modern radiofrequency generator is a microprocessor
45 to 508C is critical for neurodestructive lesioning, as this is where based system designed not only to make the lesion and monitor
neural tissue is killed.18 temperature, but also to provide feedback information to the
The temperature generated in the tissue is transferred to the active user to enhance safety and improve target determination.26
electrode, and is measured. In an ideal electrode system at equili- Radiofrequency generators serve as nerve stimulators, and can
brium, the tip temperature will be nearly equal to the temperature output current in both pulsed and continuous mode; critical func-
of the hottest tissue surrounding it. In the historical development tions include continuous monitoring of temperature, impedance,
of lesioning systems, optimizing the shape of the electrode and voltage current and wattage.27 Sophisticated features can include
monitoring the electrode temperature improved the consistency of programmable waveform output generations, adjustments and
the size and shape of radiofrequency-generated lesions and thus alarms for power, voltage, current, time, and device status.
increased the safety of this practice.18 Temperature monitoring and Advanced feedback circuits can allow the generator to achieve tight
maintaining temperatures below 1008C avoided overheating and temperature control to prevent overheating, and accurate tempera-
resulting tissue boiling, charring and sticking of the electrode, the ture maintenance. Microprocessor controls also allow for sophisti-
removal of which might lead to hemorrhage.18 Additionally, tem- cated display output and recording capabilities, and can alert for
perature monitoring per se was considered a more reliable parameter system faults such as short circuits or open circuits, which can be
than voltage, current or their tissue application time, based the useful in clinical practice.26
In clinical practice, for each lesion, key variable parameters condition, and the diagnosis of the presenting condition must be
should be recorded and included in procedure documentation, reasonably suspected. History, physical examination, supportive
and can be used for reference and in quality control programs; objective evidence, and the thought processes regarding the pro-
these include impedance, temperature, voltage, current, and time. posed procedure should be documented prior to its performance.
Routine recording and monitoring under normal conditions estab- Ideal candidates are those capable of understanding the reasons for
lishes a baseline and range of normal limits with which the operator the choice of the procedure; its relevant risks, potential benefits, and
achieves familiarity, and deviation from which will alert the opera- alternatives; and expected outcome of the procedure and are able to
tor to the potential for problem.26 provide informed consent to the procedure. The patients must be
reliable and able to provide accurate information regarding health
and the use of medications and must be able to follow instructions
EQUIPMENT CHECKS prior to, during, and after the procedure is performed. Familiarity
of the practitioner with the patient’s conditions and cognitive func-
The temperature reading at an electrode tip in situ should reflect tions, including language, that might affect his or her ability to
body temperature; deviation from this is a sign of problem, and tolerate positioning or ability to cooperate is essential. In some
conversely, appropriate readings imply that the thermistor, elec- instances, the presence of a responsible party to accompany the
trode and the temperature monitoring circuitry are functional.28 patient after the procedure is necessary.
With the importance of temperature monitoring previously dis-
cussed, the absence of appropriate temperature monitoring
should preclude continuing until the problem is resolved. Complications
Temperature readings over 808C require closest scrutiny, as the
tissue boiling point (1008C) is not far away. Modern radiofrequency Specific complications associated with RFL are discussed separately
systems are based on setting the temperature directly. These systems based on the procedure but are dependent upon patient selection,
automatically adjust power output and current in a feedback con- methods used, and nature of reporting of follow-up. In general,
trol to achieve the temperature setting. During lesioning, observa- complications may be classified as procedure nonspecific (occurring
tion of the rise and fall of actual temperature versus desired with any invasive procedure) or procedure specific (depending upon
temperature is important to prevent under- or overheating. At all the nature of the procedure). Examples of the former include stress-
times, the operator should have the ability to stop power output related reactions, such as bradycardia due to increased vagal tone
easily if necessary, as may occur with system malfunction, patient and hypoventilation secondary to sedation. Examples of procedure-
movement, and the like.28 specific complications can be further classified as occurring because
A properly functioning RF generator is critical for safe, consis- of inadvertent needle or electrode placement with or without tissue
tent lesioning, and modern, microprocessor-controlled systems destruction and can be immediate or delayed—pneumothorax, vas-
decrease the likelihood of patient injury due to malfunction. The cular penetration with bleeding and hematoma, central nervous
cables and electrodes must also be functioning properly. They are system penetration with cerebrospinal fluid leak, infection with
more susceptible to damage and malfunction secondary to multiple abscess formation—or can be due to intended tissue destruction
use and sterilization cycles. Spare sets of cables and electrodes with unintended results such as neuroma formation or neuritis.28
should be available and ready to use in the event of an equipment RFL-specific complications may include burns, which are unusual
failure or breach in sterility. The number of sets of redundant cables during RF procedures but may result from electrical faults, generator
should depend upon the frequency of their use and the sterilization malfunction, or insulation breaks in the electrode.28,29
turnover time. Integrity of cables suspected of malfunction can be
assessed in real time by an impedance monitor.28
Electrodes or electrode introducers should be checked for the FACET RHIZOTOMY
integrity of the insulation. Faulty insulation may lead to leakage of
RF voltage, failure to achieve the intended lesion, and nontarget Zygapophyseal joint (Z-joint) arthropathy is a common cause of
tissue damage. In such a case, despite appropriate impedance, vol- neck and back pain and can be due to traumatic or degenerative
tage, and current, tip temperature might not rise as expected. This changes. Apophyseal articulations are formed by the superior and
stresses the importance of continuous close observation and reac- inferior articular facets from adjacent vertebral levels, and they allow
tion during RFL. The dispersive electrode is another critical com- for spinal mobility. The joint capsule is richly innervated. It is gen-
ponent subject to monitoring. The surface area of the dispersive erally accepted that the major afferent supply to each articular facet
electrode must be relatively large in comparison with that of the joint is by the medial branch of the posterior primary ramus from the
active electrode to prevent the concentration of electric fields, heat adjacent vertebral level and from one level above.30,31 Arthropathy
generation, and burns. Good contact between the skin and the of the facet joints is usually caused by osteoarthritis; however,
entire surface of the overlying electrode is necessary, and care other rare but identifiable causes can be found, such as infection,
should be taken to avoid air pockets or poor contact. Newer dis- systemic inflammatory arthropathy, or fracture, and these should
posable dispersive electrode systems can continually monitor the be ruled out. Whereas facet degenerative changes often follow
function of the electrode and signal or inhibit output in a fault disk degeneration at the same level, symptomatic facet arthropathy
situation.28 Obviously, the performance of any invasive procedure and symptomatic disk degeneration rarely occur at the same level.
should be done in an environment appropriately equipped with
patient monitors, equipment, and resuscitation medications readily
available in the event of a medical emergency. Diagnosis
Clinical features of lumbar Z-joint pain and lumbar facet syndrome
have been described. Patients with lumbar facet pain often com-
CLINICAL APPLICATION AND USAGE plain of dull, aching paravertebral or low back pain that can be
referred to the buttocks, hip, thighs, or knees.32 On physical exam-
Patient Selection ination, there is often tenderness to palpation over the facet joints,
which may be associated with low back pain with lateral lumbar
As with any procedure, proper patient selection is critical. The pro- flexion or extension.32 The neurologic examination may be normal
cedure must be deemed appropriate to treat the presenting with patients suffering solely from facet joint pain.
Despite these common findings, the literature does not sup- patient selection, an excellent understanding of the anatomy, and a
port findings by history, physical examination, or imaging studies meticulous technique. Pain originating in the Z-joints can cause
to be pathognomonic for facet-based pain.32–34 In addition, the symptoms of neck pain, cervicogenic headache, shoulder pain,
presence of individual clinical features has not been shown to be suprascapular and scapular pain, and upper extremity pain.37
predictive of the response to facet blockade.33 The term facet Diagnosis of cervical facet syndrome cannot, currently, be based
syndrome was coined by Ghormley, and based upon pathomor- on clinical or radiographic signs, because these signs are unreliable.
phologic study of the joint, it was believed that denervating the The diagnosis is made by specifically anesthetizing the nerves that
joint would stop the pain emanating from it. Subsequently, study supply the Z-joint.38 Two or more positive diagnostic cervical
of facet-related joint pain arose based on pain patterns evoked by medial branch blocks are required to confirm the diagnosis of
the injection of saline into the facet joints of healthy volunteers, cervical facet syndrome. A single successful block has been shown
or by the direct injection of local anesthetic and corticosteroid to be false positive 27% of the time.39 A validated method of per-
solutions into the facet joint or over the medial branch of the forming controlled comparative diagnostic blocks of the dorsal
dorsal ramus, or by direct probing of the joint capsule during rami supplying the symptomatic Z-joint has been described by
decompressive spinal surgery. Consequently, many investigators Lord and colleagues.40 Either lidocaine or bupivacaine is used.
developed methods of diagnosing ‘‘facet-mediated’’ pain by The patient should be blinded to the specific local anesthetic uti-
blocking the joint either by direct intra-articular injection or by lized. A positive response of greater than 80% pain relief should be
specific nerve blocks.35 Based upon the inconsistency by which subsequently treated with a repeat block, using the alternative local
physical testing identifies or even localizes lumbar Z-joint pain, anesthetic. Only those patients reporting a greater duration of
practice patterns have evolved that seek to establish the diagnosis pain relief with the longer-acting bupivacaine should be consid-
of lumbar facet pain via invasive diagnostic blocking, and radio- ered a positive diagnostic response. Because RF neurotomy of the
graphically controlled diagnostic blocks have become the stan- medial branch of the posterior primary ramus is associated with
dard approach.36 minimal postprocedure complications, it is also argued that diag-
The basis for RFL is the placement of the active electrode as close nostic blocks are not necessary. Those arguing this position recom-
to the target nerve as possible while minimizing its proximity to mend performing cervical Z-joint RFL on the basis of clinical
surrounding tissue whose destruction is not desirable. Such techni- suspicion alone.
ques that help to refine electrode placement increase the chances of The cervical Z-joints are innervated by the medial branches of
a successful lesion and minimize the potential injury of surrounding the posterior primary ramus. The C3 dorsal ramus nerve supply is
tissue. Testing by stimulating target sensory nerves prior to their slightly different from the lower cervical levels. Two medial
lesioning helps to quantify the relative contribution of the target branches arise from the C3 dorsal ramus, the superficial and deep
nerve as a pain generator in the overall pain syndrome. Similarly, branches. The deep medial branch hugs the waist of the C3 articular
testing by stimulating for the presence of a motor nerve within pillar to supply the C3–4 Z-joint. The superficial medial branch,
proximity to the active electrode minimizes the potential for unde- otherwise known as the third occipital nerve, wraps laterally and
sired loss of motor function. This functional stereotactic approach posteriorly around and supplies the C2–3 Z-joint. Below the C3
is used after gross and fine fluoroscopically guided electrode place- level, the dorsal rami of the exiting spinal nerves divide into
ment has been established. medial and superficial branches. The branches cross the waist of
Low-voltage stimulation of sensory nerves should elicit concor- the adjacent articular pillars, midway between the superior and the
dant pain. The absence of concordant pain suggests improper inferior articular processes. The medial branches supply the Z-joint
needle placement or that the stimulated nerve is not a pain at that level as well as sending articular branches to supply the
generator; in either case, lesioning should not proceed. Accurate Z-joint below. Therefore, each Z-joint below the level of C3 has
stereotaxy requires reliable feedback from an awake, cooperative dual innervations from the medial branch at that level and from the
patient; as such, sedation is not recommended and should be one above.41
avoided. Medications that impair a patient’s ability to sense and
compare these stimuli with their pain patterns and to detect subtle
motor stimulation will decrease the potential efficacy and safety of Technique
the procedure. In rare instances, short-acting and reversible analge-
sics may be used to facilitate a patient’s cooperation; however, the There are two approaches, namely, the posterior approach
appropriateness of a stereotactic RF procedure as a treatment mo- described by Lord and colleagues40 and the lateral approach. The
dality must consider the patient’s ability to participate. posterior approach is more commonly used in the United States,
Once approximate electrode placement with fluoroscopic guid- whereas the lateral and supine approach is favored in Europe.
ance has been achieved, low-voltage sensory stimulation in the During the procedure, sedation is not used; this optimizes contin-
range of 0.2 to 0.5 V is applied with a pulse duration of 1 msec uous communication with the patient.
and a frequency of 50 Hz. This should reproduce concordant pain
and cause contraction of the ipsilateral multifidus muscle. Electrode
Posterior Approach
placement at a nonsymptomatic level will elicit ipsilateral multifidus
contraction, and may elicit generalized tightness or paresthesias in The posterior approach was described by Lord and colleagues in
the back, but will not reproduce concordant pain. Once concordant 1995.40 Under aseptic conditions and with the patient in the prone
pain is reliably elicited, subtle repositioning of the electrode to position, the C-arm is positioned to generate an anteroposterior
maximize its proximity to the target nerve should allow reproduc- view. In a coaxial approach, the skin entry point lies directly over
tion of concordant pain between 0.15 and 0.3 V. There should be the target point. The target point in this approach is the lateral
no production of paresthesias, with or without stimulation, in the margin of the superior articular pillar. A skin wheal of local anes-
distribution of any spinal nerve root that may be in the vicinity of thetic is raised. The RFL cannula is then carefully advanced in
the electrode. tunnel vision until the bone of the supra-articular pillars is reached.
The cannula is then ‘‘walked off’’ the lateral edge. The depth
of the cannula tip is checked in the lateral view. The resulting
CERVICAL Z-JOINT RFL plane of electrode insertion optimizes the length of electrode tip
that produces the lesion. In this plane, the electrode lies parallel to
Percutaneous RF neurotomy is useful in treating pain emanating the target nerve. RF testing and lesioning are performed as for the
from cervical Z-joints. The success of this technique relies on proper posterolateral approach.
A randomized, double-blind, sham-controlled trial of whiplash nerve as it passes over the anterolateral aspect of the pillar. The
injury patients with neck pain first established the efficacy of RFL of second parasagittal path is performed to target the nerve as it
the cervical Z-joints.42 In this study, the median time that elapsed crosses the lateral aspect of the SAP. This group described a
before pain returned to 50% of preprocedure levels was 263 days in target site at the lateral aspect of the C2–3 Z-joint. The skin punc-
the treatment group and 8 days in the sham-control group. ture should lie directly over the target site. The cannula is carefully
McDonald and coworkers43 helped determine long-term efficacy advanced under anteroposterior fluoroscopic guidance. The needle
of RFL of the cervical Z-joint. In a follow-up of 28 patients diag- is advanced until the posterior aspect of the C2–3 Z-joint is con-
nosed with cervical Z-joint pain, based on diagnostic blocks, tacted. The cannula is walked off the lateral edge of the superior
they noted a median duration of relief of 219 days. If the patients C3 SAP. Under lateral fluoroscopic guidance, one of three target
who failed the initial procedure were excluded, these authors noted points is used; the superior, middle or lower one third of the SAP.
a median duration of relief of 422 days. In addition, after Cannula contact with the bone medially is confirmed with oblique
repeat procedures, they described a median duration of relief of views. Two more electrodes are placed at the remaining target
219 days. The evidence available on this procedure involves small points on the SAP. The space between adjacent electrodes should
patient groups. To make definitive conclusions on the efficacy of not be greater than one electrode diameter to optimize success of
RFL of the cervical Z-joint, larger studies are required. the neurotomy. Once the electrode is in position, local anesthetic
is injected through the cannula and RFL is performed at 808C for
90 seconds. Govind and associates45 described a second set of
Lateral Approach
lesions in a sagittal plane. In anteroposterior fluoroscopic view,
The patient is positioned supine on the operating table with moni- new skin puncture points were made directly over the target, the
tors attached. The operative area is prepared with an antiseptic lateral edge of the C3 SAP. Just as before, the cannula was carefully
solution. The C-arm is rotated obliquely 308 to the side to be advanced and walked off the lateral edge of the SAP. Lateral views
denervated. The obliquity should be optimized so that the pedicles confirmed placement of the cannula at one of three target points on
are seen slightly anterior to 50% of the vertebral body. This pro- the SAP, the superior middle or lower one third. The uninsulated
vides a safety margin between the electrode tip and the spinal nerve part of the electrode was confirmed to be in contact medially with
exiting that neuroforamen. In this view, the medial branch of the bone. Two more electrodes are placed in a similar manner at the
dorsal primary ramus is presumed to run over the base of the other two targets. Again, the electrodes must lie within one diam-
superior articular process (SAP). The skin entry point is marked eter of the electrode adjacent to it. The lesion was performed as for
at a position just caudal and posterior to the posterior edge of the the original oblique pass. After the procedure, patients may expe-
facet column. A skin wheal of 1% lidocaine can be raised at this rience ataxia and unsteadiness. Postoperative guidelines should be
point. Limited amounts of local anesthetic should be injected to adjusted accordingly. In helping to establish the efficacy of RFL for
avoid interfering with sensory stimulation, which is used to identify headaches related to the third occipital nerve, Govind and associ-
the medial branch. Either a straight or a curved RFL needle may ates45 found that 43 of 49 patients (88%) who underwent their
then be carefully advanced until bone is contacted at the target described procedure achieved a successful outcome. They defined
point. An anteroposterior fluoroscopic view should check that the a successful outcome as complete relief of headache and return to
needle tip is lying adjacent to the articular pillars. The waist of the normal activities. These patients experienced an average of 297 days
articular pillars appears as a concavity in this view. In this of relief.
approach, the position of the vertebral artery should be noted as
anterior in the neuroforamen. The same technique is applied for
the other Z-joints at C3–4 to C6–7. The proximity of the needle tip THORACIC Z-JOINT RFL
to the medial branch nerve is then confirmed by sensory testing at a
frequency of 50 Hz. Tingling sensations in the neck should be noted Traditionally, the superior edge of the junction between the trans-
at under 0.5 V. Further testing at a frequency of 2 Hz confirms verse process and the SAP has been the target point for thoracic
needle tip position and provides a safety feature to prevent segmen- Z-joint RFL. Anatomic evidence suggests that at the thoracic level,
tal motor nerve lesioning. At 2 Hz, contraction of the ipsilateral the current utilized target is not in close proximity to the course of
multifidus muscle should be elicited. In addition, no shoulder or the medial branch nerve. The medial branches of the thoracic dorsal
arm muscle contraction should be noted. If testing has confirmed rami most often cross the superolateral edge of the transverse pro-
optimal needle placement, then 0.5 ml of 1% or 2% lidocaine can cess and then course medially and inferiorly over the posterior sur-
be administered at each level to be lesioned. RFL can proceed at face of the transverse process. However, at the T5–8 levels, the
808C for 90 seconds. Impedance of 300 to 800 ohms must be inflection point has been found to occur superior to the superolat-
confirmed. eral edge of the transverse process. In a study of four cadavers,
no medial branch nerves were found crossing the junction between
the transverse process and the SAP.46 The superolateral corner of
THIRD OCCIPITAL NERVE RFL the transverse process has been advocated by some as the target
point for RFL. However, Stolker and colleagues47 published a
The C2–3 Z-joint is supplied by the superficial medial branch of the study of 40 patients who underwent RFL with the target at the
posterior primary ramus, as described earlier. The anatomic posi- junction of the thoracic SAP and the transverse process. At 18- to
tion of this nerve is variable as it courses over the SAP. Most 54-month follow up, they found 16 of 36 patients (44%) had com-
commonly, the third occipital nerve crosses the middle third of plete pain relief, 14 (39%) had more than 50% pain relief, and
the articular pillar but is also seen to cross at the superior or infe- 6 (17%) had poor response.48 The variability in the course of this
rior one third.44 Lord and colleagues40 described a posterior nerve highlights the need for meticulous sensory and motor testing
approach to the third occipital nerve but reported a high technical prior to performing RFL.
failure rate. Govind and associates in 200345 described a validated,
revised technique of percutaneous RF neurotomy for third occipital
nerve headache. Their technique is performed with the patient in Technique
the lateral position and under sterile conditions. The technique
requires multiple lesions in two passes in different planes. The The patient is positioned prone and monitors are attached. The
first of the two electrodes passes runs in an oblique plane, 308 patient is not sedated. An anteroposterior fluoroscopic view
from the sagittal. This pass runs ventral and medial to reach the of the affected thoracic level is obtained. The vertebral endplates
are leveled by a slight caudal tilt. The junction between the SAP and sacral ala. This target is best viewed in anteroposterior projection
the transverse process is optimized by obliquing the camera angle to with a curved contour of the ala. An oblique fluoroscopic view at
the affected side. The skin entry point is anesthetized by raising a this level risks obstructing the cannula approach by the overlying
skin wheal of local anesthetic. A coaxial view of the RFL cannula is iliac crest.
then obtained. Careful advancement of the cannula under fluoro- The original technique for lumbar Z-joint RFL was described by
scopic guidance is performed. Once the cannula reaches the bone of Shealy in 1975.51 Multiple modifications have since been made to
the target junction, it is walked a few millimeters off the bone so this technique. The efficacy has been studied in a systematic review
that it lies on the anterolateral edge of this junction. A lateral view of randomized, clinical, controlled trials. In this review, Geurts and
of the cannula should confirm that the tip lies posterior to the coworkers52 found moderate evidence that RFL lumbar Z-joint
posterior edge of the neuroforaminal canal. Meticulous sensory denervation was more effective for chronic low back pain than
and motor testing, as described previously, should confirm ade- was placebo. Only two randomized, controlled studies made it
quate proximity to the medial branch nerve. After administering through their validation screening process. A recent systematic
0.5 ml of 1% to 2% lidocaine, RFL at 808C for 90 seconds can be review of randomized, controlled trials in the Cochrane database
performed. assessed the effectiveness of RFL in treating musculoskeletal pain
disorders.53 Three randomized, controlled trials met the authors’
inclusion criteria and provided conflicting scientific evidence for the
LUMBAR Z-JOINT RFL short-term effectiveness of lumbar Z-joint neurotomy. Van Kleef
and associates’ study54 included 31 patients with chronic low back
Pain from the lumbar Z-joints has a prevalence of 15% to 40% in pain who were diagnosed by dorsal rami nerve blocks and under-
patients with low back pain.49,50 The lumbar Z-joints are supplied went RFL or a sham procedure. Follow-up at 3 and 12 months
by the medial branch of the posterior primary ramus as it runs noted significant short- and long-term reduction in pain and
dorsally and caudally in the groove between the SAP and the trans- improvement is disability scores when compared with the control
verse process. The medial branch nerve also supplies branches that group. Gallagher and colleagues’ study55 used the original Shealy
innervate the Z-joint at the level below. This nerve also supplies the technique. They randomized 41 patients to a sham group or a treat-
lumbar multifidus muscle. Successful neurotomy can be objectively ment group. They reported statistically significant improvements in
determined by segmental electromyography of the multifidus. In visualanalog scale (VAS) and McGill Pain Questionnaire scores at
clinical practice, however, this is seldom required. Clinical suspicion both 1 and 6 months.55 Leclaire and coworkers56 studied 70 patients
of pain emanating from the Z-joint is raised by reproducing con- randomized to sham therapy or neurotomy. This group found sig-
cordant pain when pressure is applied directly over the joint. nificant improvement in the Roland Morris score at 4 weeks but not
However, as with cervical and thoracic Z-joints, diagnosis is con- in the Oswestry or VAS score. At 12 weeks, neither scoring system
firmed only with two or more diagnostic blocks of the medial showed any effect.56
branch. Although randomized, controlled trials are the ‘‘gold standard’’
in evaluating the validity of treatment procedures, prospective and
retrospective studies continue to be published on the efficacy of the
Technique procedure. Dreyfus and associates57 followed 15 patients, diagnosed
as having Z-joint pain by diagnostic blocks. All patients had lumbar
The procedure is similar to that for cervical and thoracic Z-joint medial branch neurotomy. Electromyography of the multifidus
RFL. No sedation is used in order to maintain optimal communi- muscle confirmed accuracy of the neurotomy. They reported that
cation with the patient. The patient is positioned prone with pillows 60% of the patients obtained at least 90% pain relief at 12 months
under the abdomen to minimize the lumbar lordosis. An antero- and 87% had at least 60% relief. Schofferman and Kine49 investi-
posterior fluoroscopic view of the target vertebral level is obtained. gated the effectiveness of repeating neurotomy for lumbar facet
The vertebral endplates are squared off by caudal/cephalad tilt. The pain. They reviewed charts on 20 patients. They noted a mean
fluoroscope is obliqued to the same side as the Z-joint until the duration of relief of 10.5 months (range 4–19 mo). The 20 patients
junction between the SAP and the transverse process is optimally had a repeat procedure of which 17 (85%) were successful. The
seen (158). This junction is the RFL target point. A skin wheal of mean duration of relief in 16 of the 17 patients was 11.6 months
local anesthetic is raised at the puncture point directly over the (the remaining patient had continued relief). Sixteen patients had a
target area. The RFL cannula is carefully advanced under fluoro- third procedure. Fifteen were successful, with a mean relief in
scopic guidance in a coaxial view. When bone contact is made, the 9 patients of 11.2 months (relief continued in the other 6). Eight
cannula is carefully walked off the cephalad lateral edge of the junc- patients had a fourth neurotomy that was successful in 7, with a
tion. The cannula should not be advanced more than 1 to 2 mm off mean duration of 9 months.49
this edge. A lateral fluoroscopic view is obtained to ensure that the
cannula tip has not been advanced into the intervertebral neuro-
foramen. An anteroposterior view confirms medial contact of the RFL FOR PAINORIGINATING IN THE
cannula with bone. In this position, the RFL cannula should lie SACROILIAC JOINT
parallel to the medial branch nerve. The RFL electrode is then
placed in the cannula and impedance confirmed in the range of Sacroiliac joint (SIJ) pain is a challenging area for pain physicians
300 to 800 ohms. Sensory and motor testing is then performed as because the anatomy, etiology, diagnosis, and treatment are still
for the cervical and thoracic levels. Some practitioners consider debated in the literature. SIJ syndrome affects between 15% and
sensory testing to be superfluous if correct placement of the RFL 25% of patients with low back pain.58 The cause of pain may be
cannula has been achieved. This can be confirmed by motor testing intra- or extra-articular. Intra-articular causes include spondylar-
and monitoring the subsequent multifidus response alone. thropathy, arthritis, and infection, whereas extra-articular causes
Movement of the cannula during testing at 2 Hz suggests multifidus include enthesiopathy, fractures, and ligamentous injury.
contractions. If no lower extremity fasiculations occur, lesioning Diagnosing the condition has proved difficult. History and physical
can proceed. One percent to 2% lidocaine is injected through the examination, including Fortin Finger, Gaenslen’s, and Patrick’s
cannula. RFL is performed at 808C for 90 seconds. tests as well as sacral sulcus tenderness and joint play, have been
At the level of the L5–S1 Z-joint, there is no transverse process. shown to have little value in diagnosing SIJ pain.59 The referral
At this level, the medial branch runs caudally and posteriorly at the pattern of pain from the SIJ is inconsistent. Slipman and collea-
junction between the SAP of the sacrum and its upper border, the gues60 described the most common areas of referred pain to be
the ipsilateral buttock (94%), lower lumbar region (72%), lower diagnostic blocks). A total of 9 patients obtaining greater than
extremity (50%), and groin (14%). 50% pain relief with lateral branch blocks proceeded to RF dener-
The International Association for the Study of Pain has defined vation of L4–5 primary dorsal rami and S1–3 lateral branches. Eight
diagnostic criteria for SIJ syndrome61: of 9 patients reported greater than 50% pain relief after a 9-month
follow-up. Although encouraging, randomized, controlled trials are
1. Pain in the region of the SIJ with possible radiation to the
required before validity of RF denervation of the SIJ can be
groin, medial buttocks, and posterior thigh.
established.
2. Reproduction of concordant pain by stressing the joint.
3. Elimination of pain with intra-articular injection.
4. Absence of radiographic abnormalities.
A consensus within the literature suggests that of these criteria CRANIOFACIAL RFL
only an analgesic response to two or more intra-articular blocks
confirms the diagnosis, although the validity of such blocks remains Trigeminal Neuralgia
unproved.
The innervation of the SIJ also remains ambiguous. The poste- Trigeminal neuralgia (tic douloureux) is the most common cranio-
rior SIJ is supplied predominantly by sacral dorsal rami,62 possibly facial neuralgia. It occurs with a mean incidence of 4 to 5 per
through lateral branches of S1–4.63 There may also be additional 100,000. It is seen more often in females (60%) between the ages
innervation from L4 and L5 lateral branches.63,64 Anteriorly, the of 50 and 70.70,71 The etiology of trigeminal neuralgia is not fully
joint is probably supplied by the direct branches of the lumbrosacral understood, although an overlying vascular structure compressing
trunk, the superior gluteal nerve, and the obturator nerve.65 the trigeminal nerve root is the most frequent finding in surgical
However, a cadaveric study showed marked variation of the exploration of the cerebellopontine angle. Currently, investigations
number and location of nerves innervating the SIJ between and on the pathophysiology underlying trigeminal neuralgia are focused
within individual cadavers.66 on the observation that the trigeminal nerve root’s entry zone
Despite the confusion surrounding SIJ syndrome and the lack of becomes demyelinated in this disease.
any randomized, controlled trials to support the use of RF neurot- The trigeminal nerve has three branches, as its name suggests:
omy of the SIJ, it is performed in clinical practice. Two techniques ophthalmic, maxillary, and mandibular. The pain associated with
have been described. The first technique attempts to create a ‘‘strip trigeminal neuralgia is often confined to a facial region supplied by
lesion’’ or a continuous band of coagulum via bipolar RF ablation. one branch of the trigeminal nerve. The pain is described as
This strip lesion is created by adjacent RF cannulae positioned along ‘‘recurrent’’ and ‘‘lancinating’’ in nature. The trigeminal ganglion
the portion of the SIJ that can be reached percutaneously. is named after the anatomist Johann Gasser and is called the gas-
serian ganglion. It lies within a cavelike structure of the cranium,
Meckel’s cavity. It is bordered superiorly by the temporal lobe,
Technique medially by the cavernous venous sinus, and posteriorly by the
brainstem. RFL of the trigeminal nerves provides the unique advan-
In an awake, prone patient under fluoroscopic guidance, an RF tage of a percutaneous controlled selective lesion over alternative
cannula is positioned near the inferior part of the posterior SIJ. therapies such as glycerol rhizolysis, microvascular decompression,
A second cannula is positioned adjacent and cephalad to the first. and percutaneous trigeminal balloon microcompression. The oph-
The two probes should be within 4 to 6 mm of each other to thalmic branch should be lesioned with extreme care. Lesions of the
ensure contiguous strip lesion.67 After 1 to 2 ml of local anes- sensory fibers of the ophthalmic branch can lead to loss of the
thetic is injected intra-articularly, RFL electrodes are inserted corneal reflex, which can lead to corneal ulceration and keratitis.
into the cannulae. Impedance should be checked. RFL at 908C RFL targets the Ad- and C-fibers; however, lesions may affect the
for 90 seconds is administered. Multiple lesions are created by sensory fibers. This should be checked during the procedure by
‘‘leapfrogging’’ the most cephalad probe and placing another can- testing the corneal reflexes.
nula 4 to 6 mm cephalad. This procedure is repeated until the
posterior joint capsule cannot be accessed cephalad to the previ-
Technique
ous cannula.
Ferrante and coworkers68 studied the use of this technique in The patient is positioned supine while the head is taped to the bed
33 patients with SIJ syndrome (confirmed by one diagnostic block). to prevent unexpected movement during the procedure. A short-
These results were marginal in this uncontrolled study. They acting intravenous anesthetic agent such as propofol or methohex-
reported that 12 of 33 (36%) patients had at least a 50% decrease ital is used as the ganglion is first punctured and when lesioning
in VAS at 6 months. The technique used in Ferrante and coworkers’ is performed. At other times, the patient should be able to appro-
study denervates only a small posteroinferior portion of the SIJ, priately communicate with the physician. A submentovertex pro-
which may account for the high failure rate. jection of the C-arm should open up the foramen ovale at
The second technique attempts to lesion the dorsal rami of L4–5 approximately 308 to the side affected and 308 caudal. The C-arm
and the lateral branches of S1–3. In an awake, prone patient, the should be adjusted to provide an oval appearance to the foramen
skin overlying the targets is anesthetized. The fluoroscope is posi- ovale. The RFL cannula can now be carefully advanced under guid-
tioned either slightly oblique (L4 dorsal ramus), anteroposterior (L5 ance from the fluoroscope. An index finger may be placed intrao-
dorsal ramus), or cephalocaudad (several lateral branches). The rally on the lateral buccal mucosa to help guide the cannula and
lateral branches of S1–3 typically arise from 2 o’clock to 6 o’clock prevent perforation into the oral cavity. Once in the foramen ovale,
(right) or 6 o’clock to 10 o’clock (left) if the sacral foramen are the cannula is advanced under a lateral view to check the depth of
considered as clock faces.66 Correct placement of the RFL electrode insertion. This decreases the chance of perforating the dura and
must, however, be confirmed with sensory testing at 50 Hz. This causing liquorrhage.70 The RFL cannula target depends on which
should produce concordant pain at below 0.6 V. Motor testing at division of the trigeminal nerve is causing the pain. The ganglion is
2 Hz should confirm the absence of leg muscle contractions. Then, somatropically organized. The ophthalmic branch is located at the
0.3 ml of local anesthetic is administered at each site prior to RFL. dorsal pole, the maxillary branch is intermediate, and the mandib-
The RFL is performed at 808C for 90 seconds. ular branch is located at the ventral pole. Once the electrode is in
Cohen and Abdi69 performed a retrospective, uncontrolled position, sensory and motor testing can commence in an awake,
review of 18 patients with SIJ pain (confirmed by two or more verbally responsive patient. Sensory testing at 50 Hz should produce
sensation in the affected region. Motor testing at 2 Hz should pro- subgroup that had chronic headaches. Mean time to follow-up
vide no movement in the muscles of mastication at 0.6 to 1 V. The was 29 and 24 months, respectively.
lesion is performed three times, for 60 seconds, at 658C, 708C, and
728C to 75

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1600 John F.

CURRENT THERAPY IN PAIN ISBN: 978-1-4160-4836-7

Copyright ! 2009 by Saunders, an imprint of Elsevier Inc.

Library of Congress Cataloging-in-Publication Data

Current therapy in pain / [edited by] Howard S. Smith. – 1st ed.

Executive Publisher: Natasha Andjelkovic

Printed in United States of America

Allen L. Carl, MD Daniel Clayton, MD, PhD Andrew Dubin, MD, MS

Richard Field, MD Greg Hobelmann, MD Clete A. Kushida, MD, PhD, RPSGT

John D. Markman, MD Mila Mogilevsky, DO, PT Ike Onyedika, BS

Eric M. Pearlman, MD, PhD Scott S. Reuben, MD ThomasT. Simopoulos, MD

Steven Stanos, DO Chris Warfield, BA James P.Wymer, MD, PhD

Chapter 1 These disputes form an interesting adjunct to classification and

Box 11 IDEAL CLASSIFICATION Box 13 MEDICAL CLASSIFICATION

Box 12 TYPES OF CLASSIFICATION

Rather, it is necessary to have a structured method of characterizing

Chapter 2 severe tissue damage, chronic and/or neuropathic pain is persistent

Rather, it is necessary to have a structured method of characterizing

Chapter 2 severe tissue damage, chronic and/or neuropathic pain is persistent

Table 22. Spinocerebral Ascending Pathways

should be noted that other types of receptors (e.g., metabotropic

Chapter 3 discovered therein have clinical relevance (with exceptions).57

An abundance of reliable and valid instruments are available to

II ASSESSMENT OF PAIN AND ITS TREAT MENT

Chapter 5 an episode of critical illness who are unable to communicate

Chapter 5 an episode of critical illness who are unable to communicate

in older cancer patients,26 and approximately 22% in nursing home

CHALLENGE OF DELIRIUM FOR PAIN

Delirium Subtype Behavioral Symptoms Behavior Examples

Is pain behavior present

Search for pathology and treat

Maintain vigilance: monitor symptoms and response to therapy.

No Do pain Yes Are basic

Provide for Do pain No Figure 5^1. Pain assessment in elders

Issue Key Considerations

Tool Name Items/Scoring Range Reliability Validity Feasibility/Utility Summary

II ASSESSMENT OF PAIN AND ITS TREAT MENT

Tool Name Items/Scoring Range Reliability Validity Feasibility/Utility Summary

II ASSESSMENT OF PAIN AND ITS TREAT MENT

Table 6^1. Comparison of Items within Five Neuropathic ScreeningTools*

LANSS{ DN4{ NPQ painDETECT ID Pain

INTERVIEW OF THE PATIENT

Question 3: Is the pain located in an area where the physical

Table 6^2. ID Pain Questionnaire Neuropathic pain

by trained pain specialists, starting with a complete and thorough

mechanical and thermal hyperalgesia/allodynia as well as a

detailed, more traditional neurologic examination. The combina-

will allow the examiner at the conclusion to be able to accurately

whether various agents (e.g., capsaicin) exacerbate, alleviate, or do

not affect preexisting spontaneous pain, and analysis of skin punch

biopsies. In addition, the future information from PET imaging or

Table 6^4. Provisional Clinical Trial Outcome Measures

Outcome Domain and Measure Type of Improvement* Method{ Change

Box 6^2 STEPWISE PHARMACOLOGIC MANAGEMENT OF NEUROPATHIC PAIN

fMRI BRAIN IMAGING IN EXPERIMENTAL

NEUROPATHIC PAIN SYMPTOMS

Non nociceptive Nociceptive

CONTINUOUS PAROXYSMAL ALLODYNIA HYPERALGESIA

Ins*** S 2*** vStr*

CRPS I (formerly known as sympathetic reflex dystrophy) is char-

Chapter 8 There is a burgeoning interest in the development of tools that

Chapter 8 There is a burgeoning interest in the development of tools that

ASSESSING OPIOID THERAPYADVERSE

Box 11 IDEAL CLASSIFICATION Box 13 MEDICAL CLASSIFICATION

Box 12 TYPES OF CLASSIFICATION

Table 22. Spinocerebral Ascending Pathways

Chapter 3 discovered therein have clinical relevance (with exceptions).57

Ins* S 2* vStr*

Appendix 82 any improvements in your socializing, recreational activities,

114 Chapter 16 HEADACHES OTHER THAN MIGR AINE