Supported by an unrestricted educational grant

from Endo Pharmaceuticals.

Opioid Analgesics for Pain Management:

Critical Thinking to Balance Benefits & Risk

Release date: June 2007

Expiration date: June 2009
Target audience: Primary care physicians
This program is sponsored by the University of Nebraska
Medical Center, Center for Continuing Education.
Faculty
Bill H. McCarberg, MD (Chair) Perry G. Fine, MD Steven D. Passik, PhD
Kaiser Permanente University of Utah Memorial Sloan-Kettering Cancer Center
Escondido, CA Salt Lake City, UT New York, NY
Gavril Pasternak, MD, PhD Raymond S. Sinatra, MD, PhD
Memorial Sloan-Kettering Cancer Center Yale University School of Medicine
New York, NY New Haven, CT

Accreditation
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for
Continuing Medical Education through the joint sponsorship of the University of Nebraska Medical Center, Center for Continuing Education
and PharmaCom Group.
The University of Nebraska Medical Center, Center for Continuing Education is accredited by the Accreditation Council for Continuing Medical
Education to provide continuing medical education for physicians.
The University of Nebraska Medical Center, Center for Continuing Education designates this educational activity for a maximum of 1.5 AMA
PRA Category 1 CreditsTM. Each physician should only claim credit commensurate with the extent of their participation in the activity.
Estimated time to complete this activity: 1.5 hours.
To complete the posttest and evaluation, visit www.unmc.edu/dept/cce/opioid_criticalthinking.htm (see page 12).
Please call 402.559.4152 or toll-free 877.832.6924 with any questions.

Disclosures
Dr Fine is on the Advisory Board for Cephalon, Endo Pharmaceuticals, Lilly, and Merck; and is a Speaker for Cephalon.
Dr McCarberg is on the Speakers Bureau for Endo Pharmaceuticals, Forest, Lilly, Merck, Pfizer, PriCara, and Purdue Pharma L.P.
Dr Passik is a Consultant for Alpharma, Cephalon, Endo Pharmaceuticals, and Ligand/King; receives Grants from Cephalon and Lilly;
and is on the Speakers Bureau for Cephalon and Ligand/King.
Dr Sinatra is a Consultant for Endo Pharmaceuticals, Upjohn-McNeil, and Merck and Company.
Dr Pasternak is on the Advisory Board and Speakers Bureau for Adolor Corporation, Cephalon, Endo Pharmaceuticals, EpiCept, J&J, Limerick
Neurosciences, Ortho-McNeil, and Sarentis.

Learning Objectives
At the conclusion of this activity, the participant will be able to:
1. Discuss factors affecting the selection of an opioid analgesic for individual patients.
2. Select appropriate patients for long-term opioid therapy.
3. Differentiate aberrant drug-related behaviors.

Practice Recommendations
Recommendations Evidence Source

Self-report should be the primary source of pain assessment when B. There is evidence of types II, III, or IV, and www.guideline.gov/s
possible.(B) findings are generally consistent. ummary/summary.as
px?doc_id=3691

Opioid analgesic drugs may help relieve moderate to severe pain, Level I: Evidence from at least one properly www.guideline.gov/s
especially nociceptive pain. Opioids for episodic (noncontinuous) pain randomized, controlled trial. ummary/summary.as
should be prescribed as needed, rather than around the clock. Long-acting A. Good evidence to support the use of a px?doc_id=3365
or sustained-release analgesic preparations should be used for continuous recommendation; clinicians should do this all the
pain. Breakthrough pain should be identified and treated by the use of time.
fast-onset, short-acting preparations.(IA)

Patients taking analgesic medications should be monitored closely. Level I: Evidence from at least one properly www.guideline.gov/s
Patients should be reevaluated frequently for drug efficacy and side randomized, controlled trial. ummary/summary.as
effects during initiation, titration, or any change in dose of analgesic A. Good evidence to support the use of a recom- px?doc_id=3365
medications.(IA) mendation; clinicians should do this all the time.

The clinician should watch for signs of opioid use for inappropriate Level III: Evidence from respected authorities, based www.guideline.gov/s
indications (eg, anxiety, depression, grief, loss). Requests for early refills on clinical experience, descriptive studies, or reports ummary/summary.as
should include evaluation of tolerance, progressive disease, inappropriate of expert committees. px?doc_id=3365
behavior, or drug diversion by others.(IIIA) A. Good evidence to support the use of a recom-
mendation; clinicians should do this all the time.

Constipation and opioid-related gastrointestinal symptoms should be Level I: Evidence from at least one properly www.guideline.gov/s
prevented. Assessment of bowel function should be part of the initial randomized, controlled trial. ummary/summary.as
assessment and of every follow-up visit for all patients receiving A. Good evidence to support the use of a px?doc_id=3365
analgesics. A prophylactic bowel regimen should be initiated with the recommendation; clinicians should do this all the
commencement of persistent opioid therapy.(IA) time.

Fixed-dose combinations of opioid with acetaminophen or NSAIDs may Level I: Evidence from at least one properly www.guideline.gov/s
be useful for mild to moderate pain. The maximum recommended dose randomized, controlled trial. ummary/summary.as
should not be exceeded, to minimize acetaminophen or NSAID toxicity. If A. Good evidence to support the use of a px?doc_id=3365
a maximum safe (nontoxic) dose is reached without sufficient pain relief recommendation; clinicians should do this all the
because of limits imposed by the maximum safe acetaminophen or NSAID time.
dose, switching to noncombination preparations is recommended.(IA)
 C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K 1

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Principles of Prescribing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Opioid Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Multiple Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Short-Acting Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Long-Acting Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Managing Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Incomplete Cross-Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Patient Selection for Long-Term Opioid Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Assessing Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Assessing Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Individualized Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Periodic Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Differentiating Aberrant Drug-Related Behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
Changing Course: Discontinuing Opioid Therapy (Exit Strategy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
The Case of Mr K: A 25-Year-Old Man With Acute Ankle Sprain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
The Case of Mrs T: A 60-Year-Old Woman With Osteoarthritis of the Knees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
The Case of Mrs J: An 82-Year-Old Woman With Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
The Case of Mr A: A 45-Year-Old Man With Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12

Introduction Principles of Prescribing

Chronic pain in America remains a prevalent, challenging, and
expensive problem.1 A recent national telephone survey found
that more than half of Americans live with chronic or recurrent
pain.2 However, while 63% of Americans report having sought
medical help for pain, fewer than half report that they have a
lot of control over their pain, and fewer than one third had
complete or a great deal of pain relief.2;3 The impact of pain is
substantial, with 4 in 10 Americans reporting that pain
interferes with their enjoyment of life, mood, sleep, and
activities.2 In addition to affecting quality of life (QOL), pain also
interferes with ability to work. The American Productivity Audit
of more than 28,000 US workers found that lost productive
time resulting from pain conditions costs employers $61.2
billion each year.4
Opioid Analgesics
When opioids are indicated for pain conditions not effectively
managed by nonopioids, selecting an agent requires due
consideration of a number of factors. The selection is based on
the severity and pattern of pain; the patients age, medical
comorbidities, and prior opioid exposure and experience
(including efficacy and adverse effects); drug-specific
differences; available formulations; cost; and personal
experience.6 The availability of long-acting opioids has increased
focus on the role of dosing intervals as a consideration in opioid
therapy.7 Most short-acting opioids require a dosing interval of
4 to 6 hours; however, these may be favored initially because
they are easier to titrate than long-acting opioids.

It is not surprising that pain is among the most common
reasons for office visits, and that nonsteroidal anti-inflammatory
drugs (NSAIDs), opioids, and nonopioid analgesics are among
the most frequently prescribed therapeutic classes.5 When
treating patients whose pain is not adequately managed with
nonopioids, it is important that primary care physicians (PCPs)
have sufficient knowledge of the pharmacology of opioids in
order to prescribe them in a fashion that maximizes benefits
and minimizes risk to patients.
Although there is no evidence for the efficacy of one mu-opioid
agonist over another in populations, individual patients may
display a much better response to one drug over another, which
is why consideration should be given to agents that the patient
has found helpful in the past. A number of explanations for this
interindividual response to opioids have been proposed.
Multiple Receptors
The 3 major opioid receptor families are mu, kappa, and delta.8
The primary site of action of most clinically used opioid
2 O P I O I D A N A L G E S I C S F O R PA I N M A N A G E M E N T
analgesics is the mu-opioid receptor,9;10 which is expressed at a
spinal level in the dorsal horn and in multiple regions within
the brain.10 The interindividual variability in response to mu-
opioid analgesics can be explained in part by multiple mu-
opioid receptorssplice variantswith different mechanisms
of action and different distributions within a cell, regionally
within the nervous system (brain and spinal cord), and in the
peripheral nervous system.8;9;11
Pharmacogenetics
The observed interindividual variability in response to opioids
may be due in part to genetic polymorphisms.10 Studies have
identified significant differences in the genotype of patients who
required switching to alternative opioids compared with patients
who responded to morphine.10 Response to an opioid depends
on a number of factors, including drug absorption, distribution,
metabolism, and elimination.10 Therefore a patients response to
a particular opioid is potentially influenced by genetic variation in
the alleles of several candidate genes.10;12 An example is the
variable response to codeine in individuals with a polymorphism
of the cytochrome P450 (CYP450) 2D6 gene, which prevents
metabolism of the prodrug codeine to the active drug
morphine.7;10 Up to 10% of people will have a poor analgesic
response to codeine because they lack normal CYP2D6
activity.13 Morphine, although active alone, is also metabolized
to a very active metabolite, morphine-6-glucuronide (MG6),
chiefly through conjugation by uridine diphosphate glucuronyl
transferase (UGT) enzymes.13;14 It has not yet been determined
if polymorphisms in genes controlling the metabolism of
morphine explain interindividual variability in response to
morphine, but this may be related to patient characteristics
such as age and renal and hepatic function.10;15;16 In many
patients with renal failure, accumulation of the pharmacologically
active morphine metabolite MG6 may cause toxicity.15;17
Drug Interactions
Most opioids are metabolized through the liver microsomal
CYP450 system, which is responsible for the metabolism of a
wide variety of drugs.7 Codeine, hydrocodone, methadone,
oxycodone, and tramadol are chiefly metabolized through
oxidative reactions by CYP2D6, while fentanyl, meperidine,
and buprenorphine are metabolized by CYP3A4.7 Concomitant
treatment with drugs that inhibit or induce CYP450 enzymes
can alter the levels of these opioids and their metabolites;
this may change their analgesic or side-effect profile and
cause possible opioid overdose or acute withdrawal.7;13;14
Morphine, hydromorphone, and oxymorphone are metabolized
chiefly through conjugation reactions with UGT enzymes.13;14
Because they are not oxidatively metabolized by CYP450
enzymes, inhibition/induction or genetic polymorphisms of
CYP450 enzymes should have little to no effect on the
metabolism and clearance of these drugs.14
Short-Acting Opioids
Short-acting opioids are available as single-entity agents or in
combination with a nonopioid with a complementary
mechanism of action (NSAIDs or acetaminophen). If pain is
present for only a few brief periods during the day, patients
may take an as-needed dose of a short-acting mu opioid.18 For
persistent pain, a long-acting agent is recommended to control
baseline pain around the clock and avoid breakthrough pain
(BTP). But in most cases, a short-acting opioid is used to
initiate and titrate around-the-clock therapy and, if necessary,
as-needed dosing can be added to regular dosing in order to
control or avoid BTP.
When initiating an opioid trial in an opioid-nave patient, the
dose should be individualized to the patient by starting at the
lowest likely effective dose, which should be increased
incrementally, with both the size of the increment and the
interval between increments influenced by the degree of pain
relief, functional improvements, and side effects experienced
by the patient.7;11;18 Starting doses for common oral short-acting
opioids to treat moderate to severe pain in opioid-nave adults
are shown in TABLE 1.6 A dose increment of 30% to 50% is
safe and usually large enough to observe a meaningful
change in analgesia.7 If pain is severe and the patient is not
predisposed to opioid toxicity, a higher incrementup to
100% of the existing dosemay be considered.7 In
ambulatory care, an additional consideration with regard to
dose titration is the availability of an individual at home with
the patient who is a reliable observer for potential adverse
effects. An alternative approach in patients who receive
additional as-needed opioids for BTP is to sum the amount of
supplemental drug used per day during the previous few days
and convert it into the fixed-schedule administration.7
There is no predictable maximal therapeutic dose (ceiling
effect) for analgesia with single-entity opioid agonists, but
dose-limiting adverse effects can occur.11;18 In contrast, the
doses of opioids marketed in combination with a nonopioid
are limited by the maximum dose of the nonopioid (eg,
acetaminophen dose limit: 4 g per day in patients without
compromised liver function or without a history of alcoholism).18
If significant adverse events occur before adequate analgesia
is achieved, the dose may be reduced and the events should
be treated. After a stable dose is achieved with a short-acting
opioid, it may be converted to a long-acting opioid, for example,
if there is a desire for a simplified regimen to optimize
adherence, among other possible reasons.
Long-Acting Opioids
Long-acting opioids administered around the clock to treat
persistent baseline pain can be given along with additional as-
needed doses of short-acting opioids for exacerbations of pain
(ie, BTP), to permit activity such as physical therapy, and for
TA B L E 1 Commonly Used Oral Short-Acting Opioids
Starting oral dose* in opioid-nave
Name adults with moderate to severe pain
lower range: higher range:
unmonitored outpatients monitored setting
Codeine 30-60 mg q3-4h
Hydrocodone 5-10 mg q3-4h
Hydromorphone 4-8 mg q3-4h
Morphine 15-30 mg q3-4h
Oxycodone 10-30 mg q4h
Oxymorphone 10-20 mg q4-6h
Tramadol 50-100 mg q6h
*Reduce initial dose by up to 50% in frail, older patients and titrate upward based
on therapeutic response and undesirable side effects; If deemed necessary to
initiate therapy at a lower dose, patients may be started with 5 mg oxymorphone.
Adapted from: American Pain Society. Guideline for the Management of Cancer
Pain in Adults and Children. Clinical Practice Guideline No. 3. Glenview, IL:
American Pain Society; 2005.
 C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K 3

incident pain.11;18;19 Although many PCPs have not adopted the
practice of using long-acting opioids for indications other than
cancer pain, there are significant benefits from using these agents
for long-term pain, including improved control of baseline pain
and the need for smaller quantities of pills. The most commonly
used long-acting opioids are sustained-release (SR) preparations
of short-acting opioids. Some SR opioids can be initiated in opioid-
nave patients, although not all have been systematically evaluated
as an initial agent, and most experts would recommend starting
a short-acting agent before using a long-acting agent (TABLE 2).
Once initiated, the long-acting opioid dose can also be titrated
by incorporating the as-needed short-acting doses into the daily
long-acting dose. Patients should be advised to swallow SR oral
opioid formulations whole, and not to break, crush, or chew
tablets in order to prevent the rapid release of potentially
dangerous opioid levels (refer to prescribing information for
individual agents). Some formulations also have warnings
regarding use with alcohol that can cause dumping of the
opioid content all at once, rather than in a sustained fashion.
Managing Adverse Effects
Treatment of opioid-induced side effects is integral to opioid pain
management. A number of adverse effects are associated with
the use of opioid analgesics. The most common are opioid-
induced bowel dysfunction (constipation), sedation, nausea and
vomiting, pruritus, sweating, dry mouth, and weakness.11;18;20;21
Other adverse effects include respiratory depression, urinary
retention, confusion, hallucinations, nightmares, myoclonus,
dizziness, dysphoria, and the very rare hypersensitivity reaction
of anaphylaxis. With the exception of bowel dysfunction,
tolerance often develops rapidly to some of the common opioid-
related side effects, such as nausea and vomiting. Therefore,
routine prophylactic administration of an antiemetic agent is not
typically indicated, except in patients with a history of severe
opioid-induced nausea.7;11;19 Opioid-induced bowel dysfunction
should be anticipated and treated prophylactically with a
stimulating laxative to increase bowel motility, with or without
stool softeners as indicated by stool consistency.11;18;19
Nonpharmacologic approaches for all patients include:7
Increase fluid intake as tolerated.
Increase dietary fiber as tolerated (unless patient is severely
debilitated or bowel obstruction is suspected).
Encourage mobility and ambulation if appropriate.
Ensure comfort and privacy for defecation.
Encourage bowel movements at the same time each day.
Rule out or treat impaction.
TABLE 3 shows examples of the pharmacologic management
of common opioid-induced adverse effects.7 In some patients
who poorly tolerate one opioid, it may be necessary to change
to a different opioid.18
Incomplete Cross-Tolerance
Patients often exhibit limited cross-tolerance when one opioid
is substituted for another, which might reflect their differing
selectivities for the mu-opioid receptor subtypes (mu-opioid
receptor splice variants).22;23 Clinicians have long made use of
the incomplete cross-tolerance among mu-opioid analgesics by
using the concept of opioid rotation, in which highly tolerant
patients are rotated to a different drug to regain analgesic
sensitivity.8;22 Incomplete cross-tolerance among opioids affects
the conversion from one opioid to another.9 When switching
between opioids in an opioid-tolerant patient, it is recommended
to calculate the equianalgesic dose based on the predicted

TA B L E 2 Long-Acting Opioids

Opioid Administration Starting dose* in opioid-nave patients Notes

Fentanyl
Duragesic q72h For use only in opioid-tolerant patients
Methadone: Use not recommended without significant expertise. Repeated administration at short intervals may lead to
accumulation in plasma and delayed adverse effects because the prolonged half-life is greater than the duration of analgesia.
Morphine
Avinza q24h 30 mg q24h; adjust in increments not 60, 90, and 120 mg capsules are
greater than 30 mg every 4 days for use only in opioid-tolerant patients
Kadian q12 or q24h No systematic evaluation Patients who do not have a proven tolerance
to opioids should initially receive only the
20 mg strength, and the dosage usually
should be increased at a rate not greater
than 20 mg q48h
MS Contin q12h No systematic evaluation 200 mg tablets for use only in
opioid-tolerant patients
Oramorph SR q12h No systematic evaluation
Oxycodone
OxyContin q12h 10 mg q12h; except for the increase from 80 and 160 mg tablets for use only
10 mg to 20 mg q12h, the total daily in opioid-tolerant patients
oxycodone dose usually can be increased
by 25% to 50% of the current dose at
each increase
Oxymorphone
Opana ER q12h 5 mg q12h; it is recommended that the
dose be individually titrated, preferably at
increments of 5-10 mg q12h every 3-7 days

*Individualize dose for each patient; Not approved for initiation of therapyadvisable to begin treatment with immediate-release opioid.
4 O P I O I D A N A L G E S I C S F O R PA I N M A N A G E M E N T
equivalent dose in conversion tables, which were determined
by relative potency studies in opioid-nave patients, and then cut
the calculated dose by at least 50% in order to account for
incomplete cross-tolerance.9;22 Using this method, shortfalls in
efficacy for the sake of safety can be compensated for in the
short term by using immediate-release (IR) opioid (rescue)
doses, with corrections in around-the-clock dosing determined
after steady state is achieved with the new drug, which requires
3- to 5-times the half-life of the drug.
Patient Selection for Long-Term Opioid Therapy
Most patients with pain do not need opioids, but such therapy
may be required to effectively control moderate to severe
pain.24;25 However, recent reports suggest that certain
populations receiving long-term opioid therapy are particularly
at risk for poor outcomes.26;27 It is certainly true that poor
patient selection for opioid therapy, opioid monotherapy in the
absence of comprehensive management, and inadequate
follow-up of patients can be detrimental to patients. At the
same time, most PCPs have some experience of treating
patients for whom opioid therapy is appropriate and effective,
with good long-term outcomes. Because the potential long-
term benefits of chronic opioid therapy can be contentious,
careful patient selection, comprehensive management, and
appropriate follow-up are crucial.
Opioids alone are not the optimal therapy, but when used in
conjunction with nonopioid analgesics, such as an NSAID or
adjuvant, and psychologic and physical approaches, they can
help to maximize patient outcomes.18;28 For certain populations,
such as chronic low back pain and headache patients, and
those with a personal or family history of substance abuse,
some PCPs may decline to prescribe opioids or defer initiating
TA B L E 3 Pharmacologic Interventions for Opioid Adverse Effects
Adverse effects
Opioid-induced bowel dysfunction*
Intermittent use (q2-3d) of osmotic laxative
Trial of daily softening agent alone
Intermittent use (q2-3d) of contact cathartic
Daily use of cathartic preparation ( softening agent)
Daily use of lactulose or sorbital
Daily use of polyethylene glycol
Nausea and vomiting
Neuroleptics
Anticholinergic drugs
Antihistamines
Prokinetic drugs
Corticosteroids
Benzodiazepines
Cannabinoids
5-HT3 receptor antagonists
Somnolence and cognitive impairment
Psychostimulants
Myoclonus
Low-dose benzodiazepines
Anticonvulsants
Baclofen
Pruritus
Antihistamines
Sedative hypnotics
Selective serotonin reuptake inhibitors
*Adjust dose and dosing schedule of selected therapy to optimize effects. Switch or combine conventional approaches if initial therapy is inadequate;
Decrease opioid dose. Adapted from: Fine PG, Portenoy RK. A clinical guide to opioid analgesia. McGraw-Hill, 2004.
opioid therapy until specialist evaluation and support is
obtained. When opioid treatment is warranted, a treatment plan
should state objectives that will be used to determine
treatment success, such as pain relief, improved physical and
psychosocial function, manageable side effects, and drug-taking
that follows the rules of appropriate behavior.
Assessing Pain
Selecting patients for long-term opioid analgesic therapy
requires a comprehensive assessment of pain, including
obtaining, evaluating, and documenting a thorough medical
history and physical examination, as well as patient and disease
characteristics.7;25;29 Because pain is inherently subjective, patient
self-report is the gold standard for assessment.7 Pain
assessment should focus on the type and quality of pain,
source, intensity, location, duration/time course, associated
factors that exacerbate or relieve pain, pain affect, and effects on
lifestyle and functional status.7;29 Numerous tools are available to
measure pain intensity, such as the numerical rating scale, the
verbal rating scale, visual analog scales, and the faces of pain
scale.29 These tools are simple to use and sensitive enough to
detect changes that occur during pain treatment.
As well as the nociceptive input, pain can also be composed of
psychologic and emotional overlays, such as anxiety, depression,
and fear. Analgesics such as opioids, however, are only effective
in reducing pain intensity, and will not address other aspects of
patients pain experiences. If the PCP suspects these conditions
are present, it is important to assess and address these domains
at the same time as the nociceptive pain. This may be necessary
at the initial visit, or there may be no indications of a problem
until a subsequent visit or, for example, after an early refill
request. Several short, accurate, and easy-to-use instruments to
detect depression are available (eg, Beck Depression Inventory,
Examples of pharmacologic interventions
Magnesium hydroxide, magnesium citrate, sodium phosphate
Sodium docusate
Senna, bisacodyl
Senna, bisacodyl
Prochlorperazine, chlorpromazine, haloperidol
Scopolamine
Promethazine, meclizine, diphenhydramine, dimenhydrinate,
hydroxyzine, trimethobenzamide
Metoclopramide
Dexamethasone
Lorazepam
Dronabinol
Ondansetron, granisetron, dolasetron
Methylphenidate, dextroamphetamine, modafinil
Clonazepam
Diphenhydramine, hydroxyzine
Lorazepam
Paroxetine

Zung Self-Depression Scale).30 Brief instruments, including
asking the patient 2 questions about the presence of depressed
mood and anhedonia (Over the past 2 weeks, have you felt
down, depressed, or hopeless? and Over the past 2 weeks,
have you felt little interest or pleasure in doing things?), appear
to perform as well as longer instruments.30
Information about medical and surgical conditions, history of
chronic pain, and previous pain treatments is also important.7
Identifying the etiology, syndrome, or pathophysiology of
pain can help guide the selection of treatment and suggest
the prognosis.7
Assessing Risk
The potential for misuse, abuse, and addiction should be
addressed when considering long-term opioid analgesic
treatment. Assessing risk is not intended to deny high-risk
patients treatment for their pain, but rather to match the
degree of clinical monitoring and controls to the degree of risk
in order to achieve better clinical outcomes and minimize
misuse. There are many ways to assess risk, including a
psychiatric interview and the use of one or more of an
increasing number of screening tools (eg, Opioid Risk Tool
[ORT], Screener and Opioid Assessment for Patients with Pain
[SOAPP], DIRE score).31-33 Such tools should be used by
clinicians, for example, when considering initiating opioid
analgesic therapy for a chronic pain problem or for a patient
being treated with opioids for an acute pain problem that is
becoming chronic and long-term opioid therapy is an option.
A patient who displays an aberrant drug-related behavior that
raises concern (eg, requests an early opioid refill) or does not
seem to be doing well requires attention, such as asking him
or her to come in to complete a screening tool for addiction,
social problems, or other psychologic distress, rather than
automatically writing a refill.
Informed Consent
It is an ethical and often regulatory duty to describe in under-
standable terms the risks and benefits of the use of long-term
opioid analgesic therapy with the patient or persons designated
by the patient.25 The physician can consider the use of a written
agreement outlining the treatment plan, expectations, and the
responsibilities of the patient and physician.25;34 Although
physicians often feel uncomfortable asking patients to sign an
agreement, a signed plan of care is particularly important if the
patient is at high risk for medication abuse, and may be required
in some states.25;34 It is also important to outline the procedures
or actions that will be taken should problems arise and the
patient does not adhere to the terms of the agreement.34 A
sample opioid treatment agreement is available at the
American Academy of Pain Medicine Website: www.painmed.
org/productpub/statements/pdfs/controlled_substances_sample
_agrmt.pdf. Clinicians should take care to follow the
guidelines in the written agreements that they utilize or they
risk exposing themselves to potential liability.34 They should
adapt an agreement so that the language provides flexibility
for them to make clinical decisions when managing patients
(eg,Early refills will generally not be given).
Individualized Therapy
Clinical treatment of pain with opioids requires individualization
of therapy, due to variability in efficacy, side effects, tolerance
profiles, and risk of drug abuse among patients.8;9;12;35 Some
patients may respond far better to one mu opioid than to
C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K 5
another with respect to both analgesia and side effects.8;9;15
For example, patients unable to tolerate morphine due to
severe nausea/vomiting may be able to take another mu
agonist without a problem.8;10 Patients also vary in their sensitivity
to a specific opioid, with some needing higher or lower doses
to achieve optimal analgesia.9 At present, it cannot be
predicted which patients are likely to achieve adequate
analgesia or develop intolerable adverse effects from a given
opioid, and in clinical practice, therapy often needs to be
switched from one opioid to another to identify the most
effective.9;10 The availability of a wide variety of opioids allows
clinicians to better match the drug to the patient.35 Increased
options become available when novel opioid analgesic
molecules are developed and when existing drugs are
reformulated into different delivery systems (eg, transdermal
delivery system, SR oral tablet) or have a different mode of
administration (eg, patient-controlled analgesia, computer-
assisted delivery).35
Periodic Review
Patients should be monitored regularly to assess their response
to therapy, to identify and manage side effects, and to identify
and manage aberrant drug-related behavior. The frequency of
follow-up should be as often as clinically necessary and in
compliance with state regulations, where present. Continuation
or modification of controlled substances for pain management
therapy depends on the evaluation of progress toward
treatment objectives. The Four As of pain medicine will help
to direct therapy and support the pharmacologic options taken
(TA B L E 4 ).36;37 The Four As serve as a mnemonic device to
remind clinicians that a successful outcome in pain therapy
involves more than lowering pain scores. Equally important
outcomes include stabilization or improvement in psychosocial
functioning and sleep, tolerable side effects, optimization of
physical functioning, and absence of aberrant behaviors.38
Urine drug testing can be an important tool to assist in
monitoring adherence to a treatment plan when managing
patients receiving opioid therapy.39;40 Controversies exist
regarding their clinical value, partly because many current
methods are designed for, or adapted from, forensic or work-
place deterrent-based testing for illicit drug use.40;41 As a result,
they are not necessarily optimized for clinical applications where
a number of licit prescription drugs must also be included.40
However, when used with an appropriate level of understanding,
urine drug testing can improve a physicians ability to manage
therapy with opioids and identify substance misuse.39;40
As more PCPs prescribe opioid analgesics for the management
of chronic moderate to severe pain, the questions of how to
monitor adherence to the therapeutic regimen and when to
refer a patient for additional evaluation and treatment in order to
achieve treatment objectives have become important issues.25;42
TA B L E 4 The Four As of Pain Medicine36;37
Analgesia (meaningful pain relief)
Activities of daily living (stabilization & improvement in psychosocial
function & specifically identified functional [physical activity] goals)
Adverse effects (side effects)
Aberrant drug-related behaviors (adherence to plan of care &
addiction-related outcomes)
6 O P I O I D A N A L G E S I C S F O R PA I N M A N A G E M E N T

In general, referral to a pain specialist or pain center is
appropriate when the clinician has exceeded his or her
expertise in any specific area of opioid-related pain
management. Reasons may include the dose of opioids
prescribed, the patients inability to adhere to the prescribed
regimen, an inability to achieve adequate pain control despite
increasing the dose or switching to different opioids,
unresolved troublesome side effects, or unresolved issues of
substance misuse.42 Special attention should be given to
patients who are at high risk for medication misuse, abuse,
or diversion, and especially those with a known history of
drug addiction.
Differentiating Aberrant Drug-Related Behaviors
No behavior is absolutely predictive of addictive disease, and
these behaviors exist along a continuum, with certain behaviors
being less problematic and others being more so (TABLE 5).43
There are multiple explanations in the differential diagnosis of
aberrant drug-related behaviors, with criminal intent and
diversion being only one possibility.38;44 Other explanations for
nonadherent behavior include untreated pain, psychologic
distress, and addiction.45 It is important that clinicians can
distinguish between physical dependence, addiction, and
tolerance (TABLE 6), so that they do not incorrectly assume
that a patient is addicted.
Aberrant behaviors are not to be ignored, but do not mean
that prescribing should be immediately discontinued.
Clinicians should proceed with caution, set limits, be
thoughtful, and react therapeutically.45 The syndrome of drug-
seeking behaviors that arises when a patient cannot obtain
adequate relief with the prescribed dose of analgesic and
seeks alternate sources or increased doses of analgesic is
referred to as pseudoaddiction.43;46;47 This may be the result of
increasing pain due to disease progression, development of a
new condition, or inadequate instruction or dose provision by
the clinician.
Psychiatric factors, such as anxiety or depression, a
personality disorder, or changes in cognitive state, such as
mild encephalopathy due to the treatment regimen of medical
comorbidities or underlying psychiatric problems, may be
responsible for the behaviors identified.43;48 The pain patient
who escalates his or her opioid dose to self-medicate untreated
anxiety, depression, or insomnia bears resemblance to addiction
with regard to how the drug and drug procurement becomes
a central part of the patients life.38 Such patients who use
chemicals to cope with adverse life situations (also known as
chemical copers) need structure, psychiatric input, and drug
treatments that decentralize the pain medication to their
coping and prevent maladaptive opioid analgesic use.
Changing Course: Discontinuing Opioid Therapy
(Exit Strategy)
Long-term opioid therapy may need to be discontinued for a
number of reasons, including when opioids are no longer
effective for pain or to improve function, when unacceptable
side effects or toxicity occur, or when patients violate the
opioid treatment agreement or display certain aberrant drug-
related behaviors.50 When it is necessary to discontinue
treatment, withdrawal symptoms can usually be avoided by use
of a slow opioid tapering schedule (reducing the dose by 10%
to 20% each day or more slowly if symptoms occur).18 Anxiety,
tachycardia, sweating, and other autonomic symptoms that
persist may be lessened by slowing the taper or using clonidine
at an oral dose of 0.1 to 0.2 mg/day. The use of buprenorphine
for both pain and opioid dependence in the primary care office
is increasingly common, but requires certification under the
Drug Addiction Treatment Act of 2000.51

TA B L E 5 Examples of Aberrant Drug-Related Behaviors43

Less indicative of addiction More indicative of addiction

Drug hoarding during periods of reduced symptoms
Acquisition of similar drugs from other medical sources
Aggressive complaining about the need for higher doses
Unapproved use of the drug to treat another symptom
Unsanctioned dose escalation 1 or 2 times
Reporting psychic effects not intended by the clinician
Requesting specific drugs
Prescription forgery
Concurrent abuse of related illicit drugs
Recurrent prescription losses
Selling prescription drugs
Multiple unsanctioned dose escalations
Stealing or borrowing another patients drugs
Obtaining prescription drugs from nonmedical sources

TA B L E 6 Definitions of Addiction, Physical Dependence, Tolerance, and Pseudoaddiction47;49

Addiction: A primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development
and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use,
compulsive use, continued use despite harm, and craving.
Physical dependence: A state of adaptation that is manifested by a drug-class-specific withdrawal syndrome that can be produced by
abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.
Tolerance: A state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drugs
effects over time.
Pseudoaddiction: An iatrogenic syndrome of behaviors developing in direct consequence of inadequate pain management. The natural
history of pseudoaddiction is a progression through 3 characteristic phases including: (1) inadequate prescription of analgesics to meet
the primary pain stimulus; (2) escalation of analgesic demands by the patient associated with behavioral changes to convince others of
the pains severity; and (3) a crisis of mistrust between the patient and the health care team.
 C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K 7

Case Studies
The following case studies illustrate the application of the principles of prescribing opioids for pain management, ranging from a
simple acute case through to more complex patients with chronic pain and psychologic dysfunction. Although there is no question that
physicians should seek consultation when needed, such a requirement is not necessary for every case, especially if the practitioner is
knowledgeable about pain management.52 PCPs have varying levels of comfort, knowledge, and experience in the treatment of chronic
pain, which will affect the threshold for obtaining consultation or referral for each patient. Furthermore, the availability of pain specialists,
pain management programs, and addiction disease specialists varies widely depending on practice location and resources.

The Case of Mr K: A 25-Year-Old Man With Acute Ankle Sprain

Mr K, a 25-year-old male patient of yours for 6 years, presents in significant pain with a traumatic acute ankle sprain that occurred while
playing recreational tennis 2 days ago. Since the injury, he has been taking NSAIDs regularly, rested and kept the foot elevated when
possible, and used ice to reduce the swelling. He has missed 2 days of work as an architect and is anxious to return as soon as possible.
History
No prior history of ankle pain or any chronic musculoskeletal problems, apart
from a broken wrist several years ago.
He is otherwise healthy and is taking no medication other than the NSAID.

Physical Examination
Well-developed, thin male in apparent discomfort.
Localized pain that is increased upon ankle inversion.
Able to bear weight with attendant pain rated at 7-8/10.
Swelling is present.
You opt for a short course of a short-acting
Findings suggest a second-degree sprain.
(ie, IR) opioid to treat his moderate to severe
What Next? pain not controlled by the NSAID alone, so that
he can increase his activity and begin
Continue ice and elevation, but add gradual motion and motility with use of an
rehabilitation.53 Options include hydrocodone,
ankle support. Achilles tendon stretching should begin 48 to 72 hours after ankle oxycodone, and tramadol. Mr K related that
injury since tissues contract after trauma with immobility. hydrocodone relieved his pain following a wrist
Hydrocodone/acetaminophen 5 mg/500 mg 20 tablets, q4-6h. fracture several years ago.

Outcome:
Mr K presents at the follow-up visit in 2 weeks able to walk with care without
opioid analgesia, with only mild pain.
Two hydrocodone/acetaminophen 5 mg/500 mg tablets are left.
He has returned to his employment as an architect, with temporary
modifications to minimize his need to walk.
Advise him to continue a progressive physical therapy (PT) program, and caution
him that full strength may not return for a number of months.

The Case of Mrs T: A 60-Year-Old Woman With Osteoarthritis of the Knees

Mrs T is a 60-year-old woman with osteoarthritis (OA) who has been your patient for many years. She has progressively
increasing pain in her knees, rated at 7/10 with activity, for which she currently takes around-the-clock naproxen and
acetaminophen. She has been at the maximum acetaminophen and NSAID doses for 7 months, and although initially alleviating
her symptoms, this regimen no longer controls her pain with activity, and she feels restricted in what she is able to do.
Past Medical History
Mrs T had an acute myocardial infarction (MI) 2 years ago, following which she
experienced major depression, which was treated to remission with fluoxetine.
Hysterectomy 3 years ago.
A 5-year history of OA of the knee. You previously recommended weight reduction and
physical exercise, which she complied with (losing 5 Ibs), but she is finding it difficult to
complete her exercise regimen (45 minutes cardio and strength training, 4 times a week).
Knee injections by an orthopedic specialist provided only short-term relief.
No allergies.

Medication Use
Naproxen and acetaminophen.
Glucosamine sulfate and chondroitin sulfate supplements.
Timolol maleate 10 mg q12h.
ASA 81 mg + multivitamin q24h.

Family History
Her father died of an MI at age 63 years and her mother died of old age.
She has no siblings.
8 O P I O I D A N A L G E S I C S F O R PA I N M A N A G E M E N T

Psychosocial History
Mrs T works part-time (2 days per week) as a bookkeeper. Her husband is
retired, but their investment income is comfortable; they have comprehensive
medical insurance.
One son lives out of state.
She does not use alcohol.
She is unwilling to consider evaluation for joint replacement.

Physical Examination
Mrs T is a pleasantly interactive, slightly overweight female in no acute distress.
She is fully cooperative with the history and physical examination.
Pain with limited range of motion (ROM) in both knees.
What Next?
Discontinue naproxen.
Initiate IR tramadol at 25 mg/day qAM, titrate in 25 mg increments as separate
doses every 3 days to reach 100 mg/day (25 mg q6h), and increase by 50 mg
every 3 days to reach 200 mg/day (50 mg q6h).
One Week Later
Pain control is good, but to provide a more convenient regimen you switch Mrs T
to SR tramadol, 200 mg q24h.
Interim Phone Call
Pain control and function are good.
Mrs T is experiencing tremors and has become hypertensive.
Initiate SR oxymorphone 5 mg q12h, with instructions to increase the dose to
10 mg q12h after 3 days if pain is not adequately controlled.
Prescribe IR oxymorphone 5 mg to use as needed prior to exercising.
Ask her to call the office in 5 days to review her need for supplemental
oxymorphone.
Prescribe a stimulating laxative to prevent constipation.
Any continuous NSAID use poses some degree
of gastrointestinal (GI), cardiovascular, and renal
risks. Mrs T is an elderly woman with a personal
and family history of MI.
You ask her about her prior experience with
opioids for painmorphine prescribed for her
post-hysterectomy was not effective and caused
a great deal of nausea and vomiting for the 5 days
that she had taken it. You select tramadol to add
to her current acetaminophen regimen.
This patient is a good candidate for long-acting,
around-the-clock analgesia for chronic OA; options
include transdermal fentanyl and SR morphine,
oxycodone, oxymorphone, and tramadol. Because
IR tramadol is providing good pain relief, you
convert her regimen to ER tramadol.
Tremor and hypertension are common side
effects of tramadol. To avoid these side effects,
you switch to another SR opioid.

Interim Phone Call

Pain was well controlled with oxymorphone 10 mg q12hshe used 1 IR
oxymorphone 5 mg tablet about an hour prior to going to the gym 4 days a week,
and occasionally if her pain was exacerbated (2 to 3 times a week).
Bowel function is normal.

Two Months Later

Mrs T is doing well on her current regimen (SR oxymorphone 10 mg q12h with
IR oxymorphone 5 mg [30 tablets/month]). She is not experiencing adverse
effects and is able to work and to exercise.
Continue her regimen and schedule a follow-up appointment for 2 months.

The Case of Mrs J: An 82-Year-Old Woman With Osteoarthritis

Pain from OA has been present in Mrs Js hips, knees, ankles, and shoulders for more than 10 years, for which occasional use
of NSAIDs (ibuprofen, naproxen) had been sufficient. However, her pain intensity with activity is now 6/10, and she experiences
increasing dyspepsia with NSAID use.
This case represents shared decision-making
Past Medical History over a number of years with an elderly
Osteoporosis with degenerative disk disease (no vertebral fractures). patient who has progressive disease and her
Type 2 diabetes mellitus managed with diet alone. caregiver daughter.
Hysterectomy for fibroids.
Mild dementia from Alzheimers disease.

Medication Use
NSAIDs.
Glucosamine sulfate and chondroitin sulfate supplements.
Alendronate.
Donepezil 5 mg q24h.
ASA 81 mg + multivitamin q24h.

Family History
Both parents died of old age. Her mother was in considerable pain, all bent over
for many years. Her father used a cane and had trouble walking from arthritis.
 C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K 9

Her sister died of uterine cancer.

Her brother had coronary artery bypass graft surgery at age 57 years and died
of a cerebrovascular accident at age 68 years.
Psychosocial History
Mrs J graduated from teachers college and taught until motherhood.
Her husband died suddenly 8 years ago of an acute MI and she lives alone on a
fixed income from Supplemental Security Income (SSI) and her husbands annuity;
basic living expenses are covered, but not much is left over.
One daughter lives close by and is supportive, and 2 children live out of state.
Relies on Medicare supplemental insurance (co-pay: $25 for brand drugs, $10 for generics).
She does not use alcohol.
She has no living will or written advanced directives.
Review of Systems
Progressive short-term memory loss, occasional confusion, and increasing difficulty
with routine tasks.
No chest pain, dyspnea at rest, melena, or hemoptysis.
Sleep, mood, and bowel/bladder function unremarkable.

Physical Examination
Well groomed, in no obvious distress.
Alert and oriented to time, place, person, and objects, but unable to subtract Acetaminophen carries a lower risk of GI
serial 7s and could not recall 3 objects. complications than NSAIDs.54-56 It should be
No visual or hearing changes, normal gait and balance. considered early in the management of OA pain
No cardiac, peripheral vascular, or pulmonary problems. because of its safety profile at daily doses not
exceeding 4 g (avoid in patients with chronic
Kyphosis of the spine, but no localized tenderness or tender points. alcohol abuse and use with caution in patients
Limited ROM in the spine and joints, but no erythema or swelling. with liver disease). Recent data suggests elevated
alanine aminotransferase levels in healthy adults
Description of Pain
receiving 4 g daily, but the transient elevations
Dull and constant, with sharp exacerbations in the low back, knees, and hips with usually resolve with continued acetaminophen
walking, bending, or prolonged standing. treatment, and are not accompanied by signs of
No radicular complaints, burning, paresthesias, loss of grip strength, or loss of liver injury.57;58
bowel or bladder control. Findings are suggestive of nociceptive pain due to
moderate to advanced OA without a neuropathic component.
Consider a physical activity program for all older
What Next?
patients that includes exercises to reduce
Discontinue NSAIDs. stiffness and improve flexibility, ROM, strength,
Initiate acetaminophen 1 g q6h. and endurance.54
Recommend arthroswim through the Arthritis Foundation Aquatic Program.

Interim Phone Call

Chronic pain can have a tremendous psychologic
Pain is 1-2/10 at rest and tolerable (3-4/10) with activity.
impact and can lead to both physiologic and
Mrs J is reluctant to travel to her YMCA for arthroswim. Warm baths feel good emotional decline.
and help her sleep. You suggest that she exercise when pain and stiffness are
minimal (eg, after a warm bath or application of superficial moist heat).59
Two Months Later Select celecoxib because of a history of GI
intolerance with nonselective NSAIDs.
Pain has increased to 8/10 with activity and she has difficulty sleeping:
I cant get comfortable.
She is experiencing difficulties with self-care and mood disturbance:
Rather than increase the celecoxib dose to 200 mg
I dont care about anything anymore.
bid (because of GI, renal, and cardiovascular
Initiate 200 mg celecoxib q24h. risk), you select opioid therapy. Opioids are
Two Weeks Later recommended when moderate to severe OA pain
not controlled by other treatments affects the
Pain is improved, with no apparent adverse events, but still keeps her less active
patients QOL.29 You select single-entity tramadol,
than she would like. a weak mu-opioid agonist and inhibitor of
Her daughter reports that Mrs Js mood, sleep, energy, self-care, and general serotonin and norepinephrine reuptake, to add to
appearance seem better, but she cringes with activity and pain is intolerable her current acetaminophen as the combination
product is more expensive.18
when walking.
What Next?
Discontinue celecoxib and initiate tramadol 25 mg qAM, increased by 25 mg every
3 days to 100 mg/day (25 mg q6h) and by 50 mg every 3 days to 200 mg/day
(50 mg q6h).
Although more expensive, the long-acting agent
Convert IR tramadol to SR tramadol 200 mg q24h.
taken once daily will simplify dosing.
10 O P I O I D A N A L G E S I C S F O R PA I N M A N A G E M E N T
One Year Later
She is experiencing exacerbation and progression of her OA. Pain is minimal at
rest, but is real bad in the low back, hips, and lower extremities after walking
50 feet: My legs feel like rubberlike theyre someone elses.
Good tissue perfusion and pulses; no focal neurologic signs, atrophy, or
tender points.
She sleeps well, but feels stiff in the morning.
Exerts all her time and energy performing basic ADLs.
Blood pressure remains high normal.
She has developed neurogenic claudication secondary to probable spinal stenosis.
The daughter reports more confusion, occasional disorientation, and forgetfulness
about medicine. She is worried about Mrs Js ability to care for herself.
What Next?
Review goals of therapy with Mrs J and her daughter.
A series of epidural injections were not beneficial.
Discuss surgery, but the daughter wants to manage the patient medically.
Discontinue tramadol; initiate SR morphine 15 mg q12h.
Initiate a prophylactic bowel regimen with a senna stimulant and stool softener.54
Encourage adequate diet and fluid intake, regular toileting habits, and physical
activity.54 Advise her to avoid bulking agents, which should be used with caution
in patients who are immobile and with questionable hydration.54 Remind the
daughter to check on adherence to the bowel regimen.
Several Months Later
Incident pain is worsening and unremitting after any amount of standing or walking.
Pain in the low back is 5-6/10, nonradiating at rest but referred down her legs
with activity. Mrs J believes that morphine has stopped working and makes
her feel bad.
The daughter notices some twitching in her hands.
No problems with bowel/bladder function or changes in muscle strength.
Discontinue SR morphine, initiate SR oxycodone 20 mg q12h.
Oxycodone IR 5 mg prior to activities that incite breakthrough pain (BTP).
One Year Later
Mrs J did well for the first few months of SR opioid therapy with IR medications,
rating her pain as 3/10 on average, but has gradually required increased doses to
maintain pain control and function (currently SR oxycodone 20 mg q8h).
She is forgetting doses and the resulting pain interferes with self-care.
Her daughter worries that Mrs J will take too little oxycodone and suffer
or take too much and overdose.
Mrs J is losing memory and struggles with simple tasks. While there is
still cognitive capacity for decision-making, you discuss advance directives
and review goals of therapy, her living situation, and what to expect as
Alzheimers disease progresses. You emphasize the importance of
pain evaluation and control because of the adverse effects on
neuropsychologic and physical function.
Discontinue SR oxycodone and initiate transdermal fentanyl 25 g q72h.
After 3 weeks increase dose to a 50 g fentanyl patch (using 12 g
patches for dose titration).
Instruct the daughter to evaluate her mothers verbal and behavioral
responses to activity and supplement/pre-treat with oxycodone IR
as needed. She leaves one 10 mg oxycodone/325 mg acetaminophen
tablet available to her mother and checks on her throughout the day to
replace it, if necessary.
Long-Term Outcome
Several months later, Mrs J moves in with her daughter. Home hospice
care is initiated when she progresses to end-stage Alzheimers disease.
Pain control is maintained with transdermal fentanyl and oxycodone
solution for BTP for her remaining 2 weeks.
The daughter wonders whether the confusion is due
to progressing dementia or opioid-related toxicity.
However, while medications used to treat pain can
result in cognitive disruption, pain itself also affects
cognitive function.60,61 Older adults with pain often
demonstrate more neuropsychologic impairment and
physical disability compared with pain-free older
adults, but long-term opioid therapy has been shown
to improve neuropsychologic performance.61-65
Now that the pain is not responding to tramadol,
you suggest continuous opioid therapy with a full
mu agonist. Experience in chronic pain supports
the use of long-acting opioids for continuous pain
to improve patient adherence and minimize side
effects as well as drug level peaks and troughs.54,29
Drug co-pay is straining Mrs Js budget. Although
methadone costs less than other long-acting opioids,
it should be used with caution due to risk of drug
accumulation and adverse events prior to achieving
steady state. Long-acting opioid options are
morphine, oxycodone, oxymorphone, and fentanyl.
Both patient and daughter are reluctant to consider
narcotics. It is important to understand an older
persons attitude toward opioids, because this can
negatively impact adherence to therapy.60 Patients
and families should be asked about concerns and
educated to alleviate them. After counseling Mrs J
and her daughter regarding continuous opioid
therapy, they agree to a trial of SR morphine, with
a follow-up visit scheduled for 2 weeks later to
assess therapeutic and adverse effects.
Mrs J has likely become tolerant to morphine and/
or her disease is slowly progressing. You decide to
exploit the incomplete cross-tolerance among mu-
opioid analgesics by rotating to an alternative SR
opioid to regain analgesic sensitivity.8 You select SR
oxycodone, 20 mg q12h, from the available choices.
Add oxycodone IR 5 mg prior to activities that
predictably incite BTPtransitory exacerbations
of otherwise stable, persistent pain.60 BTP is well-
recognized in cancer, affecting 40% to 80% of
patients. It is less studied with various types of
chronic noncancer pain, and additional research is
needed to evaluate whether the clinical impact
and therapeutic challenges posed by BTP in this
heterogeneous population are comparable to the
cancer population.66 However, BTP is prevalent in
chronic pain patients and should be addressed as
it is shown to add to morbidity in cancer patients,
including decreased functioning and increased
anxiety and depression.60,66
Pain assessment of older persons can be
challenging given the multiple comorbidities that
are often present.60 In addition to the general
issues that affect the pain assessment of people
of any age, specific concerns are:60
Myths that pain is natural for older adults and
that pain perception will decrease with time,
and therefore no further therapy is indicated.
Exaggerated fears about the possibility of
addiction to opioids.
Increased stoicism prevents some older
patients from reporting pain.
Sensory and cognitive impairments with
progressive dementia.
Transdermal fentanyl simplifies the management
of Mrs J, who is forgetting to take medications.
 C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K
The Case of Mr A: A 45-Year-Old Man With Low Back Pain
Mr A is a 45-year-old male with pain in the low back radiating into the right buttock for many years. He is new to your practice
requesting a refill of hydrocodone/acetaminophen 5 mg/500 mg, which he began 7 months ago because he was experiencing
increasing dyspepsia with regular use of NSAIDs. His pain intensity with activity is 8/10, prohibiting him from working or
participating in other activities; he is able but sometimes unwilling to perform ADLs.
Oral Medical History
After a back injury at work 6 years ago, he went through extensive workup
including multiple courses of PT, physical medicine review, anesthetic procedures,
and acupuncture.
MRIs have shown 3 bulging discs and a narrow canal.
His medical history is otherwise remarkable only for hypertension.
He has tried codeine/acetaminophen 60 mg/300 mg q6h, several NSAIDs,
lidocaine patch 5%, gabapentin 600 mg q8h, and amitriptyline 25 mg qhs,
but claims they all stopped working or he was unable to tolerate them.
His current medication regimen is atenolol 50 mg q24h and hydrocodone/
acetaminophen 5 mg/500 mg 2 q6h.
Family and Psychosocial History
His father had an MI at age 65 years and is still living. He is an alcoholic
who would return from the bar after work and beat the patient as a child.
His mother died of breast cancer 6 years ago. She was submissive to the
husbands aggressive behavior and was withdrawn and anxious.
Two children in their early 20s live locallyone has undergone drug
rehabilitation and the other uses no alcohol.
Mr A used marijuana frequently as a teenager. He currently smokes cigarettes,
drinks 2 beers a day, and occasionally the hard stuff. Alcohol and Vicodin
help his nerves.
He lives with his wife, relying on a modest fixed income from SSI and her
income; his wife resents his lack of employment.
Review of Systems
Blood pressure is 135/85.
Sleep is poor and the patient states his mood is okay, but looks depressed.
Physical Examination
The patient is not well groomed and has a ruddy complexion.
He answers in short sentences and seems in a hurry to leave with his
hydrocodone prescription.
The exam is unremarkable except for mild tenderness to light touch over
the midline of the back from L3-S1 and mild tenderness in the right SI joint.
Normal reflexes, strength, and sensations; no atrophy noted. Normal straight
leg raise and normal but slow gait.
What Next?
Administer the Opioid Risk Tool (ORT): Mr A is at high risk for opioid abuse.
Implement a written opioid treatment agreement outlining the conditions under
which you will prescribe opioid therapy.
Request his past medical records to verify his verbal report.
Prescribe hydrocodone/acetaminophen 5 mg/500 mg 2 q6h, 56 tablets
for 1 week.
Five Days Later
Mr A calls for an early refill. Hydrocodone is not helping his pain, but along
with alcohol is the only thing that helps his anxiety and sleep.
Medical records confirm his stated history.
Ask him to come in for evaluation. Review the treatment agreement and
the fact that he violated it, and obtain a urine sample.
Your nurse arranges a referral to a psychiatrist in 2 weeks and a local pain
specialist in 12 weeks.
Prescribe 2 transdermal fentanyl patches 25 g q72h with a follow-up visit
in 6 days.
11
You are concerned that Mr A is requesting a
controlled substance without your first reviewing
his previous medical records.
Mr As family and psychosocial history are very
suggestive of addiction problems.
Opioids do not address psychologic or emotional
problems. Patients who use drugs ( alcohol) to
cope with adverse life situations need structure and
psychiatric input to prevent maladaptive opioid use.
A written agreement is advised when there are
concerns about appropriate use or adherence to
the plan of care.25,54 Among the provisions in the
opioid agreement are permission for you to talk
freely with family members, pharmacists, or other
health care professionals; early refills will generally
not be given; he will not seek controlled substances
from another physician; one pharmacy will be used
to fill controlled substance prescriptions; he will
safeguard his medication; he will submit to urine
drug tests; and lost medications may not be replaced.
The visit takes longer than anticipated, but the extra
time is needed with this patient to begin to build a
therapeutic relationship.
Mr A is at high risk for opioid abuse, but this does
not necessarily invalidate his report of pain. He readily
provided the contact details for his prior physician
and permission to request past medical records. You
give him a limited supply of hydrocodone (1 week)
while awaiting his records, but explain that therapy
is not directed at just pain relief, but also to increase
function and overall QOL, and that continued
therapy is contingent on evidence of benefit. You
want to establish a therapeutic relationship with
the patient who is at high risk for addiction, which
can be started by frequent office visits.
Early refill requests should trigger evaluation for
tolerance, progressive disease, aberrant behavior,
or drug diversion.54 You request a urine sample
from him to reinforce that you are serious about
the treatment agreement, but do not submit this
sample for testing.
At this point you might want to refer the patient.
There is a 3-month wait to see a local pain
physician, but only 2 weeks for a psychiatric
referral. In the meantime, you do not prescribe
more hydrocodone, which he has demonstrated
difficulty managing. This may be a good time to
try a long-acting opioid, with fewer doses and
more steady blood levels. Options include fentanyl,
morphine, oxycodone, oxymorphone, and tramadol.
12 O P I O I D A N A L G E S I C S F O R PA I N M A N A G E M E N T
Interim Call
Mr As wife is worried about the patient lying around the house doing nothing.
You ask her to accompany Mr A on his visit that week.
Six Days Later
Mr A keeps his appointment but complains that his pain is out of control
and that he needs more medication. The patches dont stay on.
His wife reiterates that he lies around all day, is not bathing, and it appears
to be because his pain is uncontrolled. She is eager for her husband to
improve his function.
Prescribe SR morphine q24h 30 mg, 7 tablets.
Seven Days Later
The psychiatrist diagnoses Mr A as depressed and initiates fluoxetine.
He is unable to make a determination about his pain or addiction.
Mr A comes in looking disheveledhe states that he lost his morphine
the previous day.
His wife states that his function has not improved.
Another urine sample is sent to the laboratory for testing.
The results 24 hours later reveal hydrocodone, marijuana, and morphine.
What Next?
Explain that because opioids are clearly not improving his function
you will not continue to prescribe them, at least until his referral
to the pain specialist in 10 weeks. Mr A is angry, but you reiterate
that the opioid therapy is harmful to him.
Refer Mr A to a substance abuse specialist and prescribe clonidine to
treat withdrawal.
You arrange for Mr A to attend a weekly physical rehabilitation program.
Further explain that you will see him every week to support him
through this time. He agrees to come to the office the following week,
and continues to do so.
Twelve Weeks Later
The pain physician tries an epidural steroid injection, with little success.
No other evaluation or treatments were offered.
You refer the patient to a pain psychologist for weekly visits and
continue to see him every 2 weeks.
Outcome
The pain psychologist recommends you initiate a regimen of SR morphine
q24h 30 mg, 7 tablets weekly, to be doled out daily by Mr As wife.
The patient achieves some relief from this regimen and continues to
work with the psychologist.
Conclusion
Chronic pain is a common presenting complaint in many
practice settings and has substantial effects on patients QOL
and ability to work. Opioid analgesics may be required to
relieve moderate to severe pain and it is therefore important
for physicians to identify when opioids might be useful, by
careful patient assessment, selection, and monitoring, and to
understand the principles of prescribing opioids. At the same
time, it is just as essential that physicians are able to identify
patients for whom opioid analgesia may create more harm
than not using this treatment option. Physicians should be
prepared to develop an exit strategy for such patients
already being treated with opioids, and to formulate a plan to
manage and support these patients with other pharmacologic
and nonpharmacologic modalities.
Family members can be a therapeutic ally when
managing a patient on opioid therapy. They can also
be part of the problem, so it is important to obtain
collateral information from them. This includes
talking with family members to determine their
concerns and whether or not they are onboard with
the treatment plan, and documenting this discussion.
Many PCPs will want to refer the patient at this
point, although it is still appropriate for physicians
who are confident and experienced in managing
such patients to continue doing so.
It is a week until Mr As psychiatry referral. The
fentanyl may not be working for a number of reasons
and Mr A may be exhibiting pseudoaddiction. You
switch to SR morphine, but do not provide any
short-acting agents for BTP as you do not want to
reinforce his maladaptive opioid use.
He appears to show signs of withdrawal. You
counsel Mr A to refrain from use of illicit drugs
and encourage him to participate in a substance
abuse program, which he is reluctant to do.
This is a difficult patient to manage. When a
patient displays consistent aberrant drug-taking
behavior, it may be necessary to refuse to
prescribe opioidsthey are not appropriate for all
patients with pain. Consider prescribing them
again in comanagement with a pain specialist.
A pain psychologist can help patients to make
changes in their lifestyle and derive a sense of
acceptance, including the limitations of what can
be expected from analgesics.
The patients wife accompanied her husband to
some sessions with the psychologist and is eager
to see Mr A continue to improve his function.
Estimated time to complete this
activity: 1.5 hours
Release date: June 2007
Expiration date: June 2009
Instructions to obtain CME credit:
Read the monograph.
Visit www.unmc.edu/dept/cce/opioid_
criticalthinking.htm to complete the
posttest and evaluation.
Pass the posttest and print your certificate.

References
1. Arnst C. No pain, some gain. Bus Week. 2005.
2. ABC News/USA Today/Stanford University Medical Center Poll: Pain. Broad
experience with pain sparks a search for relief. 2005. Available at:
http://www.abcnews.go.com/images/Politics/979a1TheFightAgainstPain.pdf.
3. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane
Database Syst Rev. 2006;3:CD005522.
4. Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton R. Lost productive time
and cost due to common pain conditions in the US workforce. JAMA.
2003;290:2443-2454.
5. Middleton KR, Hing E. National Hospital Ambulatory Medical Care Survey: 2004
outpatient department summary. Adv Data. 2006;1-27.
6. American Pain Society. Guideline for the Management of Cancer Pain in Adults
and Children. Clinical Practice Guideline No. 3. Glenview, IL: American Pain
Society; 2005.
7. Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. New York: McGraw-
Hill; 2004.
8. Pasternak GW. Multiple opiate receptors: dja` vu all over again.
Neuropharmacology. 2004;47(suppl 1):312-323.
9. Pasternak GW. Molecular biology of opioid analgesia. J Pain Symptom Manage.
2005;29:S2-S9.
10. Ross JR, Rutter D, Welsh K, et al. Clinical response to morphine in cancer
patients and genetic variation in candidate genes. Pharmacogenomics J.
2005;5:324-336.
11. Cherny NI. Opioid analgesics: comparative features and prescribing guidelines.
Drugs. 1996;51:713-737.
12. Landau R. One size does not fit all: genetic variability of mu-opioid receptor and
postoperative morphine consumption. Anesthesiology. 2006;105:235-237.
13. Armstrong SC, Cozza KL. Pharmacokinetic drug interactions of morphine,
codeine, and their derivatives: theory and clinical reality, Part II.
Psychosomatics. 2003;44:515-520.
14. Armstrong SC, Cozza KL. Pharmacokinetic drug interactions of morphine,
codeine, and their derivatives: theory and clinical reality, Part I. Psychosomatics.
2003;44:167-171.
15. Riley J, Ross JR, Rutter D, et al. No pain relief from morphine? Individual
variation in sensitivity to morphine and the need to switch to an alternative
opioid in cancer patients. Support Care Cancer. 2006;14:56-64.
16. Ross JR, Riley J, Quigley C, Welsh KI. Clinical pharmacology and
pharmacotherapy of opioid switching in cancer patients. Oncologist.
2006;11:765-773.
17. DHonneur G, Gilton A, Sandouk P, Scherrmann JM, Duvaldestin P. Plasma and
cerebrospinal fluid concentrations of morphine and morphine glucuronides after
oral morphine. The influence of renal failure. Anesthesiology. 1994;81:87-93.
18. American Pain Society. Principles of Analgesic Use in the Treatment of Acute
Pain and Cancer Pain. 5th ed. Glenview, IL: American Pain Society; 2003.
19. Brunton LL, Parker KL, Buxton ILO, Blumenthal DK (eds). Goodman & Gilmans
The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill;
2005.
20. Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain. 2002;
18:S3-S13.
21. Bruera E, Kim HN. Cancer pain. JAMA. 2003;290:2476-2479.
22. Pasternak GW. Incomplete cross tolerance and multiple mu opioid peptide
receptors. Trends Pharmacol Sci. 2001;22:67-70.
23. Pasternak GW. The pharmacology of mu analgesics: from patients to genes.
Neuroscientist. 2001;7:220-231.
24. Savage S, Covington E, Gilson AM, Gourlay D, Heit HA, Hunt JB. Public
policy statement on the rights and responsibilities of healthcare professionals
in the use of opioids for the treatment of pain. A consensus document from
the American Academy of Pain Medicine, the American Pain Society, and the
American Society of Addiction Medicine; 2004. Available at:
www.ampainsoc.org/advocacy/pdf/rights.pdf.
25. Federation of State Medical Boards of the United States, Inc. Model policy for
the use of controlled substances for the treatment of pain. 2004.
26. Eriksen J, Sjogren P, Bruera E, Ekholm O, Rasmussen NK. Critical issues on
opioids in chronic non-cancer pain: an epidemiological study. Pain.
2006;125:172-179.
27. Martell BA, OConnor PG, Kerns RD, et al. Systematic review: opioid treatment
for chronic back pain: prevalence, efficacy, and association with addiction. Ann
Intern Med. 2007;146:116-127.
28. Malan TP, Jr, Marsh G, Hakki SI, Grossman E, Traylor L, Hubbard RC. Parecoxib
sodium, a parenteral cyclooxygenase 2 selective inhibitor, improves morphine
analgesia and is opioid-sparing following total hip arthroplasty. Anesthesiology.
2003;98:950-956.
29. American Pain Society. Guideline for the Management of Pain in Osteoarthritis,
Rheumatoid Arthritis, and Juvenile Chronic Arthritis. Clinical Practice Guideline
No. 2. Glenview, IL: American Pain Society; 2002.
30. Pignone MP, Gaynes BN, Rushton JL, et al. Screening for depression in adults:
a summary of the evidence for the U.S. Preventive Services Task Force. Ann
Intern Med. 2002;136:765-776.
31. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated
patients: Preliminary validation of the Opioid Risk Tool. Pain Med.
2005;6:432-442.
32. Akbik H, Butler SF, Budman SH, Fernandez K, Katz NP, Jamison RN. Validation
and clinical application of the Screener and Opioid Assessment for Patients
with Pain (SOAPP). J Pain Symptom Manage. 2006;32:287-293.
33. Belgrade MJ, Schamber CD, Lindgren BR. The DIRE score: predicting
outcomes of opioid prescribing for chronic pain. J Pain. 2006;7:671-681.
34. Fishman SM, Bandman TB, Edwards A, Borsook D. The opioid contract in
the management of chronic pain. J Pain Symptom Manage. 1999;18:27-37.
C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K
35. Chevlen E. Recent advances in clinical use of opioids. Curr Pain Headache Rep.
2004;8:205-211.
36. Passik SD, Kirsh KL. Chronic pain management and substance abuse.
Assessing and optimizing outcomes. Elder Care. 2002; September:1-3.
37. Passik SD, Kirsh KL, Whitcomb L, et al. A new tool to assess and document
pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther.
2004;26:552-561.
38. Passik SD, Kirsh KL. Managing pain in patients with aberrant drug-taking
behaviors. J Support Oncol. 2005;3:83-86.
39. Heit HA, Gourlay DL. Urine drug testing in pain medicine. J Pain Symptom
Manage. 2004;27:260-267.
40. Gourlay DL, Heit HA, Caplan YH. Urine drug testing in clinical practice: dispelling
the myths & designing strategies. Stamford, CT: PharmaCom Group, Inc; 2006.
41. Hammett-Stabler CA, Pesce AJ, Cannon DJ. Urine drug screening in the
medical setting. Clin Chim Acta. 2002;315:125-135.
42. Sinatra R. Opioid analgesics in primary care: challenges and new advances in
the management of noncancer pain. J Am Board Fam Med. 2006;19:165-177.
43. Kirsh KL, Whitcomb LA, Donaghy K, Passik SD. Abuse and addiction issues in
medically ill patients with pain: attempts at clarification of terms and empirical
study. Clin J Pain. 2002;18:S52-S60.
44. Schnoll SH, Weaver MF. Addiction and pain. Am J Addict. 2003;12(suppl 2):
S27-S35.
45. Passik SD. Pain management misstatements: ceiling effects, red and yellow
flags. Pain Med. 2006;7:76-77.
46. Compton P, Darakjian J, Miotto K. Screening for addiction in patients with
chronic pain and problematic substance use: evaluation of a pilot assessment
tool. J Pain Symptom Manage. 1998;16:355-363.
47. Weissman DE, Haddox JD. Opioid pseudoaddictionan iatrogenic syndrome.
Pain. 1989;36:363-366.
48. Portenoy RK, Savage SR. Clinical realities and economic considerations: special
therapeutic issues in intrathecal therapytolerance and addiction. J Pain
Symptom Manage. 1997;14:S27-S35.
49. Savage S, Covington E, Heit H, et al. A consensus document from the
American Academy of Pain Medicine, American Pain Society, and American
Society of Addiction Medicine. Definitions related to the use of opioids for the
treatment of pain. 2001. Available at http://www.ampainsoc.org/advocacy/
opioids2.htm.
50. Gallagher R. Opioids in chronic pain management: Navigating the clinical and
regulatory challenges. J Fam Pract. 2004;53:S23-S32.
51. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of
Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement
Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939. 2004. Rockville,
MD: Substance Abuse and Mental Health Services Administration.
52. Pain & Policy Studies Group. Achieving Balance in State Pain Policy: A Progress
Report Card. 2nd ed. 2006. University of Wisconsin Comprehensive Cancer
Center. Madison, Wisconsin. Available at: http://www.painpolicy.wisc.edu/
Achieving_Balance/PRC2006.pdf.
53. Institute for Clinical Systems Improvement. Health Care Guideline. Assessment
and management of acute pain. 2006. Available at: www.icsi.org.
54. The management of persistent pain in older persons. J Am Geriatr Soc.
2002;50:S205-S224.
55. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G.
Acetaminophen for osteoarthritis. Cochrane Database Syst Rev.
2006;CD004257.
56. Chou R, Helfand M, Peterson K, Dana T, Roberts C. Comparative effectiveness
and safety of analgesics for osteoarthritis. Comparative Effectiveness Review
No. 4. (Prepared by the Oregon Evidence-based Practice Center under Contract
No. 290-02-0024.) 2006. Rockville, MD: Agency for Healthcare Research and
Quality. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
57. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in
healthy adults receiving 4 grams of acetaminophen daily: a randomized
controlled trial. JAMA. 2006;296:87-93.
58. Kuffner EK, Temple AR, Cooper KM, Baggish JS, Parenti DL. Retrospective
analysis of transient elevations in alanine aminotransferase during long-term
treatment with acetaminophen in osteoarthritis clinical trials. Curr Med Res
Opin. 2006;22:2137-2148.
59. Exercise prescription for older adults with osteoarthritis pain: consensus
practice recommendations. A supplement to the AGS Clinical Practice
Guidelines on the management of chronic pain in older adults. J Am Geriatr
Soc. 2001;49:808-823.
60. 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(suppl 1):S1-S43.
61. Weiner DK, Rudy TE, Morrow L, Slaboda J, Lieber S. The relationship between
pain, neuropsychological performance, and physical function in community-
dwelling older adults with chronic low back pain. Pain Med. 2006;7:60-70.
62. Heyer EJ, Sharma R, Winfree CJ, et al. Severe pain confounds
neuropsychological test performance. J Clin Exp Neuropsychol. 2000;22:
633-639.
63. Jamison RN, Schein JR, Vallow S, Ascher S, Vorsanger GJ, Katz NP.
Neuropsychological effects of long-term opioid use in chronic pain patients.
J Pain Symptom Manage. 2003;26:913-921
64. Tassain V, Attal N, Fletcher D, et al. Long term effects of oral sustained release
morphine on neuropsychological performance in patients with chronic non-
cancer pain. Pain. 2003;104:389-400.
65. Apkarian AV, Sosa Y, Krauss BR, et al. Chronic pain patients are impaired on an
emotional decision-making task. Pain. 2004;108:129-136.
66. Portenoy RK, Bennett DS, Rauck R, et al. Prevalence and characteristics of
breakthrough pain in opioid-treated patients with chronic noncancer pain.
J Pain. 2006;7:583-591.
PharmaCom Group, Inc. PSRST STD
76 Progress Drive U.S. Postage
PAID
Stamford, CT 06902 Utica, NY
Permit #566

Published by PharmaCom Group. Copyright 2007. Printed in the USA.