FIBROMYALGIA

Oleh : dr Sugianto SpS, Mkes, PhD

What is Fibromyalgia (FMS)?

A clinical syndrome characterized by

widespread muscular pain (usually
chronic),
fatigue and
muscle tenderness (tender points)

What is FMS? (cont.)

Additional symptoms are common and
include:
poor sleep almost always
headaches
irritable bowel syndrome
cognitive and memory problems
numbness and tingling in fingers and
toes

What is FMS? (cont.)

-

irritable bladder
temporomandibular joint (TMJ) disorder
restless leg syndrome
dry eyes and dry mouth
morning stiffness
anxiety and depression

Symptoms including pain may wax and

wane over time

The disease symptoms exacerbate in

stress, fear, cold, humidity and fatigue.
It should be emphasized that
fibromyalgia can also be induced by
emotional stress, surgery, trauma or
hypothyroidism.

What causes FMS?

Cause is unknown
Abnormally high levels of Substance P in
spinal fluid in some patients
Substance P important in transmission
and amplification of pain signals to and
from brain
Volume control is turned up too high in
brains pain centers

What causes FMS? (cont)

Familial tendency to develop FMS

suggests genetic role
Can be triggered by physical, emotional
or environmental stressors such as car
accidents, repetitive injuries and certain
diseases
Patients with Rheumatoid arthritis and
SLE (Lupus) are more likely to develop
FMS

What causes FMS? (cont.)

Other conditions such as Lyme disease

and obstructive sleep apnea (OSA) have
been associated with FMS
Sleep deprivation with disruption of
delta-wave sleep (non-REM stage IV) is
associated with day-time fatigue and
fibromyalgia syndrome

Who gets FMS?

Affects as many as 1 in 50 Americans

Most common in middle-aged women
Men and children may also develop the
disorder
Patients with RA, SLE and Ankylosing
spondylitis are more likely
Women who have a family member with
FMS are more likely to develop it

Symptoms in Fibromyalgia
Syndrome
SYMPTOMS
(%)

MEAN

Musculoskeletal
Pain at multiple sites

100

Stiffness

76

Hurt all over

62

Swollen feeling in tissues

52

SYMPTOMS
MEAN (%)
Depression
37
Cognitive dysfunctione (27)
61
Mental stress
61

Nonmusculoskeletal
General fatigue

87

Morning fatigue

75

Sleep difficulties
Paresthesia

72
54

Dizziness/vertigo (23, 24)

59

Tinnitus (24)

17

Anxietyd

60

Selected Associated Syndromes

Headaches
54
Dysmenorrhea
43
Irritable bowel syndrome
38
Restless legs syndrome (28)
31
Female urethral syndrome (29, 30)
15

Modulating Factors of Fibromyalgia

Syndrome Pain
Aggravating Factors
Weather (cold/humid)
Poor sleep
Anxiety/stress
Physical inactivity
Noise (6, 44)

%
65
70
61
49
22

Relieving Factors
Local heat
Rest
Moderate activities
Massage
Stretching exercise

58
54
46
40
43

How is FMS diagnosed?

A diagnosis is made by evaluation of

symptoms and presence of tender
points
American College of Rheumatology
Classification Criteria for Fibromyalgia
(1990).widespread pain for at least
3 months and
pain in 11 out of 18 tender point sites
on digital palpation

ACR classification criteria: fibromyalgia

Both criteria must be satisfied
History of widespread pain for more than 3
months, on both sides of the body, above and
below the waist, and axial skeleton (cervical
spine, anterior chest, thoracic pain, or low back)
Pain in 11 of 18 tender point sites on digital
palpation with approximate force of 4 kg.
Presence of second clinical disorder does not
exclude diagnosis of fibromyalgia.

Fibromyalgia: tender points

(diagram)

How is FMS diagnosed?

(cont.)

X-rays, blood tests, specialized scans such

as nuclear medicine and CT, muscle
biopsies are all normal
Objective markers of inflammation such
as ESR (erythrocyte sedimentation rate)
are normal
Must be distinguished from other common
diffuse pain conditions such as RA, SLE,
Hypothyroidism and Polymyalgia
Rheumatica (PMR)

American College of Rheumatology Criteria

for Classification of Fibromyalgia

Widespread pain for at least three

months, defined as the presence of all of
the following:
Pain on the right and
left sides of the body
Pain above and below the waist
(including
shoulder and buttock pain)
Pain in the axial skeleton (cervical,
thoracic
or lumbar spine, or anterior
chest)

American College of Rheumatology Criteria

for Classification of Fibromyalgia
B. Pain induced by digital palpation pressure at tender points in at least 11
out of the following 18 locations:
1. occiput: both sides, suboccipital muscle insertions,
2. lower part of the cervical spine: both sides, anterior aspects of C5C7
intertransverse spaces,
3. trapezius muscle: both sides, midpoint of upper border
4. supraspinatus muscle: both sides, origins, above the spatula spine, near
medial border,
5. the 2nd rib: both sides, upper lateral surface of second costochondral
junction,
6. lateral epicondyle: both sides, 2 cm distal from to the epicondyles,
7. gluteal muscle: both sides, upper outer buttock, anterior fold of the
muscle,
8. greater trochanter: both sides, posterior to the trochanter prominence,
9. knee joint: both sides, medial fat pad, just proximal to medial condyle.

Differential Diagnosis

The thyroid-stimulating hormone level should

be checked routinely because hypothyroidism
can mimic the symptoms of fibromyalgia.
Drug-induced myopathies (particularly those
associated with the statin class of lipidlowering agents), polymyalgia rheumatica and
other rheumatologic syndromes.
Myofascial pain syndrome may be confused
with fibromyalgia. myofascial pain arises from
trigger points in individual muscles.

Comorbid Conditions
Associated with Fibromyalgia

Migraine headache
Chronic fatigue
Irritable bowel syndrome
Depression
Restless legs syndrome
Temporomandibular joint syndrome
Myofascial pain syndrome

Fibromyalgia is characterised by chronic

widespread debilitating musculoskeletal
pain, increased pain sensitivity including
allodynia and hyperalgesia and stiffness
throughout the body (White and Harth,
2001; Neumann and Buskila, 2003).
In addition, patients with fibromyalgia
complain of fatigue, sleep disturbances,
anxiety, depression and concentration,
cognitive and memory dysfunction, often
referred to as fibro fog

The prevalence of fibromyalgia has been

estimated to be about 2.0% of the general
population and seven times more common in
women than in men
The prevalence increases with age, with highest
values attained between 60 and 70 years where it
can exceed 7% of the general population in
women.
Fibromyalgia significantly impairs function,
increases work absenteeism and general
healthcare use and results in a profound
deterioration of the quality of life of patients
(Hoffman and Dukes, 2008; White et al., 2008).

ACUTE AND CHRONIC PAIN

Acute pain is self-limiting and serves to

protect biological function by warning of
tissue damage. It is rarely associated
with psychological symptoms other than
mild anxiety.
Chronic pain serves no protective
biological function and instead it is a
disease process itself. Chronic pain is not
self-limiting and can persist for years.

Chronic Pain Defined by

Mechanisms

Peripheral
(nociceptive)

Primarily due to
inflammation or damage in
periphery
NSAID, opioid responsive
Behavioral factors minor
Examples

Central (nonnociceptive)

OA

pain models
(e.g. third molar, postMixed
surgery)
Neuropathic
RA
Cancer pain

Primarily due to a central

disturbance in pain
processing
Tricyclic responsive
Behavioral factors more
prominent
Examples

Acute

Fibromyalgia
Irritable bowel
syndrome
Tension and migraine
headache
Interstitial cystitis /
vulvodynia, non-cardiac
chest pain / etc.

Overlap between Fibromyalgia

and Other Systemic
Syndromes:
FIBROMYALGIA
MULTIPLE CHEMICAL
Chronic
Multi-symptom
Illnesses
2 - 4% of population;
SENSITIVITY - symptoms in
defined by widespread
pain and tenderness

EXPOSURE
SYNDROMES e.g.
Gulf War Illnesses, silicone
breast implants, sick building
syndrome

multiple organ systems in

response to multiple
substances
CHRONIC FATIGUE
SYNDROME 1% of
population; fatigue and
4/8 minor criteria
SOMATOFORM
DISORDERS 4% of
population; multiple
unexplained
symptoms - no
organic findings

PAIN PATHWAYS AND MODULATORS OF

PAIN PERCEPTION

Peripheral afferent neurons conduct

nociceptive input from the periphery to
the dorsal horn of the spinal cord and
through various nuclei to higher brain
centres such as the cortex, thalamus and
hypothalamus, which play a role in pain
perception.

The periaqueductal gray (PAG) processes both

ascending and descending pain signals, from
and to the dorsal horn, and represents a link
between higher cerebral structures and the
spinal cord.
Descending excitatory connections from the
PAG go to the rostral ventromedial medulla
(RVM) and dorsolateral pontine structure
(DLP), which, in turn, send inhibitory
projections to the spinal cord thus modulating
antinociceptive effects.

In the dorsal horn, excitation of

peripheral afferent neurons causes the
release of the excitatory transmitter,
glutamate, which acts at postsynaptic
NMDA (N methyl-D-aspartate) and AMPA
(a-amino-3-hydroxy- 5-methyl-4isoxazole propionic acid) receptors
localised on the dorsal horn projection
neurons.

These signals are modulated by neurokinins,

such as substance P and neurokinins A and B
which are coreleased from primary afferent
nerve terminals with glutamate and act at
postsynaptic NK1, NK2 and NK3 receptors.
Vasoactive intestinal peptide (VIP), calcitonin
gene-related peptide (CGRP), and
somatostatin are also released from
peripheral afferent neurons to act at their
respective postsynaptic receptors localised
on the dorsal horn projection neurons

the nocturnal fall in saturation, which

might also underlie other disease
symptoms, also suggests that muscle
hypoxia contributes to the pain etiology.
Serotonin deficiency and increased P
substance levels in the cerebrospinal
fluid play an important role in the
pathogenesis of the disease.

Pharmacologic Treatments

Pharmacotherapy for FM has been most successful

with antidepressant, muscle relaxant, or
anticonvulsant drugs. These drugs affect the
release of various neurochemicals (eg, serotonin,
norepinephrine, substance P) that have a broad
range of activities in the brain and spinal cord,
including modulation of pain sensation and
tolerance.
First-line medications for FM pain are low doses of
tricyclic antidepressants or cyclobenzaprine .
These medications provide dual benefits including
improvement of mood and central sensitization.

Pain is subjective; the only measure of pain

is a patient's report.
Optimal treatment of pain requires
addressing the physical, psychological,
social, and spiritual/existential dimensions
of the person experiencing the pain.
Pharmacologic treatment of pain requires
an understanding of the underlying
pathophysiology of the pain (ie, whether
pain is nociceptive, neuropathic, or mixed).

Neuropathic pain

Neuropathic pain, caused by various

central and peripheral nerve disorders, is
especially problematic because of its
severity, chronicity and resistance to
simple analgesics.
The condition affects 2%3% of the
population

Acute vs Chronic Pain

Characteristic
Cause

Acute Pain
Generally known

Chronic Pain
Often unknown

Duration of pain

Short,
well-characterized

Persists after healing,

3 months

Treatment
approach

Resolution of
underlying cause,
usually self-limited

Underlying cause and pain

disorder; outcome is often
pain control, not cure

Domains of Chronic Pain

Quality of Life
Physical functioning
Ability to perform
activities of daily living
Work
Recreation

Psychological Morbidity
Depression
Anxiety, anger
Sleep disturbances
Loss of self-esteem

Social Consequences

Socioeconomic

Marital/family
relations
Intimacy/sexual activity
Social isolation

Consequences

Healthcare costs

Disability

Lost workdays

Nociceptive vs Neuropathic
Pain
Nociceptive
Pain

MixedType

Caused by activity in
neural pathways in
response to potentially
tissue-damaging stimuli

Caused by a
combination of both
primary injury and
secondary effects

Neuropathic
Pain
Initiated or caused by
primary lesion or
dysfunction in the
nervous system
CRPS*

Postoperative
pain

Arthritis

Mechanical
low back pain

Sickle cell
crisis

Sports/exercise
injuries
*Complex regional pain syndrome

Postherpetic
neuralgia

Trigeminal
neuralgia

Neuropathic
low back pain

Central poststroke pain

Distal
polyneuropathy
(eg, diabetic, HIV)

Possible Descriptions
of Neuropathic Pain

Sensations

numbness
tingling
burning
paresthetic
paroxysmal
lancinating
electriclike
raw skin
shooting
deep, dull, bonelike ache

Signs/Symptoms

allodynia: pain from a

stimulus that does not
normally evoke pain
thermal
mechanical
hyperalgesia: exaggerated
response to a normally
painful stimulus

Physiology of Pain Perception

Transduction
Transmission
Modulation
Perception
Interpretation
Behavior

Injury

Brain

Descending
Pathway

Peripheral
Nerve

Dorsal
Root
Ganglion

Ascending
Pathways
C-Fiber
A-beta Fiber
A-delta Fiber

42

Dorsal
Horn
Spinal Cord

Adapted with permission from WebMD Scientific American Medicine.

Neuropathic pain, caused by a lesion of

the nervous system, is especially
problematic because (a) it is often
experienced in parts of the body that
otherwise appear normal, (b) it is
generally chronic, severe and resistant
to over-the-counter analgesics, and (c) it
is further aggravated by allodynia
(touch-evoked pain).

It may result from various causes that

affect the brain, spinal cord and
peripheral nerves, including cervical or
lumbar radiculopathy, diabetic
neuropathy, cancer-related neuropathic
pain, postherpetic neuralgia, HIV-related
neuropathy, spinal cord injury, trigeminal
neuralgia and complex regional pain
syndrome type II, among others.

Clinical presentation

The blockade of nerve conduction in neuropathic

conditions causes nerve dysfunction, which can
result in numbness, weakness and loss of deep
tendon reflexes in the affected nerve area.
Neuropathic conditions also cause aberrant
symptoms of spontaneous and stimulus-evoked
pain. Spontaneous pain (continuous or
intermittent) is commonly described as burning,
shooting or shock-like. Stimulusevoked pain
includes allodynia (pain evoked by a nonpainful
touch) and hyperalgesia (increased pain evoked
by a painful stimulus).

Man with postherpetic neuralgia in the left fifth and sixth

thoracic dermatomes. Red lines delineate area of sensory loss,
and black dashed lines delineate area of allodynia (touchevoked
pain). Extension of allodynia above and below the originally
affected dermatomes is a feature of central sensitization

Pathophysiology

Regeneration after nerve injury results in

the formation of neuromas and sprouting
of new nerve projections among
uninjured neighbouring neurons.
Collateral sprouting then leads to altered
sensory properties that may be realized
as expanded receptive fields.

Highlights the clinical and

pathophysiologic features of common
neuropathic pain syndromes that are
caused by nerve injury or dysfunction.
Knowledge of the cellular and molecular
mechanisms of neuropathic pain has
advanced with the development of
various experimental models of nerve
injury

Peripheral mechanisms

Regeneration after nerve injury results in

the formation of neuromas and sprouting
of new nerve projections among
uninjured neighbouring neurons.
Collateral sprouting then leads to altered
sensory properties that may be realized
as expanded receptive fields

Peripheral mechanisms
(1)

Uncontrolled neuronal firing after

experimental nerve injury is largely attributed
to increased expression of sodium channels.
This mechanism is supported by several lines
of evidence, including blockade of neuropathic
pain with sodium-channelblocking local
anesthetics.
Demyelination of diseased nerves may be
another cause of increased neuronal
excitability.

Peripheral mechanisms
(2)

calcium channels is also increased

following nerve injury. Calcium entry
through voltage-gated calcium channels is
necessary for the release of substance P
as well as glutamate from injured
peripheral nerves.
Within the dorsal root ganglion, increased
expression of the -2-delta subunit of
voltage-gated calcium channels correlates
with onset and duration of allodynia.

Central mechanisms

Sustained painful stimuli result in spinal

sensitization, which is defined as
heightened sensitivity of spinal neurons,
reduced activation thresholds and
enhanced responsiveness to synaptic
inputs (i.e., more likely to transmit pain to
the brain).
Central sensitization is largely mediated
by the N-methyl-Daspartate (NMDA)
receptor.

Sympathetically
maintained pain

The importance of the sympathetic nervous

system in neuropathic pain has been
demonstrated by analgesia following
sympathectomy in animals and humans, and
by pain exacerbation through activation of the
sympathetic nervous system.
Sympathetically maintained pain may be
explained by sprouting of sympathetic neurons
into dorsal root ganglia of injured sensory
neurons and postinjury sprouting of
sympathetic fibres into the dermis.

Painful Diabetic
Neuropathy

Mechanisms of Pain

The current understanding of general mechanisms of

neuropathic pain may provide insights into the
abnormalities leading to pain in diabetic neuropathy.

Damage to peripheral nerves results in hyperexcitability

in primary afferent nociceptors (peripheral sensitization)
that leads to hyperexcitability in central neurons (central
sensitization) and generation of spontaneous impulses
within the axon as well as the dorsal root ganglion of
these peripheral nerves

Painful Diabetic
Neuropathy

Mechanisms of Pain

Hyperexcitability of the peripheral nerves results in

central hyperexcitability, and persistent nerve
stimulation activates N-methyld aspartate (NMDA)
receptors located postsynaptically in the dorsal horn,
with subsequent glutamate release Glutamate is an
excitatory neurotransmitter that causes neuronal
membrane depolarization, allowing stimuli to produce
much larger postsynaptic potentials than usuala
process known as synaptic potentiation. Long-term
synaptic potentiation has been shown in various pain
states

Pathophysiology of common
neuropathic pain syndromes

Hyperglycemia,hyperlipidemia,hypoinsuli
nemia, growth factor deficiency
oxidative stress and autoimmunity
progressive demyelination and axonal
loss sensory loss, paresthesia,
dysesthesias, pain and allodynia

Type 1
DIABETES

Hyperglycemia

Hypoinsulinemia

Polyol
pathway

AGE
production

Oxidative
stress

Neurotrophin
deficiency

Mitochondria
l
dysfunction

ATP ?

Impairment in
calcium
homeostasis

Pathological changes
in nerve, microvessel, and ganglia

Decreased
axonal
transport

Decreased
protein
synthesis

Distal axonal
degeneration

ETIOLOGICAL PATHWAYS IN DIABETIC NEUROPATHY (Phernyhough 2003

Sensory distribution of
Diabetic Peripheral Neuropathy

SEMMES WEINSTEIN MONOFILAMENT TEST

ABNORMALITIES OF ISOLATED FIBERS IN LENGTH-DEPENDENT DIABETIC PNP

@ (Said 2007)
A. Normal B. Segmental demyelination associated with distal axonal degeneration
C. Remyelination with replacement of the original internode with 2 shorter internodes &
axonal regeneration by sprouting of proximal axonal stump
D. Remyelination of axonal sprouts of the fiber

Summary

Chronic neuropathic pain is a disease, not a

symptom
Rational polypharmacy is often necessary

Treatment goals include:

combining peripheral and central nervous system

agents enhances pain relief
balancing efficacy, safety, and tolerability
reducing baseline pain and pain exacerbations
improving function and QOL

New agents and new uses for existing agents

offer additional treatment options

TENSION-TYPE HEADACHE

Pain is usually mild to moderate in

intensity , but increases with an increase
in headache frequency .
Episodic tension-type headache (ETTH)
is almost exclusively bilateral (>90%)
and is usually described as bandlike
and affects, in order of frequency, the
occipital, parietal, temporal, or frontal
areas

Diagnostic Criteria: Episodic Tension-Type

Headachea
Frequent ETTH
A.
B.

C.

At least 10 episodes occurring 1 but <15 d/mo for at least 3

mo (12 and <180 d/yr) and fulfilling criteria BD
Headache lasting from 30 min to 7 d
Headache has at least two of the following characteristics:
a.Bilateral location
b.Pressing/tightening (nonpulsating) quality
c.Mild or moderate intensity
d.Not aggravated by routine physical activity such as walking or
climbing stairs

Pain is usually bilateral (occuring on both

the left and right side of the head) and
has a pressing or tightening feeling with
a pain intensity from mild to moderate.
The pain does not increase with physical
activity and no nausea is associated with
this type of headache. It is not
uncommon for a sufferer to be overly
sensitive to light or sound.

REFERENCE

Wallace, Daniel J.; Clauw, Daniel J. 2005

Fibromyalgia and Other Central Pain
Syndromes, 1st Edition, Lippincott
Williams & Wilkins
Tomasz Podolecki, Andrzej Podolecki,
Antoni Hrycek, 2009, Fibromyalgia:
pathogenetic, diagnostic and therapeutic
concerns. Pol Arch Med Wewn.;119 (3):
157-161