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Pathogenesis of fibromyalgia

Author: Don L Goldenberg, MD

Section Editor: Peter H Schur, MD
Deputy Editor: Paul L Romain, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2018. | This topic last updated: Sep 06, 2017.

INTRODUCTION — Fibromyalgia (FM) is a chronic pain disorder with unknown etiology and unclear
pathophysiology [1,2].

There is no evidence that a single event “causes” FM. Rather, many physical and/or emotional stressors may
trigger or aggravate symptoms. These have included certain infections, such as a viral illness or Lyme
disease, as well as emotional or physical trauma [1-3].

A detailed description of the clinical manifestations of FM and an approach to the diagnosis of FM in adults
and children are presented separately. (See "Clinical manifestations and diagnosis of fibromyalgia in adults"
and "Fibromyalgia in children and adolescents: Clinical manifestations and diagnosis".)

FM is only one of many causes of widespread pain. A discussion of the differential diagnosis of FM and the
broad differential diagnosis is presented separately. (See "Differential diagnosis of fibromyalgia".)

PATHOGENESIS — Fibromyalgia (FM) is considered to be a disorder of pain regulation, classified often

under the term central sensitization [1,2,4] (see 'Altered pain processing' below). FM shares several features
with other common pain disorders that are considered to be more central rather than peripheral pain
conditions, such as migraine, tension headaches, temporomandibular joint disorder, and irritable bowel
syndrome; these features include common genetic and central nervous system pain processing
characteristics. More limited studies have suggested there might also be a role for peripheral neuropathic
mechanisms or focal tissue changes in some patients. (See 'Peripheral pain mechanisms' below.)

During much of the 20th century, FM was thought to be a muscle disease. However, controlled trials found no
evidence for significant pathologic or biochemical muscle abnormalities [1-3,5,6]. As an example, measures
of muscle function, including force generation and lactate production during exercise, and muscle pain
following exertion are remarkably similar in women with FM and sedentary female controls [7,8]. Most
investigators now believe that any muscle pathology is secondary to pain and inactivity rather than primary in
nature [1,6-8]; however, some reports suggest that oxidative stress and mitochondrial dysfunction may play a
role in the disease process [9].

Genetic predisposition — A number of observational and biologic studies suggest that chronic widespread
pain and FM have, in part, a genetic basis [10]. First-degree relatives of patients with FM are 8.5 times more
likely to have FM than relatives of patients with rheumatoid arthritis [11]. Familial aggregation of lowered
thresholds for pressure-induced pain has been documented in first-degree relatives of patients. Such reports
suggest a shared hereditary factor that may account for the overlap of chronic pain and mood disorders in
families. However, no association between chronic widespread pain and any candidate gene has yet been
conclusively documented [12].
 Candidate genes — The ability of some antidepressant drugs to improve symptoms suggested that
genes involved in serotonin and/or catecholamine metabolic or signaling pathways might be candidates for
conferring susceptibility.

The first large candidate gene study evaluated 496 FM patients and 348 chronic pain-free controls [13]. They
evaluated >350 genes known to be involved in nociception, inflammation, and affect. Significant differences
in allele frequencies between FM cases and controls were observed for three genes: GABRB3 (rs4906902, p
= 3.65x10-6), TAAR1 (rs8192619, p = 1.11x10-5), and GBP1 (rs7911, p = 1.06x10-4). These three genes and
seven other genes with suggestive evidence for association were examined in a second, independent cohort
of FM patients and controls genotyped using the Perlegen 600K platform. Evidence of association in the
replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4 genes.

The first genome-wide linkage scan for FM was performed in a cohort of 116 families from the Fibromyalgia
Family Study [14]. The estimated sibling recurrence risk ratio for FM was 13.6, based upon a reported FM
population prevalence of 2 percent. Genome-wide suggestive evidence of linkage was observed at markers
D17S2196 and D17S1294 on chromosome 17p11.2-q11.2. These markers have potential impact on various
pain pathways.

Experimental pain studies have demonstrated that the catechol-O-methyltransferase (COMT) polymorphism
affects central pain. The frequency of genetic variations associated with low COMT enzyme activity was
significantly higher in FM patients than in healthy volunteers [15]. FM patients were more sensitive to
experimental pain than healthy volunteers and, in particular, FM individuals with the Met/Met genotype
(Val158Met SNP) or the HPS-APS haplotypes showed higher sensitivity to thermal and pressure pain stimuli
than patients carrying the LPS haplotype or val alleles (Val158Met SNP). Another study demonstrated that
the Met/Met genotype was significantly higher in FM patients than healthy controls [16]. However, a 2014
meta-analysis found that the COMT gene val(158)met polymorphism was not associated with FM risk [17].

A case-control study of more than 400 Korean FM patients and 400 controls found that polymorphisms of the
COMT gene correlated with the risk for FM as well as pain sensitivity [18]. A subsequent genome-wide
profiling found that, compared with controls, FM patients had differences in expression of 421 genes, many of
which were important in pain processing [19]. They used diagnostic models and identified a subset of 10
gene signature sets that provided 95 percent sensitivity and specificity for FM.

One report evaluated the A118G rs1799971 polymorphism in the opioid receptor mu 1 gene (OPRM1) in FM
[20]. The 118G allele frequency was significantly lower in patients with FM than in the control group. The
translocator protein gene (TPSO), which is upregulated during glial activation in chronic pain states, was
associated with greater pain intensity as well as more FM symptoms [21]. These investigators then studied
the effects of three functional genetic polymorphisms on exercise-induced hypoalgesia in 130 FM patients
and matched controls [22]. They found opposing interactions between opioid and serotonergic pathways.

A few studies have focused on genes other than those involved in pain pathways. One study using whole
exome sequencing found evidence in their cohort of a gene variant in 13 percent of FM patients that was
associated with increased plasma levels of monocyte chemoattractant protein (MCP)-1 and interferon
gamma induced protein (IP)-10, compared with patients with FM who had the wild-type allele; and another
variant in 11 percent of patients that was associated with elevated levels of interleukin (IL)-12 compared with
patients carrying the wild-type [23].

Altered pain processing — Alterations in pain and sensory processing in the central nervous system are
present in FM [24]. Patients perceive noxious stimuli, such as heat, electrical current, or pressure, as being
painful at lower levels of physical stimulation than do healthy controls [1,2,5,25].

Evidence of altered pain processing includes the following:

● Temporal summation of pain – FM patients experience greater than normal increases in the perceived
intensity of pain when rapidly repetitive short noxious stimuli are administered, which is termed temporal
 summation of pain [26].

● Decreased endogenous pain inhibition – Endogenous analgesic systems appear to be deficient in FM

[24,27]. There are both a reduction in diffuse noxious inhibitory control (in which decreased pain occurs
upon stimulation with a second acutely painful stimulus) and an inability to inhibit irrelevant sensory
stimuli following repetitive nonpainful stimulation [28,29].

● Pain receptors and pain-related neuropeptides – Changes are seen in opioid receptors, including
upregulation in the periphery and a reduction in the brain [30,31]. Substance P, a neuropeptide
associated with chronic pain states, is increased in the cerebrospinal fluid compared with controls [32].
Increased brain and plasma brain-derived neurotrophic factor have been found in FM [33].

● Functional neuroimaging – Differences in activation of pain-sensitive areas of the brain have been
demonstrated by functional neuroimaging techniques, such as functional magnetic resonance imaging
(MRI) [34-37]. Areas of the brain that consistently exhibit greater activation after the same stimulus in FM
patients than controls include the secondary somatosensory cortex, insula, and anterior cingulate cortex
[24].

More limited data, using positron emission tomography, have shown reduced dopaminergic activity in the
response to pain in patients with FM compared with controls [38,39].

Functional MRI was used to compare brain activity during the anticipation of pain with the amount of the
impending pain in FM, RA, and control patients [40]. A unique temporal brain activation of the frontal
cortex was noted in patients with FM, and areas of the motor cortex and the cingulate cortex presented a
FM-specific relation between brain activity during pain anticipation and the magnitude of the subsequent
pain experience.

● Affective and cognitive factors – Both affective and cognitive factors influence pain processing in the
central nervous system [1,2,35]. Patients with FM and comorbid depression demonstrate increased
cerebral blood flow in the amygdala and anterior insula, areas important in the affective pain response
[35]. However, unlike FM, depression does not seem to affect the level of neuronal activation in sensory
pain regions such as the secondary somatosensory cortex [35].

● Morphometric analysis – Morphometric analysis by MRI in patients with FM shows, compared with
healthy controls, a significant reduction in total gray matter volume and a threefold increase in age-
associated loss of gray matter, suggesting premature aging of the brain [41]. The degree of loss was
greater in patients with a longer duration of disease. Such gray matter loss, which is also reported in
other chronic pain and stress-related disorders, was most prominent in regions related to stress and pain
processing but was also seen in areas related to cognitive function. Another study revealed similar
findings [42]. However, a different group found no significant difference in gray matter between FM
patients and controls when controlling for depression [43]. Decreased gray matter in FM patients was
associated with T1 relaxation times, a marker of water content [44]. Regional brain gray matter increases
were associated with GABAA receptor concentration, indicative of neuronal plasticity.

● Using proton magnetic resonance spectroscopy, FM patients had significantly higher levels of glutamine
within the right posterior insula compared with controls [45]. Elevated insular glutamate in FM is
associated with experimental pain. Within the right posterior insula, higher levels of glutamate were
associated with lower pressure pain thresholds.

● Patients with FM were evaluated for cortical excitability and intracortical modulation using transcranial
magnetic stimulation of the motor cortex [46]. The FM patients compared with controls had deficits in
intracortical modulation of GABAergic and glutamatergic mechanisms.

● Using MR spectroscopy, FM patients showed higher levels of glutamate and a higher

glutamine-glutamate/creatine ratio in the right amygdala compared with controls [47]. In the FM patients
 with more pain, fatigue and depressive symptoms inositol (Ins) levels were found to be significantly
higher in the right amygdala and right thalamus.

● Using proton MR spectroscopy, GABA levels in the right anterior insula were significantly lower in FM
patients compared with healthy controls [48]. No significant differences between groups were detected in
the posterior insula or occipital cortex. Within the right posterior insula, higher levels of GABA were
positively correlated with pressure-pain thresholds in the FM patients.

● FM patients exhibited less robust activations during both anticipation of pain and anticipation of relief
within regions commonly thought to be involved in sensory, affective, cognitive, and pain-modulatory
processes [49]. Reduced reward/punishment signaling in FM may be related to the augmented central
processing of pain and reduced efficacy of opioid treatments in these patients.

● FM patients showed a lack of pain reduction impact from a positive emotional context [50]. Compared
with controls, there was less activation in the secondary somatosensory cortex, insula, orbitofrontal
cortex, and anterior cingulate cortex during positive picture pain trials.

● Structural changes and functional connectivity of the brain during application of intermittent pressure-
pain stimuli were compared between 26 patients with FM and 13 age- and sex-matched healthy controls
[51]. The patients displayed a distinct overlap between decreased cortical thickness, decreased brain
volumes, and decreased functional regional coherence in the rostral anterior cingulate cortex. The
structural changes correlated with duration of symptoms.

● Diffusion weighted imaging has demonstrated white matter changes in FM that may be associated with
alterations in pain intensity [52]. The FM group demonstrated lower fractional anisotropy in the left body
of the corpus callosum. These values were negatively associated with sensory pain, suggesting
disruption of white matter micro-structure and an association with clinical pain intensity.

● A systematic review of imaging studies in FM found moderate evidence that central sensitization is
correlated with a gray matter volume decrease in specific brain regions (mainly anterior cingulate cortex
and prefrontal cortex) [53]. They found evidence of decreased functional connectivity in the descending
pain-modulating system in FM patients.

● In one study, abnormal resting state functional connectivity of the periaqueductal gray was noted in FM
subjects compared with controls [54]. The authors suggested that the changes result in impaired
descending pain inhibition. Altered functional connectivity with the default mode network was noted in
FM subjects compared with controls [55]. These alterations varied between brain regions and this
correlated with pain and mood.

● A brain signature that characterizes FM was identified with functional MRI responses to painful pressure
and nonpainful multisensory stimuli. The FM patients demonstrated a greater neurologic pain signature
[56]. Specific pain-related multisensory patterns classified FM patients versus controls with 92 percent
sensitivity and 94 percent specificity. The authors suggested that such brain signatures could result in
objective neurologic targets for therapy.

Sleep abnormalities — Underlying central nervous system dysfunction is suggested by the sleep and mood
disturbances noted in the majority of FM patients [1,2,57]. Phasic alpha sleep activity is most characteristic of
FM [58]. An increase in cyclic alternating patterns of sleep has been noted in FM and has been correlated
with the severity of symptoms [59]. Some data suggest that disordered sleep patterns precede the
development of pain and that abnormal sleep and pain predict depressive symptoms [57].

Some findings suggest a generalized hyperarousal state in FM. As an example, women with FM have similar
nocturnal sleep disturbance to women with rheumatoid arthritis, but FM patients report greater self-rated
daytime sleepiness and fatigue [60].
A longitudinal study of 12,350 women in Norway who did not have musculoskeletal pain or physical
impairments at baseline found incident FM in 327 women at follow-up [61]. There was a dose-dependent
association between sleep problems and risk of FM, with an adjusted relative risk (RR) of FM of 3.43 (95% CI
2.26-5.19) among women who reported having sleep problems often or always, compared with women who
never experienced sleep problems. Age-stratified analysis showed that women age ≥45 years who reported
having sleep problems often or always had an adjusted RR of FM of 5.41 (95% CI 2.65-11.05), while the
corresponding RR for women ages 20 to 44 years who reported having sleep problems often or always was
2.98 (95% CI 1.76-5.05).

In a prospective, population-based study, 19 percent of more than 4000 older adults (≥50 years of age)
reported new widespread pain at follow-up. Nonrestorative sleep was the strongest independent predictor of
new-onset widespread [62].

Compared with patients with osteoarthritis and healthy controls, sleep quality was lowest and there was
greater anxiety and depression in FM patients [63]. However, there were no significant differences in
polysomnographic measures of total sleep time, sleep latency, and total wake-after-sleep onset in the three
groups. Furthermore, levels of alpha-delta sleep were statistically similar in FM and osteoarthritis.

Neurohormonal perturbations — Hyperactivity of the stress response, demonstrated by abnormalities of

the hypothalamic-pituitary-adrenal (HPA) axis, has been found using different baseline and provocative
testing, although the precise nature of these changes has not been elucidated [64-69]. Some neurohormonal
abnormalities have included:

● A correlation between cerebrospinal levels of corticotropin-releasing factor, sensory pain, and variation in
autonomic function in FM that was not associated with chronic fatigue [66]. Altered HPA axis activity may
be linked to childhood trauma, especially physical abuse [67].

● A strong correlation between cortisol levels and pain upon awakening and one hour after waking in
patients with FM compared with controls [68]. Correlations were made between HPA axis function and
lymphocyte glucocorticoid reaction in FM patients [70].

● Abnormal levels of growth hormone in some but not all reports [71]. There is no good evidence to
suggest that there are alterations of sex hormones in FM [72].

Autonomic nervous system dysfunction — Abnormal function of the autonomic nervous system in those
with FM is suggested by the following:

● Patients with FM have been found to have orthostatic hypotension, and increased pain was noted in
response to tilt table testing. FM patients also had significantly abnormal values in a number of
autonomic tests as determined by the Composite Autonomic Symptom Scale (COMPASS) [73].

● Decreased responsiveness to beta-adrenergic stimulation in those with FM was demonstrated by in-vitro

testing of beta adrenergic receptor mediated cyclic AMP generation [74]. The alterations of
cardiovascular regulation that had been postulated to be pathologically important in FM are significantly
affected by deconditioning [75].

● In a study involving 58 women, including FM patients and healthy age-matched controls, urinary
catecholamines and heart rate were assessed for a 24-hour period in a controlled hospital setting
(including relaxation, a test with prolonged mental stress, and sleep) and during daily activity [76].The
catecholamine levels were lower in FM patients than in controls. Patients with FM had significantly lower
adrenaline levels during the night and the second day and had significantly lower dopamine levels during
the first day, the night, and the second day. Overall, heart rate was significantly higher in patients than in
controls.

● In another approach, plasma catecholamines, ACTH, and cortisol were reduced in 16 FM patients
compared with 16 healthy controls as they performed static knee extension until exhaustion [77].
 ● Nocturnal heart rate variability indices were significantly different in FM women compared with healthy
individuals [78]. In FM patients, these HRV parameters correlated with several symptoms including pain
severity.

● Another report found that blunted heart rate response to exercise was noted in FM adolescents
compared with matched controls [79]. Delayed heart rate recovery suggested autonomic cardiac
impairment in FM.

Immune system changes — There is little evidence to support the concept that FM is an immune mediated
disorder [1,2]. Autoantibodies with affinity for a 68/48 kD protein have been found in a subset of patients with
FM but not in healthy controls [80]. Other cytokine changes have been reported, but studies have not been
consistent or controlled well for mood disturbances and activity levels [81].

A 2011 systematic review and meta-analysis concluded that the role of cytokines in FM is unclear [82]. In
general, FM patients had higher serum levels of IL-1 receptor antagonist, IL-6, and IL-8 and had higher
plasma levels of IL-8. Meta-analysis of eligible studies showed that FM patients had higher plasma IL-6 levels
compared with controls (standardized mean difference = -0.34 [95% CI -0.64 to -0.03]). The majority of
investigated cytokines did not differ between patients and controls. Subsequently, one small study found that
patients with FM exhibited a reduction in TH2 cytokines such as IL-4, IL-5, and IL-13 [83].

Peripheral pain mechanisms — FM patients often have focal tissue abnormalities including myofascial
trigger points, ligamentous trigger points, or osteoarthritis of the joints and spine. These are important
peripheral pain generators that may initiate or perpetuate chronic pain [84]. Other studies have found
evidence of peripheral neuropathic changes, including neurologic examination findings and reductions in
epidermal nerve fiber density suggestive of small fiber neuropathy [85-88].

Examples of studies suggesting a role for peripheral pain mechanisms include:

● Sustained isometric muscle contraction recruits segmental and/or extra-segmental descending inhibition
in healthy subjects but not in FM [89]. Descending pain modulation shifts from descending inhibition
toward descending facilitation following muscle nociception in FM. Peripheral mechanical hyperalgesia
and descending facilitation counterbalance the effect of descending inhibition in FM.

● Several studies have suggested that there may be a relationship in some patients between FM and small
fiber neuropathy [85-88]. However, these studies have not carefully controlled for levels of physical
fitness and activity, and some of the observed abnormalities could be a consequence of pain and
deconditioning.

• A case-control study compared the function and morphology of small nerve fibers in 25 patients with
FM syndrome with patients with depression and with healthy controls [85]. Patients with FM
syndrome had increased levels of neuropathic pain based upon responses to questionnaires
designed to assess this type of pain. Additionally, patients with FM syndrome but not patients with
depression had impaired small fiber nerve function compared with controls, demonstrating
increased cold- and warm-detection thresholds in quantitative sensory testing, increased N1
latencies upon stimulation at the feet, and reduced amplitudes of pain-related evoked potentials
upon stimulation of face, hands, and feet. In skin biopsies, total and regenerating intraepidermal
nerve fibers at the lower leg and upper thigh were reduced in patients with FM syndrome compared
with the control subjects. Accordingly, a reduction in dermal unmyelinated nerve fiber bundles was
found in skin samples of patients with FM syndrome compared with patients with depression and
with healthy controls, while myelinated nerve fibers were spared.

• A study involving 27 patients with FM and 30 controls found that a significantly greater proportion of
patients with FM had abnormal skin biopsies demonstrating findings consistent with small fiber
peripheral neuropathy (41 versus 3 percent), suggesting that an underlying small-fiber
polyneuropathy may cause symptoms sometimes identified as being due to FM [86]. Another
 uncontrolled study of patients referred for the evaluation of primary FM without associated medical
comorbidities identified 6 of 20 patients who met criteria for small fiber neuropathy; electrodiagnostic
studies were normal in all patients [87].

• A study involving 41 patients with FM and 47 healthy controls reported findings suggestive of both a
diffuse and a length-dependent neuropathic process [88]. There was evidence of stocking
distribution hypesthesia in all patients with FM, Mean calf and thigh epidermal nerve fiber density
(ENFD) was reduced in the group with FM compared with the controls, although there was
substantial overlap in the values. Other results included a weak but statistically significant inverse
correlation between calf ENFD and age in the FM patients but not the controls. Among several
immunologic studies that were performed the one abnormality noted was an inverse correlation
between calf nerve fiber density in FM and serum levels of the IL-2 receptor.

● Some studies have suggested that metabolic changes may be present in the muscle of patients with FM
[90]. In one study, comparing 19 patients with FM and 14 controls, concentrations of adenosine
triphosphate (ATP) and phosphocreatinine (PCr) were significantly lower (28 to 29 percent) in quadriceps
muscle in the patients with FM [90]. The quadriceps muscle fat content was significantly greater in the
patients with FM, who also exhibited lower physical capacity in the hands and legs, which correlated with
the reduced concentrations of ATP and PCr. These findings were consistent with changes that could
result from a combination of inactivity related to pain and muscle mitochondrial dysfunction.

● One study has suggested that alterations in skeletal muscle, such as altered muscle fiber size
distribution and decreased capillary density, may contribute to postexertional fatigue in FM [91]. In this
study, FM patients exhibited greater variability in muscle fiber size and altered fiber size distribution
compared with controls. FM patients with the highest percentage of type-1 muscle fibers recovered
strength most effectively, and this was correlated with capillary density. However, overall, capillary
density was lower in the FM patients.

SUMMARY

● There is conclusive evidence that alterations in central nervous system pain processing are responsible
for many of the features of fibromyalgia (FM). Studies suggest that a neurologic signature may be useful
diagnostically and in future therapeutic trials [56].(See 'Pathogenesis' above and 'Altered pain
processing' above.)

● Genetic and environmental factors likely interact to promote a state of chronic central and peripheral
nervous system hyperirritability. (See 'Genetic predisposition' above and 'Candidate genes' above.)

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Topic 5626 Version 13.0

Contributor Disclosures
Don L Goldenberg, MD Consultant/Advisory Boards: Pfizer [Fibromyalgia (pregabalin)]. Peter H Schur,
MD Nothing to disclose Paul L Romain, MD Nothing to disclose

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