INTRODUCTION — The characteristic feature of fibromyalgia (FM) is chronic widespread pain in the absence of peripheral musculoskeletal inflammation or structural damage. FM may complicate many rheumatic diseases or occur independently. FM is only one of many causes of widespread pain. (See "Overview of chronic widespread (centralized) pain in the rheumatic diseases".)
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 [1,2].
The pathogenesis of fibromyalgia is presented here. A detailed description of the clinical manifestations of FM and an approach to the diagnosis and differential 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" and "Differential diagnosis of fibromyalgia".)
TERMINOLOGY AND PAIN CLASSIFICATION — Fibromyalgia (FM) is considered to be a disorder of pain regulation, often classified under the term central sensitization [1-3] (see 'Central nervous system altered pain processing' below). Central sensitization has been defined as an amplification of neural signaling within the central nervous system (CNS) resulting in pain hypersensitivity [3]. The International Association for the Study of Pain has suggested a new mechanism description, nociplastic pain, to encompass conditions characterized by altered pain sensitization [3].
During much of the 20th century, FM was thought to be a muscle disease or related to soft-tissue inflammation, hence the term fibrositis. However, controlled comparisons found no evidence for significant pathologic or biochemical muscle abnormalities [1,2,4-6]. 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 controls [5,6]. Soft-tissue tender points, initially part of the FM diagnostic criteria, represent CNS pain dysregulation rather than localized pathology [1-3].
FM shares several clinical and pathophysiologic 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. Clinical characteristics of each of these conditions include widespread pain, fatigue, and sleep and mood disturbances. These conditions also share common genetic and CNS pain processing mechanisms with FM. 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.)
GENETIC PREDISPOSITION AND CANDIDATE GENES — A number of observational and biologic studies suggest that chronic widespread pain and fibromyalgia (FM) have, in part, a genetic basis [7]. First-degree relatives of patients with FM are 8.5 times more likely to have FM than relatives of patients with rheumatoid arthritis [8]. 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 clear association between chronic widespread pain and any single candidate gene has yet been conclusively documented [9].
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. Pain-related genes that have been potentially associated with FM include those for catechol-O-methyltransferase (COMT), mu-opioid receptors, voltage-gated sodium channels, GTP cyclohydrolase 1, and gamma-aminobutyric acid (GABA)ergic pathways [7,9].
The first large candidate gene study evaluated 496 patients with FM and 348 chronic pain-free controls [10]. 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 patients with FM 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 [11]. 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.
A subsequent genome-wide profiling found that, compared with controls, patients with FM had differences in expression of 421 genes, many of which were important in pain processing [12]. They used diagnostic models and identified a subset of 10 gene signature sets that provided 95 percent sensitivity and specificity for FM.
A genome-wide association study of nearly 7000 patients with chronic widespread pain found an association with the RNF123 locus and possible association with the ATP2C1 locus, both involved in calcium regulation [13]. This study could not confirm the association with COMT in chronic widespread pain.
Experimental pain studies have demonstrated that the COMT polymorphism affects central pain [7]. COMT regulates the catabolism of catechol neurotransmitters, including epinephrine, norepinephrine, and dopamine. The frequency of genetic variations associated with low COMT enzyme activity was significantly higher in patients with FM than in healthy volunteers [14]. Patients with FM 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 patients with FM than healthy controls [15].A case-control study of more than 400 Korean patients with FM and 400 controls found that polymorphisms of the COMT gene correlated with the risk for FM as well as pain sensitivity [16]. However, other studies have not found a direct association of COMT haplotypes with FM, including one report of over 2700 patients with FM [17]. In that report, the minor COMT alleles were overrepresented, suggesting that COMT may indirectly influence FM.
Specific genes involved in the serotonin pathway also increase the risk of conditions like FM, although it has been difficult to determine whether this is a marker of psychological status or pain propensity [18]. Polymorphisms in the serotonin receptor gene (HTR1A) did not differ in patients with FM compared with controls and did not correlate with pain or other symptoms in patients with FM [19].
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 patients with FM and matched controls [22]. They found opposing interactions between opioid and serotonergic pathways. Polymorphisms of the u-opioid receptor gene were found to influence brain pain processing in patients with FM [23]. G-allele carriers demonstrated increased activation in the precentral gyrus but decreased functional connectivity with the frontal control network with painful stimuli.
Genotype frequencies in 314 Spanish women with FM were compared with controls [24]. Single nucleotide polymorphism associations of guanosine triphosphate cyclohydrolase 1, COMT, and opioid receptor (OPRM1) genes with FM were found. There has also been an association of FM with brain-derived neurotrophic factor (BDNF) gene polymorphisms [25].
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 patients with FM 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 [26].
Epigenetics, which involves the study of hereditary changes not attributable to alterations in DNA sequence, may provide new approaches to gene-environment interactions in conditions like FM. For example, DNA methylation and histone modification alter gene expression without changes in DNA. DNA methylation in patients with FM differed from healthy controls, including in genes involved in DNA repair and membrane transport [27]. The epigenetics of BDNF was studied in patients with FM and comorbid myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [28]. The serum BDNF were elevated, and lower BDNF methylation predicted higher BDNF levels and correlated with patients' symptoms and widespread pain in the FM/ME/CFS subjects.
In a study of FM in 26,749 individuals undergoing elective surgery, younger patients with an FM phenotype had a stronger genetic component than older individuals [29]. Overall, the FM phenotype had an estimated heritability of 14 percent.
CENTRAL NERVOUS SYSTEM ALTERED PAIN PROCESSING — Multiple lines of evidence have demonstrated that fibromyalgia (FM) is a disorder of pain processing, including the following:
●Temporal summation of pain – Patients with FM 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 [4,30].
●Decreased endogenous pain inhibition – Endogenous analgesic systems appear to be deficient in FM [31]. 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 [32,33].
●Pain receptors and pain-related neuropeptides – Changes are seen in opioid receptors, including upregulation in the periphery and a reduction in the brain [34,35]. Substance P, a neuropeptide associated with chronic pain states, is increased in the cerebrospinal fluid compared with controls [36]. Increased brain and plasma brain-derived neurotrophic factor have been found in FM [37].
●The increased pain sensitivity in FM is part of a generalized hypersensitivity to sensory stimuli, including to visual, auditory, and olfactory stimuli. Patients with FM, compared with healthy controls, have exhibited increased brain responses to both pain onset and pain offset [38]. Quantitative sensory testing (QST) demonstrated hypersensitivity to sound, as well as to heat and mechanical pain, in patients with FM compared with healthy controls [39].
BRAIN NEUROIMAGING
Heightened pain response to experimental pain stimulus — Functional magnetic resonance imaging (fMRI) demonstrated that patients with FM had greater neuronal activity in pain-processing brain regions compared with controls, following the same pressure stimuli [40]. Differences in activation of pain-sensitive areas of the brain have also been noted with fMRI [41]. Areas of the brain that consistently exhibit greater activation after the same stimulus in patients with FM than controls include the secondary somatosensory cortex, insula, and anterior cingulate cortex [41].
fMRI has also been utilized to demonstrate the important role of comorbid psychological factors on pain perception in patients with FM [42]; patients with FM and comorbid depression demonstrate increased cerebral blood flow in the amygdala and anterior insula, areas important in the affective pain response. However, unlike FM, depression does not seem to affect the level of neuronal activation in sensory pain regions such as the secondary somatosensory cortex.
Patients with FM 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 [43]. 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.
Patients with FM showed a lack of pain reduction impact from a positive emotional context [44]. Compared with controls, there was less activation in the secondary somatosensory cortex, insula, orbitofrontal cortex, and anterior cingulate cortex during positive picture pain trials.
fMRI demonstrated that, compared with controls, patients with FM had greater neuronal activity during catastrophizing, particularly in regions of the posterior cingulate cortex [45]. However, an arterial spin labelling study found no significant differences in resting state blood flow in pain processing areas between patients with FM and healthy controls [46].
Changes in brain morphology — 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 [47]. 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 [48]. However, a different group found no significant difference in gray matter between patients with FM and controls when controlling for depression [49]. Decreased gray matter in patients with FM was associated with T1 relaxation times, a marker of water content [50]. Regional brain gray matter increases were associated with GABAA receptor concentration, indicative of neuronal plasticity.
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 rostral anterior cingulate cortex in the patients with FM exhibited decreased cortical thickness, brain volume, and regional functional connectivity compared with the controls. 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 patients with FM.
Altered neurotransmitter function — Using proton magnetic resonance (MR) spectroscopy, patients with FM had significantly higher levels of glutamine within the right posterior insula compared with controls [54]. 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. More limited data, using positron emission tomography, have shown reduced dopaminergic activity in the response to pain in patients with FM compared with controls [55].
Patients with FM were evaluated for cortical excitability and intracortical modulation using transcranial magnetic stimulation of the motor cortex [56]. The patients with FM compared with controls had deficits in intracortical modulation of GABAergic and glutamatergic mechanisms. Using MR spectroscopy, patients with FM showed higher levels of glutamate and a higher glutamine-glutamate/creatine ratio in the right amygdala compared with controls [57]. In the patients with FM 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 patients with FM compared with healthy controls [58]. 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 patients with FM.
Changes in resting-state functional connectivity — fMRI has been particularly useful in evaluating brain connectivity [41,59]. In one study, abnormal resting state functional connectivity of the periaqueductal gray was noted in FM subjects compared with controls [60]. The authors suggested that the changes result in impaired descending pain inhibition. Altered functional connectivity with the default mode network, a region active when the brain is at rest, and the insula, a key pain-processing region, was noted in FM subjects compared with controls [61]. Altered spinal cord neuronal activity between the ventral and dorsal spinal cord was found in FM but not in controls [62]. Resting-state fMRI demonstrated altered hub structure, regions that effectively transmit neural information, in FM compared with controls [63]. Altered hub topology within the insula was associated with clinical pain intensity. The neural organization of intrinsic functional brain hubs or communities in patients with FM differed from that of controls without FM, demonstrating decreased neural stability [64]. Changes in this neural organization correlated with levels of pain.
fMRI was utilized to identify a brain signature that may characterize FM by following responses to painful pressure and nonpainful multisensory stimuli [2]. Specific pain-related multisensory patterns classified patients with FM versus controls with 92 percent sensitivity and 94 percent specificity. The neuroimaging brain response to pain-related fear was explored as a brain signature of FM and found to be a predictor of FM as well as its treatment response [65].
SLEEP/MOOD/COGNITIVE ABNORMALITIES — Underlying central nervous system (CNS) dysfunction is suggested by the sleep, mood, and cognitive disturbances noted in the majority of patients with fibromyalgia (FM) [1,2,66]. Phasic alpha sleep activity is most characteristic of FM [67]. Some data suggest that disordered sleep patterns precede the development of pain and that abnormal sleep and pain predict depressive symptoms [66]. 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 patients with FM report greater self-rated daytime sleepiness and fatigue [68].
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 [69]. 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 pain [70].
Sleep, mood, and cognitive disturbances are each interconnected and correlate with pain severity in FM, as noted in brain imaging studies discussed above [42-44]. Compared with patients with osteoarthritis and healthy controls, sleep quality was lowest and there was greater anxiety and depression in patients with FM [71]. 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. The quality of sleep was a strong mediator of attention, cognitive tests, and pain severity in FM [72].
STRESS/AUTONOMIC NERVOUS SYSTEM (ANS) DYSFUNCTION — The association of pain with sleep, mood, and cognitive abnormalities has been linked to stress reactivity and autonomic nervous system (ANS) dysfunction in fibromyalgia (FM). Sleep disturbances increase pain, which increases sympathetic cardiovascular reactivity [73].
Hypothalamic pituitary axis (HPA) and stress — 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 [74]. There was a correlation between cerebrospinal levels of corticotropin-releasing factor, sensory pain, and variation in autonomic function in patients with FM [75]. There was also a strong correlation between cortisol levels and pain upon awakening and one hour after waking in patients with FM compared with controls [76]. Subjects with chronic widespread pain had higher serum cortisol levels than controls, and there was a significant correlation of HPA axis dysfunction with developing chronic widespread pain [77]. Serum cortisol levels, considered a proxy for stress, varied with the severity of neuropsychological deficits in patients with FM [78], and a systematic review failed to find a correlation of cortisol levels or reactivity with pain in patients with FM [79].
Evidence for ANS dysfunction include:
●Decreased responsiveness to beta-adrenergic stimulation in those with FM was demonstrated by in-vitro testing of beta adrenergic receptor-mediated cyclic AMP generation [80].
●In a study involving 58 women, including patients with FM 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 [81].The catecholamine levels were lower in patients with FM 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 and ACTH were reduced in 16 patients with FM compared with 16 healthy controls as they performed static knee extension until exhaustion [82].
●Nocturnal heart rate variability (HRV) indices were significantly different in women with FM compared with healthy individuals [81]. In patients with FM, these HRV parameters correlated with several symptoms including pain severity.
●Nocturnal HRV indices indicative of sympathetic predominance were significantly different in women with FM when compared with healthy individuals [83]. In patients with FM, these HRV parameters correlated with several symptoms including pain severity. Opposite associations were seen in controls. They concluded that nocturnal HRV analyses are potential FM biomarkers. Patients with FM often demonstrate a hypertonic stress response, including increased blood pressure, when exposed to a painful stimulus [84].
●Alterations in skin conductance, an indirect measure of sweating, were found in patients with FM compared with controls, and skin conductance varied less with stress and pain in FM [85].
PERIPHERAL PAIN MECHANISMS — Peripheral pain generators in fibromyalgia (FM) patients may include myofascial trigger points, ligamentous trigger points, or osteoarthritis of the joints and spine [86]. For example, FM is more common in patients with systemic rheumatic diseases or regional pain, such as chronic low back pain or complex regional pain syndrome. (See "Overview of chronic widespread (centralized) pain in the rheumatic diseases".)
●Small fiber neuropathy – Several studies have suggested that there may be a relationship between FM and small fiber neuropathy (SFN) [87-90]. SFN has been defined by a skin biopsy demonstrating reduced intraepidermal nerve fiber (IENF) density in these reports.
•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 [87]. 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 (QST), increased N1 latencies upon stimulation at the feet, and reduced amplitudes of pain-related evoked potentials upon stimulation of face, hands, and feet.
•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 [88]. 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 [89].
•A study involving 41 patients with FM and 47 healthy controls reported findings suggestive of both a diffuse and a length-dependent neuropathic process [90]. There was evidence of stocking distribution hypesthesia in all patients with FM.
•A systematic review of 222 patients with FM reported an estimated prevalence of 30 to 76 percent of SFN in FM, with a moderately high level of heterogeneity [91]. The authors concluded that 49 percent of patients with FM have "structural abnormalities of the small nerve fibers." One-hundred and fifty-five patients with FM with neuropathic symptoms underwent skin biopsies for SFN and nerve conduction studies [92]. Sixty percent were skin biopsy negative, 28 percent demonstrated distal extremity-reduced IENF density, and 12 percent had proximal extremity-reduced IENF density. Sural and medial plantar nerve conduction slowing correlated with reduced IENF density, as did markers of metabolic syndrome. However, pain quality and intensity did not distinguish patient subgroups.
However, there is a lack of consensus whether the association of reduced IENF with FM has any pathophysiologic significance [93]. For example, reduced IENF density has been found in conditions not typically associated with pain, such as amyotrophic lateral sclerosis [94]. SFN has been commonly noted in patients with complex, chronic pelvic pain [95], and there has been no correlation of reduced IENF density with neuropathic pain symptoms [96].
Clinically, SFN presents with a very different pain profile than FM. The finding of SFN in the lower extremities would not account for the chronic widespread pain involving the neck, shoulders, chest wall, and trunk or the chronic fatigue, mood and sleep disturbances characteristic of FM. Brain imaging in patients with SFN demonstrates structural and functional changes characteristic of central sensitization [97,98]. In a proof-of-concept animal study, increasing endogenous glutamate in the insula caused pain behavior and decrease in IENF density [99].
●Although there has been no evidence for structural muscle abnormalities in FM [5,6], a few reports have noted metabolic changes in the muscle of patients with FM [100]. 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 [100]. 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 [101]. In this study, patients with FM exhibited greater variability in muscle fiber size and altered fiber size distribution compared with controls. patients with FM 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 patients with FM.
IMMUNE ABNORMALITIES — There is limited evidence to support the concept that fibromyalgia (FM) is an immune-mediated disorder [1]. A 2011 systematic review and meta-analysis concluded that the role of cytokines in FM is unclear [102]. A systematic analysis found significant differences in peripheral blood cytokine profiles in patients with FM compared with healthy controls, but there was no distinct pro- or anti-inflammatory pattern [103]. The secretion of interleukin 5 (IL-5) was associated with pain and specific monocyte subsets in patients with FM [104].
SUMMARY
●There is conclusive evidence that alterations in central nervous system (CNS) pain processing are responsible for many of the features of fibromyalgia (FM). Brain imaging has provided the strongest evidence for this central sensitization, including an exaggerated pain response to experimental pain stimulus, altered structural and neurotransmitter function, and changes in resting-state functional connectivity. Studies suggest that an FM neurologic signature may be useful diagnostically and in future therapeutic trials [2]. (See 'Introduction' above and 'Terminology and pain classification' above and 'Central nervous system altered pain processing' above.)
●Sleep, mood, and cognitive disturbances, as well as stress-related factors involving the autonomic nervous system (ANS), each contribute to the CNS hyperirritability. (See 'Sleep/mood/cognitive abnormalities' above.)
●Genetic and environmental factors likely interact to promote a state of chronic central and peripheral nervous system hyperirritability. (See 'Genetic predisposition and candidate genes' above.)
●Peripheral factors that may augment central pain processing include peripheral nerves and muscle. Small fiber neuropathy (SFN), defined by skin biopsy demonstrating reduced intraepidermal nerve fiber density, has been noted commonly in FM, although its causal role is controversial.
