Version May 2024
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]. FM is often best viewed as a syndrome rather than a disease.
The pathogenesis of FM 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]. Among patients with FM, central sensitization may be accompanied by peripheral pain mechanisms, including neuropathic pain, such as small fiber neuropathy (SFN) [4], and nociceptive pain, such as an inflamed joint. (See 'Peripheral pain mechanisms' below.)
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 [1,2,5-7]. 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 [6,7]. 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, vulvodynia, irritable bladder 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 [8].
●Familial studies – First-degree relatives of patients with FM are 8.5 times more likely to have FM than relatives of patients with rheumatoid arthritis [9]. 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 [10-12].
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 [13]. Overall, the FM phenotype had an estimated heritability of 14 percent. FM patients were found to have a relatively unique family genetic risk profile that differed markedly from that of classic autoimmune diseases or major depression but overlapped with that for irritable bowel and chronic fatigue syndromes [14].
●Genome-wide association studies – Candidate gene studies in FM have demonstrated significant differences in allele frequencies between FM cases and controls [11]. A genome-wide linkage study found an estimated sibling recurrence risk ratio for FM of 13.6, based upon a reported FM population prevalence of 2 percent [12].
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 [15]. Another 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 [16]. This study could not confirm the association with catechol-O-methyltransferase (COMT) in chronic widespread pain.
●Epigenetic studies – Epigenetics, which involves the study of hereditary changes not attributable to alterations in deoxyribonucleic acid (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 [17]. The epigenetics of brain-derived neurotrophic factor (BDNF) was studied in patients with FM and comorbid myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [18]. 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.
●Serotonin and opioid pathways – 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 COMT, mu-opioid receptors, voltage-gated sodium channels, guanosine triphosphate (GTP) cyclohydrolase 1, and gamma-aminobutyric acid (GABA)ergic pathways [8,10].
Specific genes involved in the serotonin and opioid pathways have been evaluated in FM, although it is difficult to distinguish their impact on pain, fatigue, mood, or to control for patient lifestyle variables [19].
FM studies suggest that there are opposing genetic interactions between opioid and serotonergic pathways [20]. Polymorphisms of the mu-opioid receptor gene were found to influence brain pain processing in patients with FM [21].
CENTRAL NERVOUS SYSTEM ALTERED PAIN PROCESSING — Even prior to the advances in brain imaging studies in fibromyalgia (FM), multiple lines of evidence had demonstrated that 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 [5,22].
●Decreased endogenous pain inhibition – Endogenous analgesic systems appear to be deficient in FM [23].
●Pain receptors and pain-related neuropeptides – Changes are seen in opioid receptors, including upregulation in the periphery and a reduction in the brain [24,25], as well as an increased brain and plasma brain-derived neurotrophic factor (BDNF) [26].
●Central hypersensitivity – 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 [27]. Quantitative sensory testing demonstrated hypersensitivity to sound, as well as to heat and mechanical pain, in patients with FM compared with healthy controls [28].
PATHOPHYSIOLOGIC STUDIES IN FIBROMYALGIA
Heightened pain response to experimental pain stimulus — Functional magnetic resonance imaging (fMRI) demonstrated that patients with fibromyalgia (FM) had greater neuronal activity in pain-processing brain regions compared with controls, following the same pressure stimuli [29]. Differences in activation of pain-sensitive areas of the brain have also been noted with fMRI [30].
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 [31]. 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 [32]. 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 [33]. 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 [34].
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 [35]. 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.
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 [36]. 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 [37]. 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 microstructure 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) [38]. Multimodal brain imaging demonstrated that the reduced gray-matter volumes in FM patients correlated with decreased tissue water content rather than gamma-aminobutyric acid (GABA) receptor concentration, suggesting neuronal plasticity [39].
Altered neurotransmitter function — Using proton MR spectroscopy, patients with FM had significantly higher levels of glutamine within the right posterior insula compared with controls [40]. 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 [41]. 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 [42]. 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 [43]. 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 — Abnormal resting-state functional connectivity of the periaqueductal gray was found in FM subjects compared with controls [44]. 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 [45]. Altered spinal cord neuronal activity between the ventral and dorsal spinal cord was found in FM but not in controls [46]. Resting-state fMRI demonstrated altered hub structure, regions that effectively transmit neural information, in FM compared with controls [47]. 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.
Specific pain-related multisensory patterns classified patients with FM versus controls with 92 percent sensitivity and 94 percent specificity [2]. 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 [48]. Many of the structural and functional changes noted in FM have also been demonstrated in overlapping disorders, including chronic fatigue syndrome (CFS) and irritable bowel syndrome (IBS) [49].
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) [1,2,50]. Phasic alpha sleep activity is most characteristic of FM [51]. Some data suggest that disordered sleep patterns precede the development of pain and that abnormal sleep and pain predict depressive symptoms [50]. 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 [52].
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 [53]. 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.
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 [54].
Compared with patients with osteoarthritis and healthy controls, sleep quality was lowest and there was greater anxiety and depression in patients with FM [55]. 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 [56].
STRESS/AUTONOMIC NERVOUS SYSTEM 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 [57].
Hypothalamic-pituitary-adrenal axis 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 [58]. There was a correlation between cerebrospinal levels of corticotropin-releasing factor, sensory pain, and variation in autonomic function in patients with FM [59]. 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 [60]. 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 [61]. Serum cortisol levels, considered a proxy for stress, varied with the severity of neuropsychological deficits in patients with FM [62], and a systematic review failed to find a significant alteration of blood levels of cortisol, adrenocorticotropic hormone (ACTH), corticotrophin-releasing hormone (CRH) and epinephrine in FM [63].
Evidence for ANS dysfunction includes:
●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 [64]. 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.
●Nocturnal heart rate variability (HRV) indices indicative of sympathetic predominance were significantly different in women with FM when compared with healthy individuals [65]. 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 [66].
●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 [67]. The association of tonic sweating and ANS abnormalities in FM patients may be important in driving central sensitization [68].
PERIPHERAL PAIN MECHANISMS — Although fibromyalgia (FM) is considered to be a nociplastic pain disorder, peripheral pain mechanisms are often involved. The three traditional pain categories (nociceptive, neuropathic, and nociplastic) overlap. In a patient with FM, both neuropathic and nociceptive pain must be considered [69]. (See "Overview of chronic widespread (centralized) pain in the rheumatic diseases".)
Small fiber neuropathy — Several studies have suggested that FM is often associated with a small fiber neuropathy (SFN) [70-73]. SFN may be defined by a skin biopsy demonstrating reduced intraepidermal nerve fiber (IENF) density or electrochemical skin conductance (ESC) [4]. Clinically, FM may present with hyperesthesia in a stocking distribution, and there may be evidence of both a diffuse and length-dependent neuropathic process [73].
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 [74]. 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 [75]. 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 [76]. For example, reduced IENF density has been found in conditions not typically associated with pain, such as amyotrophic lateral sclerosis [77]. SFN has been commonly noted in patients with complex, chronic pelvic pain [78], and there has been no correlation of reduced IENF density with neuropathic pain symptoms [79].
Central sensitization may be the driving force of SFN in FM [4]. 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 [80,81]. In a proof-of-concept animal study, increasing endogenous glutamate in the insula caused pain behavior and decrease in IENF density [82]. The reduction of IENF density may be very localized and distal or more generalized, and those FM patients with a generalized reduction of skin innervation had greater symptoms [83].
Muscles and tendons — Although there has been no evidence for structural muscle abnormalities in FM [6,7], one study reported lower concentrations of adenosine triphosphate (ATP) and phosphocreatinine (PCr) in quadriceps muscle in the patients with FM compared with controls [84]. 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.
Another report found that patients with FM exhibited greater variability in muscle fiber size and altered fiber size distribution compared with controls [85].
Myofascial trigger points have been considered to be a discrete source of pain in FM, although there has been controversy regarding their nature and pathology [86].
IMMUNE ABNORMALITIES — Fibromyalgia (FM) is not considered to be a classic systemic immune disorder [1]. A 2011 systematic review and meta-analysis concluded that the role of cytokines in FM is unclear [87]. 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 antiinflammatory pattern [88]. However, the immune system interacts with both peripheral and central pain mechanisms resulting in a neuroinflammatory loop with upregulated pain peripherally and centrally [89].
This suggests that immune/inflammatory pathways sensitize peripheral and central pain pathways, creating “bottom-up” nociplastic pain.
In an animal model of FM, immunoglobulin (IgG) from FM patients injected into mice caused increased pain sensitivity in the mice and altered pain nerve fiber density [90]. Subsequently, a subset of FM patients had elevated levels of anti-SGC antibodies that correlated with symptom severity [91]. Such studies suggest that the immune system may activate glial and other brain cells, driving the chronic pain process.
SUMMARY
●Genetics – Familial, genome-wide association, and epigenetic studies imply a genetic role in fibromyalgia (FM), possibly through alteration of the serotonin and opioid pathways, but no specific candidate gene has been identified. (See 'Genetic predisposition and candidate genes' above.)
●Central sensitization – There is conclusive evidence that alterations in central nervous system (CNS) pain processing are responsible for many of the features of 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. (See 'Introduction' above and 'Terminology and pain classification' above and 'Central nervous system altered pain processing' above.)
●Nervous system hyperirritability – Fibromyalgia is associated with hyperirritability of the CNS, peripheral nervous system, and autonomic nervous system (ANS).
•Central nervous system – Sleep, mood, cognitive disturbances, stress, genetics, and environmental factors each contribute to the CNS hyperirritability. (See 'Sleep/mood/cognitive abnormalities' above.)
•Peripheral nervous system – 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.)
Other 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 (IENF) density, has been noted commonly in FM, although its causal role is controversial. (See 'Peripheral pain mechanisms' above.)
•Autonomic nervous system – Patients with fibromyalgia may also have dysfunction of the ANS, leading to a hyperactive stress response. (See 'Stress/autonomic nervous system dysfunction' above.)
●Role of peripheral nociceptive mechanisms – Peripheral nociceptive mechanisms are not typically thought to play an important role in FM pathogenesis, particularly in patients with no concurrent immune or inflammatory disorder. However, especially in patients with systemic, inflammatory disease, peripheral nociceptive mechanisms are important and interact with immune/inflammatory pathways. (See 'Peripheral pain mechanisms' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
