Fibromyalgia

While the cause of fibromyalgia remains unclear, it is thought to be one of many chronic pain disorders that co-aggregate strongly in individuals and families, including irritable bowel syndrome, temporomandibular joint disorder, interstitial cystitis, vulvodynia, and tension headaches. The preferred terms for these conditions are 'central sensitisation syndrome' and chronic overlapping pain conditions (COPCs).

The underlying mechanism of pain originating from the central nervous system is now referred to as nociplastic pain. Individuals will sometimes only have one of these 'idiopathic' pain syndromes over the course of their lifetime; but more often, people with one of these entities, and their family members, are likely to have several of these conditions.[16][17] A variety of chronic pain conditions are highly familial, and specific genetic polymorphisms that increase or decrease pain processing are rapidly being identified.[18][19][20]

Some patients may have comorbid psychiatric conditions, the most common being depression/major depressive disorder.[21] However, studies demonstrate that these pain syndromes differ and are separable from depression and anxiety, and have strong genetic underpinnings.[22][23][24][25]

Women are more likely to have these disorders than men (approximately 1.5 times as likely), but the sex difference is much more pronounced in fibromyalgia than in other chronic pain conditions due to unintended consequences of requiring a certain number of tender points in the 1990 American College of Rheumatology criteria. In addition, clinical samples (especially in tertiary care) tend to over-represent females compared with population-based samples.[26][27]

The pathophysiology of fibromyalgia remains unclear, it is unlikely there is any single cause. Evidence supports the involvement of the central nervous system, autonomic nervous system, the peripheral nervous system, neuroendocrine changes, sleep changes, immune alteration, and genetic changes.

Central nervous system

Evidence suggests that patients with fibromyalgia experience altered pain processing, leading to temporal summation of pain, decreased endogenous pain inhibition, and increased pain receptors and pain-related neuropeptides, leading to altered neurotransmitter function, blood flow changes, and eventually general hypersensitivity.[28][29][30][31][32][33][34]

Studies have demonstrated increased pain sensitivity, hypersensitivity to visual, auditory and olfactory sensory stimuli in patients with fibromyalgia.[35][36]

Sleep changes

Brain imaging studies suggest that sleep, mood/emotion, and cognitive disturbances are connected and may correlate with the severity of pain in patients with fibromyalgia (FM).[37][38][39][40][41]

Studies have demonstrated that disordered sleep patterns are antecedent of the development of pain and that abnormal sleep and pain may predict depressive symptoms.[42][43][44][45] It has been suggested that patients with FM suffer from a generalised state of hyperarousal.[46]

When compared with patients with osteoarthritis, patients with FM have significantly lower quality of sleep, and significantly higher levels of anxiety, and depression.[47] Prospective longitudinal data infer a dose-dependent association between the risk of FM and disordered sleep in women with FM.[48]

Neuroendocrine changes

It has been proposed that patients with FM experience cortisol dysregulation. Studies suggest that patients with FM have a higher level of cortisol, some of whom have shown an association between the degree of cortisol elevation and pain.[49][50] The results of one meta-analysis which assessed the relationship between cortisol reactivity and pain symptoms in patients with FM indicate some individual effects of therapeutic interventions on both cortisol levels and several measures of pain, though the overall effect sizes were not significant.[51]

Dysfunction of the autonomic nervous system

Abnormalities of the hypothalamic-pituitary-adrenal axis found in patients with fibromyalgia suggest a hyperactivity of stress response.[52][53][54]

Other measures of autonomic nervous system dysfunction in patients with fibromyalgia have been demonstrated by studies measuring catecholamine levels, adrenocorticotropic hormone levels (ACTH), and nocturnal heart rate variability (HRV). Urinary and plasma catecholamine levels and ACTH levels have been found to be lower in patients with FM, compared with healthy matched controls.[55][56]

HRV is harmonised by the effect of the sympathetic and parasympathetic branches of the autonomic nervous system on the sinus node. In resting conditions, a lower HRV reflects sympathetic predominance on the sinus node. Sympathetic predominance means either higher sympathetic activity or decreased parasympathetic activity, or both.[57] Nocturnal HRV of patients with FM has been found to be significantly lower compared with healthy matched controls.[58] A subsequent meta-analysis comparing HRV in patients with medically unexplained physical symptoms (MUPS), including patients with FM, with healthy controls concluded that autonomic nervous system dysregulation, particularly lower parasympathetic activity, may play a role in patients with MUPS.[59]

Dysfunction of the peripheral nervous system

Small fibres of peripheral nerves may be abnormal (i.e., decreased number, increased tortuosity) in some individuals with fibromyalgia, or there may be structural abnormalities of the brain.[60][61][62][63] This theory aligns with other evidence in the pain field, suggesting that chronic pain may be associated with significant neuroplasticity.[64] Many groups have used either voxel-based morphometry or diffuse tensor imaging to identify abnormalities in brain structure in people with fibromyalgia.[65][66][67][68][69] In the largest such study, some of these abnormalities may have been due to frequently comorbid psychiatric conditions that are known to demonstrate the same changes.[70] It would be difficult for these changes to account for the widespread pain seen in patients with FM. Thus, if there are structural abnormalities or damage to tissues in fibromyalgia, most evidence for this is involving neural tissues rather than the regions of the body where people with this condition experience pain.

Immune alteration

There is a growing body of evidence that proposes fibromyalgia is an immune-mediated disorder though a distinct pro- or anti-inflammatory pattern has not yet been found.[71][72][73] The evidence supports the role of mast cells in maintaining pain conditions such as musculoskeletal pain and central sensitisation, that is mast cells can mediate microglia activation through the production of proinflammatory cytokines such as interleukin (IL)-1-beta, IL-6, and tumour necrosis factor (TNF)-alpha.[72] In addition, levels of chemokines and proinflammatory cytokines are enhanced in serum and could contribute to inflammation at systemic level.[72]

Genetics

A potential genetic basis for FM has been identified by family studies which report a strong familial aggregation for FM and related conditions.[16][74][75][76][77] Although the mode of inheritance of FM is unknown, it is thought to be polygenic.[76]

A role for polymorphisms of genes in the serotoninergic, dopaminergic, and catecholaminergic systems in the pathogenesis of FM has been suggested.[77][78][79][80][81]

Clinical classification

Primary fibromyalgia is the more common form of fibromyalgia, whereby another cause for pain is not found.[1]
Secondary or concomitant fibromyalgia is sometimes used to refer to fibromyalgia that accompanies another painful disorder or follows an inciting event.[1] Some recommend against using this designation because there is no evidence that the pathophysiology is different in these patients, except that treating the root problem (e.g., a comorbid rheumatic disease or 'peripheral pain generator') can sometimes make the fibromyalgia itself better.
Stressors that may incite fibromyalgia include:
1. Significant infection (e.g., Epstein-Barr virus [EBV] infection, Lyme disease)
2. Injury, physical trauma such as motor vehicle collision
3. Emotional trauma or war deployment
4. Major surgical procedures
5. Peripheral pain syndrome such as osteoarthritis, rheumatoid arthritis.

Pathophysiology

Classification

Clinical classification