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Fibromyalgia
Definition
Fibromyalgia is the term that describes chronic widespread musculoskeletal pain, for which no alternative cause can be identified. If fatigue rather than pain is the presenting complaint, individuals are often diagnosed with chronic fatigue syndrome. , Gastroenterologists often see the exact same patients and focus on their gastroenterologic complaints, and often use the terms functional gastrointestinal disorder, irritable bowel syndrome, nonulcer dyspepsia, noncardiac chest pain, or esophageal dysmotility to explain the patient’s symptoms ( Chapter 123 ). Neurologists see these patients for their headaches ( Chapter 367 ) or unexplained facial pain, urologists for pelvic pain ( Chapter 219 ) and urinary symptoms (and use labels such as interstitial cystitis, chronic prostatitis [ Chapter 114 ], vulvodynia, and vulvar vestibulitis), dentists for temporomandibular disorders, and so on. Although many individuals will have only one “idiopathic” pain syndrome over the course of their lifetime, more often, individuals with one of these entities, as well as their family members, are likely to have several of these conditions. Newer terms to describe this group of conditions include chronic overlapping pain conditions or nociplastic pain.
Epidemiology
Chronic widespread pain is typically operationalized as pain above and below the waist, involving the left and right sides of the body, and also involving the axial skeleton. Population-based studies of chronic widespread pain suggest that roughly 4 to 12% of the population has this symptom at any given point in time. Chronic regional pain is found in 20 to 25% of the population. Both chronic widespread and regional pain occur about 1.5 times more often in women than in men. These findings are very similar in different countries, ethnicities, and cultures.
Various types of environmental stressors, including but not limited to psychological factors, most likely trigger the development of fibromyalgia ( Table 253-1 ). Fibromyalgia and related disorders are found at much higher than expected rates in individuals who have experienced specific infections (e.g., Epstein-Barr virus, Lyme disease, Q fever, viral hepatitis), and it is also likely that the long haul post-coronavirus disease (COVID) 2019 syndrome has significant nociplastic contributions.
TABLE 253-1
STRESSORS CAPABLE OF TRIGGERING FIBROMYALGIA AND RELATED CONDITIONS
|
COVID = coronavirus disease 2019; EBV = Epstein-Barr virus.
Fibromyalgia is also more common after trauma (e.g., motor vehicle accidents) and wartime military service. It is also likely that part of the reason these different stressors can seemingly lead to worsening of fibromyalgia or fibromyalgia symptoms is because of how these stressors affect activity level, sleep, or overall distress, any of which then can lead to worsening of pain and other symptoms.
Secondary fibromyalgia is frequently found as a comorbid condition in other chronic pain conditions such as osteoarthritis and autoimmune rheumatic diseases. As many as 25% of patients correctly diagnosed with generalized inflammatory disorders such as systemic lupus erythematosus, rheumatoid arthritis, and ankylosing spondylitis will also fulfill diagnostic criteria for fibromyalgia. However, in clinical practice this co-expression often goes unrecognized, especially when the fibromyalgia develops after the autoimmune disorder or regional pain syndrome. In this setting when comorbid fibromyalgia goes unrecognized, patients are often unnecessarily treated more aggressively with potentially toxic biologics and immunosuppressive agents.
The “primary” form of fibromyalgia is also associated with serious comorbid conditions, with early life and ongoing stressors. Many if not most such patients have a lifetime history of a psychiatric disorder such as depression or anxiety ( Chapter 362 ). There is typically more psychiatric and psychological comorbidity noted in individuals who are refractory to treatment. The bidirectional relationship between fibromyalgia and psychiatric conditions is likely due at least in part to common triggers to both sets of conditions, as well as shared pathophysiology. Potentially modifiable risk factors for developing fibromyalgia or worsening its course include poor sleep, obesity, physical inactivity, and job or life dissatisfaction. Cognitive factors such as catastrophizing (irrational thinking that the pain is much worse or more serious than it actually is) or fear of movement have been found to be poor prognostic factors in fibromyalgia and other chronic pain states.
Pathobiology
Contemporary terms used to describe conditions such as fibromyalgia, irritable bowel syndrome, temporomandibular disorders, chronic fatigue syndrome, vulvodynia, and many other entities include “centralized pain” or “central sensitization” to imply that the central nervous system (CNS) is playing a prominent role in amplifying or causing the pain in most individuals with these syndromes ( Table 253-2 ). Although peripheral nociceptive input might be involved for some such pain, CNS factors are probably amplifying it, thereby leading to other associated symptoms such as fatigue, memory problems, and disturbances of sleep and mood. Many of these findings also have been noted in chronic fatigue syndrome, but the various pathophysiologic theories of chronic fatigue syndrome vary widely and are the source of considerable contention.
TABLE 253-2
MECHANISTIC CHARACTERIZATION OF PAIN
| NOCICEPTIVE | NEUROPATHIC | CENTRALIZED/NOCIPLASTIC | |
|---|---|---|---|
| Cause | Inflammation or damage | Nerve damage or entrapment | CNS or systemic problem |
| Clinical features | Pain is well localized, consistent effect of activity on pain | Follows distribution of peripheral nerves (i.e., dermatome or stocking/glove), episodic, lancinating, numbness, tingling | Pain is widespread and accompanied by fatigue, sleep, memory and/or mood difficulties, as well as history of previous pain elsewhere in body |
| Screening tools | PainDETECT | Body map or fibromyalgia survey | |
| Treatment | NSAIDs, injections, surgery, opioids | Local treatments aimed at nerve (surgery, injections, topical) or CNS-acting drugs | CNS-acting drugs, nonpharmacologic therapies |
| Classic examples | Osteoarthritis Autoimmune disorders Cancer pain |
Diabetic painful neuropathy Post-herpetic neuralgia Sciatica, carpal tunnel syndrome |
Fibromyalgia Functional GI disorders Temporomandibular disorder Tension headache Interstitial cystitis, bladder pain syndrome |
Variable degrees of any mechanism can contribute in any disease.
CNS = central nervous system; GI = gastrointestinal; NSAIDs = nonsteroidal anti-inflammatory drugs.
Genetic Factors
The strong familial predisposition to fibromyalgia and other chronic pain conditions has led many to study specific genetic polymorphisms that may be associated with a higher risk of developing fibromyalgia. First, candidate gene studies showed that genetic findings such as the serotonin 5-HT2A receptor polymorphism T/T phenotype, serotonin transporter, dopamine 4 receptor, and catecholamine o -methyl transferase (COMT) polymorphisms all were noted in higher frequency in fibromyalgia patients than in controls. Subsequent studies confirmed some of these associations, whereas others did not. Subsequent larger genome-wide linkage and candidate gene studies identified other putative targets. The linkage studies confirmed the strong genetic contribution to fibromyalgia and suggested linkage of fibromyalgia to the chromosome 17p11.2-q11.2 region. The large candidate gene study identified significant differences in allele frequencies between cases and controls that were observed for three genes: GABRB3, TAAR1, and GBP1 . In light of the fact that classic genetic studies have not yet identified strong, reproducible polymorphisms or haplotypes associated with fibromyalgia, and because there is clear evidence of environmental factors such as stress playing a prominent role in the pathogenesis, other groups have postulated that epigenetic findings might be important in fibromyalgia.
Disturbances in Pain and Sensory Processing
The pathophysiologic hallmark of fibromyalgia is augmented central pain processing. Individuals with fibromyalgia are more tender everywhere in the body, not just in the 18 regions originally considered to be “tender points.” Several potential mechanisms have been experimentally found to be potentially responsible for pain amplification in fibromyalgia, including a decrease in the activity of descending analgesic pathways, and a diffuse increase in the processing of all sensory stimuli (not just pain). Affected individuals have a CNS–mediated problem with augmented pain or sensory processing that is contributing to the pain and other somatic sensitivities the individual is experiencing, rather than simply a nociceptive focus confined to the region of the body where pain is currently being experienced.
Brain Imaging Studies
Functional, chemical, and structural brain neuroimaging studies have provided the best “objective” evidence that the pain of fibromyalgia and related pain amplification syndrome is “real.” Functional MRI (fMRI) studies have demonstrated that in individuals with fibromyalgia the application of mild pressure or heat stimulus, which other individuals would sense as touch rather than pain, is experienced as pain. Individuals with or without fibromyalgia utilize similar brain activation patterns and brain areas involved in pain processing. The insula is a brain region that is consistently hyperactive and is likely to play a key pathogenic role in fibromyalgia and related conditions. This region has been noted to play a critical role in sensory integration, with the posterior insula serving a purer sensory role, and the anterior insula being associated with the emotional processing of sensations.
Patients with fibromyalgia have increased connectivity between brain regions involved in increasing pain transmission and neural networks not normally involved in pain. During a painful stimulus, connectivity is decreased between key antinociceptive regions and a region identified as a potential source of dysfunctional pain inhibition in fibromyalgia. Quantitative sensory testing studies have demonstrated that fibromyalgia patients are more sensitive to a number of sensory stimuli other than pain, and that machine learning paradigms using functional neuroimaging data can accurately distinguish fibromyalgia patients from individuals without fibromyalgia with over 90% accuracy. Some of these functional connectivity findings related to the insula and default mode network may be present early in life before children develop pain. Although conditions such as fibromyalgia have generally not been thought to have an immune basis, low-grade inflammation may exist in both the periphery and perhaps even the central nervous system.
Imaging techniques also have been used to identify the neurotransmitter abnormalities that may be “driving” the pain amplification seen in fibromyalgia and other chronic pain disorders. Decreased mu opioid receptor availability (possibly due to increased release of endogenous mu opioids) has been reported in fibromyalgia. This finding, as well as previous studies showing increases in endogenous opioids in the cerebrospinal fluid of fibromyalgia patients, has been suggested as evidence of why opioid analgesics appear not to be efficacious in fibromyalgia.
Using proton spectroscopy to probe other neurotransmitters, fibromyalgia patients have been shown to have increases in brain concentrations of the body’s major excitatory neurotransmitter, glutamate, in pain processing regions such as the insula. Drugs such as pregabalin and gabapentin are likely working in part in fibromyalgia by reducing glutamatergic activity. Individuals who have fibromyalgia and who have the highest pretreatment levels of glutamate in the posterior insula are most likely to respond to pregabalin. When pregabalin leads to improvement in symptoms in these individuals, functional MRI normalizes, thereby suggesting that this neurotransmitter is playing a critical role in the pathogenesis of fibromyalgia at least in some individuals. These studies also help clarify why no single class of CNS analgesic is likely to be effective in every patient with pain of CNS origin.
The Role of Peripheral Factors
Peripheral factors also play an important role in the pathogenesis and treatment of many individuals with fibromyalgia. For example, some elements of the processes of central sensitization can be worsened or driven by ongoing nociceptive input. Many individuals who have fibromyalgia also have comorbid conditions that cause ongoing peripheral nociceptive input (e.g., myofascial pain, osteoarthritis, obesity). In fact, one of the major areas of study needed into these conditions is to try to differentiate which individuals with these phenomena are being driven from the CNS (top down) and which may be driven by ongoing peripheral nociceptive input (bottom up).
Clinical Manifestations
The majority of patients with fibromyalgia develop their pain symptoms in multiple body regions early in life, frequently beginning in childhood or adolescence. Individuals who eventually progress to develop fibromyalgia are more likely to experience headaches, dysmenorrhea, temporomandibular disorders, chronic fatigue syndrome, myofascial pain, irritable bowel syndrome and other functional gastrointestinal disorders, interstitial cystitis/painful bladder syndrome, endometriosis, and other regional pain syndromes (particularly with back and neck pain). In many cases, what may appear to a health care provider to be an entirely new type of acute or subacute pain is in fact only another region of the body involved with pain. The concept is evolving among pain specialists that these “centralized” pain disorders actually represent a single lifelong disease with a spectrum of symptoms in different regions of the body over time.
Other CNS-mediated symptoms that are seen commonly in fibromyalgia and related conditions include fatigue and sleep and memory issues. Subsets of individuals with any chronic pain condition (e.g., low back pain, osteoarthritis, autoimmune disorders, sickle cell disease, etc.) also have the same phenotypic features and underlying mechanisms as those seen in fibromyalgia. Many pain experts now think that much chronic pain itself is a neural disease and that many of the underlying mechanisms operative in these heretofore considered idiopathic or functional pain syndromes may be similar no matter whether that pain is present throughout the body (e.g., in fibromyalgia) or localized to the low back, the bowel, or the bladder.
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