Fibromyalgia …

J W G Jacobs MD PhD

Headache & Pain

Updated 02.10.2024
Released 12.03.2014
Expires For CME 02.10.2027

Fibromyalgia

Author: J W G Jacobs MD PhD

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Editor: Peter J Koehler MD PhD

Fibromyalgia

In This Article

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Introduction

Overview

This article depicts the history, etiology, epidemiology, pathophysiology, and management of fibromyalgia. The article includes a description of the development of clinically useful diagnostic criteria as well as a summary of the evolving understanding of pathophysiologic mechanisms of this chronic pain disorder and management modalities.

Key points

	• Fibromyalgia syndrome is a chronic generalized primary pain disorder.
	• Fibromyalgia is best understood by central sensitization to pain.
	• Fibromyalgia is a clinical diagnosis based on patients’ self-reports of widespread, functionally limiting pain, with tenderness of muscles, tendons, and ligaments, after the exclusion of another disease accounting for all symptoms by history taking and physical exam.
	• Fibromyalgia can be a comorbid condition of inflammatory rheumatic diseases, such as rheumatoid arthritis; a comorbid disease does not rule out fibromyalgia.
	• Multidisciplinary care, including patient education, pharmacologic and nonpharmacologic methods, and improving patients’ self-efficacy, is the most appropriate approach for managing fibromyalgia.

Historical note and terminology

Fibromyalgia syndrome is a recognized clinical entity with accepted diagnostic criteria. Its name and the understanding of disease mechanisms have developed over time. In the nineteenth century, physicians used the term “muscular rheumatism” to refer to a condition characterized by pain and stiffness of the muscles and soft tissues. This entity was described as “recurrent pain in the fleshy parts” and “pulling, tearing, shooting, sticking” pains with stiffness and immobility of the affected parts (22). However, “muscular rheumatism” is a too broad, imprecise umbrella term for fibromyalgia; the term is sometimes also used for localized noninflammatory conditions and for polymyalgia rheumatica.

In 1904, Sir William Gowers coined the term “fibrositis,” referring to a chronic pain syndrome that was thought to be due to focal nodules and inflammatory exudates in rheumatic muscle. This term and initial hypotheses about the pathology of this disorder have since been abandoned. Shortly thereafter, several physicians began to describe fibromyalgia based on tender points (rather than nodules), which were affected by physical activity, weather, and emotions. These points were commonly found near origins or insertions of muscle. For centuries, scientists had understood the disease as a muscle disorder; however, patients also described symptoms of hyperalgesia and allodynia, so central nervous involvement came to mind. In 1920, Lindstedt introduced the idea of central sensitization, describing muscular rheumatism as “a pathologic increase in the general sensitivity of the nervous system” felt to be secondary to sensory reflex phenomenon.

In the late 1930s, the term “trigger point” was introduced to refer to radiating pain or referred pain that could be produced from stimulation of a local area, the trigger point. In 1942, the term “myofascial pain syndrome” was introduced based on work by Janet Travell that described pain referred from “trigger points” in skeletal muscles to various locations, including the chest, neck, and head (48). Myofascial pain syndrome is now recognized as distinct from fibromyalgia. In the 1970s, Smythe laid the foundation of fibromyalgia syndrome as it is seen now, by describing widespread pain and tender points (41; 26). Because definite etiological structural lesions of the nervous system had not been identified, fibromyalgia was excluded from the diagnosis of neuropathic pain in 2011. However, small fiber pathology is observed in approximately 50% of people with fibromyalgia (20). This small fiber pathology may be a specific feature of fibromyalgia, not a comorbid small fiber neuropathy, as the clinical phenotype of small fiber pathology in fibromyalgia seems distinct from that of small fiber neuropathy (50).

Clinical manifestations

Presentation and course

	• Fibromyalgia is a chronic diffuse or multifocal pain syndrome characterized by primary pain, predominantly in muscles and tendons, and generalized burning, throbbing, or tingling in the body.
	• Symptoms also include fatigue and insomnia, amongst many others.
	• ICD-11 classifies fibromyalgia as a chronic widespread pain disorder.
	• Several sets of diagnostic criteria for fibromyalgia exist.

Fibromyalgia syndrome is classically described as a chronic generalized pain syndrome. The Classification of Diseases, version 11 (ICD-11), classifies fibromyalgia as a chronic widespread pain disorder.

Fibromyalgia among central sensitization syndromes and ICD-11

(Contributed by Dr. J W G Jacobs.)

Patients describe deep aching muscle pain and generalized burning, throbbing, or tingling in the body. The pain is diffuse or multifocal and often migratory. Patients may note discomfort when touched and exhibit signs of global sensory hyperresponsiveness (09). The pain is typically of gradual onset, though it can be acute in onset following an emotional or physical trauma. The course is usually not progressive. Patients also report fatigue, impaired cognition, mood disorders, restless legs syndrome, chronic headache, dysesthesias, poor balance, and sleep disturbances. Nonrestorative sleep has been reported in more than 90% of patients with fibromyalgia syndrome (07). Assignment of patients with fibromyalgia into four clusters based on the severity of symptoms has shown to be stable over a 2-year follow-up with little reassignment from one group to another (25).

Diagnostic criteria. Several sets of classification and diagnostic criteria for fibromyalgia exist. Two generally used diagnostic sets are described here.

2016 American College of Rheumatology criteria for fibromyalgia. The 2016 American College of Rheumatology diagnostic criteria for fibromyalgia (60) evolved from the 2010 preliminary criteria for fibromyalgia and its update in 2011. A patient satisfies the modified 2016 criteria if the following three conditions are met:

(1) Widespread pain index (WPI) ≥ 7 and symptom severity scale (SSS) score ≥ 5 OR WPI of 4–6 and SSS score ≥ 9.

(2) Generalized pain, defined as pain in at least four of five regions, must be present. Jaw, chest, and abdominal pain are not included in the definition of generalized pain.

(3) Symptoms have generally been present for at least 3 months.

A diagnosis of fibromyalgia is valid irrespective of other concomitant diagnoses. A diagnosis of fibromyalgia does not exclude the presence of other clinically important illnesses.

WPI. WPI is the sum of the number of areas in which the patient has had pain over the last week. The score will be between 0 and 19.

Left upper body (four areas)
	• Jaw, left • Shoulder girdle, left • Upper arm, left • Lower arm, left
Right upper body (four areas)
	• Jaw, right • Shoulder girdle, right • Upper arm, right • Lower arm, right
Axial body region (five areas)
	• Neck • Upper back • Lower back • Chest • Abdomen
Left lower body (three areas)
	• Hip (buttock, trochanter), left • Upper leg, left • Lower leg, left
Right lower body (three areas)
	• Hip (buttock, trochanter), right • Upper leg, right • Lower leg, right

SSS score. First, for each of the symptoms, a) fatigue, b) waking unrefreshed, and c) cognitive issues, indicate the level of severity over the past week using the following scale:

0 = no problem
1 = slight or mild problems, generally mild, or intermittent
2 = moderate, considerable problems, often present and/or at a moderate level
3 = severe: pervasive, continuous, life-disturbing problems

The SSS score (range 0–12) is the sum of the symptom score above (range 0–9) plus the sum (0–3) of the number of the following symptoms the patient has been bothered by that occurred during the previous 6 months: headaches (0–1), pain or cramps in lower abdomen (0–1), and depression (0–1).

The fibromyalgia severity scale, also known as the polysymptomatic distress scale, is the sum of the WPI and SSS scores.

AAPT criteria. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION), in partnership with the FDA and the American Pain Society, developed a diagnostic system for fibromyalgia, the AAPT-criteria (02). It is simpler to use in practice than the 2016 fibromyalgia syndrome diagnostic criteria and exists for the following core criteria:

(1) Multisite pain defined as six or more pain sites from a total of nine possible sites.

(2) Moderate to severe sleep problems or fatigue.

(3) Multisite pain plus fatigue or sleep problems must have been present for at least 3 months.

Note. The presence of another pain disorder or related symptoms does not rule out a diagnosis of fibromyalgia. However, a clinical assessment is recommended to evaluate for any conditions that could fully account for the patient’s symptoms or contribute to the severity of the symptoms.

Nine areas for self-assessment by patients with fibromyalgia

This figure shows the nine areas for self-assessment by patients. Patients are asked to check the areas in which they experience pain on the 2-view manikins. Alternatively, patients may use the checklist of body sites. The numb...

Other symptoms and overlapping syndromes

In addition to chronic pain, fatigue, sleep problems, and dysautonomia, which is manifested clinically as heart rate variability and orthostasis, several other symptoms are reported in fibromyalgia that overlap with those of other chronic sensitivity syndromes. Fibromyalgia also shares symptoms with postviral syndromes, such as post-treatment Lyme disease and long COVID.

Overlapping (central sensitivity) syndromes*
	• Female urethral syndrome • Pelvic pain syndromes • Multiple chemical sensitivity • Periodic limb movements in sleep • Restless legs syndrome • Temporo-mandibular disorders • Chronic migraine • Tension -type headache • Irritable bowel syndrome • Chronic fatigue syndrome / myalgic encephalitis (40) • Posttraumatic stress disorder
* Probably not a fully comprehensive list.

ICD-11

In the International Classification of Diseases, Tenth Revision (ICD-10), fibromyalgia was assigned a unique code, classified in chapter XIII, “Diseases of the musculoskeletal system and connective tissue,“ as M79.7 Fibromyalgia. In the present ICD-11 (International Classification of Diseases, Eleventh Revision (ICD-11), World Health Organization (WHO) 2019/2021 https://icd.who.int/browse11), fibromyalgia no longer has a unique code. It is classified under chapter 21, “Symptoms, signs or clinical findings, not elsewhere classified” as the inclusion term “Fibromyalgia syndrome” under MG30.01 Chronic widespread pain. Because fibromyalgia was included in a diseases chapter with a unique code in ICD-10 but in a symptoms chapter without a unique code in ICD-11, it might be interpreted that fibromyalgia is no longer considered a (serious) disease, with possible consequences for patient care, research, and disability benefits (23). However, a disability assessment should not be based on the dichotomous basis of the presence or absence of an objectifiable disease but on assessing the disorder’s impact on an individual.

Prognosis and complications

Publications about the prognosis of fibromyalgia syndrome are limited and may reflect the variable experience of this disorder across patients. Some studies have identified mindset (acceptance or optimism vs. catastrophizing), pain-avoidance factors, and social support as prognostic factors that play a role in the functionality and well-being of these patients. Several studies have identified a multidisciplinary approach as correlating with improved symptoms and functionality (55; 19). There is no known cure for fibromyalgia syndrome, and most patients have to manage this condition forever. Similarly, the majority (greater than 80%) of patients with juvenile fibromyalgia syndrome continue to experience fibromyalgia syndrome symptoms into adulthood (29). The rate of mortality is not increased in patients with fibromyalgia syndrome.

Complications of fibromyalgia syndrome are further physical deconditioning, ensuing disability with loss of paid jobs and limitations in free time activities, and depression.

Clinical vignette

A 46-year-old woman presented with gradual onset of pain over the past 3 years. She described chronic generalized pain as affecting her bilateral arms, legs, and upper back diffusely and not specifically localized to joints. Her pain migrated and fluctuated over the course of a day and was not always in the same location. She described the pain as aching, cramping, and burning, with additional sensations of electric shooting pain. She also endorsed daily headaches, which were holocranial and described as pressure or throbbing and associated with nausea and sensitivity to light and sound. She reported poor sleep initiation and maintenance and daily chronic fatigue that prevented her from engaging in physical activities that she previously enjoyed. She endorsed a depressed mood. She could not identify any trigger for the onset of her pain and denied social or environmental stressors at its onset. She did not have a history of physical or sexual abuse. She reported that her mother suffered from similar pain but was doing well on pregabalin therapy. She reported no weight loss.

On examination, the patient looked healthy but was diffusely tender and experienced pain with light palpation of musculature throughout. Otherwise, her general medical and neurologic examinations yielded normal results; there was no tachycardia or abnormal muscle weakness. Based on her medical history and physical-diagnostic examination, routine lab workup, thyroid studies, vitamin D level assessment, and central nervous system imaging were not performed.

She was diagnosed with fibromyalgia syndrome based on history and clinical examination. After an extensive explanation of fibromyalgia, in shared decision-making, the patient was placed on nortriptyline for treatment of diffuse pain and migraine headaches and for assistance with sleep initiation and maintenance. She was started at 10 mg at bedtime and increased by 10 mg per week to an initial goal dose of 50 mg at bedtime. She initially reported dizziness on the medication; by slowing down her titration by increasing by 10 mg every 2 weeks, she was able to tolerate it. At 50 mg, she reported significantly improved headache pain and some improvements in sleep and mood. She continued to report difficulties with diffuse body pain but recognized that she had been more social and more active since starting the medication. She was also referred to a fibromyalgia workshop, a 1-day seminar that provides education and community to patients with fibromyalgia. She started cognitive-behavioral therapy with a local psychologist, which she found beneficial for control of her mood as well as for coping mechanisms for pain.

Biological basis

Etiology and pathogenesis

	• Multiple factors are involved in the pathophysiology of fibromyalgia, including genetic, environmental, and psychosocial.
	• It is not clear whether the multiple factors involved in fibromyalgia are potential etiologic or moderating mechanisms and whether they cause or are a consequence of the condition, or both: association is not equal to causation. The relative importance of pathophysiologic and etiologic factors varies among individual patients with fibromyalgia.
	• There is evidence for dysregulation of pain processing in the central nervous system of patients with fibromyalgia: central sensitization.
	• A novel model of fibromyalgia proposes an imbalance of central nervous threats and soothing systems as the etiologic mechanism.

The etiology of fibromyalgia syndrome is largely unknown, but multiple factors are involved (37).

Model of multiple factors involved in fibromyalgia

(Contributed by Dr. J W G Jacobs.)

Fibromyalgia is viewed as a chronic pain syndrome caused or moderated by dysfunction of the central nervous system responsible for regulating sensory inputs (24). One pathophysiologic paradigm conceives of fibromyalgia as a nociplastic pain condition with many features of central sensitization. As such, it is classed as one of several acknowledged central sensitivity syndromes. Overactive threat systems and underactive soothing systems may keep the midcingulo-insular network (also known as the “salience network”) in continuous alert mode, with amplification of a variety of sensory input, which then is perceived as unpleasant or threatening (37). Normally not very painful stimuli and even innocuous stimuli are perceived as (more) painful or unpleasant (eg, hyperalgesia, allodynia, and multiple chemical sensitivity); perceived threats of painful stimuli may result in sleep disorders, distress, and negative affect. Herein, several peripheral and central (cognitive-emotional) mechanisms may play a modulating or pathophysiologic role (45; 37). An indication that peripheral mechanisms play a role is the finding that fibromyalgia has a higher prevalence in several chronic rheumatic inflammatory autoimmune diseases, such as rheumatoid arthritis (15; 13), compared to the general population. Functional MRI findings support that fibromyalgia is related to central dysfunction (32).

Experimental laboratory findings. The role of neurotransmitters in central sensitization is unclear, but many studies have examined the role of decreased serotonin in patients with fibromyalgia syndrome versus controls in the modulation of pain. However, there is no convincing evidence of the long-term efficacy of selective serotonin reuptake inhibitors in the treatment of fibromyalgia. Some data suggest increased levels of norepinephrine, dopamine, and substance P (endogenous opioid system) in patients with fibromyalgia syndrome, but they are unable to modulate pain in these patients.

Patients with fibromyalgia syndrome may have increased levels of cortisol and adrenocorticotropic hormone, which has been postulated to be secondary to low serotonin, which regulates the hypothalamic-pituitary axis. High serum levels of neuropeptide Y in patients with fibromyalgia suggest an association with dysautonomia, which is manifested clinically as heart rate variability and orthostasis.

Tests performed on patients with fibromyalgia syndrome for clinical research, but not for diagnostic or management purposes, have shown an increase in substance P and glutamate and a decrease in norepinephrine in the cerebrospinal fluid. They also have lower serum L-tryptophan and serotonin and decreased cortisol response (47). There is an imbalance of free amino acids in the serum of patients with fibromyalgia syndrome, and increased glutamate could explain the deficit in monoaminergic transmission involved in pain (42). In a large cross-sectional study, serum C-reactive protein, a biomarker of systemic inflammation, was significantly elevated in patients with fibromyalgia, but values remained within the reference values of patients with fibromyalgia (18). This finding would imply modest systemic inflammation in patients with fibromyalgia. Several proteomic biomarkers that have been correlated with the levels of pain, depression, and dysautonomia in patients with fibromyalgia may play a role in the pathophysiology and might be potential biomarkers for the diagnosis and evaluation of fibromyalgia (21). Again, it is not clear whether these findings are a cause, consequence, or moderator of fibromyalgia, or both cause and consequence, leading to persistence of the syndrome. The assumption that many of these rather nonspecific findings are secondary to fibromyalgia seems reasonable. Due to prevalent research and publication bias (predominantly research with positive results is published), a search of the published literature will reveal many seemingly associated findings that are likely based on chance alone (52). Furthermore, associations are often falsely interpreted as causal mechanisms. In all, no valid laboratory test for fibromyalgia exists (17), nor does any single effective therapy for fibromyalgia; any publication that claims to present a valid laboratory test or effective therapy should be read with scrutiny. One retrospective study suggesting that fibromyalgia patients with elevated glycated hemoglobin HbA1c levels (greater than 5.8%), which is a biomarker of insulin resistance, had marked improvement of pain following treatment with metformin was retracted by the journal because of severe methodological issues (38).

Genetic factors. First-degree relatives of patients with fibromyalgia syndrome have an approximate 8-fold increased risk of developing fibromyalgia syndrome themselves. Family members are more likely to suffer from irritable bowel syndrome, headaches, and other chronic pain syndromes and have a lower pain threshold. Of course, nature and nurture and psychosocial influences are difficult to separate; increased risk in first-degree relatives is not necessarily due to genetic factors. To sort this out, a large longitudinal study in identical twins who were separated from each other at an early age and their parents would be necessary, which is nearly impossible, or a large longitudinal study among identical and nonidentical twins. It has been postulated that genetic factors are due to polygenic inherited dysregulation of neurotransmitters (34), although this dysregulation might not be a cause, but a consequence, of fibromyalgia.

Angiotensin converting enzyme and methylenetetrahydrofolate reductase gene polymorphisms are associated with the susceptibility of a person to development of fibromyalgia syndrome (27).

Psychological, behavioral, and social factors. These play a major role in the pathogenesis of fibromyalgia syndrome. Patients with fibromyalgia syndrome are more likely to suffer from psychiatric conditions, including depression, anxiety, obsessive-compulsive disorder, and posttraumatic stress disorder. This may result from common triggers such as early-life stress or trauma.

Physical inactivity, obesity, and fear that movement or social interaction could worsen symptoms can enhance the experience of pain in these patients. Physical or emotional trauma are deemed the most common triggers. A review of longitudinal cohort studies on the risk factors associated with the development of fibromyalgia and chronic widespread pain identified a multiplicity of predictors, supporting the view that “there are many etiological routes into fibromyalgia” (11; 37). Depression, sleep disorders, somatic symptoms, and dysfunctional illness behaviors were the strongest predictors. Other risk factors included early life adversity, demographic variables (female sex, middle age and above), lifestyle factors, and premorbid illnesses (11). The obvious interrelationships between all these factors highlight the difficulty in disentangling them.

Differential diagnosis

Confusing conditions

Fibromyalgia syndrome is a clinical diagnosis based on history and physical examination. There are no fibromyalgia-specific key laboratory tests or imaging that can be performed to confirm the diagnosis (06). Fibromyalgia is not a diagnosis of exclusion because it may, and often does, exist alongside other conditions, eg, rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis (06). Patients should be examined for treatable comorbid conditions. Clinicians should look for and exclude discriminatory signs and symptoms of (rheumatoid) arthritis (ie, swelling of joints), Sjogren syndrome (ie, dry eyes and mouth), polymyalgia rheumatica (more acute onset, weight loss, elderly age, lacking other symptoms of fibromyalgia except for headache in those with concomitant temporal arteritis), inflammatory myositis (muscle weakness), metabolic myopathies, hypothyroidism (bradycardia, myxedema), peripheral neuropathies, and cancer (weight loss). In the absence of signs or symptoms of a specific rheumatic disease, clinicians are advised against performing laboratory studies, such as testing for antinuclear antibody (ANA), neutrophil anticytoplasmic antibody, rheumatoid factor, SSA, or double-stranded DNA, given the risk of false positive test results in that setting. Similarly, no screening test without clinical indication (history or physical exam) of the disease it screens for can be recommended; this includes laboratory studies (eg, thyroid studies, vitamin D level, and creatine kinase) as well as x-ray studies (eg, electromyography).

For clinical management, fibromyalgia should be differentiated from similar conditions, such as generalized myofascial pain or widespread pain syndrome not fulfilling the diagnostic criteria of fibromyalgia, only if doing so would have clinical implications for the patient; if so, then the management would be completely different. The Royal College of Physicians states that “diagnostic uncertainty should not preclude agreeing [on] a shared plan using the best evidence for the management of chronic widespread pain and any associated symptoms” (06). The following table differentiates key disorders from fibromyalgia.

Medical disorder		Differentiating signs and symptoms
Endocrine
	• Addison disease	Postural hypotension, nausea, vomiting, skin pigmentation, weight loss
	• Cushing syndrome	Hypertension, diabetes, hirsutism, moon facies, weight gain
	• Hyperparathyroidism	Increased thirst and urination, kidney stones, nausea/vomiting, decreased appetite, thinning bones, constipation
	• Hypothyroidism	Cold intolerance, mental slowing, constipation, weight gain, hair loss
Infectious
	• Hepatitis	Right upper quadrant pain, nausea, decreased appetite
	• Lyme disease	Rash, arthritis, or arthralgia; occurs in areas of endemic disease
Neurologic
	• Multiple sclerosis	Visual changes (unilateral partial or complete loss, double vision); ascending numbness in a leg or bandlike, truncal numbness; slurred speech (dysarthria)
	• Neuropathy	Shooting or burning pain, tingling, numbness, weakness
Rheumatologic
	• Osteomalacia	Diffuse bone pain, fractures, proximal myopathy with muscle weakness
	• Polyarticular osteoarthritis	Joint stiffness, crepitus, multiple painful joints
	• Polymyalgia rheumatica	Proximal shoulder and hip girdle pain, weakness, stiffness, more common in the elderly
	• Polymyositis, other myopathies	Symmetric, proximal muscle weakness and pain
	• Rheumatoid arthritis	Predominant joint pain, symmetric joint swelling, joint line tenderness, morning stiffness for more than 1 hour
	• Spondyloarthropathy	Localization of spinal pain to specific sites in the neck, mid-thoracic, anterior chest wall, or lumbar regions; objective limitation of spinal mobility due to pain and stiffness
	• Systemic lupus erythematosus	Multisystem involvement, joint or muscle pain, rash, photosensitivity, fever
(02)

Associated or underlying disorders

One fourth of all patients with fibromyalgia have been reported to suffer from a major depressive disorder (31). In a study of female patients with fibromyalgia referred to a physical therapy clinic, polysomnography revealed that 66% had obstructive sleep apnea with daytime sleepiness (35). Patients with fibromyalgia syndrome are also likely to have symptoms that also exist as solitary conditions, mostly central sensitivity syndromes (there is relevant overlap with these disorders) and conditions classified as chronic overlapping pain conditions (61; 53).

Diagnostic workup

	• Careful history and general physical examination are paramount to check the differential diagnosis.
	• The diagnosis of fibromyalgia is a clinical one and is not purely based on diagnostic criteria, but diagnostic criteria can be helpful.
	• Routine laboratory tests as pure screening tools, including erythrocyte sedimentation rate, C-reactive protein, complete blood count, and tests for rheumatic conditions and thyroid, are not recommended.
	• Laboratory tests may be used in the differential diagnosis if there is a clinical indication in an individual to perform a laboratory test.
	• The diagnosis of a rheumatic condition, eg, rheumatoid arthritis, does not rule out concomitant fibromyalgia.
	• FM/a^® is a biomarker-based test that, as yet, cannot be recommended for diagnosing fibromyalgia.

Fibromyalgia syndrome is a clinical diagnosis, and diagnostic workup should begin—and often ends—with careful history taking and a general physical examination. Typically, the physical exam is unremarkable in patients with fibromyalgia syndrome, with the exception of diffuse tenderness and hyperalgesia to touch or palpation. If tenderness is localized to joints or additional features are noted, such as joint swelling or skin changes, systemic autoimmune conditions should be considered. Similarly, other symptoms and signs could raise clinical suspicion of other diagnoses. It is unwise to limit the history taking and general physical examination to assessment of diagnostic criteria of fibromyalgia due to the risk of missing clinically relevant diagnoses in situations in which fibromyalgia is a false diagnosis or fibromyalgia is a comorbid diagnosis.

The FM/a^® blood test, based on a cytokine assay of in vitro stimulated peripheral blood mononuclear cells, has been developed to diagnose fibromyalgia. It costs around $1000. However, the research used to develop this test has severe methodological flaws (46). In the many years since the development of this test, no research has been completed on its validity among individuals with signs and symptoms that could be caused by fibromyalgia or another disorder (as a differentiating tool). Further, the clinical relevance of the test results for patients has not been assessed. Therefore, this test cannot be recommended.

Other laboratory tests may be useful for ruling out conditions in the differential diagnosis if there is clinical suspicion based on the history and physical examination. It is important to draft the differential diagnosis after, and on the basis of, the specifics of the individual’s history and physical exam and not to apply a generic differential diagnosis list from, for instance, a textbook. Lab studies as a pure screening tool, without clinical indication in an individual, might give a false feeling of diagnostic comprehensiveness but are, in fact, a sign of diagnostic incompetence.

Routine neuroimaging and, in fact, any routine workup are not used in the diagnostic workup of fibromyalgia syndrome. Research has demonstrated changes on single-photon emission computerized tomography, functional magnetic resonance imaging, positron emission tomography, and magnetic resonance spectroscopy in patients with fibromyalgia syndrome as compared to controls (47). The conundrum of whether these changes are primary and etiologic or secondary and a consequence of fibromyalgia has yet to be resolved. These findings do not have any clinical consequences for the individual fibromyalgia patient.

Management

	• The first step in managing fibromyalgia is providing information and patient education.
	• Treatment of fibromyalgia is not simply the management of pain but of the whole spectrum of symptoms, as well as improving the function of the patient.
	• Management of fibromyalgia is multidisciplinary, including pharmacological and nonpharmacological therapies.
	• Most trials of therapeutic modalities show a limited short-term effect; long-term therapeutic trials are lacking.
	• Although there is no cure, most patients with fibromyalgia can be adequately managed. The control of symptoms requires long-term care.

Patients with fibromyalgia should be taken seriously, and they should be informed. The patient should not be told, “There is no reason for your pain,” “There is nothing wrong with you,” or “I can't find anything wrong with you,” “It is all in your head,” “It is psychological,” “There is nothing we/anyone can do” without providing further information (06). Treatment should aim to increase function, not simply to improve reported pain experience, because the potential improvement in pain is limited. In fact, one should reconsider the diagnosis if a patient with presumed fibromyalgia shows great improvement in pain. Treatment is probably most successful when pharmacologic and nonpharmacologic interventions can be combined. Most trials of therapeutic modalities show a limited short-term effect; long-term therapeutic trials are lacking.

Nonpharmacologic treatment. The most effective nonpharmacologic interventions are patient education, exercise, self-management, and cognitive-behavioral therapy. The magnitude of the treatment response for these therapies, albeit modest, often exceeds that for pharmaceuticals. Education about the condition and encouragement that the patient should play an active role in their care is recommended. Education should include information regarding the nature of the condition (that symptoms are real, but that there is no harmful underlying disease process and that graded exercise cannot do harm) and the importance of sleep, exercise, and stress self-management.

Physical exercise and adaptations and medical devices. Adaptations (eg, to homes) and medical devices could result in further physical deconditioning and, thus, an increase in signs and symptoms of fibromyalgia if they limit physical efforts. Vice versa, if they enable patients to engage in activities that would otherwise not have been possible, they could positively affect physical deconditioning and, of course, quality of life. If adaptations and medical devices enable patients to have a paid job, they could also be cost-effective.

Transcranial therapies. Transcranial direct current stimulation (tDCS) is a noninvasive technique of neurostimulation to modulate cortical excitability by using constant, low current delivered to the brain area of interest via electrodes placed on the scalp. It has been found useful in the management of chronic and neuropathic pain. A review of published studies shows that anodal tDCS over the primary motor cortex is more likely than sham tDCS to relieve fibromyalgia-related pain (62). Studies of the effects of tDCS and aerobic exercise, alone or in combination, show that these can be optimized by combination and provide an understanding of the neural mechanisms underlying pain processing, with the potential for optimizing precision therapy of fibromyalgia (14).

Other nonpharmacologic therapies. Far infrared radiation (FIR) has a wavelength of 0.7 to 1.4 μm and transfers energy in the form of heat, which can be perceived by the thermoreceptors in human skin. FIR-emitting heat lamps and FIR-saunas have been used to relieve pain in fibromyalgia. Garments made of fibers impregnated with FIR-emitting nanoparticles are being used to deliver thermal radiation effects. A randomized, placebo-controlled study showed that regular use of bioceramic undergarments as a source of FIR is effective in reducing pain and the impact of fibromyalgia (44).

A prospective, randomized, active control, crossover clinical trial of hyperbaric oxygen therapy provided evidence that it may improve the symptoms and quality of life of patients with fibromyalgia (16). Hyperbaric oxygen treatment comprised 40 sessions using 100% oxygen at a pressure of twice the atmospheric pressure exerted at sea level for 90 minutes 5 days per week. During the first 10 to 20 sessions, 29% of subjects experienced unexplained intensification of pain, which later ameliorated. Analysis of single photon emission computed tomography imaging showed that hyperbaric oxygen was significantly associated with normalization of abnormal brain activity in pain-related areas of patients with fibromyalgia. Also, in another study of 17 patients with fibromyalgia, reduced symptoms were sustained at a 3-month follow-up assessment. However, therapy-related adverse events included mild middle-ear barotrauma in three patients and new-onset myopia in four patients (12).

Alternative nonpharmacologic therapies. High-quality evidence to support the use of complementary or alternative therapies is lacking; however, engaging in therapies, such as chiropractic manipulation, massage therapy, tai chi, and acupuncture, amongst others, can provide some benefit and allow patients to feel that they have more control over their outcome. A randomized controlled trial showed that tai chi mind-body treatment resulted in similar or greater improvement in symptoms than aerobic exercise for a variety of outcomes for patients with fibromyalgia (57). A pilot study of comparison of acupuncture with physiotherapy modalities (hot packs, ultrasound, and transcutaneous electrical stimulation) applied to trigger points showed that both are equally effective for relief of pain in fibromyalgia (36). A randomized controlled trial found that meditation awareness training, a second-generation mindfulness-based intervention for the treatment of fibromyalgia syndrome, was more effective than the first-generation mindfulness-based interventions in the placebo group (51). Reduction of attachment to self in this approach appears to ameliorate symptoms of fibromyalgia and pain perception. Points for the individual patient to consider before engaging in a specific complementary therapy are whether it might be harmful and the financial costs. When contemplating the start of such therapy, the patient should discuss what the level of improvement would and could be with the therapist, as well as how many sessions would be required and the risks. The patient would then decide whether this therapy would be worthwhile. If this clinically relevant, predefined target is not achieved after the predefined number of sessions, treatment should be discontinued and should not be justified with reasoning (eg, “If you had not had this therapy, you would have been worse off.”). Of course, these considerations apply to every kind of therapy, but specifically to nonevidence-based ones for which making money could be a motive for the therapy providers.

Walking is recommended for fibromyalgia. Aerobic exercise benefits pain management, likely secondary to activation of endogenous analgesic systems (59). A randomized trial comparing muscle stretching and resistance training concluded that stretching was more effective for relieving pain and improving physical functioning, whereas resistance training was more effective for reducing depression (03). A synergistic response is seen when exercise is integrated into a multidisciplinary treatment approach.

Neuromodulation with transcranial magnetic stimulation has been used to treat fibromyalgia patients with comorbid major depressive disorder with amelioration of pain (30).

Pharmacologic treatment. Pharmacologic treatment is most often used in conjunction with nonpharmacologic interventions, if necessary, and in shared decision-making with the patient. It is recommended to start medications at low doses and titrate slowly because many patients with fibromyalgia are also sensitive to medications. Effective therapies may work by altering neurotransmitters involved in pain transmission. Several classes of drugs have been used for treating fibromyalgia syndrome with variable evidence of efficacy. These include tricyclic compounds, gabapentin, serotonin norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors, antiepileptic drugs, low-dose naltrexone, and cannabinoids. Nonsteroidal antiinflammatory drugs, opioids, and corticosteroids are usually not very effective for treating fibromyalgia syndrome. A Cochrane systematic review found only two studies of gabapentin for treating fibromyalgia and concluded that there is insufficient evidence to support or refute the suggestion that gabapentin reduces pain in fibromyalgia (10). Another Cochrane review found no convincing, unbiased, high-quality evidence that nabilone, a synthetic cannabinoid, is useful for treating fibromyalgia; rather, the tolerability of nabilone was low in patients with fibromyalgia (56). According to a Cochrane review, approved SNRIs, duloxetine, and milnacipran provided no clinically relevant benefit over placebo in the frequency of pain relief of 50% or greater in patients with fibromyalgia (58). The benefits of duloxetine and milnacipran in fibromyalgia were outweighed by their potential adverse effects. There is no evidence that combinations of various drugs improve the efficacy for management of fibromyalgia.

Although the evidence is still limited and not without risks, including psychiatric, cognitive, and addiction risks, data suggest a positive effect of cannabis and cannabidiol in fibromyalgia (05).

Personalized approach to fibromyalgia. Multiple factors involved in the pathogenesis and maintenance of the condition require a multimodal treatment approach. Because there are fibromyalgia subgroups with different clinical characteristics, individually tailored treatment should be considered (45). This is already the case if the major realistic goal(s) of management are assessed in shared decision-making.

Outcomes

Most patients with fibromyalgia can be managed rather adequately with multidisciplinary approaches, and the control of persisting symptoms requires long-term care. Results of a study to follow progression of fibromyalgia in a geographically diverse cohort over a 2-year period suggest that some patients with fibromyalgia and chronic widespread pain experience fluctuation in symptoms such as pain, physical function, and sleep over time, which may reflect the waxing and waning nature of fibromyalgia and affect diagnosis as well as treatment (01). This fluctuation in symptoms corresponds with clinical experience for patients with fibromyalgia.

Although the Fibromyalgia Impact Questionnaire reveals modest but statistically significant improvements in standard measures of pain severity following treatment, more substantial pain improvement is noted when using alternative measures for assessing pain and functional improvement (33). Outcome depends on associated disorders as well. For example, fibromyalgia patients with concomitant rheumatic diseases have worse pain as assessed by the 36-item Short Form Health Status Questionnaire and show less improvement in these measures following treatment than patients without rheumatic diseases (28). Another instrument to assess the severity of fibromyalgia is the fibromyalgia severity scale, or the polysymptomatic distress scale.

Special considerations

Pregnancy

A prospective case-control study found that anxiety and depression in pregnant women with fibromyalgia syndrome were higher than in the non-fibromyalgia control group (04). Various studies have identified a significant increase in chronic pain symptoms during pregnancy, particularly in the third trimester of women with a diagnosis of fibromyalgia syndrome. Women with fibromyalgia syndrome who have gone through a pregnancy complain that they had increased muscle cramps, enhanced nausea, uterine contractions throughout pregnancy, increased fatigue, and increased generalized muscle pain, especially in the third trimester.

Few studies have attempted to examine if carrying a diagnosis of fibromyalgia syndrome has any effect on the health of the pregnancy. One study identified fibromyalgia syndrome as an independent risk factor for intrauterine growth restriction (63). Another study identified a prolonged stage 2 of labor compared to pregnant controls (43). A study found that fibromyalgia had no negative effect on the outcome of gravidity, parity, and duration of breastfeeding (49).

Anesthesia

Despite increasing knowledge of the pathophysiology of fibromyalgia syndrome and effective pharmacologic treatments in the outpatient setting, anesthesiologists do not individualize care for patients with fibromyalgia syndrome in the perioperative setting. There are no data to support or refute the use of opioids for pain control in the perioperative setting, though poor response to opioids has been noted in the outpatient setting. Although there is a clear but limited positive response to pregabalin and gabapentin in the outpatient setting, this medication is not routinely used in patients with fibromyalgia syndrome in the perioperative period. An individualized approach to anesthetics and pain control has been proposed in the anesthesia community for patients with altered pain processing, though this is not the standard of care (08).

Surgery

When considering surgery for a condition in a fibromyalgia patient, the surgeon should be aware of nociplastic pain and poorer pain relief from surgery, eg, joint replacement for (concomitant) osteoarthritis. This should be communicated effectively before surgery. If surgery is indicated, involvement of a multidisciplinary team may be helpful for optimal outcomes (06).

Media

References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

J W G Jacobs MD PhD

Dr. Jacobs of University Medical Center Utrecht has no relevant financial relationships to disclose.
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Editor

Peter J Koehler MD PhD

Dr. Koehler of Maastricht University has no relevant financial relationships to disclose.
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Former Authors

K K Jain MD†
Nicole Reams MD (original author)

Patient Profile

Age range of presentation: Fibromyalgia can present at any age, and juvenile fibromyalgia syndrome is well described. Age of peak prevalence varies as it changes with gender; men reach peak prevalence at middle age, and the prevalence in women increases steadily with age.
Sex preponderance: Fibromyalgia is more common in women.
Heredity: Hereditary factors probably play a (minor) role.

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Fibromyalgia

Associated Disorders

major depressive disorder
obstructive sleep apnea with daytime sleepiness
central sensitivity syndromes
chronic overlapping pain conditions

Differential Diagnosis

rheumatoid arthritis
systemic lupus erythematosus
ankylosing spondylitis
Sjogren syndrome
polymyalgia rheumatica
- inflammatory myositis
- metabolic myopathies
- hypothyroidism
- peripheral neuropathies
- cancer
- generalized myofascial pain
- widespread pain syndrome not fulfilling the diagnostic criteria of fibromyalgia

	• The prevalence of fibromyalgia syndrome is 6% in the United States.
	• Patients with fibromyalgia are likely to have comorbid major depressive disorder.

	• There are no clear methods of primary prevention of development of fibromyalgia syndrome.
	• Secondary prevention, ie, prevention of full-blown fibromyalgia in patients showing some signs and symptoms of the disorder, seems possible.

Fibromyalgia

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Other symptoms and overlapping syndromes

ICD-11

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Surgery

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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