Clinical manifestations

Presentation and course

	• Fibromyalgia is a chronic diffuse or multifocal pain syndrome characterized by muscle pain and generalized burning, throbbing, or tingling in the body.
	• Comorbid symptoms include insomnia and fatigue.
	• Prognosis is guarded due to lack of definite treatment, but most patients learn to adapt to maintain functionality.

Fibromyalgia syndrome is classically described as a chronic pain syndrome. Patients describe deep aching pain of the muscles and generalized burning, throbbing, or tingling in the body. The pain is diffuse or multifocal and often migratory. Patients may note discomfort when they are 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 describe comorbid symptoms of fatigue, impaired cognition, mood disorders, restless legs syndrome, chronic headache, dysesthesias, poor balance, and sleep disturbance. Nonrestorative sleep has been reported in more than 90% of fibromyalgia syndrome patients (06). Assignment of fibromyalgia patients into 4 clusters based on severity of symptoms has shown to be stable over a 2-year follow-up with little reassignment from 1 group to another (19).

Revised diagnostic criteria of American College of Rheumatology offered an alternative method for assessing fibromyalgia syndrome based on patients’ self-reported symptoms rather than objective tender points (48; 47). The publication included a self-report survey that asked patients about locations of pain, presence of fatigue, sleep disturbance, memory difficulties, headache, irritable bowel, and mood problems. The advantage of the newer criteria is the focus on the concept of centralized pain or augmentation of pain processing rather than using discrete tender points for diagnosis. Despite the official 2010 fibromyalgia syndrome diagnostic criteria and the diagnostic proposal of 2011 and 2016, complaints from health professionals and patients continue (14). 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 with the following core criteria for usefulness in practice (03):

(1) Multisite pain defined as 6 or more pain sites from a total of 9 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.

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 mind set (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 (42; 15). There is no known cure for fibromyalgia syndrome, and patients often manage this condition for many years. The majority (> 80%) of juvenile fibromyalgia syndrome patients continue to experience fibromyalgia syndrome symptoms into adulthood (23). The rate of mortality is not increased in patients with fibromyalgia syndrome.

No direct complications of fibromyalgia syndrome are known.

Clinical vignette

A 46-year-old woman presented with gradual onset of pain over the past 3 years. She described the pain as affecting her bilateral arms, legs, and upper back in a diffuse manner 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 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.

On examination, the patient was diffusely tender and experienced pain with light palpation of musculature throughout. Otherwise, her general medical examination and neurologic examination were normal. Lab work-up included thyroid studies and vitamin D level and were normal. No central nervous system imaging had been obtained.

She was diagnosed in clinic with fibromyalgia syndrome based on history and clinical examination. No further laboratory or imaging investigation was warranted. The patient was placed on nortriptyline for treatment of diffuse pain, 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 began 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 etiology of fibromyalgia including genetic, environmental, and psychosocial factors.
	• There is some evidence for dysregulation of pain processing in the central nervous system of fibromyalgia patients resulting in central hypersensitivity.

The etiology of fibromyalgia syndrome is largely unknown but multiple factors are involved. Fibromyalgia is viewed as a chronic pain syndrome caused by dysfunction of the central nervous system responsible for regulating sensory inputs (18). Peripheral sensitization is unlikely because no structural abnormalities or source of chronic stimulation of pain afferents have been found in patients with fibromyalgia. Central hypersensitivity can explain exaggerated pain in the presence of minimal and undetectable tissue damage as the nociceptive signal is amplified by the hyperexcitable neurons. Findings that support fibromyalgia being related to central dysfunction include reduction of regional cerebral blood flow in patients with fibromyalgia and improvement of the condition by some centrally acting drugs. This hypothesis is supported by neuroimaging and EEG studies. In addition, an exaggerated excitability of spinal cord neurons following a repeated painful stimulus is mediated by N-methyl-D-aspartate (NMDA) receptors in the dorsal horn of the spinal cord that transmit nociceptive information to the brain. Glial cells are activated by painful stimuli and release proinflammatory cytokines, nitric oxide, prostaglandins, and reactive oxygen species that prolong spinal cord hyperexcitability. This leads to increased responses to stimuli and clinical experience of hyperalgesia and allodynia. There is some evidence for dysregulation of pain processing in the central nervous system of fibromyalgia patients.

Neurotransmitters. The role of neurotransmitters in central sensitization is unclear, but many studies have examined the role of decreased serotonin in fibromyalgia syndrome patients versus controls in the modulation of pain. There is no convincing evidence of efficacy of selective serotonin reuptake inhibitors in treatment of fibromyalgia. There are some data suggesting 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. Neuroendocrine and autonomic dysfunction may also play a role and helps us understand that fibromyalgia syndrome is a stress-related disorder. Patients with fibromyalgia syndrome 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 dysautonomia, which is manifested clinically as heart rate variability and orthostasis.

Insulin resistance. A retrospective study of laboratory findings in patients with fibromyalgia showed that those with elevated glycated hemoglobin HbA1c levels (> 5.8%), which is a biomarker of insulin resistance, had marked improvement of pain following treatment with metformin suggesting a pathogenetic relationship between fibromyalgia and insulin resistance (30).

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. It has been postulated that these genetic factors are due to polygenic inherited dysregulation of neurotransmitters (27).

Angiotensin converting enzyme and methylenetetrahydrofolate reductase gene polymorphisms are associated with susceptibility of a person for development of fibromyalgia syndrome (21).

Role of environmental factors. Fibromyalgia shares some nonspecific clinical as well as laboratory features with undifferentiated connective tissue disease (UCTD) triggered by environmental factors, and both may resemble autoimmune/inflammatory syndrome induced by adjuvants (ASIA) (eg, exposure to vaccines). Findings of a case-control study focusing on environmental exposures, such as metals, suggest that nearly half of patients with undifferentiated connective tissue disease may fall within the autoimmune/inflammatory syndrome induced by adjuvants spectrum (02).

Psychological, behavioral, and social factors. These factors also play a major role in the pathogenesis of fibromyalgia syndrome. Fibromyalgia syndrome patients 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 the most common triggers.

Epidemiology

	• The prevalence of fibromyalgia syndrome is 6% in the United States.
	• Patients with fibromyalgia are likely to have comorbid diseases, including musculoskeletal pain, sleep disorders, and major depressive disorder.

Chronic pain is one of the most frequent complaints seen in medical practice, with an estimated 20% of the adult population being afflicted by this issue. Fibromyalgia syndrome is one of the main causes of chronic pain, with a prevalence of approximately 6% in the USA. The disease is more common in women. The prevalence is higher in populations with lower socioeconomic status and lower education. Fibromyalgia syndrome 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. There is no consensus on changes in prevalence in rural versus urban communities, or according to marital status or body weight. There is no change in prevalence when comparing the 1990 and 2010 ACR diagnostic criteria (31).

Patients with fibromyalgia syndrome are likely to have comorbid diseases, including musculoskeletal pain, sleep disorders, psychological disorders, gastrointestinal disorders, cardiovascular disorders, and endocrinologic disorders. One fourth of all patients have major depressive disorder (25). In a study on female patients with fibromyalgia referred to a physical therapy clinic, polysomnography revealed that 65.9% had obstructive sleep apnea with daytime sleepiness (28). There is also a significant overlap with low back pain, chronic headache, temporomandibular dysfunction, panic attacks, and posttraumatic stress disorder.

Prevention

• There are no clear methods of prevention for the development of fibromyalgia syndrome.

There are no clear methods of prevention for the development of fibromyalgia syndrome or central pain sensitization. Exercise is discussed as an effective method of eliminating stress, improving sleep regulation, and improving mood, all of which can be mediators of centralized pain. This is most often described as a method of treatment rather than a true preventive measure for disorder (41).

Differential diagnosis

Confusing conditions

Fibromyalgia syndrome is a clinical diagnosis based on history and physical examination. As such, there are no key laboratory studies or imaging to be performed to confirm the diagnosis. For this reason, careful attention must be paid to diseases that can present similarly to fibromyalgia syndrome as treatment can vary significantly.

Clinicians should consider rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, inflammatory myositis, metabolic myopathies, hypothyroidism, peripheral neuropathies, and psychosomatic disorders. Fibromyalgia syndrome will differ from autoimmune or rheumatic conditions in laboratory studies (ie, will be normal in fibromyalgia syndrome, and there may be presence of positive antinuclear antibody (ANA), neutrophil anticytoplasmic antibody, rheumatoid factor, SSA, double-stranded DNA, or erythrocyte sedimentation rate (ESR), amongst others, in autoimmune conditions). Additionally, autoimmune conditions often have additional features such as skin changes, sicca syndrome, or abnormalities of joints on plain film x-ray. Electromyography and creatine kinase would be expected to be abnormal in inflammatory myopathy, and electromyography would be abnormal in metabolic myopathy; both would be normal in fibromyalgia syndrome.

Fibromyalgia should be differentiated from myofascial pain syndrome. Although myofascial pain is typically a localized disorder with trigger points and without systemic manifestations, occasionally it may be generalized and appear confusingly similar to fibromyalgia, but does not fulfill the diagnostic criteria of fibromyalgia.

Small fiber neuropathy caused by a variety of metabolic, infectious, genetic, and inflammatory diseases can be mistaken for fibromyalgia. However, it can be differentiated from fibromyalgia by biomarkers, autonomic tests, and skin punch biopsy (49).

Diagnostic workup

	• Careful history and physical examination to check for criteria of diagnosis.
	• Routine laboratory tests including ESR, CRP, and CBC, which usually do not show any abnormality.
	• Laboratory tests as mentioned in differential diagnosis to rule out competing conditions.
	• FM/a® is a biomarker-based test for fibromyalgia.

Fibromyalgia syndrome is a clinical diagnosis, and diagnostic workup should begin with a careful history. A patient meets criteria for a diagnosis of fibromyalgia syndrome based on self-report of symptoms of multisite pain plus fatigue or sleep problems that are present for at least 3 months and pain involves 6 or more of the following 9 sites (03):

(1) Head (2) Left arm (3) Right arm (4) Chest (5) Abdomen (6) Upper back and spine (7) Lower back, spine, and buttocks (8) Left leg (9) Right leg

Typically, the physical exam is unremarkable in patients with fibromyalgia syndrome, though patients often display diffuse tenderness and hyperalgesia to touch or palpation. If the tenderness is localized to joints, or additional features are noted (such as nodules or skin changes), alternative systemic autoimmune conditions should be considered.

Patients with an uncertain diagnosis who have at least 4 of the typical symptoms of fibromyalgia can be tested with the FM/a® blood test (37). FM/a® blood test is based on biomarkers, and the FM/a® test is a cytokine assay of in vitro stimulated peripheral blood mononuclear cells. Production of cytokines by stimulated immune cells in patients with fibromyalgia has been shown to be significantly different from that of healthy control patients. A positive test confirms the diagnosis of fibromyalgia if the result is above 50 in a 1 to 100 scoring system. A positive FM/a test result has a sensitivity of 93% and a specificity of 89%. The FDA-compliant FM/a® test cost around $1000 but is covered by Medicare and most insurance plans. Those who test positive can enroll in a no-cost exome sequencing study at the University of Illinois, Chicago or University of California, Los Angeles. The genetic survey will lead to a comprehensive genetic testing study to determine the cause of fibromyalgia.

Laboratory testing may be useful for ruling out items in the differential diagnosis. One may consider thyroid studies, ESR, C-reactive protein, ANA, and rheumatoid factor to investigate for competing diagnoses.

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 (38). There is an imbalance of free amino acids in serum of patients with fibromyalgia syndrome, and increased glutamate could explain the deficit in monoaminergic transmission involved in pain (33). 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 reference values of patients with fibromyalgia (13). This finding implies 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 major role in the pathomechanism and serve as useful biomarkers for diagnosis and evaluation of fibromyalgia (16).

Neuroimaging is not routinely used in the diagnostic work-up of fibromyalgia syndrome. However, research has demonstrated changes on single-photon emission computerized tomography, functional magnetic resonance imaging, positron emission tomography, and magnetic resonance spectroscopy in fibromyalgia syndrome patients as compared to controls (38).

Management

	• Treatment of fibromyalgia is not simply management of pain but of comorbidities as well to improve the function of the patient.
	• Management of fibromyalgia is multidisciplinary, including pharmacological, nonpharmacological, and alternative therapies.
	• Although there is no cure, most patients with fibromyalgia can be managed adequately, and the control of symptoms requires long-term care.

Treatment should aim to increase function, not simply improve reported pain experience. Treatment is most successful when pharmacologic and nonpharmacologic interventions can be combined.

Nonpharmacologic treatment. The most effective nonpharmacologic interventions are patient education, exercise, and cognitive-behavioral therapy. The magnitude of the treatment response for these therapies 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 may include information regarding the nature of the condition (that there is no harmful or progressive underlying disease process) and the importance of sleep, exercise, and stress management.

Alternative therapies. High-quality evidence to support 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 (44). 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 (29). 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 (40). Reduction of attachment to self in this approach appears to ameliorate symptoms of fibromyalgia and pain perception.

Exercise. Walking is recommended for fibromyalgia. Aerobic exercise has beneficial effects on pain management, likely secondary to activation of endogenous analgesic systems (46). 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 (04). A synergistic response is seen when exercise is integrated into a multidisciplinary treatment approach.

Transcranial direct current stimulation. 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 (50). Studies of the effects of tDCS and aerobic exercise both alone as well as combined show that these can be optimized by combination, and also provide an understanding of the neural mechanisms underlying pain processing with potential for optimizing precision therapy of fibromyalgia (11).

Transcranial magnetic stimulation. Neuromodulation with transcranial magnetic stimulation has been used to treat fibromyalgia patients with comorbid major depressive disorder with amelioration of pain (24).

Far infrared radiation (FIR). Infrared category of electromagnetic radiation has a wave length 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 for relief of 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 source of FIR are effective in reducing pain and the impact of fibromyalgia on patients (35).

Hyperbaric oxygen therapy. A prospective, randomized, active control, crossover clinical trial has provided evidence that hyperbaric oxygen therapy can improve the symptoms and quality of life of patients with fibromyalgia (12). Hyperbaric oxygen treatment comprised 40 sessions using 100% oxygen at pressure of 2ATA (atmospheres absolute) for 90 minutes 5 days/week. During the first 10 to 20 sessions, 29% of subjects experienced unexplained intensification of pain, which later ameliorated. However, analysis of single photon emission computed tomography imaging showed that hyperbaric oxygen can significantly normalize the abnormal brain activity in pain-related areas of patients with fibromyalgia syndrome.

Pharmacologic treatment. Pharmacologic treatment is most often used in conjunction with nonpharmacologic interventions. It is recommended to start medications at low doses and to titrate slowly as many fibromyalgia syndrome patients are sensitive to medications. Effective therapies 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 not effective for treatment of fibromyalgia syndrome. A Cochrane systematic review found only 2 studies of gabapentin for treatment of 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 (43). 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 (45). 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.

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 (36).

Outcomes

Most patients with fibromyalgia can be managed adequately with multidisciplinary approaches, and the control of 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).

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 (26). Outcome depends on associated disorders as well. For example, fibromyalgia patients with 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 (22).

Special considerations

Pregnancy

A prospective case-control study found that anxiety and depression in pregnant women with fibromyalgia syndrome were higher than the control group, and this increases the likelihood of developing fibromyalgia syndrome at a statistically significant level (05). Serotonin levels in pregnant women with fibromyalgia were lower than in the control group but this correlation is not statistically significant. 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 (51). Another study identified a prolonged stage 2 of labor as compared to pregnant controls (34).

Anesthesia

Despite increasing knowledge of the pathophysiology of fibromyalgia syndrome and effective pharmacologic treatments in the outpatient setting, anesthesiologists do not individualize care for fibromyalgia syndrome patients 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. Additionally, there is a clear positive response to pregabalin and gabapentin in the outpatient setting, but this is not routinely used in patients with fibromyalgia syndrome, specifically 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 currently the standard of care (07).