Richard B. Gremillion, MD
THE PHYSICIAN AND SPORTSMEDICINE - VOL 26 - NO. 4 - APRIL 2021
In Brief: The noninflammatory, diffuse pain syndrome recognized as fibromyalgia primarily affects women between puberty and menopause. Symptoms, in addition to musculoskeletal pain and tender points, can include fatigue, nonrestorative sleep, and depression. A precipitating event such as abrupt cessation of exercise, physical injury, or prior debilitating illness can often be identified. Aerobic exercise is usually protective, but sporadic training patterns or other precipitants can place even well-trained athletes at risk. Patients need to know that they can alter the course of this syndrome. Treatment should include attempts to reverse the precipitating event, plus education, aerobic exercise, correction of any sleep disturbance, analgesia, and physical therapy.
Fibromyalgia (FM) is a noninflammatory, diffuse pain syndrome of unknown cause, with symptoms that include multiple musculoskeletal tender points, fatigue, nonrestorative sleep, diarrhea, abdominal cramping, morning stiffness, and depression. The syndrome affects 3.5% of women and 0.5% of men, and costs the US economy more than $10 billion annually (1). Over 85% of patients are women, most of whom develop symptoms in the years between puberty and menopause.
With an overall prevalence of approximately 2% in the general population, FM is more common than rheumatoid arthritis and is observed in up to 6% of patients in general medical practices (2).
A Recently Recognized Disease
The constellation of symptoms recognized today as FM was first described by William Balfour, a British surgeon, in 1816 (3). In 1904 another British physician, Sir William Gowers, classified chronic soft-tissue syndromes under the heading of fibrositis (4). He described the population at risk as "ladies of blameless habits and abstemious clergymen" and prescribed "perspiration" (exercise) instead of aspirin for their "muscular rheumatism."
The term "fibrositis" first appeared in a North American rheumatology textbook in 1940. Then, in 1979, a group from Toronto convincingly associated systemic symptoms such as fatigue and sleep abnormalities with the syndrome (5). In 120211, the connection of fibrositis to systemic symptoms, and studies showing that inflammation was not present, prompted an Illinois rheumatologist, Mohammed Yunus, to suggest the term "fibromyalgia" as more descriptive of the syndrome (6).
It was not until 120217 that the American Medical Association recognized today's second most commonly diagnosed musculoskeletal disorder (after osteoarthritis) as an illness and major cause of disability. In 1990 the American College of Rheumatology (ACR) published diagnostic criteria (7). The World Health Organization subsequently adopted these criteria and established FM as an officially recognized syndrome on January 1, 1993.
FM continues to be a hot area of research and much debate, and is often misunderstood by both patients and physicians. Despite its prevalence and specific diagnostic criteria, many patients find that a diagnosis is still difficult to come by. The average FM patient visits more than five medical practitioners, spends thousands of dollars, and has symptoms for 5 years before an accurate diagnosis is made. A diagnosis of FM, however, can be reassuring to patients when they learn that the disease is not progressive or fatal.
The most common symptoms of FM are debilitating fatigue and severe muscle pain. Patients often have diffuse pain that is perceived to originate within muscles, joints, or both, and thus it may be confused with the early stages of a diffuse inflammatory arthropathy, such as rheumatoid arthritis. By definition, FM is a noninflammatory syndrome; if a joint effusion, synovial proliferation, deformity, or warmth is found, another disease process is present.
Muscle pain typically clusters around the neck and lower back. FM is usually associated with morning stiffness similar to that seen in rheumatoid arthritis. The pain typically waxes and wanes from day to day and is commonly exacerbated by vigorous exercise, a sudden, large decrement in activity, a change in sleep pattern, emotional stress, barometric pressure fluctuations, or painful flare-ups of a coexisting disease.
In addition to myalgias, patients frequently have profound fatigue, sleep disturbance, depression, headache, paresthesias, or Raynaud's phenomenon. The symptoms are chronic (more than 3 months), and laboratory evaluation is usually unremarkable. Physical exam and pathologic investigation reveal no evidence of joint, bone, or soft-tissue inflammation or destruction. Controlled studies have failed to demonstrate a convincing role for the muscles in the pathophysiology of FM (see "The 'Tender Points' of Fibromyalgia," page 57). With the help of a physician, many patients are able to identify a precipitating event such as abrupt cessation of exercise, physical injury, extreme weight gain, emotional trauma, localized pain from other causes, withdrawal from medication, or an antecedent debilitating illness.
Patients must satisfy two criteria before a diagnosis of FM can be made (7): First, bilateral, widespread pain above and below the waist, involving the axial skeleton, must be present for at least 3 months; and second, the patient must verbally declare the presence of pain (not tenderness) at 11 of 18 sites on application of pressure. These ACR criteria identify FM with a specificity of 81.1% and a sensitivity of 88.4%.
One series of investigations demonstrated that the association of at least 6 tender points with typical symptoms reliably identifies patients as having FM. Because the pathophysiology of this syndrome is unclear, clinicians should consider a diagnosis of FM in patients with classic symptoms but fewer than 11 tender points (8).
It is also important to establish the presence of nontender control points, such as the midforehead or anterior thigh, prior to establishing a diagnosis. Control sites allow the clinician to distinguish between FM and a conversion reaction (psychogenic rheumatism), in which perceived pain is bodywide.
FM is probably not the diagnosis for a patient who has musculoskeletal pain but whose laboratory values are abnormal.
Chronic fatigue syndrome. Unfortunately, no published study has directly compared patients with chronic fatigue syndrome (CFS) and FM, but the overlap of symptoms having no apparent underlying cause in CFS and FM patients is striking (table 1: not shown).
The currently accepted, 1994 revised case definition for CFS (9) requires that two criteria be met before a diagnosis of CFS can be made. First, there must be a 6-month history of clinically evaluated, unexplained fatigue that is of new or definite onset, not a result of ongoing exertion and not substantially alleviated by rest, and that results in substantial reduction in levels of occupational, educational, social, or personal activities. Second, there must be four or more concurrent symptoms present on a persistent or recurrent basis during 6 or more consecutive months of illness, none of which may predate the fatigue. Possible symptoms include subjective short-term memory loss or concentration impairment, sore throat, tender cervical or axillary lymph nodes, muscle pain, polyarticular pain, new type of headache, nonrestorative sleep, and postexertional malaise lasting more than 24 hours.
Many CFS symptoms are also seen in viral syndromes, but no one infectious agent has shown a statistically significant association with CFS. A small number of trials using antiviral agents have shown modest benefit in CFS, but these results have not been replicated.
Many investigations have documented the presence of immunologic, infectious, and psychological factors in CFS. However, the incidence of these factors in FM is no greater than in controls. Of interest is the fact that up to 70% of FM patients meet strict criteria for CFS, and conversely up to 70% of those with CFS-like illnesses have concurrent FM (10).
Trials have shown that as many as half of both CFS and FM patients meet criteria for depression; this, however, may develop secondarily. It remains controversial whether CFS and FM are related, or perhaps even the same condition.
Depression and other psychiatric conditions. Several studies have found that at least 20% of FM patients have a psychiatric disorder and that 50% of patients have or have had major depression (11). Some believe that FM and depression may represent two variations of a single syndrome. A different theory suggests that alterations of neuroendocrine regulation in depression may induce the FM syndrome. Anxiety and mild depression may be the sequelae of FM or of any chronic pain or debilitating syndrome.
Other disorders. FM patients may have no concurrent disease or may be experiencing one of many different painful syndromes, including rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, or traumatic injury (12,13). For example, in a cross-sectional study of 102 patients who had lupus, 22% met the diagnostic criteria for FM (9).
One theory about these associations is that chronic pain causes miniarousals and transitional sleep, resulting in less stage 1 and restorative rapid-eye-movement (REM) sleep. The disruption of delta-wave sleep by alpha waves is characteristic of FM. This pattern can also be observed during periods of emotional stress, pain, athletic overtraining, or sleep apnea.
However, because sleep pathology correlates poorly with severity of FM symptoms, and treatment of the sleep disorder results in only moderate improvement in symptoms, it is felt that sleep disorders and changes in sleep architecture are largely comorbid rather than causative.
FM is also associated with dysmenorrhea, migraine headaches, irritable bowel syndrome, and tension headaches. These conditions have many common features, including female preponderance, muscle pain, and lack of abnormal laboratory tests and pathologic features. Some investigators believe that these associations categorize FM with the affective spectrum disorders.
Hypothyroidism and Lyme disease have also been associated with FM (2).
Fitness and Incidence
The incidence of FM in well-trained active people is much lower than in the general population (1). However, active women who abruptly stop physical training at the end of a sports season or because of a chronic pain syndrome or trauma have a risk for development of FM closer to that of the general population (1). Overtraining that leads to excessive muscle fatigue and tenderness can also alter sleep dynamics enough to precipitate FM. The best preventive advice for a well-trained athlete is to reduce activity levels slowly in the off-season and maintain a moderate aerobic fitness program throughout the year.
Tests for Differential Diagnosis
Laboratory tests (table 2) should be performed on the basis of clinical suspicion after a full history and physical exam and should be carefully selected to rule out disorders that mimic FM (table 3). Other diseases that produce nonarticular musculoskeletal pain or stiffness with limited physical findings can be confused with FM. Other, more specific laboratory evaluations such as the rheumatoid factor and antinuclear antibody tests or plain radiography should be obtained only if evidence suggests a diagnosis other than FM.
Table 2. Recommended Laboratory Tests for Suspected Fibromyalgia
Complete blood count
Counseling. Counseling in the presence of a support group of family or friends can be extremely valuable. Those who suffer from FM will do much better when they realize that they can change the course of the disease. The patient should understand that overcoming the disease is a group effort and that many people are available to assist them in their recovery effort.
With the help of a physician, many patients are able to identify a precipitating event, and the treatment regimen should always include attempts to reverse it. For example, when stress or emotional difficulties that lead to overeating are addressed, weight can be reduced and the ability to function increases.
Patients should be given reading materials, reputable FM Website addresses, or phone numbers for support groups and help lines (see "Fibromyalgia Resources," below). Patients should also be educated about sleep hygiene, muscle deconditioning, and depression management.
Above all, patients and support groups should understand that fibromyalgia is a real and objective disease. This knowledge is particularly important to those patients, family, and friends who have been told that FM symptoms are purely imagined or the direct result of psychological instability. Patients also need to know that no life-threatening, serious disorder, such as cancer or destructive arthritis, is causing their disease (assuming that none exists).
Exercise. FM patients can become deconditioned over time as a result of chronic pain. It has been postulated that deconditioned muscle is more susceptible to microtrauma from minor activity. This microtrauma could result in greater pain, which would further reduce activity, resulting in a vicious cycle of muscle inactivity, deconditioning, microtrauma, and pain.
In light of this progression, the benefits of exercise are obvious (14). Not only does exercise improve muscle conditioning, but it also improves restorative sleep, increases endogenous endorphins within the central nervous system, and has a profound antidepressant effect.
Because FM patients almost always experience pain after exercise, the intensity of the workout must start low and be increased gradually. Exercise should be aerobic (enough activity to produce shortness of breath and sweating) and nonimpact, such as water aerobics, bicycling, or fast walking with proper footwear. Thirty minutes four times a week is usually adequate. Patients will be better motivated to exercise when involved in group exercise programs. A physical therapist can be invaluable in helping patients design and adjust programs to fit their individual needs.
Pharmacologic therapy. Sleep disturbances, pain, and tender points can be measurably improved in some FM patients with low-dose tricyclic antidepressants (TCAs) taken before bedtime. However, if the patient's most troubling symptom is fatigue rather than pain, fluoxetine hydrochloride (20 mg per day) may be the best choice. TCAs should be used only at low doses. Amitriptyline hydrochloride should be used at doses ranging from 10 to 25 mg, 1 to 3 hours before bedtime. Adverse effects commonly include morning drowsiness, dry mouth, and constipation. If a low dose of amitriptyline is not helpful, it is better not to increase the dose and the risk of side effects, but instead to add the anxiolytic alprazolam, 1 to 2 mg before bedtime, or the major tranquilizer perphenazine, 2 to 4 mg before bedtime. A different TCA such as cyclobenzaprine hydrochloride might also be substituted if amitriptyline is not efficacious.
Additional analgesia may be obtained with acetaminophen at doses of 2 to 4 g/day. Nonsteroidal anti-inflammatory drugs should not be used routinely because, though their efficacy is equal to acetaminophen's, they are more likely to cause side effects. Also, prednisone, in one double-blind, controlled study (15), was shown to have no therapeutic benefit.
Other therapies. It is often beneficial to try interventions offered by a physical therapist, such as stretching, massage, and local heat. Herbal therapies (such as St John's Wort) have helped some patients but have not been tested to determine safety and efficacy for FM. Interventions such as transcutaneous nerve stimulation, hypnotherapy, electromyography, biofeedback, and acupuncture have similarly not been subjected to rigorous testing and should not be recommended for routine use (2).
In a recent prospective, longitudinal study (16) of 538 patients, it was shown that FM, managed by experts (using traditional therapies outlined here), does not get better, in general, over an average 7-year follow-up period. However, poor outcomes suggested in this and most other studies may reflect selection bias because patients were drawn from tertiary care centers. A single community-based study (17) reported that 25% of patients were asymptomatic and an additional 25% were substantially improved after conventional therapy. Despite these conflicting data, a sympathetic attitude toward the patient and an organized approach to therapy can lead to substantial improvement in many patients who have FM.
The 'Tender Points' of Fibromyalgia
The term "tender points" refers to localized painful areas in a muscle, muscle-tendon junction, fat pad, or bursal region. Sensitivity to pressure at 11 or more of 18 defined points (figure A) is one of two criteria for diagnosing fibromyalgia (FM). As opposed to control patients, patients who have FM experience pain at multiple tender points when 4 kg/cm2 of pressure (enough to blanch the examiner's thumbnail) is applied.
In addition, in a patient who has FM, these tender points are much more sensitive than other sites (control points) in the same patient. Control points include the midforehead, thumbnail, volar surface of the midforearm, and anterior midthigh. Control points are never painful in patients who have FM, but they are almost always painful in patients who have a somatization disorder (1). With FM, pain does not radiate on tender point palpation as it does in myofascial pain syndrome.
No Muscle Pathology
No published studies have yet explained the development of tender points or clearly demonstrated muscle pathology in FM. Reduced pain thresholds at tender points cannot be explained on the basis of primary muscle abnormalities, either structural or functional. Since 1957, nine studies have looked at muscle biopsies in FM patients (2). Many of these studies purportedly showed pathologic changes in muscle but were subsequently found to have major design flaws.
In 120216, a well-designed, controlled, blinded study from Yunus et al (3) at the University of Illinois laid the issue to rest by showing "no more muscle abnormalities in people with FM than in pain-free control subjects." Recent studies of muscle metabolism using magnetic resonance spectroscopy have failed to reveal any significant abnormalities. Studies using electromyography (EMG) show no evidence of excessive muscle tension or defective sympathetic nervous function. However, one EMG study (4) demonstrated that fibromyalgic muscle is unable to relax between contractions.
National Fibromyalgia Research Association
USA Fibromyalgia Association
The UK Fibromyalgia Association
Dr Gremillion is a senior fellow in rheumatology and immunology in the division of immunology and rheumatology at the Stanford University Medical Center in Stanford, California. Address correspondence to Richard B. Gremillion, MD, Division of Immunology and Rheumatology, S-021, Stanford University Medical Center, Stanford, CA 94305; e-mail to [email protected].
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