DANEL J. ClAUW M.D., Georgetown University School of Medicine, Washington, D.C.
Fibromyalgia is a common condition characterized by diverse musculoskeletal
pain and fatigue. The syndrome is defined by the presence of musculoskeletal
tender points on physical examination. Additionally, persons with this
syndrome have a high incidence of headaches, ocular and vestibular complaints,
paresthesias, esophageal dysmotility, "allergic" symptoms, irritable bowel
syndrone, genitourinary symptoms and affective disorders. Recent reasearch
has revealed a number of objective biochemical, hormonal and neurotransmitter
abnormalities associated with fibromyalgia, making it a clearly idenifiable
condition. These abnor malities may clarify our understanding
of the pathogenests and treatment of fibromyalgia.
Fibromyalgia is a common musculoskeletal syndrome characterrized by generalized pain, fatigue and a variey of associated symptoms Although the term fibromyagia", was not introduced until 1976, this symptom complex was described as muscular rheumatism, fibrositis, fibromyositis and psychogenic rheumatism as early as the 17th century. Further complicating the diagnosis of fibromyalgia is the considerable overlap with conditions such as myofascial pain syndrome and chronic fatigue syndrome, since some persons meet criteria for more than one of these diagnoses.
The confusion surrounding the diagnosis of fibromyalgia was reduced considerably by a multicenter study sponsored by the American College of Rheumatology (ACR) that developed criteria for the diagnosis of fibromyalgia. These criteria, generally referred to as the 1990 ACR criteria, are listed in Table 1. These criteria are particularly useful for the standardization of patient groups in studies examining the epidemiology or pathogenesis of fibromyalgia but, as with most diagnostic criteria, they should not be too rigidly applied when making a diagnosis.
Epidemiology
Several breakthroughs in our understanding of fibromyalgia have been
made in the past few years. Recent studies have examined the prevalence
of fibromyalgia in the general population. All of these studies used
the 1990 ACR criteria for diagnosis but used disparate methods for subject
selection, and all reached similar conclusions. The data suggest
that at a given point in time, 3 to 6 percent of the population (including
children) meet criteria for this diagnosis. Since the ACR criteria
indicate that pain must be present in all four quadrants of the body and
that 11 of 18 tender points must be found at the time
of examination, this figure probably represents a conservative estimate
of the prevalence of fibromyalgia in the population.
These studies also demonstrated that women are more likely to have fibromyalgia
than men. However, studies show that at any given age women have
a lower pain threshold than men, even if those with fibromyalgia are excluded
from analysis. The other primary determinant of tenderness is age.
Tenderness increases linearly with ages in both men and women. Persons
with fibromyalgia who are identified through epidemiologic studies are
older (mean age: 55 to 60 years) and generally have fewer concurrent
symptoms (irritable bowel syndrome, sleep disturbance, affective disorders)
than those who seek medical
attention.
Pain and Tender Points
Widespread pain and tenderness are the cardinal features of fibromyalgia.
Although to meet the 1990 ACR criteria pain must be present in all four
quadrants of the body, many persons with unilateral pain or pain that only
affects the upper or lower half of the body clearly have fibromyalgia.
The pain in fibromyalgia tends to be migratory and to tax and wane.
Stiffness in the morning or after remaining in one position for a prolonged
period is common, and patients will frequently note the pain is worsened
by weather changes, physical activity, stress or menses. Although
patients often report swelling the regions of
pain (a common report is that rings no longer fit), no objective evidence
of swelling or synovitis is apparent on examination.
Points of tenderness
Occiput: at the suboccipital muscle Cervical:at the anterior aspects
of the intertransverse spaces at C5 C7
Trapezius: at the midpoint of the upper back
Supraspinatus: at origins above the scapular spine near the medial
border
Second rib: at the second costochondrial junctions
Lateral epicondyle: 2 cm distal to epicondyle
Gluteal: in upper outer quadrants of buttoxs in anterior fold of muscle
Greater trochanter: posterior to trochanter prominences
Knees: at the medial fat pad proximal to the midline
A tender point is defined as an anatomic site where pain is elicited
when 4 kg (approximately 9 lb) of pressure is applied. Although the
presence of tender points on physical examination is the hallmark of fibromyalgia,
it is not the entire clinical
presentation. Several studies have suggested that persons with
fibromyalgia are more sensitive to pain throughout the body, not simply
in areas recognized as tender points. In fact, visceral as well as
peripheral pain sensitivity may be increased in fibromyalgia, as has been
noted in related conditions such as irritable bowel syndrome. Also,
it is normal to have some tenderness in these anatomic regions of the body,
with a mean of 3.7 "positive" tender points in persons reporting no pain.
Finally, nociception is probably influenced by a number of factors besides
the patient's age and sex, with aerobic fitness, poor sleep and depression
probably having significant effects. Since so many variables influence
nociception, diagnostic criteria that use tenderness as the principal determinant
have limited specificity and sensitivity.
Most patients with fibromyalgia complain of fatigue, but this symptom is not universal and is not required for diagnosis. In some person, fatigue may be severe and debilitating, but in others it is either not present or it has been accepted because of its chronic nature. A careful sleep history should be obtained in patients who are suspected of having fibromyalgia, especially men, since some data suggest that a significant number of men with fibromyalgia may have underlying sleep apnea.
Early work by Moldofsky and colleagues indicated that the fatigue associated with fibromyalgia, as well some of the other clinical symptoms, was thought to be due to a disruption of deep sleep. However, many persons with this condition have normal sleep patterns, and the sleep anomalies seen in some patients with fibromyalgia are also seen in some persons without fibromyalgia as well as in patients with other conditions. In addition, only a small percentage of persons with primary sleep disorders (e.g., sleep apnea) have fibromyalgia, and improvement in fibromyalgia symptoms with pharmacological treatment does not correlate with improvement in' sleep. At present, the role of sleep disturbances in the pathogenesis of fibromyalgia is unclear.
NEURALGIC SYMPTOMS
Patients with fibromyalgia have a higher incidence of both tension and migraine headaches than normal persons. A number of other neurologic symptoms in this group of patients, however, are not as well recognized. Numbness or tingling is common and may occur anywhere in the body; it is typically fleeting in nature and does not follow a dermatomal distribution. In one serious, 84 percent of persons with fibromyalgia complained of these paresthesias.
Hearing, ocular and vestibular abnormalities have also been noted, including a low tolerance for painful sound, exaggerated nystagrnus and ocular dysmotility, and asymptotic low frequency sensorineural hearing loss. Cognitive complaints, difficulty with concentration and short term memory, are also common. Results of standard neurologic examinations, nerve conduction tests and imaging studies are normal in these persons, but results, of more subtle testing (including evoked responses and functional assessment) may be abnormal. Because of the variety of neurologic symptoms seen in patients with fibromyalgia, once a person is diagnosed it is prudent to use neurodiagnostic tests only when objective abnormalities are apparent on physical examination.
ALLERGIC SYMPTOMS
Patients with fibromyalgia display a wide array of "allergic" symptoms. These symptoms range from adverse reactions to drugs and environmental stimuli (many patients meet criteria for "multiple chemical hypersensitivity syndrome") to a highher than expected incidence of rhinitis, nasal congestion and lower respiratory symptoms. It is unlikely that all of these symptoms have a true allergic basis; instead, these symptoms may be the result of the central nervous system activation seen in fibromyalgia.
CARDIAC, PULMONARY AND GASTROINTESTINAL SYMPTOMS
For many years it has been believed that patients with fibromyalgia
have a number of symptoms of "functional" disorders of visceral organs,
including a high incidence of recurrent non cardiac chest pain, heartburn,
heart palpitations and irritable bowel
syndrome. However, prospective studies of randomly selected patients
with fibromyalgia have detected evidence of objective abnormalities of
visceral organs, including a 75 percent incidence of echocardiographic
evidence of mitral valve prolapse, a 40 to 70 percent incidence of esophageal
dysmotility, and diminished static inspiratory and expiratory pressures
on pulmonary function testing. These studies suggest that the symptoms
have a physiologic mechanism that is likely to be centrally mediated.
GENITOURINARY SYMPTOMS
Patients with fibromyalgia have a higher incidence of dysmenorrhea, urinary frequency and urgency than normal persons. Fibromyalgia may also be associated with other genitourinary conditions such as interstitial cystitis, vulvar vestibulitis or vulvodynia (which are characterized by dyspareunia and sensitivity of the vulvar region).
AFFECTIVE DISORDERS
Patients with fibromyalgia have a higher incidence of psychiatric disorders, including current and lifetime major depression (20 percent and 50 percent, respectively). Considerable controversy surrounds the relationship between these psychiatric conditions and the concurrent physical symptoms. Some believe that fibromyalgia is primarily a psychiatric condition and the related symptoms are the result of somatization, whereas others believe that psychiatric problems largely occur as a onsequence of the chronic pain, fatigue and disability that these patients have. This debate becomes less relevant if the psychiatric disturbances are considered in the same light as physical symptoms in that there is a common neurotransmitter or hormonal imbalance responsible, and thus both occur in increased frequency in patients with fibromyalgia.
Diagnosis
Fibromyalgia can occur either in an isolated form (formerly termed "primary"
fibromyalgia) or in association with other diseases (formerly termed "secondary"
fibromyalgia). Table 2 lists conditions that may mimic fibromyalgia or
that may occur in
association with the syndrome.
Table 2
Conditions Simulating
or Associated with Fibromyalgia
Rheumatic
Early rheumatoid arthritis*
Polymyalgia rheumatica*
Systemic lupus erythematosus
Sjogren's syndrome
Polymyositis/dermatomyositis
Scleroderma
Endocrine/metabolic
Hypothyroidism*
Hyperparathyroidism
Hypoparathyroidism
Hypercalcemia
Alcoholic or metabolic myopathy
Hypokalemia
Osteomalacia
Paget's disease
Neoplastic
Carcinomatosis
Multiple myeloma
Lymphoma
Infectious
Human immunodeficiency virus infection
virral hepatitis
Parasitic infections
Subacute bacterial endocarditis
*This disorder should always be excluded because of similarity of clinical features.
In many cases, a triggering event can be identified, such as physical or emotional trauma or infection. Even in cases in which the full-blown syndrome develops after a triggering event, a pre morbid history frequently suggests a high lifetime incidence of related conditions. This fact, in addition to studies suggesting familial aggregation of fibromyalgia and associated syndromes, 28 suggests that there may be a genetic tendency toward the development of this disorder, which may express itself following an inciting event either in childhood or later.
The conditions listed in Table 2 should be considered in the differential diagnosis when a patient presents with symptoms suggestive of fibromyalgia. In general, a supportive history and a physical examination that is normal except for the presence of tender points are strongly suggestive of the diagnosis.
Initial screening laboratory tests should include a complete blood count with differential, a chemistry and thyroid panel, and an erythrocyte sedimentation rate. Further testing (tests for antinuclear antibody and rheumatoid factor, or imaging studies such as magnetic resonance imaging [MRI]) should be avoided initially unless specifically indicated, not only because of the associated expense but because these tests are associated with false positive results.
It must be emphasized that it is common for fibromyalgia to coexist with other disorders. However, caution is urged before attributing the patient's symptoms to another coexisting disorder. For example, even if a patient is found to have abnormalities on skeletal MRI or plain radiographs, or if evidence of an inflammatory disorder (systemic lupus erythematosus, rheumatoid arthritis, Lyme disease) is found, fibromyalgia may be responsible for the majority of the symptoms.
Pathophysiology
Although the pathogenesis of fibromyalgia remains elusive, a review of the current knowledge may facilitate a better understanding of this disorder.
Table 3 outlines the most pertinent neurotransmitter, hormonal
and biochemical abnormalities in fibromyalgia. Insulin like growth
factor I (IGF I/somatomedin C) is a hormone produced in the liver, primarily
in response to growth hormone. Most patients with fibromyalgia have
low serum levels of IGF I, and this test has good specificity and
sensitivity in detecting fibromyalgia.
Substance P is a neuropeptide stored in the secretory granules of sensory nerves and is released by axonal stimulation. Cerebrospinal fluid levels of substance P are quite high in patients with fibromyalgia, with little overlap between the levels seen in these patients and levels seen in normal control subjects. Serum levels of serotonin and its precursor, tryptophan, are low in persons with fibromyalgia.
The hypothesis that low levels of serotonin may be responsible
for fibromyalgia is intriguing because many of the associated conditions,
including affective disorders, migraine headaches and irritable bowel
syndrome, are known or thought to be due to low levels of serotonin.
Low tissue levels of magnesium in fibromyalgia (despite normal serum
levels) have been demonstrated and the efficacy of magnesium repletion
is currently being tested. Abnormalities of the hypothalamic pituitary
adrenal axis are seen in fibromyalgia and are likely responsible
for the low IGF noted, but these abnormalities are also in a number of
other disorders, making the significance of this finding uncertain.
TABLE 3
Hormonal, Neurotransmitter and Biochemical Abnormalities in Fibromyalgia
Test
Abnormality
Sensitivity Specificity
Serum insulin like growth factor I
Low High
Moderate
Cerebrospinal fluid substance P
High
High
?
Serum serotonin
Low
Moderate Low
Serum tryptophan
Low
Moderate Low
Tissue magnesium
Low
High
?
Hypothalamic pituitary adrenal laxis
Deranged
Low
Low
The data suggest that objective hormonal, biochemical and neurotramsmitted abnormalities can be identified in patients with fibromyalgia. Which of these abnormalities are causal and which are "epipha nomena" is not clear at present. Although these tests should not be used for screening purposes, many of them compare favorably with commonly ordered tests such as rheumatoid factor, which has sensitivity of 80 percent and a comparable specificity for the diagnosis of rheumatoid arthritis.
Management
Without an effective management plan, care for patients with fibromyalgia can be frustrating and time consuming. With an effective management plan, clinicians have a considerable positive impact on patients with fibromyalgia.
EDUCATION
At initial diagnosis the physician and patient must discuss the symptoms of fibromyalgia in depth. The physician should explain to the patient that death or organ or tissue damage will not occur as a result of this condition, but that there is no known cure and that the condition is likely to be chronic with a fluctuating course.
Patients should be encouraged to take an active role in management of their condition. A passive approach by the patient is rarely successful in this disorder. A number of excellent pamphlets are available for patient education, including one from the Arthritis Foundation, 1314 Spring St. N., Atlanta, GA 30309, or call 404 872 7100.
BEHAVIOR MODIFICATION
Some simple suggestions may make tremendous difference for patients with fibromyalgia. The physician should emphasize the importance the importance of sleep. Some patients chronically attempt to subsist on less sleep than their body requires, and pointing this out can be helpful. Patients should be informed that consumption of caffinated or alcoholic beverages near bedtime may aggravate fibromyalgia because deep sleep is impaired. Emotional stress should be minimized. More formal behavioral modification such as pain programs may also be helpful, especially programs focusing on time based pacing skills (many patients will do so much on a "good" day that they hurt for several days thereafter), scheduling pleasant activities that can act as distracters from chronic pain, or cognitive therapy to decrease victimization or 'learned helplessness' behavior.
WESTERN PHARMACOLOGIC THERAPY
Drugs for the treatment of fibromyalgia that have been studied most
are low nighttime doses of the tricyclic compounds amitriptyline (Elavil,
Endep) and cyclobenzaprine (Flexeril). Although it is sometimes helpful
to explain to patients that the clinical benefit from these drugs occurs
as a result of improved deep sleep, this is not likely the reason that
they are effective, since improvement in sleep status with these medications
does not correlate with clinical improvement. With either of these medications,
the starting dose should be 10 mg one to two hours before bedtime (or in
patients who have had adverse
reactions to many medications, perhaps half of a 1 mg tablet). This
dose should be continued for at least one week before it is increased by
10 mg. The physician should explain that the first several nights that
this medication is taken, or whenever the dose is increased, the patient
is likely to have vivid dreams or nightmares, will need more than the usual
amount of sleep and may feel "hungover" the following day (it is sometimes
useful to suggest that medication be initiated on a Friday evening for
this reason). It should also be explained that the improvement as a result
of these medications cannot occur for four to six weeks.
Titration to the optimal dose is difficult. It is sometimes useful
to use the sleep cycle to make this determination, with the goal being
to identify the dose of either medication that is necessary to keep the
patient sleeping soundly throughout the night but not "hungover." This
dose may be increased up to a maximum of 70 to 80 mg of amitriptyline or
up to 40 mg of cyclobenzaprine. Anticholinergic side effects occur with
either of these medications and, if one medication is not well tolerated,
the patient may respond to the other. Nonsteroidal anti inflammatory drugs
may be useful in this condition. However, if an empirical trial of a few
drugs from this class is ineffective, then they probably should be discontinued.
The selective serotonin reuptake inhibitors fluoxetine (Prozac), sertraline
(Zoloft) and paroxetine (Paxil), as well as venlafaxine (Effexor), may
also be of benefit in selected patients. It is possible that patients with
concurrent depression may respond best to this class of drugs. Also, in
patients who cannot tolerate therapeutic doses of a triyclic compound,
occasionally the addition of a selective serotonin reuptake inhibitor in
a low dose may be of benefit.
Benzodiazepines and narcotics should be avoided if possible in patients with fibromyalgia, not only because of the associated addictive potential but also because of the detrimental effect on deep sleep. If a hypnotic agent must be used, zolpidem (Ambien) may be a reasonable choice since it does not appear to impair deep sleep.
EXERCISE
It is helpful to explain that exercise is vital to improvement
of symptoms of fibromyalgia, since it is vital to improvement of symptoms
of fibromyalgia, since it is rare for patients to have a lasting improvement
unless they become involved in an aggressive program of low- impact aerobic
and stretching exercises. Although exercise can be done with the
help of a
physical therapist, psychologically it may be useful to avoid using
a therapist and encourage independence.
Low-impact aerobic exercises such as water exercise classes, stationary bicycling, rowing machines or cross-country skiing machines can be used. The patient should be instructed to begin at the level or exercise that results in mild tenderness on the following day, but no more. This level should be slowly and gradually increased, and the patient should be instructed that it may several months until a benefit is seen.
OTHER MODALITIES
Injections of tender points with a topical anesthetic, either alone or in combination with corticosteroids, may be of benefit, especially when one region is particularly bothersome. Biofeedback, acupuncture, massage therapy and spinal manipulation may all be of benefit in selected patients.
Final Comment
Fibromyalgia is a common condition. Although the syndrome is defined by its musculoskeletal features, virtually any area of the body may be affected. If the conventional paradigm for the clinical expression of fibromyalgia is represented in "Figure 1", "figure 2" represents a new paradigm. This disease causes decreased pain tolerance throughout the body, rather than only at tender points, and patients with fibromyalgia display a higher incidence of a number of other symptoms and syndromes than normal persons. Most of these allied conditions are characterized by dysmotility of abnormal tone in skeletal or smooth muscle and by increased peripheral or visceral nociception. A number of objective bio-chemical, hormonal and other abnormalities have been identified in patients with fibromyalgia, and it is likely that this syndrome and associated conditions, including affective disorders, have common centrally mediated causes. Although this condition has no cure, prompt recognition and proper management often lead to substantial symptomatic improvement.
The Author
DANIEL J. CLAUW, M.D. is assistant professor of medicine at Georgetown
university School of Medicine, Washington, D.C. He received his medical
degree from the University of Michigan Medical School, Ann Arbor, and served
a residency in internal medicine and a fellowship in rheurnatology at Georgetown
University Medical Center. Address correspondence to Daniel J. Clauw, M
D., Georgetown Univcrsity Medical Center, 3800 RcscrT'oir Rd. NW, Washington,
DC 20007.