Definition
Fibromyalgia is a chronic syndrome that occurs predominantly in women and is marked by generalized pain, multiple defined tender points [see Figure 1],1 fatigue, disturbed or non-restorative sleep, and numerous other somatic complaints. It is not a discrete disease; rather, it lies at the far end of a continuum of psychological distress and chronic pain in the population. Currently, fibromyalgia is best classified as one of a series of disorders that are variously termed symptom-based condi-tions,2 functional somatic syndromes,3 or affective spectrum disorders.4 Advances in our understanding of the psychophysiologic dysregulation5 in these illnesses undoubtedly will lead to revision of such classification in the future. There appear to be discrete subgroups of patients with respect to pain sensitivity and psychological factors,6,7 and these subgroups vary in response to therapy and in prognosis.8
Fibromyalgia largely overlaps with other syndromes with unexplained symptoms, such as chronic fatigue syndrome and irritable bowel syndrome, all of which are related to, but not fully dependent on, depression and anxiety.9 Fibromyalgia frequently coexists with organically defined disease, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis.
Epidemiology
Otherwise-unexplained widespread pain occurs in about 10% of the general adult population in Western countries, with approximately half of those, mostly women, meeting American College of Rheumatology classification criteria for fibromyalgia.
Fibromyalgia becomes more common after 60 years of age but occurs not infrequently in children. On a typical day, primary care physicians should expect to interact with several patients with fibromyalgia, many of whom will be seeking care for illness other than fibromyalgia. For example, more than 25% of patients with SLE exhibit painful tender points and other clinical and psychological features of fibromyalgia.
Etiology
The cause of fibromyalgia is unknown. Despite extensive research, no definitive organic pathology has been identified. Psychological factors associated with chronic distress appear to be very important.11 Most researchers believe that pain in fi-bromyalgia reflects an abnormality of central pain processing, but there is no consensus regarding the mechanism. Nevertheless, current research-based biomedical and sociobehavioral data are now sufficient for a clinically useful understanding of some of the variables that contribute to chronic pain and fatigue in this disorder.
BIOPSYCHoSOCIAL MoDEL
At one level, the pain and associated symptoms of fi-bromyalgia can be viewed according to Engel’s biopsychoso-cial model12 of chronic illness: health status and outcomes are influenced by the interaction of biologic, psychological, and sociologic variables. Important biologic variables are genetics, gender, sleep, physical condition, stress/neuroendocrine and autonomic dysregulation, and central sensitization to pain. Psychological (cognitive-behavioral) variables contributing to the chronic pain and fatigue of fibromyalgia include pain beliefs/attributions, mood, depression, anxiety, personality traits/disorders, pain behaviors, hypervigilance, coping strategies, and perceived self-efficacy for pain control. Sociologic (environmental and sociocultural) variables consist of experiences influenced by life and culture that have impact on the course of chronic pain and fatigue, such as psychosocial experiences during childhood, family support, work environment, job satisfaction, and ethnologic factors.
Biologic Variables
Genetics Genetic analysis of community-based popula-tions13 and twins14 suggests that somatic symptoms, such as pain and fatigue, are etiologically distinct from symptoms of anxiety and depression and reflect, at least in part, the action of genes. The short (S) allele of the promoter region of the serotonin transporter gene 5-HTT has been associated with depression and suicidality in response to stressful life events,15 and a higher frequency of the S/S genotype has been reported in patients with fibromyalgia than in healthy control subjects.16 An association with 5-HTT or its alleles is not evident in fibromyal-gia without accompanying depression and psychological distress, however. Other susceptibility genes undoubtedly will be discovered in the near future.
Figure 1 Tender points in fibromyalgia.
Female gender In general, females exhibit higher pain sensitivity than males and are at greater risk for many pain condi-tions.17 Central pain-modulatory systems and inflammatory cy-tokine levels in females are influenced by phasic alterations in reproductive hormone levels; and females appear to lack diffuse noxious inhibitory control (DNIC), a pain-inhibitory mechanism that is found in normal males.18 Stressful or aver-sive stimuli evoke greater sympathetic nervous system, neu-roendocrine, and psychological responses in females than in males. Reporting of unexplained symptoms, independent of psychiatric morbidity, also is more common in females.19 Certain data suggest that the neural circuits activated by emotional experiences and those involved in encoding of emotional experiences into memory show much more overlap in females than in males.20 Together with the higher prevalence of abuse in women, these biologic variables may explain, at least in part, the increased susceptibility to fibromyalgia in women.
Sleep disturbance Poor sleep is almost universal in fi-bromyalgia, but fibromyalgia is not primarily a sleep disorder, as had been thought. Pain interferes with sleep, and disturbances in sleep contribute to the experience of pain.21 In turn, nonrestful sleep and pain underlie the experience of fatigue.
Psychological distress and the stress response system The number of painful tender points in patients with fibromyalgia correlates strongly with their levels of psychological distress.22 Much evidence suggests that there is an association between chronic, unrelieved psychological stress/distress and functional alterations of the stress-response system (the autonomic nervous system and hypothalamic-pituitary-adrenocortical [HPA] axis) that, in turn, contributes to symptoms of anxiety, pain, and fatigue.5,23,24 It is unclear, however, whether abnormalities in the stress-response system reflect preexisting vulnerability to fi-bromyalgia or are a consequence of chronic pain and fatigue.
External triggers Fibromyalgia patients often have fixed beliefs that minor traumatic events, pathogens, chemicals, or other physical agents caused their illness. The available evidence does not support any of those factors as causes, and furthermore, such beliefs can be a barrier to recovery.
Psychological Variables
Cognitive-behavioral variables play a central role in the development and maintenance of persistent pain and functional disability. For example, negative emotions (depression and anxiety), other negative psychological factors (loss of control, unpredictability in one’s environment), and certain cognitive aspects (negative beliefs and attributions, catastrophic interpretation of events) can lower pain thresholds and tolerances.25 Pain behaviors are the actions or expressions by which an individual communicates feelings of pain to the outside world. The response of the outside world (e.g., spouse, physician, employer) then positively or negatively reinforces the pain experience.
Environmental and Sociocultural Variables
Multiple experiences related to forces in the environment, life, and culture can influence the course of chronic pain and fatigue. These influences can be either positive (e.g., good job satisfaction in a patient with work-related back strain) or negative (e.g., a physician’s suggestion that a minor traffic accident may have left the patient with long-term damage). In the United States, negative sociocultural elements include the promotion of fear and suggestibility by the media and by society in general, as well as focus on definable causes by patients, physicians, and attorneys. Adverse experiences during childhood, such as poor family environment or childhood sexual abuse, increase susceptibility to the development of chronic pain in adulthood.
Pathophysiology
There are four principal categories of pain: nociceptive, neuropathic, psychogenic, and chronic pain of complex etiology. Nociceptive pain involves stimulation of peripheral pain receptors during inflammation, injury, or destruction of tissues, and it is characterized by a pain experience that corresponds with the noxious stimulus. Neuropathic pain results from direct injury to nerves, such as the radiculopathic pain of degenerative spondylosis. Psychogenic pain occurs in more strictly psychiatric illness, such as somatization disorder or hysteria. Chronic pain of complex etiology is the type of pain characteristic of fi-bromyalgia, as well as of various regional pain syndromes.
Although chronic pain of complex etiology is as yet incompletely understood, many of the biologic elements operant in the abnormal pain modulation and the associated symptoms seen in fibromyalgia have been identified. Such elements include increased levels of inflammatory cytokines, decreased serotonin levels, increased levels of substance P in the cere-brospinal fluid, deficiency of biogenic amines that normally regulate the release of substance P, glial activation,27 decreased somatomedin C levels, intrusion of alpha waves into the brain’s electrical field during non-random eye movement sleep, and dysregulation of the stress response system. Such dysregulation may manifest as neurally mediated hypoten-sion; a hypofunctional sympathetic reflex response to stressors; or abnormalities of the HPA axis and other neuroendocrine axes, such as growth hormone secretion in response to exercise.
Table 1 Symptoms of Fibromyalgia Syndrome48
|
Musculoskeletal |
Pain at multiple sites |
|
Stiffness |
|
|
"Hurt all over" |
|
|
Swollen feeling in soft tissues |
|
|
Nonmusculoskeletal |
Fatigue (most times of the day) |
|
Morning fatigue (symptom of nonrestora-tive sleep) |
|
|
Poor sleep |
|
|
Paresthesias |
|
|
Associated symptoms |
Self-assessed anxiety |
|
Headaches |
|
|
Dysmenorrhea |
|
|
Irritable bowel syndrome |
|
|
Self-assessed depression |
|
|
Restless legs syndrome |
|
|
Sicca symptoms |
|
|
Raynaud phenomenon |
|
|
Female urethral syndrome |
In fibromyalgia, negative psychological elements constituting stress and distress are a major contributor to the development of increased pain sensitivity and myriad other symptoms. Functional magnetic resonance imaging of the brain during the application of painful pressure in fibromyalgia patients has demonstrated augmented central pain processing.28 There is no consensus, however, regarding the relative contribution to pain in fibromyalgia of so-called central sensitization (enhanced excitability of dorsal neurons of the spinal cord), dysfunction of descending inhibitory pain control systems (e.g., DNIC), windup (temporal summation of second pain, described as "dull," "aching," or "burning"), thalamic activity, neuroglial activation,29 and genes.
Diagnosis
Clinical Manifestations
Pain is the hallmark of fibromyalgia. The pain radiates diffusely from the axial skeleton and is localized to muscles and muscle-tendon junctions of the neck, shoulders, hips, and extremities. Fibromyalgia patients describe the pain with such terms as exhausting, miserable, or unbearable. Generalized hy-peralgesia is a cardinal feature. Patients frequently complain that even gentle touch is unpleasant, a condition known as allo-dynia—pain from normally nonpainful stimuli.
In addition to their persistent widespread pain, fibromyalgia patients experience severe fatigue, insomnia, and low mood or depression [see Table 1]. Fatigue occurring most times of the day on most days, together with subjective weakness and non-restorative sleep, is almost universal. Cognitive complaints, such as difficulties with concentration and memory, may be prominent. Depression, anxiety disorders, and personality disorders contribute to ongoing psychological distress. Other complaints result from somatization, which can be defined as translating psychological distress into somatic symptoms (which are considered more socially acceptable) and seeking care for those symptoms.
Patients with fibromyalgia have a strong tendency toward external attribution of symptoms, with fixed beliefs that minor trauma, viruses (e.g., Epstein-Barr), Candida, mold (e.g., so-called black mold), toxic chemicals, or other physical agents (e.g., silicone breast implants) caused their illness. This can be a barrier to recovery, as can ongoing litigation regarding causation of fibromyalgia, disability determination proceedings, or workers’ compensation claims.
Functional impairment is usually present, at least in patients with fibromyalgia who seek care. Patients report difficulty doing usual activities of daily living and lack of exercise—indeed, fear and avoidance of exercise.
Regional pain syndromes, such as headache, temporo-mandibular joint syndrome, or irritable bowel syndrome, are extremely common in fibromyalgia. It is essential that the physician not automatically attribute all such symptoms to fi-bromyalgia, however, because fibromyalgia frequently coexists with other organically defined disorders. Optimum therapy requires recognition of both fibromyalgia and comorbid disease.
In taking the history, the physician should inquire about sleep quality, ongoing and past stressors, and feelings of anxiety or depression. Recognition of difficulties in these areas is essential in the overall management of chronic pain and fatigue. Onset of fibromyalgia usually antedates clinical diagnosis by years. Exploration of life events surrounding the onset often reveals major stressors, such as breakup of marriage, loss of job, or bankruptcy. The open-ended question, "During your childhood, did you have any bad experiences, such as physical, emotional, or sexual abuse?" not infrequently leads to a catharsis of a significant psychological burden. Current research on the biology of emotion suggests that traumatic experiences during childhood, a period when the brain is still developing, profoundly shape emotions and the subsequent development of functional somatic pain in adulthood. The consequences of abuse are not limited to children; adult domestic violence is an important antecedent of fibromyalgia.30
It is valuable to ask whether the patient has previously sought treatment for manifestations of fibromyalgia. Discussion of what treatments have been prescribed and how the patient responded can guide the physician in developing a therapeutic plan. Narcotic use and unsuccessful prior referrals to multidisciplinary pain centers suggest a poor prognosis. Fi-bromyalgia patients are especially likely to use complementary and alternative medicine (CAM), in part because of the limited efficacy of conventional medical care. Because some CAM agents are not safe and many have the potential to interact with conventional pharmacologic agents, questions about CAM use are an important part of the history.
Physical Examination Findings
A patient with uncomplicated fibromyalgia will have normal results on general physical examination. This reassures both the physician and the patient that a significant alternative cause for the symptoms is unlikely. Evidence of synovitis (joint effusion, warmth over joint, pain on joint motion), objective muscle weakness, or other definite physical or neurologic signs suggests the presence of either comorbid disease or an alternative diagnosis. It is essential to identify concomitant painful diseases such as osteoarthritis of individual joints, degenerative spondylosis, bursitis, or other inflammatory soft tissue conditions, because the nociceptive pain from such common problems is amplified in fibromyalgia. Many patients exhibit signs of regional pain syndromes that are often associated with depression or anxiety, such as tenderness in the jaw area (tem-poromandibular disorder), subtle lower abdominal tenderness to palpation (irritable bowel syndrome), psychomotor slowing (depression), and irritability or hostility (anxiety, panic disorder, or personality disorder).
Tender Points
Eighteen specific tender points have been identified in fi-bromyalgia [see Figure 1].1 A patient with fibromyalgia will have pain, not just tenderness, on palpation at many of these tender points. Palpation is performed with the thumb, using approximately 4 kg of pressure—about the pressure necessary to blanch the examiner’s thumbnail. Attempting to confirm pain at all 18 tender points is not necessary for diagnosis and is often uncomfortable for patients, many of whom find tender-point palpation quite distressing. If an algometer is available, it can provide semiquantitative information regarding pressure pain threshold at tender points. Some fibromyalgia patients complain of pain when pressure is applied anywhere on the body, even relatively insensitive areas such as the forehead or thumbnail. Unfortunately, in situations of potential secondary gain (e.g., injury litigation, pending disability determination), the physician must be alert for malingering; some of these patients are well informed regarding the location of tender points. Firm pressure over the trapezii or posterior thorax with a stethoscope, rather than a thumb, can provide insight in such cases.
Laboratory Tests
There are no specific laboratory test abnormalities in fi-bromyalgia. Nevertheless, it is appropriate to conduct limited screening for commonly associated disorders and for other diseases that can cause pain and fatigue.
Blood Tests
Useful tests in fibromyalgia include the following: antinu-clear antibody (ANA), complete blood count, erythrocyte sedimentation rate (ESR) or C-reactive protein, thyroid-stimulating hormone (TSH), creatine kinase (CK), aspartate aminotrans-ferase, and alanine aminotransferase. Tests for Lyme disease, Epstein-Barr virus infection, and endocrinologic status (e.g., measurement of estrogen, testosterone, growth hormone, and dehydroepiandrosterone) are usually unnecessary.
Other Tests
Urinalysis may be useful. Tests for autonomic dysfunction (tilt-table test), studies of nerve conduction velocity and elec-tromyography, and imaging studies should not be done unless there is a specific indication.
Differential Diagnosis
The differential diagnosis of fibromyalgia is very broad [see Table 2]. Nevertheless, extensive laboratory testing or imaging studies should not be done unless the patient has objective indications of other disease on physical or neurologic examination. Major causes of diffuse musculoskeletal pain and key clinical and laboratory features are as follows:
• Fibromyalgia (diffuse pain, tenderness, fatigue, stiffness, tender points, normal laboratory findings)
• Rheumatoid arthritis (symmetrical synovitis, presence of rheumatoid factor, elevated ESR and C-reactive protein)
• SLE (constitutional symptoms, rash, arthralgias, presence of ANA and other autoantibodies)
• Polymyalgia rheumatica (age greater than 50 years, shoulder and hip girdle pain, very high ESR)
• Spondyloarthropathy (morning back pain and stiffness, asymmetrical oligoarthritis, sacroiliitis on pelvic x-rays)
• Inflammatory myopathy (muscle tenderness, objective proximal muscle weakness, elevated serum CK)
• Hypothyroidism (myalgias, weight gain, dry skin, fatigue, cold sensitivity, hyporeflexia, elevated TSH level)
• Osteomalacia (diffuse bone pain and tenderness, proximal myopathy with weakness, low serum phosphate and 25-hydroxyvitamin D levels)
It is usually not helpful clinically to distinguish fibromyalgia from chronic fatigue syndrome or the many regional pain syndromes. Giving patients a name for their illness, however, often enables them to concentrate on getting better, rather than continuously searching for a cause and cure.
Treatment
Four principles govern the treatment of fibromyalgia: (1) validation of distress, (2) diagnostic and therapeutic conservatism, (3) an individualized combination of pharmacologic and nonpharmacologic measures, and (4) care rather than cure. Validation of the patient’s symptoms and distress begins with the initial history and physical examination, when the physician explores adverse developmental, social, and behavioral variables and past and current stressors. Failure to provide validation, initially or later in the therapeutic relationship, serves only to perpetuate pain and fatigue and may constitute an insurmountable barrier to treatment.
Strong evidence for therapeutic efficacy in fibromyalgia on the basis of randomized, controlled trials has been difficult to obtain. Confounding factors include the current poor understanding of the syndrome’s origin and pathophysiology, the complexity of its symptoms, lack of consensus regarding nosology and clinically meaningful outcome measures, small sample size, short trial duration, and a strong placebo effect because of the close attention patients receive in trials. Much current treatment is empirical and based on proposed, rather than established, models of pathophysiology. Nevertheless, a wealth of published information on treatment of fibromyalgia is now available, including two monographs31,32 and a series of systematic reviews and meta-analyses of controlled trials.33-35 Clinical practice guidelines are pending from the American Pain Soci-ety36 The available data suggest that the pain, fatigue, non-restorative sleep, depression, and anxiety respond to a multi-faceted therapeutic approach that combines drug therapy with physical, psychological, and behavioral treatments. An overarching goal of therapy is the promotion of self-efficacy—the patient’s firmly held belief that he or she can control symptoms of pain and fatigue.
Table 2 Differential Diagnosis of Fibromyalgia
|
Major Disorder Group |
Selected Specific Disorders |
|
Rheumatologic |
Systemic lupus erythematosus* |
|
Rheumatoid arthritis, Sjogren syndrome* |
|
|
Polyarticular osteoarthritis, degenerative spondylosis |
|
|
Polymyalgia rheumatica* |
|
|
Polymyositis, statin myopathy |
|
|
Regional pain syndromes* |
|
|
Osteomalacia |
|
|
Hypermobility syndromes |
|
|
Neurologic |
Carpal tunnel syndrome* |
|
Cervical radiculopathy* |
|
|
Metabolic myopathies |
|
|
Multiple sclerosis* |
|
|
Cervical cord compression |
|
|
Chronic infection |
Subacute bacterial endocarditis |
|
Brucellosis |
|
|
Hepatitis HIV |
|
|
Endocrine |
Hypothyroidism* |
|
Diabetes mellitus type 2 |
|
|
Hyperparathyroidism |
|
|
Neoplastic |
Metastatic (e.g., breast, lung, prostate) Myeloma |
|
Psychiatric |
Pain disorder associated with psychological factors* (formerly, somatoform pain disorder) |
|
Somatization disorder (hysteria, Briquette syndrome) |
Treatment in Geriatric and Pediatric Cases
Treatment of diffuse pain in older persons37 and in children38 requires special approaches. Pain in older persons is often neglected or ignored. Compared with younger persons, older persons exhibit more physical abnormalities, are more sensitive to opioids, have lower self-efficacy, and use fewer cognitive coping methods. There are many barriers to accurate pain assessment in older persons, including fear of diagnostic tests or medications and reluctance to report pain because pain is an expected part of aging.
The general principles of treatment in the elderly are as follows: discuss goals, hopes, and trade-offs openly; start medications at a low dose and raise the dose slowly; pay attention to timing of medications; be aware of economic barriers; include nonpharmacologic treatment as an integral part of management; and educate the patient and caregiver.
In the pediatric population, unexplained diffuse or localized pain is most common in preadolescent to adolescent girls, often in association with incongruent affect; disproportionate impairment of performance in school; and psychological distress in the child, the family, or both. Key aspects of therapy in this population are discontinuance of all medications, psychological evaluation and psychotherapy if necessary, and a program of intense exercise. Prognosis is good for most children with persistent unexplained pain.
