Primary care physicians are often faced with the challenge of caring for patients with fibromyalgia syndrome (FMS). FMS is a complex condition characterized by pain amplification, musculoskeletal discomfort, and systemic symptoms. In the United States, it is the third or fourth most common reason for a rheumatology referral.

Definition

Approximately 10% to 12% of the general population has widespread chronic pain. FMS is a concept designed to account for such generalized chronic and idiopathic pain. The 1990 classification criteria of the American College of Rheumatology (ACR) is based on the analysis of more than 300 variables such as symptoms, physical findings, and laboratory and radiologic studies by a study committee.¹ The mandatory defining symptom is widespread pain not explained by an inflammatory or degenerative musculoskeletal disorder.

The ACR criteria for diagnosis of FMS have two components. The first is widespread pain for at least 3 months (pain in the left side of the body, plus right side of the body, plus pain above the waist, plus pain below the waist, plus axial pain; axial pain includes pain in the cervical spine, or thoracic pain, or pain in the low back or anterior chest wall). The second is the presence of 11 tender points among 18 specified sites as shown in Figure 1. Pressure of 4 kg/cm (enough to whiten the examiner’s fingernail) should be applied to each point for a few seconds.²

It is important to remember that there are more than 600 muscles in the human body, each of which might theoretically contain a tender point. The 18 tender points recommended by the ACR represent only a sample of widespread pain in any given patient. If a patient has widespread pain in many other areas, it is entirely possible that he or she has fibromyalgia.³

The presence of many tender points on digital palpation validates the diagnosis. According to the ACR criteria, the finding of 11 of 18 specified tender points provided a sensitivity of 88% and a specificity of 81% in distinguishing fibromyalgia from other chronic causes of musculoskeletal pain. ¹ In addition, the criteria committee found that several other disorders are often associated with FMS, including sleep disturbance, fatigue, paresthesias, anxiety, and headache or irritable bowel syndrome. Frederick Wolfe, the chairman of the criteria committee, later wrote that the presence of seven (40%) of the tender points and at least three of the six features mentioned earlier are highly suggestive of FMS.

It is now widely accepted that numerous other conditions can overlap with FMS (Box 1). These include irritable bowel syndrome, tension-type headaches, migraine, temporomandibular dysfunction, myofascial pain syndrome, chronic fatigue syndrome, restless legs syndrome, and multiple chemical sensitivities, to name just a few.

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Prevalence

The prevalence of FMS in the general community is 2% for both genders. Women are affected more than men; the prevalence is 3.4% for women and 0.5 % for men. The prevalence increases with age, reaching 7% in women ages 60 to 79 years.⁴

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Pathophysiology

A heightened pain response is present in patients with FMS. This is now known to be caused by altered processing of nociceptive stimuli by the central nervous system.^5,6 Levels of substance P and abnormal antinociceptive peptides are elevated in the cerebrospinal fluid of patients with FMS.⁷ FMS might be best understood as a heightened response of the entire nervous system, as if the volume has been turned up.^8,9 Inheritance of a short allele of the serotonin transporter promoter gene has taken serotonin metabolism to center stage and suggests a possible heritable mechanism in the pathogenesis of FMS.¹⁰ Other studies have postulated serotonin deficiency as a pathophysiologic mechanism in FMS.¹¹ A group of excitatory amino acids—l-tryptophan, alanine, histidine, lysine, proline and serine, to name a few—are also decreased in the spinal fluid in patients with FMS.¹²

Although some reports have suggested that muscle tissue is normal in FMS, others have found increased moth-eaten and ragged red type I and type II fiber atrophy on light microscopy.^13,14 Other clinicians have found myofibril lysis or swollen abnormal mitochondria on electron microscopy.^13,14 However, it is unclear whether these changes are due to deconditioning or to FMS itself.²

Slow-wave sleep abnormalities are also present, and a significantly increased amount of alpha-wave intrusion into delta-wave sleep during non–rapid eye movement (non-REM) sleep is responsible for more awakenings and other symptoms of nonrestorative sleep. Sleep apnea and restless legs syndrome, nocturnal myoclonus, and bruxism have been reported in some studies. ² Severe dysautonomia, or reflex sympathetic dystrophy, coexists with FMS and is believed by some clinicians to be a subtype of FMS. ²

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Predisposing Factors

One half of all FMS cases have no apparent cause. The most common cause of secondary FMS is trauma. Even trivial trauma can act as the inciting agent and lead to the development of widespread pain within 3 months. Numerous infectious agents such as herpes viruses, parvovirus, Borrelia burgdorferi, human immunodeficiency virus, and Brucella species have been implicated as the causes of a postinfectious fatigue–like syndrome. ² To date, however, no clinical or serologic studies have proved an etiologic role for Epstein-Barr virus, parvovirus or, indeed, any virus. Heavy lifting and bending, or prolonged sitting at word processing stations, might induce secondary FMS. Heroin, cocaine, and alcohol withdrawal can also induce a FM-like syndrome, as can administration of interferon alfa or interleukin-2. Life-altering events such as death of a loved one, loss of a job, or divorce in the presence of poor coping mechanisms can bring out FMS. ² Emotional trauma such as physical or sexual abuse or posttraumatic stress disorder can act as triggers.

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Clinical Manifestations

All patients have widespread pain and tender points. Although stiffness may be present in the early hours, pain is worse in the late afternoon and early evening. Most patients report that symptoms are worsened by cold and humid weather, winter months, poor sleep, mental stress, or physical inactivity and are improved by warm and dry weather, summer months, rest, moderate physical activity, good sleep, and relaxation. ¹⁵ Approximately 80% of patients experience fatigue, poor sleep, and complaints of weakness with normal muscle strength. Most persons with FMS have anxiety or depression, often related to pain. A sense of bloatedness, numbness, or tingling may also be present. Dysautonomia may be the cause of dry eyes, skin hyperemia, skin tenderness to touch, and bloating. Some patients complain of fever and swollen glands. Indeed, if these are present, alternative diagnoses should be entertained. In the elderly, fewer functional symptoms such as anxiety, stress, and unrefreshed sleep are present. However, the elderly have more musculoskeletal complaints than their younger counterparts. FMS can be confused with polymyalgia rheumatica, primary Sjögren’s syndrome, or rheumatoid arthritis in the elderly.

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Workup

The physical examination should be a fibromyalgia-focused approach. Routine vital signs should be taken, with special attention paid to blood pressure measurements in the recumbent and standing positions. Several findings relevant to FMS should be noted during the first few minutes of the encounter (e.g., posture and mood). Lymphadenopathy and thyroid swellings should be sought. Often, what was first believed to be a tender lymph node is, on re-examination, in fact a tender carotid artery.

Tender points should be sought and other systems examined as suggested by the history. Diagrams can be used by the patient to highlight tender points. A fibromyalgia patient can have osteoarthritis, inflammatory arthritis, bursitis, tendinitis, or adhesive capsulitis. However, these diagnoses are not justified in the absence of a history of trauma, presence of calcification, or a swollen bursa on radiograph or magnetic resonance imaging. Paresthesias in the presence of objective weakness should warrant a full neurologic examination because conditions such as cervical spinal stenosis and Chiari malformations can mimic some of the symptoms of FMS. A patient with a Chiari malformation has worsening of radicular symptoms on neck flexion or abnormal neurologic signs such as brisk lower-limb reflexes or weakness in the upper extremities. Instruments such as the Beck Depression Index, the Fibromyalgia Impact Questionnaire, and the Epworth Sleep Scale can provide valuable insights.

No special laboratory or radiologic testing is necessary to make a diagnosis of FMS. A reasonable initial workup should include a complete blood cell count, complete metabolic panel, and a urinalysis. Tests of creatine kinase and thyroid-stimulating hormone may be performed if clinically indicated. One of the common referrals to the rheumatology clinic is a positive antinuclear antibody (ANA) test. This test should not be ordered unless there is a clinical suspicion of connective tissue disease. In a study by Yunus and colleagues, 11% of female patients with FMS had positive findings on ANA tests. Importantly, 10% of healthy female controls also had a positive ANA. ¹⁶ Sleep studies may be indicated if the history suggests heavy snoring, daytime sleepiness, or leg movements.

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Diagnosis and Differential Diagnosis

Classification criteria are not designed to diagnose disease in an individual patient. Rather, a careful history and physical examination should remain the cornerstones of diagnosis, as with any disease or syndrome. To meet the criteria for FMS, patients with FMS must have chronic widespread pain, fatigue, and associated symptoms such as sleep disturbances and headaches to begin with. FMS should be differentiated from rheumatoid arthritis, osteoarthritis, and other systemic illnesses.

The differential diagnosis of FMS includes hypothyroidism, polymyalgia rheumatica, osteomalacia, metabolic and inflammatory polyarthropathies, spondyloarthropathy, radiculopathy, pleuritic or cardiac pain syndromes, and extrapyramidal disease.

Common pitfalls in dealing with FMS patients include concurrent medical or psychiatric illnesses. Spondyloarthropathy can have very subtle clinical findings and can be misdiagnosed as having FMS. FMS may be misdiagnosed as osteoarthritis in elderly patients, the pertinent clinical findings being pain on movement and a more localized pain in osteoarthritis. FMS is present in 40% of patients with systemic lupus erythematosus and in 10% to 30% of patients with rheumatoid arthritis. FMS can also be misdiagnosed as Lyme disease or systemic lupus erythematosus. Approximately 25% to 50% of patients referred to Lyme disease clinics turned out to have FMS, ^17,18 and 25% of patients referred to rheumatology clinics based on positive ANA test results had FMS. ¹⁹

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Treatment

If the diagnosis is made early enough, patients with FMS tend to do well with simple management techniques. ²⁰ FMS as a syndrome is poorly understood in the primary care setting. In one study, patients received a diagnosis of FMS after seeing an average of three doctors with the same complaints. ²¹ Patients might undergo unnecessary and extensive workups including myelograms, cancer workups, adrenal evaluations, and even laparotomies in some cases.

Patient education remains a cornerstone in the management of FMS. Providing patients with literature regarding their illness and explaining to them that they are indeed dealing with a real disorder is an ideal starting point. At the same time, patients need to be reassured that they are dealing with a nondestructive, although not necessarily benign, illness.

Response to treatment can be assessed in a variety of ways as suggested in a review by Bennett. ³ Questionnaires that provide information about quality of life give the best details from a patient’s perspective about overall self-assessment of change. The Short Form 36 (SF 36) is one of the health questionnaires that can be used. Pain can be assessed using the visual analogue scale (VAS). If depression is an issue, this can be monitored using a daily diary or the Beck Depression Inventory. ³ A questionnaire that provides an overall view of the many problems a patient experiences in fibromyalgia can be assessed using the Fibromyalgia Impact Questionnaire (FIQ). ²² The FIQ is currently the most widely used questionnaire and by one survey the most useful. ³

Treatment in FMS can be divided into nonpharmacologic and pharmacologic means. It is important that a multidisciplinary program use both strategies. ²³

Nonpharmacologic Treatments

Nonpharmacologic treatments include cardiovascular fitness training, electromyogram biofeedback, hypnotherapy, acupuncture, and cognitive-behavioral therapy.

Exercise is often recommended as a treatment for FMS. Many trials have now proved that aerobic exercise produces significant positive changes in experimental groups of FMS patients. ²⁴ The aerobic exercise recommended should be of low impact, such as isometric exercises, swimming, or aerobic walking. Ferraccioli and colleagues found improvements lasting up to 6 months in patients treated with electromyographic biofeedback. ²⁵ Improvement was defined in this study as decreases in tender point counts, decrease in early morning stiffness (measured in minutes) and decrease in pain as measured by the visual analogue scale (VAS).

Buckelew and colleagues found that biofeedback in conjunction with low-impact exercise produced better results than each of the modalities on its own. ²⁶

Deluze and colleagues found that that significant improvements in pain occur when patients with FMS are treated with real electroacupuncture as opposed to sham treatment. ²⁷ However, because patients still continued with cotreatments during this study, confounding results were always possible. Assefi and colleagues compared real acupuncture with a sham procedure in 100 FMS patients. ²⁸ Patients experienced 20% improvement with both procedures, demonstrating that real acupuncture was no better than sham acupuncture.

Haanen and colleagues showed significant improvement in five outcome measures in a group treated with hypnotherapy as compared with a physical therapy program.²⁹ However, there was a lack of standardization of physical therapy in this study.

In a systematic review evaluating the evidence from randomized controlled trials for nonpharmacologic treatments in FMS, Sim and Adams concluded that few studies tested comparable interventions, the methodologic quality of such studies was generally poor, the statistical power was low, and statistical analyses were insufficient. ³⁰

Pharmacologic Treatments

Pharmacologic treatment for FMS (Box 2) remains largely empirical and aimed at individual symptoms. Pain is the symptom most amenable to pharmacologic intervention. Pharmacologic treatment should also be used for coexisting conditions in FMS such as irritable bowel and bladder syndromes or migraine headaches.

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) act on peripheral pain generators and can address issues such as myofascial pain, bursitis, and tendinitis in patients with FMS. Patients with FMS at the severe end of the spectrum do not respond to simple analgesics and need more aggressive interventions. Central pain is not responsive to NSAIDs, and in these cases, centrally acting analgesics are the preferred mode of treatment.

Opioids

Opioids are effective in acute and chronic pain states. The use of opioid analgesics in FMS is a widely debated issue. True addiction develops in 0.5% of patients prescribed opioids for treatment of chronic pain. ³¹ The more problematic issues of long-term opioid use are effects on cognition, reduced motivation to pursue nonpharmacologic approaches in FMS, aggravation of depression, and stigmatization by society and physicians.

All patients are expected to develop dependency; that is, these drugs cannot be abruptly withdrawn without causing unpleasant side effects such as pruritus, nausea, and drowsiness. It is important to screen patients for previous problems with opioid use and benzodiazepine dependence before embarking on this route in the treatment of FMS. Frequent re-evaluation of the patient is especially important in this setting, with the goal being improved function rather than mere pain relief. If improved function is not achieved, if severe side effects are encountered, or if maladaptive behavior develops, patients should be weaned from these agents and not restarted on them. ³²

Tramadol is also effective in FMS patients with mild to moderate pain and may be the only centrally acting analgesic necessary in an office setting. Abuse has been documented in less than one case per 100,000 patients. ³³ If tramadol is chosen, the dose should be low to begin with and then increased gradually to avoid nausea and dizziness. Seizures have been reported, especially when this agent is combined with antidepressants. ³⁴

Activation of N-methyl-d-aspartate (NMDA) receptors can lead to abnormal modulation of nociceptive impulses. Good experimental evidence exists that pain in FMS can be ameliorated by blocking NMDA receptors. A Swedish group was able to abolish pain by infusing ketamine in patients with FMS. ³⁵

Antidepressants

Antidepressants have been crucial in the management of many chronic pain states including FMS. Antidepressants improve sleep, fatigue, pain, and well-being. They do not specifically improve tender points. ³²

Three classes of antidepressants were evaluated in a large meta-analysis of antidepressants in FMS: ³⁶ tricyclic antidepressants (TCAs, nine trials), selective serotonin reuptake inhibitors (SSRIs, three trials), and S-adenosylmethionine (SAMe, two trials). The odds ratio for improvement with therapy in this meta-analysis was 4:2. The efficacy of TCAs is short lived, at least in the tertiary care setting. The SSRIs have disappointing analgesic effects in FMS, although these agents help improve concomitant mood disorders. A combination of fluoxetine and amitriptyline was found to be more effective than either agent alone or placebo. ³⁷ Controlled trials of duloxetine and milnacipram have documented benefit versus placebo. ^38,39

Experts in FMS have found that nonselective serotonin reuptake inhibitors, especially those with a noradrenergic component (venlafaxine, nefazadone, or bupropion) seem to be more effective for treating fatigue, which is the most difficult symptom in FMS to treat pharmacologically.

Miscellaneous Agents

α₂-Adrenergic agonists such as tizanidine have been used successfully in chronic pain disorders. There have been no trials of these agents in FMS. Tizanidine has antinociceptive, antispasmodic, and sedating effects, which might explain its anecdotal benefit in FMS.

Serotonin antagonists have been the subject of many recent trials in FMS. These drugs have been used in the control of nausea and vomiting in patients who have received chemotherapy or radiation. Tropisetron was evaluated in a short-term, double-blinded study involving 418 patients with FMS. In that study, 40% of patients reported a 55% reduction in pain scores. ⁴⁰ Preliminary results of studies using serotonin antagonists in FMS have been encouraging, and results of long-term placebo-controlled studies are awaited.

Pregabalin, an anticonvulsant with analgesic properties, has been shown to produce global improvement in a large (459 patient) placebo-controlled trial at a dose of 450 mg a day. A high incidence of dizziness (49.2%) and somnolence (28%) limits its usefulness. ⁴¹

Sodium oxibate is chemically related to the naturally occurring metabolite of the human central nervous system that promotes stages three and four non-REM sleep, g-hydroxybutyrate. Sodium oxibate has been shown to reduce pain in FMS when taken at a nightly divided dose of 6 g in a small controlled trial. ⁴² Because it is also known as the “date rape” drug, it is only available in a prescription from physicians who enroll in a special program sponsored by the makers.

Treatment of Specific Symptoms

Sleep

Before pharmacologic treatment is initiated, certain measures must be tried. Caffeinated beverages should be avoided 4 to 6 hours before the patient goes to bed. The bedroom should be used only for sleep and sexual activities. Relaxation techniques such as yoga, gentle stretching, or listening to soothing music are all helpful. Pure sedatives such as benzodiazepines, antihistamines, and antidepressants are the pharmacologic therapies available. Restless legs syndrome often responds to low-dose clonazepam (0.5 to 1 mg at bedtime), carbidopa/levodopa (10/100 mg at the evening meal), or low-dose narcotics at bedtime. Care should be taken when clonazepam is used on a long-term basis because it causes prominent withdrawal symptoms when discontinued abruptly. Patients with sleep apnea require continuous positive airway pressure. Specific symptoms should be sought in the history that point to a diagnosis of sleep apnea, because this diagnosis is often missed. ³²

Mood Disturbances

Patients with FMS often suffer from dysphoria or frank clinical depression. Although antidepressants are used in the treatment of FMS itself, the doses used are often suboptimal for the treatment of depression. SSRIs, which have fewer side effects than TCAs, are useful in managing depression in the FMS patient. The nonselective serotonin reuptake inhibitors with a noradrenergic component, such as venlafaxine, nefazadone, and bupropion, are better tolerated in this group of patients. ³²

Fatigue

The pathophysiology of fatigue is poorly understood, which makes it one of the most difficult symptoms to treat in FMS. Nonselective serotonin reuptake inhibitors show encouraging results. Also, the serotonin-receptor antagonist tropisetron shows a beneficial effect in FMS-related fatigue and in chronic fatigue syndrome. ³²

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Future directions

Controversy regarding the very existence of FMS persists today, as it did a century ago. Medical professionals and patients in one camp believe that FMS is not a true syndrome per se because it does not fit into a biomedical cause-and-effect model. In another camp are those who believe that FMS is a nonentity defined by physicians’ and society’s perceptions of psychosocial stress. However, an infective or immune cause cannot always explain a disease process. Rarely does a costly evaluation of FMS find a cause or suggest a definitive diagnosis. There is no clear evidence that FMS is a disease of muscle. There is also no evidence of pathologic abnormalities at tender points or trigger points.

In reviews by Goldenberg, ^19,43 the author suggests that future research should focus on how FMS ties in with other poorly understood syndromes such as irritable bowel syndrome and migraine headaches. Genetic factors, physical or sexual abuse, and chronic psychological stress might provide a premorbid susceptibility to FMS. Neurohormonal dysregulation might result in abnormal blood flow to some areas of the brain that regulate pain perception, such as the thalamus and caudate nucleus.

As has been mentioned, randomized clinical trials in FMS suffer from methodologic weaknesses. In trials evaluating the impact of medical treatments on FMS, cointerventions such as exercise or education have not been measured. The long-term outcome in FMS has been evaluated in very few studies. Natural history reports indicate that complete remissions are unusual and that patients continue to be symptomatic, but gradual and modest improvement with time is common. ⁴³ It may be said that a single cause for syndromes such as FMS, irritable bowel syndrome, chronic fatigue syndrome, or irritable bladder syndrome might never be found. Each of these entities might fit into a psychosocial rather than a biomedical model.

Summary

• Fibromyalgia syndrome is the muscle pain component of altered central nervous system processing, and because of this it is associated with many other symptoms.
• The pathophysiology of fibromyalgia syndrome is intimately related to the effects of psychological distress and disordered sleep on the central nervous system.
• The simple, effective approach to treatment employs the combination of patient education, improved mood and sleep, and aerobic exercise.

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