A Review of Fibromyalgia

Characterized by chronic widespread joint and muscle pain,fibromyalgia is a syndrome of unknown etiology. The AmericanCollege of Rheumatology's classification criteria for fibromyalgiainclude diffuse soft tissue pain of at least 3 months' duration andpain on palpation in at least 11 of 18 paired tender points.Symptoms are often exacerbated by exertion, stress, lack of sleep,and weather changes. Fibromyalgia is primarily a diagnosis ofexclusion, established only after other causes of joint or musclepain are ruled out. The initial workup for patients who present withwidespread musculoskeletal pain should include a complete bloodcount, erythrocyte sedimentation rate, liver function tests, hepatitisC antibody, calcium, and thyrotropin. The musculoskeletal system,the neuroendocrine system, and the central nervous system, particularlythe limbic system, appear to play major roles in the pathogenesisof fibromyalgia. The goal in treating fibromyalgia is todecrease pain and to increase function without promotingpolypharmacy. Brief interdisciplinary programs have been shownto improve subjective pain. Fibromyalgia is a complex syndromeassociated with significant impairment on quality of life and functionand substantial financial costs. Once the diagnosis is made,providers should aim to increase patients' function and minimizepain. This can be accomplished through nonpharmacological andpharmacological interventions. With proper management, the rateof disability appears to be significantly reduced.

(Am J Manag Care. 2004;10:794-800)

fibrositis

Fibromyalgia is a syndrome of unknown etiologycharacterized by chronic widespread joint andmuscle pain. Fibromyalgia was previouslyreferred to as , a term coined by Sir WilliamGowers¹ in Europe referring to regional pain syndromesassociated with profound fatigue and sleep disturbance.Fibromyalgia affects approximately 6 million people inthe United States,² or up to 6% of the patients seen ingeneral medical practices.³ Patients are usually diagnosedbetween the ages of 20 and 50 years, but the incidencerises with age so that, by age 80, approximately8% of adults meet the classification criteria establishedby the American College of Rheumatology.⁴ The ratio ofwomen to men with fibromyalgia varies between 9:1⁵ and 20:1.⁶ One prospective study⁷ showed that patientswith fibromyalgia have approximately 10 outpatientclinic visits per year, 1 hospitalization per 3 years, andmore than $2000 per year in medical costs. Anotherprospective study⁸ showed that total annual costs forfibromyalgia patients were close to $6000, comparedwith $2500 for typical patients. Six percent of thesecosts were attributable to fibromyalgia-specific claims.However, there may have been other hidden costs relatedto disability from fibromyalgia. This study alsoshowed that, for every dollar spent on fibromyalgia-specificclaims, the employer spent $57 to $143 on additionaldirect and indirect costs.

The American College of Rheumatology's criteria forfibromyalgia include diffuse soft tissue pain of at least 3months' duration and pain on palpation in at least 11 of18 paired tender points.⁴ These criteria are approximately88% sensitive and 81% specific for the diagnosisof fibromyalgia. Symptoms are often exacerbated byexertion, stress, lack of sleep, and weather changes. Inhalf of all patients, symptoms appear after a flu-like illnessor after physical or emotional trauma.⁹ Approximately 30% of patients with fibromyalgia arediagnosed as having concurrent depression or anxietydisorders (Figure).¹⁰

DIAGNOSIS

The main challenge in evaluating patients with suspectedfibromyalgia is that there is no gold standard testfor diagnosis. It is primarily a diagnosis of exclusion,established only after other causes of joint or muscle painare ruled out. The initial workup for patients who presentwith widespread musculoskeletal pain should include acomplete blood count, erythrocyte sedimentation rate,liver function tests, hepatitis C antibody, calcium, andthyrotropin. Some experts recommend that patients withsuspected fibromyalgia have a limited amount of testingbefore assigning the diagnosis. The clinician should keepin mind that an antinuclear antibody is often of low yieldwhen other features of systemic lupus erythematosus orother antinuclear antibody—associated diseases areabsent. In addition, false-positive results are common. Inone series, 10% of patients with fibromyalgia had a positiveantinuclear antibody.¹¹ Up to 30% of healthy womenmay test positive as well.¹² Similarly, imaging tests andneurophysiological studies are not recommended as initialscreening tests.¹³

In most cases, the patient's history can distinguishfibromyalgia from other systemic illnesses. However,fibromyalgia often coexists with and has a tendency tomimic other illnesses. Estimates of its concomitancewith systemic lupus erythematosus range as high as45%. In one study¹⁴ of patients with lupus, 22% of thepatients also met criteria for fibromyalgia. Thesepatients had no difference in the measures of theirlupus activity. However, they experienced greater disabilityassociated with their illnesses. Twelve percentof patients with rheumatoid arthritis and 7% of patientswith osteoarthritis meet the criteria for fibromyalgia.¹⁵ Twenty-five to 50% of patients with fibromyalgia haveRaynaud phenomenon or have symptoms consistentwith sicca syndrome.¹² Patients with fibromyalgia mayinitially be misdiagnosed as having seronegativespondyloarthropathies, such as ankylosing spondylitis,because they share the common complaints of neck,spine, and back pain. However, in the absence of otherinflammatory disease, patients with fibromyalgia havenormal erythrocyte sedimentation rates and normalfindings on radiographic studies. In older adults, thesyndrome is most commonly confused with polymyalgiarheumatica, which typically presents with persistentsevere morning stiffness in the shoulders, pelvis,and torso. The erythrocyte sedimentation rate will beelevated in 80% to 90% of patients with polymyalgiarheumatica, and its symptoms respond to low-dose systemiccorticosteroids. Fibromyalgia symptoms do notrespond to corticosteroids,¹⁶ consistent with the noninflammatorynature of this disorder. However, patientswith polymyalgia rheumatica who are tapered off corticosteroidstoo rapidly can occasionally develop symptomssimilar to those of fibromyalgia. Most patientswith chronic fatigue syndrome meet the criteria forfibromyalgia, and 70% of fibromyalgia patients meetcriteria for chronic fatigue syndrome.¹⁷

In nonrheumatic illnesses, patients may present withsymptoms similar to fibromyalgia. Hypothyroidism canpresent with muscle pain similar to fibromyalgia.¹² Patients with hepatitis C have a higher prevalence offibromyalgia.¹⁸ Research suggests that Lyme disease canalso trigger fibromyalgia.¹⁹ In one study,²⁰ patients withfibromyalgia had a greater number of desaturations perhour of sleep compared with healthy control subjects.Those patients complaining of daytime hypersomnolencehad a higher number of tender points, about twiceas many arousals per hour, and lower sleep efficiencycompared with the other patients.

In terms of psychiatric morbidity, an estimated 30%of patients with fibromyalgia will have depression oranxiety at some point during their lifetime. One study²¹ found that 40% of patients with fibromyalgia haddepression, compared with 29% of patients withrheumatoid arthritis. The likelihood of depression inpatients with musculoskeletal complaints was highest inpatients with nonarticular diseases such as fibromyalgiaor myofascial pain syndrome.²² Fibromyalgia patientsdemonstrate higher levels of anxiety and depressionthan healthy control groups.²³ This may exacerbate ortrigger their somatic complaints. However, according tosome investigations, measures of depression, anxiety,and stress are comparable in patients with fibromyalgiaand patients with other chronic medical conditions.²⁴ Therefore, patients with fibromyalgia may exhibit signsand symptoms of anxiety and depression, and theircomplaints should not be attributed to psychological illnessalone.

PATHOGENESIS

The musculoskeletal system, the neuroendocrinesystem, and the central nervous system, particularly thelimbic system, appear to play major roles in the pathogenesisof fibromyalgia.

Musculoskeletal

Many soft tissue injuries are thought to follow chronicmuscle-tendon overload and muscle fiber "microtrauma."Continual vibration or muscle twisting along withrepetitive muscle movements over time can lead tomuscle spasm and nerve irritation. In fibromyalgiapatients, it has been postulated that there is an inabilityto relax the shoulder flexor muscles between isokineticmuscle contractions.²⁵ This, over time, could leadto muscular pain.

Some studies^26,27 suggest that patients with fibromyalgiahave abnormalities in muscle energy metabolism andmuscle tissue oxygenation. For example, in fibromyalgiapatients, biopsy specimens of tender areas of the trapeziusmuscle contain more ragged red fibers and fewerhigh-energy phosphate compounds than specimens ofnontender muscles in these patients.²⁸ Some musclebiopsies of the tissue surrounding tender points haveshown structural changes described as "moth-eatenfibers," mitochondrial changes, and type II atrophy,indicating dysfunction in the muscle microcirculation.²⁹ Together, these data may support the hypothesis thatlocal tissue hypoxia contributes to the pain associatedwith fibromyalgia. However, it is not clear whether thesemuscle changes are a cause or an effect of fibromyalgia.The fact that local treatment of tender points is generallyineffective suggests 1 of 2 possibilities: eitherfibromyalgia is a systemic disease rather than an aggregateof localized muscle disturbances, or we simply donot have effective local therapies.³⁰

Other more recent investigations show that there areno differences between fibromyalgia patients and sedentarycontrols in terms of adenosine triphosphate levels,lactate levels, muscle tension, hypoxia, or intracellularpH.³¹ Results demonstrate that measures of musclefunction such as force generation and lactate productionduring exercise, and muscle pain after exertion, aresimilar between women with fibromyalgia and healthysedentary female control patients.³¹ This suggests thatthe cause of fibromyalgia symptoms is unlikely to be apathologic abnormality of the muscle itself.

Neuroendocrine

The neuroendocrine dysfunction in fibromyalgiainvolves the hypothalamic-pituitary-adrenal axis, thehypothalamic-pituitary-thyroid axis, the growth hormoneaxis, and the locus caeruleus—norepinephrinesympathetic nervous system. With respect to the hypothalamic-pituitary-adrenal axis, some findings suggestthat fibromyalgia patients may have low adrenal responsiveness.³² Griepet al³³ showed that in these patients,when corticotrophin-releasing hormone is releasedfrom the hypothalamus, there is a disproportionatelyhigh level of corticotropin released from the pituitary inresponse and an unexpectedly small amount of cortisolthat are eventually released by the adrenal glands intothe bloodstream. This suggests that these patients mayhave a blunting of the normal stress response and maynot react appropriately to events such as infection orphysical or emotional trauma.³⁴

However, these same patients, when injected withsynthetic corticotropin, showed a similar increase intheir cortisol levels compared with healthy control subjects.³³ This shows that adrenal tissue in fibromyalgiapatients may have a differing sensitivity to exogenousversus endogenous corticotropin. Therefore, perhapsthese patients have a blunted response to endogenouscorticotropin due to a downregulation of receptors, asmight be found in settings of chronic stress, rather thantrue adrenal insufficiency.

Multiple studies have shown that fibromyalgiapatients have elevated cortisol levels with a flatteneddiurnal pattern³⁵ and lack of suppression by dexamethasone.³⁶ Results have shown that patients withdepression also have elevated levels of corticotropin andcortisol, with a flattening of the diurnal pattern.³⁷

Investigations of the hypothalamic-pituitary-thyroidaxis in fibromyalgia patients suggest that, when thyrotropin-releasing hormone is released, thyrotropin, triiodothyronine,and thyroxine are secreted, but to alesser degree than expected.³⁸ These data imply thatthere is some pituitary dysfunction in these patients,perhaps related to a dampened stress response.

It is also thought that sleep disorders may induceneuroendocrine dysfunction, which, in turn, promotesdisease development. During stage 4 sleep, the bodyproduces most of its growth hormone. In patients withfibromyalgia, stage 4 sleep is often disrupted.³⁹ Althoughfactors such as weight and age were not controlled for,the patients who were studied appeared to have adecreased level of somatomedin C, the precursor togrowth hormone.⁴⁰ It has been suggested that this relativegrowth hormone deficiency may account forpoor healing of muscle microtrauma, thereby contributingto nociceptive input.⁴⁰ It has been shownthat patients with fibromyalgia have increased levelsof corticotropin³³ and that corticotropin increases thesecretion of somatostatin in the hypothalamus.⁴¹ Somatostatinis one of the hormones that is able to inhibitgrowth hormone via the hypothalamic-pituitary portalsystem.⁴² This may also contribute to the relativegrowth hormone deficiency in fibromyalgia patients.Approximately 30% of patients with fibromyalgia havegrowth factor deficiency if defined by low insulin-likegrowth factor 1 levels.⁴³ However, these low levels maybe more common than clinically significant growth hormone.⁴³ Another study⁴⁴ showed impaired reactivity ofthe hypothalamic-pituitary axis in one third of thepatients with fibromyalgia, but did not show the presenceof severe growth hormone deficiency. Somepatients have experienced pain relief with injections ofsubcutaneous growth hormone versus placebo.⁴⁵

Neurological

Fibromyalgia patients often exhibit allodynia, a phenomenonwhereby formerly innocuous stimuli becomepainful. One showed that fibromyalgia patients have significantlyhigher scores than controls on an index ofsensory discrimination for various mechanical stimuliat tender and control points. This is consistent with thetheory that they receive increased neural input to stimulirelative to controls. Weigent et al³⁴ showed that thethresholds for detecting stimuli were similar betweenfibromyalgia patients and healthy controls. However,the points at which heat, electrical stimulation, andpressure became painful were different. Regional bloodflow investigations using functional magnetic resonanceimaging showed that, when the patients had similar subjectivediscomfort, they had the same level of blood flowto the corresponding regions of their brains.⁴⁶ For thesame amount of pressure applied, however, thefibromyalgia patients experienced greater discomfortand increased regional blood flow and neurological activationthan healthy controls.

Fibromyalgia patients generally have a greater sensitivityto stimuli diffusely, suggesting that there may be acentral or a peripheral nervous system disturbance.This theory is supported by the fact that patients have2 to 3 times normal levels of substance P, a pain modulator,in their cerebrospinal fluid.⁴⁷ Stress may potentiatethe nociceptive effects of substance P in fibromyalgiaby stimulating nerve growth factor. Fibromyalgiapatients may have an increased amount of this factorin their cerebrospinal fluid.⁴⁸ This, in turn, may promoteperipheral nerve growth and abnormal pain perception.These patients' cerebrospinal fluid alsocontains elevated levels of calcitonin gene—relatedpeptide and dynorphin A, which normally increaseafter injury. Although there are multiple potentialexplanations for this change, one possibility is thatthere may have been an insult to the nervous systemin fibromyalgia patients.

Serotonin is a neurotransmitter in the spinal cordthat inhibits the transmission of pain. It is derived fromλ-tryptophan, an amino acid that appears to bedecreased in the cerebrospinal fluid of patients withfibromyalgia.⁴⁹

Research by the National Cardiology Institute ofMexico has suggested that dysautonomia is frequent inpatients with fibromyalgia.⁵⁰ They found that the sympatheticnervous system is persistently hyperactive atbaseline, but hypoactive in response to stress.

MANAGEMENT

The goal in treating fibromyalgia is to decrease painand to increase function without promoting polypharmacy.Brief interdisciplinary programs have beenshown to improve subjective pain. A high pretreatmentlevel of impairment was significantly associated with abetter response to treatment.⁵¹

Critical elements in developing a self-managementprogram for patients are improving self-efficacy, physicaltraining, and cognitive-behavioral techniques.⁵¹ In investigationsof patients with rheumatoid arthritis, changesin self-efficacy were shown to significantly predictchanges in pain, depression, and health status, regardlessof changes in medical regimens.⁵² Self-efficacy ispromoted by mastery, modeling, social persuasion, andphysiological feedback. To develop mastery, patientsmust have the chance to practice skills until they areable to succeed at them and use incremental successesas positive reinforcement for their continued efforts.Finally, physiological feedback such as pain scales mayhelp patients visualize marginal improvements.⁵²

Cognitive strategies that emphasize restructuring ofnegative thoughts and catastrophic generalizationsabout pain are powerful ways to cope with fibromyalgiapain and fatigue.⁵³

Patients with fibromyalgia may be aerobically unfit⁵⁴ because of inactivity due to pain. Unaccustomed exercisemay exacerbate the pain and lead to delayed-onsetmuscle soreness in the short run. Despite this, controlledtrials of exercise demonstrate that people withfibromyalgia can increase their levels of physical fitness,with associated decreases in pain.^55,56 Bicycling, walking,and water aerobics are among the best-toleratedexercises. Perhaps this is because aerobic exerciseincreases the body's production of endogenous opioids.These powerful endorphins act through the limbic systemto decrease pain and to induce the euphoria commonlyknown as runner's high. It has not been shown,however, that endorphin levels are decreased infibromyalgia patients. Also, exercise facilitates sleep.Because sleep dysfunction compounds the symptoms offibromyalgia, restoring sleep could disrupt the cycle inwhich increased pain leads to decreased sleep, whichthen results in increasing pain and disability. In addition,aerobic exercise increases oxygenation and circulationto muscle tissue.⁵⁶ Exercise can also havepsychologically beneficial effects, such as promoting asense of well-being and a sense of accomplishment.Randomized controlled trials have shown that exerciseimproves mood and decreases disability in patients withfibromyalgia.⁵⁷ Therefore, patients should be encouragedto perform aerobic exercise at least 3 times a week.Flexibility training alone can improve symptoms, but toa lesser extent.⁵⁸ A systematic review of randomizedcontrolled trials of nonpharmacological interventions infibromyalgia between 1980 and 2000 did not providestrong evidence for any single treatment.⁵⁹ However, itshowed moderate support for aerobic exercise as a therapeuticintervention.

Almost all patients with fibromyalgia have sleep dysfunctioncharacterized by light unrefreshing sleep.⁶⁰ Tricyclic antidepressants may be helpful as a form oftreatment, perhaps because they improve sleep andmay reduce morning stiffness.⁶¹ They may also act byinhibiting serotonin and norepinephrine reuptake,thereby suppressing polysynaptic neuronal discharge.⁶² A randomized controlled trial of low-dose amitriptylinehydrochloride and naproxen sodium showed thatpatients improve with tricyclic antidepressants in termsof pain, sleep difficulties, fatigue on awakening, andtender point score.⁶³ Nonsteroidal anti-inflammatorydrugs may have an additive effect,⁶⁴ although theireffect may be analgesic rather than anti-inflammatory.Fluoxetine hydrochloride may improve symptoms ofdepression and fatigue, but has not been shown todecrease the number of tender points.⁶⁵ Amitriptylineand fluoxetine may work better in combination thaneither one alone.⁶⁶ Trazodone hydrochloride has alsobeen shown to be effective, perhaps because it increasesthe duration of stage 3 and stage 4 sleep and decreasesthe alpha-delta sleep abnormality common infibromyalgia.⁶⁷ Zolpidem tartrate does not appear toimprove the pain of fibromyalgia, but may improvesleep and daytime energy.⁶⁸ Cyclobenzaprinehydrochloride may decrease the severity of pain andimprove the quality of sleep in fibromyalgia patients,but it does not appear to alleviate the fatigue or morningstiffness.⁶⁹ Opioids may be helpful in treatingfibromyalgia pain, but may be habit-forming, toleragenic,and associated with adverse effects such as constipation,sedation, and nausea.

Transcutaneous electrical nerve stimulation, lasertreatment, and acupuncture appear to have limited painefficacy. Although there are no controlled trials demonstratingbenefit, 1% lidocaine hydrochloride injections,botulinum toxin injections, and dry needling are sometimesoffered to patients with fibromyalgia.⁷⁰ Despite asuggestion of relative growth hormone deficiency in personswith fibromyalgia and reports of improvementafter receiving injections of growth hormone, adverseeffects, frequent injections, and cost have dampenedenthusiasm for this approach.

Relaxation strategies for the relief of muscle tensionand anxiety are also effective.⁷⁰ Electromyograms withfeedback exercises and hypnosis are therapeutic modalitiesthat are being investigated.

Treatment of concomitant conditions may improvesymptoms of fibromyalgia. For example, fibromyalgiamay be particularly difficult to treat when untreateddepression, anxiety, or sleep apnea is also present.

PROGNOSIS

Follow-up of patients with fibromyalgia after 14 yearsshows that patients may have minor change in theirsymptoms, but do not develop progressive disabilityfrom the disease.⁷¹ Remissions are rare after many yearsof disease, but may occur in the first year or 2, especiallyin milder community-based settings. One study⁷² of ambulatory patients showed that 47% no longer fulfilledthe American College of Rheumatology's criteriafor fibromyalgia syndrome. Remissions were identifiedin 24.2% of patients. Therefore, patients who are basedin the community may have a good outcome. Thirty-fivepercent of patients who are able to be managed bytheir primary care physicians experience resolution ofsymptoms after 2 years.⁷³ One longitudinal prospectivestudy⁷⁴ suggested that most fibromyalgia patients showimprovement in terms of overall status, pain, fatigue,and function at 40 months. The only predictors forfavorable outcome in this study were younger age andless sleep disturbance. However, it appears that patientssent to referral centers generally have no change intheir pain, fatigue, sleep disturbance, anxiety, ordepression symptoms after 8 years.⁷⁵

Problems that may interfere with the employment ofpatients with fibromyalgia include difficulty in performingrepetitive motor tasks, prolonged sitting or standing,loss of mental acuity, anxiety about poor performance,and workplace stressors.⁷⁶ One study⁷⁷ used computerizedworkstations in simulated work environments tophysically stress the shoulders, spines, wrists, andelbows of fibromyalgia patients, patients with rheumatoidarthritis, and healthy controls. Patients withfibromyalgia could only perform 59% of the work performedby their healthy counterparts, compared withpatients with rheumatoid arthritis, who could perform62% of that workload.

Disability secondary to chronic pain appears toresult from a combination of patients' past experiences,self-esteem, motivation, psychological distress, fatigue,ethnocultural background, education, income, andpotential financial compensation.⁵³ Disability in chronicpain does not appear to be related to the severity ofthe pain.⁷⁸ Thirty percent of patients with fibromyalgiaare disabled, compared with 2% of the general population.⁷⁸ Patients with other forms of chronic pain have adisability rate of approximately 10%.⁷⁹

CONCLUSION

Fibromyalgia is a complex syndrome associated withsignificant impairment on quality of life and functionand substantial financial costs. Although its cause is notwell understood, it is clear that interdisciplinaryapproaches to its management are probably the mostbeneficial. Therefore, once the diagnosis is made,providers should aim to increase patients' function andminimize their pain complaints. This can be accomplishedthrough different nonpharmacological and pharmacologicalinterventions. With proper management,the rate of disability appears to be significantly reduced.

From the Spaulding Rehabilitation Hospital, Harvard Medical School (DEN), and BethIsrael Deaconess Medical Center (RHS), Boston, Mass.

Address correspondence to: Devi E. Nampiaparampil, MD, Spaulding RehabilitationHospital, Department of Physical Medicine and Rehabilitation, 125 Nashua Street,Boston, MA 02114. E-mail: dnampiaparampil@partners.org.

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