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pdate on Fibromyalgia Therapyicha Abeles, MD,a Bruce M. Solitar, MD,b,c Michael H. Pillinger, MD,b,c Aryeh M. Abelesa,b,c

Division of Rheumatology, Department of Medicine, The University of Connecticut School of Medicine, Farmington; bDivisionf Rheumatology, Department of Medicine, New York University School of Medicine/NYU Hospital for Joint Diseases, New York;

New York Harbor VA Healthcare System, New York Campus; New York.

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ABSTRACT

rimary fibromyalgia, a poorly-understood chronic pain syndrome, is characterized by widespread mus-uloskeletal pain, nonrestorative sleep, fatigue, psychological distress, and specific regions of localizedenderness, all in the absence of otherwise apparent organic disease. While the etiology of fibromyalgia isnclear, accumulating data suggest that disordered central pain processing likely plays a role in theathogenesis of symptoms. Although various pharmacological treatments have been studied and espousedor treating fibromyalgia, no single drug or group of drugs has proved to be particularly useful in treatingbromyalgia patients as a whole, and only one drug to date has earned U.S. Food and Drug Administrationpproval for treating the syndrome in the United States. This review critically and systematically evaluateslinical investigations of medicinal and nonmedicinal treatments for fibromyalgia dating from 1970 to 2007. 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, 555-561

KEYWORDS: Complementary therapy; Fibromyalgia; Fibrositis; Pharmacotherapy

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ibromyalgia is characterized by widespread musculoskel-tal pain, nonrestorative sleep, fatigue, psychological dis-ress, and specific regions of localized tenderness, all in thebsence of otherwise apparent organic disease. The etiologyf fibromyalgia is unclear, although accumulating data sug-est that disordered central pain processing plays a role ints pathogenesis.1 While numerous controversies surroundhe cause and nature of fibromyalgia, few clinicians wouldisagree that fibromyalgia patients are in need of effectivereatment.

Despite the various pharmacotherapies studied and es-oused for treating fibromyalgia, only one drug has earnedS Food and Drug Administration (FDA) approval for

reating the syndrome (pregabalin, in June 2007). Neverthe-ess, scores of drugs are used for the treatment of fibromy-lgia, with varying success. One 5-year prospective surveyf 214 patients with fibromyalgia from 114 rheumatologyractices revealed a total of 74 different medications beingsed for treatment, suggesting that no specific drug or classf drugs is particularly useful for fibromyalgia patients as aroup.2

Requests for reprints should be addressed to Aryeh M. Abeles, MD,ew England Musculoskeletal Institute, Medical Arts & Research Build-

ng, UConn Health Center, 263 Farmington Avenue, Farmington, CT6030-5352.

n: aabeles@uchc.edu

ront matter © 2008 Elsevier Inc. All rights reserved.ed.2008.02.036

Given the controversial nature of fibromyalgia, it is noturprising that physicians continue to debate which treat-ents are useful. While several recent reviews conclude that

here is “strong evidence”3 to support the use of a variety ofedications and nonpharmacologic approaches to fibromy-

lgia, and that “symptoms can be controlled to a moderateegree with various treatments,”4 a long-term, multicenterutcomes study has refuted these conclusions, noting thatespite treatment, individuals followed for up to 7 yearsemonstrated no change in symptoms.5 That study mighttself have been skewed, because its data were culled fromertiary care rather than a community setting,6 and commu-ity fibromyalgia patients appear to have better prognoseshan those seen in specialty clinics.7 However, as both thebromyalgia criteria and many therapeutic trials to dateave been based on patients in tertiary centers, we are leftith conflicting data sets on the value of fibromyalgia treat-ent. In addition, many therapeutic trials for fibromyalgia

ave been small or not well controlled, with results that cane of limited use.

One difficulty of assessing therapeutic options for anndividual patient is that many clinical trials have not ac-ounted for the heterogeneity of fibromyalgia.8,9 The pres-nce of co-morbidities, such as depression, may indepen-ently predict a poor response to treatment.9,10 In addition,

ondrug treatment approaches, considered by many physi-

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ians to be among the most useful fibromyalgia treatments,re frequently discordant with patient preferences.11 Addingo the confusion of how to appropriately manage the syn-rome, the Outcome Measures in Rheumatology 7 work-hop concluded that when it comes to fibromyalgia therapy,here is “little standardization ofn approach to trials or of out-ome measures used.”12 In this ar-icle, we attempt to create a modi-um of clarity in the currentandscape, by providing a criticaleview of the evidence for variousreatments of fibromyalgia.

The authors reviewed thereatments of fibromyalgia byearching the PubMed databaseor English-language reports oflinical trials and meta-analysesddressing fibromyalgia treat-ent, published between 1970

nd 2007. The main search termsere fibromyalgia and fibrositis,

n combination with treatment,linical trials, and pharmaco-herapy. Secondary search termsncluded exercise, alternative therapy,nd cognitive-behavioral ther-py. These search terms resultedn the identification of 409 re-orts for possible inclusion. After an initial triage by onef the authors (AMA), selecting for studies conducted asandomized control trials investigating specific interven-ions and their effects on improved outcomes, 131 arti-les remained and were scored semiquantitatively byach of the 4 authors. Each author scored each report onscale of 0-3 in 2 overarching domains: 1) the quality ofethodology (authors were instructed to considerhether studies were randomized double-blind control

rial vs randomized open label control trials, large vsmall enrollment, independent vs industry-supported,ength of study, and appropriateness of outcomes mea-ures); and 2) the relevance of the study to the illness ofbromyalgia (authors were instructed to consider param-ters such as the degree of efficacy reported, degree tohich the drug is currently used in practice, degree tohich the study was unique in examining a particular

gent, and level of attention that the study has subse-uently received among practitioners). The maximumcore any article could receive from a single evaluatoras 6, and the maximum total score any article could

eceive from all authors combined was 24. All manu-cripts receiving total scores of �16 were considered fornclusion by the authors in consensus discussions; a totalf 55 manuscripts were discussed. Of these, 10 additionalanuscripts were excluded, based on a high degree of

CLINICAL SIGNIF

● Fibromyalgia issyndrome of uncthe literature suapy is broadly ef

● Medications shothe treatment oantidepressants achannel blockers.

● Evidence suggesttary therapies als

● Clinical experiemodal therapy pthan individualhypothesis hastested.

uthor discrepancy with regard to study quality or rele- i

ance. The remaining 45 research articles were includedn the analysis. Our review was not funded.

HARMACOLOGICAL TREATMENTS

Tricyclic AgentsThe tricyclic antidepressants werethe first drugs to be intensivelystudied in fibromyalgia. Tricyclicantidepressants increase synapticconcentrations of both serotoninand norepinephrine in the centralnervous system; increased avail-ability of these neurotransmittersreduces pain signaling. Amitripty-line is the tricyclic antidepressantmost extensively studied. Short-term studies indicate benefit in upto one third of patients13-15; if ef-fective, benefit is usually evidentwithin the first 2 weeks of ther-apy.16 Long-term studies havebeen less promising, however, andprospective studies have not shownany prolonged beneficial effect.17 Inone study, initial improvementnoted at 6 to 12 weeks was lost at 26weeks.17 When employed, amitrip-tyline dosing should start at 10 mg,

ecause anticholinergic side effects are more likely at higheroses. Studies suggest that increasing the dose to 25-50 mg cane effective in short-term trials.13,14 The tricyclic antidepres-ant nortriptyline has a better side-effect profile than amitrip-yline and also might be useful, although it requires slightlyigher dosing.18

Cyclobenzaprine shares its tricyclic structure with am-triptyline and nortriptyline but does not function as anntidepressant. Instead, cyclobenzaprine acts at the braintem to induce skeletal muscle relaxation.19 The idea thatuscle spasm may play a role in fibromyalgia pain (de-

pite electromyographic studies showing no evidence ofpasm) led to investigations of cyclobenzaprine.20-22

hort-term (12-week) studies suggest that 10-40 mg peray of cyclobenzaprine reduces fibromyalgia pain andleep disturbance,20,22 although in one cross-over study,here was no effect on pain.23 Moreover, long-term stud-es have not shown any advantage of cyclobenzaprinever placebo.17 A meta-analysis of cyclobenzaprine treat-ent of fibromyalgia found only 5 articles of adequate

uality to include in the study,24 and concluded that somehort-term benefit may result with cyclobenzaprine use,ut that the number needed to treat in order for oneatient to experience a benefit was 5. Adding to theifficulty of interpreting cyclobenzaprine studies is theigh incidence of side effects (85%), which makes blind-

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ewer Anti-Depressantselective serotonin reuptake inhibitors (SSRIs) also might

heoretically be useful because of their ability to increaseerotonin availability at the neuronal synapse. While initialeports found no improvement in pain symptoms with flu-xetine,25 follow-up studies suggested that this SSRI was asffective as amitriptyline. The 2 medications combinedhowed greater efficacy than either alone.26 A more recentlacebo-controlled 12-week study using a more flexibleuoxetine-dosing regimen (up to 80 mg/day) demonstratedreduction in pain regardless of effect on depression.27 In

ddition, both fluoxetene and amitriptyline appear to im-rove anaerobic, but not aerobic, performance among fe-ale fibromyalgia patients.28 Although other SSRIs are

egularly used in clinical practice, studies of these variousrugs have been limited, lacking, or inconclusive.29,30 Fornstance, a recent 12-week study investigating the efficacyf extended-release paroxetine (doses ranging from 12.5 mgo 62.5 mg daily) demonstrated that while paroxetine im-roved Fibromylagia Impact Questionnaire (FIQ) scores vslacebo, it did not improve pain scores.30

Serotonin-norepinephrine reuptake inhibitors (SNRIs, orual-reuptake inhibitors) may have greater antinociceptiveroperties than pure SSRIs. Short-term (12 weeks) studiesf SNRIs indicate benefit to their use.31 In one double-blindrial comparing duloxetine with placebo, patients receivinguloxetine had significant overall improvement in their FIQcores, although not on the FIQ subscales of pain or fatigue.econdary outcome measures, including Brief Pain Inven-

ory scores, also showed statistically significant improve-ents. Common side effects included insomnia, dry mouth,

onstipation, increase in heart rate, and elevated aspartateransaminase, creatine phophokinase, and cholesterol. Ef-ective doses ranged from 60 mg daily to 60 mg twice aay.31

Milnacipran (unavailable in the US), a SNRI that isomewhat selective for norepinephrine reuptake inhibition,lso has been studied. A 12-week study found that milnaci-ran significantly improved both global assessment and FIQain visual analogue scale scores. Despite randomization,ood disorders were much more common in the placebo

roup. Side effects were similar to those seen with dulox-tine. Milnacipran 100 mg twice daily was more effectivehan at 200 mg once a day.32

ther Central Nervous System-Acting Agentsregabalin was originally FDA-approved for diabetic neu-opathy and postherpetic neuralgia, but in June 2007 alsoas approved for the treatment of fibromyalgia. It disruptseuronal signaling by binding to the �-2-� subunit of volt-ge-gated calcium channels in the central nervous system.n 8-week double-blind placebo-controlled trial studied 3xed doses of pregabalin (150 mg/day, 300 mg/day, and50 mg/day).33 The highest dose (450 mg/day) was signif-cantly more effective than placebo in reducing pain score

48.4% vs 27.1% response, respectively) at 8 weeks. Pre- t

abalin also was associated with decreased fatigue, im-roved sleep and health-related quality of life. Commonide effects included dizziness (49.2%) and somnolence28%). No long-term data are yet available, although ans-yet unpublished study demonstrated that, over 6 months,regabalin retained its effectiveness in pregabalin-respond-rs. The study was unusual in that it randomized patientsho had been pregabalin-responders (�50% improvementn visual analogue scale) in an open-label phase to receiveither pregabalin or placebo in the double-blinded portion ofhe study; the primary endpoint of the double-blinded studyas time to loss of efficacy. By study’s end, 61% of placeboatients had lost their therapeutic response, compared with2% of those who continued with pregabalin.34

Gabapentin is FDA-approved as an anticonvulsant andor postherpetic neuralgia, and is frequently prescribed foriabetic neuropathy and other chronic pain conditions. Al-hough structurally related to gamma-aminobutyric acid,abapentin does not, in fact, bind to gamma-aminobutyriccid receptors, but instead appears to inhibit the same volt-ge-gated calcium channels as pregabalin. In a 12-weekandomized controlled trial, gabapentin was statisticallyore effective than placebo in improving pain scores (51%

s 31%, clinically significant improvement defined as30% improvement in pain severity), sleep quality, and

bromyalgia impact questionnaire scores. The dose rangeas between 1200 and 2400 mg per day, with an average of800 mg. No serious adverse events were noted in theabapentin-treated groups. The most common side effectsere dizziness, sedation, and lightheadedness.35

nti-Inflammatorieshile the use of nonsteroidal anti-inflammatory drugs for

bromyalgia is a fairly common practice,5 little objectivevidence is available upon which to assess the efficacy ofhese agents. In one double-blind, placebo-controlled trial,buprofen was no better than placebo.36 Similarly, naproxened to minor but insignificant improvement in symptoms.14

ne trial of corticosteroid use in fibromyalgia found ste-oids to be inefficacious.37

ure Analgesicsespite their employment in clinical practice, no short- or

ong-term data are available to inform the use of purepiates in fibromyalgia. In contrast, some studies supporthe use of the mixed opiate agonist tramadol. Tramadol is aentrally acting synthetic opioid analgesic that binds to the-opioid receptors and also weakly inhibits norepinephrinend serotonin reuptake.38 In a 91-day, multicenter, random-zed controlled trial evaluating tramadol plus acetamino-hen in fibromyalgia, the primary endpoint was cumulativeime to discontinuation of drug. A large number of dropoutsccurred in both treatment arms, but fewer in the activereatment group (48% in the active treatment vs 62% inhe placebo arm). Tramadol/acetaminophen combination-

reated patients experienced reduced pain, as measured on a

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isual analogue scale, compared with patients in a placeborm, but it is questionable whether the reported reductionas clinically significant.39 However, another tramadol/

cetaminophen study investigating health-related quality-f-life measures in moderate-to-severe fibromyalgia alsohowed improvement in the active treatment group, com-ared with controls.40

iscellaneous Oral Medicationsespite its continuing prominence on Internet websites,uaifenesin was no more effective than placebo in a formaltudy.41 A reported benefit of combining alprazolam andbuprofen was based on a response in 7 of 15 patients usinghis combination, compared with 4 of 14 patients respond-ng to placebo (in a study underwritten by the manufacturerf those products)42; no large studies of benzodiazepinesave been performed. The hypnotic zolpidem improvedleep but not pain in fibromyalgia patients.43 Studies ofalic acid and chlomipramine have a number of shortcom-

ngs, including small subject numbers and lack of confir-atory studies.44,45

ONPHARMACOLOGICAL INTERVENTIONSrecent review by Goldenberg suggested “strong evidence

or efficacy” for a variety of nonmedicinal interventions,ncluding cardiovascular exercise, cognitive behavioralherapy, patient education in group format, and multidisci-linary therapy, as well as “moderate evidence for efficacy”or a number of other adjunctive treatments.3 In contrast tohe Goldenberg review, 2 other systematic reviews came toess sanguine conclusions about the value of nonpharmaco-ogical interventions. Karjalainen et al46 analyzed studies ofultidisciplinary rehabilitation for fibromyalgia. Seven

tudies met the authors’ inclusion criteria, although noneere considered “high quality.” Karjalainen concluded that

here was little evidence for the effectiveness of a multidis-iplinary approach but that high-quality prospective trialsre needed. Sim and Adams47 reviewed all randomizedontrolled trials of nonpharmacologic fibromyalgia inter-entions from 1980 to 2000.47 Most had small sample size,eading to low statistical power and a high probability ofype II error. The authors concluded that most interventionshowed marginal efficacy but that, owing to the poor qualityf the studies, no meaningful conclusions could be derived.evertheless, the authors felt that combination approaches

eemed to result in better outcomes than single-approachnterventions.

Presently, aerobic exercise is widely recommended forbromyalgia, based on the belief that patients with fibro-yalgia are not aerobically fit, and that lack of aerobictness contributes to pain.48 The concept that fibromyalgiand poor physical fitness are intertwined was originallyased on the resistance of 3 aerobically fit male volunteerso developing fibromyalgia-like symptoms despite stage IVleep deprivation.49 From this finding, a hypothesis evolved

sserting that sedentary lifestyle results in muscle decondi- p

ioning and a greater risk of muscle microtrauma, in turneading to increased pain.50 The hypothesis was tested in atudy that compared a flexibility exercise program withardiovascular training51; no significant differences wereound between groups with regard to pain intensity scores.ther studies also suggest that physical training does not

ignificantly contribute to the reduction of pain, improve-ent of psychological symptoms, or functional disability.52

n the other hand, a combined cardiovascular fitness train-ng and flexibility program provided significantly greatermprovement than a psychologically based muscle relax-tion technique.53 Recent studies indicate that isometricxercise reduces mechanical pain thresholds (ie, inducesain) in fibromyalgia patients, in contradistinction to normalontrols.54 Some clinicians suggest that this observationeflects a “transition problem”—that is, fibromyalgia pa-ients may not benefit from exercise unless they can first berought to a level of minimal exercise capacity withoutxacerbating their symptoms. Water-based exercise is betterolerated by fibromyalgia patients and may therefore be ofarticular benefit as an initial regimen. Short-term studies ofquatherapy with small numbers of subjects note improve-ent in quality-of-life measures and pain.55,56

In one study of behavioral insomnia therapy for fibro-yalgia patients, 8 of 14 participants demonstrated sleep

mprovement.57 The effect on pain was modest.

OMPLEMENTARY AND ALTERNATIVEHERAPIES FOR FIBROMYALGIAssessment of complementary and alternative approaches

o fibromyalgia treatment is limited by a paucity of clinicalrials, with the few completed trials sharing the drawbackshat afflict other fibromyalgia studies.

Meditation-based stress reduction showed benefit in onetudy that lacked a control group.58 Dehydroepiandros-erone provided no benefit in pain, fatigue, mood, or func-ional abilities.59 Melatonin has not been studied in alinded fashion.60

Acupuncture is commonly tried by fibromyalgia patients,ut the evidence for acupuncture in fibromyalgia is conflict-ng. One randomized sham-controlled study demonstratedo subjective improvement in pain between acupuncturend sham acupuncture.61 A more recent randomized trial,owever, demonstrated that patients who received acupunc-ure (vs sham acupuncture) had significantly greater im-rovements in FIQ scores at 1 and 7 months after treat-ent.62 An earlier study suggested that electroacupunctureas more effective than sham therapy for fibromyalgia, but

he study may not have been adequately blinded.63

The alternative therapies purported to treat fibromyalgiare numerous, unregulated, unstudied, and easily found indvertisements in lay fibromyalgia publications. Examplesbound in a recent issue of Fibromyalgia Aware maga-ine.64 An advertisement for infrared therapy, for instance,akes various claims for relief of pain and stiffness, im-

roved energy, and a better sense of well-being. Another ad

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romotes a mattress claiming to relieve “the pressureoints” that will allow for “REM sleep.” Yet another ad-ertisement purports a simple solution for the abnormal foottructure that, the ad claims, perpetuates fibromyalgia pain.n an advertisement for bottled water, aches, pains, and evenatigue are apparently magnified by the slightest hint ofehydration. A brand of moistened towelette claims it haseen “clinically shown to relieve pain associated with fibro-yalgia.” While such alternative therapies can range from

Table Drugs with Positive Effects on Fibromyalgia in Randomiz

rug Mechanism of Action Dose

mitriptyline Increases synaptic availabilityof both serotonin andnorepinephrine in thecentral nervous system bydecreasing their uptake

10 mg qhs/25-5

yclobenzaprine Reduces tonic activity ofalpha and gamma motorneurons, leading to musclerelaxation; structurallysimilar to tricyclicantidepressants

10 mg qhs/10 mmg bid

luoxetine Inhibits reuptake of serotoninin the central nervoussystem, increasing itssynaptic availability

20 mg qd/20-80

uloxetine Inhibits reuptake of serotoninand norepinephrine in thecentral nervous systemcentral nervous system;weak inhibitor of centralnervous system dopaminereuptake

30 mg qd/60 mgmg bid

ilnacipran Inhibits reuptake of serotoninand norepinephrine in thecentral nervous system

25 mg qd/100 m

ramadol Blocks ascending painpathways by weakly bindingto �-opiate receptors inthe central nervous system;weak reuptake inhibitor ofnorepinephrine andserotonin in the centralnervous system

50 mg/50 mg titid

regabalin In the central nervoussystem, binds to �2-�subunit of voltage-gatedcalcium channels, thusinhibiting excitatoryneurotransmitter release

50 mg tid/100 mtid-150 mg ti

Abbreviations: qhs � at bedtime; bid � twice a day; qd � every day;

ensible to bizarre, none have been adequately validated. w

PPROACH TO THE PATIENT WITHIBROMYALGIA: PRACTICE-BASED EVIDENCE INHE ABSENCE OF EVIDENCE-BASED PRACTICEespite a paucity of solid data in support of many fibromy-

lgia therapies, the physician caring for a fibromyalgia pa-ient is confronted with an individual whose discomfort isignificant, and whose need for melioration is unquestion-ble. A number of treatments have shown clinical benefit

trolled Trials

Positive Effect(s) inFibromyalgia Drawbacks

hs Several clinical trials havedemonstrated short-termimprovement in pain andsleep

Has anticholinergic,antihistaminic, and anti-adrenergic side effects

20 One placebo-controlled trialhas demonstratedimprovement in pain andfatigue; subsequentstudies have not shown adifference betweenplacebo andcyclobenzaprinetreatment

High incidence of side-effects

2 RCTs have demonstratedshort-term improvementin sleep and pain (thelatter at �20 mg/day)

2 RCTs have demonstratedshort-term improvementin pain and mostsecondary outcomefibromyalgia measures

High incidence of side effectsoften lead to drugdiscontinuation

One RCT showed significantimprovement in pain andsecondary outcomemeasures

Not available in the US

mg One of 2 RCTs has shownvery modest short-termimprovement in pain

Has abuse potential and maycause dependence

One RCT showedimprovement in painonly with 450 mg/day;improved sleep qualityand fatigue at �300 mg/day

Cam be used in combinationwith any of the abovetherapies

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uently not in a majority of the patients studied. Indeed, theeterogeneity of fibromyalgia patients renders a “one-size-ts-all” approach unlikely to be broadly efficacious, andontrolled trials that fail to account for heterogeneity alsoight fail to tease out useful effects in subsets of patients.dditionally, most fibromyalgia patients exhibit multiple

ymptoms in addition to pain and tenderness, and thereforeequire simultaneous treatment for multiple aspects of theirllness. While the use of combination therapy may offer theest hope for fibromyalgia management, almost all clinicalrials for fibromyalgia have tested only single therapies.

Clinical experience suggests that particular treatmentsork in some patients, sometimes despite failure in clinical

rials. Thus, fibromyalgia treatment choices must be maden an empiric basis, informed wherever possible by evi-ence. For most patients, the agent of first choice probablyemains amitriptyline or nortriptyline at bedtime, initiated at0 mg and increased incrementally as needed to maximumenefit. If these are not tolerated, low-dose cyclobenzaprinet bedtime may be initiated; other muscle relaxants alsoight be efficacious. A patient who presents with isolated

eneralized pain without other associated symptoms mayespond to a simple analgesic such as tramadol. Patientsith depression may particularly benefit from SSRIs orNRIs. Patients who fail analgesics, muscle relaxants, orntidepressants may benefit from the use of pregabalinr gabapentin. For most of these therapies, patients needo be reminded that at least several weeks may be re-uired to derive benefit. A failure to respond to oneherapy indicates a need for a trial (or addition) of an-ther agent. Because therapeutic responses are rarelyurable, clinicians should not be disheartened when aedication loses its initial efficacy. Successful treatment

f fibromyalgia may require regular reassessment andossible rotation of medications.

Although no particular physical therapies have defini-ively proven to be of benefit in fibromyalgia, we encouragell our fibromyalgia patients to participate in some form ofow-impact exercise, such as aquatherapy. Patients need toe reminded to not be discouraged by limited exerciseapacity at the outset. Moreover, fibromyalgia patientshould be encouraged to increase their exercise very grad-ally; an overly aggressive regimen may lead to significantostexercise discomfort and future noncompliance.

Finally, it is of paramount importance to provide fibro-yalgia patients with education, emotional support, and

eassurance. Patients should be reassured that, despite theeverity of their pain, fibromyalgia is an otherwise benignondition that does not lead to bodily damage or death. Thereating physician needs to acknowledge the patient’s expe-ience of pain, because fibromyalgia patients frequentlyave had their symptoms ignored or dismissed. The chal-enge is to produce a compassionate and comprehensivereatment program for all aspects of the fibromyalgia pa-

ient’s illness.

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