REVIEW

Update on Fibromyalgia Therapy

Micha Abeles, MD,a Bruce M. Solitar, MD,b,c Michael H. Pillinger, MD,b,c Aryeh M. Abelesa,b,c
a

Division of Rheumatology, Department of Medicine, The University of Connecticut School of Medicine, Farmington; bDivision of Rheumatology, Department of Medicine, New York University School of Medicine/NYU Hospital for Joint Diseases, New York; c New York Harbor VA Healthcare System, New York Campus; New York.

ABSTRACT Primary bromyalgia, a poorly-understood chronic pain syndrome, is characterized by widespread musculoskeletal pain, nonrestorative sleep, fatigue, psychological distress, and specic regions of localized tenderness, all in the absence of otherwise apparent organic disease. While the etiology of bromyalgia is unclear, accumulating data suggest that disordered central pain processing likely plays a role in the pathogenesis of symptoms. Although various pharmacological treatments have been studied and espoused for treating bromyalgia, no single drug or group of drugs has proved to be particularly useful in treating bromyalgia patients as a whole, and only one drug to date has earned U.S. Food and Drug Administration approval for treating the syndrome in the United States. This review critically and systematically evaluates clinical investigations of medicinal and nonmedicinal treatments for bromyalgia 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

Fibromyalgia is characterized by widespread musculoskeletal pain, nonrestorative sleep, fatigue, psychological distress, and specic regions of localized tenderness, all in the absence of otherwise apparent organic disease. The etiology of bromyalgia is unclear, although accumulating data suggest that disordered central pain processing plays a role in its pathogenesis.1 While numerous controversies surround the cause and nature of bromyalgia, few clinicians would disagree that bromyalgia patients are in need of effective treatment. Despite the various pharmacotherapies studied and espoused for treating bromyalgia, only one drug has earned US Food and Drug Administration (FDA) approval for treating the syndrome (pregabalin, in June 2007). Nevertheless, scores of drugs are used for the treatment of bromyalgia, with varying success. One 5-year prospective survey of 214 patients with bromyalgia from 114 rheumatology practices revealed a total of 74 different medications being used for treatment, suggesting that no specic drug or class of drugs is particularly useful for bromyalgia patients as a group.2
Requests for reprints should be addressed to Aryeh M. Abeles, MD, New England Musculoskeletal Institute, Medical Arts & Research Building, UConn Health Center, 263 Farmington Avenue, Farmington, CT 06030-5352. E-mail address: aabeles@uchc.edu

Given the controversial nature of bromyalgia, it is not surprising that physicians continue to debate which treatments are useful. While several recent reviews conclude that there is strong evidence3 to support the use of a variety of medications and nonpharmacologic approaches to bromyalgia, and that symptoms can be controlled to a moderate degree with various treatments,4 a long-term, multicenter outcomes study has refuted these conclusions, noting that despite treatment, individuals followed for up to 7 years demonstrated no change in symptoms.5 That study might itself have been skewed, because its data were culled from tertiary care rather than a community setting,6 and community bromyalgia patients appear to have better prognoses than those seen in specialty clinics.7 However, as both the bromyalgia criteria and many therapeutic trials to date have been based on patients in tertiary centers, we are left with conicting data sets on the value of bromyalgia treatment. In addition, many therapeutic trials for bromyalgia have been small or not well controlled, with results that can be of limited use. One difculty of assessing therapeutic options for an individual patient is that many clinical trials have not accounted for the heterogeneity of bromyalgia.8,9 The presence of co-morbidities, such as depression, may independently predict a poor response to treatment.9,10 In addition, nondrug treatment approaches, considered by many physi-

0002-9343/$ -see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.02.036

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vance. The remaining 45 research articles were included cians to be among the most useful bromyalgia treatments, in the analysis. Our review was not funded. are frequently discordant with patient preferences.11 Adding to the confusion of how to appropriately manage the syndrome, the Outcome Measures in Rheumatology 7 workPHARMACOLOGICAL TREATMENTS shop concluded that when it comes to bromyalgia therapy, there is little standardization of Tricyclic Agents an approach to trials or of outThe tricyclic antidepressants were come measures used.12 In this arthe rst drugs to be intensively CLINICAL SIGNIFICANCE ticle, we attempt to create a modistudied in bromyalgia. Tricyclic cum of clarity in the current Fibromyalgia is a heterogeneous pain antidepressants increase synaptic landscape, by providing a critical concentrations of both serotonin syndrome of unclear etiology. Review of review of the evidence for various and norepinephrine in the central the literature suggests no single thertreatments of bromyalgia. nervous system; increased availapy is broadly efcacious. The authors reviewed the ability of these neurotransmitters Medications showing some benet in treatments of bromyalgia by reduces pain signaling. Amitriptysearching the PubMed database the treatment of bromyalgia include line is the tricyclic antidepressant for English-language reports of antidepressants and voltage-gated Ca most extensively studied. Shortclinical trials and meta-analyses channel blockers. term studies indicate benet in up addressing bromyalgia treatto one third of patients13-15; if ef Evidence suggests that some complemenment, published between 1970 fective, benet is usually evident tary therapies also might be benecial. and 2007. The main search terms within the rst 2 weeks of therwere bromyalgia and brositis, apy.16 Long-term studies have Clinical experience suggests multiin combination with treatment, been less promising, however, and modal therapy provides greater benet clinical trials, and pharmacoprospective studies have not shown than individual interventions, but this therapy. Secondary search terms any prolonged benecial effect.17 In hypothesis has yet to be rigorously included exercise, alternative therapy, one study, initial improvement tested. and cognitive-behavioral thernoted at 6 to 12 weeks was lost at 26 apy. These search terms resulted weeks.17 When employed, amitripin the identication of 409 retyline dosing should start at 10 mg, ports for possible inclusion. After an initial triage by one because anticholinergic side effects are more likely at higher of the authors (AMA), selecting for studies conducted as doses. Studies suggest that increasing the dose to 25-50 mg can randomized control trials investigating specic intervenbe effective in short-term trials.13,14 The tricyclic antideprestions and their effects on improved outcomes, 131 artisant nortriptyline has a better side-effect prole than amitripcles remained and were scored semiquantitatively by tyline and also might be useful, although it requires slightly each of the 4 authors. Each author scored each report on higher dosing.18 a scale of 0-3 in 2 overarching domains: 1) the quality of Cyclobenzaprine shares its tricyclic structure with ammethodology (authors were instructed to consider itriptyline and nortriptyline but does not function as an whether studies were randomized double-blind control antidepressant. Instead, cyclobenzaprine acts at the brain trial vs randomized open label control trials, large vs stem to induce skeletal muscle relaxation.19 The idea that small enrollment, independent vs industry-supported, muscle spasm may play a role in bromyalgia pain (delength of study, and appropriateness of outcomes measpite electromyographic studies showing no evidence of sures); and 2) the relevance of the study to the illness of spasm) led to investigations of cyclobenzaprine.20-22 bromyalgia (authors were instructed to consider paramShort-term (12-week) studies suggest that 10-40 mg per eters such as the degree of efcacy reported, degree to day of cyclobenzaprine reduces bromyalgia pain and which the drug is currently used in practice, degree to sleep disturbance,20,22 although in one cross-over study, which the study was unique in examining a particular there was no effect on pain.23 Moreover, long-term studagent, and level of attention that the study has subseies have not shown any advantage of cyclobenzaprine quently received among practitioners). The maximum over placebo.17 A meta-analysis of cyclobenzaprine treatscore any article could receive from a single evaluator ment of bromyalgia found only 5 articles of adequate was 6, and the maximum total score any article could quality to include in the study,24 and concluded that some receive from all authors combined was 24. All manushort-term benet may result with cyclobenzaprine use, scripts receiving total scores of 16 were considered for but that the number needed to treat in order for one inclusion by the authors in consensus discussions; a total patient to experience a benet was 5. Adding to the of 55 manuscripts were discussed. Of these, 10 additional difculty of interpreting cyclobenzaprine studies is the manuscripts were excluded, based on a high degree of high incidence of side effects (85%), which makes blinding difcult. author discrepancy with regard to study quality or rele-

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Fibromyalgia Therapy

557 gabalin also was associated with decreased fatigue, improved sleep and health-related quality of life. Common side effects included dizziness (49.2%) and somnolence (28%). No long-term data are yet available, although an as-yet unpublished study demonstrated that, over 6 months, pregabalin retained its effectiveness in pregabalin-responders. The study was unusual in that it randomized patients who had been pregabalin-responders ( 50% improvement on visual analogue scale) in an open-label phase to receive either pregabalin or placebo in the double-blinded portion of the study; the primary endpoint of the double-blinded study was time to loss of efcacy. By studys end, 61% of placebo patients had lost their therapeutic response, compared with 32% of those who continued with pregabalin.34 Gabapentin is FDA-approved as an anticonvulsant and for postherpetic neuralgia, and is frequently prescribed for diabetic neuropathy and other chronic pain conditions. Although structurally related to gamma-aminobutyric acid, gabapentin does not, in fact, bind to gamma-aminobutyric acid receptors, but instead appears to inhibit the same voltage-gated calcium channels as pregabalin. In a 12-week randomized controlled trial, gabapentin was statistically more effective than placebo in improving pain scores (51% vs 31%, clinically signicant improvement dened as 30% improvement in pain severity), sleep quality, and bromyalgia impact questionnaire scores. The dose range was between 1200 and 2400 mg per day, with an average of 1800 mg. No serious adverse events were noted in the gabapentin-treated groups. The most common side effects were dizziness, sedation, and lightheadedness.35

Newer Anti-Depressants
Selective serotonin reuptake inhibitors (SSRIs) also might theoretically be useful because of their ability to increase serotonin availability at the neuronal synapse. While initial reports found no improvement in pain symptoms with uoxetine,25 follow-up studies suggested that this SSRI was as effective as amitriptyline. The 2 medications combined showed greater efcacy than either alone.26 A more recent placebo-controlled 12-week study using a more exible uoxetine-dosing regimen (up to 80 mg/day) demonstrated a reduction in pain regardless of effect on depression.27 In addition, both uoxetene and amitriptyline appear to improve anaerobic, but not aerobic, performance among female bromyalgia patients.28 Although other SSRIs are regularly used in clinical practice, studies of these various drugs have been limited, lacking, or inconclusive.29,30 For instance, a recent 12-week study investigating the efcacy of extended-release paroxetine (doses ranging from 12.5 mg to 62.5 mg daily) demonstrated that while paroxetine improved Fibromylagia Impact Questionnaire (FIQ) scores vs placebo, it did not improve pain scores.30 Serotonin-norepinephrine reuptake inhibitors (SNRIs, or dual-reuptake inhibitors) may have greater antinociceptive properties than pure SSRIs. Short-term (12 weeks) studies of SNRIs indicate benet to their use.31 In one double-blind trial comparing duloxetine with placebo, patients receiving duloxetine had signicant overall improvement in their FIQ scores, although not on the FIQ subscales of pain or fatigue. Secondary outcome measures, including Brief Pain Inventory scores, also showed statistically signicant improvements. Common side effects included insomnia, dry mouth, constipation, increase in heart rate, and elevated aspartate transaminase, creatine phophokinase, and cholesterol. Effective doses ranged from 60 mg daily to 60 mg twice a day.31 Milnacipran (unavailable in the US), a SNRI that is somewhat selective for norepinephrine reuptake inhibition, also has been studied. A 12-week study found that milnacipran signicantly improved both global assessment and FIQ pain visual analogue scale scores. Despite randomization, mood disorders were much more common in the placebo group. Side effects were similar to those seen with duloxetine. Milnacipran 100 mg twice daily was more effective than at 200 mg once a day.32

Anti-Inammatories
While the use of nonsteroidal anti-inammatory drugs for bromyalgia is a fairly common practice,5 little objective evidence is available upon which to assess the efcacy of these agents. In one double-blind, placebo-controlled trial, ibuprofen was no better than placebo.36 Similarly, naproxen led to minor but insignicant improvement in symptoms.14 One trial of corticosteroid use in bromyalgia found steroids to be inefcacious.37

Pure Analgesics
Despite their employment in clinical practice, no short- or long-term data are available to inform the use of pure opiates in bromyalgia. In contrast, some studies support the use of the mixed opiate agonist tramadol. Tramadol is a centrally acting synthetic opioid analgesic that binds to the -opioid receptors and also weakly inhibits norepinephrine and serotonin reuptake.38 In a 91-day, multicenter, randomized controlled trial evaluating tramadol plus acetaminophen in bromyalgia, the primary endpoint was cumulative time to discontinuation of drug. A large number of dropouts occurred in both treatment arms, but fewer in the active treatment group (48% in the active treatment vs 62% in the placebo arm). Tramadol/acetaminophen combinationtreated patients experienced reduced pain, as measured on a

Other Central Nervous System-Acting Agents

Pregabalin was originally FDA-approved for diabetic neuropathy and postherpetic neuralgia, but in June 2007 also was approved for the treatment of bromyalgia. It disrupts neuronal signaling by binding to the -2- subunit of voltage-gated calcium channels in the central nervous system. An 8-week double-blind placebo-controlled trial studied 3 xed doses of pregabalin (150 mg/day, 300 mg/day, and 450 mg/day).33 The highest dose (450 mg/day) was significantly more effective than placebo in reducing pain score (48.4% vs 27.1% response, respectively) at 8 weeks. Pre-

558 visual analogue scale, compared with patients in a placebo arm, but it is questionable whether the reported reduction was clinically signicant.39 However, another tramadol/ acetaminophen study investigating health-related qualityof-life measures in moderate-to-severe bromyalgia also showed improvement in the active treatment group, compared with controls.40

The American Journal of Medicine, Vol 121, No 7, July 2008 tioning and a greater risk of muscle microtrauma, in turn leading to increased pain.50 The hypothesis was tested in a study that compared a exibility exercise program with cardiovascular training51; no signicant differences were found between groups with regard to pain intensity scores. Other studies also suggest that physical training does not signicantly contribute to the reduction of pain, improvement of psychological symptoms, or functional disability.52 On the other hand, a combined cardiovascular tness training and exibility program provided signicantly greater improvement than a psychologically based muscle relaxation technique.53 Recent studies indicate that isometric exercise reduces mechanical pain thresholds (ie, induces pain) in bromyalgia patients, in contradistinction to normal controls.54 Some clinicians suggest that this observation reects a transition problemthat is, bromyalgia patients may not benet from exercise unless they can rst be brought to a level of minimal exercise capacity without exacerbating their symptoms. Water-based exercise is better tolerated by bromyalgia patients and may therefore be of particular benet as an initial regimen. Short-term studies of aquatherapy with small numbers of subjects note improvement in quality-of-life measures and pain.55,56 In one study of behavioral insomnia therapy for bromyalgia patients, 8 of 14 participants demonstrated sleep improvement.57 The effect on pain was modest.

Miscellaneous Oral Medications

Despite its continuing prominence on Internet websites, guaifenesin was no more effective than placebo in a formal study.41 A reported benet of combining alprazolam and ibuprofen was based on a response in 7 of 15 patients using this combination, compared with 4 of 14 patients responding to placebo (in a study underwritten by the manufacturer of those products)42; no large studies of benzodiazepines have been performed. The hypnotic zolpidem improved sleep but not pain in bromyalgia patients.43 Studies of malic acid and chlomipramine have a number of shortcomings, including small subject numbers and lack of conrmatory studies.44,45

NONPHARMACOLOGICAL INTERVENTIONS
A recent review by Goldenberg suggested strong evidence for efcacy for a variety of nonmedicinal interventions, including cardiovascular exercise, cognitive behavioral therapy, patient education in group format, and multidisciplinary therapy, as well as moderate evidence for efcacy for a number of other adjunctive treatments.3 In contrast to the Goldenberg review, 2 other systematic reviews came to less sanguine conclusions about the value of nonpharmacological interventions. Karjalainen et al46 analyzed studies of multidisciplinary rehabilitation for bromyalgia. Seven studies met the authors inclusion criteria, although none were considered high quality. Karjalainen concluded that there was little evidence for the effectiveness of a multidisciplinary approach but that high-quality prospective trials are needed. Sim and Adams47 reviewed all randomized controlled trials of nonpharmacologic bromyalgia interventions from 1980 to 2000.47 Most had small sample size, leading to low statistical power and a high probability of type II error. The authors concluded that most interventions showed marginal efcacy but that, owing to the poor quality of the studies, no meaningful conclusions could be derived. Nevertheless, the authors felt that combination approaches seemed to result in better outcomes than single-approach interventions. Presently, aerobic exercise is widely recommended for bromyalgia, based on the belief that patients with bromyalgia are not aerobically t, and that lack of aerobic tness contributes to pain.48 The concept that bromyalgia and poor physical tness are intertwined was originally based on the resistance of 3 aerobically t male volunteers to developing bromyalgia-like symptoms despite stage IV sleep deprivation.49 From this nding, a hypothesis evolved asserting that sedentary lifestyle results in muscle decondi-

COMPLEMENTARY AND ALTERNATIVE THERAPIES FOR FIBROMYALGIA

Assessment of complementary and alternative approaches to bromyalgia treatment is limited by a paucity of clinical trials, with the few completed trials sharing the drawbacks that afict other bromyalgia studies. Meditation-based stress reduction showed benet in one study that lacked a control group.58 Dehydroepiandrosterone provided no benet in pain, fatigue, mood, or functional abilities.59 Melatonin has not been studied in a blinded fashion.60 Acupuncture is commonly tried by bromyalgia patients, but the evidence for acupuncture in bromyalgia is conicting. One randomized sham-controlled study demonstrated no subjective improvement in pain between acupuncture and sham acupuncture.61 A more recent randomized trial, however, demonstrated that patients who received acupuncture (vs sham acupuncture) had signicantly greater improvements in FIQ scores at 1 and 7 months after treatment.62 An earlier study suggested that electroacupuncture was more effective than sham therapy for bromyalgia, but the study may not have been adequately blinded.63 The alternative therapies purported to treat bromyalgia are numerous, unregulated, unstudied, and easily found in advertisements in lay bromyalgia publications. Examples abound in a recent issue of Fibromyalgia Aware magazine.64 An advertisement for infrared therapy, for instance, makes various claims for relief of pain and stiffness, improved energy, and a better sense of well-being. Another ad

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Table Drug Amitriptyline

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559

Drugs with Positive Effects on Fibromyalgia in Randomized Controlled Trials Mechanism of Action Dose Positive Effect(s) in Fibromyalgia Drawbacks Has anticholinergic, antihistaminic, and antiadrenergic side effects

Increases synaptic availability 10 mg qhs/25-50 mg qhs Several clinical trials have demonstrated short-term of both serotonin and improvement in pain and norepinephrine in the sleep central nervous system by decreasing their uptake 10 mg qhs/10 mg qhs-20 One placebo-controlled trial Cyclobenzaprine Reduces tonic activity of mg bid has demonstrated alpha and gamma motor improvement in pain and neurons, leading to muscle fatigue; subsequent relaxation; structurally studies have not shown a similar to tricyclic difference between antidepressants placebo and cyclobenzaprine treatment 2 RCTs have demonstrated Fluoxetine Inhibits reuptake of serotonin 20 mg qd/20-80 mg qd short-term improvement in the central nervous in sleep and pain (the system, increasing its latter at 20 mg/day) synaptic availability 2 RCTs have demonstrated Duloxetine Inhibits reuptake of serotonin 30 mg qd/60 mg qd-60 mg bid short-term improvement and norepinephrine in the in pain and most central nervous system secondary outcome central nervous system; bromyalgia measures weak inhibitor of central nervous system dopamine reuptake Milnacipran Inhibits reuptake of serotonin 25 mg qd/100 mg bid One RCT showed signicant and norepinephrine in the improvement in pain and central nervous system secondary outcome measures Tramadol Blocks ascending pain 50 mg/50 mg tid-100 mg One of 2 RCTs has shown pathways by weakly binding tid very modest short-term to -opiate receptors in improvement in pain the central nervous system; weak reuptake inhibitor of norepinephrine and serotonin in the central nervous system Pregabalin In the central nervous 50 mg tid/100 mg One RCT showed system, binds to 2tid-150 mg tid improvement in pain only with 450 mg/day; subunit of voltage-gated improved sleep quality calcium channels, thus and fatigue at 300 mg/ inhibiting excitatory day neurotransmitter release
Abbreviations: qhs at bedtime; bid twice a day; qd every day; tid 3 times a day; RCT

High incidence of side-effects

High incidence of side effects often lead to drug discontinuation

Not available in the US

Has abuse potential and may cause dependence

Cam be used in combination with any of the above therapies

randomized controlled trial.

promotes a mattress claiming to relieve the pressure points that will allow for REM sleep. Yet another advertisement purports a simple solution for the abnormal foot structure that, the ad claims, perpetuates bromyalgia pain. In an advertisement for bottled water, aches, pains, and even fatigue are apparently magnied by the slightest hint of dehydration. A brand of moistened towelette claims it has been clinically shown to relieve pain associated with bromyalgia. While such alternative therapies can range from sensible to bizarre, none have been adequately validated.

APPROACH TO THE PATIENT WITH FIBROMYALGIA: PRACTICE-BASED EVIDENCE IN THE ABSENCE OF EVIDENCE-BASED PRACTICE
Despite a paucity of solid data in support of many bromyalgia therapies, the physician caring for a bromyalgia patient is confronted with an individual whose discomfort is signicant, and whose need for melioration is unquestionable. A number of treatments have shown clinical benet when compared with placebo (see Table), although fre-

560 quently not in a majority of the patients studied. Indeed, the heterogeneity of bromyalgia patients renders a one-sizets-all approach unlikely to be broadly efcacious, and controlled trials that fail to account for heterogeneity also might fail to tease out useful effects in subsets of patients. Additionally, most bromyalgia patients exhibit multiple symptoms in addition to pain and tenderness, and therefore require simultaneous treatment for multiple aspects of their illness. While the use of combination therapy may offer the best hope for bromyalgia management, almost all clinical trials for bromyalgia have tested only single therapies. Clinical experience suggests that particular treatments work in some patients, sometimes despite failure in clinical trials. Thus, bromyalgia treatment choices must be made on an empiric basis, informed wherever possible by evidence. For most patients, the agent of rst choice probably remains amitriptyline or nortriptyline at bedtime, initiated at 10 mg and increased incrementally as needed to maximum benet. If these are not tolerated, low-dose cyclobenzaprine at bedtime may be initiated; other muscle relaxants also might be efcacious. A patient who presents with isolated generalized pain without other associated symptoms may respond to a simple analgesic such as tramadol. Patients with depression may particularly benet from SSRIs or SNRIs. Patients who fail analgesics, muscle relaxants, or antidepressants may benet from the use of pregabalin or gabapentin. For most of these therapies, patients need to be reminded that at least several weeks may be required to derive benet. A failure to respond to one therapy indicates a need for a trial (or addition) of another agent. Because therapeutic responses are rarely durable, clinicians should not be disheartened when a medication loses its initial efcacy. Successful treatment of bromyalgia may require regular reassessment and possible rotation of medications. Although no particular physical therapies have denitively proven to be of benet in bromyalgia, we encourage all our bromyalgia patients to participate in some form of low-impact exercise, such as aquatherapy. Patients need to be reminded to not be discouraged by limited exercise capacity at the outset. Moreover, bromyalgia patients should be encouraged to increase their exercise very gradually; an overly aggressive regimen may lead to signicant postexercise discomfort and future noncompliance. Finally, it is of paramount importance to provide bromyalgia patients with education, emotional support, and reassurance. Patients should be reassured that, despite the severity of their pain, bromyalgia is an otherwise benign condition that does not lead to bodily damage or death. The treating physician needs to acknowledge the patients experience of pain, because bromyalgia patients frequently have had their symptoms ignored or dismissed. The challenge is to produce a compassionate and comprehensive treatment program for all aspects of the bromyalgia patients illness.

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