User Rating: / 0
PoorBest 

Written by Susan | 31 January 2010
Posted in Research

http://www.nature.com/nrrheum/archive/rheum_s8_current_archive.html

A symptom-based approach to pharmacologic management of fibromyalgia

Chad S. Boomershine¹ & Leslie J. Crofford² About the authors

Abstract

Fibromyalgia is a prevalent disorder that is characterized by widespread pain along with numerous other symptoms, including fatigue, poor sleep, mood disorders, and stiffness. Previous guidelines for the management of fibromyalgia recommended an approach that integrates pharmacologic and nonpharmacologic therapies selected according to the symptoms experienced by individual patients. However, they offered no recommendations for a system of patient assessment that would provide a basis for individualized treatment selection. We present a simple, rapid and easily remembered system for symptom quantitation and pharmacologic management of fibromyalgia that combines visual analogue scale symptom scores from a modified form of the disease-neutral Fibromyalgia Impact Questionnaire, with a review of medications that can be used to treat the individual symptoms. This symptom-based approach is amenable to caring for patients with fibromyalgia in a busy clinical practice.

Key points

• Effective treatment of fibromyalgia requires the management of all clinically relevant symptoms, using an individualized, integrative approach that combines pharmacologic and nonpharmacologic modalities
• Pregabalin, duloxetine and milnacipran are the only FDA-approved medications for the management of fibromyalgia
• Additional pharmacologic treatment should focus on symptoms of fatigue, insomnia (sleep quality), blues (depression and anxiety), rigidity (stiffness) and 'ow!' (pain and work interference), recalled using the mnemonic 'FIBRO'
• The modified visual analogue scale of the Fibromyalgia Impact Questionnaire can be used to individualize pharmacologic therapy and monitor treatment response for FIBRO symptoms
• Symptoms of fatigue, poor sleep, mood disorders, stiffness and pain can be treated with stimulants, sleep aids, antidepressants, muscle relaxants, and analgesics, respectively
• The use of narcotics and benzodiazepines should be avoided when treating patients with fibromyalgia; steroids and NSAIDs should only be used to treat underlying inflammatory conditions if present

Introduction

Fibromyalgia is of particular importance to rheumatologists. Between 10% and 20% of new patients presenting to rheumatology clinics are afflicted with the disorder, which disproportionately affects the type of patients commonly cared for by rheumatologists, including women, the elderly and patients with inflammatory autoimmune conditions.¹ In fact, 20% of patients with rheumatoid arthritis (RA) and 50% of patients with systemic lupus erythematosus suffer from fibromyalgia, and the presence of this disorder has a detrimental effect on disease outcomes for inflammatory disorders.^{2, 3} As rheumatologists often manage fibromyalgia that is secondary to a primary inflammatory rheumatic condition, the high prevalence of fibromyalgia, coupled with shortages in the rheumatology workforce, creates difficulty in managing high volumes of referrals in many practices. The specific exclusion of patients with fibromyalgia from rheumatology practices is sometimes justified by commonly held misconceptions about the disease. One such misconception is that fibromyalgia patients require too much time and cannot be effectively managed in a busy clinical practice. Furthermore, despite the availability of effective treatments for managing its symptoms, many rheumatologists have had little success in treating fibromyalgia, which has led some to wrongly conclude that it cannot be successfully managed. Other rheumatologists refuse to treat patients with fibromyalgia because of controversy over the existence of fibromyalgia as a discrete disease entity.⁴

We believe that the care of patients with fibromyalgia can be improved by using a symptom-based approach. As the effective management of fibromyalgia requires the identification and treatment of individual symptoms,⁵ a symptom-based management scheme would limit treatment failures that could arise from an exclusive focus on pain—a by-product of the American College of Rheumatology (ACR) fibromyalgia classification criteria, which are centered around widespread pain to the exclusion of other common symptoms.⁶ A symptom-based approach is hampered, however, by the inability of many patients to effectively articulate their symptom burden, and the inability of clinicians to interpret the patient's complaints into a coherent, intellectual framework from which to make treatment decisions. Furthermore, although self-report questionnaires that quantify symptom severity exist, their length and complexity preclude their use in busy clinical practice settings.

Symptom quantitation

The Fibromyalgia Impact Questionnaire (FIQ) is the most widely used measure for quantifying global fibromyalgia disease severity; it includes a combination of 11 questions on difficulty with activities of daily living (ADL), 2 day-of-the-week questions that ask "how many days in the past week did you feel good?" and "how many days did you miss work, including housework, because of fibromyalgia?" and 7 visual analogue scale (VAS) questions that assess the severity of work difficulty, pain, fatigue, sleep quality, stiffness, anxiety and depression caused by fibromyalgia that can be used to direct decisions on patient care.⁷ The ADL questions have been criticized, however, both for their gender bias and on psychometric grounds,^{8, 9} and the length and scoring complexity of the ADL and day-of-the-week questions make the FIQ difficult to use in routine clinical care. Also, patients are often unable to dissect the specific contribution fibromyalgia makes to their disability, and physicians uneasy with the concept of this disorder might refuse to administer the FIQ owing to the specific reference to fibromyalgia. Fortunately, the VAS of the FIQ can be modified to become disease-neutral, and can be combined with each other to produce a global disease severity score that correlates highly with the full FIQ global score.¹⁰ In addition, VAS scores can be used individually to quantify the severity of individual fibromyalgia symptoms (Figure 1).¹⁰ A modified VAS of the FIQ (mVASFIQ) provides a rapid, individualized assessment of symptom burden that can provide the basis for initial pharmacologic choices and can also be used to monitor therapeutic response over time. The mVASFIQ measure is ideally suited to directing patient management in clinical practice, as it can be administered in paper form, or can be easily recalled (using the FIBRO mnemonic discussed below) for verbal use.

Figure 1 | The modified visual analogue scale of the Fibromyalgia Impact Questionnaire.

The FIBRO mnemonic can be used to remember the items on this questionnaire (mVASFIQ). VASFIQ modified with permission from RM Bennett. Adapted with permission from The Journal of Rheumatology © Burckhardt, C. S., Clark, S. R. & Bennett, R. M. The fibromyalgia impact questionnaire: development and validation. J. Rheumatol. 18, 728–734 (1991).

• High resolution image and legend (52 KB)
• Figures and tables index
• Download Power Point slide (106 KB)

Pharmacologic management of symptoms

Four general points should be kept in mind when considering pharmacologic treatments for patients with fibromyalgia. First, primary disorders that can mimic fibromyalgia symptoms—including vitamin deficiencies, anemia, or metabolic, psychiatric, oncologic or inflammatory disorders—should be identified and treated before symptom-specific therapies are initiated. A comprehensive history should be taken, and physical and appropriate laboratory examination done including, but not limited to, CBC, metabolic panel, erythrocyte sedimentation rate, C-reactive protein and thyroid function studies (Figure 2). Fibromyalgia, however, frequently coexists with other diseases, and those patients who remain symptomatic despite adequate treatment of their primary disorder should be treated for fibromyalgia. Second, while a discussion of fibromyalgia diagnosis is beyond the scope of this article, the ACR classification criteria were not intended for clinical use: reliance on criteria fulfillment for diagnosis misses 46% of fibromyalgia patients.¹¹ A clinical diagnosis must, therefore, be made, and this Review is intended to apply to all patients who are clinically diagnosed, irrespective of whether they meet the ACR criteria. Third, as over half of patients with fibromyalgia have multiple medication intolerances,¹² treatments should be started individually at low doses that are slowly increased and/or combined with other medications; furthermore, multiple medications or combinations might need to be tried before a regimen is found that the patient will tolerate. Finally, even though this Review focuses on pharmacologic treatments, medications have a limited role in fibromyalgia treatment; that role is to manage symptoms so that patients can, in the long-term, also benefit from non-pharmacologic therapies, including exercise, education and behavioral therapies (Figure 2).⁵

Figure 2 | Proposed algorithm for the symptom-based management of fibromyalgia in clinical practice.

Patients with fibromyalgia are identified and then assessed with the mVASFIQ. The first-line treatment incorporates drugs specifically indicated for fibromyalgia, as well as nonpharmacologic measures. Treatment is customized by use of the mVASFIQ. Patients should be reassessed with the mVASFIQ at each visit, with treatment modified as required, as adverse effects of medications for one symptom can worsen others. ^aOnly pregabalin, duloxetine and milnacipran are approved by the FDA for management of fibromyalgia. Abbreviations: mVASFIQ, modified visual analogue scale of the Fibromyalgia Impact Questionnaire; OSA, obstructive sleep apnea; RLS, restless legs syndrome; SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

• High resolution image and legend (138 KB)
• Figures and tables index
• Download Power Point slide (188 KB)

Approved medications

As pregabalin, duloxetine and milnacipran are all FDA-approved for fibromyalgia management, it is reasonable to consider these as 'anchor' drugs, analogous to the use of methotrexate in RA. All three drugs have shown similar efficacy in ameliorating pain,¹³ but their abilities to manage other fibromyalgia symptoms differ greatly, which, along with their different pharmacodynamic and safety profiles, often make one a better initial choice than the others for an individual patient. Pregabalin is an calcium-channel antagonist that acts by limiting the neuronal release of excitatory neurotransmitters. Pregabalin has shown a capability to decrease sleep latency and modify sleep architecture by improving slow-wave sleep, making it a particularly good choice for fibromyalgia patients with sleep complaints.¹⁴ Pregabalin has multiple possible adverse effects, however, including dizziness, somnolence, weight gain and peripheral edema, the risks of which increase with increasing dose. Whereas the approved dosage is 300–450 mg per day, divided into two doses, we recommend beginning pregabalin treatment with a single small dose (25–75 mg) at dinner or with an evening snack, as food slows the absorption of the drug and can limit dizziness, and titrating upwards weekly until the maximal effect is achieved. Many patients respond to once-daily night-time dosing, but those with severe peripheral neuropathy or allodynia might benefit from twice-daily dosing. Patients on pregabalin should be monitored closely for worsening of fatigue. Being an adjunctive antiepileptic medication, pregabalin should be discontinued gradually, as stopping administration abruptly could, in theory, precipitate seizures in susceptible patients. Gabapentin, an older drug with the same mechanism of action, has also been effective in the treatment of patients with fibromyalgia, and is discussed below.¹⁵

Duloxetine and milnacipran belong to the serotonin–norepinephrine reuptake inhibitor (SNRI) class of antidepressants, which improve symptoms of pain by increasing the activity of noradrenergic antinociceptive pathways. These drugs should be considered as first-line agents in fibromyalgia patients with severe symptoms of depression (N.B. milnacipran is approved for treating major depressive disorder in Europe and Japan, but it is not FDA-approved for treating this disorder in the US). Also, as it has a higher affinity for the norepinephrine transporter than does duloxetine, milnacipran may be better for patients with severe fatigue and/or cognitive dysfunction (the so-called fibrofog).¹⁶ The indicated dose of duloxetine is 60 mg once daily, but we recommend starting with a single dose of 20 mg or 30 mg in the morning, with dose increases every 2 weeks to a maximum dose of 60 mg if necessary. The indicated dose of milnacipran is 100 mg daily, divided into two doses, but we recommend starting with a single 12.5 mg morning dose and gradually increasing the morning dose to 50 mg, if needed, before adding an evening dose. Common adverse effects of duloxetine and milnacipran include nausea and decreased appetite, which might make them a better choice than pregabalin for obese patients. Owing to its hepatic metabolism and potential drug–drug interactions, duloxetine should be avoided in patients with severe hepatic or renal impairment, and caution is advised when combining duloxetine with other agents. With appropriate dosage adjustments, pregabalin and milnacipran can both be used in patients with hepatic or renal impairment, and they share properties that make them safer for use with other agents, including minimal hepatic metabolism, low capacity for binding to plasma proteins, and low likelihood of being involved in clinically relevant pharmacokinetic drug interactions.^{17, 18} As with all serotonin-activating medications, duloxetine and milnacipran can increase the risk of bleeding and/or suicidal tendencies, and should be used with caution in patients with a history of, or who are at risk for, these conditions. Also, duloxetine and milnacipran can both affect blood pressure; monitoring is recommended.

The important therapeutic property of both duloxetine and milnacipran is reuptake inhibition of norepinephrine and serotonin. This effect can be achieved with other medications, although they are not approved specifically for fibromyalgia. For example, reuptake inhibition of both norepinephrine and serotonin can be accomplished by combining a specific serotonin reuptake inhibitor, such as fluoxetine, which has been shown to be effective in fibromyalgia,¹⁹ with an agent that inhibits norepinephrine reuptake, such as trazadone. However, combining multiple serotonin-active medications risks the development of serotonin syndrome, and patients should be warned and monitored for relevant signs and symptoms.²⁰ Although not submitted to the FDA for approval in a fibromyalgia indication, amitriptyline also provides balanced reuptake inhibition and has been shown in multiple meta-analyses to be effective in patients with fibromyalgia.^{21, 22} Its use is also discussed below.

Given the differing therapeutic mechanisms and adverse effect profiles of calcium-channel antagonists and SNRIs, synergy achieved through a combination strategy could benefit patients who fail to respond to either drug alone. A trial of combination therapy with the SNRI venlafaxine and the antagonist gabapentin, for instance, improved symptoms of pain, fatigue, mood disturbance and insomnia in patients with neuropathic pain who did not respond to gabapentin monotherapy.²³ The potential for additive adverse effects should be borne in mind, however, and randomized, combination trials are needed to confirm the safety and efficacy of such an approach.

Symptom management by the FIBRO method

Patients with fibromyalgia often fail to respond adequately to a single 'anchor' medication. Patients might have a response for one symptom (typically pain) but lack responses in other associated fibromyalgia symptoms, or some symptoms might worsen while others improve. Owing to the heterogeneity and complexity of symptoms experienced by individual fibromyalgia patients, a brief, comprehensive assessment tool suitable for use in busy clinics was needed. The FIBRO mnemonic was developed as a memory aid to recall key fibromyalgia symptoms, and the mVASFIQ questions were used to assess them (Figure 1). The letter 'F' indicates fatigue, 'I' insomnia (sleep quality), 'B' blues (including depression and anxiety), 'R' rigidity (stiffness), and 'O' 'ow!' (pain and work disability). mVASFIQ questions can be administered as printed forms, or patients can be queried verbally with answers rated on a 0–10 numeric scale. The mVASFIQ scores can be summed to provide a global disease severity measure and can also be considered individually to assess the severity of individual symptoms.¹⁰ By administering the mVASFIQ at baseline and follow-up visits, the patient's response to therapy can be monitored and treatments can be individualized. As previously stated, we recommend a 'start low and go slow' approach to fibromyalgia management, beginning with a single medication at a low dose and gradually titrating before adding additional medications. Drug combinations should be chosen carefully in order to limit the risk of drug–drug interactions, and patients should be monitored closely for signs or symptoms of toxic effects. The following sections will expand the information presented in Figure 2 and describe medications used to manage each FIBRO symptom.

Fatigue (stimulants)

Many patients with fibromyalgia experience debilitating symptoms of fatigue, which manifest physically as severe exhaustion and mentally as difficulties in memory and attention (termed 'fibrofog'). The long-term management of fatigue should rely on improving physical fitness through regular physical activity, but stimulants can improve the ability of patients to participate in such therapy and to manage their ADLs. Modafinil is a wakefulness-promoting agent that is pharmacologically distinct from other stimulants and is currently FDA-approved for the treatment of somnolence associated with obstructive sleep apnea, narcolepsy and shift-work syndrome.²⁴ Modafinil has been shown to be effective in improving fatigue associated with multiple disorders, and three published reports indicate that it possibly has a benefit in treating fibromyalgia-associated fatigue.^{25, 26, 27} In these studies, effective doses were in the 50–400 mg range, given primarily as a single morning dose but with a second, smaller dose added at noon if fatigue symptoms returned late in the day. Modafinil affects multiple cytochrome P450 isoenzymes and has the potential to interact with numerous drug classes. Maximum doses should be lower in the elderly and in patients with hepatic or renal disease. Although modafinil is structurally distinct from other stimulants, its adverse effect profile is similar; patients with insomnia, hypertension and anxiety disorders should be closely monitored for worsening of their signs and symptoms.²⁵ It is important to note that stimulants have addiction potential, and caution is urged when using these agents in patients with a history of drug abuse. In fact, we would discourage the use of these medications in patients with a history of addiction to alcohol or drugs.

Although methylphenidate has not been specifically studied as a treatment for fibromyalgia, it is the most commonly used stimulant in fibromyalgia therapy, owing to its low cost and the lack of insurance restrictions on its use. Psychostimulants could potentially be very helpful in fibromyalgia patients with 'fibrofog', as it can be considered analogous to adult attention deficit/hyperactivity disorder and treated similarly.²⁸ Excellent reviews of the diagnosis of adult attention deficit/hyperactivity disorder and its management with stimulant therapies—including methylphenidate, dexmethylphenidate, amphetamine salts and atomoxetine—have been published elsewhere.^{29, 30} A thorough discussion of these agents is, therefore, not included here. However, if the practitioner elects to prescribe psychostimulants, we recommend a 'start low and go slow' approach, using a small dose of short-acting stimulant given upon awakening and an additional dose added at noon if necessary, before considering extended-release formulations once daily. Also, given the relatively high prevalence of bipolar disorder in patients with fibromyalgia symptoms,³¹ close monitoring for the development of mania should be maintained in stimulant-treated patients.

Insomnia (sleep aids)

Improving sleep quality is a vital aspect of disease management for the majority of patients with fibromyalgia. Over 90% of fibromyalgia patients complain of sleep problems, and sleep disruption has been implicated in the pathogenesis of the disease.^{32, 33} All fibromyalgia patients should be screened for the presence of underlying sleep disorders before symptom-specific pharmacologic therapies are prescribed. Patients at high risk of obstructive sleep apnea–hypopnea syndrome should be referred for formal sleep evaluation.³⁴ Relevant patients fulfill at least two of three Berlin Questionnaire criteria, including persistent snoring, daytime somnolence or the presence of hypertension or obesity. As one-third of patients with fibromyalgia also have restless legs syndrome (RLS),³⁵ all patients should be screened for this disorder with the four-question International RLS Study Group criteria.³⁶ Patients with primary RLS should be treated with a dopamine agonist to determine whether resolving RLS improves their sleep before other sleep medications are used. Two dopamine agonists, pramipexole and ropinirole, have been approved by the FDA for the treatment of RLS, and both have been demonstrated to be efficacious in managing fibromyalgia symptoms.^{37, 38} Dopamine agonists are started at a low dose (0.125 mg per day for pramipexole and 0.25 mg per day for ropinirole) 2 h before bedtime and gradually increased in weekly intervals until symptoms of RLS have resolved or patients become intolerant of the treatment.^{39, 40} Although the recommended maximum daily doses for RLS treatment are 0.5 mg for pramipexole and 4 mg for ropinirole, higher doses have frequently been used to improve fibromyalgia symptoms, with a mean dose of 4.5 mg for pramipexole and 6 mg for ropinirole.^{37, 38} Owing to the high cost of pramipexole and ropinirole, we have used generic carbidopa–levodopa (25 mg/100 mg) combination tablets, which have successfully treated RLS in patients with fibromyalgia (CS Boomershine and LJ Crofford, unpublished data).

In patients with fibromyalgia who have difficulty falling asleep and who fail to respond to psychological and behavioral treatment modalities, FDA-approved pharmacologic therapies for insomnia should be considered.⁴¹ Although benzodiazepines have long been the mainstay of insomnia therapy, we avoid their use in fibromyalgia patients because of their detrimental effects on sleep architecture, cognition and their addiction potential.⁴² Ramelteon and eszopiclone are the only nonbenzodiazepine, FDA-approved therapies for insomnia. Ramelteon is a selective melatonin-receptor agonist that is administered as a single, 8 mg tablet 30 min before bedtime. Eszopiclone is a hypnotic agent given as a 1 mg, 2 mg or 3 mg tablet immediately before bedtime. The administration of ramelteon or eszopiclone with high-fat meals should be avoided, as this slows the absorption of these drugs and decreases their efficacy. As with all sedatives, patients using these agents should be closely monitored for worsening depression or suicidal ideation, and concomitant use of other sedatives should be avoided. Adverse effects of ramelteon are uncommon, but eszopiclone can cause headache and an unpleasant taste, which can limit its use. Sedating antidepressants can also be beneficial for improving symptoms of insomnia in the one-third of fibromyalgia patients with severe depressive symptoms, and are discussed below.

Whereas some fibromyalgia patients experience insomnia, many sleep for 12 h or more without feeling refreshed upon awakening. This phenomenon of nonrestorative sleep requires management with medications that improve sleep quality as opposed to sleep quantity.⁴³ Pregabalin is the recommended first-line agent, as it improves sleep architecture at recommended doses and is approved by the FDA for fibromyalgia management.¹⁴ However, improvements in sleep restoration are often transient, which renders pregabalin a poor long-term choice for many patients. Chlorpromazine 100 mg at bedtime can increase slow-wave sleep and improve symptoms of pain and mood in fibromyalgia patients,⁴⁴ but poor tolerance has limited its clinical use. Quetiapine, an atypical antipsychotic agent, improves sleep architecture⁴⁵ through effects on sleep quality and numerous other fibromyalgia symptoms at doses of between 25 mg and 100 mg per day.⁴⁶ While generally well tolerated, quetiapine doses of 100 mg per day have been associated with increased periodic limb movements; thus, the lowest effective dose should be used. Sodium oxybate, the commercial form of a naturally occurring neurochemical approved for cataplexy management, improves sleep and other fibromyalgia symptoms given as two divided doses of 3 mg at bedtime and 4 h later.⁴⁷ This drug is, however, tightly regulated owing to its substantial abuse potential, and routine clinical use cannot be recommended at this time.

Blues (antidepressants and anxiolytics)

The identification and treatment of mood disorders is crucial in the management of fibromyalgia, as one-third of patients complain of major problems with depression and/or anxiety that can severely hamper disease management and notably increase suicidality.^{48, 49} As duloxetine is approved by the FDA for the treatment of fibromyalgia as well as depression and anxiety, it is the recommended first-line treatment for patients with mood disorders in the US. Although daily doses as high as 120 mg are often used clinically, doses greater than 60 mg per day are poorly tolerated and not recommended.⁵⁰ As milnacipran is an SNRI approved as an antidepressant in Europe and Japan, and as a fibromyalgia management option at 50 mg twice daily in the US, it is the recommended first-line agent for depressed fibromyalgia patients in these regions. In addition, milnacipran has a higher specificity for norepinephrine reuptake inhibition than duloxetine, so it may be more effective for patients with severe fatigue and/or 'fibrofog'.¹⁶ Venlafaxine is a generic SNRI that has efficacy in fibromyalgia management at a dosage of 75 mg per day, and is a reasonable alternative for patients who cannot afford branded SNRIs.⁵¹ Caution should be used when discontinuing venlafaxine, however, as rebound depression is common.⁵² Older selective serotonin reuptake inhibitors, such as fluoxetine and paroxetine, may be effective in treating fibromyalgia as they also inhibit norepinephrine reuptake at high doses (40–80 mg per day), but these doses are often poorly tolerated.⁵³

Sedating antidepressants can be particularly helpful in managing depressed fibromyalgia patients with insomnia. Tricyclic antidepressants (TCAs), including amitriptyline and the structurally related cyclobenzaprine, have long been used to treat pain and insomnia at low evening doses (5–10 mg cyclobenzaprine, 10–50 mg amitriptyline). Whereas intolerance to high doses often makes TCA monotherapy insufficient to manage mood disorders, combining low-dose TCAs with fluoxetine 20 mg per day can synergystically treat fibromyalgia symptoms with minimal adverse effects.⁵⁴ Mirtazapine increases serotonergic and noradrenergic neurotransmission via a novel mechanism that could enable its use in patients who do not tolerate traditional SNRIs; doses of 15–30 mg at night have been shown to improve symptoms of pain, insomnia, fatigue, and depression in patients with fibromyalgia.⁵⁵ Somnolence with mirtazapine is inversely proportional to dose, so patients experiencing excessive sedation at a dose of 15 mg should increase to 30 mg. As the most-sedative second-generation antidepressant, trazodone is best suited for patients with insomnia refractory to other drugs. Although trazodone has not been studied as a treatment for fibromyalgia, an evening dose of 100 mg improved sleep architecture in patients with somatoform pain disorder.⁵⁶

Rigidity (muscle relaxants)

Muscle and joint stiffness is a symptom affecting over 75% of patients with fibromyalgia.⁶ The etiology of these symptoms is unknown, but they probably result from inactivity and deconditioning combined with the central nervous system abnormalities that underlie fibromyalgia. The management of rigidity should focus on decreasing symptoms enough to enable patients to maintain employment and encourage them to participate in physical activities that improve range of motion and fitness, including yoga, tai chi and other low-impact aerobic activities. Centrally acting muscle relaxants can be helpful as adjunctive therapy in patients with substantial stiffness. An excellent review of the use of muscle relaxants for musculoskeletal conditions has been published that thoroughly describes risks and benefits of the class;⁵⁷ this section will focus on the use of muscle relaxants in fibromyalgia.

Cyclobenzaprine is the most widely used muscle relaxant for treating fibromyalgia, and has many properties that make it particularly well suited for managing this disorder. Cyclobenzaprine is structurally a TCA, and thus can improve mood and pain symptoms. Whereas the use of cyclobenzaprine during the day can cause problematic sedation, it can treat insomnia when used at night. A meta-analysis of randomized, placebo-controlled trials showed that cyclobenzaprine significantly improved global fibromyalgia symptoms, along with symptoms of pain, sleep, and tender points, with excellent tolerability.⁵⁸ Cyclobenzaprine can be particularly useful in managing fibromyalgia 'flares' (acute exacerbations of symptoms); however, doses of 10 mg four or five times daily are often needed, which are larger than those commonly used to treat back pain (5–10 mg three times daily). Patients receiving these higher doses should be monitored for worsening fatigue, counseled to avoid concomitant use of central nervous system depressants and monitored for anticholinergic adverse effects (dry mouth, urinary retention, etc). Tizanidine, a muscle relaxant with similar sedative properties to cyclobenzaprine, should be started with a 4 mg dose at night and gradually increased to a maximum dose of 36 mg divided over the day if needed. Along with anticholinergic adverse effects, tizanidine can cause hepatotoxic effects, and laboratory monitoring is required. Methocarbamol and metaxalone are less-sedating muscle relaxants, but evidence for their effectiveness in managing fibromyalgia symptoms is limited. Benzodiazepines should be avoided in fibromyalgia patients owing to addiction potential and worsening of sleep. No evidence supports the use of antispastic agents (such as baclofen or dantrolene) in fibromyalgia, but they can be helpful for managing muscle spasms. Tramadol has been shown to substantially improve fibromyalgia-associated stiffness, and will be discussed in the next section.

'Ow!' (analgesics)

Pain has long been considered the defining feature of fibromyalgia syndrome. While the approved agents have demonstrated efficacy in relieving fibromyalgia pain, they often are not sufficient when taken alone. Paracetamol (acetaminophen) has some efficacy in the management of pain symptoms in fibromyalgia, but treatment failures are common as the required dose is usually near the maximum recommended dose of 4,000 mg/day, and patients are often noncompliant with the required frequency of administration. Assuming patients have normal renal and hepatic function, dosing with extended-release formulations of 1,000 mg paracetamol four times daily can improve compliance in comparison to the eight doses that are required daily for patients taking immediate-release 500 mg tablets. However, patients often fail to respond to treatment with paracetamol. Furthermore, the majority of fibromyalgia patients prefer to use NSAIDs.⁵⁹ Although all NSAIDs have similar analgesic effects, evidence of their efficacy in fibromyalgia management is lacking. NSAIDs are not recommended in the absence of a concomitant inflammatory condition or osteoarthritis, which often serve as pain triggers in patients with fibromyalgia.

Tramadol, a unique narcotic that combines -opioid agonist–antagonist and SNRI activities, is effective when used to manage fibromyalgia.⁵ One or two tramadol–paracetamol (37.5 mg/325 mg) combination tablets taken four times daily can substantially lessen pain, stiffness and work interference in patients with fibromyalgia.⁶⁰ Common adverse effects of this treatment are nausea, pruritis and constipation. The risk of abuse and dependence with tramadol is low, and 97% of such cases occur in patients with a history of substance abuse.⁶¹ Traditional narcotics should be avoided in the treatment of fibromyalgia, as their efficacy is poor and weaning patients off narcotics can be very difficult owing to the rebound pain phenomenon (analogous to rebound headaches) that can worsen pain symptoms when patients attempt to discontinue them.

Gabapentin is an ₂ calcium-channel antagonist, similar to pregabalin, that has proven efficacy in multiple neuropathic pain syndromes, including fibromyalgia.¹⁵ However, gabapentin has pharmacologic properties that make it more difficult to achieve an effective, tolerable dose than with pregabalin. An NIH-sponsored, investigator-initiated trial that showed that gabapentin was effective in improving pain, sleep, and global fibromyalgia symptoms attempted to titrate dosing up to 2,400 mg per day (divided into three doses),¹⁵ but, due to patient intolerance, the mean dose achieved in the trial was only 1,800 mg per day. Patients should be started on a single low dose of gabapentin (100–300 mg) at bedtime, with additional doses at breakfast and lunch added after 1 week and subsequent increases made to the evening dose. Adverse effects of gabapentin use are similar to those seen with pregabalin, including somnolence, dizziness, fatigue and weight gain. As with pregabalin, patients should be slowly tapered off gabapentin because of a theoretical risk of precipitating seizures.

Conclusions

Multiple meta-analyses show conclusively that improvement in fibromyalgia symptoms can be achieved by use of numerous pharmacologic and nonpharmacologic treatments.^{62, 63} Following the approval of three agents for the management of fibromyalgia by the FDA, clinicians treating patients with fibromyalgia should develop a framework for the use of these drugs in clinical practice to maximize patient response to therapy. We have presented a rapid, symptom-based method for the assessment and pharmacologic management of fibromyalgia that is suitable for use in busy clinics. Our method focuses on symptom identification and management that promotes a holistic, patient-centered view of disease that can improve care regardless of the patient's underlying disorder.

Review criteria

English-language articles in the Medline database were identified by use of the following search terms, alone and in combination: "fibromyalgia", "review", "treatment", "pregabalin", "insomnia", "modafinil", "stimulant", "attention", "atomoxetine", "dopamine", "sodium oxybate", "methylphenidate", "lupus", "rheumatoid", "suicide", "fatigue", "depression", "anxiety", "tizanidine", "baclofen", "dantrolene", "trazodone", "amitriptyline" and "meta-analysis". No date restrictions were placed on the search.

Competing interests statement

 

The authors declare competing interests.

References

1. Wolfe, F., Ross, K., Anderson, J., Russell, I. J. & Hebert, L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 38, 19–28 (1995).

1. • Article
   • PubMed
   • ISI
   • ChemPort

2. Wolfe, F. & Michaud, K. Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic disadvantage characterize RA patients with fibromyalgia. J. Rheumatol. 31, 695–700 (2004).

2. • PubMed

3. Middleton, G. D., McFarlin, J. E. & Lipsky, P. E. The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus. Arthritis Rheum. 37, 1181–1188 (1994).

3. • Article
   • PubMed
   • ChemPort

4. Berenson, A. Drug approved. Is disease real? (online 14 January 2008) [http://www.nytimes.com/2008/01/14/health/14pain.html] (accessed 29 September 2008).

5. Carville, S. F. et al. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann. Rheum. Dis. 67, 536–541 (2008).

5. • Article
   • PubMed
   • ChemPort

6. Wolfe, F. et al. The American College of Rheumatology 1990 criteria for the classification of fibromyaglia. Arthritis Rheum. 33, 160–172 (1990).

6. • Article
   • PubMed
   • ISI
   • ChemPort

7. Bennett, R. The Fibromyalgia Impact Questionnaire (FIQ): a review of its development, current version, operating characteristics, and uses. Clin. Exp. Rheumatol. 23, S154–S162 (2005).

7. • PubMed
   • ChemPort

8. Wolfe, F. et al. The assessment of functional impairment in fibromyalgia (FM): Rasch analyses of 5 functional scales and the development of the FM Health Assessment Questionnaire. J. Rheumatol. 27, 1989–1999 (2000).

8. • PubMed
   • ChemPort

9. Zachrisson, O. et al. A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). J. Psychosom. Res. 52, 501–509 (2002).

9. • Article
   • PubMed

10. Boomershine, C. S. et al. Five visual analogue scales quantify global disease severity and identify clinically significant symptoms in fibromyalgia syndrome. Arthritis Rheum. 58, S686–S687 (2008).

11. Katz, R. S., Wolfe, F. & Michaud, K. Fibromyalgia diagnosis: a comparison of clinical, survey, and American College of Rheumatology criteria. Arthritis Rheum. 54, 169–176 (2006).

11. • Article
    • PubMed
    • ISI

12. Slotkoff, A. T., Radulovic, D. A. & Clauw, D. J. The relationship between fibromyalgia and the multiple chemical sensitivity syndrome. Scand. J. Rheumatol. 26, 364–367 (1997).

12. • PubMed
    • ChemPort

13. Boomershine, C. S. First pregabalin and now duloxetine for fibromyalgia syndrome: closer to a brave new world? Nat. Clin. Pract. Rheumatol. 4, 636–637 (2008).

13. • Article
    • PubMed
    • ChemPort

14. Hindmarch. I., Dawson, J. & Stanley, N. A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep 28, 187–193 (2005).

14. • PubMed

15. Arnold, L. M. et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 56, 1336–1344 (2007).

15. • Article
    • PubMed
    • ISI
    • ChemPort

16. Stahl, S. M., Grady, M. M., Moret, C. & Briley, M. SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr. 10, 732–747 (2005).

16. • PubMed

17. Milnacipran package insert [http://www.fda.gov/cder/foi/label/2009/022256lbl.pdf] (accessed 30 January 2009).

18. Pregabalin package insert [http://www.fda.gov/cder/foi/label/2007/021446s010lbl.pdf] (accessed 30 January 2009).

19. Arnold, L. M. et al. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am. J. Med. 112, 191–197 (2002).

19. • Article
    • PubMed
    • ChemPort

20. Boyer, E. W. & Shannon, M. The serotonin syndrome. N. Engl. J. Med. 352, 1112–1120 (2005).

20. • Article
    • PubMed
    • ISI
    • ChemPort

21. Uçeyler, N., Häuser, W. & Sommer, C. A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome. Arthritis Rheum. 59, 1279–1298 (2008).

21. • Article
    • PubMed

22. Nishishinya, B. et al. Amitriptyline in the treatment of fibromyalgia: a systematic review of its efficacy. Rheumatology (Oxford) 47, 1741–1746 (2008).

22. • Article
    • PubMed
    • ChemPort

23. Simpson, D. A. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J. Clin. Neuromuscul. Dis. 3, 53–62 (2001).

23. • Article
    • PubMed
    • ChemPort

24. Kumar, R. Approved and investigational uses of modafinil: an evidence-based review. Drugs 68, 1803–1839 (2008).

24. • Article
    • PubMed
    • ChemPort

25. Schwartz, T. L. et al. Modafinil treatment for fatigue associated with fibromyalgia. J. Clin. Rheumatol. 13, 52 (2007).

25. • Article
    • PubMed

26. Pachas, W. N. Modafinil for the treatment of fatigue in fibromyalgia. J. Clin. Rheumatol. 9, 282–285 (2003).

26. • Article
    • PubMed

27. Schaller, J. L. & Behar, D. Modafinil in fibromyalgia treatment. J. Neuropsychiatry Clin. Neurosci. 13, 530–531 (2001).

27. • ChemPort

28. Glass, J. M. Fibromyalgia and cognition. J. Clin. Psychiatry 69 (Suppl. 2), S20–S24 (2008).

29. Culpepper, L. & Mattingly, G. A practical guide to recognition and diagnosis of ADHD in adults in the primary care setting. Postgrad. Med. 120, 16–26 (2008).

29. • PubMed

30. Rostain, A. L. Attention-deficit/hyperactivity disorder in adults: evidence-based recommendations for management. Postgrad. Med. 120, 27–38 (2008).

30. • Article
    • PubMed

31. Wallace, D. J. & Gotto, J. Hypothesis: bipolar illness with complaints of chronic musculoskeletal pain is a form of pseudofibromyalgia. Semin. Arthritis Rheum. 37, 256–259 (2008).

31. • Article
    • PubMed

32. Moldofsky, H., Scarisbrick, P., England, R. & Smythe, H. Musculoskeletal symptoms and non-REM sleep disturbance in patients with "fibrositis syndrome" and healthy subjects. Psychosom. Med. 37, 341–351 (1975).

32. • PubMed
    • ChemPort

33. Moldofsky, H. & Scarisbrick, P. Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosom. Med. 38, 35–44 (1976).

33. • PubMed
    • ChemPort

34. Netzer, N. C., Stoohs, R. A., Netzer, C. M., Clark, K. & Strohl, K. P. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann. Intern. Med. 131, 485–491 (1999).

34. • PubMed
    • ChemPort

35. Yunus, M. B. & Aldag, J. C. Restless legs syndrome and leg cramps in fibromyalgia syndrome: a controlled study. BMJ 312, 1339 (1996).

35. • PubMed
    • ChemPort

36. Walters, A. S. Toward a better definition of the restless legs syndrome. Mov. Disord. 10, 634–642 (1995).

36. • Article
    • PubMed
    • ISI
    • ChemPort

37. Holman, A. J. & Myers, R. R. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum. 52, 2495–2505 (2005).

37. • Article
    • PubMed
    • ChemPort

38. Holman, A. J. Ropinirole, open preliminary observations of a dopamine agonist for refractory fibromyalgia. J. Clin. Rheumatol. 9, 277–279 (2003).

38. • Article
    • PubMed

39. Pramipexole package insert [http://www.fda.gov/medwatch/safety/2006/Nov_PIs/Mirapex_PI.pdf] (accessed 30 January 2009).

40. Ropinirole package insert [http://www.fda.gov/medwatch/SAFETY/2005/MAY_PI/Requip_PI.pdf] (accessed 30 January 2009).

41. Morgenthaler, T. et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. An American Academy of Sleep Medicine report. Sleep 29, 1415–1419 (2006).

41. • PubMed

42. Becker, P. M. Pharmacologic and nonpharmacologic treatments of insomnia. Neurol. Clin. 23, 1149–1163 (2005).

42. • Article
    • PubMed

43. Moldofsky, H. The significance, assessment, and management of nonrestorative sleep in fibromyalgia syndrome. CNS Spectr. 13 (Suppl. 5), 22–26 (2008).

44. Moldofsky, H. & Lue, F. A. The relationship of alpha and delta EEG frequencies to pain and mood in 'fibrositis' patients treated with chlorpromazine and L-tryptophan. Electroencephalogr. Clin. Neurophysiol. 50, 71–80 (1980).

44. • Article
    • PubMed
    • ChemPort

45. Cohrs, S. et al. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology (Berl.) 174, 421–429 (2007).

46. Hidalgo, J., Rico-Villademoros, F. & Calandre, E. P. An open-label study of quetiapine in the treatment of fibromyalgia. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 71–77 (2007).

46. • Article
    • PubMed
    • ChemPort

47. Russell, I. J. Sodium oxybate relieves pain and improves function in fibromyalgia syndrome: a randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 60, 299–309 (2009).

47. • Article
    • PubMed
    • ChemPort

48. White, K. P., Nielson, W. R., Harth, M., Ostbye, T. & Speechley, M. Chronic widespread musculoskeletal pain with or without fibromyalgia: psychological distress in a representative community adult sample. J. Rheumatol. 29, 588–594 (2002).

48. • PubMed

49. Ratcliffe, G. E., Enns, M. W., Belik, S. L. & Sareen, J. Chronic pain conditions and suicidal ideation and suicide attempts: an epidemiologic perspective. Clin. J. Pain 24, 204–210 (2008).

49. • Article
    • PubMed

50. Russell, I. J. et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: Results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Pain 136, 432–444 (2008).

50. • Article
    • PubMed
    • ChemPort

51. Sayar, K., Aksu, G., Ak, I. & Tosun, M. Venlafaxine treatment of fibromyalgia. Ann. Pharmacother. 11, 1561–1565 (2003).

51. • Article
    • ChemPort

52. Effexor^® (venlafaxine hydrochloride) package insert [http://www.fda.gov/cder/foi/label/2007/020151s043,020699s069lbl.pdf] (accessed 30 January 2009).

53. Clauw, D. J. Pharmacotherapy for patients with fibromyalgia. J. Clin. Psychiatry 69 (Suppl. 2), 25–29 (2008).

54. Goldenberg, D., Mayskiy, M., Mossey, C., Ruthazer, R. & Schmid, C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 39, 1852–1859 (1996).

54. • Article
    • PubMed
    • ChemPort

55. Samborski, W., Lezanska-Szpera, M. & Rybakowski, J. K. Open trial of mirtazapine in patients with fibromyalgia. Pharmacopsychiatry 37, 168–170 (2005).

55. • Article
    • ChemPort

56. Saletu, B. et al. Insomnia in somatoform pain disorder: sleep laboratory studies on differences to controls and acute effects of trazodone, evaluated by the Somnolyzer 24 7 and the Siesta database. Neuropsychobiology 51, 148–163 (2005).

56. • Article
    • PubMed

57. See, S. & Ginzburg, R. Choosing a skeletal muscle relaxant. Am. Fam. Physician 78, 365–370 (2008).

57. • PubMed

58. Tofferi, J. K., Jackson, J. L. & O'Malley, P. G. Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis. Arthritis Rheum. 51, 9–13 (2004).

58. • Article
    • PubMed
    • ChemPort

59. Wolfe, F., Zhao, S. & Lane, N. Preference for nonsteroidal anti-inflammatory drugs over acetaminophen by rheumatic disease patients: a survey of 1,799 patients with osteoarthritis, rheumatoid arthritis, and fibromyalgia. Arthritis Rheum. 44, 2451–2455 (2001).

59. • Article
    • PubMed

60. Bennett, R. M. et al. Impact of fibromyalgia pain on health-related quality of life before and after treatment with tramadol/acetaminophen. Arthritis Rheum. 53, 519–527 (2005).

60. • Article
    • PubMed

61. Cicero, T. J. et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend. 57, 7–22 (1999).

61. • Article
    • PubMed
    • ChemPort

62. Abeles, M., Solitar, B. M., Pillinger, M. H. & Abeles, A. M. Update on fibromyalgia therapy. Am. J. Med. 121, 555–561 (2008).

62. • Article
    • PubMed
    • ChemPort

63. Goldenberg, D. L. Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain. Best Pract. Res. Clin. Rheumatol. 21, 499–511 (2007).

63. • Article
    • PubMed
    • ChemPort

 

 

Author affiliations

 

1. Vanderbilt University, Nashville, TN, USA.
2. University of Kentucky, Lexington, KY, USA.

Correspondence to: CS Boomershine, T3219 MCN, 1161 21st Ave South, Nashville, TN 37232–2681, USA
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it