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Treatment of fibromyalgia in adults

Treatment of fibromyalgia in adults
Literature review current through: Jan 2024.
This topic last updated: Jan 29, 2024.

INTRODUCTION — Fibromyalgia is a chronic, widespread musculoskeletal pain disorder that is often accompanied by fatigue, sleep disturbances, mood disorders, and overlapping conditions, such as irritable bowel syndrome, chronic fatigue syndrome, and chronic headaches. Treatment is initiated with nonpharmacologic measures that include patient education, cognitive (psychological) intervention, and physical activity and exercise. Many patients will benefit from medications, although pharmacotherapy is always prescribed in conjunction with nonpharmacologic management. Patients generally respond best to a multidisciplinary, individualized treatment program that incorporates both clinician and nonclinician providers, including primary care clinicians, physical therapists, and mental health specialists [1,2].

The treatment of fibromyalgia in adults who do not have comorbid rheumatic disease will be reviewed here. Chronic widespread pain in rheumatic diseases is discussed separately (see "Overview of chronic widespread (centralized) pain in the rheumatic diseases"). Other aspects of fibromyalgia are reviewed elsewhere, including:

Pathogenesis (see "Pathogenesis of fibromyalgia")

Clinical manifestations and diagnosis (see "Clinical manifestations and diagnosis of fibromyalgia in adults")

Differential diagnosis (see "Differential diagnosis of fibromyalgia")

Fibromyalgia in children and adolescents (see "Fibromyalgia in children and adolescents: Clinical manifestations and diagnosis" and "Fibromyalgia in children and adolescents: Treatment and prognosis overview")

OVERVIEW OF THE CLINICAL APPROACH

Individualizing the treatment approach — The combination of pharmacologic and nonpharmacologic therapies used to treat fibromyalgia should be tailored to the specific patient's clinical manifestations and comorbid conditions through shared decision-making, as supported by expert guidelines [3]. We individualize choices among the available nonpharmacologic modalities and medications based upon patient preference, symptoms, comorbidities, and our clinical experience with particular agents. We ask patients about the following issues to optimize their treatment plan [1,4]:

Prominent symptoms, including pain, fatigue, sleep disturbance, and depression

Past experience with or contraindications to medications used to treat these symptoms

Comorbid conditions and concurrent treatments, especially major mood or sleep disturbance (see 'Addressing comorbidities' below)

Level of physical fitness and any barriers to exercise

Social determinants of health that may impact symptoms and/or the ability to engage with a particular treatment

Insurance, copays for medications and other services, and other regulatory restrictions affecting treatment choices

Referral to subspecialists, therapists, and/or social work may be required depending on the needs that are identified

Addressing comorbidities — Patients who present with fibromyalgia and who have certain comorbid conditions may require subspecialist referral . At the initial patient evaluation, any patient with possible major mood disorder or a primary sleep disturbance should be referred to the appropriate specialist:

Major mental health disorders – These include depression, anxiety, and posttraumatic stress disorder (PTSD). Anxiety and depression are especially common in patients with fibromyalgia [1]. A significant cohort of fibromyalgia patients have comorbid physical, psychological, or emotional trauma and PTSD [5]. (See "Unipolar major depression in adults: Choosing initial treatment" and "Generalized anxiety disorder in adults: Management" and "Posttraumatic stress disorder in adults: Treatment overview".)

Primary sleep disorders – These include obstructive sleep apnea and restless legs syndrome. (See "Obstructive sleep apnea: Overview of management in adults" and "Overview of the treatment of insomnia in adults" and "Management of restless legs syndrome and periodic limb movement disorder in adults".)

Patients with fibromyalgia who have other comorbidities may also require adjustments in their treatment plan and potential collaboration with other subspecialists to optimize care:

Patients with polypharmacy – Many patients with fibromyalgia have multiple comorbid diseases and struggle with polypharmacy [6]. Providers should perform a careful medication reconciliation and identify medications that may worsen fibromyalgia symptoms (eg, antihistamines, anticholinergics, beta blockers, opioids, and benzodiazepines). If a prescription may be worsening symptoms, providers can consider altering therapy as medically appropriate after consultation with other members of the patients' medical team.

Conditions causing peripheral (nociceptive) pain – If there is concern regarding comorbid systemic autoimmune rheumatic disease (eg, active rheumatoid arthritis), the patient should be referred to a rheumatologist. If there is consideration of mechanical or regional musculoskeletal disorders (eg, osteoarthritis, shoulder pain), the patient should be referred to a physical medicine and rehabilitation specialist or a rheumatologist. (See 'When to refer' below.)

Patients taking chronic opiates – We refer patients who are taking chronic opiates to a pain specialist.

There is overlap in clinical phenotype between myalgic encephalomyelitis/chronic fatigue syndrome as well as long coronavirus disease (COVID); these conditions are discussed in detail elsewhere. (See "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome" and "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)

Screening for comorbid conditions in fibromyalgia is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Additional evaluation'.)

EXPLAINING FIBROMYALGIA TO PATIENTS — The approach to working with patients who have fibromyalgia is distinct. Aside from increased sensitivity to pain, there are often not objective measures on physical examination or medical tests to guide diagnosis and treatment. Therefore, the patient and provider must intentionally build a common understanding of the patient's symptoms and illness experience, causes of those symptoms, and realistic goals of care.

Making time for the patient experience — There is significant patient (and provider) confusion regarding the origins, legitimacy, and management of fibromyalgia. Time needs to be set aside at the initial patient visit to discuss these confusing issues. It is important to listen to patients with fibromyalgia and genuinely validate the pain and other symptoms that they experience. Providers should reassure the patient that fibromyalgia is a significant illness and dispel myths about the pain not being "physical" or "real." Acknowledging the patient experience is the foundation for building a therapeutic alliance and understanding how to individualize the treatment plan.

Validation by a provider can often be an emotional experience. We recommend making space for this with a few seconds of silence, as patients will often express relief, sadness, or frustration. Effective patient-centered communication skills allow this initial interaction to occur in a busy practice without feeling rushed (and generally does not take more than a minute or two).

In an era predicated on the importance of objective metrics in the diagnostic and therapeutic process, fibromyalgia patients often feel unseen and unheard and/or are told that their pain is "just in their heads." Patients often struggle with stigma and may think that providers do not believe that their pain is real, listen to them, or want to take care of them [7]. Many patients have had fibromyalgia for years before diagnosis and may feel rejected by the medical profession. They may also have struggled to explain symptoms to others in their life who cannot see a visible cause of their pain.

Explaining the cause of symptoms — There are several important concepts to include when explaining fibromyalgia symptoms to patients.

No persistent causal factor – Providers should assure patients that there is no evidence that fibromyalgia is related to persistent tissue damage, injury, or ongoing infection. While these may be precipitating factors in the illness, they are not directly related to treatment.

Centralized pain – We tell patients that there are multiple ways to conceptualize and treat pain. We explain definition and basic mechanisms of centralized pain disorders [8]. As an example, we describe that peripheral or nociceptive pain can be caused by inflammation and tissue damage (eg, pain from rheumatoid arthritis), while centralized or nociplastic pain results from maladaptive processing in the central nervous system (CNS) including the spinal cord and brain.

Fibromyalgia is the prototypical centralized pain syndrome. Centralized pain disorders are associated with pathologically amplified signaling in the CNS, which drives a widespread hypersensitivity, or a lower threshold to pain, throughout the body. One fibromyalgia expert uses an analogy of a guitar amplifier exaggerating the sound of a normal guitar [9]. We also explain that central and peripheral pain can be bidirectional. For example, localized knee or neck pain may aggravate fibromyalgia and vice versa.

The relationship of neurohormones to pain perception, fatigue, abnormal sleep, and mood disturbances should be discussed [8]. This approach helps patients understand that chronic pain may begin and persist without a peripheral cause such as tissue damage and provide a conceptual basis for various aspects of their treatment plan (eg, the use of cognitive therapy and medications that are also used to treat anxiety and depression, and lack of a role for immunosuppressive therapy). (See "Overview of chronic widespread (centralized) pain in the rheumatic diseases" and "Pathogenesis of fibromyalgia", section on 'Central nervous system altered pain processing'.)

Fibromyalgia is often grouped together with overlapping disorders, including myalgic encephalomyelitis/chronic fatigue syndrome, irritable bowel syndrome, chronic pelvic and bladder pain, and musculoskeletal headaches. These conditions are best explained with a biopsychosocial, rather than a biomedical, perspective.

Setting realistic treatment expectations — Fibromyalgia symptoms are often challenging to treat and patients may become frustrated if treatment is not meeting their expectations [7]. Having open discussions about concrete, achievable, short- and long-term treatment goals can help patients and providers set more realistic expectations and recognize when treatment plans need to be changed. We identify goals related to meaningful tasks in patients' lives that are both measurable and important to them. As an example, instead of setting a goal to decrease pain from 10 to 1 on a numerical scale, a more actionable goal might be to increase the amount of time per week that a patient can play with their grandchild. This individualized goal-setting approach allows for more direct assessment of improvement or lack thereof.

Providers should also explain to patients that there is no pharmacologic "cure" or single, highly effective therapy for fibromyalgia. This is in contrast to treatment of conditions such as rheumatoid arthritis, where medications can blunt systemic inflammation and induce low disease activity fairly rapidly. At this time, there is no such treatment for fibromyalgia.

Treatment for fibromyalgia entails the use of a multimodal approach, including nonpharmacologic tools, with the intention to make incremental improvements in quality of life over time. Ultimately, various medications may be helpful. Patients need to appreciate that while symptoms do improve with therapy, they will wax and wane and some pain and fatigue will often persist. Many patients in primary care do have complete resolution of symptoms over time. The majority of patients live normal and active lives. Patients should also be told that fibromyalgia is not life-threatening and does not cause physical deformities. (See 'Prognosis' below.)

GOALS OF FIBROMYALGIA TREATMENT — Treatment in fibromyalgia is focused on symptomatic relief and empowering patients with strategies to minimize the impact symptoms have on their daily activities. Broadly, treatment goals include:

Reduce major symptoms, such as chronic widespread pain, fatigue, sleep disturbance, and mood disturbances

Increase patient self-efficacy with empowerment through patient education, patient-centered communication, and providing concrete implementation strategies for nonpharmacologic interventions

Tailor pharmacologic and nonpharmacologic therapies to an individual patient's symptoms

Recognize and treat comorbid conditions that impact fibromyalgia symptoms and/or the ability to participate effectively in treatment

INITIAL TREATMENT

Core nonpharmacologic interventions — For all patients with fibromyalgia, we recommend using nonpharmacologic interventions for initial therapy instead of pharmacotherapy alone. The three main components of nonpharmacologic therapy for all patients with fibromyalgia are patient education, cognitive (psychological) therapy, and increased activity and exercise. Nonpharmacologic interventions may be sufficient for initial therapy, especially for patients who have a shorter duration of symptoms, do not have coexisting major mood or sleep disorders, and/or prefer not to use or have contraindications to available pharmacotherapy.

Incorporating these three core nonpharmacologic interventions in initial management is supported by a number of systematic reviews and meta-analyses, which have found that patient education, cardiovascular exercise, and multidisciplinary interventions, as well as cognitive-behavioral therapy (CBT) and other psychological therapies, provide benefit in patients with fibromyalgia [1-3,8,10]. These approaches are also consistent with the 2017 revised European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) guidelines [3]. Education, CBT, aerobic exercise, and sleep hygiene were recommended as core treatments for all fibromyalgia symptoms by an international, multidisciplinary Delphi consensus of experts [10].

Patient education — For all patients with fibromyalgia, we suggest providing patient education. Patient education includes a discussion of fibromyalgia as well as several nonpharmacologic strategies (eg, sleep hygiene, nutrition) that can improve symptoms.

Explanation of fibromyalgia – Providers should review the diagnosis of fibromyalgia, focusing on the following aspects:

The noninflammatory origins of centralized pain, its nondeforming nature, and the distinction between centralized pain from the more classic nociceptive or inflammatory pain (see 'Explaining the cause of symptoms' above)

The helpful though limited effects of pharmacologic therapy and thus the role for a multimodal collaborative process to optimize concrete functional goals (see 'Setting realistic treatment expectations' above)

The importance of treating comorbidities – Providers should educate patients about the bidirectional relationship between many comorbid conditions and fibromyalgia symptoms, where the presence of either one can exacerbate symptoms of the other. As an example, being in pain is often depressing, and depression can also impact pain perception, coping, and ability to participate in treatment. Patients with comorbid conditions that impact fibromyalgia should be strongly encouraged to obtain specific treatment for these conditions. (See "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Coexisting disorders' and 'Addressing comorbidities' above.)

Sleep disturbances and sleep hygiene – Sleep disturbances are present in the vast majority of fibromyalgia patients. As noted above, every patient should be screened for primary sleep disturbances, specifically sleep apnea and restless leg syndrome. Patients with suspected primary sleep disturbances should be referred to a sleep specialist. In other patients, components of optimal sleep hygiene should be reviewed, including:

Sleeping in a dark, quiet, and cool environment

Avoiding stimulants that may affect sleep (eg, blue light from electronics, caffeine, continuously scrolling through social media prior to sleep, and alcohol)

Avoiding or managing factors that may adversely affect sleep quality (eg, disruptive pets or co-sleepers, medical conditions or habits causing frequent nighttime awakenings for urination)

It will sometimes become apparent during this conversation that there are factors impeding sleep which require collaboration with social work (eg, the patient does not have a bed or a safe place to sleep).

Delivery of patient education – Providers should direct patients to resources that can be reviewed independently and discussed at subsequent visits (eg, handouts, online resources). Providers should exercise caution when referring patients to online materials, as the quality of online health information for fibromyalgia is highly variable. Studies have noted that not-for-profit organizations provide the most complete and accurate information, while other webpages and YouTube searches provide low-quality education [7,11]. Web-based education and cognitive training programs have also been developed and well received by patients [12]. It may be helpful to include family members in patient education when possible. Information on pain is available from the University of Michigan [9] and a free online handout for patients can be accessed there. (See "Patient education: Fibromyalgia (Beyond the Basics)".)

Efficacy – Patient education in the initial approach to fibromyalgia treatment is supported by guidelines for the management of fibromyalgia issued by EULAR and other countries [3]. While the exact content and format of educational interventions vary and double-blinded, randomized studies are rare, there is evidence that patient education can improve fibromyalgia symptoms. In a 2019 systematic review of generally low-quality evidence, patient education significantly reduced pain intensity, anxiety, and catastrophizing [13]. Even single educational interventions may be beneficial, as shown with a 1.5-day educational intervention given by a multidisciplinary team that found improvement in patient-reported function, fatigue, stiffness, and anxiety scores measured at baseline and at one month after the intervention [14]. A systematic review found that patient education was not effective as a standalone intervention but was effective when combined with other nonpharmacologic management [15], such as group exercise [16].

Increasing physical activity and exercise — Patients with fibromyalgia who do not have a contraindication to exercise will usually benefit from various forms of exercise and activity, including cardiovascular fitness training, resistance exercise (strength and flexibility training), and movement therapies such as tai chi. Exercise may increase physical function and restorative sleep and improve pain and fatigue and is strongly recommended in fibromyalgia treatment guidelines [3,10]. We always include low-impact aerobic exercise for patients who are able to tolerate this. The type and intensity of the exercise program should be individualized based upon patient preference and physical status. Physical therapists or exercise physiologists familiar with fibromyalgia can provide helpful instruction.

Individualizing an exercise program – Before recommending a particular program, we assess the following elements to help create a tailored exercise program:

Current level of physical activity and exercise tolerance

Comorbidities that may impact exercise ability (eg, osteoarthritis, asthma, cardiovascular disease)

Availability and accessibility of fitness-related resources (eg, access to a pool, availability of childcare)

Preference for or interest in various forms of exercise (eg, land- versus water-based exercise, yoga, tai chi)

Interest in receiving guidance from a physical therapist

Optimal cardiovascular fitness training generally requires a minimum of 30 minutes of aerobic exercise three times per week in a range near target heart rate. Patients may not achieve this goal but should be encouraged to continue exercising regularly at whatever level they can maintain. While regular exercise is most likely to be beneficial, even modest increases in daily physical activity may benefit patient-assessed physical function [17]. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease", section on 'The exercise prescription'.)

Adherence to exercise programs is generally fair but comparable to other chronic illnesses and dropout from exercise is less when supervision, such as a physical therapist, is included [18].

Addressing potential increase in pain – Patients often experience worsening pain and fatigue when initiating an exercise program. It is therefore important to set patient expectations and stress the importance of gradually increasing activity, often referred to as pacing. Most patients should start with short, low-intensity exercise sessions and slowly increase the duration, intensity, and frequency as tolerated over weeks to months. Exercise education programs have proven effective in lessening patients’ exercise-induced pain (eg, education about pain neurophysiology) [19].

Efficacy – Various forms of low-impact aerobic exercise have been effective in fibromyalgia studies, including fast walking, biking, swimming, or water aerobics (especially in warm water) [1-3]. The strongest evidence of significant improvement in symptoms has been with low-impact aerobic exercise and strength training or programs that combine aerobic and resistance exercise [20,21]. Other types of exercise that have been helpful include resistance training (eg, using weights or resistance bands) and mixed exercise programs (eg, a combination of aerobic and strength training) [1-3]. Tai chi, qigong, yoga, and flexibility exercise have each demonstrated some efficacy in fibromyalgia clinical trials. The evidence for improvement has been strongest for tai chi [22]. Randomized trial data have shown tai chi to result in similar or greater symptomatic improvement compared with aerobic exercise [23].

Cognitive (psychological) therapy — For most patients with fibromyalgia, we suggest using cognitive or psychologic interventions. The specific interventions should be individualized based upon patient preference and available resources and may include cognitive-behavioral therapy (CBT), mindfulness-based stress reduction (MBSR), and/or meditation and relaxation [24-27]. Limited access to CBT and other psychological therapies may be a significant barrier for patients. CBT can be done individually or in group sessions.

A role for various cognitive therapies, particularly CBT, in the treatment of fibromyalgia is well-supported by evidence from meta-analyses, individual trials, and observational studies [24-27]. A 2015 systematic review concluded that psychological interventions may be effective in improving physical functioning, pain, and low mood for adults with fibromyalgia in comparison with usual care controls, but the improvements were of questionable clinical significance and the overall quality of the evidence was low [27].

Various forms of CBT have shown promise for patients with or at risk of developing fibromyalgia, including in-person, online, and telephone interventions, especially when patient education and cognitive therapy are integrated [28,29]. The emergence of digital training programs is on the horizon, making it substantially easier for patients to access evidenced-based cognitive therapies for fibromyalgia [30].

Initial pharmacologic therapy

When to start pharmacologic therapy — For patients with moderate to severe symptoms or with mild symptoms that do not respond adequately to nonpharmacologic interventions, we recommend adding pharmacotherapy. The most common medications prescribed for patients with fibromyalgia are tricyclic antidepressants (tricyclics, eg, amitriptyline and cyclobenzaprine), serotonin-norepinephrine reuptake inhibitors (SNRIs; eg, duloxetine and milnacipran), and alpha-2 ligands (eg, pregabalin and gabapentin).

Overall efficacy — It is important for clinicians and patients to understand that medications in fibromyalgia are, at best, modestly effective in less than 50 percent of patients. In a report of 4000 fibromyalgia patients followed in an Israeli health service organization, less than one-half continued on any prescribed medication for more than 20 percent of the year [31]. Ninety percent had discontinued tricyclics and 74 percent discontinued SNRIs or selective serotonin reuptake inhibitors (SSRIs) during the one-year follow-up. A 2012 meta-analysis found that only a minority of patients experienced substantial improvement with antidepressant medications (eg, amitriptyline, duloxetine, and milnacipran) and that adverse side effects were common [32]. A 2021 systematic review and meta-analysis concluded that many of the pharmacologic and nonpharmacologic therapies recommended for fibromyalgia have limited evidence for significant efficacy [33]. There was high-quality evidence for antidepressants for pain reduction and improved quality of life in the short to medium term.

Choice of initial agent based on clinical presentation — Patients with fibromyalgia may have different clinical presentations with different symptoms and/or comorbidities that could impact treatment choice. Most patients presenting with characteristic widespread pain and fatigue should initially be given a trial of a low-dose tricyclic medication, such as amitriptyline, close to bedtime. In patients with concurrent major mood or sleep disturbances, we recommend alternative initial medications as detailed below. There is no strong evidence supporting clinical efficacy of one pharmacotherapy over another for all patients with fibromyalgia. In general, drugs should be started at low doses, built up slowly over time, and maintained at the lowest dose possible that produces therapeutic benefit.

Amitriptyline and related tricyclic medications were the first medications found to be effective in fibromyalgia clinical trials, but these medications were generic and used off-label. Duloxetine, milnacipran, and pregabalin are the three drugs approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia in the United States [1]. Randomized trials and meta-analyses comparing these agents and other related medications with placebo have demonstrated benefit for treating fibromyalgia, as described below.

There have been few direct comparisons of one drug with another, particularly with the tricyclic medications [34-36]. A 2011 meta-analysis of the relative efficacy of duloxetine, pregabalin, and milnacipran, involving 7739 patients in 17 studies, found that all three were superior to placebo for pain relief, although duloxetine and pregabalin were superior to milnacipran [34]. The drugs also differed in their effects on sleep disturbance and depression and in alleviating fatigue. Headaches and nausea were more likely with duloxetine and milnacipran; diarrhea was more likely with duloxetine; and cognitive defects and weight gain were more likely with pregabalin. A systematic review and network meta-analysis of randomized clinical trials found that duloxetine had greater efficacy for treating pain and depression, while amitriptyline had better efficacy for improving sleep, fatigue, and overall quality of life [37].

In an attempt to better predict different pharmacologic response, machine-learning models have been explored for chronic pain treatment. Brain functional connectivity patterns were able to predict clinical response to pregabalin and milnacipran in fibromyalgia patients [38]. However, more work is needed to help translate such work into clinical practice.

Diffuse, widespread pain without major mood or sleep disturbances (most common fibromyalgia presentation) — In most patients with fibromyalgia who do not have major mood or sleep disturbances, we suggest initiating therapy with a low dose of amitriptyline (eg, 5 to 10 mg) at nighttime. We often initiate therapy with a low dose of a tricyclic medication because these drugs are often effective, widely available, and far less costly for most patients than some of the newer agents. The tricyclics may be limited by adverse side effects, especially in older adults. There is more evidence available to support the benefits of amitriptyline but a lack of evidence to indicate that either amitriptyline or cyclobenzaprine have an advantage over the other.

Amitriptyline and related tricyclic antidepressants — We take the following approach to use of amitriptyline and related tricyclic medications (including cyclobenzaprine, desipramine and nortriptyline):

Dosing – We start with a low dose of amitriptyline (eg, 5 to 10 mg) taken one to three hours before bedtime. A 5 mg dose is appropriate for patients expected to be more sensitive to the drug or more likely to experience adverse effects, including older patients. The dose may be increased by 5 mg no more frequently than every two weeks; the final dose should be set jointly by the patient and prescribing clinician, based upon efficacy and side effects, always keeping the dose as low as possible. A dose of 20 to 30 mg is adequate in most patients. The doses of amitriptyline studied have been 25 to 50 mg, often given as a single bedtime dose [39]. Of note, these doses of amitriptyline are lower than those typically used to treat depression and neuropathic pain.

Duration – In patients who respond to medication, we continue the lowest dose that achieves a meaningful response for at least 12 months. Some patients may stay on that medication indefinitely, whereas others can be weaned off. More detailed information about discontinuing tricyclics is described elsewhere. (See "Discontinuing antidepressant medications in adults", section on 'Tricyclics'.)

Adverse effects – Potential adverse effects of amitriptyline and other tricyclics include anticholinergic effects (eg, dry mouth, constipation, urinary retention), central nervous system (CNS) depression (eg, drowsiness, confusion, fatigue), serotonin syndrome, cardiac conduction abnormalities, increased bleeding, hyponatremia, fluid retention, and weight gain. Such side effects often limit use in older patients. More detailed information on adverse effects of tricyclics is described elsewhere. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects", section on 'Side effects'.)

Efficacy – Multiple meta-analyses support using amitriptyline as the initial pharmacotherapy for fibromyalgia and describe greater improvements in fibromyalgia symptoms (including pain, fatigue, sleep disturbance, and depressed mood) and health-related quality of life when compared with patients taking other therapies, including SNRIs (eg, duloxetine or milnacipran) and SSRIs (eg, fluoxetine). Individual randomized trials have demonstrated that clinically important improvement occurs in 25 to 45 percent of patients treated with tricyclics, compared with 0 to 20 percent of those treated with placebo. However, their use is limited by a lack of uniform effectiveness and by a relatively high frequency of side effects. In addition, the efficacy of the tricyclics may decrease over time in some patients [35,36,39-46]. Most trials using tricyclics in fibromyalgia have been less than three months in duration.

Cyclobenzaprine — In patients with mild to moderate symptoms, cyclobenzaprine is an alternative to amitriptyline. Cyclobenzaprine is similar to other tricyclics in its structure and presumed mode of action in fibromyalgia, although not used to treat depression.

Dosing – We usually start with a low dose (5 to 10 mg) near bedtime and increase as tolerated. In general, the dose and schedule that has been evaluated in clinical trial is similar to that of amitriptyline [43]. However, we generally limit the dose to 10 to 20 mg near bedtime due to more prominent sedation.

Adverse effects – Adverse effects of cyclobenzaprine are similar to those of amitriptyline and include anticholinergic effects (eg, dry mouth, constipation, urinary retention), CNS depression (eg, drowsiness, confusion, fatigue), and serotonin syndrome.

Efficacy – A meta-analysis of randomized trials found that patients with fibromyalgia receiving cyclobenzaprine were 21 percent more likely to have self-reported global improvement than those receiving placebo, suggesting that approximately five patients would need to be treated with cyclobenzaprine for one to improve (odds ratio [OR] 3.0, 95% CI 1.6-5.6) . This degree of benefit relative to placebo is similar to that observed when comparing amitriptyline with placebo [43-46]. There is also some evidence to support very low-dose cyclobenzaprine (1 to 4 mg) orally [47] or sublingually [48]. The sublingual dose of 2.8 to 5.6 mg of cyclobenzaprine was found to be significantly better than placebo in fibromyalgia pain reduction and was well-tolerated [48].

Patients with severe fatigue and/or depression — In patients with severe fatigue or who require concomitant drug therapy for depression, we suggest using a SNRI, such as duloxetine, as initial therapy. Duloxetine is available in many countries for the treatment of depression and diabetic neuropathy. Milnacipran is an alternative to duloxetine in patients with severe fatigue, although it is not as widely available. We generally do not use venlafaxine because data supporting its efficacy in treatment of fibromyalgia are more limited compared with duloxetine or milnacipran, and withdrawal symptoms may be more common due to the short half-life [49]. When treating patients with significant depression and fibromyalgia, treatment should be coordinated with a clinician who has expertise in depression to assure that both the depression and the fibromyalgia are being addressed effectively and safely.

Selective serotonin-norepinephrine reuptake inhibitors — The SNRIs, which are sometimes also referred to as dual reuptake inhibitors, inhibit both norepinephrine and serotonin reuptake.

Dosing

Duloxetine – We usually start with a dose of 20 to 30 mg daily, given in the morning with food. The dose may be gradually increased by 20 mg increments every few weeks to 60 mg daily as tolerated. The average effective dose in fibromyalgia clinical trials has been 60 mg daily [50,51]; however, the dose should be individualized, and doses as low as 20 to 30 mg daily may be effective for some patients.

Milnacipran – We initiate therapy with 12.5 mg each morning, gradually titrating up by 12.5 mg every few weeks as tolerated to 50 to 100 mg once or twice daily. The average recommended dose in clinical trials has been 100 mg daily [51,52].

Adverse effects – Potential adverse effects of SNRIs include hepatotoxicity, bleeding, fragility fractures, hyponatremia, orthostatic hypotension, and serotonin syndrome. Patients may also experience withdrawal symptoms, such as fatigue, anxiety, and insomnia, either with gradual or abrupt discontinuation, usually within 1 to 10 days of stopping. More information on adverse effects can be found elsewhere. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Adverse effects'.)

EfficacyDuloxetine and milnacipran, which are both available for the treatment of fibromyalgia in the United States, have shown benefit in multiple randomized trials, while venlafaxine has received more limited study [52-60]. These drugs have been compared indirectly with amitriptyline and other agents.

Duloxetine – A systematic review and meta-analysis found that duloxetine (60 mg daily) was significantly more likely than placebo to reduce pain by at least 50 percent at 12 weeks (risk ratio [RR] 1.57, 95% CI 1.20-2.06) and at 28 weeks (RR 1.58, 95% CI 1.10-2.27). The number needed to benefit at 12 weeks was 8 (95% CI 4-21). Adverse effects caused 12.6 percent of patients to stop the medication, but serious adverse effects were rare. A subsequent open-label, long-term extension study found that duloxetine was safe and effective for patients with fibromyalgia during an average duration of one year of follow-up [61].

Milnacipran – Multiple randomized trials have found that patients receiving milnacipran have more improvement in pain and global wellbeing than patients receiving placebo. Milnacipran provides moderate levels of pain relief (at least 30 percent) to approximately 40 percent of patients receiving the active drug, compared with approximately 30 percent of those receiving placebo who achieved the same level of pain relief [51,62]. Responses to milnacipran were sustained among patients responding initially in randomized trials during follow-up with continued treatment for periods of up to one year [63,64].

Prominent sleep disturbance — In patients with prominent sleep disturbance, we suggest pregabalin as initial therapy. We substitute gabapentin when the use of pregabalin is limited by cost or regulatory requirements. These agents have both been effective in randomized trials [65-68]. If there is concern regarding a primary sleep disturbance, such as sleep apnea or restless leg syndrome, the patient should be referred to a sleep specialist.

Alpha-2 ligands (pregabalin and gabapentin) — Pregabalin and gabapentin are alpha-2/delta calcium channel modulators, also termed alpha-2 ligands. Pregabalin and gabapentin have similar effects on cellular calcium channels and may exert their analgesic effects by blocking the release of various neurotransmitters. The mechanism of action in fibromyalgia may be related to reduced brain gray matter volume within the posterior insula [69]. Cost and/or regulatory requirements sometimes complicate prescribing pregabalin; in these cases, we substitute gabapentin. The pharmacologic properties of these medications are discussed in detail elsewhere. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

Dosing

Pregabalin – We begin with a dose of 25 to 50 mg at bedtime before increasing by 25 to 50 mg every two to four weeks, either all in the evening or in two split doses, as tolerated. The recommended dose of pregabalin from clinical trials has been 300 to 450 mg daily [65,67]. Some patients may respond to lower doses (eg, 100 to 300 mg daily) and do not require further dose escalation.

Gabapentin – We begin with a dose of 100 mg at bedtime before titrating the dose upwards by 100 mg every few weeks as tolerated The recommended dose is 1200 to 2400 mg daily (usually in divided doses taken up to three times daily), but some patients may respond to lower doses [68].

Adverse effects – Potential adverse effects of pregabalin include CNS and respiratory depression, dizziness, blurred vision, peripheral edema, weight gain, and suicidal ideation. Gabapentin may cause similar adverse effects, although peripheral edema and weight gain are not reported as frequently.

Efficacy – The efficacy of these agents was best described in a meta-analysis of five placebo-controlled randomized trials (four with pregabalin and one with gabapentin) consisting of 2918 patients with fibromyalgia [66]. Compared with placebo, active therapy significantly reduced pain and improved sleep and quality of life, while improvements on depressed mood, anxiety, and fatigue were marginal.

Pregabalin – A systematic review found that pregabalin resulted in a major reduction in pain intensity over three to six months for only a small number of fibromyalgia patients, approximately 10 percent more than placebo, and that its efficacy was similar to that of milnacipran and duloxetine [70]. Studies of longer-term efficacy have demonstrated a sustained response in most patients who continue pregabalin for a period of 6 to 12 months, without changes in safety or tolerability [71,72].

Gabapentin – One trial of gabapentin randomly assigned patients to receive gabapentin (1200 to 2400 mg daily) or placebo for 12 weeks and found that a greater proportion of patients receiving gabapentin were responders (defined as at least a 30 percent decrease in the Brief Pain Inventory [BPI] score) than were those in the placebo group (51 versus 31 percent, respectively) [73]. However, based upon only this single trial, a systematic review concluded that "there is insufficient evidence to support or refute the suggestion that gabapentin reduces pain in fibromyalgia" [68].

EVALUATING RESPONSE TO INITIAL TREATMENT — Evaluating the treatment response for patients with fibromyalgia can be challenging for several reasons. Some patients have a rapid and significant improvement in symptoms. This may be more likely to occur in patients with mild or moderate pain and sleep disturbances, who often respond within days to low doses of tricyclics or alpha-2 ligands at bedtime. However, often significant improvement in fibromyalgia takes several months. Furthermore, the symptoms of fibromyalgia often fluctuate over time and may temporarily worsen as patients increase physical activity.

Patients who do respond – In patients with a meaningful clinical response to a medication, we generally keep patients on that medication indefinitely, if tolerated. However, sometimes patients wish to stop medication even when they do respond, as the improvement due to medications may be of questionable clinical significance [33,51,66].

Patients who do not respond – We consider a patient to be refractory to initial therapy if they have persistent or worsening symptoms despite an adequate trial of both nonpharmacologic management and at least one of the initial medications discussed above. That initial management trial should be of adequate duration, usually one to three months, unless adverse effects have occurred. Providers should assess changes in pain and progress in meeting functional goals. If patients report improved pain but are unable to accomplish their functional goals, this discrepancy should be explored to see if the medication is truly beneficial and if functional goals are relevant and realistic. By contrast, if patients are progressing in meeting functional goals but report the same level of pain, there may be beneficial effects of the medication that are underappreciated.

TREATMENT OF REFRACTORY SYMPTOMS

Clinical reassessment — Patients who are nonresponsive to initial management need to be clinically reevaluated. We review their response to both pharmacologic and nonpharmacologic aspects of fibromyalgia treatment. Providers should ask patients about their experience with the various treatment modalities including perceived treatment efficacy, acceptability, accessibility, and adverse effects, as well as other barriers to implementation or maintenance. This approach reaffirms the multimodal treatment approach and active patient participation that are required for effective fibromyalgia treatment.

Response to medications – It is important to understand how the initial pharmacotherapy has "failed" in order to move forward with switching or combining therapies. We review the following components:

Did they experience any benefit from the medication, or was it completely ineffective?

Were there rate-limiting adverse effects that prevented up-titration to therapeutic doses?

The two most common reasons that fibromyalgia patients cite for stopping medications or not adhering to medication recommendations are adverse medication events (reported by 40 percent of patients) and lack of medication efficacy (reported by 23 percent of patients) [74]. In a large study of insurance claims data, only 31 percent of patients with fibromyalgia initiated one of the medications listed in the American College of Rheumatology (ACR) guidelines; most did not receive the recommended doses and adherence to the recommended dose was suboptimal [75]. Failure to reach the recommended dose was especially common for patients using pregabalin, where 73 percent of patients were not receiving the optimal dose [76].

Experience with nonpharmacologic interventions – We also review patients' experience with the core nonpharmacologic interventions:

Physical activity and exercise – How have they attempted to improve their overall activity levels?

Cognitive (psychological therapy) – Have they had the opportunity to pursue cognitive (psychological) treatments?

Sleep hygiene – How has their sleep routine has changed? What are the barriers to improving their sleep?

Management of comorbid conditions – In addition, we ask patients about their experience and success with treatment of comorbid conditions that may affect fibromyalgia symptoms (eg, using continuous positive airway pressure [CPAP] for obstructive sleep apnea).

Evaluation for peripheral pain – Finally, it is important to recognize that patients with fibromyalgia may have or develop conditions that cause noncentralized, peripheral or nociceptive pain, which may add to their overall burden of symptoms. Therefore, patients who have ongoing pain should be reevaluated for alternative sources of pain depending on the type and location of their symptoms, such as peripheral neuropathy, tendonitis, bursitis, osteoarthritis, and inflammatory arthritis. Patients with nociceptive pain may require other agents depending on the cause of the pain (eg, physical therapy and nonsteroidal antiinflammatory medications for greater trochanteric pain syndrome). (See 'When to refer' below.)

Pharmacologic therapy for patients not responding to initial medications — Patients with refractory fibromyalgia symptoms may benefit from a trial of alternative pharmacotherapy or combination drug therapy.

Switching to an alternative pharmacologic therapy — If the patient has adverse effects to a single drug at low to moderate doses or if moderate to higher doses do not provide relief (primary treatment failure), it is reasonable to switch to another single medication. There is no strong evidence to guide the optimal way to switch medications. We select a different form of monotherapy based on patients' most prominent symptoms, any adverse events from prior medications, and the general class of medications, similar to the process of choosing the initial agent. As an example, for patients who do not tolerate or respond well to initial therapy with a tricyclic, we switch to a serotonin-norepinephrine reuptake inhibitor (SNRI), especially if they have prominent fatigue. If the patient had persistent sleep disturbance, an alpha-2 ligand would be a reasonable alternative. (See 'Choice of initial agent based on clinical presentation' above and 'Selective serotonin-norepinephrine reuptake inhibitors' above and 'Alpha-2 ligands (pregabalin and gabapentin)' above.)

When discontinuing moderate to high doses of fibromyalgia medications, the medications should be tapered over time (as opposed to abruptly discontinued) to avoid withdrawal-like symptoms. Withdrawal syndromes are most prominent with gabapentin and pregabalin, though are possible across all classes of medication. A detailed discussion of tapering tricyclics and SNRIs is provided elsewhere. (See "Discontinuing antidepressant medications in adults", section on 'Tricyclics' and "Discontinuing antidepressant medications in adults", section on 'SNRIs'.)

Using combination drug therapy — We suggest the use of combination drug therapy in patients unresponsive to one or more medications, based upon the symptoms that most affect the patient. Importantly, this assumes that the current regimen is tolerated well: if a drug is causing adverse effects, we do not recommend continuing this drug as a part of combination therapy. We combine drugs of different classes to take advantage of multiple mechanisms of action for reducing pain and to target different symptoms. A variety of combinations may be effective, and selection of specific agents depends upon patient tolerance, drug availability and cost, and the presence of comorbidities. Combining two drugs at lower than the usual fibromyalgia recommended dose of a single drug is commonly done.

We use the following combinations, although there have been insufficient data to support the routine use of any specific drug combination in fibromyalgia [77]. Examples of drug combinations that have been evaluated include the following:

A low dose of an SNRI (eg, duloxetine or milnacipran) or a selective serotonin reuptake inhibitor (SSRI; eg, fluoxetine) in the morning with a low dose of a tricyclic (eg, 10 to 20 mg of amitriptyline) in the evening: In a small randomized trial, there was significantly greater improvement in pain with the combination of agents compared with fluoxetine or amitriptyline alone or with placebo [78].

A low dose of an SNRI (eg, duloxetine or milnacipran) in the morning with a low dose of an alpha-2 ligand (eg, pregabalin) in the evening: An open-label randomized trial involving patients with fibromyalgia who had an inadequate response to treatment with pregabalin (300 or 450 mg daily) alone found that patients who began taking combination therapy with milnacipran (100 mg daily) experienced significantly greater pain reduction and global improvement compared with patients continuing pregabalin alone [79]. By contrast, another randomized trial found that the combination of pregabalin and milnacipran was similar to pregabalin alone, with some improvement in both groups but no significant difference between them [80].

In addition, the medication adherence for the combinations of pregabalin with either duloxetine, milnacipran, or venlafaxine was better than monotherapy with each of those four medications [81]. However, total health care costs were higher with the combination therapy.

Other medications

Selective serotonin reuptake inhibitors – SSRIs may be useful in the treatment of fibromyalgia, but data supporting their use are limited. We use SSRIs in patients who cannot take other first-line pharmacologic therapies (eg, cost of treatment). There have been small, clinical trials demonstrating possible efficacy of fluoxetine (20 to 80 mg daily), paroxetine (12.5 to 62.5 mg daily), and fluvoxamine in fibromyalgia [82].

Analgesic and antiinflammatory medications – Analgesic and antiinflammatory drugs have been used in the treatment of fibromyalgia, although there is little evidence of their efficacy [1,83]. Nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids should not be used in fibromyalgia unless there is evidence of peripheral pain. Several small randomized trials have failed to show that antiinflammatory medications are effective forms of treatment; therapeutic doses of naproxen and ibuprofen were each found to be no better than placebo in these trials, which generally also permitted the use of acetaminophen as needed [].

Tramadol is a weak opioid with dual mechanisms of action: it is a mu opioid receptor agonist and also inhibits the reuptake of serotonin and norepinephrine, which may contribute to its analgesic effect in chronic pain. There is limited evidence suggesting benefit of tramadol and acetaminophen for fibromyalgia [84-86]. However, we limit tramadol therapy to the shortest time possible due to concern regarding the long-term potential for abuse [85].

Avoidance of opiates – We do not use opioids other than tramadol for treatment of fibromyalgia due to risk of harm and lack of evidence of benefit. If patients with fibromyalgia are taking opioids on a long-term basis for other conditions, we prefer that a pain specialist be involved to assist with management.

A number of reports suggest that opioids may adversely affect patients with fibromyalgia [87,88]. This may be related to interference with the benefits of psychological and multidimensional therapy in fibromyalgia [89], a higher frequency of sleep disturbances [90], or other mechanisms. Similarly, a 2015 systematic review of the effectiveness and risks of long-term opioid therapy for chronic pain found insufficient evidence to determine the effectiveness of such therapy, but it did find evidence of a dose-dependent risk for a range of harms, such as overdose, opioid abuse, fractures, myocardial infarction, and sexual dysfunction [91]. A 2014 position paper of the American Academy of Neurology concluded that the risks from chronic opioid therapy for some chronic conditions, including fibromyalgia, are likely to outweigh the benefits of these medications [92].

Low-dose naltrexone – Low-dose naltrexone (LDN) refers to a dose of roughly 5 mg. It is thought to reduce chronic pain through enhancement of the endogenous opioid system and antagonism of non-opioid immune receptors (TLR-4), with consequent modulation of central nervous system (CNS) microglial cells [93].

We do not advise LDN be used as first-line therapy. However, it may remain an option for second- or third-line therapy for patients who are interested given that it is non-immunosuppressive, generally safe and well tolerated, and cost effective. Rare reported adverse effects include vivid dreams and gastrointestinal distress. LDN should not be prescribed to anyone on opioids (including tramadol). While naltrexone itself is inexpensive, pharmacies usually dispense 50 mg tablets; thus, LDN may require a compounding pharmacy.

Evidence to support the use of LDN is mixed. One small, double-blind study that randomized 31 females with fibromyalgia to LDN or placebo found that pain was reduced more for those taking LDN compared with placebo (29 versus 18 percent) [94]. However, two subsequent, larger double-blind trials comparing LDN with placebo failed to identify a meaningful difference in pain relief [95,96].

Cannabinoids – There has been low-quality evidence that cannabinoids lead to short-term improvements in pain for patients with fibromyalgia, as well as evidence for improved sleep [97]. Cannabinoids may be less effective and have more adverse effects in patients with higher fibromyalgia severity, although this relationship may be influenced by how patients with severe fibromyalgia substitute cannabis for more medication classes (eg, opioids and benzodiazepines) [98]. More information on the medical use of cannabinoids is described elsewhere. (See "Medical use of cannabis and cannabinoids in adults".)

Nonpharmacologic therapies — Many other types of nonpharmacologic therapies have been suggested for the treatment of fibromyalgia [99]. As examples, music, relaxation, hot bath, and local heat have been endorsed as possible adjunctive treatments by an international, multidisciplinary Delphi consensus of experts [10]. The evidence to support these therapies is generally limited. More detail on several nonpharmacologic strategies is provided below.

Nutrition and diet — There are no uniform dietary guidelines for fibromyalgia, but body mass index (BMI) is correlated with development of fibromyalgia and the severity of symptoms [100]. As such, there is an evolving interest in exploring the impact of dietary changes and weight loss on fibromyalgia symptoms.

Caloric restriction and weight loss may improve fibromyalgia symptoms. An observational study placed 123 obese individuals with chronic pain on a very low-calorie diet (800 kcal/day) for approximately 12 weeks [101]. They found that weight loss correlated with improvement in both weightbearing and non-weightbearing pains (eg, jaw), overall symptom severity, and depression; improvement was greater among those who lost more than 10 percent of their body weight compared with those who did not. A follow-up observational study of the same diet in patients with obesity and fibromyalgia reported that most patients had improvement in symptoms by the third week, despite not losing weight [102]. There is also evidence that substantial weight loss after bariatric surgery decreases central pain sensitization [103].

A systematic review of different diets in fibromyalgia found evidence that some diets, including plant–based diets, seemed to improve symptoms [104].

Injection therapies and other physical measures — Many types of injection therapies and physical measures have been suggested for the treatment of fibromyalgia, including acupuncture, trigger or tender point injections, dry needling, massage therapy, chiropractic, and electromyography (EMG) biofeedback. The proposed mechanism for many of these therapies is modulating local pain signals and therefore decreasing central pain sensitization [2,3].

Acupuncture – Systematic reviews and a number of clinical trials have demonstrated that traditional acupuncture or electroacupuncture have been effective in fibromyalgia [105,106]. The mechanism for pain improvement may be related to changes in insular functional connectivity and pain-related neurotransmitters [107].

Trigger/tender point injections – In a small study, treating active trigger point injections improved localized pain, fibromyalgia symptoms, and analgesic consumption compared with "placebo-like" injections [107]. Trigger point injections are usually performed by physical medicine and rehabilitation or pain specialists and rheumatologists [108].

Massage and manual therapy – There has been some evidence that massage and various forms of manual therapy have been helpful in fibromyalgia [109,110].

Other therapies – There have been a few small studies suggesting that EMG-biofeedback and chiropractic therapy may be helpful, but the quality of these studies has been poor [111].

Neuromodulation — Several forms of neuromodulation have been tested in patients with fibromyalgia, in both peripheral (eg, transcutaneous electrical nerve stimulation [TENS]) and central forms (eg, transcranial magnetic stimulation [TMS]). The proposed mechanism for neuromodulation is reducing central excitability and activation of central inhibition pathways.

Peripheral nerve stimulation – Trials of TENS have had mixed results, possibly due to study design issues [112,113]. In a randomized trial, more patients with fibromyalgia receiving four weeks of TENS improved movement-evoked pain, resting pain, and fatigue compared with patients receiving placebo TENS and no TENS [112]. A randomized trial of a TENS designed for extended home wear did not achieve the primary endpoint but did show modest improvement in pain and function in the active- compared with sham-treated patients [113]. The authors concluded that TENS can decrease pain in fibromyalgia when applied with high intensity or over multiple sessions. TENS is approved by the US Food and Drug Administration (FDA) for fibromyalgia patients.

Central neuromodulation – Noninvasive brain stimulation includes transcranial direct current stimulation (tDCS) and repetitive TMS (rTMS). Central neuromodulation has been investigated in pain research centers for the treatment of treatment refractory chronic pain and depression. Systematic reviews and meta-analysis have concluded that these techniques result in decreased pain perception and reduced fatigue and depression in patients with fibromyalgia [114,115]. Most studies have found that specific brain regions and stimulus intensity are important in pain reduction [116,117].

There have been a few small, uncontrolled reports of occipital and vagus nerve stimulation as well as vestibulocortical stimulation in patients with fibromyalgia, but these should be considered experimental and confined to experienced pain centers [118,119].

WHEN TO REFER — The long-term management of fibromyalgia and the role of specialty care is controversial. Most treatment guidelines recommend that the initial management of patients with fibromyalgia can and should be carried out in the primary care setting [3,120] and that rheumatologists be consulted primarily for diagnostic uncertainty.

Patients with certain comorbid conditions may require subspecialty referral as part of their initial treatment for fibromyalgia (see 'Addressing comorbidities' above). Later in the course of treatment of fibromyalgia, patients may also need a subspeciality referral for various reasons, including the following:

Difficulty increasing physical activity despite physical therapy referral – We refer patients to physiatry when assistance is needed in achieving a sufficient level of low-impact aerobic exercise or physical functioning despite a trial of a supervised physical therapy program, or for treatment of regional myofascial pain (eg, trigger point injections and other techniques).

Diagnostic uncertainty and/or peripheral pain – When a provider suspects a peripheral cause of pain in a patient with fibromyalgia, referral to a subspecialist should be considered. We refer patients to rheumatology when there is diagnostic uncertainty about fibromyalgia and possible systemic, inflammatory disease (eg, a symmetric small joint polyarticular arthritis and/or other red, swollen joints).

Patients who have persistent, localized pain should also be evaluated for peripheral pain sources such as peripheral neuropathy, tendonitis, bursitis, and myofascial pain. Such patients may benefit from antiinflammatory medications, local injections of anesthetic agents, and/or referral to a rheumatologist or physiatrist.

Patients not responding to initial therapy – In patients not responsive to initial therapy, an individualized, multidisciplinary treatment program should be considered. The goal of these programs is to provide a structured, multimodality treatment program under one roof over a relatively brief timeframe. Such programs may involve an array of providers including physiatrists, physical therapists, mental health professionals, pain specialists, and/or rheumatologists. Programs may also be based in various locations, such as centers for pain or physical medicine and rehabilitation. This type of program may be especially helpful in patients who are resistant to drug therapy, take chronic opioids, and/or have complicated psychosocial issues, including disability proceedings. Optimal efficacy from any multicomponent treatment program requires tailoring the specific therapy to individual needs [121].

A meta-analysis of multicomponent treatment programs (including at least one educational or other psychological therapy and at least one exercise therapy) found improvements for patients in the program compared with patients receiving various forms of placebo treatment (eg, no treatment, usual treatment, or a lower intensity intervention) [122]. Improvements in physical fitness persisted at longer-term follow-up (median of seven months), but improvements in fibromyalgia symptoms, health-related quality of life, and self-efficacy for pain (belief in one’s ability to accomplish a task or cope with pain) did not persist. Multiple subsequent randomized trials of interdisciplinary management of fibromyalgia patients have also demonstrated significant improvement in multiple outcomes [123-126]. Multidisciplinary rehabilitation programs may also help reduce the use of opioids and other analgesics in patients taking these medications [127].

Prominent mood or sleep disturbances – Patients who develop symptoms suggestive of mental health and/or sleep disorders should be referred to a mental health professional or sleep specialist, respectively. (See 'Addressing comorbidities' above.)

PROGNOSIS — Most patients with fibromyalgia have chronic symptoms. Persistence of symptoms may vary by care setting, with studies of patients treated in primary care describing higher rates symptom resolution compared with patients treated in tertiary referral centers. Demographic and psychosocial factors also substantially impact the prognosis and outcome for patients with fibromyalgia.

Persistent symptoms – An observational study of 538 patients with fibromyalgia in a tertiary care setting found that pain, fatigue, sleep disturbances, anxiety, and depression were essentially unchanged over a period of approximately eight years [128]. Nonetheless, two-thirds of patients reported that they were working full-time and that fibromyalgia interfered only modestly with their lives. In another observational study of 1555 patients with fibromyalgia followed for up to 11 years by rheumatologists in the United States, there was little clinically meaningful change in mean symptom severity, with patients reporting generally continuing high levels of symptoms and distress [129]. There was a slight trend toward improvement, with approximately 25 percent of patients experiencing at least moderate improvement of pain over time.

In contrast with the patient population studied from tertiary referral centers, patients treated by primary care clinicians in the community have a much better prognosis. In one community survey of 141 fibromyalgia subjects, only 35 percent of those with chronic widespread pain at the initial assessment still had widespread pain two years later [130].

More severely symptomatic patients with fibromyalgia experience greater morbidity, more comorbidities, and increased cost of care [131].

Impact of demographic and psychosocial factors – Demographic and psychosocial factors have substantial impact on prognosis; depression, a history of abuse, catastrophizing, and excess somatic concern have been the most important factors in adverse outcomes for patients with fibromyalgia [132-134]. Female sex, low socioeconomic status, and being unemployed are also associated with worse outcomes [135,136]. This underscores the importance of addressing mental health and social determinants of health as part of a comprehensive approach to therapy.

Disability – Studies in multiple countries describe a higher rate of disability in patients with fibromyalgia compared with the general population. Several Canadian studies have reported that 10 to 30 percent of patients with fibromyalgia report being disabled [137,138]. In a North American study of persons with fibromyalgia under 65 years of age, almost 10-fold more individuals reported that they were unable to work because of health compared with those without fibromyalgia (55.8 versus 5.8 percent) [139].

Mortality and suicidality – There has been an increased risk of suicide among patients with fibromyalgia, as shown in a number of reports [140,141]. In a study of 1361 Danish patients with fibromyalgia referred over a 16-year period, the standardized mortality ratio (SMR) for an increased risk of death from suicide was significantly increased, although the absolute number of suicides was low (SMR 10.5, 95% CI 4.5-20.7, eight suicides) [140].

Although most studies did not reveal an increased mortality rate from other causes, a systematic review found a 27 percent increased all-cause mortality and increased risk of mortality from infections and suicide (SMR 1.66, 95% CI 1.15-2.38; and SMR 3.37, 95% CI 1.52-7.50, respectively) [142].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fibromyalgia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient education: Fibromyalgia (The Basics)" and "Patient education: Good sleep hygiene (The Basics)" and "Patient education: Daytime sleepiness (The Basics)")

Beyond the Basics topics (see "Patient education: Fibromyalgia (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Overview of the clinical approach – Treatment is initiated with nonpharmacologic measures and also includes pharmacotherapy for most patients. Patients generally respond best to a multidisciplinary, individualized treatment program. (See 'Overview of the clinical approach' above.)

Explaining fibromyalgia to patients – Providers must intentionally build a common understanding of the patient's symptoms and illness experience, causes of those symptoms, and realistic goals of care. It is important to listen to patients with fibromyalgia and validate the pain and other symptoms that they experience. (See 'Explaining fibromyalgia to patients' above.)

Initial treatment – Treatment should be individualized and multidisciplinary, involving both nonpharmacologic measures and, in most patients, drug therapy.

Core nonpharmacologic interventions – Core nonpharmacologic interventions include patient education, cognitive (psychological) therapy, and increasing physical activity and exercise. Nonpharmacologic interventions may be sufficient for initial therapy, especially for patients who have a shorter duration of symptoms, do not have coexisting mood or sleep disorders, and/or prefer not to use or have contraindications to available pharmacotherapy. (See 'Core nonpharmacologic interventions' above.)

-Patient education – Components of patient education should include an explanation of fibromyalgia and several nonpharmacologic strategies (eg, sleep hygiene, nutrition) that can improve symptoms. (See 'Patient education' above.)

-Increasing physical activity and exercise – For most patients with fibromyalgia, we suggest prescribing regular exercise (Grade 2C). The best evidence supports aerobic exercise. Strength and flexibility training and structured movement therapies (eg, tai chi) are also appropriate. The type and intensity of the program should be individualized and should be based upon patient preference and the presence of any other comorbidities. (See 'Increasing physical activity and exercise' above.)

-Cognitive (psychological) therapy – For all patients with fibromyalgia, we suggest using cognitive or psychologic interventions, such as cognitive-behavioral therapy (CBT), mindfulness-based stress reduction (MBSR), and/or meditation and relaxation (Grade 2C). The specific interventions should be individualized based upon patient preference and available resources. (See 'Cognitive (psychological) therapy' above.)

Initial pharmacologic therapy – For patients with moderate to severe symptoms and/or with an inadequate response to nonpharmacologic interventions, we tailor the choice of initial pharmacotherapy based on prominent symptoms (eg, pain, fatigue, and sleep disturbance), and the presence of comorbid mood disturbances or peripheral pain. In general, drugs should be started at low doses, built up slowly over time, and maintained at the lowest dose possible that produces therapeutic benefit. (See 'When to start pharmacologic therapy' above and 'Choice of initial agent based on clinical presentation' above.)

-Diffuse widespread pain without comorbid major mood or sleep disturbances (most common) – In such patients, we suggest initiating therapy with a low dose of amitriptyline near bedtime (Grade 2C). In patients with mild to moderate symptoms, cyclobenzaprine is an alternative to amitriptyline. (See 'Diffuse, widespread pain without major mood or sleep disturbances (most common fibromyalgia presentation)' above.)

-Severe fatigue and/or depression – In patients with severe fatigue and/or depression, we suggest using duloxetine as initial therapy (Grade 2C). Milnacipran is an alternative to duloxetine in patients with severe fatigue, although it is not as widely available. (See 'Patients with severe fatigue and/or depression' above.)

-Prominent sleep disturbance – In patients with prominent sleep disturbance, we suggest pregabalin as initial therapy (Grade 2C). We substitute gabapentin when the use of pregabalin is limited by cost or regulatory requirements. (See 'Prominent sleep disturbance' above.)

Evaluating response to initial treatment – We consider a patient to be refractory to initial therapy if they have persistent or worsening symptoms despite an adequate trial of both nonpharmacologic management and at least one medication. That initial management trial should be of adequate duration, usually one to three months, unless adverse effects have occurred. (See 'Evaluating response to initial treatment' above.)

Treatment of refractory symptoms

Switching to an alternative pharmacologic therapy – If the patient has adverse effects to a single drug at low to moderate doses or if moderate to higher doses do not provide relief (primary treatment failure), we switch to a single medication from a different class. When discontinuing moderate to high doses of fibromyalgia medications, the medications should be tapered over time (as opposed to abruptly discontinued) to avoid withdrawal-like symptoms. (See 'Switching to an alternative pharmacologic therapy' above.)

Using combination drug therapy – In patients unresponsive to monotherapy, we often use combination drug therapy, rather than continuing monotherapy alone. We combine drugs of different classes to take advantage of multiple mechanisms of action for reducing pain and to target different symptoms. (See 'Using combination drug therapy' above.)

When to refer – The initial management of patients with fibromyalgia is most often in the primary care setting. Rheumatologists are consulted primarily for diagnostic uncertainty. Any patient with major mood disturbances should be referred to a mental health professional and those with a primary sleep disturbance referred to a sleep specialist. Physical medicine and rehabilitation and pain specialists are often appropriate referrals depending on the patient's symptoms and comorbid conditions. Multidisciplinary treatment programs are ideal for patients with fibromyalgia who have not responded well to initial treatment. (See 'When to refer' above.)

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Topic 5627 Version 42.0

References

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