INTRODUCTION — Fibromyalgia is a chronic widespread musculoskeletal pain disorder that is often accompanied by fatigue and disrupted sleep, cognitive disturbance, and multiple somatic and psychiatric symptoms. Management is directed at reducing the major symptoms of this disorder and employs a variety of both nonpharmacologic and pharmacologic therapies, which are often provided in combination in a stepwise approach (table 1). Fibromyalgia can be challenging to treat; patients generally respond best to a multidisciplinary, individualized treatment program that incorporates both clinician and non-clinician providers, including physical medicine, rehabilitation, and mental health specialists [1,2].
The initial steps in the treatment of fibromyalgia in adults will be reviewed here. The treatment of fibromyalgia in adults who do not respond to initial therapies; the pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of fibromyalgia; and fibromyalgia in children and adolescents are discussed separately. (See "Treatment of fibromyalgia in adults not responsive to initial therapies" and "Pathogenesis of fibromyalgia" and "Clinical manifestations and diagnosis of fibromyalgia in adults" and "Differential diagnosis of fibromyalgia" and "Fibromyalgia in children and adolescents: Clinical manifestations and diagnosis".)
GOALS AND OVERVIEW — Treatment of fibromyalgia is directed at reducing the major symptoms of this disorder, including chronic widespread pain, fatigue, insomnia, and cognitive dysfunction. Treatment should be individualized and multidisciplinary, involving both nonpharmacologic and pharmacologic measures. Some patients, particularly among those presenting initially to primary care clinicians and without major mood or sleep disturbances, may respond adequately to nonpharmacologic measures alone. In most patients, medications will be necessary for symptom control, along with nonpharmacologic treatment.
PRETREATMENT EVALUATION — We individualize choices among the available nonpharmacologic modalities and medications based upon patient preference, symptoms, comorbidities, and our clinical experience with particular agents. Information that should be elicited to facilitate optimal treatment decisions includes [1,3]:
●The relative prominence of particular symptoms and disorders, including fatigue, nonrestorative sleep, insomnia, and depression.
●Past experience, tolerance, and potential adverse effects of specific drugs in a given patient.
●Patient cost, and insurance and regulatory restrictions affecting prescription choice.
●Presence of comorbidities, including sleep disorders, psychiatric conditions, other musculoskeletal pain disorders, and cardiovascular disease; and treatments for concurrent disorders. (See 'Addressing comorbidities' below.)
●Level of physical fitness and ability to exercise.
INITIAL TREATMENT — Treatment of fibromyalgia is directed at reducing the major symptoms of this disorder, including chronic widespread pain, fatigue, insomnia and nonrestorative sleep, and cognitive dysfunction. Treatment should be individualized and multidisciplinary, involving both nonpharmacologic measures and, in most patients, drug therapy. Some patients, particularly among those presenting initially to primary care clinicians and those who do not present with either a coexisting mood or sleep disorder, may respond adequately to nonpharmacologic measures alone. The initial approach to most patients with fibromyalgia includes:
●Patient education, including cognitive behavioral therapy (CBT) (see 'Patient education' below)
●Addressing comorbidities (see 'Addressing comorbidities' below)
●An exercise program (see 'Exercise' below)
●Drug monotherapy (see 'Tricyclic antidepressants and related drugs' below)
The inclusion of patient education and other nonpharmacologic therapies in initial management is supported by a number of systematic reviews and meta-analyses, which have found that cardiovascular exercise, patient education, and multidisciplinary interventions, as well as CBT and other psychological therapies, may provide benefit in patients with fibromyalgia, particularly short-term improvements in pain and health-related quality of life [1,3-8]. These approaches are also consistent with the 2017 revised European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) guidelines [9]. (See 'Patient education' below and 'Exercise' below.)
The issue of who should assume primary responsibility for the treatment of patients with fibromyalgia has been controversial. Most treatment guidelines recommend that the initial management of patients with fibromyalgia can and should be carried out in the primary care setting [5,9-11]. Ideally, treatment should include an integrated, multidisciplinary nonpharmacologic and pharmacologic approach, but there have been relatively few trials that have formally evaluated such a combined approach to therapy. An integrated, multidisciplinary team management program, similar to that often used in diabetes, is ideal for fibromyalgia treatment [2] (see "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Multidisciplinary treatment programs'). However, primary care providers seldom have the time, expertise, or resources to provide integrated, team management. Patients with fibromyalgia often express more health care frustration than those with other chronic medical disorders, particularly in regard to not feeling believed or listened to. Therefore, innovative approaches to such team health care should be accessed, and it is appropriate to consider new models of care for chronic illnesses such as fibromyalgia [12].
Rheumatology referral is recommended if there is diagnostic uncertainty and in patients who have not responded to initial therapy. One study in a large urban and academic center in Canada found that one-third of primary care patients with fibromyalgia were referred to rheumatologists, but the average wait time to see the rheumatologist was 184 days [13].
Patient education — Patient education includes teaching and counseling regarding the disease, including uncertainty regarding the pathogenesis; treatment approaches and the patient's role in management; good sleep hygiene and the adverse effects of poor sleep on pain; and the importance of treating comorbidities that may contribute to symptoms, including mood or sleep disorders, and musculoskeletal and other pain conditions. There is substantial evidence that being overweight or obese has an adverse effect on fibromyalgia symptoms and quality of life [14]. Therefore, weight reduction should be encouraged in significantly overweight patients. When possible, such education should also include family members. Most patients have had fibromyalgia for years before the diagnosis is finally made. They have often undergone multiple diagnostic evaluations and consulted with many different specialists. Some patients may feel rejected by the medical profession, while others may fear that a life-threatening illness will eventually be found. A Google search of 200 webpages on fibromyalgia found online health information generally poor despite the majority being sent from health care professionals [15]. Not-for-profit organizations provided the most complete and accurate information. Similarly, the majority of medical information found during a YouTube search of information on fibromyalgia was of poor quality [16].
●Key elements of patient education – Patient education should be individualized with respect to the priority given to each of its different aspects; it should include:
•Reassurance that fibromyalgia is a real illness – The patient should be reassured that fibromyalgia is a real illness and is not imagined or "in your head." The benign nature of the disorder should also be emphasized. As an example, patients should be told that this is not a deforming or physically deteriorating condition and that it is neither a life-threatening nor a cosmetic problem. The relationship of neurohormones to pain perception, fatigue, abnormal sleep, and mood disturbances should be discussed [17]; in our experience, this will help the patient to understand the rationale for therapy with medications such as tricyclic and other antidepressants and antiseizure medications. (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)
•Explain centralized pain – Patients will benefit from an explanation of fibromyalgia as the prototypic centralized pain disorder. Centralized pain, also termed nociplastic pain, includes any chronic pain disorder with a primary mode of action in the central nervous system [18,19]. Such a discussion promotes the notion that chronic pain is a disease in itself. It also provides the patient with a model that chronic pain may begin and persist without a peripheral cause and without structural or organ pathology. A biopsychological, rather than a biomedical, illness model should be discussed.
•Lack of evidence of persistent infection – Patients should be assured that there is no evidence that fibromyalgia is related to persistent infection, although infections may be precipitating or triggering factors. Some patients with fibromyalgia, particularly those who also meet the criteria for chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), may believe that their illness is caused by an undiagnosed infection. In our experience, patients generally have a better response to treatment when they understand that they are not harboring some infectious agent over which they have no control. (See "Pathogenesis of fibromyalgia".)
Symptoms of fibromyalgia and CFS often overlap. Diagnostic criteria for the classification of CFS are similar to those for fibromyalgia, and the majority of patients with CFS meet tender point criteria for fibromyalgia. Similarly, approximately 70 percent of patients with fibromyalgia meet the criteria for CFS [20]. (See "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome".)
There has been concern that fibromyalgia and CFS will increase as a result of the coronavirus disease 2019 (COVID-19) pandemic, especially in patients subject to greater social and medical isolation [21]. In a web-based survey of 616 post-COVID survivors, 30 percent met criteria for fibromyalgia six months after the initial infection [22].
•Stress and mood disorders – A review of the role of stress and mood disturbances in fibromyalgia will encourage the patient to learn simple relaxation techniques and to consider formal stress-reduction programs. This should also be discussed within a biopsychological illness model. Patients often worry that doctors think, "It is all in my head." Rather, patients must understand that chronic pain and depression share biologic and environmental features and that emotional stress may precipitate or aggravate fibromyalgia. Additionally, approximately 30 percent of patients with fibromyalgia have major depression at the time of diagnosis. In patients with fibromyalgia, the lifetime prevalence of depression is 74 percent, and that of an anxiety disorder is 60 percent [1]. Patients with mood disorders should be strongly encouraged to obtain treatment for these conditions, which may be provided by primary care clinicians or by experts in psychiatric care. (See "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Coexisting disorders' and "Pathogenesis of fibromyalgia".)
•Cognitive behavioral therapy – Education about maladaptive chronic illness behavior should be provided, either by the primary care provider or in conjunction with a more formal CBT program [23]. Patients with fibromyalgia often catastrophize, and catastrophizing adversely impacts pain and outcome. Self-efficacy should be a goal of treatment. CBT can be done individually or in group sessions. CBT or similar mind-body therapies such as mindfulness-based stress reduction could be considered as a component of the initial management of fibromyalgia in selected patients, particularly if it is readily available.
CBT was found to be the most cost-effective treatment for fibromyalgia, but its implementation in primary care would require widespread public access [24]. A short course of CBT was provided by telephone to individuals at high risk for developing chronic, widespread pain [25]. Compared with control subjects receiving usual care, those who got the telephone CBT had better quality of life, and the telephone-based CBT was very cost-effective. CBT also focuses on patient self-management, and there is evidence that self-management improves physical function and reduces pain in fibromyalgia [26]. (See "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Psychological therapies'.)
•Sleep disorders and sleep hygiene – Patients should be educated regarding good sleep hygiene and the potential benefit of correcting poor sleep habits and of recognizing and obtaining treatment for sleep disorders that may contribute to pain and other symptoms of fibromyalgia. The more common of the sleep disorders that may require intervention include obstructive sleep apnea and restless legs syndrome [1,3]. (See "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Coexisting disorders' and "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults" and "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)
Factors considered part of good sleep hygiene should also be reviewed and addressed, such as sleeping in a dark, quiet, and cool environment; avoidance of stimulants that may affect sleep (such as blue light from television, computers, and cell phones; caffeine; and alcohol), avoiding or managing factors that may adversely affect sleep quality (eg, disruptive pets in bed, bed partner with restless leg syndrome, habits or disease causing frequent nighttime awakenings for urination); and avoidance of screen use soon before bedtime. (See "Evaluation and diagnosis of insomnia in adults".)
•Role of exercise – We counsel patients regarding the importance of exercise for reconditioning and for functional capacity and caution that a temporary increase in myalgias may occur upon initiating an exercise program. A belief held by some patients is that blood flow to muscle and skin may be sluggish in fibromyalgia. In our experience, a discussion of the role of muscle "spasm" and deficient muscle blood flow is useful when prescribing exercise and physical therapy.
We stress the importance of movement and activity and discuss the evidence that being sedentary is a major risk factor for fibromyalgia.
•Prognosis – Patients need to appreciate that their symptoms will wax and wane but that some pain and fatigue generally persist. Despite the presence of these chronic symptoms, it is reassuring to emphasize that the great majority of patients live normal and active lives.
These educational elements must be tailored to the individual (see 'Pretreatment evaluation' above). For example, patients who have been reluctant to exercise will require more information about the importance of activity and exercise programs, while those who tend to catastrophize may require more formal cognitive behavior restructuring.
Although many primary health care providers do not have the time or expertise to provide all of the patient education noted above, web-based education and cognitive training programs have been developed and well received by patients [27]. (See 'Information for patients' below.)
●Effectiveness of patient education – A range of evidence indicates that patient education, including making or confirming the diagnosis, and education regarding the nature of the disorder and the rationale for the treatment approach have a beneficial effect [1,3,5,9,27]. Individualized shared decision making is also supported by expert guidelines [9].
Several studies have found that the recognition and diagnosis of fibromyalgia leads to a decrease in resource use, including subsequent testing and overall health care costs, despite concerns that diagnostic labels such as fibromyalgia would promote illness behavior and drive up health care costs. (See "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Benefits of establishing the diagnosis'.)
Evidence of benefit from further education is illustrated by:
•A 2019 systematic review found that patient education significantly reduced pain intensity and anxiety, as well as catastrophizing, and concluded that it should be considered the first step in self-management of fibromyalgia [28].
•A 2004 systematic review of treatment of fibromyalgia assessed the effectiveness of educational interventions compared with controls either waiting for care or receiving training in gentle stretching [3]. The studies reviewed were typically unblinded. Small group sessions, printed materials, lectures, and demonstrations were used to inform patients of the nature of fibromyalgia. Numbers of sessions ranged from 6 to 17. Those receiving the educational intervention had significantly more improvement than the controls in one or more of several outcomes used, including pain, sleep, fatigue, self-efficacy, quality of life, and the six-minute walk, and beneficial effects lasted from 3 to 12 months after the sessions ended.
•A single intensive educational intervention was also beneficial, as in a study in which patients received education from a multidisciplinary team over 1.5 days [29]. One month later, there was significantly less pain, as well as more improvement in self-reported function, fatigue, stiffness, anxiety, and depressed mood, in those who received the educational intervention.
•Trials demonstrating the benefit of multidisciplinary nonpharmacologic treatment programs have frequently included a significant patient education component [30,31]. Additionally, education focusing on self-management, combined with exercise, enhances the benefits of exercise in fibromyalgia [32]. (See 'Exercise' below.)
Addressing comorbidities — Comorbidities, including sleep and mood disturbances, headaches, and irritable bowel syndrome, should be explained as interrelated components of fibromyalgia and likely to respond to the overall treatment plan. Nevertheless, fibromyalgia patients must be screened for specific comorbidities that may adversely affect disease severity and the response to treatment if they are not managed adequately; these conditions should be identified and treated, if present, and include sleep and psychiatric disorders, as well as musculoskeletal and other pain conditions:
●Sleep disturbances and disorders – Clinical assessment should include screening for the presence of sleep disorders, including obstructive sleep apnea and restless legs syndrome, and other factors that may interfere with good sleep. These conditions may interfere with therapy and require evaluation and management distinct from treatments for fibromyalgia per se. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults" and "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Additional evaluation' and "Evaluation and diagnosis of insomnia in adults" and "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Consultation and referral'.)
Factors considered part of good sleep hygiene should also be reviewed and addressed. (See 'Patient education' above and "Cognitive behavioral therapy for insomnia in adults", section on 'Sleep hygiene' and "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Additional evaluation' and "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Consultation and referral'.)
●Psychiatric symptoms and disorders – Assessment of psychiatric symptoms to determine if a disorder, such as depression, that may adversely affect mood, sleep, and pain symptoms and sleep quality is also present and requires treatment. This may also affect choice of drug or other therapy for fibromyalgia. (See "Screening for depression in adults" and "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Additional evaluation' and "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Consultation and referral'.)
●Other painful conditions – Evaluation for the presence of other comorbidities that may cause musculoskeletal or other pain, such as a systemic autoimmune rheumatic disease (eg, active rheumatoid arthritis) or a mechanical or regional musculoskeletal disorder (eg, osteoarthritis, shoulder pain), and that may require treatment to reduce concurrent nociceptive (ie, noxious, rather than centralized pain) and may worsen pain symptoms directly or indirectly. (See "Overview of chronic widespread (centralized) pain in the rheumatic diseases" and "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Treating peripheral pain'.)
Exercise — We recommend cardiovascular fitness training, usually with low-impact aerobic exercise, for patients with fibromyalgia. This approach is supported by data from individual randomized trials and systematic reviews [4,6-8]. Exercise can be of significant benefit for pain and function, and may be of benefit for sleep. However, in practice, it can be difficult for fibromyalgia patients to start and maintain a structured cardiovascular exercise program because patients generally perceive that their pain and fatigue worsen as they begin to exercise. Thus, it is important to instruct patients in the principles and methods of gradual incremental cardiovascular fitness programs. Even modest increases in daily physical activity may benefit patient-assessed physical function [33].
●Choice of exercise program – The specific cardiovascular fitness program should be individualized based upon patient preference and physical status. Before recommending a particular program, it is useful to assess the patient's current level of physical activity, exercise tolerance, and fitness; their preferred aerobic exercise activities (eg, land- versus water-based exercise); and preferences or interest in self-directed versus therapist-directed stretching and strengthening exercise and in techniques such as yoga and tai chi.
Low-impact aerobic activities such as fast walking, biking, swimming, or water aerobics (especially in warm water) are most successful among the interventions that have been studied and in our experience [4,6-8]. The type and intensity of the program should be individualized and should be based upon patient preference and the presence of any other cardiovascular, pulmonary, or musculoskeletal comorbidities. Physical therapists or exercise physiologists familiar with fibromyalgia can provide helpful instruction. Some patients need to start with a low level and shorter duration per exercise session and to very gradually increase the intensity and frequency of exercise as tolerated over a number of weeks to months.
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. However, even with gradual increases in exercise, some patients may not achieve this goal, and patients should be encouraged to continue exercising regularly. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease", section on 'The exercise prescription'.)
Additional forms of exercise that have shown some benefit in fibromyalgia but that are not primarily directed at developing aerobic fitness include tai chi and yoga. Randomized trial data have shown tai chi to result in similar or greater symptomatic improvement compared with aerobic exercise and better overall patient attendance to tai chi sessions [34]; these data support the view that tai chi could be considered as an initial treatment approach in fibromyalgia. (See "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Tai chi' and "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Yoga'.)
●Efficacy of exercise – A 2017 systematic review found that exercise improves health-related quality of life and low-quality evidence that aerobic exercise decreases pain and improves physical function [35]. Aerobic exercise was well tolerated [35]. The 2017 revised EULAR report found that the only "strong" therapy recommendation for fibromyalgia management was exercise [9].
Strength training and flexibility exercises have not been extensively studied; however, there is evidence of benefit from strength training in some small trials that used several different types of resistance training programs [4]. In one trial, a muscle strength training program reduced pain severity with comparable results to those of an aerobic exercise program [36]. Strength training also improved exhaustion in fibromyalgia subjects [37]. A systematic review found that water exercises have been effective in fibromyalgia [6], and a randomized trial found that swimming lessened pain and improved function in patients with fibromyalgia [38].
A six-month exercise training program in women with fibromyalgia resulted in improvements in a number of key health domains that were maintained over 30 months [39]. Exercise improves both depression and anxiety in fibromyalgia patients [40,41].
Adherence to exercise programs has been generally fair or poor unless there is persistent health care supervision and coaching [1,3]. Walking and water exercise prescriptions result in better long-term adherence [42].
The more intense the level of physical activity and a lesser amount of sedentary time correlate with better scores for pain and improved quality of life in women with fibromyalgia [43].
Mixed exercise programs that utilize a variety of techniques, including aerobic and strength training, may be better tolerated, although there are insufficient studies to demonstrate superior efficacy over any single exercise modality [44].
Home web-based exercise programs have been developed for fibromyalgia patients with good preliminary results [45].
Tricyclic antidepressants and related drugs — We take a stepwise approach to drug therapy (table 1). In most patients we suggest initiating therapy with a low dose of a tricyclic medication (eg, amitriptyline 10 mg) at nighttime, because these drugs are often effective, widely available, and far less costly for most patients than some of the newer agents. The dose may be limited by adverse side effects, especially in older adults. In patients with mild to moderate symptoms, the bedtime use of cyclobenzaprine is an alternative to amitriptyline. 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. In general, drugs should be started at low doses and should be built up slowly.
In patients with particularly severe fatigue or depression, a serotonin-norepinephrine reuptake inhibitor (SNRI) is a reasonable alternative to a tricyclic for initial therapy. (See 'Serotonin-norepinephrine reuptake inhibitors' below.)
In patients with more severe sleep disturbance, a reasonable alternative for initial therapy is one of the alpha-2/delta (α2δ) calcium channel modulators, also termed alpha2-ligands, including the anticonvulsants pregabalin and gabapentin. (See 'Anticonvulsants (alpha2-ligands)' below.)
We take the following approach to use of amitriptyline or related agents:
●Amitriptyline and related tricyclic antidepressants – Regardless of the agent chosen, patients with fibromyalgia should be started on very low doses; a typical starting dose of amitriptyline is 5 to 10 mg one to three hours before bedtime. The lower dose is appropriate in 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 many patients, and we do not exceed a dose of 75 mg in most patients. Another related tricyclic medication, cyclobenzaprine, is also effective in patients with fibromyalgia, but it is not used to treat depression (see below).
In patients who respond to medication, the lowest dose that achieves a meaningful response is usually continued for at least 12 months. Some patients may stay on that medication indefinitely whereas others can be weaned off the drug.
Individual randomized trials have demonstrated that clinically important improvement occurs in 25 to 45 percent of patients treated with these medications, compared with 0 to 20 percent of those treated with placebo [46-51]. 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 tricyclic drugs may decrease over time in some patients [49,52]. Most trials using tricyclic antidepressants in fibromyalgia have been less than three months in duration.
The doses of amitriptyline studied have been 25 to 50 mg, usually given as a single bedtime dose. These doses are usually lower than those required to treat depression. Nevertheless, even at low doses, dry mouth, constipation, fluid retention, weight gain, grogginess, and difficulty concentrating are common. Such side effects and possible cardiotoxicity limit use in older patients.
Desipramine is a tricyclic antidepressant that has been less well studied for fibromyalgia but that remains a possible alternative because it generally has fewer anticholinergic side effects.
The comparative efficacy and side effects of amitriptyline and the other available agents that are also used as antidepressants are illustrated by the following:
•A 2011 systematic review and meta-analysis provided an indirect comparison that suggested greater efficacy of amitriptyline compared with duloxetine and milnacipran in reducing pain, sleep disturbance, and fatigue, without differences in acceptability [53]. The strength of the conclusions was limited, to some degree, by the lower methodologic quality of the amitriptyline trials.
•A 2009 meta-analysis comparing antidepressants for the treatment of fibromyalgia included 18 randomized trials of a variety of agents, finding evidence for efficacy of antidepressants for pain relief, fatigue, depressed mood, sleep disturbance, and improvement in health-related quality of life [54]. The effect sizes for tricyclic antidepressants were larger than those for selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine) and for SNRIs (eg, duloxetine or milnacipran). However, the comparisons were largely indirect, and authors of the meta-analysis concluded that the data did not allow for "a definitive conclusion regarding the superiority of one class of antidepressants over another." This meta-analysis did not include two additional placebo-controlled randomized trials also suggesting benefit with use of the SNRI milnacipran, which were published subsequently [55,56]. (See 'Milnacipran' below.)
•A 2015 review of systematic reviews and meta-analyses of amitriptyline and other agents also supported the view that low doses of amitriptyline at bedtime should be first-line therapy in the treatment of fibromyalgia [57].
●Cyclobenzaprine as alternative initial drug – In patients with mild to moderate symptoms, cyclobenzaprine is an alternative to amitriptyline. The medications have a similar tricyclic structure and presumed mode of action in fibromyalgia, although cyclobenzaprine is thought to have minimal antidepressant effect [48,58].
We usually start with doses of 5 to 10 mg near bedtime and increase as tolerated to higher doses (30 to 40 mg daily) as required. In patients who find an initial dose of 10 mg too sedating, we reduce the dose to 5 mg before bedtime.
The efficacy of cyclobenzaprine is illustrated by the following:
•A 2004 meta-analysis of five randomized trials included 312 patients [49]. Self-reported improvement (measured in three studies) was more likely in subjects receiving cyclobenzaprine than placebo (odds ratio [OR] 3.0, 95% CI 1.6-5.6); the absolute difference in the rate of improvement was 21 percent, suggesting that approximately five patients would need to be treated with cyclobenzaprine for one to improve. The degree of benefit relative to placebo was similar to that observed with amitriptyline in trials comparing the latter drug with placebo [50,51]. Pain decreased more in those who received cyclobenzaprine than placebo for four weeks, but the change in pain was not significantly different in active or placebo groups after 8 or 12 weeks. Changes in pain and in the number of tender points did not differ between the groups at any time.
•A randomized eight-week trial performed subsequent to the meta-analysis above and involving 36 patients found that use of very low-dose cyclobenzaprine (1 to 4 mg at bedtime) improved the symptoms of fibromyalgia, including pain, fatigue, and depression, compared with symptoms at baseline and with use of placebo, which did not result in significant improvement [59]. More patients who received the low-dose cyclobenzaprine had improved restorative sleep, based upon analysis of cyclic alternating pattern sleep by electroencephalography; the increase in nights with improved sleep by this measure correlated with improvements in fatigue and depression. The authors proposed that improvement in cyclic alternating sleep may be a biomarker for treatment efficacy.
INADEQUATE RESPONSE — Patients with an inadequate response to a tricyclic agent are likely to require switching to an alternative medication. However, such patients should also be reassessed to exclude other factors that may interfere with effective therapy. (See 'Assessment of adherence and management of comorbidities' below and 'Selection of further drug therapy' below.)
Assessment of adherence and management of comorbidities — Issues that can interfere with the benefits of potentially effective therapies are discussed in more detail separately. Briefly, these include:
●Poor adherence to pharmacologic and nonpharmacologic measures and reasons for such nonadherence (see "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Nonadherence to treatment recommendations')
●Comorbidities that might also render medical and other therapies less effective, such as a coexistent sleep disorder or psychiatric illness (see 'Addressing comorbidities' above)
●A coexisting painful condition that requires further intervention (see "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Treating peripheral pain')
Patients may thus benefit from a detailed review of their understanding of the disease and self-management strategies; preferred forms of exercise and their adherence to a gradual progressive exercise program; adverse effects of medications and strategies for increasing adherence or, alternatively, the need to change drug therapy; a review of their medical history and physical findings to identify painful and other relevant comorbid conditions.
These considerations are discussed in more detail separately. (See "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Factors limiting treatment efficacy' and 'Addressing comorbidities' above.)
Selection of further drug therapy — In patients who do not respond to an adequate trial (usually one to three months) of low-dose tricyclics or who have intolerable side effects, we switch from a tricyclic to a serotonin-norepinephrine reuptake inhibitor (SNRI; eg, duloxetine or milnacipran) or an alpha2-ligand anticonvulsant (eg, pregabalin). Either drug class may be effective; we base our preferences in individual patients upon the patient's symptoms when either fatigue, depression, or difficulties with sleep are especially prominent. These medications may also be used as an alternative to amitriptyline for initial therapy. We take the following approach:
●Prominent fatigue or depression – In patients who have more severe problems with fatigue, we suggest an SNRI (eg, duloxetine or milnacipran) at breakfast. Duloxetine may be preferred in patients with depression requiring drug therapy, but, in such cases, care should be coordinated with a clinician with expertise in psychopharmacology of depression to assure that both the depression and the fibromyalgia are being addressed effectively and safely. In addition, regulatory factors may limit availability of one or the other agent (eg, there are differences between the United States and Europe regarding which of these medications has regulatory approval for the treatment of mood disorders). (See 'Serotonin-norepinephrine reuptake inhibitors' below and 'Duloxetine' below and 'Milnacipran' below.)
●Prominent sleep disturbance – In those patients with more severe problems with sleep, we suggest pregabalin taken at bedtime. Gabapentin is an acceptable alternative for patients for whom cost or regulatory constraints limit the availability of pregabalin. (See 'Anticonvulsants (alpha2-ligands)' below and 'Pregabalin' below and 'Gabapentin' below.)
We usually try at least one drug from each class, slowly building to the recommended dose, for at least three months, before switching agents, provided there are no adverse side effects. The efficacy of these drugs compared with placebo has been demonstrated in randomized trials and meta-analyses, but there have been few direct comparisons of one with another, particularly with the older drugs [53,54,60]. Pregabalin, duloxetine, and milnacipran are the three drugs approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia in the United States [1].
The SNRIs have been compared indirectly with each other and with other antidepressants and pregabalin in several studies. The medications differed from one another in efficacy for particular symptoms and in their side effect profiles. A 2010 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 [60]. 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.
In a 2013 systematic review and meta-analysis involving 6038 patients in 10 randomized trials that compared SNRIs with placebo, both duloxetine and milnacipran provided a small incremental benefit over placebo in pain reduction [61]. The most common symptoms leading to stopping these medications were nausea, dry mouth, constipation, headache, somnolence, dizziness, and insomnia. A 2018 update including eight additional trials with 1979 further participants had similar findings but concluded that the potential benefits of these two drugs might be outweighed by potential harms [62]; although there was no difference in serious adverse events between those using the active agents and placebo, a higher proportion of patients on duloxetine or milnacipran, compared with placebo, discontinued the drug due to adverse events.
The medications have also been compared with amitriptyline and other antidepressant agents. (See 'Tricyclic antidepressants and related drugs' above.)
Serotonin-norepinephrine reuptake inhibitors — The serotonin-norepinephrine reuptake inhibitors (SNRIs), which are sometimes also referred to as dual reuptake inhibitors, include duloxetine, milnacipran, and venlafaxine, which inhibit both norepinephrine and serotonin reuptake and have been evaluated in patients with fibromyalgia. They may be preferred over other agents in patients with prominent symptoms of fatigue or with depression. (See 'Duloxetine' below and 'Milnacipran' below and 'Venlafaxine' below.)
Duloxetine 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 [55,56,63-69]. These drugs have been compared indirectly with amitriptyline and other agents. (See 'Tricyclic antidepressants and related drugs' above and 'Selection of further drug therapy' above.)
Duloxetine — In patients unresponsive to or intolerant of amitriptyline and in patients who have severe fatigue or who require concomitant drug therapy for depression in addition to pain, we suggest treatment with duloxetine in place of amitriptyline. It is also available in many countries for the treatment of depression and diabetic neuropathy. Duloxetine should be used in the morning at breakfast. The usual starting dose in patients with fibromyalgia is 20 to 30 mg/day, which is gradually increased to the manufacturer's recommended dose of 60 mg/day. In one 12-week trial, a dose of duloxetine of only 30 mg daily did not result in statistically significant pain reduction in fibromyalgia patients when compared with placebo [70].
The benefits of duloxetine in fibromyalgia have been shown in a 2014 systematic review that identified six randomized trials involving 2249 patients in which duloxetine was compared with placebo [71]. On meta-analysis of the data, 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).
The efficacy of duloxetine in patients with fibromyalgia was initially demonstrated in two multicenter trials of 12 weeks' duration [63,64]. As an example, in one trial, pain was reduced by at least 30 percent in a greater proportion of patients receiving duloxetine (60 mg once or twice daily) compared with those taking placebo (55 and 54 versus 33 percent, respectively) [64].
Longer-term benefit was demonstrated in a subsequent six-month, multicenter, randomized, double-blind, placebo-controlled trial of 520 patients who were assigned to a single daily dose of either 60 mg or 120 mg of duloxetine or to placebo [65]. Duloxetine reduced pain severity (measured on a 0 to 10 scale) in patients receiving duloxetine at three and six months (-2.0 and -2.3 versus -1.4 at both time points). The reductions in pain were seen in the first week of therapy and occurred in patients with and without major depression. Mental fatigue improved, but general fatigue did not. The most common side effects were nausea, headache, and dry mouth. They usually occurred within the first three months of therapy.
In our experience, sustained responses are seen in most patients receiving duloxetine who initially benefit from treatment when such patients are followed for more than one year on continued therapy. A study from Japan found that duloxetine was safe and effective during an average duration of one year of follow-up [72].
Milnacipran — Milnacipran is an alternative to duloxetine in patients with severe fatigue in addition to pain. We initiate therapy with 12.5 mg each morning, gradually titrating as tolerated to 50 mg twice daily. Some patients will require a higher dose; up to 100 mg twice daily may be needed.
In randomized trials, it improved pain and global well-being more than placebo [55,56,66-69]. As an example, in one trial, 1196 patients were randomly assigned to treatment with one of two doses of milnacipran or to placebo [55]. Primary outcomes were improvement in a composite of pain, patient-reported global status, and self-reported physical function after 15 weeks of treatment. A greater than 30 percent improvement in the composite measure was more likely among those receiving milnacipran at either dose (100 mg/day or 200 mg/day) than among the placebo group (odds ratio [OR] 1.79, 95% CI 1.14-2.8, and 1.75, 95% CI 1.11-2.75, respectively). Greater improvements in individual component scores (ie, pain, global status, and physical function) were also noted in the milnacipran-treated patients compared with the placebo group. As an example, patient-reported pain (on a 100-point scale) improved from baseline levels by a statistically greater degree in the patients receiving milnacipran than those receiving placebo (-15.7 and -17.4 versus -13).
Adverse effects leading to discontinuation of the study drug were more common in the milnacipran-treated subjects than in the placebo group (19 to 24 percent versus 9.5 percent, respectively). Commonly reported adverse effects were nausea, headache, and constipation.
The other major trial randomly assigned 888 patients, followed similar efficacy measures, and also noted greater efficacy for milnacipran than placebo for pain relief, improvement in global well-being, and physical function [56]. Nausea and headache were the most frequent adverse effects.
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 [73,74].
The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority of patients in the treatment of pain due to fibromyalgia, providing 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 [61,75].
Venlafaxine — We generally do not use venlafaxine, although, as a selective SNRI, it might be expected to provide similar benefit to that observed with other SNRIs. Additionally, it may be available to some patients at lower cost than the other SNRIs. However, there are more limited data regarding the efficacy of venlafaxine for fibromyalgia compared with duloxetine or milnacipran, and withdrawal symptoms may more readily occur because of the short half-life of this medication if a dose is missed. A small study using a flexible dose design in which the final mean dose of venlafaxine was 167 mg per day suggested that this agent may also be effective [76].
Anticonvulsants (alpha2-ligands) — The alpha-2/delta (α2δ) calcium channel modulators, also termed alpha2-ligands, including the anticonvulsants pregabalin and gabapentin, are beneficial for the treatment of fibromyalgia and other conditions causing chronic pain. They may be preferred over other agents in patients with especially prominent sleep disturbance. These two agents are the only anticonvulsants for which there is convincing evidence of benefit in fibromyalgia [77,78]. Pregabalin and gabapentin have similar effects on cellular calcium channels and may exert their analgesic effects by blocking the release of various neurotransmitters. Imaging studies demonstrate the analgesic proof of principle for pregabalin in fibromyalgia [79].
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 [80]. Compared with placebo, active therapy significantly reduced pain and improved sleep and quality of life. Evidence in support of the efficacy of each agent is described separately below. (See 'Pregabalin' below and 'Gabapentin' below.)
Studies to define the mechanisms of action for these central nervous system-acting drugs in fibromyalgia are ongoing. For example, treatment with pregabalin significantly reduced brain gray matter volume within the posterior insula bilaterally [79].
The pharmacologic properties of these medications are discussed in detail elsewhere. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)
Pregabalin — In patients unresponsive to or intolerant of amitriptyline and in patients with more severe sleep disturbance in addition to pain, we suggest the use of pregabalin. We begin with a dose of 25 to 50 mg at bedtime before adjusting the dose upwards as tolerated to the recommended dose of 300 to 450 mg/day. Some patients may respond to lower doses, such as 100 to 300 mg/day, and do not require further dose escalation.
The efficacy and safety of pregabalin has been evaluated in randomized trials and in systematic reviews and meta-analyses [77,78,80]. In a 2009 meta-analysis involving three randomized trials and a total of 1890 patients, those allocated to receive pregabalin in any one of three doses (600, 450, and 300 mg daily) were more likely to respond to treatment, defined as a ≥30 percent reduction in pain score, compared with patients receiving placebo (ORs 1.7, 95% CI 1.27-2.29; 1.92, 95% CI 1.49-2.12; and 1.53, 95% CI 1.18-1.98, respectively) [77]. Some trials also documented improvements in sleep, fatigue, health-related quality of life, and global well-being compared with placebo [81-86]. Adverse events led to withdrawal from treatment in 25 percent of patients; these side effects included dizziness, somnolence, dry mouth, weight gain, and peripheral edema, and occurred with all three doses.
A 2013 meta-analysis, involving five randomized trials with 3256 patients, used a higher threshold to define benefit; a ≥50 percent reduction in pain was achieved more often in the pregabalin-treated patients, compared with those receiving placebo (22 versus 14 percent, relative risk 1.59, 95% CI 1.33-1.90) [86]. A small benefit was also seen in reducing problems with sleep, but in this analysis, pregabalin did not significantly reduce fatigue.
The durability of pregabalin was studied in a six-month trial during which patients were initially treated with increasing doses of pregabalin for six weeks [83]. Among patients randomly assigned to pregabalin or placebo after initially responding to pregabalin, more of the patients continuing pregabalin maintained their response than those using placebo (68 versus 39 percent). Another report found that the efficacy of pregabalin at doses of 75 to 300 mg twice daily persisted for one year without changes in safety or tolerability [87].
A systematic review in 2016 found that pregabalin, at doses of 300 to 600 mg, 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 [88]. There were similar improvements in other symptoms, as well as quality of life and function. The authors concluded that these results were similar to those of milnacipran and duloxetine.
A 2018 summary review of the clinical trials, related open-label extensions, meta-analyses, combination studies, and post-hoc analyses for pregabalin confirmed that pregabalin improved pain, sleep, and overall patient status, and that its efficacy was sustained in a wide range of patient demographics and clinical features [89].
Pregabalin has also been compared indirectly with the SNRIs. (See 'Selection of further drug therapy' above.)
Gabapentin — We use gabapentin, for which evidence is more limited, as an alternative to pregabalin in patients for whom cost of the medication or regulatory requirements limit the use of pregabalin. We begin with a dose of 100 mg at bedtime before titrating the dose upwards as tolerated and as required. The usual dose is 1200 to 2400 mg/day (usually in divided doses taken up to three times daily), based upon the study described below. As with pregabalin, some patients may respond to lower doses.
The efficacy and safety of gabapentin were assessed in a trial that randomly assigned 150 patients to receive gabapentin (1200 to 2400 mg/day) or placebo for 12 weeks [90]. A response was defined as at least a 30 percent decrease in the Brief Pain Inventory (BPI) score. A greater proportion of patients receiving gabapentin were responders than were those in the placebo group (51 versus 31 percent, respectively), and the difference in the mean BPI scores between the two groups also favored gabapentin treatment. Gabapentin was generally well tolerated, although dizziness, sedation, lightheadedness, and weight gain were reported more often by those in the gabapentin group. There was no difference in the incidence of serious adverse events. 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" [91].
Inefficacy of analgesics — Little benefit is obtained from the use of acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), and opioid analgesics; and opioid use may be associated with increased harm and should be avoided in fibromyalgia. There is no evidence that nonopioid analgesics, including acetaminophen and NSAIDs, are effective in fibromyalgia, although they are often prescribed as initial adjuncts to therapy [92]. Similarly, opioids continue to be prescribed in fibromyalgia despite lack of evidence for their efficacy [93]. Furthermore, fibromyalgia patients on opioids have poorer outcomes than those not taking opioids [93].
PATIENTS NOT RESPONSIVE TO INITIAL THERAPIES — Many patients experience continued symptoms despite initial nonpharmacologic measures and treatment with pharmacologic monotherapies at the maximum tolerated dose. Patients should first be evaluated to identify poor medication adherence and its cause and to address associated conditions that may reduce treatment effectiveness, including sleep disorders, depression, and other painful conditions. (See 'Assessment of adherence and management of comorbidities' above.)
In general, adherence to the approved fibromyalgia medications has been poor. Despite the clinical trial efficacy, in "real-world experience," the majority of fibromyalgia patients do not achieve great benefit from any single medication [94]. However, patients often receive less than the label-recommended dose of medication. This was especially true for pregabalin, with only 27 percent receiving the recommended maintenance dose compared with 80 to 90 percent of patients maintained on duloxetine or milnacipran [95].
Medications in fibromyalgia are, at best, modestly effective in a minority 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 [96]. Ninety percent had discontinued tricyclic antidepressants and 74 percent discontinued serotonin-norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) during the one-year follow-up. A 2020 systematic review and meta-analysis concluded that many of the pharmacologic and nonpharmacologic therapies recommended for fibromyalgia have limited evidence for significant efficacy [97]. There was high-quality evidence for cognitive behavioral therapy (CBT) to provide short-term pain reduction and for antidepressants for pain reduction and quality of life in the short to medium term.
There are several approaches we advise in patients resistant to the initial therapies described here, depending upon patient preference and upon available resources and expertise, including use of combinations of drugs; other medications for which there is less evidence; mind-body techniques; and alternative movement therapy, such as tai chi and yoga; and specialist consultation. These interventions are discussed in detail separately. (See "Treatment of fibromyalgia in adults not responsive to initial therapies".)
Briefly, potential specialty consultations may include:
●Referral for a supervised physical therapy evaluation and treatment program.
●Referral for psychological interventions for pain management, including CBT, mind-body stress reduction (MBSR), and other interventions.
●Consultation with one or more specialists, such as a rheumatologist, physiatrist, psychiatrist, sleep specialist, psychologist, or pain management specialist, depending upon the specific expertise needed.
●Assessment and care in a specialized multidisciplinary program, particularly for patients with disease refractory to other interventions or for those on chronic opioids.
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 [98].
PROGNOSIS — Most patients with fibromyalgia continue to have chronic pain and fatigue, although most long-term longitudinal studies of outcome in fibromyalgia have been from tertiary referral centers. Patients treated in primary care settings in the community have better outcomes. Patients with fibromyalgia experience more work disability than the general population and demographic and psychosocial factors substantially impact the prognosis and outcome. Indeed, although the antidepressants used in fibromyalgia, including amitriptyline, duloxetine, and milnacipran, are considered first-line medications, a 2012 meta-analysis found that only a minority of patients experienced substantial improvement with these drugs and that adverse side effects were common [94,99]. Moderate degrees of benefit were seen in pain and sleep, but effects on fatigue and quality of life were small [99].
As an example of patients in a tertiary care setting, one study of 538 patients followed at six referral centers found that pain, fatigue, sleep disturbances, anxiety, and depression were essentially unchanged over a follow-up period of approximately eight years [100]. Similarly, in the author's experience at a referral rheumatology center, there has been little change in the patients' symptoms. Nonetheless, two-thirds of patients reported that they were working full-time and that fibromyalgia interfered only modestly with their lives [100].
In an observational study involving 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 [101]. 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 [102].
Approximately 10 to 30 percent of patients with fibromyalgia report that they are work disabled, a higher incidence than some other groups with chronic pain. In a Canadian study, for example, the incidence of disability was evaluated in 100 patients with fibromyalgia, 76 patients with widespread musculoskeletal pain, and 135 control individuals [103]. The proportions reporting being work disabled were 31, 11, and 2 percent, respectively. Fibromyalgia patients were also much more likely to be receiving a disability pension (26, 9, and 3 percent, respectively).
In a subsequent 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) [104]. Consistent with this observation, persons with fibromyalgia below 65 years filed Social Security disability applications at any time much more often than individuals without fibromyalgia (50.5 versus 5.8 percent). Additionally, disability payments were made more frequently in the last year to those with fibromyalgia compared with those without the condition (30.2 versus 2.8 percent). In an Australian study, only 16 percent of fibromyalgia patients were currently working full-time compared with more than 50 percent at the time of diagnosis [105]. Almost 50 percent were not working at all. Thirty-five percent were receiving financial support because of work disability associated with their fibromyalgia. In a Canadian study, 30 percent of fibromyalgia patients reported being disabled [106]. Disabled patients had more often been employed in manual or service professions. Participation in productive work, defined in a Spanish study as economically remunerated work, correlated with better physical and cognitive function in women with fibromyalgia [107].
Demographic and psychosocial factors have substantial impact; depression, a history of abuse, catastrophizing, and excess somatic concern have been the most important factors in adverse outcome [108-110]. Female sex, low socioeconomic status, and being unemployed have had adverse effects on outcome [111,112]. Obesity has also been associated with increased symptoms in women with fibromyalgia [113]. A higher body mass index (BMI) was associated with poor quality of life and greater pain in women with fibromyalgia [114].
More severely symptomatic patients with fibromyalgia experience greater morbidity, more comorbidities, and increased cost of care [115]. Overall mortality rates do not appear to be increased in patients with fibromyalgia, but an increased risk of suicide may be present among such patients, as shown in other studies of non-cancer-related chronic pain [116-118]. In a study of 1361 Danish patients with fibromyalgia referred over a 16-year period, using the Danish Mortality Register, the standardized mortality ratio (SMR) for an increased risk of death from suicide was significantly increased (SMR 10.5, 95% CI 4.5-20.7) [116]. In another study, there was a mild risk for suicide overall in fibromyalgia but a marked risk in those patients with comorbidities, compared with matched control individuals with neither fibromyalgia nor comorbidities, with hazard ratios ranging from 1.5 to 8.2 [119]. Outpatient health care engagement was found to be a protective factor against suicide in fibromyalgia patients [120].
A separate study found that women with fibromyalgia had a greater risk of cardiovascular disease than controls [121]. Pain that interferes significantly with daily life rather than just having persistent pain was associated with increased mortality [122].
GUIDELINES OF PROFESSIONAL ORGANIZATIONS — Our approach is generally consistent with the recommendations of various expert panels and with the guidelines from professional organizations that have been proposed for treatment of adults with fibromyalgia [3,5,9-11]. Most of these guidelines preceded the regulatory approval of pregabalin, duloxetine, and milnacipran for fibromyalgia treatment.
As an example of such guidelines, a Canadian task force recommended that fibromyalgia care be initiated in the primary care setting, incorporating nonpharmacologic and pharmacologic strategies in a multimodal approach with active patient participation [5]. The proposed treatment objectives were reduction of symptoms, as well as improved function using a patient-tailored treatment approach that is symptom-based. Self-management strategies combining good lifestyle habits and fostering a strong locus of control were considered imperative. The 2017 revised European Alliance of Associations for Rheumatology (EULAR) recommendations and expert opinion also focused on individualized therapy, tailored to the patient's most disturbing symptoms [2,9].
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)")
●Beyond the Basics topics (see "Patient education: Fibromyalgia (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Goals and overview – Treatment of fibromyalgia is directed at reducing the major symptoms of this disorder, including chronic widespread pain, fatigue, insomnia, and cognitive dysfunction. Treatment should be individualized and multidisciplinary, involving both nonpharmacologic measures and, in most patients, drug therapy (table 1). Some patients, particularly among those presenting initially to primary care clinicians and without major mood or sleep disturbances, may respond adequately to nonpharmacologic measures alone. (See 'Initial treatment' above.)
●Patient education – Patients should be educated regarding the disease, including uncertainty regarding the pathogenesis; treatment approaches and the patient's role in management; good sleep hygiene and the adverse effects of poor sleep on pain; and the importance of treating comorbidities that may contribute to symptoms, including mood or sleep disorders. Weight reduction should be encouraged in significantly overweight patients. Psychosocial factors should focus on a biopsychological illness model of chronic pain. Treatment techniques such as cognitive behavioral therapy (CBT) should be introduced. (See 'Patient education' above.)
●Role of management of related comorbidities – Particular comorbidities may adversely affect disease severity and the response to treatment if they are not managed adequately; these conditions should be identified and treated, if present, and include sleep and psychiatric disorders, as well as musculoskeletal and other pain conditions. (See 'Addressing comorbidities' above.)
●Aerobic cardiovascular fitness and other exercise – For all patients with fibromyalgia, we recommend aerobic cardiovascular fitness training (Grade 1A). Low-impact aerobic activities such as walking, biking, swimming, or water aerobics are most successful. The type and intensity of the program should be individualized and should be based upon patient preference and the presence of any other comorbidities. Water exercise and/or tai chi may be preferable in some patients. (See 'Exercise' above.)
●Initial drug management – For patients who do not have mild disease that responds to educational measures, CBT, and exercise, we recommend the addition of a medication (eg, amitriptyline, duloxetine, milnacipran, or pregabalin) as the next step for the treatment of the symptoms associated with fibromyalgia, rather than nonpharmacologic measures alone (Grade 1A). In general, drugs should be started at low doses and should be built up slowly. (See 'Initial treatment' above and 'Tricyclic antidepressants and related drugs' above and 'Inadequate response' above.)
●Treatment with tricyclics and related agents – For most patients, we suggest initiating therapy with a low dose of a tricyclic medication at nighttime (eg, amitriptyline) (Grade 2B). The initial amitriptyline dose is usually 5 to 10 mg one to three hours before bedtime, increased by 5 mg at intervals no more frequently than every two weeks to the minimal dose required (eg, 25 to 50 mg). An initial dose of 5 mg may be preferred in patients expected to be more sensitive to the drug, and the dose may be limited by adverse side effects, especially in older adults. In patients with mild to moderate symptoms, cyclobenzaprine is an alternative to amitriptyline. (See 'Tricyclic antidepressants and related drugs' above.)
●Patients with inadequate response to tricyclics – For patients who do not respond to trials of low-dose tricyclics or who have intolerable side effects, the choice of medications is guided by patient preference, by the patient's symptoms, and by comorbidities. (See 'Inadequate response' above.)
•Prominent fatigue – For patients who have more severe problems due to fatigue, we suggest use of a dual uptake inhibitor (Grade 2C). Examples include duloxetine 20 to 30 mg at breakfast, gradually increased to 60 mg/day, or milnacipran 12.5 mg each morning, gradually increased as tolerated to 50 mg twice daily. (See 'Serotonin-norepinephrine reuptake inhibitors' above and 'Duloxetine' above and 'Milnacipran' above.)
•Prominent sleep disturbance – For patients with more severe problems with sleep, we suggest treatment with pregabalin taken at bedtime (Grade 2C). Treatment is initiated at a dose of 25 to 50 mg at bedtime and is adjusted upwards as tolerated to 300 to 450 mg/day. Gabapentin is an acceptable alternative for patients for whom cost or regulatory constraints limit the availability of pregabalin. (See 'Anticonvulsants (alpha2-ligands)' above and 'Pregabalin' above and 'Gabapentin' above.)
●Patients not responsive to initial therapies – For patients unresponsive to a program including education, exercise, and drug monotherapy, we use additional interventions, such as drug combinations, psychological interventions, and supervised physical therapy, and may obtain additional consultation with other specialists. (See 'Patients not responsive to initial therapies' above and "Treatment of fibromyalgia in adults not responsive to initial therapies".)
●Prognosis – The prognosis of fibromyalgia varies. Patients treated by primary care clinicians in the community have a better prognosis than the population of patients seen in tertiary referral centers. Despite continued chronic pain and fatigue in the latter population, the majority of patients are not disabled and most benefit from continuing to work and to be active. The prognosis varies with psychosocial factors and individual patient response to chronic pain. (See 'Prognosis' above.)
