INTRODUCTION — Fibromyalgia is a chronic pain disorder that is often difficult to treat. Effective interventions include a number of nonpharmacologic and pharmacologic therapies that are often provided in combination. Patients with fibromyalgia generally respond best to a multidisciplinary, individualized treatment program that incorporates the primary treating clinician and other healthcare providers, including physical medicine, rehabilitation, and mental health specialists [1].
The treatment of fibromyalgia in adults who are not responsive to initial therapies will be reviewed here. The initial treatment and prognosis of fibromyalgia in adults; the pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of fibromyalgia; and fibromyalgia in children and adolescents are discussed separately. (See "Initial treatment of fibromyalgia in adults" 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".)
OVERVIEW OF TREATMENT — Treatment of fibromyalgia is directed at reducing the major symptoms of this disorder, including chronic widespread pain, fatigue, insomnia, and cognitive dysfunction [2-4]. A variety of modalities are employed, using a stepwise approach (table 1). (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)
Initial therapy — Our initial approach to the treatment of patients with fibromyalgia is discussed in detail separately. (See "Initial treatment of fibromyalgia in adults".)
Briefly, the initial steps in therapy include:
●Patient education regarding the disease, the treatment approaches, good sleep hygiene, and the importance of treating comorbidities that may contribute to symptoms, including mood or sleep disorders (see "Initial treatment of fibromyalgia in adults", section on 'Patient education')
●An exercise program, including aerobic conditioning, stretching, and strengthening (see "Initial treatment of fibromyalgia in adults", section on 'Exercise')
●Drug monotherapy for treatment of symptoms not relieved by nonpharmacologic measures (see "Initial treatment of fibromyalgia in adults")
Patients not responsive to initial therapy — Many patients experience continued symptoms despite initial nonpharmacologic measures and treatment with a single drug at the maximum tolerated dose; we advise the continued use of several different treatment modalities in such patients, including both nonpharmacologic and pharmacologic treatment measures. The specific intervention depends upon symptoms, patient preferences regarding the types of therapies, available resources, and expertise. These interventions are not mutually exclusive and may include:
●Combinations of drugs. (See 'Combination drug therapy' below.)
●Referral for a supervised physical medicine and rehabilitation evaluation and treatment program. (See 'Exercise and physical therapy' below.)
●Referral for psychological interventions for pain management, including cognitive behavioral therapy and other interventions. In patients with significant cognitive dysfunction despite other therapies, referral to an expert in cognitive impairment, such as a neurologist, may be of benefit to determine whether other causes for cognitive dysfunction are present and if further diagnostic and therapeutic interventions are required. Some patients may also benefit from consultation with a clinical psychologist for neuropsychological (psychometric) testing. (See "Evaluation of cognitive impairment and dementia" and "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment" and "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment", section on 'Neuropsychological testing'.)
●Consultation with one or more specialists, depending upon the specific expertise needed, such as a rheumatologist, physiatrist, psychiatrist, psychologist, sleep specialist, or pain management specialist. (See 'Consultation and referral' below.)
●Assessment and care in a specialized multidisciplinary program, particularly for patients with disease refractory to other interventions or on chronic opioids. (See 'Multidisciplinary treatment programs' below.)
●Other treatments, including medications for which there is more limited evidence, and complementary and alternative measures, including "mind-body" therapies such as tai chi and yoga. (See 'Analgesic and antiinflammatory drugs' below and 'Selective serotonin reuptake inhibitors' below and 'Complementary and alternative therapies' below.)
Nonpharmacologic interventions are important in the initial management of fibromyalgia; these and other nonpharmacologic interventions are also beneficial to patients with disease that does not respond to initial therapies. Some patients respond sufficiently well without drug therapy to avoid the need for medications; this is more common among those presenting in the primary care setting. The 2017 European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) revised treatment recommendations for fibromyalgia suggest that initial therapy should consist of patient education and nonpharmacologic management [4]. (See "Initial treatment of fibromyalgia in adults", section on 'Prognosis' and "Initial treatment of fibromyalgia in adults".)
COMBINATION DRUG THERAPY — We suggest the use of combination drug therapy in most patients unresponsive to monotherapy, based upon the symptoms that most affect the patient. These recommendations are based largely upon clinical experience, as there is relatively little data regarding the relative benefits or adverse effects of drug combinations. The evidence for efficacy of each of the individual drugs is discussed separately. A systematic review found that there were insufficient data to support the routine use of any specific drug combination in fibromyalgia [5].(See "Initial treatment of fibromyalgia in adults".)
In clinical practice, 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, cost to the patient, and comorbidities that may be present, such as psychiatric illness. Examples of combinations that have been evaluated include the following:
●There has been evidence for combining a low dose of a selective serotonin reuptake inhibitor (SSRI; eg, fluoxetine) or a serotonin and norepinephrine reuptake inhibitor (SNRI) in the morning with a low dose of tricyclic antidepressant (eg, amitriptyline) in the evening [6]. In that trial, there was significantly greater improvement in pain with the combination of agents compared with fluoxetine or amitriptyline alone or with placebo (visual analogue pain scale score, with maximum of 100, of 43 versus 58 and of 64 versus 82). (See 'Selective serotonin reuptake inhibitors' below and "Initial treatment of fibromyalgia in adults", section on 'Tricyclic antidepressants and related drugs'.)
●A low dose of an SNRI (eg, duloxetine or milnacipran) in the morning with a low dose of an anticonvulsant (eg, pregabalin) in the evening. This combination has thus far been evaluated in an open-label randomized trial involving 364 patients [7]. In this trial, fibromyalgia patients with an inadequate response to treatment with pregabalin (300 or 450 mg daily) experienced significantly greater pain reduction and global improvement with the addition of an SNRI, milnacipran (100 mg daily), compared with patients continuing pregabalin alone. (See "Initial treatment of fibromyalgia in adults", section on 'Pregabalin' and "Initial treatment of fibromyalgia in adults", section on 'Duloxetine'.)
●The combination of duloxetine and pregabalin were compared in a randomized trial with each as monotherapy [8]. The combination resulted in greater improvement in a number of clinical outcomes, including pain, function, and sleep. Another trial, involving 143 patients with fibromyalgia, compared the combination of the antiviral agent famciclovir with celecoxib with placebo, noting greater improvement in scores with the combination for pain, function, and fatigue [9]. 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 [10]. However, total health care costs were higher with the combination therapy.
By contrast, another small randomized trial, involving only 58 patients, found that the combination of pregabalin and milnacipran was similar to pregabalin alone, with no significant difference between the groups, although both groups showed some improvement [11]. There was greater dropout rate in the monotherapy group.
Clinicians with insufficient experience in the use of these medications or drug combinations may wish to consult with an expert in the pharmacologic treatment of fibromyalgia, such as a rheumatologist. In patients who also have a comorbid psychiatric illness, we advise consultation with a psychiatrist for assistance in medication management and coordination of care. (See 'Consultation and referral' below.)
EXERCISE AND PHYSICAL THERAPY — In patients who have had difficulty achieving a sufficient level of low-impact aerobic exercise on their own, we encourage participation in a supervised physical exercise program. Evidence supporting the efficacy of exercise training is described separately. (See "Initial treatment of fibromyalgia in adults", section on 'Exercise'.)
We refer patients with continued difficulties with exercise or physical functioning to a physiatrist and/or a physical therapist for further evaluation and for assistance in management and improvement in physical functioning (see 'Consultation and referral' below). Self-efficacy ratings by patients with fibromyalgia regarding confidence in walking quickly and in performing normal physical activities were helpful for therapists to tailor individual exercise programs [12]. When specific neurophysiology education was added to exercise programs, there was greater improvement in physical function [13].
Aerobic exercise has been the best-studied form of exercise in fibromyalgia and, along with strength training, has demonstrated improvement in pain and quality of life [14]. Most studies, however, have been of short duration. Exercise has also been moderately effective for improving fatigue in fibromyalgia patients [15]. A number of reports have demonstrated the efficacy of web-based exercise programs in fibromyalgia [16].
Water-based therapies are also effective [17,18]. In one trial, swimming improved pain and functional capacity comparably to a walking program [18]. In some countries, treatment with balneotherapy, such as immersion in thermal or mineral water (eg, spa treatment), is used for treating patients with fibromyalgia [19].
A 2017 meta-analysis found that exercise training improved anxiety in patients with fibromyalgia [20]. Resistance training was found to reduce pain and fatigue and to improve strength, leptin, and insulin-like growth factor (IGF)-1 levels in lean women with fibromyalgia but not in those who were overweight or obese [21].
Additional forms of exercise that have shown some benefit in fibromyalgia but which are not primarily directed at developing aerobic fitness include "mind-body" interventions such as tai chi and yoga. (See 'Tai chi' below and 'Yoga' below.)
PSYCHOLOGICAL THERAPIES — In patients whose symptoms do not respond adequately to initial therapies, we suggest referral through a multidisciplinary treatment program or to a behavioral specialist for psychological interventions, such as cognitive behavioral therapy (CBT); the specific interventions should be individualized based upon patient preference and available resources [22,23]. Psychological interventions should be integrated with multidisciplinary treatment that also includes pharmacologic therapy, education, and exercise. (See 'Consultation and referral' below and 'Multidisciplinary treatment programs' below.)
A role for psychological therapies, particularly CBT, in the treatment of fibromyalgia is well-supported by evidence from meta-analyses, individual trials, and observational studies [24]. CBT is also established as a therapy for insomnia (see "Cognitive behavioral therapy for insomnia in adults"). In addition to CBT, measures that are helpful include mindfulness-based treatments, relaxation, biofeedback, behavioral treatments, and educational interventions [25]. Additionally, education, focusing on self-management, combined with exercise enhances the benefits of exercise in fibromyalgia [26]. (See "Initial treatment of fibromyalgia in adults", section on 'Patient education'.)
The cost utility of CBT was shown in a six-month randomized trial in which CBT was more cost-effective than a combination of pregabalin and duloxetine or usual care [27].
A 2015 systematic review of 61 trials involving 4234 patients 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 overall quality of the evidence was low [28]. An internet-delivered cognitive behavioral pain management course given to 30 fibromyalgia patients significantly improved symptoms compared with 30 waitlisted controls [29]. Pain, depression, and patient satisfaction improved during the five-lesson course delivered over eight weeks. A long-term economic evaluation of cognitive behavioral therapy for functional somatic syndromes, including fibromyalgia, found significant short- and long-term benefit [30]. There were 7184 euros cost savings during the third year after treatment. Cognitive behavioral therapy, compared with patient education, reduced catastrophizing in fibromyalgia patients [31]. This correlated with brain primary somatosensory cortex (S1)-insula, suggesting that cognitive behavioral therapy may normalize pain-related hyperreactivity in fibromyalgia.
FACTORS LIMITING TREATMENT EFFICACY — Several factors may limit the degree of benefit achieved with prescribed medications or other interventions, including nonadherence to treatment interventions or comorbidities that cause peripheral pain and that require additional interventions to those used for treatment of the fibromyalgia. (See 'Nonadherence to treatment recommendations' below and 'Treating peripheral pain' below.)
Nonadherence to treatment recommendations — A lack of adherence to the prescribed treatment program is common in fibromyalgia and should also be evaluated as a potential cause of persistent symptoms [32-36]. Noncompliance, whether due to forgetfulness, due to carelessness, or as an exercise of patient autonomy, may contribute to a lack of effectiveness of medications prescribed for patients with fibromyalgia. Adherence to advice by patients with fibromyalgia cared for by 10 rheumatologists was assessed in a study of 127 women with fibromyalgia recruited from both tertiary care hospitals and the community [32]. Overall, 47 percent of the women reported noncompliance with medications. The degree of discordance between a clinician’s and patient’s assessments of communication during, as well as patient satisfaction at the conclusion of, a clinician-patient encounter was a significant determinant of overall compliance.
A large study using insurance claims data from the United States found that only 31 percent of fibromyalgia patients initiated treatment with one of the medications listed in the American College of Rheumatology (ACR) guidelines [33]. These medications included pregabalin, gabapentin, duloxetine, milnacipran, cyclobenzaprine, tramadol, amitriptyline, and venlafaxine. Many of these subjects did not receive the recommended dose, and adherence was suboptimal for each of the ACR recommended medications. Approximately 50 percent of patients received a second analgesic within one year. Patients using pregabalin have been especially likely to have been started on and maintained on lower–than-recommended doses [34].
Treating peripheral pain — We treat other sources of pain, such as arthritis or regional pain syndromes, which may also contribute to the patient’s symptoms. Patients with nociceptive pain may require other agents, such as analgesics or antiinflammatory or immunosuppressive drugs, depending upon the condition (eg, osteoarthritis or rheumatoid arthritis) causing such pain.
Treating peripheral pain generators, such as myofascial trigger points, may also improve symptoms of fibromyalgia. The local and referred pain pattern induced from active myofascial trigger points bilaterally in the upper trapezius muscle was similar to the ongoing pain pattern in the neck and shoulder region in fibromyalgia [37]. Furthermore, treating active trigger points improved localized pain, as well as fibromyalgia symptoms and analgesic consumption [37]. The proposed mechanism by which localized muscle and joint pain affects significantly on fibromyalgia is through increased central sensitization by peripheral input. Dry needling of myofascial trigger points also improved spinal mobility in fibromyalgia patients [38]. (See "Overview of soft tissue musculoskeletal disorders", section on 'Myofascial pain syndrome'.)
CONSULTATION AND REFERRAL — The long-term management of fibromyalgia and the role of specialty care is controversial. Approximately one-third of primary care providers refer fibromyalgia patients to a specialist, most often a rheumatologist [39]. Referral to rheumatologists has been complicated by long wait times, with an average of 184 days [39]. In patients who have not responded adequately to initial therapies and combination drug therapy with major agents (eg, tricyclics, dual-uptake inhibitors [serotonin and norepinephrine reuptake inhibitors (SNRIs)], and pregabalin), we obtain the following specialty consultations for further evaluation and assistance in management, depending upon the expertise of the treating clinician and upon the patient's symptoms and comorbidities:
●We advise consultation with a rheumatologist for the following indications:
•In patients for whom assistance is needed in prescribing combination drug therapies or in coordinating multidisciplinary management
•For confirmation of the diagnosis and for reevaluation of the treatment program in patients unresponsive to initial therapies and combination drug therapy
•For evaluation and assistance in management of comorbid musculoskeletal conditions
●We advise consultation with a physiatrist for the following indications:
•In patients who have had difficulty achieving a sufficient level of low-impact aerobic exercise or who have had continued difficulties with exercise or physical functioning, despite a trial of a supervised physical therapy program. (See 'Exercise and physical therapy' above.)
•For treatment of regional myofascial pain using trigger point injections and other techniques, which may be of benefit for both the local and the more generalized pain symptoms.
●We advise consultation with a psychiatrist for the following indications:
•In patients who continue to experience symptoms of a mood disorder despite treatment or for whom assistance in treatment is needed
•In patients in whom a mood disorder or other psychiatric condition is present and for whom assistance is needed in management of multiple agents with potential psychopharmacologic effects that are being employed for treatment of fibromyalgia
●We advise referral for formal testing for a sleep disorder and assistance in management in patients with symptoms of a sleep disorder, such as obstructive sleep apnea or restless legs syndrome. (See "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".)
Although there is adequate rationale for specialty referral in these situations, there has been no good evidence that ongoing specialist care has been more effective than continued primary care in patients with fibromyalgia [40].
Multidisciplinary treatment programs — In patients resistant to initial therapy, an individualized, multidisciplinary treatment program should be considered. Such programs may be developed in physical medicine and rehabilitation centers by physiatrists or in chronic pain units. Rheumatologists or others may also provide this care, particularly if they work closely with physiatrists, physical therapists, and mental health professionals. The advantage of such a program is to provide a structured, multimodality treatment program under one roof and in a relatively brief time frame. This type of program may be especially helpful in patients who are resistant to drug therapy, in those patients on chronic opioids, and in those patients with the most complicated psychosocial issues, including disability proceedings.
Significant benefits of multicomponent treatment were documented in a 2009 meta-analysis involving 1119 patients with fibromyalgia in nine randomized trials [41]. For inclusion in the meta-analysis, multicomponent treatment needed to include at least one educational or other psychological therapy and at least one exercise therapy; the controls for comparison with the multicomponent treatment also varied but were required to be a control receiving no treatment, receiving treatment as usual, or receiving another well-defined treatment with a lower intensity than the multicomponent intervention. There was evidence of significant reductions in pain, fatigue, depressive symptoms, and limitations to health-related quality of life (HRQOL), and patients had improved self-efficacy for pain (belief in one’s ability to accomplish a task or cope with pain) at the end of the treatment program but not after longer term follow-up (median of seven months). Physical fitness was improved both after treatment and after follow-up.
As an example, in one randomized trial that examined this approach, a six-week interdisciplinary treatment combining a coordinated psychological, medical, educational, and physiotherapeutic component demonstrated significant improvements, which persisted for 6 to 12 months, in quality of life, physical function, and pain compared with controls [42].
Multidisciplinary rehabilitation programs may also aid in reducing use of opioids and other analgesics in patients taking these medications. As an example, an uncontrolled study admitted 159 fibromyalgia patients to a multidisciplinary pain rehabilitation program based upon cognitive behavioral therapy [43]. Physical and emotional function improved, and the use of analgesics, including opioids, was reduced.
Three further randomized trials of interdisciplinary management of fibromyalgia patients have also demonstrated significant improvement in multiple outcomes [44-46].
A 2013 network meta-analysis that indirectly compared a variety of both pharmacologic and nonpharmacologic interventions for fibromyalgia noted that evidence of clinical effectiveness of these treatments is limited and that additional, adequately sized, high-quality, randomized trials are needed. Based upon the available evidence, the authors hypothesized that combinations of pregabalin or SNRIs with multidisciplinary therapies, exercise, or cognitive behavioral therapy hold promise and should be evaluated in adequately sized, high-quality, randomized trials to provide better data regarding their potential benefit [47].
Some of these programs have been web-based, utilizing telemonitoring and improving cost-utility [16,48]. A population-based randomized controlled trial of telephone-based cognitive behavioral therapy (CBT) for patients with chronic, widespread pain was cost-effective and demonstrated improved quality of life [49]. Optimal efficacy from any multicomponent treatment program requires tailoring the specific therapy to individual needs [50].
Role of pain clinics — We favor the use of pain clinics that are participants in or centers for a multidisciplinary approach to fibromyalgia therapy. Such centers are typically accessed through consultation with other providers with expertise in the care of patients with fibromyalgia. We generally avoid referral to pain clinics that lack such interest and expertise, as many of the approaches typically employed in latter types of centers include strategies that have not proven effective in the chronic management of fibromyalgia, such as interventional procedures and chronic opioid use.
In a study of more than two million subjects in the Veterans Health Administration system with various forms of chronic pain approximately 6 percent were attending pain clinics [51]. A diagnosis of fibromyalgia was the strongest independent correlate of pain clinic attendance. Veterans attending pain clinics had more comorbid psychiatric disorders and were more often on opioids. Pain clinic referral for patients with fibromyalgia should take into account the importance of coexisting mood disturbances.
OTHER THERAPIES — Several approaches may be tried in patients who do not respond to the specific therapies outlined above, including both nonpharmacologic and pharmacologic therapies. Most of these additional approaches are supported by more limited evidence. These include:
●Analgesics and antiinflammatory drugs (see 'Analgesic and antiinflammatory drugs' below and 'Analgesics' below and 'Antiinflammatory medications' below)
●Alternative antidepressants (see 'Selective serotonin reuptake inhibitors' below)
●Complementary and alternative therapies (see 'Complementary and alternative therapies' below)
Analgesic and antiinflammatory drugs — Analgesic and antiinflammatory drugs other than antidepressants and other established central nervous system (CNS) active medications have been used in the treatment of fibromyalgia, although there is little evidence of their efficacy [1-4].
Analgesics — We use acetaminophen or tramadol, alone or in combination, in patients who require additional pain relief on a temporary basis for a disease exacerbation or in whom other therapies have been inadequate for controlling pain. They are generally used in combination with CNS active medications when the latter are not effective alone. 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. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Opioids'.)
There is limited evidence suggesting benefit of these agents for fibromyalgia [52-54]. As an example, the modest clinical efficacy of the fixed combination of these two agents (up to 650 mg acetaminophen and 75 mg tramadol four times daily) in relieving pain was illustrated in a three-month trial that randomly assigned 315 predominantly White female patients to active combination therapy or to placebo [52]; patients on the active drug combination discontinued therapy less often and experienced greater reductions in pain, although nausea was more common on these agents.
There is some concern regarding the long-term potential for abuse of tramadol [53]. Short-term use of strong opioids (eg, morphine, oxycodone, oxymorphone, hydrocodone, hydromorphone) in fibromyalgia is controversial, and we prefer that a pain management specialist be involved in the care of those patients who are receiving strong opioids on a long-term basis [55]. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Opioids'.)
There is no evidence that opioids other than tramadol are effective in the treatment of fibromyalgia, and a number of reports suggest that they adversely affect outcome [55]. 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 [56]. 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 [57].
Long-term opioid use has been associated with worse outcomes in patients with fibromyalgia [58]. There is some evidence that opioids interfere with the benefits of psychological and multidimensional therapy in fibromyalgia [59], and that fibromyalgia patients receiving long-term opioids have greater sleep disturbances [60].
Antiinflammatory medications — We do not use nonsteroidal antiinflammatory drugs (NSAIDs) as the primary drug for pain in patients with fibromyalgia, and we do not use glucocorticoids in this condition. Several small randomized trials have failed to show that antiinflammatory medications are effective forms of treatment; therapeutic doses of naproxen, ibuprofen, and prednisone (15 mg/day) were each found to be no better than placebo in these trials, which generally also permitted the use of acetaminophen as needed [1-3,61].
A Cochrane database review concluded that there is only a modest amount of very low-quality evidence addressing the use of NSAIDs in fibromyalgia, which comes from small, largely inadequate studies with potential risk of bias [62]. Such bias would be expected to increase the apparent benefits of NSAIDs. One randomized trial study did find some benefit of etoricoxib compared with placebo in patients with fibromyalgia [63]. There may be some adjunctive role when NSAIDs are utilized along with the American College of Rheumatology (ACR) guideline-approved fibromyalgia medications (eg, pregabalin, gabapentin, duloxetine, milnacipran, cyclobenzaprine, and amitriptyline).
Selective serotonin reuptake inhibitors — Other CNS active medications that have some efficacy in fibromyalgia (in addition to tricyclics, serotonin and norepinephrine reuptake inhibitors [SNRIs], and anticonvulsants) include the selective serotonin reuptake inhibitors (SSRIs). However, trials of fluoxetine have shown mixed results [64,65], and small trials of citalopram [66], paroxetine [67], and fluvoxamine [68] have been inconclusive. A 2015 systematic review and meta-analysis of randomized trials of SSRIs, combining data from 383 patients in seven trials, found that somewhat more patients showed a 30 percent pain reduction in pain with SSRIs compared with placebo (33 versus 23 percent), and significant global improvement (30 versus 16 percent), although most trials were of low quality [69]. Neither fatigue nor sleep improved, but levels of depression decreased in the treated patients, and the drugs were well-tolerated.
Thus, in some patients a trial of these agents may be warranted, particularly if cost to the patient precludes use of a more effective alternative. (See "Initial treatment of fibromyalgia in adults".)
The available evidence regarding the efficacy of SSRIs for fibromyalgia includes the following:
●Fluoxetine – One study found that a fixed dose of fluoxetine (20 mg/day) was not superior to placebo [65], while another that allowed dose escalation, from 20 mg/day to a maximum of 80 mg/day, found fluoxetine to be significantly more effective than placebo [64]. In this study, the effect on pain was independent of change in mood.
●Paroxetine – In a trial that randomly assigned 116 patients either to an escalating dose of a continuous release formulation of paroxetine (12.5 to 62.5 mg/day) or to placebo, composite scores on the Fibromyalgia Impact Questionnaire (FIQ) were followed from baseline to 12 weeks [67]. Significantly more of those assigned to paroxetine than to placebo achieved a ≥25 percent improvement in FIQ score (57 versus 33 percent). Among those who completed the assigned treatment, the response rates were higher in those receiving paroxetine than placebo (66 versus 33 percent, respectively).
●Fluvoxamine – Fluvoxamine was compared with amitriptyline in a study that randomly assigned 68 patients to one of the two active treatments for four weeks [68]. Withdrawals were more common in the amitriptyline group than in the fluvoxamine group (40 versus 16 percent). Pain relief was not significantly different in the two groups.
●Citalopram – Inconsistent results have been noted in small studies using citalopram to treat patients with fibromyalgia [66].
Complementary and alternative therapies — There is evidence that tai chi, yoga, and acupuncture may have benefit in fibromyalgia (see 'Meditative movement therapies' below and 'Acupuncture' below). These interventions may be of particular interest to some patients, especially those who wish to avoid the use of additional medications or the use of any medications at all.
Efficacy of complementary and alternative therapies was evaluated in a 2015 systematic review of many forms of such therapies in fibromyalgia, which found consistently positive results for tai chi, yoga, meditation and mindfulness-based interventions, hypnosis or guided imagery, electromyogram (EMG) biofeedback, and balneotherapy/hydrotherapy [70]. They found inconsistent results for qigong, acupuncture, chiropractic interventions, electroencephalogram (EEG) biofeedback, and nutritional supplements. Inconclusive results were found for homeopathy and phytotherapy.
Meditative movement therapies — A systematic review and meta-analysis of seven randomized trials involving 362 patients found that meditative movement therapies, including qigong, tai chi, and yoga, significantly improved fibromyalgia-related sleep disturbances, fatigue, depression and quality of life, but not pain, compared with controls [71]. Yoga and tai chi each significantly improved pain only in single randomized trials among those evaluated.
Tai chi — Tai chi, which combines mind-body practice with gentle, flowing movement exercises, has shown some benefit for fibromyalgia symptoms, in comparison with both aerobic exercise [72] and educational interventions [73,74], although it has not been extensively studied for this condition.
In a randomized trial involving 226 patients with fibromyalgia, tai chi was at least or more effective than aerobic exercise, and a longer duration of tai chi was more effective than a shorter duration [72]. In this trial, supervised Yang-style tai chi (for 12 or 24 weeks, once or twice weekly) was compared with supervised aerobic exercise (for 24 weeks, twice weekly). After 24 weeks, improvements from baseline in revised fibromyalgia impact questionnaire (FIQR) scores were greater for the combined tai chi groups than the aerobic exercise group. Tai chi was also of greater benefit when administered with the same intensity (twice weekly) and duration (24 weeks) as aerobic exercise. Improvement from baseline in all groups at weeks 24 and 52 exceeded the estimated minimally clinically important difference in FIQR, although the trial lacked a control group for comparison. Greater improvement was achieved by patients with 24 weeks rather than 12 weeks of supervised tai chi, but benefits were comparable with once- versus twice-weekly sessions.
Tai chi has shown benefit compared with control groups receiving either education only or education and stretching. As an example, one randomized trial involving 66 patients compared tai chi (one-hour sessions twice weekly) with a control intervention of wellness education and stretching, with improvement in the FIQ score in the group receiving tai chi after 12 weeks of the intervention [73,74]. Improvements were maintained at 24 weeks, and no adverse events were observed. Another randomized 12-week trial involving 101 patients also showed benefit from tai chi [74]. In this trial, tai chi (practiced for 90 minutes twice weekly) was significantly more likely than a control intervention of education to provide worthwhile improvement in common fibromyalgia symptoms, including pain and functional mobility.
Yoga — A randomized controlled trial evaluated a specific form of yoga, called Yoga of Awareness, in 53 fibromyalgia patients who were compared with waitlisted standard care. Those receiving the yoga program demonstrated greater improvements in pain, fatigue, and mood and in pain catastrophizing, acceptance, and other coping strategies [75]. Follow-up results showed that patients sustained most of their post-treatment gains, with the functional scores 21.9 percent improved at three months. Yoga practice rates were good, and more practice was associated with more benefit for a variety of outcomes [76].
Qigong — A systematic review of randomized controlled trials comparing qigong with control interventions revealed low-quality evidence for short-term improvement of pain, quality of life, and sleep quality, and very low-quality evidence for improvement of fatigue, and concluded that only a weak recommendation for qigong can be made at this point [77].
Other — Meditation awareness training was found to improve pain and other symptoms in a randomized trial [78]. There was also improvement with guided imagery/hypnosis, especially when combined with cognitive behavior therapy [79].
Acupuncture — Some studies, but not others, have found traditional Chinese acupuncture to be effective compared with various sham procedures for relieving pain in patients with fibromyalgia. Acupuncture has also been shown to reduce symptoms of chronic pain in a variety of other conditions but generally provides a similar level of benefit to sham acupuncture controls. (See "Acupuncture".)
For example, in one report, all treatment groups experienced a substantial decrease in pain from baseline; however, the mean difference in pain relief between the traditional acupuncture group and all the sham groups was insignificant (0.5 cm on a 10 cm scale, 95% CI -0.3 to 1.2 cm) [80].
A 2013 systematic review and meta-analysis of acupuncture therapy, involving 395 patients with fibromyalgia in nine randomized trials, showed evidence for improvement in pain and stiffness with acupuncture compared with no treatment and with standard therapy [81]. However, analysis of six of the trials, involving 286 patients, showed no significant differences in most measures in comparison with sham acupuncture, including pain, fatigue, sleep, or global well-being, although there was less stiffness at one month. Benefit was more likely in trials of electroacupuncture than in those evaluating manual acupuncture (not involving electrostimulation). A subgroup analysis of two trials involving a total of 104 patients found greater benefit in a variety of measures using electroacupuncture compared with sham acupuncture; as an example, there was an absolute improvement in global well-being compared with sham acupuncture of 11 percent (95% CI, 4 to 17 percent). However, the benefits lasted only one month and were not seen at six months of follow-up. A subsequent randomized trial also found benefit from acupuncture compared with sham acupuncture [82]. A 2019 meta-analysis of 12 randomized trials that compared acupuncture therapy with sham acupuncture or conventional medication reported that acupuncture was more effective than the control interventions for relieving pain and improving quality of life, although some of the studies had design limitations and follow-up was generally very limited [83].
Injection therapies and other physical measures — There have been few studies of trigger point or tender point injections, electromyography (EMG) biofeedback, chiropractic, or massage in the treatment of fibromyalgia [1,4]. Most of these reports are from small case series or lack quality control. A systematic review and meta-analysis of randomized trials of massage therapies found that treatment protocols at least five weeks in duration were associated with immediate benefit of massage for symptoms of pain, anxiety, and depression compared with control interventions [84]; however, the evidence was limited by the heterogeneity of massage techniques and programs employed, the use of a variety of different controls, and a lack of long-term follow-up in the trials.
BRAIN NEUROMODULATION
●Transcranial stimulation – Among the more promising developments for the treatment of fibromyalgia are a variety of neuromodulation techniques. The most studied has been transcranial direct current stimulation (tDCS). In the initial report 32 patients with fibromyalgia were randomly assigned to receive sham stimulation, real tDCS with the anode centered over the primary motor cortex, or stimulation of the dorsolateral prefrontal cortex [85]. Direct current stimulation consisted of 2 mA for 20 minutes on five consecutive days with the anode placed on the scalp over the appropriate brain region. The change in pain was significantly greater in those who received real tDCS to the motor cortex than in the groups receiving sham or dorsolateral prefrontal cortex stimulation.
Transcranial magnetic stimulation (TMS) of the left prefrontal cortex, administered in a two-week randomized trial involving 20 patients with fibromyalgia, significantly reduced symptoms of pain from the level at baseline compared with sham TMS (mean reduction of 29 versus 4 percent) [86]. Symptoms of depression also improved. Another randomized trial investigated the effects of five consecutive 20-minute sessions of 2-mA anodal tDCS directed to the M1 in 48 patients (45 females) with fibromyalgia. There was a small but significant improvement in pain under the active tDCS condition but not under the sham condition. Fibromyalgia-related daily functioning improved in the active tDCS group compared with the sham group. The small effect sizes indicated that the results were unlikely to reflect clinically important changes.
A 2016 systematic review concluded that in comparison with sham stimulation, repetitive TMS (rTMS) demonstrated superior effect on the quality of life of patients with fibromyalgia one month after starting therapy, and the authors recommended that further studies are needed to determine optimal treatment protocols and to elucidate the mechanisms involved with this effect [87]. A 2017 systematic review questioned the efficacy of routine use of rTMS in fibromyalgia [88], while another 2017 systematic review did find evidence for the efficacy of anodal transcranial direct current stimulation over the primary motor cortex [89].
A 2019 randomized trial found that active TMS had no significant benefit compared with sham TMS, either in pain reduction or quality of life [90], whereas another report found significant improvement from a 60-session, home-based tDCS over the dorsolateral prefrontal cortex in fibromyalgia [91]. Such a home-based program would offset the complexities of using TMS but, at present, brain neuromodulation trials require pain expert management.
●Occipital and C2 nerve stimulation – Several trials have evaluated the effect of occipital [92] and C2 nerve stimulation [93] The results were positive, but the trials were small and not well-controlled. Occipital nerve field transcranial direct current stimulation, in comparison to sham stimulation, normalized the dysfunctional brain connectivity between the pregenual cingulate cortex to the dorsal anterior cingulate cortex [94]. After occipital nerve stimulation, positron emission tomography demonstrated activation of the descending pain inhibitory pathway and the lateral pain pathway in fibromyalgia patients [95].
●Transcutaneous electrical nerve stimulation – Trials of transcutaneous electrical nerve stimulation (TENS) have had mixed results because of study design issues, although investigation of this approach is of interest because of the capacity of TENS to reduce central excitability and to activate central inhibition pathways [96-98]. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Transcutaneous electrical nerve stimulation (TENS)'.)
In a randomized trial, involving 301 patients with fibromyalgia, 4 weeks of TENS improved movement-evoked pain and other symptoms compared with placebo TENS and no TENS [99]. Resting pain and fatigue also improved in the TENS group. There were no significant adverse events. A wearable TENS designed for extended home wear and placed on the upper calf was compared with sham TENS in a three-month randomized trial [100]. There was modest improvement in pain and function in the active compared with sham-treated patients with fibromyalgia, although the primary endpoint of the study was not achieved.
PHARMACOLOGIC TRIALS WITH LIMITED DATA IN FIBROMYALGIA
●Cannabinoids – Nabilone, a synthetic cannabinoid available in Canada and the United Kingdom, but which has been discontinued in the United States, may have some beneficial effect on sleep in fibromyalgia [101], but any significant analgesic impact is unclear, and a systematic review found no evidence for cannabinoid efficacy in fibromyalgia [102]. A randomized trial of pharmaceutical-grade cannabis in 20 patients with fibromyalgia showed no greater impact on pain or electrical pain thresholds compared with placebo with a wide variability in responses, depending upon the composition of the inhaled cannabinoid [103].
A randomized trial found that ingestion of a cannabidiol oil did improve some fibromyalgia symptoms [104]. In a Canadian rheumatology clinic population, 24 percent of patients with fibromyalgia compared with 11 percent of non-fibromyalgia patients were using medical cannabis [105]. Those fibromyalgia patients using medical cannabis were more likely to be unemployed or disabled and on more medications than nonusers.
●Naltrexone – A pilot study found that low-dose naltrexone reduced pain more than placebo (29 versus 18 percent) [106]. Low-dose naltrexone was also associated with improved general satisfaction with life and with improved mood but was not associated with improved fatigue or sleep. A drug with a similar analgesic mode of action, dextromethorphan, did not demonstrate significant efficacy in a small study in fibromyalgia [107].
●Other selective noradrenaline reuptake inhibitors, such as esreboxetine and reboxetine, have been tested in fibromyalgia but are not commonly used and offer no advantages over the US Food and Drug Administration (FDA)-approved serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine and milnacipran. A number of other medications, including memantine, pramipexole, and sodium oxybate, had looked promising in early fibromyalgia clinical trials but, either from lack of efficacy or adverse side effects, are not considered current pharmacologic options.
●Vitamin D supplementation – There have been conflicting reports regarding the efficacy of vitamin D supplementation in fibromyalgia. In a trial involving 30 women with fibromyalgia whose serum calcifediol levels were less than 32 ng/mL (80 nmol/L), patients were randomly assigned to receive either cholecalciferol or placebo, with the goal in the treated patients of achieving serum calcifediol levels between 32 and 48 ng/mL (80 and 120 nmol/L) for 20 weeks [108]. There were statistically significant reductions in pain and improvement in function in the treatment group. Vitamin D replacement in subjects with chronic, widespread pain who had low levels of vitamin D did improve musculoskeletal symptoms, mood, and quality of life [109]. However, a 2018 systematic review that identified 14 reports evaluating the role of vitamin D in fibromyalgia did find that patients with fibromyalgia have low levels of vitamin D compared with healthy controls but did not find conclusive evidence that this correlated with symptoms or that supplementation was effective [110].
SPECIAL CONSIDERATIONS — As with every chronic pain disorder, the vast heterogeneity of symptom severity in patients with fibromyalgia makes its management especially challenging. Patients with fibromyalgia report unique problems with their chronic pain management, including not being believed or listened to and the notion that "No one wants to look after the fibro patient" [40]. Many experts suggest that a new model of care be developed for patients with fibromyalgia not responding to initial therapy [40].
Predicting individual potential response to therapy would be welcome. To that effect, a machine-based learning model was used to predict whether a patient with fibromyalgia would respond differently to milnacipran or pregabalin [111]. Specific functional brain imaging patterns were able to predict individual patient response to each medication.
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".)
SUMMARY AND RECOMMENDATIONS
●Goals and overview of approach – Treatment of fibromyalgia is directed at reducing the major symptoms of this disorder, including chronic widespread pain, fatigue, insomnia, and cognitive dysfunction. In patients with continued symptoms despite initial nonpharmacologic measures and treatment with single drugs at the maximum tolerated dose, we continue the use of both nonpharmacologic and pharmacologic treatment measures, and we modify or add specific interventions depending upon the symptoms, patient preferences regarding the types of therapies, available resources, and expertise (table 1). (See 'Overview of treatment' above and 'Patients not responsive to initial therapy' above.)
●Combination drug therapy when unresponsive to monotherapy – In most patients unresponsive to monotherapy, we suggest using combination drug therapy, rather than switching to or adding analgesics and rather than continuing monotherapy alone (Grade 2B). Medication selection should be guided by the symptoms that most affect the patient. We combine drugs of different classes (eg, a serotonin and norepinephrine reuptake inhibitor [SNRI] such as duloxetine in the morning, with a low dose of an anticonvulsant, such as pregabalin, in the evening; or a low dose of a selective serotonin reuptake inhibitor, such as fluoxetine or an SNRI, in the morning with a low dose of tricyclic antidepressant, such as amitriptyline, in the evening) to take advantage of multiple mechanisms of action for reducing pain and to target different symptoms. (See 'Combination drug therapy' above.)
●Supervised exercise and rehabilitation if difficulty achieving sufficient levels of exercise – In patients who have had difficulty achieving a sufficient level of low-impact aerobic exercise, we encourage participation in a supervised physical medicine and rehabilitation program. We refer patients with continued difficulties with exercise or physical functioning to a physiatrist for further evaluation and for assistance in management. (See 'Exercise and physical therapy' above.)
●Referral for CBT or other psychological interventions on an individualized basis – In patients whose symptoms do not respond adequately to initial therapies, we suggest referral for psychological interventions, such as cognitive behavioral therapy (CBT) (Grade 2B); the specific interventions should be individualized based upon patient preference and available resources. Other psychological measures that may be beneficial include mindfulness-based treatments, relaxation, biofeedback, behavioral treatments, and educational interventions. (See 'Psychological therapies' above.)
●Individually multidisciplinary treatment and specialty consultation – Treatment should generally be multidisciplinary and should be individualized with attention to the patient’s particular symptoms. In patients who have not responded adequately to initial therapies, we advise consultation with specialists in rheumatology, physiatry, psychiatry, neuropsychology, or sleep medicine for further evaluation and for assistance in management, depending upon the expertise of the treating clinician and upon the patient’s symptoms and comorbidities. Alternatively, multidisciplinary treatment and specialist consultation can be facilitated by multidisciplinary treatment programs. (See 'Consultation and referral' above and 'Multidisciplinary treatment programs' above.)
●Unresponsive to well-substantiated therapies – Several approaches may be tried in patients who do not respond to the more well-substantiated nonpharmacologic and pharmacologic therapies. Most of these additional approaches are supported by more limited evidence, including analgesics (eg, acetaminophen or tramadol), antiinflammatory drugs, alternative antidepressants, and complementary and alternative therapies (eg, tai chi or yoga). (See 'Analgesic and antiinflammatory drugs' above and 'Selective serotonin reuptake inhibitors' above and 'Complementary and alternative therapies' above.)
●Multidisciplinary pain clinic referral rather than opioids for patients resistant to other therapy – There is no evidence that opioids are effective in the treatment of fibromyalgia, and studies have suggested possible adverse effects. In patients who have not responded to multidisciplinary individualized nonpharmacologic and pharmacologic therapy, we favor the use of pain clinics that utilize a multidisciplinary approach to fibromyalgia therapy rather than pain clinics that lack such interest and expertise. (See 'Analgesics' above and 'Role of pain clinics' above.)
