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Treatment of fibromyalgia in adults not responsive to initial therapies
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Treatment of fibromyalgia in adults not responsive to initial therapies
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Jan 02, 2016.

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 [2-5]. 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", section on 'Medications')

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 (see 'Psychological therapies' below)

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. (See "Initial treatment of fibromyalgia in adults", section on 'Overview of treatment' and "Initial treatment of fibromyalgia in adults", section on 'Prognosis'.)

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 [6]. The evidence for efficacy of each of the individual drugs is discussed separately. (See "Initial treatment of fibromyalgia in adults", section on 'Medications'.)

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 we have used are:

There has been evidence for combining a low dose of a selective serotonin reuptake inhibitor (SSRI) (eg, fluoxetine) or an SNRI in the morning with a low dose of tricyclic antidepressant (eg, amitriptyline) in the evening [7]. 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 as initial drug therapy'.)

A low dose of a serotonin and norepinephrine reuptake inhibitor (SNRI) (eg, duloxetine) in the morning with a low dose of an anticonvulsant (eg, pregabalin) in the evening. This combination has thus far been evaluated in a single open-label randomized trial involving 364 patients [8]. 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 'Duloxetine' and "Initial treatment of fibromyalgia in adults", section on 'Pregabalin') However, there have been no studies of other effective medication combinations.

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.)

In patients without an adequate response to these medications or with a temporary need for additional treatment during an exacerbation of pain symptoms, other agents such as acetaminophen, tramadol, and nonsteroidal antiinflammatory drugs (NSAIDs) are adjunctive or alternative therapies that may be helpful. Other antidepressants may also be used in some patients as alternative agents; however, there is less evidence for their benefit than the tricyclics, SNRIs, SSRIs, or anticonvulsants cited above. (See 'Analgesic and antiinflammatory drugs' below and 'Selective serotonin reuptake inhibitors' below and 'Antiinflammatory medications' below.)

Other medications that have been used in patients with fibromyalgia include opioid analgesics other than tramadol, muscle relaxants, and stimulants, but there is insufficient evidence for their efficacy or safety in the treatment of fibromyalgia [4]. (See 'Other therapies' below and 'Analgesics' below.)

EXERCISE AND PHYSICAL THERAPY — In patients who have had difficulty achieving a sufficient level of low-impact aerobic exercise, we encourage participation in a supervised physical therapy program. Evidence supporting the efficacy of exercise training is described separately. (See "Initial treatment of fibromyalgia in adults", section on 'Efficacy of 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.)

Water-based therapies may be effective, and possibly comparable to land-based therapy [9,10]. In some countries, treatment with balneotherapy, such as immersion in thermal or mineral water (eg, spa treatment), is used for treating patients with fibromyalgia [11,12]; more limited data have suggested that these therapies may also provide some improvement in pain and quality of life, although benefits decrease during follow-up and further study is required [9].

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 [13,14]. 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 [2,3,13,15-22]. CBT is also established as a therapy for insomnia (see "Treatment of insomnia", section on 'Cognitive behavioral therapy'). In addition to CBT, measures that are helpful include mindfulness-based treatments, relaxation, biofeedback, behavioral treatments, and educational interventions [2,3,15,17-21]. Additionally, education, focusing on self-management, combined with exercise enhances the benefits of exercise in fibromyalgia [23]. (See "Initial treatment of fibromyalgia in adults", section on 'Effectiveness of patient education'.)

A 2010 meta-analysis of 23 studies of 30 psychological treatment conditions, involving 1396 patients, found significant short- and long-term benefit for a number of measures [15]. The authors of the meta-analysis concluded that patients with fibromyalgia should be treated with a combination of methods that include psychological interventions as a major component, such as high-dose CBT with relaxation or biofeedback. Analysis of any psychological intervention showed statistically significant but small effects on short-term pain reduction and a small to medium effect for long-term pain reduction (average follow-up 7.4 months). The level of benefit from psychological treatments was similar to that from treatment with drugs [24,25]. As an example of the level of benefit, in one small trial, there were statistically nonsignificant 18 percent reductions in self-reported pain scores compared with baseline with either CBT or with a physical exercise program [26].

A meta-analysis of randomized trials of CBT, involving 23 trials with a total of 2031 patients, found that CBT resulted in statistically significant, but small improvements in pain, mood, and disability compared with control interventions both at the end of treatment and at long-term follow-up (median of six months) [22]. As an example, CBT use was associated, compared with control, with a 0.5 point greater reduction in self-reported pain (on a 0 to 10 scale) following the intervention, and with a 0.6 point greater reduction in pain at long-term follow-up (6.3 and 4.2 percent absolute improvement, respectively). 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 meta-analysis 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 to usual care controls, but the overall quality of the evidence was low [28].

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'.)

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. 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 [29]. 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.

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 [30]. Furthermore, treating active trigger points improved localized pain, as well as fibromyalgia symptoms and analgesic consumption [31]. The proposed mechanism by which localized muscle and joint pain affects significantly on fibromyalgia is through increased central sensitization by peripheral input. (See "Overview of soft tissue rheumatic disorders", section on 'Myofascial pain syndrome'.)

CONSULTATION AND REFERRAL — In patients who have not responded adequately to initial therapies and combination drug therapy with major agents (eg, tricyclics, dual-uptake 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.)

To introduce novel physical medicine programs. For example, a neurodynamic limb mobilization program was found to reduce pain in a randomized trial involving 48 fibromyalgia patients [32].

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 "Overview of obstructive sleep apnea in adults" and "Clinical features and diagnosis of restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in adults".)

Multidisciplinary treatment programs — Treatment should generally be multidisciplinary and should be individualized with attention to the patient’s particular symptoms [2-5]. Such treatment can be facilitated by multidisciplinary treatment programs. These may be developed in physical medicine and rehabilitation centers by physiatrists or in chronic pain units [33]. Rheumatologists or others may also provide this care, particularly if they work closely with physiatrists, physical therapists, and mental health professionals [34]. 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 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 [35]. 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 [36].

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 [37]. 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 [38-40].

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 [41].

Some of these programs have been web-based, utilizing telemonitoring and improving cost-utility [42,43].

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. We usually limit referral to pain clinics that are not involved in multidisciplinary fibromyalgia treatment programs to patients with inadequate control of symptoms in whom other proven nonpharmacologic and medical interventions have been optimized.

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 [2].

Analgesics — We use analgesics, such as 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. There are limited studies that show benefit from these agents [44-46]. They are generally used in combination with CNS active medications when the latter are not effective alone. Tramadol is an analgesic that has activity at mu opioid receptors but that 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 'Choice of agent and dosing'.)

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 study that randomly assigned 315 predominantly white female patients to active combination therapy or to placebo [45]. Discontinuation rates and secondary measures such as pain, pain relief, and self-reported health status were assessed over a three-month period. The following results were noted:

A greater proportion of the patients treated with acetaminophen and tramadol had a 50 percent or greater reduction in pain (35 versus 18 percent with placebo).

Those on the active combination had significantly greater overall decrease in pain (19 versus 7 mm on a 100 mm scale).

Discontinuation rates were lower with active treatment (48 versus 62 percent). Nausea was more than twice as common among those on the active medication compared with those on placebo (9 versus 4 percent).

While these findings are encouraging, the patients had received little treatment before enrollment, and prior uses of tricyclic antidepressants, of cyclobenzaprine, and of analgesics (including acetaminophen) were criteria for exclusion. It is uncertain how effective the combination of acetaminophen and tramadol would be for patients who had tried and failed other treatments or how the combination would perform if added to ongoing treatment with one or more of the CNS active medications.

There is some concern regarding the long-term potential for abuse of tramadol, a weak opioid, although the risks and adverse effects may theoretically be less than those of more potent narcotic analgesics that have also been tried in fibromyalgia [47]. Prolonged use of such agents 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 [47]. (See "Overview of the treatment of chronic non-cancer pain", section on 'Opioids'.)

There is no evidence that opioids are effective in the treatment of fibromyalgia, and a number of reports suggest that they adversely affect outcome [48]. 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 [49]. 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 [50].

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 [2,51-53].

In addition, there is no evidence that tissue inflammation is present in patients with fibromyalgia, and glucocorticoids also have the potential for serious adverse effects when used chronically [2]. Thus, any benefit experienced with NSAIDs is likely due to the analgesic effects of these agents alone.

However, NSAIDs may have a synergistic beneficial effect on pain when combined with CNS active medications such as antidepressants or anticonvulsants [51]. NSAIDs may also provide additional benefit in patients with nociceptive pain from arthritis or other conditions.

Selective serotonin reuptake inhibitors — Other CNS active medications that have some efficacy in fibromyalgia (in addition to tricyclics, SNRIs, and anticonvulsants) include the selective serotonin reuptake inhibitors (SSRIs). However, trials of fluoxetine have shown mixed results [7,54,55], and small trials of citalopram have also been inconsistent [56,57]. Other drugs that have been studied include paroxetine [58] and fluvoxamine [59]. 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 [60]. 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", section on 'Medications'.)

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 [55], 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 [54]. 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 [58]. 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 [59]. 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 [56,57].

Complementary and alternative therapies — Some evidence has suggested that tai chi, yoga, or acupuncture may have benefit in fibromyalgia [61-63]. 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.

A systematic literature review has found insufficient evidence of efficacy for fibromyalgia of a number of oral or topically-applied complementary, alternative, and other therapies, including anthocyanidin, topical capsaicin, dietary soy, S-adenosyl methionine, or homeopathy [64].

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 [65]. 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, although it has not been extensively studied for this condition. A randomized trial involving 66 patients compared tai chi (one-hour sessions twice weekly) with a control intervention of wellness education and stretching, with significant improvement in the FIQ score in the group receiving tai chi after 12 weeks of the intervention (baseline versus 12-week scores of 63 ± 16 and 35 ± 19 versus 68 ± 11 and 59 ± 18, respectively) [61]. 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 [66]. 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 [67]. 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 [68].

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 [69].

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 [62,63,70,71]. 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) [62].

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 [70]. 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, 4-17 percent). However, the benefits lasted only one month and were not seen at six months of follow-up.

A systematic review of many forms of complementary and alternative therapies in fibromyalgia found consistently positive results for tai chi, yoga, meditation and mindfulness-based interventions, hypnosis or guided imagery, electromyogram (EMG) biofeedback, and balneotherapy/hydrotherapy. They found inconsistent results for qigong, acupuncture, chiropractic interventions, electroencephalogram (EEG) biofeedback, and nutritional supplements. Inconclusive results were found for homeopathy and phytotherapy [72].

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 [2,3]. 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 [73]; 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.

INVESTIGATIONAL APPROACHES — A number of investigational approaches have been studied in patients with fibromyalgia, including medications and other strategies [74-90]. Of note are the following:

Transcranial stimulation – One of the more promising approaches has evaluated a variety of neuromodulation techniques in FM. 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 [83]. 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) [85]. 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 systematic review concluded that in comparison with sham stimulation, 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 [91].

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.

Transcutaneous electrical nerve stimulation – Trials of transcutaneous electrical nerve stimulation (TENS) have had mixed results and are inadequate to support the use of TENS for the treatment of fibromyalgia, although investigation of this approach is of interest because of the capacity of TENS to reduce central excitability and to activate central inhibition pathways [94-97]. (See "Overview of the treatment of chronic non-cancer pain", section on 'Transcutaneous electrical stimulation'.)

A randomized crossover trial suggested that TENS may have short-term efficacy in fibromyalgia [94]. Patients reported significant decreases in pain and fatigue with movement immediately after a single course of active TENS compared with a course of treatment with placebo TENS and no TENS (improvement in pain with movement on a 10 cm visual analog scale of 1.11, 95% CI 0.59-1.63, versus 0.23, 95% CI 0.24-0.77, versus 0.26, 95% CI -0.28 to 0.75). Pressure pain thresholds increased at the site of TENS (spine) and outside the site of TENS (leg) compared with placebo or no TENS; and during active TENS, conditioned pain modulation was significantly stronger compared with placebo and no TENS.

Memantine – A randomized trial of memantine (20 mg daily), involving 63 patients, showed statistically significant reductions in pain and increases in pain threshold compared with placebo at one, three, and six months of study [90]. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is available for clinical use in the treatment of dementia.

Melatonin – Melatonin, alone or in combination with amitriptyline, reduced pain in a small fibromyalgia trial [98].

Pramipexole – Benefit from pramipexole, a dopamine agonist, was shown in a study that randomly assigned patients either to pramipexole (increased from 0.25 mg to a maximum of 4.5 mg every evening) or to placebo [74]. Significantly greater improvement in the mean pain score was seen with pramipexole after 14 weeks. Higher doses were used than many patients can tolerate, however, and patients were left on their other medications, including opioids, in many instances. Thus, further study is needed to evaluate its efficacy and safety. We suggest limiting the use of pramipexole in fibromyalgia to patients who are refractory to the multiple better-established medications and other interventions described above.

Esreboxetine – An investigational, selective norepinephrine reuptake inhibitor, esreboxetine, showed benefit compared with placebo in a multicenter, randomized, eight-week trial involving 267 patients with fibromyalgia [99]. Significantly greater improvement was seen in pain, in fibromyalgia symptoms, in functional impairment, and in overall status compared with patients receiving placebo.

Quetiapine – Treatment with quetiapine fumarate extended release (once daily) improved depression scores and had modest beneficial effects on pain and quality of life compared with placebo in a randomized, eight-week trial involving 120 patients with the dual diagnoses of both fibromyalgia and major depressive disorder [100].

Naltrexone – A pilot study found that low-dose naltrexone reduced pain more than placebo (29 versus 18 percent) [101]. 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.

Growth hormone – Growth hormone, both as monotherapy and as adjunctive therapy, improves symptoms of fibromyalgia, although cost concerns and the need for long-term efficacy and safety data are considerations limiting its use [102].

Sodium oxybate – The sedative sodium oxybate is a commercially available preparation of naturally-occurring gamma hydroxybutyrate (GHB), a potent sedative. Several randomized trials demonstrated significantly improved fibromyalgia symptoms with this drug [87-89]. The effects of GHB in fibromyalgia were similar to those seen in narcolepsy treatment trials; it improved sleep of fibromyalgia patients, increased slow-wave sleep duration as well as delta power, and reduced frequent nighttime awakenings. Furthermore, pain and fatigue were consistently reduced with nightly GHB over time. Despite its proven efficacy, GHB did not receive FDA approval in the United States for the management of fibromyalgia in 2010, mostly because of concerns about potential for abuse [87,88,103].

Other hydroxytryptamine receptor antagonists, including dolasetron, which is administered intravenously, have been studied in other countries [104]. (See "Treatment of narcolepsy in adults", section on 'Sodium oxybate'.)

Creatine supplementation – An open-label, uncontrolled, eight-week study suggested that creatine supplementation might be of benefit in fibromyalgia [105]. However, in a 16-week randomized trial, creatine supplementation resulted in no significant benefit in pain, cognitive function, quality of sleep, aerobic conditioning, or quality of life when compared with placebo, despite some improvements in muscle strength and changes in intramuscular phosphorylcreatine content [106].

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 [107]. There were statistically significant reductions in pain and improvement in function in the treatment group.

Cannabinoids – Nabilone, a synthetic cannabinoid and a controlled substance in the United States, may have some beneficial effect on sleep in fibromyalgia, but any significant analgesic impact is unclear [75,76].

Hyperbaric oxygen therapy – A preliminary study demonstrated possible efficacy of hyperbaric oxygen in fibromyalgia [108].

SUMMARY AND RECOMMENDATIONS

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. (See 'Overview of treatment' above and 'Patients not responsive to initial therapy' above.)

We suggest using combination drug therapy in most patients unresponsive to monotherapy, 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.)

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.)

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.)

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.)

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.)

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.)

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