Abstract

Background

Fibromyalgia is a clinically defined chronic condition of unknown etiology characterized by chronic widespread pain that often co‐exists with sleep disturbances, cognitive dysfunction and fatigue. People with fibromyalgia often report high disability levels and poor quality of life. Drug therapy, for example, with serotonin and noradrenaline reuptake inhibitors (SNRIs), focuses on reducing key symptoms and improving quality of life. This review updates and extends the 2013 version of this systematic review.

Objectives

To assess the efficacy, tolerability and safety of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo or other active drug(s) in the treatment of fibromyalgia in adults.

Search methods

For this update we searched CENTRAL, MEDLINE, Embase, the US National Institutes of Health and the World Health Organization (WHO) International Clinical Trials Registry Platform for published and ongoing trials and examined the reference lists of reviewed articles, to 8 August 2017.

Selection criteria

We selected randomized, controlled trials of any formulation of SNRIs against placebo or any other active treatment of fibromyalgia in adults.

Data collection and analysis

Three review authors independently extracted data, examined study quality, and assessed risk of bias. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 50% or greater and of 30% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardized mean differences (SMD) for fatigue, sleep problems, health‐related quality of life, mean pain intensity, depression, anxiety, disability, sexual function, cognitive disturbances and tenderness. For tolerability we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawals due to adverse events and for nausea, insomnia and somnolence as specific adverse events. For safety we calculated NNTH for serious adverse events. We undertook meta‐analysis using a random‐effects model. We assessed the evidence using GRADE and created a 'Summary of findings' table.

Main results

We added eight new studies with 1979 participants for a total of 18 included studies with 7903 participants. Seven studies investigated duloxetine and nine studies investigated milnacipran against placebo. One study compared desvenlafaxine with placebo and pregabalin. One study compared duloxetine with L‐carnitine. The majority of studies were at unclear or high risk of bias in three to five domains.

The quality of evidence of all comparisons of desvenlafaxine, duloxetine and milnacipran versus placebo in studies with a parallel design was low due to concerns about publication bias and indirectness, and very low for serious adverse events due to concerns about publication bias, imprecision and indirectness. The quality of evidence of all comparisons of duloxetine and desvenlafaxine with other active drugs was very low due to concerns about publication bias, imprecision and indirectness.

Duloxetine and milnacipran had no clinically relevant benefit over placebo for pain relief of 50% or greater: 1274 of 4104 (31%) on duloxetine and milnacipran reported pain relief of 50% or greater compared to 591 of 2814 (21%) participants on placebo (risk difference (RD) 0.09, 95% confidence interval (CI) 0.07 to 0.11; NNTB 11, 95% CI 9 to 14). Duloxetine and milnacipran had a clinically relevant benefit over placebo in patient's global impression to be much or very much improved: 888 of 1710 (52%) on duloxetine and milnacipran (RD 0.19, 95% CI 0.12 to 0.26; NNTB 5, 95% CI 4 to 8) reported to be much or very much improved compared to 354 of 1208 (29%) of participants on placebo. Duloxetine and milnacipran had a clinically relevant benefit compared to placebo for pain relief of 30% or greater. RD was 0.10; 95% CI 0.08 to 0.12; NNTB 10, 95% CI 8 to 12. Duloxetine and milnacipran had no clinically relevant benefit for fatigue (SMD ‐0.13, 95% CI ‐0.18 to ‐0.08; NNTB 18, 95% CI 12 to 29), compared to placebo. There were no differences between either duloxetine or milnacipran and placebo in reducing sleep problems (SMD ‐0.07; 95 % CI ‐0.15 to 0.01). Duloxetine and milnacipran had no clinically relevant benefit compared to placebo in improving health‐related quality of life (SMD ‐0.20, 95% CI ‐0.25 to ‐0.15; NNTB 11, 95% CI 8 to 14).

There were 794 of 4166 (19%) participants on SNRIs who dropped out due to adverse events compared to 292 of 2863 (10%) of participants on placebo (RD 0.07, 95% CI 0.04 to 0.10; NNTH 14, 95% CI 10 to 25). There was no difference in serious adverse events between either duloxetine, milnacipran or desvenlafaxine and placebo (RD ‐0.00, 95% CI ‐0.01 to 0.00).

There was no difference between desvenlafaxine and placebo in efficacy, tolerability and safety in one small trial.

There was no difference between duloxetine and desvenlafaxine in efficacy, tolerability and safety in two trials with active comparators (L‐carnitine, pregabalin).

Authors' conclusions

The update did not change the major findings of the previous review. Based on low‐ to very low‐quality evidence, the SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in the frequency of pain relief of 50% or greater, but for patient's global impression to be much or very much improved and in the frequency of pain relief of 30% or greater there was a clinically relevant benefit. The SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in improving health‐related quality of life and in reducing fatigue. Duloxetine and milnacipran did not significantly differ from placebo in reducing sleep problems. The dropout rates due to adverse events were higher for duloxetine and milnacipran than for placebo. On average, the potential benefits of duloxetine and milnacipran in fibromyalgia were outweighed by their potential harms. However, a minority of people with fibromyalgia might experience substantial symptom relief without clinically relevant adverse events with duloxetine or milnacipran.

We did not find placebo‐controlled studies with other SNRIs than desvenlafaxine, duloxetine and milnacipran.

Author(s)

Patrick Welsch, Nurcan Üçeyler, Petra Klose, Brian Walitt, Winfried Häuser

Abstract

Plain language summary

Serotonin and noradrenaline reuptake inhibitors for fibromyalgia

Bottom line

Duloxetine and milnacipran may reduce pain in people with fibromyalgia. However, some of these people may also experience side effects, such as nausea (feeling sick) and drowsiness. A minority of people with fibromyalgia experience symptom relief without side effects from duloxetine and milnacipran.

Background

People with fibromyalgia often have chronic (longer than three months) widespread pain, as well as problems with sleep, thinking and exhaustion. They often report poor health‐related quality of life. There is no cure for fibromyalgia at present, so the treatments aim to relieve the symptoms and to improve health‐related quality of life.

Serotonin and noradrenaline are chemicals which are produced by the human body, involved in the regulation of pain, sleep and mood. Low concentrations of serotonin have been reported in people with fibromyalgia. Serotonin and noradrenaline reuptake inhibitors (SNRIs) are a class of antidepressants that increase the concentration of serotonin and noradrenaline in the brain.

Study characteristics

In August 2017, we updated our searches for clinical trials in which SNRIs were used to treat symptoms of fibromyalgia in adults. We found eight new studies since the previous version of the review. In total, we found 18 studies with 7903 participants. The studies were four to 27 weeks long and compared the SNRIs desvenlafaxine, duloxetine and milnacipran against a fake medication (placebo). We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low‐quality evidence means that we are very uncertain about the results. High‐quality evidence means that we are very confident in the results.

Key results and quality of the evidence

Duloxetine and milnacipran were better than placebo in reducing pain by 50% or more and in improving global well‐being (low‐quality evidence). Duloxetine and milnacipran were better than placebo in improving health‐related quality of life and in reducing fatigue (low‐quality evidence). Duloxetine and milnacipran were not better than placebo in reducing sleep problems (low‐quality evidence). More people dropped out of the trial due to side effects with duloxetine and milnacipran than with placebo (low‐quality evidence). More people reported nausea and drowsiness with duloxetine and milnacipran than with placebo (low‐quality evidence). Duloxetine, milnacipran and placebo did not differ in the frequency of serious side effects experienced (very low‐quality evidence).

Author(s)

Patrick Welsch, Nurcan Üçeyler, Petra Klose, Brian Walitt, Winfried Häuser

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For people with fibromyalgia

Only a minority of people may profit from treatment with the serotonin and noradrenaline reuptake inhibitors (SNRIs) duloxetine and milnacipran in terms of meaningful relief of fibromyalgia symptoms and a good tolerability of the drug. The majority of people will not experience substantial relief of fibromyalgia symptoms or will terminate the treatment because of adverse events, or both. There is no evidence for the efficacy of other SNRIs such as desvenlafaxine and venlafaxine.

For physicians

If duloxetine or milnacipran are being considered for the treatment of fibromyalgia, a frank discussion between the physician and patient about the potential benefits and harms of both drugs is important. The contraindications (concomitant use of monoamine oxidase inhibitors, uncontrolled narrow‐angle glaucoma, substantial alcohol use or evidence of chronic liver damage) and warnings (suicidality, hepatotoxicity, serotonin syndrome, abnormal bleeding, discontinuation syndrome, elevated blood pressure, urinary hesitation and retention) are to be discussed (Häuser 2010b). Defining realistic goals of therapy (e.g. pain relief of 30% or more and/or improvement of daily functioning) by people with fibromyalgia and their physicians before starting drug treatment has been recommended (Häuser 2015b).

The recommended dosages are duloxetine 60 mg a day, and milnacipran 100 mg a day. A dose response has not been demonstrated. Higher doses are associated with more adverse events (Cording 2015; Häuser 2010b). Treatment has only been continued in responders, that is to say in people who reached the predefined treatment goals with a reasonable tolerability of duloxetine or milnacipran (Petzke 2017).

A class effect of SNRIs on fibromyalgia symptoms cannot be assumed. One study found no difference between four dosages of desvenlafaxine and placebo in mean pain intensity reduction (NCT00697787). One study found no differences between venlafaxine and placebo in all outcomes of efficacy (Ziljstra 2002).

Treating fibromyalgia with drugs only, such as SNRIs alone, is discouraged since current best practices in fibromyalgia guidelines recommend using the combination of pharmacological therapy with aerobic exercise and psychological therapies (Ablin 2013; MacFarlane 2017; Petzke 2017).This is especially true for symptoms where duloxetine and milnacipran are ineffective, but other therapies are effective, for example, aerobic exercise for fatigue (Häuser 2010c), and cognitive‐behavioral therapies for depression (Bernardy 2017).

Since relatively few participants achieve a worthwhile response with SNRIs, it is important to establish stopping rules, so that when someone does not respond within a specified time, they can be switched to an alternative treatment. This will reduce the number of participants exposed to adverse events in the absence of benefit. One study included in this review demonstrated that some people with fibromyalgia who do not respond to duloxetine might respond to milnacipran (Bateman 2013).

For policy‐makers

Since no single treatment is effective in a majority of individuals with fibromyalgia, this relatively small number who benefit may be considered worthwhile, particularly if appropriate switching or stopping rules are in place.

For funders

Treatment with duloxetine and milnacipran for fibromyalgia may be considered worthwhile, particularly if switching and stopping rules are in place in case the predefined treatment goals are not reached or the drugs are not well tolerated, or both. It is important that the treatment is supervised by a physician experienced in the treatment with duloxetine and milnacipran.

Implications for research 

General

Analysis of all studies investigating duloxetine and milnacipran in fibromyalgia at the level of individual participant data could provide important information, for example, whether or not a clinically important pain response delivers large functional and quality‐of‐life benefits. Moreover, a re‐analysis of the data using baseline observation carried forward, and responder analysis where discontinuation is classified as non‐response, would allow a determination of the true efficacy of duloxetine and milnacipran in fibromyalgia. All journals should follow the BMJ rule that reports of randomized trials will only be considered for publication if the authors commit to making the relevant anonymous participant‐level data available on reasonable request (BMJ).

Studies in any continent and the inclusion of people with inflammatory rheumatic diseases, osteoarthritis and mental disorders (depressive and anxiety disorders, post‐traumatic stress disorder) are necessary to provide external validity of the study findings.

A standardized psychiatric interview at study entry can stratify participants according to comorbid anxiety and depressive disorders.

There is bias towards studies conducted in USA. To provide generalizability of study results, study populations equally recruited from every continent are necessary.

It is necessary that the details of the assessment of adverse events (spontaneous reports, open questions, symptom questionnaires) are reported by the studies because the type and frequency of adverse events is influenced by the modes of assessment (Häuser 2012). It is mandatory that adverse events should be reported using the International Conference on Harmonization guidelines, and coded within organ classes using the Medical Dictionary for Regulatory Activities (MedDRA) (International Council for Harmonisation 2016). It is desirable that regulatory agencies standardize the assessment strategies of adverse events in RCTs.

It is important to control for potential effects of co‐interventions on outcomes.

Measurement (endpoints)

It is important to use responder criteria for a clinically relevant improvement of sleep problems, fatigue, depression and physical function (disability) (Arnold 2012b). Homogeneous outcomes for studies with an EERW design need to be defined.

Comparison between active treatments

It is important not only to compare with placebo but also with drugs with known efficacy, such as amitriptyline or pregabalin. In addition, more studies with defined subgroups (e.g. major depression, no adequate response to a specific drug treatment) are necessary.

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