Milnacipran for fibromyalgia in adults

Fibromyalgia is characterised by persistent, widespread pain and tenderness, sleep problems, and fatigue. Common pain-relieving medicines such as paracetamol and ibuprofen are not usually considered effective. Medicines used to treat epilepsy or depression can be effective in some people with fibromyalgia and other forms of chronic (persistent, long-lasting) pain where there may be nerve damage. Milnacipran is an antidepressant, and antidepressants are widely recommended for treating fibromyalgia. Milnacipran is licensed to treat fibromyalgia only in some parts of the world, particularly the USA.

This review is an update of one originally published in 2012, which examined how well milnacipran worked in both fibromyalgia and neuropathic pain conditions (pain from damage to nerves or disease affecting the nerves). Here we examine only fibromyalgia. The earlier review showed that milnacipran worked, but only in a small proportion of people with fibromyalgia. This is the same as all other fibromyalgia treatments to date, and for chronic pain conditions generally. We use a definition of 'worked' that involved both a high level of pain relief and the ability to take the tablets over a longer time without side effects being intolerable.

We searched scientific databases for studies that looked at the effects of milnacipran in adults with fibromyalgia who had moderate or severe pain. The treatment had to last at least eight weeks. The evidence is current to May 2015.

We identified six studies that satisfied the inclusion criteria, including one new study for this update. Over 4000 participants were treated with milnacipran 100 or 200 mg, or placebo, for 8 to 24 weeks at the target dose. Overall study quality was good, although the method of analysis for our primary outcomes of pain relief could overestimate treatment effect.

Milnacipran at either dose provided moderate pain relief (at least 30% reduction in pain intensity) to 1 in 10 (10%) more people than did placebo (high quality evidence). This relatively modest effect may be clinically important in this difficult-to-treat condition. Adverse events were reported by most participants in all treatment groups, but were more common with milnacipran than placebo (high quality evidence), with nausea (feeling sick) and constipation showing the greatest differences (moderate quality evidence). Serious adverse events were uncommon, fewer than 1 in 50 (2%) participants, and did not differ between treatment groups (low quality evidence). The numbers of participants dropping out of the studies (withdrawals) because of adverse events were also more common with milnacipran than placebo, and were more common with 200 mg than 100 mg (high quality evidence), while withdrawals due to lack of effect were less common with milnacipran, with no difference between doses (moderate quality evidence).

Milnacipran gives good pain relief to some people with fibromyalgia, but only a minority; it will not work for most people.

Authors' conclusions: 

The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority in the treatment of pain due to fibromyalgia, providing moderate levels of pain relief (at least 30%) to about 40% of participants, compared with about 30% with placebo. There were insufficient data to assess substantial levels of pain relief (at least 50%), and the use of last observation carried forward imputation may overestimate drug efficacy. Using stricter criteria for 'responder' and a more conservative method of analysis gave lower response rates (about 26% with milnacipran versus 17% with placebo). Milnacipran was associated with increased adverse events and adverse event withdrawals, which were significantly greater for the higher dose.

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Background: 

This is an updated version of the original Cochrane review published in Issue 3, 2012. That review considered both fibromyalgia and neuropathic pain, but the efficacy of milnacipran for neuropathic pain is now dealt with in a separate review.

Milnacipran is a serotonin-norepinephrine (noradrenaline) reuptake inhibitor (SNRI) that is licensed for the treatment of fibromyalgia in some countries, including Canada, Russia, and the United States.

Objectives: 

To assess the analgesic efficacy of milnacipran for pain in fibromyalgia in adults and the adverse events associated with its use in clinical trials.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE to 18 May 2015, together with reference lists of retrieved papers and reviews, and two clinical trial registries. For the earlier review, we also contacted the manufacturer.

Selection criteria: 

We included randomised, double-blind studies of eight weeks' duration or longer, comparing milnacipran with placebo or another active treatment in fibromyalgia in adults.

Data collection and analysis: 

We extracted efficacy and adverse event data, and two review authors examined issues of study quality independently.

Main results: 

We identified one new study with 100 participants for the pooled analysis. We identified two additional reports of a study using an enriched enrolment randomised withdrawal (EERW) design that included participants from earlier randomised controlled trials and an open-label study. Because this study used the same participants already included in our main analysis, and a different design, we dealt with it separately.

The main analysis included six studies (five from the earlier review; 4238 participants in total), all of which were placebo-controlled, and used titration to a target dose of milnacipran 100 or 200 mg, with assessment after 8 to 24 weeks of stable treatment. There were no studies with active comparators. Study quality was generally good, although the imputation method used in analyses of the primary outcomes could overestimate treatment effect.

Both doses of milnacipran provided moderate levels of pain relief (at least 30% pain intensity reduction) to about 40% of participants treated, compared to 30% with placebo, giving a number needed to treat for an additional beneficial outcome (NNT) of 6 to 10 (high quality evidence). Using a stricter definition for responder and a more conservative method of analysis gave lower levels of response (while maintaining a 10% difference between milnacipran and placebo) and increased the NNT to 11 (high quality evidence). One EERW study was broadly supportive.

Adverse events were common in both milnacipran (86%) and placebo (78%) groups (high quality evidence), but serious adverse events did not differ between groups (less than 2%) (low quality evidence). Nausea, constipation, and headache were the most common events showing the greatest difference between groups (number needed to treat for an additional harmful outcome (NNH) of 5.7 for nausea, 13 for constipation, and 29 for headache) (moderate quality evidence).

Withdrawals for any reason were more common with milnacipran than placebo, and more common with 200 mg (NNH 9) than 100 mg (NNH 23), compared with placebo. This was largely driven by adverse event withdrawals, where the NNH compared with placebo was 14 for 100 mg and 7.0 for 200 mg (high quality evidence). Withdrawals due to lack of efficacy were less common with milnacipran than placebo but did not differ between doses (number needed to treat to prevent an additional unwanted outcome (NNTp) of 41) (moderate quality evidence).

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