Abstract: 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). 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.

Plain-language summary: 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.