Mease and colleagues performed a randomized, double-blind study to confirm the safety and efficacy of milnacipran in patients with FM. This 27-week study compared milnacipran 100 mg/day and 200 mg/day with placebo.
Eligibility requirements were as follows:
- Female and male subjects were between 18 and 70 years of age.
- Patients had a diagnosis of primary FM, based on 1990 ACR criteria.
Patients were excluded from the study if they:
- had severe psychiatric illness, a current major depressive episode, or a risk of suicide.
- were abusing alcohol or drugs.
- had an autoimmune disease, a systemic infection, moderate-to-severe sleep apnea, an active peptic ulcer, or inflammatory bowel disease.
- currently had cancer or were undergoing concurrent chemotherapy.
- had a history of significant cardiovascular, respiratory, endocrine, genitourinary, liver, or kidney disease.
The 888 eligible patients from 59 centers in the U.S. were randomly assigned to receive milnacipran 100 mg/day, milnacipran 200 mg/day, or placebo in two divided doses for six months. The study involved four phases, beginning with a screening and washout phase of centrally acting therapies used for treating FM, followed by the baseline assessment phase. The next three weeks consisted of the dose-escalation phase, in which patients reached their assigned dose level. Sham dosing was implemented in the placebo patients and in the group receiving milnacipran 100 mg/day to maintain blinding. In the final phase, patients received stable doses for 24 weeks.
Baseline demographics were similar for all treatment arms. The primary efficacy measure for the treatment of FM pain was a composite response rate based on the following endpoints:
- an improvement in pain of 30% or more in VAS 24-hour morning recall
- Patient Global Impression of Change (PGIC) ratings of “very much improved” or “much improved”
At week 15, the midpoint of the study, more patients treated with milnacipran doses of 100 mg/day (27.2%; P = 0.056) and 200 mg/day (26.8%; P = 0.032) met the primary outcome criteria of FM pain responders compared with the placebo patients (19.3%). At the end of the study (at six months), more patients in both milnacipran groups met the criteria for response for treating FM pain (200 mg/day, 25.6%; 100 mg/day, 25.9%; and placebo, 18.4%).
Although the patients receiving milnacipran 100 mg/day had the highest composite response rate for the treatment of FM pain, there was only a trend toward reaching statistical significance (P = 0.072). Results for the 200-mg/day group differed significantly from those of the placebo group (P = 0.034).
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Improvements were observed during the study, but the rate of discontinuation associated with milnacipran use was extremely high. At week 27, 42.9% of patients receiving milnacipran 100 mg/day, 45.8% receiving 200 mg/day, and 35% of patients receiving placebo had discontinued therapy. Of the patients receiving milnacipran 200 mg/day, 27% withdrew from therapy because of AEs, compared with 19.6% taking milnacipran 100 mg/day and 10.3% receiving placebo.
Therapeutic failure was the second highest reason for discontinuing milnacipran; 11.1% of patients taking 200 mg/day stopped therapy, and 11.6% taking 100 mg/day withdrew. A higher percentage of patients receiving placebo (15.2%) experienced therapeutic failures.
Overall, milnacipran was associated with significant improvements in the treatment of pain associated with FM; however, higher doses were associated with more side effects.