The efficacy and tolerability of milnacipran were evaluated in a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose trial of adults with FM. Patients received milnacipran 100 mg/day or 200 mg/day or placebo for 15 weeks.
Patients were eligible for enrollment if they:
- were between 18 and 70 years of age.
- had a diagnosis of primary FM, based on 1990 ACR criteria.
- had withdrawn from centrally active therapies commonly used to treat FM.
- had discontinued treatment using transcutaneous electrical nerve stimulation (TENS), biofeedback, acupuncture, anesthetic or narcotic patches, or injections for tender and trigger points.
- had a raw score of 4 or higher on the physical function component of the Fibromyalgia Impact Questionnaire (FIQ) and 40 or more out of 100 on the mean VAS pain score.
Patients were excluded from the study if they:
- had severe psychiatric illness.
- displayed current major depressive illness based on the Mini-International Neuropsychiatric Interview or had a score higher than 25 on the Beck Depression Inventory.
- exhibited a significant suicide risk.
- were abusing alcohol, benzodiazepines, or other drugs.
- had a history of behavior that prohibited compliance.
- had coexisting cardiovascular, pulmonary, hepatic, renal, GI, or auto-immune disease (except for Hashimoto’s or Graves’ disease that has been stable for three months before screening).
- had a systemic infection at the time.
- currently had cancer (except for basal cell carcinoma), unstable endocrine disease, severe sleep apnea, prostate enlargement or other genitourinary disorder.
- were pregnant or breast-feeding.
The study took place at 86 centers in the U.S. from November 2004 to December 2006. Before the trial, therapies that had the potential to interfere with pain symptoms of FM had to be discontinued. Of the 2,270 patients who were screened, 1,196 received milnacipran 100 mg/day, milnacipran 200 mg/day, or placebo, given as two daily doses.
Patients entered a one-week to four-week period for washout of prohibited medications, followed by a two-week baseline assessment period. Milnacipran-treated patients received 12.5 mg on day 1, 12.5 mg twice daily for two days, 25 mg twice daily for four days, and 50 mg twice daily for seven days. Patients receiving 200 mg/day received 100 mg twice daily for seven days; all other patients underwent a sham dose escalation to maintain blinding. After the escalation, the dosage was unchanged from week 3 to 15 (a total of 12 weeks). Any patient who was intolerant of the medication was dropped from the trial.
Baseline demographics in all treatment arms were similar. The primary efficacy measure was a composite response rate based on these endpoints:
- pain improvement of 30% or more in VAS 24-hour morning recall
- Patient Global Impression of Change (PGIC) ratings of “very much improved” or “much improved”
- an improvement of 6 points or more on the Medical Outcome Short-Form 36 (SF-36) Physical Component Summary (PCS) score
After 15 weeks, a significantly greater number of patients receiving milnacipran 100 mg/day and 200 mg/day achieved the primary endpoints of meeting the three criteria for a FM composite response versus placebo (milnacipran doses of 100 mg/day, P = 0.01; milnacipran doses of 200 mg/day, P = 0.02). The number of patients experiencing more than a 30% improvement from baseline with 24-hour pain was highest with milnacipran 200 mg/day (39.9%), compared with 100 mg/day (37.3%) or placebo (28.7%).
The most frequently reported AE with the study drug was nausea, which occurred in 37.6% of patients taking 200 mg/day, in 34.3% of those taking 100 mg/day, and in 19.2% taking placebo. Other commonly reported AEs were dizziness, palpitations, hot flushes, hypertension, vomiting, tachycardia, hyperhidrosis, constipation, and migraines. Discontinuation rates attributable to AEs were higher with milnacipran than with placebo (23.7% with 200 mg/day, 19.5% with 100 mg/day, and 9.5% with placebo). Overall, milnacipran showed significant efficacy over placebo for treating FM; however, the higher dose of 200 mg/day was associated with more AEs.