ORLANDO, Florida—Fibromyalgia (FMS) clinical trials with duloxetine (DLX) and with milnacipran reported at the American Academy of Pain Medicine 2007 annual meeting offer hope that these new-model antidepressants might provide effective pain relief in this complicated syndrome. DLX (Cymbalta®, Eli Lilly and Co) is a serotonin and norepinephrine reuptake inhibitor. Milnacipran (Ixel®, Cypress Bioscience, Inc) is a norepinephrine serotonin reuptake inhibitor.

Efficacy, safety data for duloxetine in FMS

Lilly researchers led by Madelaine Wohlreich, MD, reported safety and efficacy data from a 6-month randomized, double-blind, placebo-controlled, fixed-dose trial of DLX 120 mg/d in 497 patients with FMS.¹

Primary efficacy measures included the Brief Pain Inventory Average Pain Score (APS), and the Patients Global Impressions of Improvement (PGI-I) questionnaire.

Pain scores at 3 months had improved significantly better with DLX than with placebo (APS score change from baseline -2.31 vs -1.38, P <.001). PGI-I scores were 2.89 vs 3.39, P = .004). The DLX group maintained greater improvement in APS at 6 months (-2.25 vs -1.42 with placebo, P = .003) and also maintained the PGI-I improvement (2.93 vs 3.37, P = .012).

Response at 6 months, defined as >e;50% reduction from baseline in APS, was 35.9% with DLX 120 mg/d versus 21.5% with placebo (P <e;.01). DLX was equally effective in patients with or without major depressive disorder (MDD). However, >25% of patients on DLX 120 mg/d discontinued treatment due to adverse events, versus 15.3% with placebo (P = .003).

DLX 60 mg/d was less effective than the higher dose regimen, but had discontinuation rates similar to those in the placebo group. "DLX 60 and DLX 120 mg/d are efficacious and safe treatment options for pain associated with FMS, whether or not MDD is present," Dr. Wohlreich concluded.

The Lilly researchers also reviewed data from clinical trials, spontaneous reports, and external databases to look at hepatic effects of DLX.² They found an association with transient elevations of transaminases in ~1% of patients, and a hepatic failure rate of 0.6 per 100,000 person-years in >5 million patients taking DLX for depression. "DLX has an effect on the liver which, in the vast majority of cases, is clinically benign. More serious cases, including liver failure have been reported, but these appear to be similar to the background rate in the general population," Dr. Wohlreich reported.

Efficacy, safety data for milnacipran in FMS

Daniel J. Clauw, MD, from the University of Michigan Medical School in Ann Arbor led a research team that studied milnacipran in FMS in trials funded by Cypress Bioscience.³ They randomized 1196 patients to placebo (n = 401), to milnacipran 100 (n = 399), or to milnacipran 200 mg/d (n = 396) for 15 weeks.

The primary outcome measure was a composite score for pain, global improvement, and physical function.  "Pain responders" were defined as having >e;30% improvement from baseline in pain and a rating of "very much improved" or "much improved" on the physician global assessment. "Syndrome responders" met these criteria plus improvement in physical function >e;6 point improvement on short form SF-36 physical component score.

At 15 weeks patients treated with milnacipran had significantly higher response rates both for pain and for the syndrome. "Milnacipran significantly improved pain within 1 week of dosing," Dr. Clauw reported. Both doses of milnacipran led to significant improvements in pain and function scores, as well as in scores on the Fibromyalgia Impact Questionnaire and the Multidimensional Fatigue Inventory. Discontinuation rates were similar between groups.

Analysis of the 1-year durability of response to milnacipran, led by Don Goldenberg, MD, of Newton-Wellesley Hospital in Massachusetts included ~600 patients maintained on milnacipran in a randomized, double-blind extension trial. Dr. Goldenberg reported that response was maintained over the entire 1-year period.⁴ "To our knowledge, this is the first demonstration of 1-year sustained efficacy in FMS," Dr. Goldenberg said.

Further efficacy and safety data were reported by researchers, again led by Daniel J. Clauw, MD, who studied  888 FMS patients randomized to placebo (n = 223), milnacipran 100 mg/d (n = 224), or 200 mg/d (n = 441) for 6 months.⁵ Endpoints were the same as for the earlier study.

Dr. Clauw reported that at 3 months, milnacipran was associated with a significant improvement in the pain composite score and in the syndrome composite score. "In patients completing the trial, composite pain response rates were 27.9%, placebo; 43.8%, 100 mg/d; and 45.2%, 200 mg/d. In the drug-treated groups, the most common side effects were nausea, headache, and constipation," he noted.

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