Neil Osterweil

June 13, 2008

June 13, 2008 (Paris) — The investigational agent milnacipran has displayed activity against multiple symptoms of fibromyalgia syndrome, according to European investigators. They reported the results of a phase 3 study here at EULAR 2008, the European League Against Rheumatism Annual Congress.

In the placebo-controlled trial, patients who received up to 12 weeks of milnacipran after a 4-week dose-escalation run-in phase had about a 2-fold improvement in a composite endpoint of pain and Patient Global Impression of Change score than placebo, said lead author Jaime Branco, MD, professor of rheumatology at the CHLO, EPE-Hospital Egas Moniz in Lisbon, Portugal.

"We saw that milnacipran is significantly better than placebo in...fibromyalgia patients," Dr. Branco told Medscape Rheumatology. "The global index, a measure of pain and function, was better in patients on milnacipran than on placebo."

The results were similar to those seen in a US trial of milnacipran, the results of which were previously reported at the American College of Rheumatology 2007 annual meeting in Boston, Dr. Branco said.

Milnacipran is a dual norepinephrine- and selective serotonin-reuptake inhibitor that has greater affinity for blocking reuptake of the former. It is currently under US Food and Drug Administration review for the treatment of fibromyalgia.

The European trial looked at 884 patients from 83 study centers in 13 countries. Patients aged 18 to 70 years with a diagnosis of fibromyalgia syndrome according to 1990 American College of Rheumatology criteria were randomly assigned to receive either 200 mg of milnacipran per day, divided into 2 doses of 100 mg each (435 patients), or placebo (449 patients).

The primary efficacy endpoint was a composite responder rate based on a reduction of 30% or more in pain from baseline in the 24-hour recall pain score recorded on an electronic diary Patient Global Impression of Change rating of either 1 (very much improved) or 2 (much improved)

The investigators also looked at the Fibromyalgia Impact Questionnaire total score change from baseline as a secondary efficacy endpoint.

A total of 678 patients completed the study (308 received milnacipran and 370 received placebo). At the end of the 12-week fixed-dose period, 24.2% of patients receiving milnacipran achieved the primary composite endpoint compared with 14.6% of those receiving placebo, with an odds ratio of 1.9 (confidence interval not shown; P = .0003).

For the secondary endpoint, there was a difference in the Fibromyalgia Impact Questionnaire score of −3 points (standard error from the mean of 1.2) in favor of milnacipran (P = .015).

Milnacipran was also significantly better at improving 24-hour recall pain as measured by a visual analog scale (P < .0001), as well as weekly pain ratings (P < .001). The effects were seen starting at week 4 — the end of the dose escalation period — and continued through the end of treatment.

Adverse events occurred in 74% of patients receiving placebo compared with 84% of patients receiving milnacipran (P value not shown).

Treatment-associated adverse events (in the placebo and milnacipran groups, respectively) included nausea (11.2% vs 26.0%), constipation (2.2% vs 12.55%), hyperhydrosis (2.9% vs 23.7%), and increased heart rate (1.4% vs 10.4%). Adverse events were similar to those seen in the US study, except for increased heart rate. In the American study, increased heart rate occurred in 0.2% of patients receiving placebo vs 5% of patients receiving milnacipran.

"We utilized the same dose of the drug as in the US study, 200 mg, [but] the body weight of patients in Europe was a mean 10 kilos less...than the United States, and it may be a difference because of that," Dr. Branco told Medscape Rheumatology. The heart rate elevations were moderate, however, and the events "were of no clinical importance, and patients had no symptoms of it."

A rheumatologist from the United Kingdom who was not involved in the study told Medscape Rheumatology that he welcomed any new development in the area of fibromyalgia.

"Any improvement in our patients is a significant thing," said Bela Szebenyi, MD, from the Grimsby Hospital in Lancashire.

Dr. Szebenyi said that although pregabalin (Lyrica, Pfizer) is approved in the United Kingdom for use in patients with fibromyalgia and documented symptoms such as anxiety, fear, or depression, "our major concern is that the pregabalin-treated population presents with a very high frequency of side effects such as nausea, vomiting, [and] fainting, and they can't tolerate it properly. Therefore, we are always looking for new things like this, and this seems to have a little bit better side-effect profile."

The study was funded by Pierre Fabre Medicament, the maker of milnacipran and holder of marketing rights outside the United States and Canada. Dr. Branco has received research support from the company. Dr. Szebenyi has disclosed no relevant financial relationships.

EULAR 2008: The European League Against Rheumatism Annual Congress: Abstract THU0365. Presented June 12, 2008.

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