Fibromyalgia is a chronic and debilitating condition that is characterized by widespread pain and decreased physical functioning. More than 6 million Americans have fibromyalgia, and it’s the second most commonly diagnosed condition in rheumatology clinics in the United States after osteoarthritis. Despite its high prevalence and severity, there are limited treatment options specifically approved for the condition. Treatments are intended to minimize symptoms and improve general health. Analgesics can be beneficial for some patients, but some specific classes of anti-seizure medications (alpha-2-delta ligands) and antidepressants (dual reuptake inhibitors) have recently been shown to be particularly effective for managing symptoms.

A New Treatment Option

In January 2009, milnacipran (Savella, Forest Laboratories, Inc. and Cypress Bioscience, Inc.), a new selective serotonin and norepinephrine dual reuptake inhibitor (SNRI), was approved by the FDA for fibromyalgia. Although the exact mechanism by which milnacipran improves symptoms is unknown, it’s believed that abnormalities in certain brain neurotransmitters may be central to the augmented pain processing seen in fibromyalgia. The agent blocks the reuptake of both norepinephrine and serotonin, with greater selectivity for the inhibition of norepinephrine reuptake in vitro. This is the most likely mechanism of action for improvement in symptoms. Milnacipran was developed in a unique clinical development program in which patients were considered responders to therapy only if they demonstrated concurrent clinically significant changes in multiple aspects of their fibromyalgia, including pain, patient global assessment, and physical function.

Analyzing the Data

The effectiveness of milnacipran was evaluated based upon the multiple symptoms included in the responder analysis. Safety and efficacy were established in two U.S. pivotal phase III clinical trials involving more than 2,000 patients with fibromyalgia. These studies showed that milnacipran led to statistically significant and clinically meaningful concurrent improvements in pain, patient global assessment, and physical function. In both studies, more patients in the milnacipran treatment arms (100 mg/day and 200 mg/day) at 3 months experienced at least a 30% reduction in pain from baseline and also rated themselves as either “very much improved” or “much improved” as compared with placebo treatment. Additionally, more patients treated with the drug met the criteria for a treatment response when compared with placebo recipients. In both studies, some patients receiving milnacipran experienced decreases in pain as early as week 1 after treatment was initiated.

Most adverse reactions reported in clinical trials were mild to moderate in nature. As noted, milnacipran is an SNRI similar to some drugs used for the treatment of depression and other psychiatric disorders. In short-term studies of major depressive disorder and other psychiatric disorders, antidepressants increased the risks (compared with placebo) for suicidality in children, adolescents, and young adults. When considering use of milnacipran in these patients, risks must be balanced with clinical need. The drug is not approved for use in pediatric patients. Individuals of all ages who are started on milnacipran should be monitored closely for clinical worsening, suicidality, or unusual changes in behavior. Contraindications include use of monoamine oxidase inhibitors concomitantly or in close temporal proximity and use in patients with uncontrolled narrow-angle glaucoma. Blood pressure and heart rate should be monitored before initiating the therapy and periodically throughout treatment. Milnacipran should be prescribed cautiously in people with seizure disorders, substantial alcohol use or chronic liver disease, and those at risk for bleeding events. If milnacipran must be discontinued, doses of the drug should be reduced gradually.

Fulfilling a Need

Milnacipran is now the third drug approved for use in fibromyalgia, but it’s unlikely that any single class of drugs will work in all fibromyalgia sufferers. However, the addition of milnacipran represents an exciting addition to the treatment armamentarium for this condition.

Daniel J. Clauw, MD, has indicated to Physician’s Weekly that he has worked as a consultant for Pfizer, Eli Lilly, Forest Laboratories, Pierre Fabre, Cypress Biosciences, UCB, Wyeth, and Proctor and Gamble. He has also received grants/research aid from Pfizer, Forest Laboratories, and Cypress Biosciences.

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