Milnacipran (Savella): Selective norepinephrine and serotonin reuptake inhibitor approved for the management of fibromyalgia

Milnacipran is a selective norepinephrine and serotonin reuptake inhibitor that inhibits norepinephrine uptake with greater potency than serotonin uptake. The precise mechanism by which this agent inhibits pain and improves the symptoms of fibromyalgia is unknown. Milnacipran was approved on January 14, 2009, for the management of fibromyalgia.

Efficacy. The efficacy of milnacipran was evaluated in 2 double-blind, placebo-controlled, multicenter studies. Eligible patients met the American College of Rheumatology (ACR) criteria for fibromyalgia. In Study 1, patients with a minimum mean baseline pain score of ≥50 mm on a 100-mm visual analog scale (VAS) were randomized to treatment with milnacipran 100 or 200 mg/d or placebo for 6 months. In Study 2, patients with a minimum mean baseline pain score of ≥40 mm were randomized to treatment with milnacipran 100 or 200 mg/d or placebo for 3 months. Across both studies, patients treated with milnacipran were more likely to experience a simultaneous reduction in pain of ≥30% (as assessed by VAS) than placebo-treated patients. Milnacipran-treated patients were also more likely to rate themselves as much improved or very much improved on the patient global assessment. A larger percentage of milnacipran-treated patients met the criteria for treatment response (a composite end point including improvement in pain [VAS], physical function, and patient global assessment) compared with placebo-treated patients. In both studies, milnacipran 200 mg/d did not lead to greater efficacy than milnacipran 100 mg/d.

Safety. Patients with depression or other psychiatric disorders may experience worsening of depression, suicidal ideation and behavior, or unusual changes in behavior; treatment with drugs that inhibit norepinephrine and/or serotonin reuptake may play a role in inducing these symptoms. Patients treated with antidepressants should therefore be monitored closely for changes in behavior, especially early in treatment and at times of dose changes. Treatment with drugs that inhibit serotonin reuptake may lead to the development of serotonin syndrome, especially when these agents are used concomitantly with serotonergic drugs and drugs that impair the metabolism of serotonin. Inhibition of norepinephrine and serotonin may lead to cardiovascular effects, particularly increases in blood pressure and heart rate. In clinical trials, treatment with milnacipran was associated with mild elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Treatment with milnacipran may lead to hyponatremia. Patients treated with this agent may have an increased risk of bleeding events. Milnacipran can affect urethral resistance and micturition. Patients treated with milnacipran have experienced mydriasis; this agent should be used with caution in patients with controlled narrow-angle glaucoma. The most common adverse events associated with milnacipran treatment include nausea, constipation, hot flush, hyperhidrosis, vomiting, palpitations, increased heart rate, dry mouth, and hypertension.