November 2009

And a One, and a Two… Exercise for Depression
As an adjunct to medication and psychotherapy or by itself, exercise can be an effective treatment for depression.

Milnacipran (Savella)
Milnacipran (Savella) is the third compound to be approved in the United States for the treatment of fibromyalgia syndrome.

Preventing Depression in Adolescents
Current depression in parents negates the positive effects of a group cognitive behavioral prevention program in preventing depression in adolescents.

Anticholinergic Medicines and Cognitive Decline in the Elderly
Anticholinergic medications can impair cognition and memory, especially in elderly patients.

In Brief
Predictors of Mortality in Depressed Patients following Cardiac Events; Disruption of Dopamine Neurotransmission in ADHD

Raising the SSRI Dose: Does It Help?
Selective serotonin reuptake inhibitors (SSRIs) do not appear to have an obvious relationship of dose to likelihood of benefit.

Generic Antidepressants: Bioequivalent?
Generic formulations of antidepressants may not have the same pharmacokinetics and clinical effects as the original brand-name versions.

Lamotrigine in Borderline Personality Disorder
Preliminary research found lamotrigine (Lamictal) superior to placebo in improving symptoms of affective instability and impulsivity in patients with borderline personality disorder.

Milnacipran (Savella)

November 2009

The third and most recent compound to receive approval from the U.S. Food and Drug Administration (FDA) as a treatment for fibromyalgia syndrome (FMS) is the serotonin-norepinephrine reuptake inhibitor (SNRI) milnacipran (Savella). Approved in many countries as an antidepressant, milnacipran's only labeled indication in the United States is FMS. Milnacipran was recently reviewed by The Medical Letter.1

Over 2000 FMS patients participated in two double-blind, randomized, controlled trials sponsored by the manufacturer comparing milnacipran, 50 and 100 mg bid, with placebo for 3 or 6 months.2,3 Both found significantly greater improvements in pain with both doses of milnacipran than with placebo after 1 week of treatment. Response, defined by decreased pain and improved functioning, similarly showed superiority of milnacipran over placebo. In the 3-month study, the percentages of patients who rated themselves much or very much improved were 48% with the 100-mg/day dose, 51% with the 200-mg/day dose, and 33% of those assigned to placebo. In the 6-month trial, a threshold of at least 30% improvement in pain was reached by 44% of the 100-mg/day group, 45% in the 200-mg/day group, but only 28% of placebo subjects. Thus, both doses of drug were superior to placebo and virtually indistinguishable from one another.

Participants in the 6-month trial were allowed to enter an additional 6-month extension.4 Milnacipran remained effective for the 449 patients who continued to take it. Patients who were randomized from placebo to milnacipran reported improvement in pain and global status. In addition to alleviating pain, milnacipran improved fatigue and cognition.

The most common side effects in drug-treated patients were nausea, headache, constipation, dizziness, insomnia, hot flushes, hyperhidrosis, vomiting, palpitations, and dry mouth. Some patients had increased blood pressure and heart rate. Milnacipran was associated with weight loss in the 3-month trial.

Men with obstructive uropathy may experience increased dysuria and urinary retention when they take milnacipran. Because it can cause mydriasis, milnacipran is contraindicated in patients with uncontrolled narrow-angle glaucoma. The drug has been associated with mild elevations in some liver enzymes and, like other serotonin reuptake inhibitors, can increase the risk of bleeding. It is classified as category C for use during pregnancy, which means that a risk cannot be ruled out.

Like all serotonergic antidepressants, milnacipran is contraindicated with a monoamine oxidase inhibitor (MAOI) because of concerns about the serotonin syndrome. Patients should be cautious when taking milnacipran with other drugs that could also increase blood pressure or heart rate.

Taken orally, milnacipran's bioavailability is 85% to 90%, protein binding is 13%, and the mean terminal elimination half-life is 6 to 8 hours. Its primary route of excretion is via urine, with 55% of ingested drug excreted unchanged.

Milnacipran is available in 12.5-, 25-, 50-, and 100-mg tablets. The recommended starting dose is 12.5 mg once daily, with a gradual increase to 50 mg bid. The dose can be further increased to 100 mg bid, although in clinical trials, 200 mg was no more effective than 100 mg against FMS symptoms. Milnacipran may cause less nausea if taken with food. The dose of milnacipran should be halved for patients with severe renal impairment, but for patients with lesser renal impairment or hepatic dysfunction, no dosage adjustment is necessary. A recent survey of retail pharmacies found the cost of milnacipran to be slightly lower than the other two patent-protected compounds currently FDA-approved for the treatment of FMS—duloxetine (Cymbalta) and pregabalin (Lyrica).

Like the three other SNRIs available in the United States—venlafaxine (Effexor and others), duloxetine, and desvenlafaxine (Pristiq)—milnacipran may cause a withdrawal syndrome. Therefore, it should be tapered rather than abruptly discontinued—something worth calling to the attention of patients, who will need to pack it in their suitcases when they travel.

Milnacipran appears to be modestly helpful for many patients with FMS. As we noted last May (BTP 2009;32:17), nonpharmacologic treatments for FMS patients include setting realistic goals, behavioral strategies incorporating relaxation, coping skills, cognitive training, exercise, and lifestyle change. How milnacipran compares to other drugs for FMS and what, if any, combinations may be safe and effective remain to be studied.

1Milnacipran (Savella) for fibromyalgia. Med Lett Drugs Ther 2009;51:45–46.

2Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, Palmer RH: The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial. J Rheumatol 2009;36:398–409.

3Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y: Milnacipran for the treatment of fibromyalgia in adults: A 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. J Clin Ther 2008;30:1988-2004.

4Goldenberg D, Claw DJ, Palmer RH, et al.: One-year durability of response to milnacipran treatment for fibromyalgia syndrome: Results of a randomized, double-blind, monotherapy extension study. 24th annual meeting of the American Academy of Pain Medicine, Orlando, FL, February 12–16, 2008.