Drug Profile

Milnacipran (SAVELLA) was approved by the Food and Drug Administration (FDA) in 2009 for the treatment of fibromyalgia in adults, which remains its only approved use.[1] The approval was controversial because later that same year the FDA’s European counterpart, the European Medicines Agency, opted not to approve milnacipran for fibromyalgia because it deemed the drug to be of only “marginal” effectiveness, and it is still not approved in Europe.[2] In 2010, we petitioned the FDA to ban milnacipran on the same grounds of inadequate effectiveness, in addition to the fact that the drug has many serious risks.[3] We therefore designate this drug as Do Not Use.

Fibromyalgia is a chronic syndrome consisting of widespread musculoskeletal pain that is accompanied by fatigue, sleep trouble, and mood and memory difficulties.[4] The causes of fibromyalgia remain unknown, but a dysfunctional nervous system is suspected to play a major role. In some people, the symptoms begin after physical trauma, surgery, infection, or major psychological stress, yet in others the symptoms develop gradually with no identifiable trigger. The condition is more common in women than in men.[4]

There is no cure for fibromyalgia, but symptoms often can be improved with lifestyle changes, such as getting more exercise and sleep, and cognitive-behavioral therapy.[4],[5] Cognitive-behavioral therapy has been shown to improve health-related quality of life and mood and to decrease level of disability, average pain, and fatigue when compared with other non-drug treatments.[5] In addition, cognitive-behavioral therapy has been proven equal or superior to drug treatments.[5] A series of studies also have shown that various types of exercise, including aerobic,[6] resistance,[7] and aquatic exercises,[8] can improve various aspects of fibromyalgia symptoms and quality of life.

A comprehensive review of evidence from clinical trials of the benefits and risks of milnacipran (and other SNRIs) for the treatment of fibromyalgia was published in 2018.[9] The review included nine randomized, controlled clinical trials that compared milnacipran with a placebo for treatment of fibromyalgia in adults. The quality of evidence from these studies was rated low. Milnacipran had no clinically relevant benefit over placebo for pain relief of at least 50, reduction of fatigue or improvement in health-related quality of life.

Another study that was published in 2015 reviewed all randomized trials of milnacipran compared with placebo for treating neuropathic pain[10] — a condition for which milnacipran is not approved, but for which it may nevertheless be used widely. The review found that there “was no evidence to support the use of milnacipran to treat neuropathic pain conditions.”

Milnacipran’s FDA-approved label lists numerous serious risks associated with the drug.[1] Among the most serious risks are suicidal thoughts and behaviors, serotonin syndrome, increased blood pressure, and increased heart rate.

Milnacipran can lead to suicidal thoughts and behaviors in users younger than 25 years of age; this risk is listed on the drug’s label (as well as on all antidepressants) as a black-box warning, the most prominent warning that the FDA can require. It is included on the label for milnacipran even though the drug is not approved for depression because it affects the body in the same way –— and therefore is expected to have similar risks — as a class of antidepressants known as SNRIs.

Serotonin syndrome can occur with milnacipran, especially when it is taken along with other serotonin-acting drugs, such as some antidepressants. Symptoms of serotonin syndrome include agitation, confusion, loss of muscle coordination, rigid muscles, heavy sweating, diarrhea, shivering, fevers, and loss of consciousness.

Increased blood pressure and heart rate have been associated with serious and often fatal cardiovascular events, such as heart attack. The fact that milnacipran, like other SNRIs, has consistently been found to elevate resting blood pressure and heart rate is therefore concerning, especially because fibromyalgia patients already may have an increased risk of coronary artery disease.[11],[12]

The following risks also are associated with milnacipran:

• Increase in frequency of seizures
• Liver toxicity
• Physical dependence and withdrawal symptoms
• Hyponatremia (low blood sodium)
• Abnormal bleeding
• Activation of mania
• Difficulty urinating
• Testicular and ejaculation problems
• Acute glaucoma attacks
• Aggravation of liver disease with alcohol use
• Hazard to a fetus or newborn if used during pregnancy
• Hazard to nursing infants
• Dangerous interactions with other drugs; for example, digoxin (LANOXIN), clomipramine (ANAFRANIL), phenelzine (NARDIL) and other antidepressants known as monoamine oxidase inhibitors, fluoxetine (PROZAC, SARAFEM, SELFEMRA, SYMBYAX), venlafaxine (EFFEXOR XR), and other selective serotonin reuptake inhibitors and SNRIs
• Gastrointestinal problems, including nausea, vomiting and constipation

You should avoid starting milnacipran if you are not currently taking it. If you are already taking it, consult with your doctor before discontinuing the drug. If you are diagnosed with fibromyalgia, you should first try lifestyle changes such as increasing exercise and improving your sleep health. Working on ways to reduce or better manage stress is also important, as is being evaluated by a health care professional for any mental health conditions, such as depression, that may be contributing to your symptoms. Cognitive-behavioral therapy also has been shown to be effective. It is important to remember that fibromyalgia is not a life-threatening condition and that there are many healthy ways to improve your symptoms without resorting to dangerous drugs.