Milnacipran For Fibromyalgia: Do Not Use

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 (EMA), opted not to approve milnacipran for fibromyalgia because it deemed the drug to have only “marginal” effectiveness, and it is still not approved in Europe.[2]

In 2010, Public Citizen’s Health Research Group 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]

Fibromyalgia

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. Fibromyalgia affects between 2 and 4 percent of people, with women more often affected than men.[5]

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.[6],[7] A series of studies have shown that various types of exercise, including aerobic,[8] resistance[9] and aquatic exercises,[10] can improve various aspects of fibromyalgia symptoms and quality of life.

Milnacipran: Ineffective and dangerous

Milnacipran’s FDA-approved label lists numerous serious risks associated with the drug (see box below).[11] 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 serotoninnorepinephrine reuptake inhibitors (SNRIs).

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 since fibromyalgia patients already may have an increased risk of coronary artery disease.[12],[13]

Recent reviews confirm marginal benefit

A comprehensive review of evidence from clinical trials of the benefits and risks of milnacipran was published in 2015.[14] The review included all randomized, double-blind studies of at least eight weeks in duration that compared milnacipran with a placebo for treatment of fibromyalgia in adults. The review found six such trials that involved approximately 4,200 subjects combined and lasted between eight and 24 weeks.

Moderate levels of pain relief (of at least 30 percent) occurred in about 40 percent of subjects given milnacipran, compared with 30 percent of subjects given placebos. The evidence was insufficient to determine whether milnacipran can provide more substantial levels of pain relief (of at least 50 percent). The authors also pointed out that even these modest levels of pain relief with milnacipran may have been overestimated due to the way data were analyzed in the trials.

These results suggest three things. First, milnacipran has only very slight effectiveness for the relief of fibromyalgia pain.

Second, 30 percent of subjects given a placebo (nearly as many as those given milnacipran) experienced significant pain reduction even though the placebo pill had no pain-relieving properties. This may indicate that fibromyalgia pain has a strong psychological component or that other aspects of being in the trials (such as increased motivation to make lifestyle improvements) helped to improve subjects’ pain with no drug intervention at all.

Third, the longest trials comparing milnacipran with placebo lasted just 24 weeks. This is concerning because it is impossible to know how many patients stop taking milnacipran in the long term, given the drug’s miniscule benefits. In addition, the short duration of the trials means that the long-term cardiovascular risks of milnacipran-induced increased blood pressure and heart rate are as yet unknown.

Another study that was published in 2015 reviewed all randomized trials of milnacipran compared with placebo for neuropathic pain[15] — a condition for which milnacipran is not approved, but for which it lifemay nevertheless be used widely. The review found that there “was no evidence to support the use of milnacipran to treat neuropathic pain conditions.”

Allegations of bribery

The brand-name version of milnacipran, Savella, was one of a number of drugs for which the drugs’ maker, Forest Laboratories (now owned by Allergan), paid kickbacks to physicians to market to their colleagues, according to allegations by the U.S. Department of Justice (DOJ) in a $38 million settlement between the DOJ and Allergan in December 2016.[16]

The DOJ alleged that Allergan provided “improper inducements” to physicians in the form of “payments and meals” to encourage fellow physicians to prescribe Savella and two other drugs. In some cases, the payments were made even when the hired physicians had not in fact performed any service in return, indicating that the payments may have been bribes to induce the physicians to prescribe the drugs themselves.

That Allergan would allegedly go to such illegal lengths to market Savella would not be surprising; the drug’s miniscule benefits likely make many physicians hesitant to prescribe it for their fibromyalgia patients.

What You Can Do

Do not use milnacipran. Instead, 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.

References

[1] Allergan, Inc. Label: milnacipran (SAVELLA). December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022256s022lbl.pdf. Accessed November 1, 2017.

[2] European Medicines Agency. Milnacipran Pierre Fabre Medicament. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001034/human_med_001311.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d125. Accessed November 1, 2017.

[3] Public Citizen. Petition to ban fibromyalgia drug milnacipran (Savella). January 20, 2010. https://www.citizen.org/our-work/health-and-safety/petition-ban-fibromyalgia-drug-milnacipran-savella. Accessed November 1, 2017.

[4] American College of Rheumatology. Fibromyalgia. https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Fibromyalgia. Accessed November 1, 2017.

[5] Ibid.

[6] Ibid.

[7] Bernardy K, Klose P, Welsch P, Häuser W. Eur J Pain. 2017 Oct 6. doi: 10.1002/ejp.1121. [Epub ahead of print].

[8] Bidonde J, Busch AJ, Schachter CL, et al. Aerobic exercise training for adults with fibromyalgia. Cochrane Database Syst Rev. 2017, Issue 6. Art. No.: CD012700.

[9] Busch AJ, Webber SC, Richards RS, et al. Resistance exercise training for fibromyalgia. Cochrane Database Syst Rev. 2013, Issue 12. Art. No.: CD010884.

[10] Bidonde J, Busch AJ, Webber SC, et al. Aquatic exercise training for fibromyalgia. Cochrane Database Syst Rev. 2014, Issue 10. Art. No.: CD011336.

[11] Allergan, Inc. Label: milnacipran (SAVELLA). December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022256s022lbl.pdf. Accessed November 1, 2017.

[12] Tsai PS, Fan YC, Huang CJ. Fibromyalgia is associated with coronary heart disease: a population-based cohort study. Reg Anesth Pain Med. 2015;40(1):37-42.

[13] Su CH, Chen JH, Lan JL, et al. Increased risk of coronary heart disease in patients with primary fibromyalgia and those with concomitant comorbidity-A Taiwanese population-based cohort study. PLoS One. 2015;10(9):e0137137.

[14] Cording M, Derry S, Phillips T, et al. Milnacipran for pain in fibromyalgia in adults. Cochrane Database of Systematic Reviews. 2015, Issue 10. Art. No.: CD008244.

[15] Derry S, Phillips T, Moore RA, Wiffen PJ. Milnacipran for neuropathic pain in adults. Cochrane Database Syst Rev. 2015, Issue 7. Art. No.: CD011789.

[16] U.S. Department of Justice. Forest Laboratories and Forest Pharmaceuticals to pay $38 million to resolve kickback allegations under the False Claims Act. December 15, 2016. https://www.justice.gov/opa/pr/forest-laboratories-and-forest-pharmaceuticals-pay-38-million-resolve-kickback-allegations. Accessed November 1, 2017.