Comparing Fibromyalgia Drugs: Which are Most Effective?

Amitriptyline, Cymbalta, Lyrica & Savella Compared

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A wide range of drug options is open to those of us with fibromyalgia, which means picking one can be difficult. Wouldn't it be great if there were a way to choose based on which one was most likely to help you? Some researchers are working toward that goal, but for now, we can find some guidance through the comparative studies that have been done.

Only three drugs are FDA-approved for treating fibromyalgia.

One, Lyrica (pregabalin), is an anti-seizure drug while the other two, Cymbalta (duloxetine) and Savella (milnacipran), are serotonin-norepinephrine reuptake inhibitors (SNRIs). One of the most common off-label medications is amitriptyline, a tricyclic antidepressant that used to be considered a front-line treatment.

For most of us, it takes a lot of experimentation to figure out what treatments work best for us. When it comes to these medications, that can be a long and difficult road. Some drugs may cause unpleasant side effects, and others may not help at all. Often, you have to take one for several weeks before seeing any effect, then increase the dosage to find real relief. Then, if you decide against it, you may have to wean off of it for a few weeks and then wait a few more weeks before starting the next one.

If you find something that works well for you, it's worth the effort. For others, though, it's a frustrating and fruitless ordeal.

How Do They Compare?

A 2013 study published in the European Journal of Pain found a changing pattern in fibromyalgia drug use – away from amitriptyline and toward the newer, FDA-approved drugs. But is that change for the best? It's hard to say.

This particular study said that the newer drugs improved pain by about 3 or 4% but didn't improve fatigue or overall function.

Meanwhile, the newer drugs are far more expensive. Researchers found "no evidence of clinical benefit" of the new drugs over amitriptyline.

An April 2012 study involving many of the same researchers urges doctors and patients to "be realistic about the potential benefits of antidepressants in fibromyalgia. Looking specifically at amitriptyline, duloxetine, and milnacipran, they say a small number of people see substantial relief of symptoms without side effects. Many more, they say, stop taking the drugs because of side effects.

In fact, according to a 2013 paper in Arthritis Care & Research, only one-fifth of people who started amitriptyline, duloxetine, pregabalin, or gabapentin (a drug closely related to pregabalin) continued treatment for more than one year. Most people did not last long enough to increase their dosage to typical treatment levels.

A major 2011 drug class review from Oregon Health & Science University revealed a lot of information about which drug may be most effective for specific patients, including:

  • Duloxetine may be better than milnacipran for pain, sleep disturbance, depressed mood, and health-related quality of life.
  • Duloxetine and milnacipran may be better than pregabalin for depressed mood.
  • Pregabalin was superior to milnacipran for reducing sleep disturbance.
  • A small amount of evidence suggests that duloxetine is not effective at reducing pain in men, non-white patients, and older patients.
  • Milnacipran was only effective in people without depression symptoms, while duloxetine and pregabalin were effective regardless of depression.
  • Pregabalin significantly improved symptoms regardless of anxiety levels.

Other Findings

We have multiple studies and reviews comparing these medications. Some of their notable findings include:

  • Similar results for all four when it came to pain and fatigue. (Smith)
  • In the German health-care system, recommendation of amitriptyline over the other three; recommendation of duloxetine if the patient also has depressive disorder or generalized anxiety disorder; pregabalin considered only if there's no comorbid mental disorder. (Sommer, et al.)
  • Drugs should be recommended with reservation because of limited effectiveness and high likelihood of side effects. Ideally, the goal should be long-term management with no drugs or minimal drugs. (Hauser, Walitt, et al.)
  • In one study, Amitriptyline appeared better for significant pain relief than duloxetine and milnacipran and the three drugs were tolerated at about the same level. (Hauser, Petzke)
  • In rats, milnacipran was as effective as amitriptyline in neuropathic pain. Milnacipran also is effective against allodynia (a common fibromyalgia pain type.) (Berrocoso)
  • In a 12-month study, 46% of participants on duloxetine and milnacipran were satisfied with their medications; a similar percentage (about 43%) were satisfied with pregabalin or a tricyclic antidepressant. (Robinson)
  • Patients on pregabalin tended to seek medical treatment more often than those on duloxetine in their first year of treatment. (Peng)
  • In spite of the limitations, these four drugs and a handful of others (nortriptyline, cyclobenzaprine, tramadol, and gabapentin) are believed to be superior to corticosteroids, non-steroidal anti-inflammatories, benzodiazepines, and opioids. (Skaer)
  • At least two studies recommend combining pregabalin with milnacipran or duloxetine because of the different mechanisms of action. (Choy, Mease)

Making Treatment Decisions

In the end, every case of fibromyalgia is unique, and every person's response to medications is unique. Learn what you can about the drugs you're considering and work with your doctor to determine which one(s) to try. Remember that just because one drug didn't work, it doesn't mean no drug will work.

You also have a lot of non-drug treatment options, and many researchers recommend exploring those to come up with your ideal treatment regimen.


Berrocoso E, et al. European journal of pharmacology. 2011 Mar 25;655(1-3):46-51. Evaluation of milnacipran, in comparison with amitriptyline, on cold and mechanical allodynia in a rat model of neuropathic pain.

Choy E, et al. Seminars in arthritis and rheumatism. 2011 Dec;41(3):335-45.e6. A systematic review and mixed treatment comparison of the fficacy of pharmacological treatments for fibromyalgia.

Hauser W, Petzke F, et al. Rheumatology. 2011 Mar;50(3):532-43. Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis.

Hauser W, Walitt B, et al. Arthritis research & therapy. 2014 Jan 17;16(1):201. Review of pharmacological therapies in fibromyalgia syndrome.

Hauser W, Wolfe F, et al. CNS drugs. 2012 Apr 1;26(4):297-307. The role of antidepressants in the management of fibromyalgia syndrome: a systematic review and meta-analysis.

Kim SD, Landon JE, Solomon DH. Arthritis care & research. 2013 Nov;65(11):1813-9. Clinical characteristics and medication uses among fibromyalgia patients newly prescribed amitriptyline, duloxetine, gabapentin, or pregabalin.

Mease PJ, et al. Therapeutic advances in musculoskeletal disease. 2013 Jun;5(3):113-26. Milnacipran combined with pregabalin in fibromyalgia: a randomized, open-label study evaluating the safety and efficacy of adding milnacipran in patients with incomplete response to pregabalin.

Peng X, et al. Journal of pain research. 2014 Jan 9;7:37-46. Real-world comparison of health care utilization between duloxetine and pregabalin initiators with fibromyalgia.

Robinson RL, et al. Pain medicine. 2013 Sep;14(9):1400-15. Logitudinal observation of treatment patterns and outcomes for patients with fibromyalgia: 12-month findings from the reflections study.

Skaer TL. Pharmacoeconomics. 2014 May;32(5):457-66. Fibromyalgia: disease synopsis, medication cost effectiveness and economic burden.

Smith B, et al. Drug Effectiveness Review Project. Online publication. Drug Class Review: Drugs for Fibromyalgia: Final Original Report.

Sommer C, et al. Schmerz. 2012 Jun;26(3):297-310. Drug therapy of fibromyalgia syndrome. Systematic review, meta-analysis and guideline.

Wolfe F, et al. European journal of pain. 2013 Apr;17(4):581-6. Longitudinal patterns of analgesic and central acting drug use and associated effectiveness in fibromyalgia.

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