Drugs to Treat Fibromyalgia Just as Likely to Harm as Help

Editor’s Note: Following is a news release about a recent review of clinical trials on the fibromyalgia drugs Cymbalta and Savella.  Below the news release is the abstract followed by a rare and much appreciated plain language summary of the study.

Drugs to Treat Fibromyalgia Just as Likely to Harm as HelpAmong fibromyalgia patients taking either of two commonly prescribed drugs to reduce pain, 22 percent report substantial improvement while 21 percent had to quit the regimen due to unpleasant side effects, according to a new review in The Cochrane Library.

People with fibromyalgia suffer from chronic widespread pain, sleep problems and fatigue. The illness affects more than 5 million Americans, 80 percent of whom are women. The cause of fibromyalgia is unknown and currently there is no cure. Using a Quality of Life (QOL) scale for fibromyalgia, the studies reviewed reported QOL ratings lower than 15 on a scale of 0 to 100 even among patients on medications. The two medications often prescribed to treat fibromalgia are duloxetine, known by the brand name Cymbalta or milnacipran, commonly known as Savella.

“A frank discussion between the physician and patient about the potential benefits and harms of both drugs should occur,” noted the reviewers, led by Winfried Häuser, M.D. of Technische Universität München.

The authors reviewed 10 high-quality studies comprising more than 6,000 adults who received either duloxetine, milnacipran, or a placebo for up to six months. A substantial majority of study participants were middle-aged, white women.

“This is a very important study,” says Fred Wolfe, M.D. of the National Data Bank for Rheumatic Diseases. “There’s an enormous amount of advertising suggesting that these drugs really help, whereas the research data show that the improvement is really minimal.”

Treatment with drugs alone “should be discouraged,” the reviewers added. Instead, the review authors recommend a multi-faceted treatment approach including medications for those who find them helpful, exercises to improve mobility and psychological counseling to improve coping skills.

“The medical field does poorly with the treatment of fibromyalgia in general,” says Brian Walitt, M.D., M.P.H., a co-author of the review and an expert in pain syndromes at Washington Hospital Center in Washington, D.C. “Chasing [a cure] with medicine doesn’t seem to work.  The people who seem to me to do best sort of figure it out on their own by thinking about things, getting to know themselves, and making changes in their lives to accommodate who they’ve become,” concludes Walitt.

The only other medication approved for fibromyalgia treatment in the U.S. is the anti-convulsant pregabalin, known by the brand name Lyrica. The Cochrane Library plans to publish a review of its effectiveness later this year.

Intensive neuroscientific research is needed to reveal the underlying causes of fibromyalgia and other pain syndromes, say the researchers. In the meantime, combinations of various medications as well as combinations of drug and non-drug treatments may offer better symptom control for sufferers.

News release by Laura Kennedy. Health Behavior News Service, part of the Center for Advancing Health, at (202) 387-2829 or hbns-editor@cfah.org.



Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
– Source: The Cochrane Library, January 31, 2013

By Winfried Hauser, et al.


Background:  Fibromyalgia syndrome (FMS) is a clinically well-defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. Patients often report high disability levels and poor quality of life (QOL). Drug therapy focuses on reducing key symptoms and improving quality of life.

To assess the benefits and harms of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo for treating FMS symptoms in adults.

Search methods:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2012, Issue 9), MEDLINE (1966 to September 2012), EMBASE (1980 to September 2012), www.clinicalstudyresults.org (U.S.-marketed pharmaceuticals) (to September 2012) and www.clinicaltrials.gov (to September 2012) for published and ongoing trials and examined the reference lists of reviewed articles.

Selection criteria:
We selected randomized, controlled trials of any formulation of SNRIs against placebo for the treatment of FMS in adults.

Data collection and analysis:
Two review authors independently extracted the data from the included studies, and assessed the risks of bias of the studies. Discrepancies were resolved by discussion.

Main results: Ten studies were included with a total of 6038 participants. Five studies investigated duloxetine against placebo, and five investigated milnacipran against placebo. A total of 3611 participants were included into duloxetine or milnacipran groups and 2427 participants into placebo groups. The studies had a low risk of bias in general.

  • Duloxetine and milnacipran had a small incremental effect over placebo in reducing pain (standardized mean difference (SMD) -0.23; 95% confidence interval (CI) -0.29 to -0.18; 6.1% relative improvement).

  • One-hundred and ninety-two participants per 1000 on placebo reported an at least 50% pain reduction compared to 280 per 1000 on SNRIs (Risk ratio (RR) 1.49, 95% CI 1.35 to 1.64; number needed to treat to benefit (NNTB) 11, 95% CI 9 to 15).

  • Duloxetine and milnacipran did not reduce fatigue substantially (SMD -0.14; 95% CI -0.19 to -0.08; 2.5% relative improvement; NNTB 17, 95% CI 12 to 29), and did not improve QOL substantially (SMD -0.20; 95% CI -0.25 to -0.14; 4.6% relative improvement; NNTB 12, 95% CI 9 to 17) compared to placebo.

  • There were no statistically significant differences between either duloxetine or milnacipran and placebo in reducing sleep problems (SMD -0.07; 95% CI -0.16 to 0.03; 2.5% relative improvement).

  • One-hundred and seven participants per 1000 on placebo dropped out due to adverse events compared to 196 per 1000 on SNRIs.

  • The dropout rate due to adverse events in the duloxetine and milnacipran groups was statistically significantly higher than in placebo groups (RR 1.83, 95% CI 1.53 to 2.18; number needed to treat to harm (NNTH) 11, 95% CI 9 to 13).

  • There was no statistically significant difference in serious adverse events between either duloxetine or milnacipran and placebo (RR 0.78, 95% CI 0.55 to 1.12).

Authors’ conclusions: The SNRIs duloxetine and milnacipran provided a small incremental benefit over placebo in reducing pain. The superiority of duloxetine and milnacipran over placebo in reducing fatigue and limitations of QOL was not substantial. Duloxetine and milnacipran were not superior to placebo in reducing sleep problems. The dropout rates due to adverse events were higher for duloxetine and milnacipran than for placebo. The most frequently reported symptoms leading to stopping medication were nausea, dry mouth, constipation, headache, somnolence/dizziness and insomnia. Rare complications of both drugs may include suicidality, liver damage, abnormal bleeding, elevated blood pressure and urinary hesitation.


Plain language summary:

Serotonin and noradrenaline reuptake inhibitors for fibromyalgia

Researchers in the Cochrane Collaboration conducted a review of research about the effects of serotonin and noradrenaline reuptake inhibitors (SNRIs) on fibromyalgia syndrome (FMS). After searching for all relevant studies, they found 10 studies with up to 6038 people. Their findings are summarized below.

Adults with FMS, who took the SNRIs duloxetine or milnacipran rather than a fake medication (placebo), were likely to have:

  • reduced pain,

  • slightly improved quality of life and reduced fatigue,

  • no improvement for sleep problems,

  • more drug-induced side effects and a greater likelihood of stopping medication.

Serious side effects such as liver damage and suicidality were very rare. There was no difference between the SNRIs duloxetine or milnacipran and fake medication for these serious side effects.

What is fibromyalgia syndrome and what are serotonin and noradrenaline reuptake inhibitors?

People with FMS suffer from chronic widespread pain, sleep problems and fatigue. There is no cure for FMS at present, so the treatments aim to relieve the symptoms and to improve quality of life.

Serotonin and noradrenaline are chemicals which are produced by the human body, involved in the regulation of pain, sleep and mood. Low concentrations of serotonin have been reported in people with FMS. SNRIs are antidepressants that increase the concentration of serotonin and noradrenaline  in the brain.

The SNRIs duloxetine and milnacipran had been approved by the US Food and Drug Administration but not by the European Medicines Agency for the management of FMS. The US and European Regulatory Authorities differed in their judgment of the efficacy and safety of both drugs. Therefore it is important to know for people with FMS and healthcare providers on the effects of SNRIs on FMS.

Best estimate of what happens to people with FMS when they take duloxetine or milnacipran after an average of 18 weeks


Pain was reduced by 50% in:

  • 29 out of 100 people taking duloxetine or milnacipran

  • 19 out of 100 people taking placebo.

  • Therefore, 10 more people in every 100 benefited from duloxetine or milnacipran than benefited from placebo (10% absolute improvement).

Sleep problems and fatigue:

People taking duloxetine or milnacipran  reported a slight reduction in fatigue and the same amount of sleep problems as people taking placebo.

Disease-related quality of life (QOL):

  • People taking duloxetine or milnacipran  scored  their quality of life  as  14 (on a scale of 0 to100),

  • People taking placebo  scored  theirs  as  10. 

  • This means that people taking duloxetine or milnacipran rated their quality of life four points higher than people taking placebo.

Stopping treatment due to the side effects:

  • 20 people out of 100 taking duloxetine or milnacipran stopped medication due to side effects.

  • 11 people out of 100 taking fake medication stopped medication due to side effects.

  • This means that 9 more people out of 100 stopped taking duloxetin or milnacipran than stopped taking fake medication because of side effects.

Serious adverse events:

There were no differences between duloxetine or milnacipran and fake medication in the number of serious adverse events.

We often do not have precise information about side effects and complications. This is particularly true for rare but serious side effects. Possible side effects may include nausea, dry mouth, headache, constipation and hyperhidrosis. Rare complications may include suicidality, liver damage, abnormal bleeding, elevated blood pressure and urinary hesitation. 

Source: The Cochrane Library, January 31, 2013. By Winfried Hauser1, Gerard Urrutia2, Sera Tort3, Nurcan Uceyler4, Brian Walitt5. 1Technische Universität München, Psychosomatic Medicine and Psychotherapy, München, Germany; 2CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Iberoamerican Cochrane Centre – IIB Sant Pau, Barcelona, Spain; 3Institute of Biomedical Research (IIB Sant Pau), Iberoamerican Cochrane Centre, Barcelona, Catalonia, Spain; 4University of Würzburg, Department of Neurology, Würzburg, Germany; 5Washington Hospital Center, Georgetown University Medical Center, Washington, DC, USA. Contact: whaeuser@klinikum-saarbruecken.de

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