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Risks of duloxetine for stress incontinence outweigh benefits, say researchers

BMJ 2016; 355 doi: (Published 15 November 2016) Cite this as: BMJ 2016;355:i6103
  1. Barbara Kermode-Scott
  1. Vancouver Island

The antidepressant duloxetine should not be used to treat stress urinary incontinence in women because the harms outweigh the benefits, authors of a new analysis have said.

Although duloxetine reduced the symptoms of stress urinary incontinence and improved women’s quality of life, the harms related to suicidality and violence were 4 to 5 times more common with duloxetine than with a placebo, a meta analysis using patient level data by researchers from the Nordic Cochrane Centre showed.1

The researchers from Rigshospitalet in Copenhagen made their comments after conducting a meta-analysis using clinical study reports submitted to the European Medicines Agency for regulatory approval of duloxetine for stress urinary incontinence in women. They first gained access to clinical study reports in 2010, following a complaint to the EU ombudsman.2

One of the authors of the analysis, Peter Gøtzsche, told The BMJ that the conclusions could not have been drawn by looking at published trials only.

“Our systematic review underlines that antidepressants not only increase the risk of suicide in children and adolescents, but also in much older people,” he said. “The women in the trials had a mean age of 52 years. It would have been quite impossible to demonstrate this, if we had only had access to published research.”

The authors said: “Given the uncertainty as to whether duloxetine leads to clinically significant improvement in quality of life . . . we question the rationale for using duloxetine for stress incontinence.”

Gøtzsche advised doctors treating women for stress urinary incontinence with the selective serotonin and noradrenaline reuptake inhibitor to gradually withdraw it.

Duloxetine, manufactured by Eli Lilly and Company, has been approved in Canada, Europe, and the US for the treatment of major depressive disorder—marketed as Cymbalta. It is also approved in Europe for the treatment of stress incontinence—marketed as Yentreve. In 2015, over £1.3m (€1.5m; $1.6m) was spent in England on prescriptions for Yentreve.3

For the study, published in the Canadian Medical Association Journal, the researchers undertook a meta-analysis of four, randomised, placebo controlled trials of duloxetine, involving a total of 1913 patients.

They found that duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes (mean difference –13.56%, 95% confidence interval [CI] –21.59% to –5.53%) and change in the Incontinence Quality of Life total score (mean difference 3.24, 95% CI 2.00 to 4.48). The authors noted that the effect sizes were small.

The research team also said that a sensitivity analysis (with removal of one trial) showed that the number needed to treat for a Patient Global Impression of Improvement rating of “much better or very much better” was 8 (95% CI 6 to 13).

Altogether 187 patients in the duloxetine group and 42 patients in the placebo group experienced core or activation events, such as self harm, agitation, anxiety, and psychotic behaviour with the risk being more than four times higher in the duloxetine group than the placebo group (risk ratio [RR] 4.45, 95% CI 3.22 to 6.14); number needed to harm 7 (95% CI 6 to 9). The risk of discontinuing because of an adverse event was more than five times higher among patients receiving duloxetine (RR 5.73, 4.00 to 8.20) than among those taking the placebo.

Gøtzsche said: “Given that the slight effect we found of duloxetine on urinary incontinence was questionable, whereas duloxetine increases the risk of suicide, I do not consider it justifiable to use duloxetine for stress urinary incontinence.”

J Scott MacGregor, global communications director for Eli Lilly (US), said: “Lilly remains committed to duloxetine and its safety and benefits.”


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