Smoking Cessation Drugs Do Not Elevate Risk of Serious Neuropsychiatric Adverse Effects

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Compared to the nicotine patch and a placebo, the smoking cessation aids varenicline (marketed as Chantix in the U.S.) and bupropion (Zyban) do not show a significant increase in neuropsychiatric adverse events, reports an international team of researchers in a study published online April 22 in the journal The Lancet.

“There are 1 billion smokers in the world and nearly 6 million smoking-related deaths each year, but there are only three approved medication treatments for quitting: nicotine replacement therapies like the patch and the two non-nicotine medications, bupropion and varenicline,” said Robert Anthenelli, MD, professor of psychiatry, director of the Pacific Treatment and Research Center at UC San Diego School of Medicine and first author of the study.

Anthenelli said the so-called EAGLES study is important because it prospectively examined the neuropsychiatric safety risks and quit-enhancing potential of the three medication classes versus placebo in a rigorous, adequately-sized, randomized controlled trial.

It is the result of a Food and Drug Administration (FDA) mandate following post-marketing reports suggesting varenicline and bupropion might cause adverse neuropsychiatric events, such as increased agitation, depression, hostility or suicidal behavior. The FDA requested that both medications carry boxed warnings in their labeling. This has resulted in limitation in use. The EAGLES study was funded by Pfizer and GlaxoSmithKline, makers of varenicline and bupropion, respectively, and designed in consultation with the FDA.

Authors sought to directly assess the safety and efficacy of varenicline and bupropion compared to the nicotine patch and to a placebo in smokers with and without psychiatric disorders. It involved a randomized, controlled, double-blind trial examining more than 8,000 smokers seeking to quit in 16 countries over a period from November 2011 to January 2015. Trial participants, investigators and research personnel were blinded to who received which treatment.  

“This is the first study to compare the safety and efficacy of the three first-line smoking cessation aids on the market, head-to-head, in smokers. It’s the largest double-blind smoking cessation medication trial to date,” said Anthenelli. “And no study has done so in smokers with current or past psychiatric disorders who consume roughly 45 percent of the cigarettes sold in the U.S.”

In terms of safety, approximately 2 percent of non-psychiatric participants reported moderate or severe adverse neuropsychiatric events for any of the treatments. Specifically, 1.3 percent for varenicline, 2.2 percent for bupropion, 2.5 percent for the nicotine patch and 2.4 percent for placebo.

In the cohort of participants with psychiatric disorders, moderate and severe adverse neuropsychiatric events were slightly higher across the board: 6.5 percent for varenicline, 6.7 percent for bupropion, 5.3 percent for the nicotine patch and 4.9 percent for placebo.

Anthenelli said the risk difference in the incidence of serious neuropsychiatric adverse events for varenicline and bupropion was not significantly higher than placebo – but that psychiatric patients trying to stop smoking are likely to have more confounding factors in treatment and appear to have a harder time quitting.

The efficacy or success rate, measured as biochemically-confirmed continuous abstinence for weeks nine to 12 after treatment began, was broadly consistent with past research and predictions. Regardless of participants’ psychiatric status, varenicline was found to be more effective at helping smokers achieve abstinence than bupropion, the patch or placebo; bupropion and patch were more effective than the placebo. Across all cohorts, the most frequent adverse events were nausea, insomnia, abnormal dreams and headache.

Co-authors include Neal L. Benowitz, UCSF; Robert West, University College, London; Lisa St. Aubin, Thomas McRae, David Lawrence and Cristina Russ, Pfizer; John Ascher, GlaxoSmithKline; Alok Krishen, Parexel International on behalf of GlaxoSmithKline; and A. Eden Evins, Massachusetts General Hospital.

Disclosure: Dr. Anthenelli provides consulting and/or advisory board services to Pfizer via an institutional consulting agreement executed through the University of California San Diego. Payment for Dr. Anthenelli’s consulting services is received by UC San Diego. The terms of this arrangement have been reviewed and approved by UC San Diego in accordance with its conflict of interest policies.