Study provides reassuring data on neuropsychiatric side effects of smoking cessation drugs

Smoking cessation medicines varenicline and bupropion do not increase the incidence of moderate or severe neuropsychiatric adverse events, compared with nicotine patches or placebo, according to new research.

The study, published in The Lancet
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(online, 22 April 2016), also found that varenicline is more effective “in helping smokers achieve abstinence” compared with placebo, nicotine patches and bupropion.

“Despite growing evidence to the contrary, significant concerns have been raised about the neuropsychiatric safety risk of the smoking cessation medications varenicline and bupropion,” says lead researcher Robert Anthenelli, professor and executive vice chair of the department of psychiatry at the University of California in San Diego. “What has been lacking until now among individuals with and without psychiatric disorders is a large, randomised controlled trial that directly compares these medications with placebo and an active comparator, and that systematically probes for neuropsychiatric adverse events while smokers are trying to quit.”

The researchers assessed the relative neuropsychiatric safety and efficacy of varenicline and bupropion compared with nicotine patches and placebo among 8,144 smokers with or without psychiatric illnesses. Participants were treated for 12 weeks, with a 12-week follow-up. Among the participants, 4,116 were included in the psychiatric cohort and 4,028 were included in the non-psychiatric cohort.

Among the non-psychiatric participants, moderate to severe neuropsychiatric adverse events were reported in 1.3% (13 of 990) of the varenicline group, 2.2% (22 of 989) of the bupropion group, 2.5% (25 of 1,006) of the nicotine patch group and 2.4% (24 of 999) of the placebo group.

Overall, there were more adverse neuropsychiatric events reported in the group with psychiatric disorders than in the group without but the researchers found there were similar rates across all treatment arms (6.5% for varenicline; 6.7% for bupropion; 5.2% for nicotine patch; and 4.9% for placebo).

The results show that varenicline was more effective at helping people stop smoking than bupropion, nicotine patches or placebo. Bupropion was about as effective as nicotine patches, and both were more effective than placebo. Overall, at 9–24 weeks, 21.8% of people on varenicline were continuously abstinent (16.2% for bupropion; 15.7% for nicotine patches; and 9.4% for placebo). Smokers with a psychiatric disorder achieved slightly lower abstinence rates than smokers without a psychiatric disorder.

The most frequent adverse events across the cohorts were nausea (25% in the varenicline group), insomnia (12% in the bupropion group), abnormal dreams (12% in the nicotine patch group) and headache (10% in placebo group).

Eden Evins, one of the researchers and director of the Massachusetts General Hospital Center for Addiction Medicine in Boston, recommends increased use of pharmacologic cessation aids among smokers, including those with a psychiatric illness.

“The results indicate that those with psychiatric illness, who smoke with greater frequency, have greater severity of nicotine dependence, and have disproportionate smoking-related mortality compared to those without psychiatric illness,” she says. “[They] should have the benefit of pharmacologic smoking cessation aids to improve their odds of quitting smoking.”

James Davis, medical director of the Duke Center for Smoking Cessation in Durham, North Carolina, points out that the study was underpowered to show differences in suicidality between varenicline and other medications. However, he adds that other studies have addressed the concern around varenicline and suicidality “with sufficient power and reassuring results”.

Davis does not believe that varenicline and bupropion will be safe for everyone. “There is, however, a more important perspective – smoking will kill most smokers,” he says. “With this in mind, neglecting to use effective quit smoking treatments may incur greater risk to our patients than using them.”

Pfizer and GlaxoSmithKline, the manufacturers of varenicline and bupropion, respectively, were asked by the US Food and Drug Administration (FDA) to conduct the study as a post-marketing requirement. The research was funded by the two companies and designed in consultation with the FDA.