No Link Between Smoking Cessation Meds and Serious Side Effects

Nancy A. Melville

April 27, 2016

The smoking cessation drugs varenicline (Chantix, Pfizer Inc) and bupropion (multiple brands) show no significant increase in the risk for serious neuropsychiatric side effects in patients with or without psychiatric disorders, results of a large, randomized controlled trial suggest.

The study, the largest to date to examine the safety and efficacy of the two drugs in comparison with nicotine patch and placebo, was requested by the US Food and Drug Administration (FDA), which requires a black box warning on varenicline and buproprion, owing to concerns of neuropsychiatric side effects.

"This was the first study to look at the three first-line smoking cessation medications in a large sample of patients with a history of recurrent psychiatric disorders," lead investigator Robert M. Anthenelli, MD, professor of psychiatry at the University of California, San Diego, told Medscape Medical News.

"We examined 16 symptom clusters [on the basis of] the drugs' warning labels and found no significant increase in the symptoms with the use of varenicline or bupropion compared with placebo or the nicotine patch," he said.

The study was published online April 22 in the Lancet.

No Suicide Risk

The study was conducted in 16 countries from 2011 to 2015 and included 8114 smokers who were motivated to quit. Participants were grouped into those with current or past stable psychiatric disorders (n = 4116, with 4074 in the safety analysis) and those without such disorders (n = 4028, 3984 in the safety analysis).

Patients in both groups were randomly assigned in the double-blind, triple-dummy trial to receive 12 weeks of treatment with either varenicline (1 mg twice a day), bupropion (150 mg twice a day), nicotine patch (21 mg per day with taper), or placebo, with 12 weeks of nontreatment follow-up. Patients received brief cessation counseling at each visit.

Among those without psychiatric disorders, there were no statistically significant differences between any of the treatment groups in rates of moderate and severe neuropsychiatric disorders. Rates of reported symptoms were 1.3% in the varenicline group, 2.2% in the bupropion group, 2.5% in the nicotine patch group, and 2.4% in the placebo group.

Rates of moderate and severe neuropsychiatric adverse events were higher in general among patients with current or past psychiatric disorders, but similarly, there were no significant differences between the groups: 6.5% in the varenicline group, 6.7% in the bupropion group, 5.2% in the nicotine patch group, and 4.9% in the placebo group.

Overall, those treated with varenicline achieved higher rates of abstinence compared with those receiving placebo (odds ratio [OR], 3.61; 95% confidence interval [CI], 3.07 - 4.24), nicotine patch (OR, 1.68; 95% CI, 1.46 - 1.93), and bupropion (OR, 1.75; 95% CI, 1.52 - 2.01).

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

The authors note that the sizes of differences were similar to those previously reported in a review of effects published in the Cochrane Review in 2013.

"The fact that this study was done in many centres in countries with widely different attitudes regarding tobacco use confirms the generalizability of these conclusions across cultures," the authors write.

The FDA issued the requirement for the box warning in part on the basis of findings from the Institute for Safe Medication Practices that showed that reports in the FDA's adverse event database of suicidal/self-injurious thoughts associated with the use of varenicline was three times higher than for any other drug. For homicidal ideation, the reports were five times higher.

Dr Anthenelli noted, however, that the use of the adverse event database has important limitations.

"You get the reports, but you don't have a denominator ― you don't have context or percentages, etc, so it's an important signal detection system, but you have to put it in the context of all of the available evidence."

He added that in the 4 years since the FDA issued the request for the current study, many other studies have been published that similarly showed no increased risk for neuropsychiatric events with the medications compared with placebo. These studies include a meta-analysis of 39 randomized controlled trials that showed no evidence of an increased risk for neuropsychiatric symptoms, which included suicide or attempted suicide, suicidal ideation, depression, or death, associated with the use of varenicline.

An important reason for the alarm likely stems from the known high rate of smoking among people who could be most vulnerable to neuropsychiatric symptoms ― those who already have psychiatric disorders.

"People with psychiatric disorders are smoking upwards of 45% of the cigarettes sold in the US, so this is a very large segment of America's smoking population," Dr Anthenelli said.

"So it is important not only that our study showed no difference in neuropsychiatric symptoms between the treatments among these subjects but that all three treatments were effective in smoking cessation, with varenicline showing significant efficacy compared to bupropion and the nicotine patch."

An important limitation of the study was the exclusion of people with untreated psychiatric disorders, including those with reported substance abuse in the past 12 months. Dr Anthenelli said it was necessary to exclude these persons in order to distinguish any neuropsychiatric symptoms associated with the treatments.

"We were really trying to find a signal for these medications, so we didn't want that confounding effect of the [untreated psychiatric disorders] or substance use disorder," he explained. "There are also ethical issues about including people with active substance abuse in a trial such as this."

New Field of Inquiry

In an accompanying commentary, Laurie Zawertailo, PhD, Department of Pharmacology and Toxicology, Centre for Addiction and Mental Health, University of Toronto, in Canada, applauded the study but said the exclusion of those with current substance abuse was "extremely disappointing and means the findings cannot be generalized to this population."

Dr Zawertailo told Medscape Medical News that the substance abuse population is in particularly high need of better evidence-based treatment approaches.

"Their smoking is often ignored by those treating their other addictions, and in many cases, they are actively discouraged from trying to quit smoking due to antiquated thinking that this may undermine their attempts to quit their other substances of abuse and will lead to relapse," Dr Zawertailo said.

"However, current evidence suggests that quitting smoking at the same time as quitting other substances actually improves long-term abstinence for both."

She added that in the psychiatric population in general, the black box label warnings on varenicline and bupropion have resulted in limited options for cessation treatment.

"The black box has scared off many practitioners and patients from using these medications," Dr Zawertailo said. "As a result, the only option left is nicotine replacement therapy, which, as the study confirmed, is not as effective as varenicline.

"Plus, for the majority of smokers, many attempts to quit are needed before finally being successful. Therefore, it is important to have different options to try in case they fail on medication but want to try something different on their next quit attempt."

Dr Zawertailo said the new findings should help push forward research into any risk factors that my make a person susceptible to neuropsychiatric side effects of smoking cessation efforts.

"It may have something to do with the neuroadaptations that occur in response to smoking, especially if smoking is initiated in early adolescence, when the brain is still developing," she speculated.

"I think these findings will open up a new field of inquiry into determining these risk factors."

The study was funded by Pfizer and GlaxoSmithKline. Dr Anthenelli has received grants from Pfizer and Alkermes and provides consulting and advisory board services to Pfizer, Arena Pharmaceuticals, and Cerecor. He received support for the study from the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse/Veterans Affairs Cooperative Studies. The other authors' disclosures are included in the study. Dr Zawertailo has received peer-reviewed research funding from the manufacturer of varenicline through the Global Research Awards in Nicotine Dependence.

Lancet. Published online April 22, 2016. Full text, Commentary

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