Acetylcholine Receptor Partial Agonist, vs Placebo or Sustained-Release Bupropion for Smoking Cessation A Randomized Controlled Trial

CIGARETTE SMOKING REMAINS the leading preventable cause of illness and premature death in the United States, claiming an estimated 438 000 lives per year. Research over the past 3 decades has identified effective treatments for smoking, including counseling, social support, and several pharmacotherapies. However, current pharmacological and nonpharmacological smoking cessation treatments have limited efficacy and are not widely disseminated to the general population of smokers. Improvements are needed, both in the efficacy of current treatment and in the dissemination of current therapies. Six smoking cessation pharmacotherapies are currently approved by the US Food and Drug Administration. Five of these are nicotine replacement products (gum, patch, nasal spray, inhaler, and lozenge). Each delivers nicotine, the agent that is responsible for the development of tobacco dependence, in a way that allows an individual to reduce nicotine withdrawal symptoms See also pp 47, 64, and 94. Author Affiliations and the Varenicline Phase 3 Study Group are listed at the end of this article. Corresponding Author: Douglas E. Jorenby, PhD, University of Wisconsin School of Medicine and Public Health, Center for Tobacco Research and Intervention, Suite 200, 1930 Monroe St, Madison, WI 53711 ([email protected]). Context Varenicline, a partial agonist at the 4 2 nicotinic acetylcholine receptor, has the potential to aid smoking cessation by relieving nicotine withdrawal symptoms and reducing the rewarding properties of nicotine. Objective To determine the efficacy and safety of varenicline for smoking cessation compared with placebo or sustained-release bupropion (bupropion SR). Design, Setting, and Participants A randomized, double-blind, placebocontrolled trial conducted between June 2003 and March 2005 at 14 research centers with a 12-week treatment period and follow-up of smoking status to week 52. Of 1413 adult smokers who volunteered for the study, 1027 were enrolled; 65% of randomized participants completed the study. Intervention Varenicline titrated to 1 mg twice daily (n=344) or bupropion SR titrated to 150 mg twice daily (n=342) or placebo (n=341) for 12 weeks, plus weekly brief smoking cessation counseling. Main Outcome Measures Continuous abstinence from smoking during the last 4 weeks of treatment (weeks 9-12; primary end point) and through the follow-up period (weeks 9-24 and 9-52). Results During the last 4 weeks of treatment (weeks 9-12), 43.9% of participants in the varenicline group were continuously abstinent from smoking compared with 17.6% intheplacebogroup(oddsratio[OR],3.85;95%confidenceinterval[CI],2.69-5.50;P .001) and29.8%in thebupropionSRgroup (OR,1.90;95%CI,1.38-2.62;P .001). Forweeks 9 through 24, 29.7% of participants in the varenicline group were continuously abstinent compared with 13.2% in the placebo group (OR, 2.83; 95% CI, 1.91-4.19; P .001) and 20.2%inthebupropiongroup(OR,1.69;95%CI,1.19-2.42;P=.003).Forweeks9through 52, 23% of participants in the varenicline group were continuously abstinent compared with 10.3% in the placebo group (OR, 2.66; 95% CI, 1.72-4.11; P .001) and 14.6% in the bupropion SR group (OR, 1.77; 95% CI, 1.19-2.63; P=.004). Treatment was discontinued due to adverse events by 10.5% of participants in the varenicline group, 12.6% in the bupropion SR group, and 7.3% in the placebo group. The most common adverse event with varenicline was nausea, which occurred in 101 participants (29.4%). Conclusions Varenicline is an efficacious, safe, and well-tolerated smoking cessation pharmacotherapy. Varenicline’s short-term and long-term efficacy exceeded that of both placebo and bupropion SR. Trial Registration clinicaltrials.gov Identifier: NCT00143364