Context: Varenicline, a partial agonist at the α4β2 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, placebo-controlled 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 the bupropion SR group (OR, 1.90;95%CI, 1.38-2.62;P<.001). For weeks 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%in thebupropiongroup(OR,1.69;95%CI, 1.19-2.42;P=.003). For weeks 9 through 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.
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