Douglas E. Jorenby

CONTEXT: Varenicline, a partial agonist at the alpha4beta2 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% in the placebo group (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.69-5.50; P<.001) and 29.8% 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 the bupropion group (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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00143364.

BACKGROUND AND METHODS: Use of nicotine-replacement therapies and the antidepressant bupropion helps people stop smoking. We conducted a double-blind, placebo-controlled comparison of sustained-release bupropion (244 subjects), a nicotine patch (244 subjects), bupropion and a nicotine patch (245 subjects), and placebo (160 subjects) for smoking cessation. Smokers with clinical depression were excluded. Treatment consisted of nine weeks of bupropion (150 mg a day for the first three days, and then 150 mg twice daily) or placebo, as well as eight weeks of nicotine-patch therapy (21 mg per day during weeks 2 through 7, 14 mg per day during week 8, and 7 mg per day during week 9) or placebo. The target day for quitting smoking was usually day 8. RESULTS: The abstinence rates at 12 months were 15.6 percent in the placebo group, as compared with 16.4 percent in the nicotine-patch group, 30.3 percent in the bupropion group (P<0.001), and 35.5 percent in the group given bupropion and the nicotine patch (P<0.001). By week 7, subjects in the placebo group had gained an average of 2.1 kg, as compared with a gain of 1.6 kg in the nicotine-patch group, a gain of 1.7 kg in the bupropion group, and a gain of 1.1 kg in the combined-treatment group (P<0.05). Weight gain at seven weeks was significantly less in the combined-treatment group than in the bupropion group and the placebo group (P<0.05 for both comparisons). A total of 311 subjects (34.8 percent) discontinued one or both medications. Seventy-nine subjects stopped treatment because of adverse events: 6 in the placebo group (3.8 percent), 16 in the nicotine-patch group (6.6 percent), 29 in the bupropion group (11.9 percent), and 28 in the combined-treatment group (11.4 percent). The most common adverse events were insomnia and headache. CONCLUSIONS: Treatment with sustained-release bupropion alone or in combination with a nicotine patch resulted in significantly higher long-term rates of smoking cessation than use of either the nicotine patch alone or placebo. Abstinence rates were higher with combination therapy than with bupropion alone, but the difference was not statistically significant.

Gender differences in smoking quit rates are frequently reported and are the subject of much speculation. This study examined the generalizability of gender differences in abstinence across study sites, treatments, and time of relapse, as well as potential mediators and moderators of gender effects. Participants were smokers who participated in 3 randomized clinical trials of the nicotine patch (N = 632). Men had higher cessation rates than women at all follow-ups. The impact of gender on abstinence was unaffected by controlling for study site, treatment, or time of relapse. There was little evidence for mediation or moderation of this relation by any of a host of predictor variables. The magnitude and consistency of the gender differential, coupled with an inability to account for it, highlights a compelling need for additional research specifically aimed at elucidating the relation between gender and abstinence.

The multiphase optimization strategy (MOST) is a new methodological approach for building, optimizing, and evaluating multicomponent interventions. Conceptually rooted in engineering, MOST emphasizes efficiency and careful management of resources to move intervention science forward steadily and incrementally. MOST can be used to guide the evaluation of research evidence, develop an optimal intervention (the best set of intervention components), and enhance the translation of research findings, particularly type II translation. This article uses an ongoing study to illustrate the application of MOST in the evaluation of diverse intervention components derived from the phase-based framework reviewed in the companion article by Baker et al. (Ann Behav Med, in press, 2011). The article also discusses considerations, challenges, and potential benefits associated with using MOST and similar principled approaches to improving intervention efficacy, effectiveness, and cost-effectiveness. The applicability of this methodology may extend beyond smoking cessation to the development of behavioral interventions for other chronic health challenges.

The accurate assessment of nicotine withdrawal is important theoretically and clinically. A 28-item scale, the Wisconsin Smoking Withdrawal Scale, was developed that contains 7 reliable subscales tapping the major symptom elements of the nicotine withdrawal syndrome. Coefficients alpha for the subscales range from .75 to .93. This scale is sensitive to smoking withdrawal, is predictive of smoking cessation outcomes, and yields data that conform to a 7-factor structure. The 7 scales predicted intratreatment smoking, chi2(7, N = 163) = 15.19, p = .034. Moreover, the questionnaire is sufficiently brief so that it can be used in both clinical and research contexts.