Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial

JAMA. 2006 Jul 5;296(1):56-63. doi: 10.1001/jama.296.1.56.


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.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Benzazepines / therapeutic use*
  • Bupropion / therapeutic use*
  • Delayed-Action Preparations
  • Dopamine Uptake Inhibitors / therapeutic use*
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Nicotinic Agonists / therapeutic use*
  • Quinoxalines / therapeutic use*
  • Receptors, Nicotinic
  • Smoking Cessation* / methods
  • Varenicline


  • Benzazepines
  • Delayed-Action Preparations
  • Dopamine Uptake Inhibitors
  • Nicotinic Agonists
  • Quinoxalines
  • Receptors, Nicotinic
  • nicotinic receptor alpha4beta2
  • Bupropion
  • Varenicline

Associated data

  • ClinicalTrials.gov/NCT00143364