A New Drug to Help Smokers Quit: The Role of Varenicline

Richard D. Hurt, MD
Professor of Medicine
Mayo Clinic College of Medicine
Director, Mayo Clinic Nicotine Dependence Center

Varenicline is the first medication in a new class of drugs that has been shown to be effective in helping smokers to stop smoking. Varenicline is a selective α4β2 nicotinic acetylcholine receptor partial agonist developed specifically for the treatment of tobacco dependence. The α4β2 nicotinic acetylcholine receptor is involved in the rewarding effects of nicotine and plays a central role in the development of nicotine dependence resulting from cigarette smoking. Varenicline is believed to work in two ways: (1)as a partial nicotine agonist it stimulates dopamine release to reduce craving and withdrawal symptoms; and (2) with its partial antagonist activity it blocks the rewarding effects of nicotine delivered by cigarette smoke if the person smokes while taking varenicline. This is the first new medication for treating tobacco dependence treatment since the release of bupropion in 1997.

In two large randomized placebo controlled trials of varenicline for 12 weeks vs. bupropion SR or placebo, varenicline significantly outperformed placebo with 44% of the subjects abstinent from smoking at the end of medication vs. 18% for placebo (OR 3.85, P<0.001). Varenicline also outperformed bupropion SR which produced a smoking abstinence rate of approximately 30% at the end of treatment (OR 1.9-1.93, P<0.001). At week 52, varenicline was nearly three times more effective than placebo (OR 2.66-3.09, P<0.001) while the difference in smoking abstinence between varenicline and bupropion SR was no longer significant (OR 1.46, 95% CI 0.99-2.17) in one study but was significant in the other (OR 1.77, 95% CI 1.19-2.63). Both varenicline and bupropion SR significantly reduced the urge to smoke, craving for cigarettes and negative affect compared with placebo.

Nausea was the most common side effect reported, occurring in about 29% of the subjects receiving varenicline. In the vast majority, the nausea was mild and tolerable and did not often lead to study discontinuation. Sleep disturbances, such as insomnia and abnormal dreams, was reported by about 30% of the subjects who received varenicline. (Approximately 30% of subjects who received bupropion SR in these studies also reported sleep disturbances).

Varenicline has also been shown to improve long-term abstinence from smoking if used for an additional 12 weeks in smokers who stopped smoking after the initial 12-week course of treatment. At week 24, varenicline users maintained smoking abstinence compared to placebo at a rate of 70.5% vs. 49.6% (OR 2.48, 95% CI 1.95-3.16). At one year the difference was narrower but still significant with smoking abstinence rates of 43.6% vs. 36.9% (OR 1.34, 95% CI 1.06-1.69).

Varenicline is an oral medication that is started 7 days before the target quit date. The dose is titrated beginning with 0.5 mg per day for three days then 0.5 mg twice daily for four days. The dose then is increased to 1.0 mg twice daily and this is continued for 12 weeks. For smokers who are abstinent from smoking at the end of 12 weeks, varenicline can be used for an additional 12 weeks in those who are worried about relapse to smoking. Many will find it necessary to use the medication even longer but that will depend upon the health care provider and the patient. Currently, varenicline is not recommended for use in combination with any nicotine replacement medication.

Varenicline should be considered a first line medication for the treatment of tobacco dependence, and it can be used in practically any adult smoker who wants to stop smoking. However, it has not been tested in adolescent, pregnant or breastfeeding smokers. Varenicline is cleared almost entirely by the kidneys and dose adjustments are necessary in the presence of severe renal failure (creatinine clearance < 30 ml/min.) and patients receiving hemodialysis. Nausea can be minimized by taking the medication with a large glass of water after eating. If patients are intolerant of 1.0 mg twice a day, a trial of 0.5 mg twice a day should be encouraged.

Gonzales D, Rennard, SI, Nides, M, et al. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs. sustained-release bupropion and placebo for smoking cessation. A randomized controlled trial. JAMA. 2006; 296:1:47-55.

Jorenby, DE, Hays, JT, Rigotti, NA, et al. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs. placebo or sustained-release bupropion for smoking cessation. JAMA. 2006;296:1:56-63

Tonstad, S, Tonnesen, P, Hajek, P, et al. Effect of maintenance therapy with varenicline on smoking cessation. JAMA. 2006;296:1:64-71.