Varenicline is a partial agonist of the α4ß2 subtype of the nicotinic acetylcholine receptor that partially mimics nicotine, yet competitively inhibits nicotine from binding. It is recommended by the NCCN as a first-line option.

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The Cochrane meta-analysis demonstrated that varenicline is more effective than placebo for increasing the likelihood of quitting (OR, 2.88; 95% CI, 2.4-3.47). It is also more effective than singular NRT, including the patch (OR, 1.51; 95% CI, 1.22-187), but has similar efficacy as combination NRT (OR, 1.06; 95% CI, 0.75-1.48). Varenicline was also demonstrated to have greater efficacy than bupropion (OR, 1.59; 95% CI, 1.29-1.96).

The EAGLES trial demonstrated that varenicline was associated with higher abstinence rates compared with placebo (OR, 3.61; 95% CI, 3.07-4.24), NRT patch (OR, 1.68; 95% CI, 1.46-1.93), and bupropion (OR, 1.75; 95% CI, 1.52-2.01).

The NCCN cautions that varenicline is associated with nausea, which can be a particular concern among patients receiving chemotherapy or other anticancer agents. In the EAGLES trial, 25% of patients taking varenicline experienced nausea. The intensity of nausea frequently decreases over time, and titration to the full dose can reduce the incidence. Other common AEs include insomnia, abnormal dreams, and headache.

The rate of serious AEs (SAEs) in the Cochrane review was similar to placebo, including for neuropsychiatric events (RR, 0.53; 95% CI, 0.17-1.67). Postmarketing reports have, however, raised concerns regarding neuropsychiatric events and resulted in a black box warning.

The EAGLES trial demonstrated that moderate and severe neuropsychiatric AEs were more common among patients with a psychiatric disorder. Among patients without a psychiatric disorder, the rate of moderate and severe neuropsychiatric AEs was 1.3% with varenicline, 2.2% with bupropion, 2.5% with NRT patch, and 2.4% with placebo. These rates increased in the psychiatric cohort to 6.5%, 6.7%, 5.2%, and 4.9%, respectively.


For patients who do not achieve cessation with combination NRT or varenicline, the NCCN recommends combination NRT plus bupropion or bupropion alone.

The Cochrane review demonstrated that bupropion monotherapy was more effective than placebo at increasing the odds of cessation (OR, 1.82; 95% CI, 1.6-2.06), with similar efficacy as singular NRT (0.99; 95% CI. 086-1.13). Bupropion was less effective, however, than combination NRT (OR, 0.68; 95% CI, 0.5-0.91).3

The EAGLES trial demonstrated that bupropion increased the rate of smoking abstinence compared with placebo (OR, 2.07; 95% CI, 1.75-2.45).

AEs occur in up to 40% of patients taking bupropion and most commonly include dry mouth and nausea. The risk of a SAE is 1:1000, and reports to the US Food and Drug Administration (FDA) resulted in warning for serious neuropsychiatric symptoms, though the relationship for this is unclear.


The NCCN-recommended first-line therapy for smoking cessation is behavioral therapy plus combined NRT or varenicline. These options have similar efficacy, though varenicline is associated with nausea. Patients who fail 1 regimen should be switch to the alternative first-line regimen. If both combined NRT and varenicline are not effective, bupropion with or without combined NRT can be used.

It is important that providers understand that relapse and repeated quit attempts are normal, and guidance and support should be continued through these events.


  1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Smoking Cessation. v 1.2017. Available at: Accessed April 2017.
  2. Stead LF, Koilpillai P, Lancaster T. Additional behavioural support as an adjunct to pharmacotherapy for smoking cessation. Cochrane Database Syst Rev. 2015;CD009670. doi: 10.1002/14651858.CD009670.pub3
  3. Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013;CD009329. doi: 10.1002/14651858.CD009329.pub2
  4. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;387:2507-20. doi: 10.1016/S0140-6736(16)30272-0