Varenicline is a recently developed medication for smoking cessation, which has been available on prescription since 2006. It is a selective
nicotinic acetylcholine receptor partial agonist, and is designed to reduce
withdrawal symptoms and to lessen the rewards of continued smoking. Our objective in this article is to assess the efficacy of
varenicline as an aid to smoking cessation and to weigh the potential benefits against the possible risks. We identified ten randomized controlled trials and one cohort study with historical controls. In total there were 7999 participants, 5112 of whom received
varenicline. Eight of the trials compared
varenicline with placebo for cessation, two compared it with
nicotine replacement therapy and one tested extended use for
relapse prevention. Three of the
varenicline/placebo trials also included a
bupropion arm. The recommended dosage of
varenicline 1 mg twice daily more than doubled the chances of quitting at 6 months or longer, with a relative risk (RR) compared with placebo of 2.38 (95% CI 2.00, 2.84). It also outperformed
bupropion (RR 1.52 [95% CI 1.22, 1.88]) and
nicotine replacement (RR 1.31 [95% CI 1.01, 1.71]). A reduced dosage regimen of 1 mg daily also increased cessation (RR 1.88 [95% CI 1.35, 2.60]). In the trials,
varenicline significantly reduced craving and other
withdrawal symptoms. The most frequent adverse event was
nausea, occurring in 30-40% of
varenicline users. However, this was generally reported at mild to moderate levels, diminished over time and was associated with attributable discontinuation rates of between 0.6% and 7.6%. Other commonly occurring adverse events included
insomnia, abnormal dreams and
headache. Serious adverse events were rare, with no treatment-related deaths during the treatment or follow-up phases. Postmarketing surveillance has raised new questions about the safety of
varenicline. In February 2008, the US FDA issued a public health advisory note, reporting a possible association between
varenicline and an increased risk of behaviour change, agitation, depressed mood, and suicidal ideation and behaviour. They have required the manufacturers to revise the labelling of
varenicline and the Summary of Product Characteristics, and to issue a medication guide. It is arguable that much of the reported behavioural and mood changes may be associated with
nicotine withdrawal, although some effects occurred in people who continued to
smoke while taking the medication. In view of the potential, if unproven, risk that
varenicline may be associated with serious neuropsychiatric adverse outcomes, patients attempting to quit smoking with
varenicline, and their families and caregivers, should be alerted about the need to monitor for neuropsychiatric symptoms, including changes in behaviour, agitation, depressed mood, suicidal ideation and suicidal behaviour, and to report such symptoms immediately to the patient's healthcare provider.