Trials that Matter: Varenicline: A Designer Drug to Help Smokers Quit

Two things are very clear to physicians and smokers alike: Smoking is bad for your health, and it is devilishly hard to quit (1, 2). Not surprisingly, therefore, many clinicians are pessimistic, even cynical, about treating smokers. “Why should I spend my limited time on this problem, when I know I am doomed to fail?” Actually, the rejoinders to this view—that smoking rates are at a historic low, that ex-smokers now outnumber current smokers, and that over 70% of smokers want to quit—are compelling. Physicians and smokers should also welcome the news that the FDA has approved a new drug, varenicline, for smoking cessation treatment. Varenicline, a partial nicotine agonist, has become the third pharmacologic agent approved by the FDA, following nicotine replacement therapy (currently available as patches, gum, lozenges, nasal spray, and an inhaler) and the psychoactive drug bupropion, approved in 1997 (3). Thus, after almost a decade, the FDA has had an opportunity to approve a new class of drug to treat the most important preventable health risk.

The development of varenicline reflects new understanding of how nicotine acts to increase craving for cigarettes. Receptors in the mesocorticolimbic area of the brain, which is targeted by most drugs of abuse, become desensitized through long-term exposure to nicotine, which subsequently reduce dopamine release. Nicotine receptors are ion channels that are activated by endogenous acetylcholine and by nicotine. The ion channel has at least 12 subunits that can combine in various ways to form many subtypes of ion channels. We now know that a particular nicotine receptor subtype (α4β₂) is both necessary and sufficient to cause nicotine-induced sensitization, reward, and tolerance. These discoveries focused attention …