Discovery and development of varenicline for smoking cessation

ABSTRACT

Introduction: Tobacco use causes one premature death every six seconds. Current smoking cessation aids include nicotine replacement therapies, bupropion, and varenicline. Although more than 70% of smokers express a desire to quit, fewer than 3% remain abstinent for more than one year, highlighting a critical need for more efficacious smoking cessation treatments.

Areas covered: The authors discuss the rationale, preclinical and clinical development of varenicline for smoking cessation. They cover the development of varenicline as a partial agonist at α₄β₂ receptors, the primary neural substrate for nicotine reward. Then, they discuss evidence from preclinical studies indicating varenicline’s efficacy in blocking nicotine reward, followed by clinical trials demonstrating safety and efficacy in sustaining abstinence in smokers. Finally, they cover post-market surveillance, including caution in heavy machine operators, putative cardiovascular risk, and the repealed warning for adverse neuropsychiatric events.

Expert opinion: Varenicline development was based on strong theoretical rationale and preclinical evidence. Clinical studies indicate that varenicline is safe and more effective in sustaining abstinence than placebo, bupropion or nicotine replacement therapies. However, given that continuous abstinence rates across studies remain low (18 ~ 30% with varenicline; 4 ~ 10% with placebo), novel and more effective medications targeting other nicotinic or glutamate receptors for smoking cessation are required.

KEYWORDS:

• Acetylcholine receptor
• addiction
• nicotine
• smoking cessation
• varenicline

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Corrigendum

Article highlights

• Smoking is the leading cause of preventable death in the United States. While more than 70% of smokers express a desire to quit, fewer than 3% remain abstinent more than one year. There is a critical need for more efficacious smoking cessation aids.

• The primary addictive component in tobacco is nicotine. In the brain, nicotine produces rewarding and psychostimulant effects mainly by binding to α₄β₂ nicotinic acetylcholine receptors on midbrain dopaminergic neurons, causing an increase in dopamine release in the nucleus accumbens, a key reward processing region.

• Varenicline was developed by Pfizer as a selective partial agonist at the α₄β₂ receptor based on a series of synthetic analgesic benzazepines, one of which lacked analgesic activity and was found to be an α₄β₂ nAChR antagonist.

• Preclinical studies indicate that varenicline suppresses nicotine-induced dopamine release and attenuates nicotine conditioned place preferences, nicotine self-administration, and nicotine- or cue-induced reinstatement of drug-seeking behaviors.

• Clinical studies indicate that varenicline is safe, well-tolerated and more efficacious in sustaining abstinence in smokers compared to placebo as well as to other currently available smoking cessation aids, including bupropion and nicotine replacement therapies.

• Although early post-marketing surveillance suggested that potentially adverse neuropsychiatric and cardiovascular events were associated with varenicline use, subsequent studies indicate that the probability of these events is low. Nonetheless, caution is warranted for varenicline use in individuals who routinely operate heavy machinery.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. One referee declares that they have received honoraria for consulting and for lectures for the manufacturer of varenicline (Pfizer) as well as from other manufacturers of drugs for smoking cessation (GlaxoSmithKline and Novartis).

Additional information

Funding

This research was supported by the Intramural Research Program of the National Institute on Drug Abuse (Z1A DA000389), National Institutes of Health, USA.