Discovery and development of varenicline for smoking cessation.

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cover post-market surveillance, including caution in heavy machine operators, putative cardiovascular risk, and the repealed warning for adverse neuropsychiatric events.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.