Varenicline: mode of action, efficacy, safety and accumulated experience salient for clinical populations.

Objective: Varenicline, a selective partial agonist of the α4ß2 nicotinic acetylcholine receptor, is a smoking cessation pharmacotherapy that more than doubles the chance of quitting smoking at 6 months compared with placebo. This article reviews salient knowledge of the discovery, pharmacological characteristics, and the efficacy and safety of varenicline in general and in specific populations of smokers and provides recommendations to support use in clinical practice.Methods: Literature searches for varenicline were conducted using PubMed, with date limitations of 2000-2018 inclusive, using search terms covering the discovery, mechanism of action, pharmacokinetics, efficacy and safety in different populations of smokers, alternative quit approaches and combination therapy. Selection of safety and efficacy data was limited to clinical trials, meta-analyses and observational studies.Results: Standard administration of varenicline is efficacious in helping smokers to quit, including smokers with cardiovascular disease and chronic obstructive pulmonary disease. Furthermore, varenicline efficacy may be improved with pre-loading, a gradual quitting approach for smokers unwilling or unable to quit abruptly, and extended treatment in smokers who have recently quit to help maintain abstinence. Initial concerns regarding the association of varenicline with increased risk of neuropsychiatric and cardiovascular adverse events have been disproven after extensive clinical evaluations, and the benefit-risk profile of varenicline is considered favorable.Conclusions: Varenicline is efficacious and safe for all adult smokers with a range of clinical characteristics. Evidence suggests that approaches offering greater flexibility in timing and duration of treatment may further extend treatment efficacy and clinical reach.

The acquisition and maintenance of voluntary ethanol drinking in the rat: effects of dopaminergic lesions and naloxone.

Wistar male rats were microinfused bilaterally with 6-hydroxydopamine or vehicle into the ventral tegmental area. After recovery, ethanol drinking was established using a sucrose-fading paradigm, i.e. rats were given twice a day access to drinks containing increasing amounts of ethanol and decreasing amounts of sucrose. Mean daily intakes at each ethanol/sucrose concentration were similar irrespective of the level of dopamine depletion that, in some animals, reached 80-90%. The percentage of rats testing as ethanol preferers in a two-bottle choice test also appeared similar in both the lesioned and control groups. After completing the sucrose-fading protocol, all rats were switched to one access per day during which they were presented with a drink containing 10% ethanol with 5% sucrose. Naloxone administration (15 min before the daily access period) decreased ethanol beverage consumption by about 50%, irrespective of the level of dopamine depletion. Total daily water intake was not altered by naloxone. In a two-bottle choice situation, naloxone suppressed intake of an ethanol drink (10% ethanol/5% sucrose), but not the intake of 5% sucrose alone. Thus, a lesion of the dopaminergic cell bodies that results in extensive depletion of dopamine in mesolimbic target regions produced no measurable effect on intake of the sweetened ethanol drinks during the acquisition phase of the sucrose-fading paradigm. Furthermore, during the maintenance phase of drinking, the marked effect of naloxone in inhibiting ethanol beverage ingestion (but not water ingestion or sucrose alone solutions) occurred despite extensive loss of dopaminergic innervation to telencephalic target regions. A preliminary account of these experiments appeared in an abstract form and as an Internet publication. (Supported by NIAAA grants P50-03510 and T32-0720).