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

Abstract

Objective: Varenicline, a selective partial agonist of the a4b2 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.

A Phase I, Open-label, Randomized, 2-Way Crossover Study to Evaluate the Relative Bioavailability of Intranasal and Oral Varenicline

“…25 The metabolism, disposition, pharmacokinetic properties, clinical efficacy, and tolerability of oral varenicline have been extensively characterized and reviewed. [25][26][27][28] Briefly, varenicline tartrate is highly soluble in water, with a recommended oral dose of 0.5 to 1 mg twice daily that exhibits linear pharmacokinetic properties. Systemic bioavailability is high (˜90%) and unaffected by food, peak plasma concentration typically occurs within 3 to 4 hours, and with ongoing use, steady state occurs within 4 days.…”

The current state of tobacco cessation treatment

“…14 Although it is recommended to start varenicline dosing at least 1 to 2 weeks before the target quit date (the "fi xed target quit date" approach), other approaches are acceptable: • Medication preloading: ie, starting pharmacotherapy while the smoker is still smoking • Flexible quit date: patient chooses a quit date within 1 month of starting medication • Reduce-to-quit approach: gradual smoking reduction with the goal of eventually quitting completely. 27 Dosing titration starts with 0.5 mg orally once daily for 3 days, with up-titration every 3 days to 1 mg orally twice daily until the end of treatment. In patients who develop adverse effects, lower doses of varenicline (eg, 0.5 mg twice daily) can be used.…”

Looking Back and Going Forward: Roles of Varenicline and Electronic Cigarettes in Smoking Cessation

“…Varenicline is a selective partial agonist at the α4β2 nicotinic acetylcholine receptor subtype, where it stimulates dopamine secretion to reduce nicotine withdrawal symptoms. It, therefore, helps counteract nicotine withdrawal symptoms by blocking the action of nicotine on the brain [ 28 ]. After the FDA placed a black box warning on varenicline in 2009 due to concerns about neuropsychiatric side effects, varenicline sales declined significantly [ 50 ].…”

“…Varenicline is a prescription-only drug in the US, while e-cigarettes have been on the open market (Table 1 ). The impact of these two contemporary additions to the tobacco control scene on smoking prevalence is reviewed to predict their potential effects on cessation rates in the years ahead [ 5 , 10 - 11 , 13 - 14 , 19 - 28 ].…”

“…Varenicline is a prescription-only drug in the US, while e-cigarettes have been on the open market (Table 1). The impact of these two contemporary additions to the tobacco control scene on smoking prevalence is reviewed to predict their potential effects on cessation rates in the years ahead [5,[10][11][13][14][19][20][21][22][23][24][25][26][27][28]. AND Smoking Cessation", "(E-cigarettes) AND Regulation", and ((E-cigarettes) AND Efficacy) AND side effects.…”