Extending Varenicline Preloading to 6 Weeks Facilitates Smoking Reduction and Cessation: A Randomised Controlled Trial

Abstract

Background: In smokers receiving varenicline cessation treatment, increasing the pre-quit period by 3 weeks reduces smoking intake prior to quit attempts and increases cessation rates; however, the lack of an intake plateau suggests longer preload periods are required. We assessed whether varenicline preloading for 6 weeks reduces pre-quit smoke intake and enhances 6-month abstinence outcomes compared with the standard 1-week preloading. Methods: This randomised controlled trial was conducted between February 2016 and July 2018 in Israel. Everyday smokers (n = 242) aged ≥ 18 years were randomly assigned (1:1) to receive extended varenicline preloading for 6 weeks (n = 121) or a placebo for 5 weeks followed by varenicline for 1 week (n = 121) before the target quit date (TQD). Both groups received standard 12-week post-TQD varenicline treatment. Participants and researchers were masked to treatment allocation. Primary outcomes were the 24-week biochemically-verified continuous abstinence rate (CAR) (weeks 6-30) and the 12-week CAR (weeks 6-18). Other measures included pre- and post-quit rewards, smoking urges, nausea, aversion, and markers of cigarette consumption. Analysis involved intention-to-treat. Findings: The 12-week CAR was 24·8% for extended preloading vs. 7·4% for standard preloading (odds ratio [OR], 4·10 [95% confidence interval [CI]: 1·85-9·08]; p < 0·001). The 24-week CAR was 23·1% for extended preloading vs. 4.1% for standard preloading (OR, 6·98 [95% CI: 2·60-18·80]; p < 0·001). Extended preloading significantly decreased pre-quit rewards and urges; nausea increased along with decreased smoke intake, including unsolicited smoking abstinence. In the post-quit period, after beginning the standard varenicline treatment, between-group differences in rewards and nausea subsided; smoking urges remained remarkably lower in the extended preloading group. Extended preloading was safe and well accepted. Interpretation: Extended preloading generated a marked reduction in ad lib smoking, enhanced cessation rates at 3 and 6 months, and increased abstinence rates by promoting a reinforcement-reduction mechanism unnoticed with the standard dosing regimen. Our data substantiate extending the standard pre-treatment period and suggest that targeting pre-quit smoking sensations should be a priority in smoking cessation treatments. Trial Registration: ClinicalTrials.gov (Identifier: NCT02634281). Funding Statement: This study was funded by a 2013 Global Research Award for Nicotine Dependence (GRAND) supported by Pfizer, Inc (#WI182915). Editorial support in the form of editing, proofing and formatting the text and preparing the manuscript for submission was provided by Elsevier Editing Services and funded by the Pulmonary Institute of Shaare Zedek Medical Center. Declaration of Interests: The authors state: None to declare. Ethics Approval Statement: The study was conducted in compliance with the recommendations guiding physicians in biomedical research involving humans adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964 and later revisions. The “Helsinki Committee” of the SZMC approved all study procedures and all participants provided written informed consent prior to any procedures.