Impact of early nausea on varenicline adherence and smoking cessation

Abstract

Background and aims: Varenicline effectiveness may be related to the level of adherence, which might be reduced by adverse effects such as nausea. The aim of the study was to test a possible effect of nausea on smoking cessation outcomes mediated by adherence.

Design: Mediation path analysis.

Setting: Multiple sites within Canada and the United States.

Participants: Treatment-seeking smokers receiving varenicline from two smoking cessation clinical trials: Quit2Live (NCT01836276; n = 449) and Pharmacogenetics of Nicotine Addiction Treatment (PNAT) (NCT01314001; n = 421).

Measurements: Nausea severity was collected through self-report and adherence was biologically assessed using varenicline concentrations (Quit2Live, plasma sample at week 4; PNAT, saliva sample at week 2). In Quit2Live, the end-points were cotinine-verified abstinence at weeks 4, 12 and 26. In PNAT, the end-points were carbon monoxide-verified abstinence at weeks 2, 12 and 26.

Findings: Early nausea was not directly associated with abstinence [odds ratio (OR) ranging from 0.73-1.28; P ≥ 0.26]. However early nausea was indirectly associated with lower cessation rates at multiple timepoints (ORs ranging from 0.92-0.94; 95% CI between 0.83-0.99) in a relationship mediated by reduced varenicline adherence (assessed by plasma varenicline concentrations) in the primary trial (Quit2Live). This relationship between nausea, adherence and cessation was similar in direction but weaker in effect size (ORs ranging from 0.98-0.99; 95% CI between 0.90-1.03) in a secondary trial (PNAT), where adherence was assessed using salivary varenicline concentrations.

Conclusions: These data suggest that early nausea during varenicline treatment may be indirectly associated with lower likelihood of smoking cessation through reducing varenicline adherence. Differences in robustness between the trials may be due to the different biological matrices (plasma vs. saliva) and/or timing used to assess varenicline adherence. The results of the first study suggest that improved management of early nausea during varenicline treatment may positively impact smoking cessation success through increasing varenicline adherence.

Keywords: Adherence; adverse events; compliance; nausea; smoking cessation; varenicline.

Conflict of interest statement

Conflict of Interest

RFT has consulted for Quinn Emanuel, Apotex and Ethismos; she is also a member of several scientific advisory boards (e.g. Health Canada, Quitta, Canadian Centre for Substance Abuse, and Brain Canada). CL and RFT received drug and packaging at no cost for varenicline used in the PNAT2 clinical trial. JSA had consulted with Lucy Gum. NLB is a consultant to Pfizer and Achieve Life Sciences, companies that market or are developing smoking cessation medications, and has served as a paid expert in litigation against tobacco companies. Remaining authors have no conflicts of interest to declare.

© 2019 Society for the Study of Addiction.

Figures

Figure 1.. (A) Study 1 - Quit2Live and (B) Study 2 - PNAT trial timelines.

Participants were prescribed varenicline under the recommended dosing schedule for 12 weeks (0.5mg once daily for three days, 0.5mg twice daily for four days, and 1.0mg twice daily for the remainder of the twelve weeks). Nausea Assessment= collection of self-reported nausea incidence and severity; Quit Assessment= biochemically-verified quit.

Figure 2 –. Quit2Live mediation path model. Association between Week 1 nausea and quit outcomes via standardized Week 4 plasma varenicline levels.

N=355 had available self-report Week 1 nausea data and provided a Week 4 plasma sample for varenicline level testing. Thin solid arrows indicate non-significant pathways; thick solid arrows indicate significant pathways (p

Figure 3 –. Quit2Live mediation path model. Association between Week 1 nausea and quit outcomes via unstandardized Week 4 plasma varenicline levels.

N=355 had available self-report Week 1 nausea data and provided a Week 4 plasma sample for varenicline level testing. Thin solid arrows indicate non-significant pathways; thick solid arrows indicate significant pathways (p

Figure 4 –. Quit2Live mediation path model. Association between Week 1 nausea and quit outcomes via standardized Week 4 salivary varenicline levels.

N=355 had available self-report Week 1 nausea data and provided a Week 4 plasma sample for varenicline level testing. Thin solid arrows indicate non-significant pathways; thick solid arrows indicate significant pathways (p

Figure 5 –. PNAT mediation path model. Association between Week 1 nausea and quit outcomes via standardized Week 2 salivary varenicline levels.

N=363 had available self-report Week 1 nausea data and provided a Week 2 salivary sample for varenicline level testing. Thin solid arrows indicate non-significant pathways; thick solid arrows indicate significant pathways (p