Impact of early nausea on varenicline adherence and smoking cessation

Addiction. 2020 Jan;115(1):134-144. doi: 10.1111/add.14810. Epub 2019 Nov 5.


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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Canada / epidemiology
  • Female
  • Humans
  • Male
  • Mediation Analysis
  • Medication Adherence*
  • Middle Aged
  • Nausea / chemically induced*
  • Smoking Cessation / methods*
  • Smoking Cessation Agents / adverse effects*
  • Smoking Cessation Agents / therapeutic use*
  • United States / epidemiology
  • Varenicline / adverse effects*
  • Varenicline / therapeutic use*


  • Smoking Cessation Agents
  • Varenicline

Associated data