Impact of early nausea on varenicline adherence and smoking cessation
Annie R Peng, Walter Swardfager, Neal L Benowitz, Jasjit S Ahluwalia, Caryn Lerman, Nicole L Nollen, Rachel F Tyndale, Annie R Peng, Walter Swardfager, Neal L Benowitz, Jasjit S Ahluwalia, Caryn Lerman, Nicole L Nollen, Rachel F Tyndale
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…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6933078/bin/nihms-1049677-f0001.jpg)
![Figure 2 –. Quit2Live mediation path model.…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6933078/bin/nihms-1049677-f0002.jpg)
Figure 3 –. Quit2Live mediation path model.…
Figure 3 –. Quit2Live mediation path model. Association between Week 1 nausea and quit outcomes…
Figure 4 –. Quit2Live mediation path model.…
Figure 4 –. Quit2Live mediation path model. Association between Week 1 nausea and quit outcomes…
Figure 5 –. PNAT mediation path model.…
Figure 5 –. PNAT mediation path model. Association between Week 1 nausea and quit outcomes…
- Predicting smoking abstinence with biological and self-report measures of adherence to varenicline: Impact on pharmacogenetic trial outcomes.Peng AR, Schnoll R, Hawk LW Jr, Cinciripini P, George TP, Lerman C, Tyndale RF. Peng AR, et al. Drug Alcohol Depend. 2018 Sep 1;190:72-81. doi: 10.1016/j.drugalcdep.2018.04.035. Epub 2018 Jun 26. Drug Alcohol Depend. 2018. PMID: 29986268 Free PMC article. Clinical Trial.
- Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial.Courtney RJ, McRobbie H, Tutka P, Weaver NA, Petrie D, Mendelsohn CP, Shakeshaft A, Talukder S, Macdonald C, Thomas D, Kwan BCH, Walker N, Gartner C, Mattick RP, Paul C, Ferguson SG, Zwar NA, Richmond RL, Doran CM, Boland VC, Hall W, West R, Farrell M. Courtney RJ, et al. JAMA. 2021 Jul 6;326(1):56-64. doi: 10.1001/jama.2021.7621. JAMA. 2021. PMID: 34228066 Free PMC article. Clinical Trial.
- Placebo-controlled randomized clinical trial testing the efficacy and safety of varenicline for smokers with HIV.Ashare RL, Thompson M, Serrano K, Leone F, Metzger D, Frank I, Gross R, Hole A, Mounzer K, Collman RG, Wileyto EP, Schnoll R. Ashare RL, et al. Drug Alcohol Depend. 2019 Jul 1;200:26-33. doi: 10.1016/j.drugalcdep.2019.03.011. Epub 2019 May 7. Drug Alcohol Depend. 2019. PMID: 31082665 Free PMC article. Clinical Trial.
- Modelling continuous abstinence rates over time from clinical trials of pharmacological interventions for smoking cessation.Jackson SE, McGowan JA, Ubhi HK, Proudfoot H, Shahab L, Brown J, West R. Jackson SE, et al. Addiction. 2019 May;114(5):787-797. doi: 10.1111/add.14549. Epub 2019 Jan 29. Addiction. 2019. PMID: 30614586 Free PMC article. Review.
- Nicotine receptor partial agonists for smoking cessation.Cahill K, Stead LF, Lancaster T. Cahill K, et al. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD006103. doi: 10.1002/14651858.CD006103.pub5. Cochrane Database Syst Rev. 2011. PMID: 21328282 Updated. Review.
- Nicotine receptor partial agonists for smoking cessation.Livingstone-Banks J, Fanshawe TR, Thomas KH, Theodoulou A, Hajizadeh A, Hartman L, Lindson N. Livingstone-Banks J, et al. Cochrane Database Syst Rev. 2023 May 5;5(5):CD006103. doi: 10.1002/14651858.CD006103.pub8. Cochrane Database Syst Rev. 2023. PMID: 37142273 Free PMC article. Review.
- The use of biomarkers to guide precision treatment for tobacco use.Siegel SD, Tindle HA, Bergen AW, Tyndale RF, Schnoll R. Siegel SD, et al. Addict Neurosci. 2023 Jun;6:100076. doi: 10.1016/j.addicn.2023.100076. Epub 2023 Feb 16. Addict Neurosci. 2023. PMID: 37089247 Free PMC article.
- Stability of Varenicline Concentration in Saliva Over 21 Days at Three Storage Temperatures.Novalen M, Chenoweth MJ, Zhao B, Hawk LW, Tyndale RF. Novalen M, et al. Nicotine Tob Res. 2022 Feb 1;24(2):270-274. doi: 10.1093/ntr/ntab173. Nicotine Tob Res. 2022. PMID: 34460924 Free PMC article.
- Cytisine versus varenicline for smoking cessation in New Zealand indigenous Māori: a randomized controlled trial.Walker N, Smith B, Barnes J, Verbiest M, Parag V, Pokhrel S, Wharakura MK, Lees T, Cubillos Gutierrez H, Jones B, Bullen C. Walker N, et al. Addiction. 2021 Oct;116(10):2847-2858. doi: 10.1111/add.15489. Epub 2021 May 4. Addiction. 2021. PMID: 33761149 Free PMC article. Clinical Trial.
- Clinical Trial
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- 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
- ClinicalTrials.gov/NCT01314001
- ClinicalTrials.gov/NCT01836276
- Full Text Sources
- Medical
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 3 –. Quit2Live mediation path model.…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6933078/bin/nihms-1049677-f0003.jpg)
Figure 4 –. Quit2Live mediation path model.…
Figure 4 –. Quit2Live mediation path model. Association between Week 1 nausea and quit outcomes…
Figure 5 –. PNAT mediation path model.…
Figure 5 –. PNAT mediation path model. Association between Week 1 nausea and quit outcomes…
- Predicting smoking abstinence with biological and self-report measures of adherence to varenicline: Impact on pharmacogenetic trial outcomes.Peng AR, Schnoll R, Hawk LW Jr, Cinciripini P, George TP, Lerman C, Tyndale RF. Peng AR, et al. Drug Alcohol Depend. 2018 Sep 1;190:72-81. doi: 10.1016/j.drugalcdep.2018.04.035. Epub 2018 Jun 26. Drug Alcohol Depend. 2018. PMID: 29986268 Free PMC article. Clinical Trial.
- Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial.Courtney RJ, McRobbie H, Tutka P, Weaver NA, Petrie D, Mendelsohn CP, Shakeshaft A, Talukder S, Macdonald C, Thomas D, Kwan BCH, Walker N, Gartner C, Mattick RP, Paul C, Ferguson SG, Zwar NA, Richmond RL, Doran CM, Boland VC, Hall W, West R, Farrell M. Courtney RJ, et al. JAMA. 2021 Jul 6;326(1):56-64. doi: 10.1001/jama.2021.7621. JAMA. 2021. PMID: 34228066 Free PMC article. Clinical Trial.
- Placebo-controlled randomized clinical trial testing the efficacy and safety of varenicline for smokers with HIV.Ashare RL, Thompson M, Serrano K, Leone F, Metzger D, Frank I, Gross R, Hole A, Mounzer K, Collman RG, Wileyto EP, Schnoll R. Ashare RL, et al. Drug Alcohol Depend. 2019 Jul 1;200:26-33. doi: 10.1016/j.drugalcdep.2019.03.011. Epub 2019 May 7. Drug Alcohol Depend. 2019. PMID: 31082665 Free PMC article. Clinical Trial.
- Modelling continuous abstinence rates over time from clinical trials of pharmacological interventions for smoking cessation.Jackson SE, McGowan JA, Ubhi HK, Proudfoot H, Shahab L, Brown J, West R. Jackson SE, et al. Addiction. 2019 May;114(5):787-797. doi: 10.1111/add.14549. Epub 2019 Jan 29. Addiction. 2019. PMID: 30614586 Free PMC article. Review.
- Nicotine receptor partial agonists for smoking cessation.Cahill K, Stead LF, Lancaster T. Cahill K, et al. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD006103. doi: 10.1002/14651858.CD006103.pub5. Cochrane Database Syst Rev. 2011. PMID: 21328282 Updated. Review.
- Nicotine receptor partial agonists for smoking cessation.Livingstone-Banks J, Fanshawe TR, Thomas KH, Theodoulou A, Hajizadeh A, Hartman L, Lindson N. Livingstone-Banks J, et al. Cochrane Database Syst Rev. 2023 May 5;5(5):CD006103. doi: 10.1002/14651858.CD006103.pub8. Cochrane Database Syst Rev. 2023. PMID: 37142273 Free PMC article. Review.
- The use of biomarkers to guide precision treatment for tobacco use.Siegel SD, Tindle HA, Bergen AW, Tyndale RF, Schnoll R. Siegel SD, et al. Addict Neurosci. 2023 Jun;6:100076. doi: 10.1016/j.addicn.2023.100076. Epub 2023 Feb 16. Addict Neurosci. 2023. PMID: 37089247 Free PMC article.
- Stability of Varenicline Concentration in Saliva Over 21 Days at Three Storage Temperatures.Novalen M, Chenoweth MJ, Zhao B, Hawk LW, Tyndale RF. Novalen M, et al. Nicotine Tob Res. 2022 Feb 1;24(2):270-274. doi: 10.1093/ntr/ntab173. Nicotine Tob Res. 2022. PMID: 34460924 Free PMC article.
- Cytisine versus varenicline for smoking cessation in New Zealand indigenous Māori: a randomized controlled trial.Walker N, Smith B, Barnes J, Verbiest M, Parag V, Pokhrel S, Wharakura MK, Lees T, Cubillos Gutierrez H, Jones B, Bullen C. Walker N, et al. Addiction. 2021 Oct;116(10):2847-2858. doi: 10.1111/add.15489. Epub 2021 May 4. Addiction. 2021. PMID: 33761149 Free PMC article. Clinical Trial.
- Clinical Trial
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- 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
- ClinicalTrials.gov/NCT01314001
- ClinicalTrials.gov/NCT01836276
- Full Text Sources
- Medical
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 4 –. Quit2Live mediation path model.…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6933078/bin/nihms-1049677-f0004.jpg)
Figure 5 –. PNAT mediation path model.…
Figure 5 –. PNAT mediation path model. Association between Week 1 nausea and quit outcomes…
- Predicting smoking abstinence with biological and self-report measures of adherence to varenicline: Impact on pharmacogenetic trial outcomes.Peng AR, Schnoll R, Hawk LW Jr, Cinciripini P, George TP, Lerman C, Tyndale RF. Peng AR, et al. Drug Alcohol Depend. 2018 Sep 1;190:72-81. doi: 10.1016/j.drugalcdep.2018.04.035. Epub 2018 Jun 26. Drug Alcohol Depend. 2018. PMID: 29986268 Free PMC article. Clinical Trial.
- Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial.Courtney RJ, McRobbie H, Tutka P, Weaver NA, Petrie D, Mendelsohn CP, Shakeshaft A, Talukder S, Macdonald C, Thomas D, Kwan BCH, Walker N, Gartner C, Mattick RP, Paul C, Ferguson SG, Zwar NA, Richmond RL, Doran CM, Boland VC, Hall W, West R, Farrell M. Courtney RJ, et al. JAMA. 2021 Jul 6;326(1):56-64. doi: 10.1001/jama.2021.7621. JAMA. 2021. PMID: 34228066 Free PMC article. Clinical Trial.
- Placebo-controlled randomized clinical trial testing the efficacy and safety of varenicline for smokers with HIV.Ashare RL, Thompson M, Serrano K, Leone F, Metzger D, Frank I, Gross R, Hole A, Mounzer K, Collman RG, Wileyto EP, Schnoll R. Ashare RL, et al. Drug Alcohol Depend. 2019 Jul 1;200:26-33. doi: 10.1016/j.drugalcdep.2019.03.011. Epub 2019 May 7. Drug Alcohol Depend. 2019. PMID: 31082665 Free PMC article. Clinical Trial.
- Modelling continuous abstinence rates over time from clinical trials of pharmacological interventions for smoking cessation.Jackson SE, McGowan JA, Ubhi HK, Proudfoot H, Shahab L, Brown J, West R. Jackson SE, et al. Addiction. 2019 May;114(5):787-797. doi: 10.1111/add.14549. Epub 2019 Jan 29. Addiction. 2019. PMID: 30614586 Free PMC article. Review.
- Nicotine receptor partial agonists for smoking cessation.Cahill K, Stead LF, Lancaster T. Cahill K, et al. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD006103. doi: 10.1002/14651858.CD006103.pub5. Cochrane Database Syst Rev. 2011. PMID: 21328282 Updated. Review.
- Nicotine receptor partial agonists for smoking cessation.Livingstone-Banks J, Fanshawe TR, Thomas KH, Theodoulou A, Hajizadeh A, Hartman L, Lindson N. Livingstone-Banks J, et al. Cochrane Database Syst Rev. 2023 May 5;5(5):CD006103. doi: 10.1002/14651858.CD006103.pub8. Cochrane Database Syst Rev. 2023. PMID: 37142273 Free PMC article. Review.
- The use of biomarkers to guide precision treatment for tobacco use.Siegel SD, Tindle HA, Bergen AW, Tyndale RF, Schnoll R. Siegel SD, et al. Addict Neurosci. 2023 Jun;6:100076. doi: 10.1016/j.addicn.2023.100076. Epub 2023 Feb 16. Addict Neurosci. 2023. PMID: 37089247 Free PMC article.
- Stability of Varenicline Concentration in Saliva Over 21 Days at Three Storage Temperatures.Novalen M, Chenoweth MJ, Zhao B, Hawk LW, Tyndale RF. Novalen M, et al. Nicotine Tob Res. 2022 Feb 1;24(2):270-274. doi: 10.1093/ntr/ntab173. Nicotine Tob Res. 2022. PMID: 34460924 Free PMC article.
- Cytisine versus varenicline for smoking cessation in New Zealand indigenous Māori: a randomized controlled trial.Walker N, Smith B, Barnes J, Verbiest M, Parag V, Pokhrel S, Wharakura MK, Lees T, Cubillos Gutierrez H, Jones B, Bullen C. Walker N, et al. Addiction. 2021 Oct;116(10):2847-2858. doi: 10.1111/add.15489. Epub 2021 May 4. Addiction. 2021. PMID: 33761149 Free PMC article. Clinical Trial.
- Clinical Trial
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- 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
- ClinicalTrials.gov/NCT01314001
- ClinicalTrials.gov/NCT01836276
- Full Text Sources
- Medical
![Figure 5 –. PNAT mediation path model.…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6933078/bin/nihms-1049677-f0005.jpg)
Source: PubMed