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The impact of three weeks of pre-quit varenicline on reinforcing value and craving for cigarettes in a laboratory choice procedure

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Abstract

Rationale

Varenicline, a partial nicotinic agonist, is theorized to attenuate pre-quit smoking reinforcement and post-quit withdrawal and craving. However, the mechanisms of action have not been fully characterized, as most studies employ only retrospective self-report measures, hypothetical indices of reinforcing value, and/or nontreatment-seeking samples.

Objectives

The current research examined the impact of pre-quit varenicline (vs. placebo) on laboratory measures of smoking and food (vs. water) reinforcement and craving.

Methods

Participants were 162 treatment-seeking smokers enrolled in a randomized controlled trial of smoking cessation (clinicaltrials.gov ID: NCT03262662). Participants completed two laboratory sessions: a pre-treatment session, ~ 1 week prior to beginning varenicline or placebo, and an active treatment session, after ~ 3 weeks of treatment. At each session, participants completed a laboratory choice procedure; on each of 36 trials, a lit cigarette, food item, or cup of water was randomly presented. Participants reported level of craving and spent $0.01–0.25 to have a corresponding 5–95% chance to sample the cue.

Results

As predicted, spending was significantly higher on cigarette trials than water trials, and varenicline resulted in a greater between-session decline in spending on cigarette trials (but not water) than did placebo. Cigarette craving was enhanced in the presence of smoking cues compared to water, but neither average (tonic) cigarette craving nor cue-specific cigarette craving was significantly influenced by varenicline. Food spending and craving were generally unaffected by varenicline treatment.

Conclusions

These laboratory data from treatment-seeking smokers provide the strongest evidence to date that varenicline selectively attenuates smoking reinforcement prior to quitting.

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Notes

  1. An additional 52 participants completed only the baseline session but were either ineligible for the study (n = 34), withdrew (n = 14 pre-intent-to-treat, n = 3 post-intent-to-treat), or were administratively withdrawn (n = 1) prior to the second lab session.

  2. Questionnaires included the Minnesota Nicotine Withdrawal Scale (MNWS) (Hughes and Hatsukami 1986), the Mood form (Diener and Emmons 1985), the Nausea Profile- GI Distress Scale (Muth et al. 1996), and the Brief Questionnaire of Smoking Urges Brief (QSU-brief) (Cox & Tiffany 2001). These assessments measured withdrawal symptomatology, negative/positive affect, experiences of nausea, and craving, respectively. The data from those questionnaires were not analyzed in this manuscript.

  3. During the Pre-Treatement session, participants also underwent training for completing ecological momentary assessments over the subsequent 9 weeks. This data is not presented in the manuscript.

  4. We did observe an unanticipated group × food vs. water cue interaction, F(1, 157) = 4.6, p = .03, ηp2 = .03. This seemed to reflect that cigarette craving was slightly but significantly higher during water cues than food cues in the varenicline group, p < .01 but not the placebo group, p = .64; see Fig. 2).

  5. Anonymous reviewers requested exploration of several moderators of treatment effects on spending and cigarette craving. These should be interpreted cautiously, given the large number of statistical tests and absence of a priori predictions.

    1. Menthol vs. non-menthol cigarette smokers: as shown in Table 1, the varenicline and placebo groups were comparable in their representation of menthol vs. non-menthol smokers. Cigarette spending did not vary as a function of smoking menthol vs. non-menthol cigarettes, all p > .15. Although cigarette craving was generally higher among smokers of menthol cigarettes (M = 3.9) compared to non-menthol cigarettes (3.3), p = .01, treatment group did not interact with whether participants smoked menthol or non-menthol cigarettes, all p > .58.

    2. CO reduction criterion met vs. not met: a comparable percentage of the varenicline and placebo groups met the 40% CO reduction criterion in both visits (68% and 63%, respectively, p = .50), but women were more likely than men to meet the CO reduction criterion (74% vs. 54%, p = .01). However, neither the main effect of CO reduction group nor any interactions were statistically significant for spending or cigarette craving, all p > .06.

    3. Trial block (first half vs. second half of the task, among participants who smoked in the first half of each session): 80% of the sample (n = 130) smoked in the first half of each session, and this did not vary between the varenicline (77%) and placebo (84%) groups, p = .30. In this subsample, spending declined across trial blocks, p < .001, but trial block did not moderate any effects of treatment group on spending, all p > .10. Cigarette craving also declined across trial blocks, p < .001. A significant group × session × trial block interaction, p = .04 appeared to be driven primarily by an unexpectedly smaller (but still significant) decline in craving from the first half to the second half of the task among the placebo group during the pre-treatment session (0.8 units) compared to all other group × session conditions (1.1–1.4 units). Consequently, the largest treatment group difference in craving was during the second half of the pre-treatment session, which does not seem readily interpretable as anything except a chance finding. There was also a 5-way group × sex × session × trial block × food vs. water interaction for cigarette craving, p = .05; follow-up tests suggested that this complex, unpredicted interaction was driven primarily by subtle changes in cigarette craving between food and water cues among women. Cigarette craving was 0.1–0.2 units greater during water than food cues for the following conditions: varenicline group, trialblock 1 of both sessions, and placebo group, triablock 2 of session 1, p < .04. For the placebo group, the pattern flipped in triablock 2 of session 2, with modestly greater craving during food compared to water cues, p = .08. Cigarette craving did not vary in any of the remaining cells of the design. We do not believe that this unpredicted, complex interaction is worth detailing further.

    4. Moderation analyses involving individual differences in quit motivation and medication adherence were not conducted due to limited variability in these constructs.

    5. We declined to add data regarding changes in smoking behavior during the 3-week period between sessions, as changes in smoking rate and biochemical exposure are primary outcomes of the larger clinical trial in which this behavioral pharmacology study is embedded.

  6. One potential concern regarding in vivo cues was raised when, anecdotally, several participants reported that olfactory smoking cues (i.e., smell of smoke) were present during some food and water trials, despite a negative pressure air filtration system designed to prevent carryover smoke. If this were to effect the findings of the current study, we would expect that it would dampen the observed effect size for cue-specific craving (cigarette vs. water cues), as olfactory smoking cues would ostensibly increase cigarette craving rated during water cues. However, we found no evidence that cue reactivity was diminished in the current study, and the effect size in the current study (ηp2 = .47) is comparable to, if not slightly higher than, effect sizes seen in other CBUCC studies (ηp2 = .45; Gass and Tiffany 2017; ηp2 = .31; Gass and Tiffany 2020), and to a study examining pre-quit varenicline on cue-specific craving in the natural environment rated across 5 weeks (ηp2 = .24–.61, Gass et al. 2012).

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Acknowledgments

The authors acknowledge the contributions of Jennifer Adams and Constance Duerr (project coordination), Win Phyo and Baltaj Sandhur (data collection), Louise Cooper and Denise Swiatek (pharmacy support), Nicolas Schlienz (logistics and technical support), and the community members who participated in this project. Pfizer provided the study medication and placebo for this study, but had no role in study design or data analysis or interpretation.

Funding

This research was supported in part by the National Cancer Institute (R01 CA206193); additional research infrastructure support was provided by the NIH National Center for Advancing Translational Sciences (UL1TR001412 and UL1TR002001). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the United States Federal Government or VA Healthcare System.

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Authors and Affiliations

  1. Department of Psychology, University at Buffalo (The State University of New York), Main Street, Buffalo, NY, 14214, USA

    Schuyler C. Lawson, Julie C. Gass, Robert K. Cooper Jr, Sarah S. Tonkin, Craig R. Colder, Martin C. Mahoney, Stephen T. Tiffany & Larry W. Hawk Jr

  2. Center for Integrated Healthcare, VA Western New York Healthcare System, 3495 Bailey Ave, Buffalo, NY, 14215, USA

    Julie C. Gass

  3. Department of Internal Medicine, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Martin C. Mahoney

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  1. Schuyler C. Lawson
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  2. Julie C. Gass
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Correspondence to Larry W. Hawk Jr.

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Conflict of interest

MCM has received study medications from Pfizer in support of randomized clinical trials and has previously served as a consultant to and speaker for Pfizer on the topic of smoking cessation; he also serves as medical director of the New York State Smokers Quit Line. There are no other financial disclosures.

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Lawson, S.C., Gass, J.C., Cooper, R.K. et al. The impact of three weeks of pre-quit varenicline on reinforcing value and craving for cigarettes in a laboratory choice procedure. Psychopharmacology 238, 599–609 (2021). https://doi.org/10.1007/s00213-020-05713-7

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