Sex-Specific Mediation of Pre-Quit Smoking Reduction: Secondary Analysis of a Randomized Controlled Trial Extending Varenicline Preloading.

Abstract

Introduction: Relative to other pharmacotherapies for smoking cessation, varenicline has significantly greater efficacy in females; however, sex-specific mechanisms have not yet been investigated. We conducted a secondary analysis of ecological momentary assessment (EMA) data to assess whether reductions in craving, negative affect, and smoking satisfaction/reward/aversion mediate effects of varenicline on next-day smoking to a greater degree in females (n=179) relative to males (n=141).

Methods: Data were from a 3-week medication manipulation period during the pre-quit phase of a double-blind randomized placebo-controlled trial investigating extended preloading (4 weeks) vs. standard preloading varenicline (1 week, preceded by 3 weeks of placebo, NCT03262662). Time-invariant multilevel moderated mediation models and time-varying mediation models were utilized.

Results: A significant time-varying indirect effect through craving that increased in magnitude over the pre-quit period was identified only in females. Exploratory analysis found that decreases in psychological reward and smoking satisfaction mediated the relationship between varenicline and reductions in craving only in females. Time-invariant multi-level models did not evidence a significant indirect effect through candidate mediators in males or females; the index of moderated mediation was not significant in any of the models.

Conclusions: Our findings suggest that the efficacy of varenicline on reductions in pre-quit smoking in females operates through reductions in craving. Furthermore, reductions in craving may be due to decreases in positive subjective experiences of smoking. Augmenting craving coping strategies as well as reducing smoking reward and satisfaction may be a beneficial approach in females.

Implications: This is the first study to investigate sex-specific mediation of varenicline on reductions in pre-quit smoking. Further investigation into varenicline-induced changes in smoking reinforcement and craving is warranted, particularly in females. For example, experimentally manipulating these mediators may inform them as mechanisms for smoking reduction.