Effects of Nicotine Metabolic Rate on Withdrawal Symptoms and Response to Cigarette Smoking After Abstinence

Abstract

This study investigated the influence of the rate of nicotine metabolism, as indicated by the nicotine metabolite ratio (NMR), on tobacco dependence. We stratified 136 smokers on the basis of saliva NMR as fast (n = 65) and slow (n = 71) metabolizers. Two "loading cigarettes" were smoked after overnight, and a "reward cigarette" was smoked after 6 hours of daytime, abstinence. Blood nicotine concentrations, expired carbon monoxide, withdrawal/craving, and reward questionnaires were collected before/after smoking and during daytime abstinence. Compared with slow metabolizers, fast metabolizers had a shorter nicotine elimination half-life (P < 0.001), lower plasma nicotine concentrations (P < 0.001), and higher withdrawal/craving scores (P < 0.05) for most times during daytime abstinence, indicating that fast metabolizers are likely smoking more to relieve withdrawal symptoms (negative reinforcement). Reward/satisfaction scores were similar in fast and slow metabolizers, suggesting that faster nicotine metabolism, assessed by NMR, is not associated with greater positive reinforcement. CYP2A6 normal (n = 82) and reduced (n = 42) genotype predicted plasma nicotine concentrations but not withdrawal symptoms.

Trial registration: ClinicalTrials.gov NCT01627392.

Conflict of interest statement

CONFLICT OF INTEREST

As an Associate Editor for Clinical Pharmacology & Therapeutics, R.F.T. was not involved in the review or decision process for this article. N.L.B. is a consultant to Pfizer and Achieve Life Sciences, companies that market or are developing smoking cessation medications, and has been a paid expert witness in litigation against tobacco companies. R.F.T. has served as a paid consultant to Apotex and Quinn Emmanuel and received unrestricted research funding from Pfizer as part of the Global Research Awards for Nicotine Dependence, an independently reviewed competitive grants program.

© 2018 American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1

Frequency of slow and fast NMR in the CYP2A6 genotype groups (n = 124). NMs and RMs assessed by CYP2A6 genotype. NM, normal metabolizer; NMR, nicotine metabolite ratio; RM, reduced metabolizer.

Figure 2

Average plasma nicotine concentrations over time based on NMR (a) and genotype (b). *P < 0.05, #P < 0.001 for differences between groups. NMs and RMs assessed by CYP2A6 genotype. Cig 1, 2, and 3, first, second, and third cigarettes of the day, respectively; NM, normal metabolizer; NMR, nicotine metabolite ratio; RM, reduced metabolizer.

Figure 3

Average MNWS score over time based on NMR (a) and genotype (b). *P < 0.05 for differences between groups. NMs and RMs assessed by CYP2A6 genotype. Cig 1, 2, and 3, first, second, and third cigarettes of the day, respectively; MNWS, Minnesota Nicotine Withdrawal Scale; NM, normal metabolizer; NMR, nicotine metabolite ratio; RM, reduced metabolizer.

Figure 4

Average QSU Global Craving Score over time based on NMR (a) and genotype (b). *P < 0.05 for differences between groups. NMs and RMs assessed by CYP2A6 genotype. Cig 1, 2, and 3, first, second, and third cigarettes of the day, respectively; NM, normal metabolizer; NMR, nicotine metabolite ratio; QSU, Questionnaire on Smoking Urges; RM, reduced metabolizer.