The available research on switching from normal nicotine to very low nicotine content cigarettes shows minimal evidence of compensatory smoking. Mathematical estimations suggest that substantial compensation after switching to very low nicotine cigarettes would be impossible. It is likely that smokers who are unable to tolerate the extent of proposed nicotine reduction would switch to other sources of nicotine, rather than try to compensate by smoking more very low nicotine content cigarettes more intensely.

The reduced nicotine content cigarette and the emergence of non-combusted nicotine products like e-cigarettes should be viewed not as alternatives but as complementary components of regulatory interventions that could virtually end combusted tobacco use.

The available research on switching from normal nicotine to very low nicotine content cigarettes shows minimal evidence of compensatory smoking. Mathematical estimations suggest that substantial compensation after switching to very low nicotine cigarettes would be impossible. It is likely that smokers who are unable to tolerate the extent of proposed nicotine reduction would switch to other sources of nicotine, rather than try to compensate by smoking more very low nicotine content cigarettes more intensely.

Reducing the addictiveness of cigarettes by reducing their nicotine content can potentially have a profound impact on public health. Two different approaches to nicotine reduction have been proposed: gradual and immediate. To determine if either of these approaches results in significant compensatory smoking behavior, which might lead to safety concerns, we performed a secondary analysis of data from studies that have utilized these two approaches. The number of cigarettes smoked per day, carbon monoxide exposure, and cotinine levels in plasma or urine were assessed while participants smoked reduced nicotine content cigarettes and compared with when they smoked their usual brand cigarettes. The results showed that in general, these two approaches led to minimal compensatory smoking and reduced levels of cotinine over the course of the experimental period, suggesting that neither of these approaches poses a major safety concern.

Background

Reducing nicotine content in cigarettes and other combustible products to levels that are not reinforcing or addictive has the potential to substantially reduce tobacco-related morbidity and mortality. The authority to reduce nicotine levels as a regulatory measure is provided in the U.S. Family Smoking Prevention and Tobacco Control Act and is consistent with the general regulatory powers envisioned under the relevant articles of the World Health Organization's Framework Convention on Tobacco Control. Many experts have considered reducing nicotine in cigarettes to be a feasible national policy approach, but more research is necessary.

Purpose

This article describes proceedings from a conference that had the goals of identifying specific research gaps, describing methods and measures to consider for addressing these gaps, and considering ways to foster collaboration.

Results and conclusion

Identified research gaps included determining the dose of nicotine that would be optimal for reducing and extinguishing cigarette use, examining approaches for reducing nicotine levels in the general and special populations of smokers, understanding how constituents other than nicotine may contribute to the reinforcing effects of tobacco, and identifying unintended consequences to determine ways to mitigate them. Methods that can be used ranged from brain imaging to large human clinical trials. The development and availability of valid biomarkers of exposure and effect are important. Infrastructures to facilitate collaboration need to be established.

Background

The reduction of the nicotine content of cigarettes to nonaddicting levels is a potential federal regulatory intervention to reduce the prevalence of cigarette smoking and related disease. Many clinical trials on the effects and safety of nicotine reduction are ongoing. An important methodologic concern is noncompliance with reduced nicotine content cigarettes in the context of freely available conventional cigarettes. We propose two approaches using biomarkers to estimate noncompliance in smokers of very low nicotine content (VLNC) cigarettes in a clinical trial.

Methods

Data from 50 subjects in a study of gradual nicotine reduction were analyzed. Using plasma cotinine concentrations measured at baseline and while smoking VLNC cigarettes, we compared within-subject ratios of plasma cotinine comparing usual brand to VLNC in relation to nicotine content of these cigarettes. In another approach, we used nicotine pharmacokinetic data to estimate absolute plasma cotinine/cigarettes per day (CPD) threshold values for compliance based on the nicotine content of VLNC.

Results

The two approaches showed concordance, indicating at least 60% noncompliance with smoking VLNC. In a sensitivity analysis assuming extreme compensation and extreme values for nicotine metabolic parameters, noncompliance was still at least 40%, much higher than self-reported noncompliance.

Conclusion

Biomarker analysis demonstrates a high degree of noncompliance with smoking VLNC cigarettes, indicating that smokers are supplementing these with conventional cigarettes.

Impact

We propose a practical approach to assessing compliance with smoking VLNC in clinical trials of nicotine reduction.

A simple approach for analyzing longitudinally measured biomarkers is to calculate summary measures such as the area under the curve (AUC) for each individual and then compare the mean AUC between treatment groups using methods such as t test. This two-step approach is difficult to implement when there are missing data since the AUC cannot be directly calculated for individuals with missing measurements. Simple methods for dealing with missing data include the complete case analysis and imputation. A recent study showed that the estimated mean AUC difference between treatment groups based on the linear mixed model (LMM), rather than on individually calculated AUCs by simple imputation, has negligible bias under random missing assumptions and only small bias when missing is not at random. However, this model assumes the outcome to be normally distributed, which is often violated in biomarker data. In this paper, we propose to use a LMM on log-transformed biomarkers, based on which statistical inference for the ratio, rather than difference, of AUC between treatment groups is provided. The proposed method can not only handle the potential baseline imbalance in a randomized trail but also circumvent the estimation of the nuisance variance parameters in the log-normal model. The proposed model is applied to a recently completed large randomized trial studying the effect of nicotine reduction on biomarker exposure of smokers.

Introduction

Both the Tobacco Control Act in the U.S. and Article 9 of the Framework Convention on Tobacco Control enable governments to directly address the addictiveness of combustible tobacco by reducing nicotine through product standards. Although nicotine may have some harmful effects, the detrimental health effects of smoked tobacco are primarily due to non-nicotine constituents. Hence, the health effects of nicotine reduction would likely be determined by changes in behavior that result in changes in smoke exposure.

Methods

Herein, we review the current evidence on nicotine reduction and discuss some of the challenges in establishing the empirical basis for regulatory decisions.

Results

To date, research suggests that very low nicotine content cigarettes produce a desirable set of outcomes, including reduced exposure to nicotine, reduced smoking, and reduced dependence, without significant safety concerns. However, much is still unknown, including the effects of gradual versus abrupt changes in nicotine content, effects in vulnerable populations, and impact on youth.

Discussion

A coordinated effort must be made to provide the best possible scientific basis for regulatory decisions. The outcome of this effort may provide the foundation for a novel approach to tobacco control that dramatically reduces the devastating health consequences of smoked tobacco.

Cigarette smoking remains highly prevalent in the U.S. and contributes significantly to cardiovascular disease (CVD). Tobacco control policies, including product regulation, can reduce smoking-related harm. One approach being considered in the U.S. is for the FDA to set a low nicotine standard for cigarettes. Such a standard could result in multiple beneficial outcomes including reduced cardiovascular toxicity related to nicotine, reduced smoking intensity in current smokers, increased cessation rates, decreased development of smoking dependence in youth, and decreased passive smoke exposure. Consequently, CVD risk in the U.S. could be dramatically improved by nicotine reduction in cigarettes. Possible pathways linking nicotine reduction in cigarettes to decreased CVD risk are discussed, while potential unintended consequences that could offset expected gains are also presented. Gaps in the literature, including limited data on CVD biomarkers and long-term CVD outcomes following the use of very low nicotine cigarettes, are discussed to highlight areas for new research.

INTRODUCTION: Because 30% of cigarettes sold in the United States are characterized as menthol cigarettes, it is important to understand how menthol preference may affect the impact of a nicotine reduction policy. METHODS: In a recent trial, non-treatment-seeking smokers were randomly assigned to receive very low nicotine cigarettes (VLNC; 0.4 mg nicotine/g tobacco) or normal nicotine cigarettes (NNC; 15.5 mg/g) for 20 weeks. On the basis of preference, participants received menthol or non-menthol cigarettes. We conducted multivariable regression analyses to examine whether menthol preference moderated the effects of nicotine content on cigarettes per day (CPD), breath carbon monoxide (CO), urinary total nicotine equivalents (TNE), urinary 2-cyanoethylmercapturic acid (CEMA), and abstinence. RESULTS: At baseline, menthol smokers (n = 346) reported smoking fewer CPD (14.9 vs. 19.2) and had lower TNE (52.8 vs. 71.6 nmol/mg) and CO (17.7 vs. 20.5 ppm) levels than non-menthol smokers (n = 406; ps < .05). At week 20, significant interactions indicated that menthol smokers had smaller treatment effects than non-menthol smokers for CPD (-6.4 vs. -9.3), TNE (ratio of geometric means, 0.22 vs. 0.10) and CEMA (ratio, 0.56 vs. 0.37; ps < .05), and trended toward a smaller treatment effect for CO (-4.5 vs. -7.3 ppm; p = .06). Odds ratios for abstinence at week 20 were 1.88 (95% confidence interval [CI] = 0.8 to 4.4) for menthol and 9.11 (95% CI = 3.3 to 25.2) for non-menthol VLNC smokers (p = .02) relative to the NNC condition. CONCLUSIONS: Although menthol smokers experienced reductions in smoking, toxicant exposure, and increases in quitting when using VLNC cigarettes, the magnitude of change was smaller than that observed for non-menthol smokers. IMPLICATIONS: Results of this analysis suggest that smokers of menthol cigarettes may respond to a nicotine reduction policy with smaller reductions in smoking rates and toxicant exposure than would smokers of non-menthol cigarettes.