Randomized Trial of Reduced-Nicotine Standards for Cigarettes

Abstract

Background: The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes.

Methods: We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6.

Results: A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups.

Conclusions: In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; ClinicalTrials.gov number, NCT01681875.).

Figure 1. Number of Cigarettes Smoked per Day According to Nicotine Content

The mean number of cigarettes smoked per day was based on the number reported by participants with the use of an interactive voice-response system. Panel A shows the mean total number of cigarettes smoked per day, including both study and nonstudy cigarettes. Panel B shows the mean number of study cigarettes smoked per day. All analyses were adjusted for the baseline number of cigarettes smoked per day. An asterisk indicates P<0.001 for the comparison at week 6 with the primary control cigarettes (those with 15.8 mg of nicotine per gram of tobacco).

Figure 2. Biomarkers of Exposure to Nicotine and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone (NNK) According to the Nicotine Content of Cigarettes

Total nicotine equivalents is a measure of nicotine exposure. Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a measure of NNK exposure. Urinary total nicotine and NNAL values are presented as geometric means adjusted for creatinine. Urine samples were collected at baseline, week 2, and week 6. All analyses were adjusted for baseline values. An asterisk indicates P≤0.01 for the comparison at week 6 with cigarettes containing 15.8 mg of nicotine per gram. Additional pairwise analyses were conducted among the reduced-nicotine groups. The group assigned to cigarettes containing 0.4 mg of nicotine per gram differed significantly from the group assigned to 5.2 mg per gram at week 6 (P = 0.001). The group assigned to 0.4 mg per gram (high tar) differed significantly from both the group assigned to 2.4 mg per gram and the group assigned to 5.2 mg per gram at week 6 (P≤0.01).

Figure 3. Nicotine Dependence According to the Nicotine Content of Cigarettes

Panel A shows total scores on the Wisconsin Inventory of Smoking Dependence Motives (score range, 11 to 77, with higher values indicating greater dependence), which is a multifactorial scale of nicotine dependence. Panel B shows total scores on the Fagerström Test for Nicotine Dependence, with the item concerning number of cigarettes smoked per day excluded (score range after exclusion of that item, 0 to 7, with higher values indicating greater dependence). All analyses were adjusted for the baseline score. An asterisk indicates P≤0.002 for the comparison at week 6 with cigarettes containing 15.8 mg of nicotine per gram.

Figure 4. Withdrawal and Craving According to the Nicotine Content of Cigarettes

Panel A shows total scores on the 8-item Minnesota Nicotine Withdrawal Scale (score range, 0 to 32, with higher values indicating more severe withdrawal), and Panel B shows total scores on the 10-item Questionnaire on Smoking Urges (score range, 10 to 70, with higher values indicating greater craving) at baseline, week 6, and after 18 or more hours of abstinence. The Minnesota Nicotine Withdrawal Scale ratings were provided with reference to how participants felt in general since their most recent scheduled visit. The Questionnaire on Smoking Urges ratings were provided in reference to how the participant felt “right now” for the product currently being used (usual brand at baseline; randomized condition at week 6 and during the abstinence assessment). All analyses were adjusted for the baseline score. An asterisk indicates P≤0.003 for the comparison at the same time point with cigarettes containing 15.8 mg of nicotine per gram.