Study of abrupt versus gradual reduction of nicotine informs FDA-proposed rule on reducing cigarette nicotine to "minimally addictive" levels.
Regular smokers who were given cigarettes with low levels of nicotine were found to smoke fewer of them and to have a greater decrease in biomarkers of smoke exposure than those using cigarettes with nicotine content that was gradually reduced in each month of a 5-month study. There was no significant difference in smoke exposure biomarker levels between those who smoked cigarettes with gradually reduced nicotine content and a control group using full nicotine content cigarettes.
"Our study showed that immediately reducing nicotine to very low levels is likely to result in less exposure to smoke toxicants over time primarily as a result of fewer cigarettes smoked," Dorothy Hatsukami, PhD, Forster Family Chair in Cancer Prevention at the Masonic Cancer Center and Professor Psychiatry, University of Minnesota, Minneapolis, MN, told MD Magazine®.
“More importantly, this approach led to greater reduced dependence and number of smoke-free days compared to the gradual nicotine reduction and normal nicotine content groups,” Hatsukami continued. “The goal is to eliminate smoke exposure, not to reduce it because any smoke exposure has potential health risks.”
In March 2018, the US Food and Drug Administration (FDA) issued an Advanced Notice of Proposed Rulemaking that would require reduction of nicotine content in cigarettes and possibly other burned tobacco products to minimally addictive levels. Hatsukami and colleagues conducted the controlled comparison of immediate vs gradual reduction of nicotine content in cigarettes to provide data that could inform the FDA on the best methods for restricting nicotine content to facilitate smokers achieving abstinence.
“This potential rule is important because it could prevent millions of lives lost to tobacco-related disease by preventing the development of tobacco dependence and facilitating quitting among millions of smokers who want to quit smoking,” Hatsukami explained. “One of the questions that the FDA raised [was regarding whether or not] the best approach to reducing levels of nicotine to minimally addictive levels was [to reduce the levels] gradually or on a targeted date, should such a rule go into effect.”
The investigators recruited over 1200 regular smokers to participate in a study that was described as an examination of how the rate of changing nicotine content in cigarettes affects smoking behavior. Subjects with no intention of quitting or reducing smoking and who regularly smoked 5 or more cigarettes per day were randomly assigned cigarettes with a minimal level of 0.4 mg nicotine/gm of tobacco, full content of 15.5 mg nicotine/gm of tobacco, or cigarettes that gradually tapered content in 5 monthly dose changes from 15.5 to 0.4 mg nicotine/gm tobacco.
The participants answered questions on the number of cigarettes smoked and on symptoms of withdrawal through a daily interactive voice response system. Furthermore, the participants underwent assessments of breath carbon monoxide (CO), safety measures such as vital signs and history of adverse events, changes in medical status and medication, and psychological well-being during weekly clinic visits for the first 4 weeks, and then biweekly for the next 16 weeks. In addition, first void morning urine samples were collected every 4 weeks (immediately prior to dose change in the taper group) for measurement of biomarkers of smoke exposure.
The primary endpoints to distinguish between classes of smoke exposure included expired CO, urinary phenanthrene tetraol (an indicator of exposure to polycyclic aromatic hydrocarbons in smoke inhalation), and a urinary mercapturic acid, 3-HPMA, metabolite of acrolein (an inhaled volatile organic compound which the investigators characterize as a cardiopulmonary toxicant).
Although an immediate reduction in nicotine content was associated with significantly less smoking and greater reductions in biomarkers of smoke exposure, the investigators reported that the group receiving low nicotine content cigarettes experienced greater discomfort from withdrawal symptoms.
"This finding would indicate that it would be important to make other sources of regulated nicotine products, such as nicotine replacement therapies with gum, patch[es], or lozenges, readily available to smokers," Hatsukami told MD Magazine®. "This would involve the active engagement of physicians and other health professionals."
The study, “Effect of Immediate vs Gradual Reduction in Nicotine Content of Cigarettes on Biomarkers of Smoke Exposure,” was published in JAMA.