Novel approaches to treating nicotine dependence remain a priority. The transdermal nicotine patch is the most widely used form of tobacco dependence treatment, but only ~1 in 5 smokers who use this treatment achieve cessation. One factor that may contribute to a poor response to transdermal nicotine is inter-individual variability in the rate of nicotine metabolism, which can be measured in saliva by the ratio of 3'hydroxycotinine (3-HC) to its precursor cotinine. Two clinical trials with transdermal nicotine have shown that the 3-HC/cotinine ratio predicts response to transdermal nicotine such that faster metabolizers of nicotine (higher 3-HC/cotinine ratios) have lower quit rates, vs. slower nicotine metabolizers. Among abstainers in these trials, the 3- HC/cotinine ratio also predicts therapeutic levels of nicotine on transdermal nicotine, with faster metabolizers of nicotine exhibiting lower nicotine. Thus, faster metabolizers of nicotine may require higher nicotine doses to achieve the same therapeutic benefit from transdermal nicotine as do slow nicotine metabolizers. To date, clinical trials have shown that, compared to the standard dose of transdermal nicotine (21mg), higher doses (42mg) have no significant effect on quit rates. However, no trial of high dose transdermal nicotine considered inter-individual variability in the rate of nicotine metabolism. Thus, as a preliminary step toward conducting a fully-powered, randomized clinical trial to assess standard vs. high dose transdermal nicotine for slow vs. fast metabolizers of nicotine, we propose to evaluate, for the first time, the efficacy of high-dose transdermal nicotine (vs. standard dose) among fast metabolizers of nicotine (i.e., upper quartile of the 3-HC/cotinine ratio distribution). We chose only fast metabolizers of nicotine for this trial since: 1) slow metabolizers of nicotine exhibit high quit rates on standard transdermal nicotine and may experience adverse effects from higher doses;and 2) as a """"""""proof of concept"""""""" R21 application, our primary objective is to test whether high doses of nicotine increase quit rates among fast metabolizers of nicotine. Specifically, 100 smokers who are fast metabolizers of nicotine will receive counseling and will be randomized to: 1) standard (1 X 21mg patch and 1 X placebo patch), or 2) high dose (2 x 21mg patches) transdermal nicotine. The primary outcome is biochemically-verified 7-day point prevalence cessation after 8 weeks of treatment. Differences in patch-related side effects and mediators of transdermal nicotine effects (e.g., nicotine levels, withdrawal) across the study conditions will also be assessed. Ultimately, this line of research hopes to provide the evidence necessary to translate research on the 3-HC/cotinine ratio to clinical practice for the treatment of tobacco dependence. Specifically, this research may show that a measure of nicotine metabolism rate could be used to maximize the therapeutic benefits of transdermal nicotine by providing slow metabolizers of nicotine with a standard patch dose and fast metabolizers of nicotine with high dose transdermal nicotine. Identifying an effective treatment for faster metabolizers of nicotine is also critical since these individuals are at increased risk for lung cancer.

Public Health Relevance

Unfortunately, we still need to assess and identify novel ways to help people quit smoking. Differences between people in terms of how fast they metabolize nicotine influences response to transdermal nicotine patches, the most popular nicotine dependence treatment, and it affects plasma levels of nicotine from treatment. These studies suggest that fast metabolizers of nicotine may show better quit rates if they receive higher doses of transdermal nicotine. This preliminary study is designed to assess, for the first time, whether fast nicotine metabolizers show higher quit rates if given high dose transdermal nicotine, vs. standard dose. The study findings may help to support a subsequent large trial to assess standard vs. high dose transdermal nicotine for slow vs. fast metabolizers of nicotine, which may lead to a more personalized approach to treating nicotine dependence using the nicotine patch to improve therapeutic benefits of transdermal nicotine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA026889-02
Application #
7851133
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Bough, Kristopher J
Project Start
2009-07-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$196,875
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Schnoll, Robert A; Wileyto, E Paul; Leone, Frank T et al. (2013) High dose transdermal nicotine for fast metabolizers of nicotine: a proof of concept placebo-controlled trial. Nicotine Tob Res 15:348-54
Schnoll, Robert A; Leone, Frank T; Hitsman, Brian (2013) Symptoms of depression and smoking behaviors following treatment with transdermal nicotine patch. J Addict Dis 32:46-52
Schnoll, R A; Shields, A E (2011) Physician barriers to incorporating pharmacogenetic treatment strategies for nicotine dependence into clinical practice. Clin Pharmacol Ther 89:345-7
Schnoll, Robert A; Martinez, Elisa; Tatum, Kristina L et al. (2011) Increased self-efficacy to quit and perceived control over withdrawal symptoms predict smoking cessation following nicotine dependence treatment. Addict Behav 36:144-7
Schnoll, Robert A; Leone, Frank T (2011) Biomarkers to optimize the treatment of nicotine dependence. Biomark Med 5:745-61
Martinez, Elisa; Tatum, Kristina L; Glass, Marcella et al. (2010) Correlates of smoking cessation self-efficacy in a community sample of smokers. Addict Behav 35:175-8
Schnoll, Robert A; Martinez, Elisa; Tatum, Kristina L et al. (2010) Nicotine patch vs. nicotine lozenge for smoking cessation: an effectiveness trial coordinated by the Community Clinical Oncology Program. Drug Alcohol Depend 107:237-43