Suppression of Nicotine Intake During Ad Libitum Cigarette Smoking by High-Dose Transdermal Nicotine NEAL L. BENOWITZ, SHOSHANA ZEVIN and PEYTON

Nicotine replacement therapy is believed to facilitate smoking cessation both by relieving withdrawal symptoms and by reducing the psychological reward from smoking. The latter might occur via down-regulation of nicotine receptors in the brain, which might require high levels of nicotine exposure. Our study examined the hypothesis that transdermal nicotine, dosed up to three times the doses currently recommended for smoking cessation, would suppress nicotine intake from ad libitum smoking in a dose-dependent manner. Eleven volunteers with no desire to quit smoking received placebo or 21, 42, and 63 mg/day transdermal nicotine, with and without cigarette smoking, in a blinded crossover study. Cigarette smoking was permitted as desired. Transdermal nicotine suppressed nicotine intake from cigarette smoking by 3%, 10% and 40% on average in the 21, 42 and 63 mg/day conditions. The number of cigarettes smoked per day declined from an average of 17.2 to 12.7 and the intake of nicotine per cigarette declined from 2.5 to 1.6 mg, comparing placebo and 63 mg nicotine conditions. Our study results suggest that high-dose transdermal nicotine has the potential to substantially suppress the intake of tobacco smoke and could be a useful strategy for smoking cessation therapy or for reducing the harm caused by smoking. Nicotine medications are used to facilitate smoking cessation therapy and have been shown to increase cessation rates ;2-fold compared with placebo (Henningfield, 1995). However, absolute cessation rates remain low, ;25% to 30% at 1 year in treatment trials, and even less with typical use in the community (Tang et al., 1994; Fiore et al., 1994). The mechanism by which nicotine replacement therapy enhances smoking cessation is not completely understood. Nicotine replacement therapy almost certainly works in part by relieving withdrawal symptoms but probably also works by blocking the reinforcing effects of nicotine in cigarette smoke by binding to and desensitizing nicotine receptors in the brain (Benowitz, 1993; James et al., 1994). Experimental studies support the idea that nicotine replacement therapy may work in part by reducing the reinforcing effects of cigarette smoking, which would be consistent with the idea of receptor desensitization (Foulds et al., 1992; Levin et al., 1994). Currently, nicotine replacement therapy is marketed as nicotine polacrilex gum, transdermal nicotine, nicotine nasal spray and nicotine inhalers. The levels of nicotine in venous blood produced by transdermal nicotine patches in doses of 21 mg/day are ;15 to 20 ng/ml, which are comparable to the levels found in the venous blood of light smokers (Benowitz, 1995). Nicotine intake from nicotine gum, nicotine nasal spray and nicotine inhalers is on average even lower than that delivered by nicotine patches (Benowitz et al., 1987, 1997). When nicotine is absorbed slowly, as from nicotine patches, arterial and venous levels of the drug are expected to be in near-equilibrium and to be similar. However, when nicotine is absorbed quickly, as occurs when smoking a cigarette, arterial levels exceed venous levels severalfold. Thus, after smoking a cigarette, arterial blood nicotine levels, which reflect concentrations reaching the brain, reach levels as high as 50 to 100 ng/ml (Henningfield et al., 1990; Gourlay and Benowitz, 1997). If nicotine replacement therapy is working by desensitizing brain nicotinic receptors, it is reasonable to hypothesize that arterial levels comparable to those achieved in smokers are necessary for adequate desensitization. There is evidence that currently recommended doses of nicotine replacement therapy are inadequate for many smokers. Higher doses (4 mg) of nicotine gum compared with lower doses (2 mg) enhance the likelihood of successful cessation in more dependent smokers (Tonnesen et al., 1988). Similar results have been reported with higher versus lower doses of transdermal nicotine, although not all studies have found the Received for publication March 12, 1998. 1 This work was supported by United States Public Health Service Grants DA02277 and DA01696 from the National Institute on Drug Abuse, National Institutes of Health, and carried out in part at the General Clinical Research Center with the support of the Division of Research Resources, National Institutes of Health (RR-00083). ABBREVIATIONS: AUC, area under the plasma concentration-time curve; COHb, carboxyhemoglobin. 0022-3565/98/2873-0958$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 287, No. 3 Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 287:958–962, 1998 958 at A PE T Jornals on A ril 8, 2017 jpet.asjournals.org D ow nladed from same results (Jorenby et al., 1995; Dale et al., 1995; Transdermal Nicotine Study Group, 1991). There is also evidence that matching levels of nicotine obtained from patch therapy with those obtained during base-line ad libitum smoking (done by adjusting patch doses to match levels of cotinine) enhances smoking cessation outcome (Sachs et al., 1995). Clinical trials and experimental studies have reported, in smokers who do not quit, reduction of smoking rates during nicotine patch use compared with placebo therapy (Hurt et al., 1990; Transdermal Nicotine Study Group, 1991; Pickworth et al., 1994; Hartman et al., 1991). Transdermal nicotine treatment has been reported to reduce the pleasure, satisfaction and taste from cigarette smoking when a cigarette is smoked (Foulds et al., 1992; Levin et al., 1994). We reasoned that higher doses of nicotine replacement therapy than have been previously tested might be even more effective at reducing the appeal and/or psychological reward of cigarette smoking. Based on these considerations, we examined the hypothesis that transdermal nicotine would suppress nicotine intake from ad libitum cigarette smoking in a dose-dependent manner. We administered doses of transdermal nicotine up to three times those currently recommended for smoking cessation and measured intake of nicotine and carbon monoxide from concurrent cigarette smoking.