Individualizing medical treatment for tobacco dependence.

Tobacco (nicotine) dependence is the chief preventable cause of respiratory disease. In many ways, nicotine dependence is a chronic medical illness, producing long-lasting structural and functional changes in the central nervous system. Tobacco dependence can be treated, but relapses to smoking are common. The responsibility of physicians to treat tobacco dependence is clear, just as it is to treat chronic obstructive lung disease (one major consequence of smoking). The main pharmacological therapy for tobacco dependence is nicotine replacement medication. However, an unresolved question is how best to use, and, in particular, how to individualize nicotine replacement therapy. In this issue of the European Respiratory Journal, PAOLETTI et al. [1] provide a significant insight towards optimizing the pharmacotherapy of tobacco addiction. Their study is the first nicotine patch trial to prospectively stratify smokers based on a measure of nicotine dependence, in this case the serum cotinine level. They define lowdependent smokers as those with a pretreatment serum cotinine level of ≤250 ng·mL-1, and high-dependent smokers as those with serum cotinine levels >250 ng·mL-1 measured whilst smoking cigarettes during the baseline evaluation period. Based on their nicotine dependency level, subjects were randomly assigned in double-blind fashion, to receive one of two doses of nicotine patch: low-dependent smokers received active standard dose (15 mg nicotine·16 h-1) vs placebo (0 mg nicotine·16 h-1); high-dependent smokers received the standard dose (15 mg·16 h-1) vs a higher dose (25 mg nicotine·16 h-1). The data of PAOLETTI et al. [1] clearly and unequivocally show that low-dependent cigarette smokers are substantially more successful in quitting smoking with an 18 week active nicotine patch treatment period, using the standard dosing (15 mg nicotine·16 h-1) compared to placebo. The continuous, one year differential in treatment success was threefold. This result is all the more remarkable, and attests to the importance of nicotine replacement therapy for low-dependent smokers, since no behavioural intervention was provided. These results confirm, prospectively, what SACHS and co-workers [2] reported previously in a retrospective analysis of a nicotine patch trial: low-dependent smokers (defined on the basis of the Fagerstrom Tolerance Questionnaire, (FTQ)) have a substantially better treatment outcome, both while receiving medication and after tapering off medication, than those who are not provided nicotine patch therapy. PAOLETTI et al. [1] also clearly showed that high-dependent smokers have a low likelihood of success, similar to that of the low-dependent smokers treated with placebo, with no difference in response comparing the two nicotine patch doses. This finding is similar to that first observed retrospectively in the study by SACHS and coworkers [2], which included a placebo patch treatment arm for the high-dependent smokers. What does the low success rate in high-dependent smokers after treatment with either 15 or 25 mg of nicotine, delivered via transdermal patch over 16 h, mean? We suggest three interpretations: 1) even a dose of 25 mg nicotine·16 h-1 is still far too low for high-dependent smokers; 2) the percentage cotinine replacement level needed is not absolute, e.g. 50, 75 or 100%, but is rather, as PAOLETTI et al. [1] suggest, a function of the level of dependence; in other words, the higher the smoker's dependence on entering treatment, the higher the degree of cotinine replacement needed to establish effective nicotine replacement therapy; and 3) nicotine patches are simply an ineffective nicotine delivery system for high-dependent smokers. This could be because the rate of absorption of nicotine into the blood stream, and thus into the central nervous system, from the patch is simply too slow to satisfy the high-dependent smoker's nicotine needs; and that a medication with a different pharmacokinetic absorption profile, such as nicotine polacrilex, 4 mg, or nicotine nasal spray, is needed. SACHS [3] has shown, in a prospective, double-blind, dose-response, placebo-controlled trial that high-dependent smokers (defined as FTQ ≥7 + baseline serum cotinine level >250 ng cotinine·mL-1 blood + baseline exhaled carbon monoxide level >15 parts per (ppm)) did substantially better at the end of the 6 week treatment period with the 4 mg dosage of nicotine polacrilex than with either the 2 mg or the placebo dosages. In fact, the continuous abstinence rates, using the same criteria as PAOLETTI et al. [1], were: 4 mg 63%; 2 mg 25%; placebo 25% (p<0.02). This contrasts with the 6 week results in the study by PAOLETTI et al. [1] for high-dependent smokers treated with either 15 or 25 mg of transdermal nicotine·day-1 of approximately 15%. Thus, the active nicotine patch results for the high-dependent smokers of PAOLETTI et al. [1] were no better than the placebo nicotine polacrilex treatment results of SACHS [3]. Also of note, SUTHERLAND et al. [4] have reported a post hoc analysis that suggested that nicotine nasal spray provides a preferential advantage to high-dependent smokers, defined based on baseline plasma nicotine concentrations. The findings of PAOLETTI et al. [1] in this issue of the EDITORIAL