The results show that smokers with reduced nicotine metabolism benefit more than NMs from extended (6-month) transdermal nicotine therapy as compared to standard (8-week) therapy. At the end of extended therapy, the treatment effect was significant among RMs by genotype and phenotype but not among NMs; however, the group-by-treatment interaction was significant only for the genotype measure. The substantial benefits of extended therapy for RMs were maintained during the treatment period, and quit rates exceeded the 6-month quit rates achieved with 12 weeks of bupropion or varenicline therapy.11
However, these benefits for RMs dissipate once treatment ends, suggesting that they may benefit more from even longer treatment.
The higher treatment-related plasma nicotine levels among RMs as compared with NMs may contribute to the greater quitting success in RMs during transdermal nicotine therapy. In addition, in RMs, the pharmacokinetics of transdermal nicotine (i.e., stable nicotine levels) may be more similar to that of nicotine derived from smoking, whereas NMs may be more accustomed to intercigarette variation (peaks and troughs) in nicotine levels from smoking. It appears that the benefit of transdermal nicotine is maintained among RMs but only as long as therapy is continued (). The differences in outcome between RMs and NMs cannot be attributed to differences in dependence or smoking rate because these variables were controlled for in the models and are not strongly associated with nicotine metabolism rate, as shown in earlier studies.12,13
As we reported previously,1
significant benefits of extended vs. standard therapy are observed in the full cohort when nicotine metabolism rate is not considered. However, a prior study reported no benefits of an extended transdermal therapy regimen.14
In addition to differences in study design and outcome assessment, it is possible that the lack of concordance of findings is partly attributable to variability in nicotine clearance rates across the two study populations. Assessment of nicotine metabolism rate in clinical trials of smoking cessation treatment may provide valuable information for interpretation of effects within and between studies.
A limitation of this study is that the study sample was restricted to Caucasians to minimize population stratification in the genotype assessment. In other populations, this benefit of extended treatment may be even more important because RMs of nicotine represent a substantially larger portion of the African-American and Asian populations.5,15,16
Similar studies in these populations are warranted to test the generalizability of these findings. Another limitation is the lack of data collected immediately following the change from active to placebo patch in the standard therapy group, leaving open questions as to the mechanisms responsible for differential efficacy.
We have shown that the benefit of extending transdermal nicotine therapy to 6 months is greatest among smokers with reduced nicotine metabolism. NMs who benefit less from standard or extended transdermal nicotine therapy may be good candidates for higher-dose nicotine replacement or for non-nicotine therapies for smoking cessation. A placebo-controlled trial of bupropion showed a substantial benefit of therapy with this drug for NMs, particularly those with the highest metabolism rates.17
If further studies confirm these results, determination of nicotine metabolism rate can be used to tailor the type, dose, and length of smoking cessation treatment in clinical practice.