Freda Patterson

Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation

Nicotine is metabolized to cotinine, and cotinine is metabolized to 3′‐hydroxycotinine (3‐HC) by the liver enzyme cytochrome P450 (CYP) 2A6. More rapid metabolism of nicotine may result in lower nicotine blood levels from nicotine replacement products and poorer smoking cessation outcomes. This study evaluated the utility of the 3‐HC/cotinine ratio as a predictor of the efficacy of nicotine replacement therapy as an aid for smoking cessation.

Effectiveness of Extended-Duration Transdermal Nicotine Therapy: A Randomized Trial

BACKGROUND Tobacco dependence is a chronic, relapsing condition that may require extended treatment. OBJECTIVE To assess whether extended-duration transdermal nicotine therapy increases abstinence from tobacco more than standard-duration therapy in adult smokers. DESIGN Parallel randomized, placebo-controlled trial from September 2004 to February 2008. Participants and all research personnel except the database manager were blinded to randomization. (ClinicalTrials.gov registration number: NCT00364156) SETTING Academic center. PARTICIPANTS 568 adult smokers. INTERVENTION In an unstratified small block-randomization scheme, participants were randomly assigned to standard therapy (Nicoderm CQ [GlaxoSmithKline, Research Triangle Park, North Carolina], 21 mg, for 8 weeks and placebo for 16 weeks) or extended therapy (Nicoderm CQ, 21 mg, for 24 weeks). MEASUREMENTS The primary outcome was biochemically confirmed point-prevalence abstinence at weeks 24 and 52. Secondary outcomes were continuous and prolonged abstinence, lapse and recovery events, cost per additional quitter, and side effects and adherence. RESULTS At week 24, extended therapy produced higher rates of point-prevalence abstinence (31.6% vs. 20.3%; odds ratio, 1.81 [95% CI, 1.23 to 2.66]; P = 0.002), prolonged abstinence (41.5% vs. 26.9%; odds ratio, 1.97 [CI, 1.38 to 2.82]; P = 0.001), and continuous abstinence (19.2% vs. 12.6%; odds ratio, 1.64 [CI, 1.04 to 2.60]; P = 0.032) versus standard therapy. Extended therapy reduced the risk for lapse (hazard ratio, 0.77 [CI, 0.63 to 0.95]; P = 0.013) and increased the chances of recovery from lapses (hazard ratio, 1.47 [CI, 1.17 to 1.84]; P = 0.001). Time to relapse was slower with extended versus standard therapy (hazard ratio, 0.50 [CI, 0.35 to 0.73]; P < 0.001). At week 52, extended therapy produced higher quit rates for prolonged abstinence only (P = 0.027). No differences in side effects and adverse events between groups were found at the extended-treatment assessment. LIMITATION The generalizability of the findings may be limited because participants were smokers without medical comorbid conditions who were seeking treatment, and differences in adherence across treatment groups were detected. CONCLUSION Transdermal nicotine for 24 weeks increased biochemically confirmed point-prevalence abstinence and continuous abstinence at week 24, reduced the risk for smoking lapses, and increased the likelihood of recovery to abstinence after a lapse compared with 8 weeks of transdermal nicotine therapy. PRIMARY FUNDING SOURCE National Institutes of Health.

Treating Tobacco Dependence: State of the Science and New Directions

Despite almost two decades of intensive tobacco control efforts, nearly one quarter of Americans continue to smoke. The two United States Food and Drug Administration-approved medications used to treat tobacco dependence, bupropion and nicotine replacement therapy, are effective for only a fraction of smokers. Investigations of medications approved for affective disorders and other forms of substance abuse, such as fluoxetine and naltrexone, have yielded mixed results as tobacco dependence treatments. A particular challenge in tobacco dependence treatment is the development of effective approaches for smokers with unique needs, such as cancer patients and pregnant women. Despite new developments in these areas, significant gaps in knowledge and practice remain. Basic research in the neurobiologic and genetic basis of nicotine dependence offers promise for the development of novel and more effective treatment approaches. For example, emerging research in pharmacogenetics explores how genetic variation in drug-metabolizing enzymes and drug targets modifies response to pharmacotherapy. These discoveries could someday help practitioners to individualize the type, dosage, and duration of tobacco dependence treatment based on genotype, and maximize the efficacy.

Reduced nicotine reward in obesity: cross-comparison in human and mouse.

RationaleTobacco use and obesity lead to significant morbidity and mortality.ObjectiveThis study was conducted to investigate the factors maintaining smoking behavior in lean and obese individuals by utilizing a mouse/human cross-validation model of nicotine reward.MethodsIn humans, a cigarette choice paradigm was used to examine the relative reinforcing value of nicotine in obese and non-obese smokers. Conditioned place preference (CPP) for nicotine was assessed in mice fed standard low fat rodent chow and mice rendered obese by a high fat diet.ResultsIn humans, obese smokers self-administered nicotine via cigarettes significantly less often than non-obese smokers and showed attenuated hedonic effects of nicotine-containing cigarettes compared to denicotinized cigarettes. Similarly, mice exposed to a high fat diet did not exhibit nicotine CPP, relative to control mice. mRNA levels for mu-opiate and leptin receptors were also downregulated in the ventral tegmental area of these mice.ConclusionsTogether, these studies provide the first evidence for reduced nicotine reward in obese subjects and suggest that this may be mediated by dietary influences on the endogenous opioid system.

Pharmacogenetics and nicotine addiction treatment

This review focuses on the current status of, and future directions for, pharmacogenetic research on nicotine dependence and smoking cessation treatment. Pharmacological treatment involving nicotine replacement therapy and bupropion for nicotine addiction and smoking cessation has been shown to be efficacious when provided in combination with behavioral support. Cessation rates remain somewhat modest, however, and one possibility is that success rates may be enhanced by offering treatments tailored to an individuals genotype. Nonetheless, research on this issue remains in its infancy, and although the scope for individualized treatment tailored to genotype is promising, there are substantial practical, ethical and social considerations that must be addressed before such research is translated into clinical practice.

Gender differences in smoking cessation in a placebo-controlled trial of bupropion with behavioral counseling

Among smokers, women may be at greater risk than men for developing smoking-related diseases, perhaps because they have greater difficulty quitting smoking, as suggested by numerous studies. In the present study, we hypothesized that bupropion would reduce this gender disparity among 314 women and 241 men enrolled in a placebo-controlled, randomized trial using behavioral counseling plus 10 weeks of bupropion (300 mg). Prolonged abstinence and biochemically verified point prevalence outcomes were measured at end of treatment (8 weeks after the quit date) and at 6-month follow-up. A logistic regression model of 6-month prolonged abstinence and a Cox regression (survival analysis) model revealed a significant gender by smoking rate by drug interaction and a main effect for marital status. This three-way interaction suggests that bupropion particularly benefited men who smoked more than one pack of cigarettes per day at baseline and, conversely, women who smoked a pack or less. The point prevalence logistic regression model showed no evidence that either gender or smoking rate modified the effect of treatment. These results suggest that bupropion treatment may reduce the gender disparity in prolonged abstinence rates among lighter smokers.

Genetic variation in mu-opioid-receptor-interacting proteins and smoking cessation in a nicotine replacement therapy trial

Extending a previous finding of an association between functional genetic variation in the mu-opioid receptor gene and response to nicotine replacement therapy, we explored the role of genetic variants in two genes encoding mu-opioid-receptor-interacting proteins, namely ARRB2 and HINT1. Participants were 374 smokers treated for nicotine dependence with either transdermal nicotine or nicotine nasal spray for 8 weeks in an open-label randomized trial. In a logistic regression model controlling for OPRM1 genotype, treatment type, and other covariates, we found no significant main effect of ARRB2 genotype on abstinence at either end of treatment or 6-month follow-up. Participants with the HINT1 TT genotype had significantly higher abstinence rates at 6-month follow-up, but this may not be a pharmacogenetic effect, given that the participants were drug free during this time. Haplotype analysis did not reveal any significant associations for either gene. We found an interaction of ARRB2 and OPRM1 genotype on abstinence at 6 months that approached significance; however, interpretation of this finding is limited by the small number of participants with the minor alleles for both genes. Although these data do not provide support for the role of genetic variation in these mu-opioid-receptor-interacting proteins and smoking cessation, further exploration of opioid pathway genes in larger prospective pharmacogenetic trials may be warranted.

Convergent Evidence that Choline Acetyltransferase Gene Variation is Associated with Prospective Smoking Cessation and Nicotine Dependence

The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 single-nucleotide polymorphisms (SNPs) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort, we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.

Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment

We evaluated the cost-effectiveness of a range of smoking cessation drug treatments, including varenicline, transdermal nicotine (TN), bupropion and the use of a genetic test to choose between TN and bupropion. We performed Monte Carlo simulation with sensitivity analysis, informing analyses with published estimates of model parameters and current prices for genetic testing and smoking-cessation therapy. The primary outcomes were discounted life-years (LY) and lifetime tobacco-cessation treatment costs. In the base case, varenicline treatment was optimal with an ICER, compared to bupropion, of

Do small lapses predict relapse to smoking behavior under bupropion treatment

2985/LY saved. In sensitivity analyses, varenicline was in all cases (and bupropion in most cases) admissible; only under favorable assumptions was the genetically tailored approach competitive. Our data suggest that an untailored approach of treatment with either bupropion or varenicline is a cost-effective form of tobacco dependence treatment, but a tailored approach for selecting between TN and bupropion can be cost-effective under plausible assumptions.