Cheryl Oncken

Varenicline versus transdermal nicotine patch for smoking cessation: Results from a randomised, open-label trial

Background: Varenicline, a new treatment for smoking cessation, has demonstrated significantly greater efficacy over placebo and sustained release bupropion (bupropion SR). A study was undertaken to compare a 12-week standard regimen of varenicline with a 10-week standard regimen of transdermal nicotine replacement therapy (NRT) for smoking cessation. Methods: In this 52-week, open-label, randomised, multicentre, phase 3 trial conducted in Belgium, France, the Netherlands, UK and USA, participants were randomly assigned (1:1) to receive varenicline uptitrated to 1 mg twice daily for 12 weeks or transdermal NRT (21 mg/day reducing to 7 mg/day) for 10 weeks. Non-treatment follow-up continued to week 52. The primary outcome was the biochemically confirmed (exhaled carbon monoxide ⩽10 ppm) self-reported continuous abstinence rate (CAR) for the last 4 weeks of the treatment period in participants who had taken at least one dose of treatment. Secondary outcomes included CAR from the last 4 weeks of treatment through weeks 24 and 52, and measures of craving, withdrawal and smoking satisfaction. Results: A total of 376 and 370 participants assigned to varenicline and NRT, respectively, were eligible for analysis. The CAR for the last 4 weeks of treatment was significantly greater for varenicline (55.9%) than NRT (43.2%; OR 1.70, 95% CI 1.26 to 2.28, p<0.001). The week 52 CAR (NRT, weeks 8–52; varenicline, weeks 9–52) was 26.1% for varenicline and 20.3% for NRT (OR 1.40, 95% CI 0.99 to 1.99, p = 0.056). Varenicline significantly reduced craving (p<0.001), withdrawal symptoms (p<0.001) and smoking satisfaction (p<0.001) compared with NRT. The most frequent adverse event was nausea (varenicline, 37.2%; NRT, 9.7%). Conclusions: The outcomes of this trial established that abstinence from smoking was greater and craving, withdrawal symptoms and smoking satisfaction were less at the end of treatment with varenicline than with transdermal NRT. Trial registration number: NCT00143325.

GABRA2 alleles moderate the subjective effects of alcohol, which are attenuated by finasteride

GABAA receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABAA receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABAA receptor α-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-α steroid reductase inhibitor), which blocks the synthesis of some neuroactive steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind, placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks. Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis. Subjects homozygous for the more common A-allele (n=7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n=20, including two homozygotes). Among the A-allele homozygotes, there was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the subjective effects of alcohol.

Immunogenicity and Smoking Cessation Outcomes for a Novel Nicotine Immunotherapeutic

NicVAX, a nicotine vaccine (3′AmNic‐rEPA), has been clinically evaluated to determine whether higher antibody (Ab) concentrations are associated with higher smoking abstinence rates and whether dosages and frequency of administration are associated with increased Ab response. This randomized, double‐blinded, placebo‐controlled multicenter clinical trial (N = 301 smokers) tested the results of 200‐ and 400‐µg doses administered four or five times over a period of 6 months, as compared with placebo. 3′AmNic‐rEPA recipients with the highest serum antinicotine Ab response (top 30% by area under the curve (AUC)) were significantly more likely than the placebo recipients (24.6% vs. 12.0%, P = 0.024, odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.14–6.37) to attain 8 weeks of continuous abstinence from weeks 19 through 26. The five‐injection, 400‐µg dose regimen elicited the greatest Ab response and resulted in significantly higher abstinence rates than placebo. This study demonstrates, as proof of concept, that 3′AmNic‐rEPA elicits Abs to nicotine and is associated with higher continuous abstinence rates (CAR). Its further development as a treatment for nicotine dependence is therefore justified.

Biomarkers to Assess the Utility of Potential Reduced Exposure Tobacco Products

To date, we have no valid biomarkers that serve as proxies for tobacco-related disease to test potential reduced exposure products. This paper represents the deliberations of four workgroups that focused on four tobacco-related heath outcomes: Cancer, nonmalignant pulmonary disease, cardiovascular disease, and fetal toxicity. The goal of these workgroups was to identify biomarkers that offer some promise as measures of exposure or toxicity and ultimately may serve as indicators for future disease risk. Recommendations were based on the relationship of the biomarker to what is known about mechanisms of tobacco-related pathogenesis, the extent to which the biomarker differs among smokers and nonsmokers, and the sensitivity of the biomarker to changes in smoking status. Other promising biomarkers were discussed. No existing biomarkers have been demonstrated to be predictive of tobacco-related disease, which highlights the importance and urgency of conducting research in this area.

Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism.

OBJECTIVE Topiramate has been shown to reduce drinking and heavy drinking in individuals with alcohol dependence whose goal was to stop drinking. The authors evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels. METHOD A total of 138 individuals (62.3% men) were randomly assigned to receive 12 weeks of treatment with topiramate (N=67), at a maximal daily dose of 200 mg, or matching placebo (N=71). Both groups received brief counseling to reduce drinking and increase abstinent days. It was hypothesized that topiramate-treated patients would be better able to achieve these goals, and it was predicted that based on prior research, the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit. RESULTS The rate of treatment completion was 84.9% and equal by treatment group. Topiramate treatment significantly reduced heavy drinking days and increased abstinent days relative to placebo. Patients receiving topiramate also had lower concentrations of the liver enzyme γ-glutamyl transpeptidase and lower scores on a measure of alcohol-related problems than the placebo group. In a European American subsample (N=122), topiramates effect on heavy drinking days was significantly greater than that for placebo only in rs2832407 C-allele homozygotes. CONCLUSIONS These findings support the use of topiramate at a daily dose of 200 mg to reduce heavy drinking in problem drinkers. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important personalized treatment option. The pharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramates effects on heavy drinking.

Nicotine Gum for Pregnant Smokers A Randomized Controlled Trial

OBJECTIVE: To estimate the safety and efficacy of treatment with 2-mg nicotine gum for smoking cessation during pregnancy. METHODS: Pregnant women who smoked daily received individualized behavioral counseling and random assignment to a 6-week treatment with 2-mg nicotine gum or placebo followed by a 6-week taper period. Women who did not quit smoking were instructed to reduce the number of cigarettes smoked by substituting with gum. Measures of tobacco exposure were obtained throughout the study. RESULTS: Participants in the nicotine (nequals;100) and placebo (nequals;94) groups were comparable in age, race/ethnicity, and smoking history. Biochemically validated smoking-cessation rates were not significantly higher with nicotine gum compared with placebo (after 6 weeks of treatment: 13% compared with 9.6%, P=.45; at 32–34 weeks of gestation: 18% compared with 14.9%, P=.56). Using a completer analysis, nicotine gum significantly reduced the number of cigarettes smoked per day (nicotine gum: −5.7 [standard deviation (SD)=6.0]; placebo: −3.5 [SD=5.7], P=.035), and cotinine concentration (nicotine gum: −249 ng/mL [SD=397]; placebo: −112 ng/mL [SD=333]; P=.04). Birth weights were significantly greater with nicotine gum compared with placebo (3,287 g [SD=566] and 2,950 g [SD=653], respectively, P<.001). Gestational age was also greater with nicotine-replacement therapy than with placebo (38.9 weeks [SD=1.7] and 38.0 weeks [SD=3.3], respectively; P=.014). CONCLUSION: Although nicotine gum did not increase quit rates, use of nicotine gum increased birth weight and gestational age, two key parameters in predicting neonatal wellbeing. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT00115687 LEVEL OF EVIDENCE: I

Adverse effects of oral naltrexone: analysis of data from two clinical trials

Abstract. Rationale: Naltrexone treatment of alcohol dependence is associated with adverse events that may limit its effectiveness. Consequently, understanding the impact of adverse events on medication compliance and treatment retention may enhance naltrexone therapy of alcoholism. Objectives: To examine the relations among adverse events, drinking behavior, medication compliance and study retention in alcoholics receiving naltrexone for relapse prevention. Methods: The current report is based on analysis of data from 92 subjects who participated in two previously published studies. Moderate or severe adverse effects were monitored weekly and categorized as either neuropsychiatric (NP) or gastrointestinal (GI). Medication compliance was determined by weekly urinary riboflavin testing. Study retention was determined by the proportion of study weeks completed by the subject. The causal relations among adverse events, medication compliance and study retention were analyzed separately for NP and GI adverse events using regression-based recursive path models. Results: Both the NP and GI models fit the data well [NP model: χ2(4)=0.59, P=0.96; GI model: χ2(4)=2.81, P=0.59]. NP adverse events exerted little influence on medication compliance (β=–0.17, P=0.071), but directly decreased the length of study retention (β=–0.35, P<0.001). In contrast, there was a significant impact of GI adverse events on medication compliance (β=–0.29, P=0.002), but not directly on study retention (β=–0.14, P=0.081). Conclusion: Future studies aimed at enhancing the effectiveness of naltrexone should examine ways of reducing both NP and GI adverse events, in order to enhance both medication compliance and treatment retention.

Alcohol and tobacco cessation in alcohol-dependent smokers : Analysis of real-time reports

Alcohol-tobacco interactions and relapse precipitants were examined among alcohol-dependent smokers in a trial of concurrent alcohol and tobacco treatment. After discharge from treatment, participants completed 14 days of electronic diary (ED) assessments of mood, self-efficacy, urges to drink or smoke, and drinking and smoking behavior. ED data revealed an increase in frequency of alcohol urges after smoking episodes. Drinking relapse episodes were predicted by prior ED ratings of low self-efficacy to resist drinking and high urge to smoke. Smoking relapse episodes were predicted by high urge to smoke and high negative, high arousal mood. Results support a cross-substance cue reactivity model of multiple substance use and a limited-strength model, but not a cross-substance coping model.

Targeted naltrexone for early problem drinkers.

Most published studies of the efficacy of naltrexone for alcohol treatment have focused on daily medication for relapse prevention among abstinent alcoholics. The present study compared the effects of naltrexone with those of placebo in a sample of early problem drinkers who received study medication either daily or targeted to situations identified by the patients as being high risk for heavy drinking. Patients (n = 153; 58% male) were randomly assigned to receive naltrexone (50 mg) or placebo on a daily or targeted basis, yielding comparable numbers of patients in each of four treatment groups. Patients were trained to use structured nightly diaries in which they recorded their alcohol consumption and medication intake. Analysis was conducted with hierarchical linear modeling. Irrespective of whether they received naltrexone or placebo, patients in the targeted condition showed a reduced likelihood of any drinking. There was a reduced likelihood of heavy drinking, both for patients who received naltrexone and for patients who were in the targeted groups (either naltrexone or placebo), although these effects diminished as the number of tablets available to the targeted groups was reduced over the 8-week treatment period. Although the effect was a modest one, daily naltrexone reduced the risk of heavy drinking in this patient group. Furthermore, use of a targeted approach to medication treatment appears to be a useful strategy for reducing both drinking and heavy drinking. Efforts to replicate these findings are warranted, since they suggest that schedules of medication administration other than daily should be evaluated for treatment of problem drinking.

Effects of short‐term use of nicotine gum in pregnant smokers

To compare blood concentrations of nicotine and cotinine and maternal and fetal hemodynamic effects resulting from use of nicotine gum versus cigarette smoking in pregnant smokers.