Transdermal Nicotine Replacement Research Articles

Exenatide as an adjunct to nicotine patch for smoking cessation and prevention of postcessation weight gain among treatment-seeking smokers with pre-diabetes and/or overweight: study protocol for a randomised, placebo-controlled clinical trial

IntroductionObesity and smoking are the two leading causes of preventable death in the USA. Unfortunately, most smokers gain weight after quitting. Postcessation weight gain (PCWG) is frequently cited as one...

377 Randomized Placebo-controlled Trial to Test the Efficacy of genetically informed biomarker Nicotine Metabolite Ratio (NMR), and transdermal nicotine replacement therapy (NRT) versus varenicline

OBJECTIVES/GOALS: The overall aim of the proposed study is to evaluate the effectiveness and clinical utility of the NMR as a biomarker of response to placebo, transdermal nicotine, and varenicline to be utilized within the clinical practice as a point-of-care predictor to tailor an individual’s smoking cessation treatment. METHODS/STUDY POPULATION: A 12-week phase II, stratified multicenter, randomized, placebo-controlled trial of 3 treatment groups to measure treatment-seeking smokers (n-900:150 slow metabolizers; 150 normal metabolizers), randomized to 12-weeks of nicotine patch (active patch + placebo pill), varenicline (active pill + placebo patch), or placebo (placebo pill + patch). At the end of treatment, patients will be followed for 12 months. Study Population: Adult smokers 18–65 years old reported smoking≥10 cigarettes/day for≥6 months (verified by carbon monoxide (CO) >10 ppm). Drug and route of administration: RESULTS/ANTICIPATED RESULTS: The study would conclude the effectiveness of the interventions well defined. DISCUSSION/SIGNIFICANCE: The report will provide robust evidence to support the effectiveness of NRT intervention on smoking cessation.

A Preliminary Examination of Nicotine-Free Electronic Cigarette Use During Cessation From Combustible Cigarettes.

Despite the availability of smoking cessation strategies, smoking cue-induced craving remains a relatively untreated relapse risk factor. Utilizing nicotine-free electronic cigarettes (e-cigarettes) to extinguish the motivational influence of smoking cues may be a viable approach to address cue reactivity. In this pilot study, 26 daily tobacco smokers used nicotine-free e-cigarettes while being maintained on daily transdermal sustained-release nicotine replacement therapy (NRT) to mitigate pharmacological withdrawal. Sensitivity to cue-induced craving, measured by the rise in craving after a visual cue exposure task, was assessed at a baseline visit after smoking as usual and again after 2 weeks of nicotine-free e-cigarette and NRT use. Participants’ pattern and amount of tobacco cigarette smoking were evaluated on both visits and 1 month posttreatment. Cue-induced craving significantly decreased after the 2-week intervention, yet withdrawal scores increased during this time. One month after study completion, participants continued to report significantly lower overall cigarette craving and conventional tobacco cigarette use. Including the 34.8% that were totally abstinent, 65.2% reported smoking fewer than 10 cigarettes per week (compared to 87.2 per week at baseline for the entire group). A linear regression revealed that greater baseline cue-induced craving predicted better outcomes, whereas more withdrawal at the e-cigarette visit was related to more smoking at 1 month. This proof-of-concept pilot study suggests that the addition of ad libitum nicotine-free e-cigarettes to an existing strategy of transdermal NRT may attenuate cue-induced craving for tobacco smoking. A larger sample that is powered for detecting additional factors and longer-term outcomes is warranted.

Does the nicotine metabolite ratio moderate smoking cessation treatment outcomes in real-world settings? A prospective study.

Background and aimsIn smoking treatment trials comparing varenicline with transdermal nicotine replacement therapy (NRT), stratified by nicotine metabolite (3‐hydroxycotinine/cotinine) ratio (NMR), the relative benefit of varenicline is greater among normal rather than slow metabolizers. This study tested if the relative effectiveness of varenicline and NRT is associated with NMR status in a natural treatment setting. A secondary aim was to test if this relationship is moderated by behavioural support.DesignProspective observational multi‐centre study with 4‐week and 52‐week follow‐up.SettingNine English Stop Smoking Services (SSS).ParticipantsData came from 1556 smokers (aged ≥ 16 years) attending SSS between March 2012 and March 2013.InterventionsParticipants received pharmacotherapy together with behavioural support.MeasurementsThe primary outcome was carbon monoxide‐verified continuous abstinence at both follow‐up times. Main explanatory variables were (1) NMR status [slow (NMR < 0.31, n = 451) versus normal (NMR ≥ 0.31, n = 1105) metabolizers]; (2) pharmacotherapy (varenicline versus NRT) and (3) behavioural support (individual versus group‐based treatment). Analyses adjusted for baseline socio‐demographic, SSS, mental/physical health and smoking characteristics.FindingsOf participants, 44.2% [95% confidence interval (CI) = 41.7–46.6%] and 8.0% (95% CI = 6.8–9.5%) were continuously abstinent at 4 and 52 weeks. Varenicline was more effective than NRT at 4 weeks (P < 0.001) but only marginally so at 52 weeks (P = 0.061). There was no or inclusive evidence that NMR status moderated relative efficacy of varenicline and NRT at 4‐ [P = 0.60, Bayes factor (BF) = 0.25] or 52‐week follow‐ups (P = 0.74, BF = 0.73). However, this relationship was moderated by behavioural support (p = 0.012): the relative benefit of varenicline over NRT at 52‐week follow‐up was greater in slow, not normal, metabolizers receiving group rather than individual support (P = 0.012).ConclusionsIn a real‐world setting, the nicotine metabolite ratio status of treatment‐seeking smokers does not appear to contribute substantially to the differential effectiveness of varenicline and nicotine replacement therapy in Stop Smoking Services, when both pharmacotherapy and behavioural support are self‐selected.

Exenatide once weekly for smoking cessation: study protocol for a randomized clinical trial.

BackgroundCigarette smoking is the greatest preventable cause of morbidity and premature mortality in the United States. Approved pharmacological treatments for smoking cessation are marginally effective, underscoring the need for improved pharmacotherapies. A novel approach might use glucagon-like peptide-1 (GLP-1) agonists, which reduce alcohol and drug use in preclinical studies. GLP-1 is produced in the intestinal L-cells and in the hindbrain. The peptide maintains glucose homeostasis and reduces food intake. Several GLP-1 agonists are used clinically to treat type 2 diabetes and obesity, but none have been tested in humans to reduce smoking.AimsWe will examine whether extended-release exenatide reduces smoking, craving, and withdrawal symptoms, as well as cue-induced craving for cigarettes.MethodsWe will enroll prediabetic and/or overweight treatment seeking smokers (n = 90) into a double-blind, placebo-controlled, randomized clinical trial. Participants will be randomized in a 1:1 ratio to receive exenatide or placebo. All participants will receive transdermal nicotine replacement therapy (NRT) and behavioral counseling. Abstinence from smoking (verified via expired CO level of ≤5 ppm), craving (Questionnaire of Smoking Urges score), and withdrawal symptoms (Wisconsin Scale of Withdrawal Symptoms score) will be assessed weekly during 6 weeks of treatment and at 1 and 4 weeks posttreatment. Cue-induced craving for cigarettes will be assessed at baseline and at 3 weeks of treatment following virtual reality exposure.Expected outcomesWe hypothesize that exenatide will increase the number of participants able to achieve complete smoking abstinence above that achieved via standard NRT and that exenatide will reduce craving and withdrawal symptoms, as well as cue-induced craving for cigarettes.

Nicotine Metabolite Ratio Is Associated With Lozenge Use But Not Quitting in Smokeless Tobacco Users.

The nicotine metabolite ratio (NMR) of 3'-hydroxycotinine to cotinine is a noninvasive marker of the rate of nicotine metabolism. Fast metabolism (ie, a high NMR) is associated with lower cigarette smoking abstinence rates using transdermal nicotine replacement. We evaluated whether the NMR can be used to predict self-reported nicotine lozenge use and tobacco abstinence among smokeless tobacco users treated for tobacco dependence. This was a secondary analysis of data from one arm of a large trial. Participants received quitting support materials and 4-mg nicotine lozenges by mail plus three coaching phone calls. Saliva kits were mailed for collection of saliva samples, which were analyzed for cotinine and 3'-hydroxycotinine. Self-reported tobacco and lozenge use were assessed at 3 months. Analyses were performed using Spearman rank correlation and logistic regression. Of the 160 saliva collection kits mailed, 152 were returned. The NMR was not significantly correlated with the baseline amount of smokeless tobacco used, the number of years of tobacco use, or the level of tobacco dependence as measured by the Severson Smokeless Tobacco Dependency Scale. The NMR was positively correlated with lozenge use (r = 0.21, P = .015), but it did not predict self-reported 7-day point prevalence abstinence at 3 months. Fast metabolizers may need to self-administer more nicotine replacement in the form of nicotine lozenges to achieve the same clinical response achieved by slower metabolizers using fewer lozenges.

Long-term quit rates after a perioperative smoking cessation randomized controlled trial.

While surgery and perioperative smoking cessation interventions may motivate patients to quit smoking in the short term, it is unknown how often this translates into permanent cessation. In this study, we sought to determine the rates of long-term smoking cessation after a perioperative smoking cessation intervention and predictors of successful cessation at 1 year. We previously reported short-term results from a perioperative randomized controlled trial comparing usual care with an intervention involving (1) brief counseling by the preadmission nurse, (2) smoking cessation brochures, (3) referral to a telephone quitline, and (4) a free 6-week supply of transdermal nicotine replacement. We now report our 1-year follow-up outcomes. Between October 2010 and April 2012, 168 patients were randomized. At 1 year, 127 patients (76%) were available for follow-up telephone interview. Smoking cessation occurred in 8% of control patients compared with 25% of patients in the intervention group (relative risk, 3.0; 95% confidence interval [CI], 1.2-7.8; P = 0.018). The number needed-to-treat to achieve smoking cessation for 1 patient at 1 year postoperatively was 5.9 (95% CI, 3.4-25.9). Multivariable logistic regression modeling found that the intervention (P = 0.020) and lower nicotine dependency at baseline (P < 0.001) were predictive of success at smoking cessation at 1 year. Poisson regression showed that adjusted for nicotine dependency, those randomized to the intervention group were 2.7 times (95% CI, 1.1-6.7; P = 0.028) more likely to achieve long-term cessation than those in the control group. Adjusted for randomization group, a low level of nicotine dependency resulted in a relative risk of quitting of 5.1 (95% CI, 2.0-12.8; P = 0.001). This study demonstrates that an intervention designed for a busy preadmission clinic results in decreased smoking rates not only around the time of surgery but also continued benefit in smoking cessation at 1 year. Perioperative care providers have a unique opportunity to assist patients in smoking cessation and achieve long-lasting results.

Differential Efficacy of Nicotine Replacement Among Overweight and Obese Women Smokers.

Rates of obesity are higher among more dependent smokers and 37%-65% of smokers seeking cessation treatment are overweight or obese. Overweight or obese smokers may possess metabolic and neurobiological features that contribute to difficulty achieving cessation using front-line nicotine replacement products. Attention to factors that facilitate effective cessation treatment in this vulnerable population is needed to significantly reduce mortality risk among overweight and obese smokers. This secondary analysis of 2 large trials of transdermal nicotine replacement in general medical practices evaluated the hypothesis that higher body mass index (BMI) would moderate the efficacy of the nicotine patch. We examined the potential for gender to further moderate the relationship between BMI and treatment efficacy. In the placebo controlled trial (N = 1,621), 21-mg patch was no more effective than placebo for assisting biochemically verified point prevalence abstinence up to 1 year after quitting for women with higher BMI, but appeared to be effective for men at normal or high BMI (gender × BMI beta = -0.22, p = .004). We did not find differential long-term cessation outcomes among male or female smokers in the 15-mg patch trial (n = 705). However, we observed significantly higher rates of early lapse among women with higher BMI treated with nicotine patch across both trials. These results suggest that increased BMI may affect the efficacy of nicotine patch on reducing risk of early lapse in women. Additional research is needed to explore mechanisms of risk for decreased efficacy of this commonly used cessation aid.

High-dose transdermal nicotine replacement for tobacco cessation

The safety and efficacy of high-dose transdermal nicotine-replacement therapy (NRT) for the treatment of tobacco-use cessation were reviewed. Transdermal nicotine doses of 7, 14, and 21 mg daily are approved by the Food and Drug Administration for use in tobacco cessation. However, studies have suggested that these doses are more adequate for people who smoke fewer than 20 cigarettes per day. A literature search was conducted to identify English-language studies that evaluated the use of transdermal nicotine doses of ≥42 mg daily. A total of 11 articles were identified, representing 10 separate trials. In terms of safety, the majority of the trials had no reports of serious adverse events related to transdermal NRT at doses of ≥42 mg daily. A dose-response relationship with adverse events occurred in most trials. In terms of efficacy, a numerically higher abstinence rate was achieved with high-dose transdermal NRT in all trials but 1. However, none of the studies showed significant differences in final abstinence rates at follow-up. Some reasons why statistical significance was not achieved in these trials may be related to the limitations of these trials, such as their small samples and the lack of a power calculation. A more robust trial is needed to support higher nicotine transdermal doses in tobacco cessation and to help elucidate which patient population would be most suitable for their use. The safety and efficacy of high-dose transdermal NRT for tobacco cessation have not been established in the medical literature.

Up in Smoke? A Preliminary Open-Label Trial of Nicotine Replacement Therapy and Cognitive Behavioral Motivational Enhancement for Smoking Cessation Among Youth in Los Angeles

In 2008–2009, we conducted a 6-week, open-label trial of transdermal nicotine replacement therapy and practical counseling for 34 adolescents seeking smoking cessation in Los Angeles. Dependent outcomes were study retention, use of the patch, and 7-day quit status at the end-of-study and at follow-up visits. Predictors of outcomes included cigarette dependence, withdrawal symptoms, demographic and psychiatric measures, and other substance use. Variables significant in bivariate analysis (p < .10) were retained in a multivariate model. Subjects had significant pre-to-post reductions in quit rates, dependence, and withdrawal symptoms. Subjects also reported a high number of comorbidities. Implications for clinicians are discussed.

Cognitive Behavioral Therapy and the Nicotine Transdermal Patch for Dual Nicotine and Cannabis Dependence: A Pilot Study

We assessed the feasibility of a new cognitive behavioral therapy (CBT) manual, plus transdermal patch nicotine replacement therapy (NRT), to treat co-occurring nicotine and cannabis dependence. Seven of 12 (58.3%) adults with DSM-IV diagnoses of both nicotine and cannabis dependence completed 10 weeks of individual CBT and NRT. Participants smoked 12.6 ± 4.9 tobacco cigarettes per day at baseline, which was reduced to 2.1 ± 4.2 at the end of treatment (F[5] = 23.5, p < .0001). The reduction in cannabis use from 10.0 ± 5.3 inhalations per day at baseline to 8.0 ± 5.3 inhalations per day at 10 weeks was not significant (F[5] = 1.12, p = .37). There was a significant decrease from the mean baseline Fagerstrom Test for Nicotine Dependence scores at weeks 4, 6, 8, and 10 of treatment (F[4] = 19.8, p < .001) and mean Client Satisfaction Questionnaire scores were uniformly high (30.6 ± 1.9). A CBT plus NRT treatment program significantly reduced tobacco smoking but did not significantly reduce cannabis use in individuals with co-occurring nicotine and cannabis dependence. There was no compensatory increase in cannabis use following the reduction in tobacco smoking, suggesting that clinicians can safely pursue simultaneous treatment of co-occurring nicotine and cannabis dependence. The intervention was well-liked by the 7 of the 12 enrollees who completed the study.

An Open Label Study investigating the Efficacy of Hypericum perforatum Special Extract (ZE117), Nicotine Patches and Combination (ZE117)/ Nicotine Patches for Smoking Cessation

Introduction: Nicotine addiction has become one of the largest international health problems, increasing the risk of cardiovascular disease, cancers, and respiratory diseases. There are several treatments available for smoking cessation with the most common transdermal nicotine replacement and anti-depressants. However current treatments are only mildly efficacious and have side effects which lead to a decrease in their effectiveness. Additional treatments for smoking cessation with lower side effects are required. Methods: We examined the efficacy of Remotiv® (Hypericum perforatum Special Extract - ZE117) compared to Nicabate® CQ Nicotine Replacement Therapy (NRT) and combination ZE117/NRT for smoking cessation over a treatment time of 10 weeks. Given the different pharmacological profiles of Ze117 and NRT it was expected that a combination treatment would be most efficacious for smoking cessation than the other two treatments alone. Sixty smokers aged between 18 and 60 years were enrolled in the study. Smoking status was assessed using CO levels measured by the Bedfont Smokerlyzer (primary outcome measure). Secondary outcome measures of anxiety, DSMIV nicotine dependence and Fagerstrom craving and symptoms were also recorded. Results: A significant main effect of reduction in the number of smokers over the course of the study was observed although there were no significant differences between any of the treatment groups on this variable after 14 weeks. Conclusions: These results indicate that the three treatment options are equally efficacious for smoking cessation. Interestingly the Ze117 treatment significantly reduced the amount of craving over the treatment duration of the study compared to the other two treatments indicating a possible mechanism by which Ze117 may assist in smoking cessation.

Osmotic Release Oral System Methylphenidate Prevents Weight Gain during a Smoking-Cessation Attempt in Adults with ADHD

Adults with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for both cigarette smoking and being overweight or obese. Although smoking cessation tends to result in weight increase, potentially initiating or exacerbating weight problems, adults with ADHD who are treated with osmotic release oral system methylphenidate (OROS-MPH) tend to lose weight. It is unclear how the use of OROS-MPH during a smoking-cessation attempt might affect the typical weight gain that accompanies cessation. We examined changes in weight and hunger during a smoking-cessation attempt in 215 adults with ADHD who completed a multisite, randomized, controlled trial and were randomized to either OROS-MPH (n = 107) or placebo (n = 108) (NCT #00253747). Both groups also received open-label transdermal nicotine replacement and counseling. Participants who received OROS-MPH lost an average of 1.6% of their body weight during the 11-week study, whereas those who received placebo gained an average of 1.3% of their weight (p < .001). Hunger ratings were lower in the OROS-MPH group (M = 1.1, SD = 0.8) than in the placebo group (M = 1.6, SD = 0.9; p < .001). The use of OROS-MPH during a smoking-cessation attempt prevents weight gain in adults with ADHD who substantially reduce or quit smoking. The potential utility of OROS-MPH in individuals with ADHD who are attempting to quit smoking and for whom weight gain would be problematic warrants further research.

Preliminary Evidence That Adherence to Counseling Mediates the Effects of Pretreatment Self-efficacy and Motivation on Outcome of a Cessation Attempt in Smokers with ADHD

Few studies have evaluated predictors of smoking cessation outcomes in smokers with attention-deficit/hyperactivity disorder (ADHD), which could help to improve suboptimal treatment outcomes in this population. The purpose of this study was to examine pretreatment thoughts about smoking abstinence (i.e., desire to quit, perceived difficulty quitting, and expected success in quitting) as predictors of smoking cessation outcomes in smokers with ADHD and to determine the extent to which treatment adherence mediates these relationships. Participants were adult smokers with ADHD (n = 255), who were enrolled in a multisite smoking cessation study and received either osmotic-release oral system methylphenidate (OROS-MPH) or placebo in combination with transdermal nicotine replacement and brief cessation counseling. Bootstrapped logistic regression models were generated to test main effects of thoughts about abstinence on smoking cessation outcomes and to examine treatment adherence as a mediator of these relationships. Desire to quit and expected success in quitting, but not perceived difficulty quitting, predicted smoking cessation outcomes, as did all of the treatment adherence variables (i.e., percent sessions attended, counselor ratings of counseling adherence, and percent patch adherence). Counseling adherence partially mediated the relationship between smoking cessation outcomes and both pretreatment desire to quit and expected success. Smokers with ADHD who have higher self-efficacy (i.e., expected success) and motivation (i.e., desire) to quit are more adherent to smoking cessation counseling and have better smoking cessation outcomes. Additional research is needed to determine whether treatment-seeking smokers with ADHD would benefit from an intervention designed to increase self-efficacy and motivation to quit.

Separate and Combined Effects of Very Low Nicotine Cigarettes and Nicotine Replacement in Smokers with Schizophrenia and Controls

The prevalence of smoking among people with schizophrenia in the United States is about 3 times that of the general population. Novel approaches are needed to reduce rates of smoking-related morbidity and mortality among these smokers. This study used a within-subjects design to investigate the separate and combined effects of sensorimotor replacement for smoking (very low nicotine content [VLNC] cigarettes vs. no cigarettes) and transdermal nicotine replacement (42 mg nicotine [NIC] vs. placebo [PLA] patches) in smokers with schizophrenia (SS; n = 30) and control smokers without psychiatric illness (CS; n = 26). Each session contained a 5-hr controlled administration period in which participants underwent the following conditions, in counterbalanced order: VLNC + NIC, VLNC + PLA, no cigarettes + NIC, no cigarettes + PLA, usual-brand cigarettes + no patches. Next, participants completed measures of cigarette craving, nicotine withdrawal, smoking habit withdrawal, and cigarette subjective effects, followed by a 90-min period of ad libitum usual-brand smoking. Smoking VLNC cigarettes during the controlled administration periods reduced cigarette craving, nicotine withdrawal symptoms, habit withdrawal symptoms, and usual-brand smoking in SS and CS relative to the no cigarette conditions. VLNC cigarettes were well accepted by both groups and did not affect psychiatric symptom levels in SS. Transdermal nicotine significantly reduced cigarette craving but did not affect usual-brand smoking. These findings suggest that reducing the nicotine content of cigarettes to nonaddictive levels may be a promising approach for reducing nicotine dependence among people with schizophrenia.

Association Between Nicotinic Acetylcholine Receptor Single Nucleotide Polymorphisms and Smoking Cessation

The α4β2 nicotinic receptor is of central importance in tobacco dependence, while the homomeric α7 receptor may also play a role. In this candidate gene study, we examine the association between 8 single nucleotide polymorphisms (SNPs) in genes coding for nicotinic acetylcholine receptor subunits α4 (rs1044396, rs2273504, rs2236196, and rs2273502), α7 (rs2133965 and rs4779969), and β2 (rs2072660 and rs2072661) and smoking abstinence in a cohort of quitters enrolled in a clinical trial of behavioral support. Data were obtained from the "Patch in Practice" study, involving 925 smokers in the United Kingdom. All participants were given an 8-week course of 15 mg of transdermal nicotine replacement therapy and blood was taken for genotyping. Logistic regression analyses assessed the association between each selected SNP and smoking abstinence at 4, 12, 26, and 52 weeks. There were no statistically significant associations with smoking cessation success or nicotine intake assessed by plasma cotinine levels. However, rs2273502 was associated with a consistent (though nonsignificant) increase in the odds of abstinence. There was no compelling evidence that these SNPs were associated with a reduced or higher chance of abstinence. However, rs2273502 may be worth investigating in future studies.

Transdermal Nicotine Replacement Therapy Safety in Patients with Cardiovascular Disease

Purpose The safety and efficacy of nicotine replacement therapy in patients with stable cardiovascular disease and following an acute coronary event are reviewed. Summary Physicians have been hesitant to prescribe nicotine replacement therapy (NRT) in patients with cardiac disease due to the reported harmful cardiovascular effects of nicotine, including an increase in heart rate and blood pressure, as well as its possible contribution to the pathogenesis of coronary artery disease and sudden cardiac death. However, several studies have shown that NRT is safe following myocardial infarction and is preferred over continued cigarette smoking. One cohort study assessed the safety and efficacy of transdermal NRT in smokers admitted for acute coronary syndromes and found no difference in mortality versus patients given a placebo. Additionally, the cost of NRT should not be viewed as a barrier due to the long-term savings in preventable hospitalizations following additional cardiovascular events. Conclusion Transdermal NRT was found to be safe and effective in patients with acute myocardial infarction and with a known history of cardiovascular disease. It has also proven to be effective in smoking cessation, which eliminates the most important risk factor for an acute coronary event. NRT showed no increased frequency in mortality or other cardiac adverse events.

A Double-Blind, Placebo-Controlled Trial of the NMDA Glycine Site Antagonist, GW468816, for Prevention of Relapse to Smoking in Females

Relapse to smoking is common after initial abstinence with pharmacotherapy and behavioral support and represents a major clinical challenge. Although mechanisms underlying relapse to smoking have not been elucidated, preclinical studies suggest that glutamate receptors may be involved. We sought to test a selective antagonist of the glycine coagonist site on the glutamate N-methyl-D-aspartate receptor, GW468816, for prevention of relapse in recently abstinent smokers. To do so, we enrolled 264 healthy female smokers in an open 8-week smoking cessation intervention with behavioral therapy and a standard dose of transdermal nicotine replacement therapy with taper and additional gum or lozenge as needed for nicotine withdrawal symptoms. Ninety-eight participants achieved 7-day point prevalence abstinence and were randomized into a 5-week double-blind, placebo-controlled, relapse-prevention trial of GW468816 (200 mg/d) and then followed for 60 days after randomization. There was no effect of treatment on abstinence rates at the end of treatment (χ² [1, n = 96] = 0.168, P = 0.838), on the rates of relapse (χ² [1, n = 98] = 0.031, P = 1.000) or lapse (χ² [1, n = 62] = 0.802, P = 0.423), or on time to relapse (χ² [1, n = 98) = 0.001, P = 0.972). No significant relationships were detected between plasma GW468816 concentrations and abstinence, time to relapse, or self-reported craving. In conclusion, despite promising preclinical data that support the use of a selective NMDA glycine site antagonist for prevention of relapse to smoking, we observed no effect of GW468816 on relapse or lapse rates, time to relapse, or craving compared to placebo.

Nicotine Replacement Therapy After Subarachnoid Hemorrhage Is Not Associated With Increased Vasospasm

A significant number of patients with aneurysmal subarachnoid hemorrhage are active smokers and at risk for acute nicotine withdrawal. There is conflicting literature regarding the vascular effects of nicotine and theoretical concern that it may worsen vasospasm. The literature on the safety of nicotine replacement therapy and its effects on vasospasm is limited. A retrospective analysis was conducted of a prospectively collected database of aneurysmal subarachnoid hemorrhage patients admitted to the neurointensive care unit from 1994 to 2008. Paired control subjects matched for age, sex, Fisher score, aneurysm size and number, hypertension, and current medication were analyzed. The primary outcome was clinical and angiographic vasospasm and the secondary outcome was Glasgow Outcome Score on discharge. Conditional logistic models were used to investigate univariate and multivariate relationships between predictors and outcome. Two hundred fifty-eight active smoking patients were included of which 87 were treated with transdermal nicotine replacement therapy. Patients were well matched for age, sex, gender, Fisher score, aneurysm size and number, hypertension, and current medications, but patients who received nicotine replacement therapy had less severe Hunt-Hess scores and Glasgow coma scores. There was no difference in angiographic vasospasm, but patients who received nicotine replacement therapy were less likely to have clinical vasospasm (19.5 versus 32.8%; P=0.026) and a Glasgow Outcome Score <4 on discharge (62.6% versus 81.6%; P=0.005) on multivariate analysis. Nicotine replacement therapy was not associated with increased angiographic vasospasm and was associated with less clinical vasospasm and better Glasgow Outcome Score scores on discharge.

Gender-stratified gene and gene–treatment interactions in smoking cessation

We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain-reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P-values for multiple correlated tests, and used a Bonferroni corrected α-level of 5 × 10−4 to determine system-wide significance. Four SNPs (rs12021667, rs12027267, rs6702335, rs12039988; r2>0.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (OR=0.5; 95% CI 0.3–0.6) at end of treatment (adjusted P<6 × 10−5). rs806365 in cannabinoid receptor 1 (CNR1) had a significant male-specific gene-treatment interaction at 6-month follow-up (adjusted P=3.9 × 10−5); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR=0.04; 95% CI 0.01–0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.