Evaluating the Effects of Varenicline on Craving, Withdrawal, and Affect in a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Varenicline for Smokeless Tobacco Dependence in India.

This study examined changes in tobacco craving, withdrawal, and affect as correlates of efficacy in a phase-2 clinical trial of varenicline for smokeless tobacco dependence in India. Smokeless tobacco users (N = 237) at the All India Institute of Medical Sciences were randomized to placebo or varenicline. Abstinence was defined as cotinine-verified seven-day point prevalence cessation at end of treatment (EOT). General Linear Model repeated measures assessed the effects of treatment condition, time, abstinence state, and interaction effects on changes in craving, withdrawal, positive (PA) and negative affect (NA) from baseline to EOT. All participants showed a significant reduction in withdrawal (p < .001), total craving (p < .001), positive reinforcement (PR) craving (p < .001), and NA (p = .02), and an increase in PA (p = .04) from baseline to EOT. However, there were no differences between placebo and varenicline participants in measures of withdrawal, craving, or affect from baseline to week 3 or at EOT. Significant interactions between time and abstinence state were found for total craving (p = .008), PR craving (p < .001), and withdrawal (p = .001), indicating reductions in these processes among those abstinent vs. those still chewing smokeless tobacco. Additional research is needed concerning the effects of varenicline on craving, withdrawal, and affect among smokeless tobacco users.

Biochemical Validation of Self-Reported Smokeless Tobacco Abstinence among Smokeless Tobacco Users: Results from a Clinical Trial of Varenicline in India.

The validity of self-reported tobacco use is often questioned given the potential for underestimation of use. This study used data from a double-blind, placebo-controlled clinical trial of varenicline for smokeless tobacco dependence in India to evaluate the accuracy of self-reported smokeless tobacco cessation using biochemical validation procedures and to evaluate correlates of reporting inaccuracy. Smokeless tobacco users attending a dental clinic at AIIMS were randomized to placebo or varenicline; all participants received counseling. Detailed smokeless tobacco use was recorded and abstinence was defined as cotinine-verified 7-day point prevalence cessation (cotinine < 50 ng/ml) and breath CO > 10 ppm at the end of 12 weeks of treatment. One-half of study completers (82/165) self-reported abstinence. Biochemical verification confirmed that (65.9%) subjects provided accurate self-reports while (34.1%) participants underreported tobacco use. These data indicate poor agreement between self-reported and biochemically confirmed abstinence (κ = -0.191). Underreporters of tobacco use had significantly higher baseline cotinine (p < 0.05), total craving (p < 0.012), and negative reinforcement craving (p < 0.001) vs. those whose self-reports were correctly verified. These findings provide evidence to support the need for biochemical validation of self-reported abstinence outcomes among smokeless tobacco users in cessation programs in India and identify high levels of pretreatment cotinine and craving levels as potential correlates of false reporting.

A double-blind placebo-controlled randomized trial of varenicline for smokeless tobacco dependence in India.

INTRODUCTION: The rate of smokeless tobacco use in India is 20%; its use causes serious health problems, and no trial has assessed behavioral or pharmacological treatments for this public health concern. This trial evaluated varenicline for treating smokeless tobacco dependence in India. METHODS: This was a double-blind placebo-controlled randomized trial of varenicline (12 weeks, 1mg, twice per day) with 237 smokeless tobacco users in India. All participants received behavioral counseling. Outcomes included self-reported and biochemically verified abstinence at the end of treatment (EOT), lapse and recovery events, safety, and medication adherence. RESULTS: Self-reported EOT abstinence was significantly greater for varenicline (43%) versus placebo (31%; adjusted odds ratio [AOR] = 2.6, 95% CI = 1.2-4.2, p = .009). Biochemically confirmed EOT abstinence was greater for varenicline versus placebo (25.2% vs. 19.5%), but this was not statistically different (AOR = 1.6, 95% CI = 0.84-3.1, p = .15). Compared with placebo, varenicline did not reduce the risk for a lapse (hazard ratio [HR] = 0.86, 95% CI = 0.69-1.1, p = .14), but it did increase the likelihood of recovery to abstinence (HR = 1.2, 95% CI = 1.02-1.4, p = .02). Greater adherence increased EOT cessation rates for varenicline (39% vs. 18%, p = .003) but not for placebo (28% vs. 14%, p = .06). There were no significant differences between varenicline and placebo in rate of side effects, serious adverse events, hypertension, or stopping or reducing medication. CONCLUSIONS: Varenicline is safe for treating smokeless tobacco dependence in India, and further examination of this medication for this important public health problem is warranted.

Rate of nicotine metabolism and smoking cessation outcomes in a community-based sample of treatment-seeking smokers.

BACKGROUND: In samples from controlled randomized clinical trials, a smoker's rate of nicotine metabolism, measured by the 3-hydroxycotinine to cotinine ratio (NMR), predicts response to transdermal nicotine. Replication of this relationship in community-based samples of treatment-seeking smokers may help guide the implementation of the NMR for personalized treatment for nicotine dependence. METHODS: Data from a community-based sample of treatment seeking smokers (N=499) who received 8weeks of transdermal nicotine and 4 behavioral counseling sessions were used to evaluate associations between the NMR and smoking cessation. Secondary outcomes included withdrawal and craving, depression and anxiety, side effects, and treatment adherence. RESULTS: The NMR was a significant predictor of abstinence (OR=.56, 95% CI: 0.33-0.95, p=.03), with faster metabolizers showing lower quit rates than slower metabolizers (24% vs. 33%). Faster nicotine metabolizers exhibited significantly higher levels of anxiety symptoms over time during treatment, vs. slower metabolizers (NMR x Time interaction: F[3,357]=3.29, p=.02). NMR was not associated with changes in withdrawal, craving, depression, side effects, and treatment adherence (p's>.05). CONCLUSIONS: In a community-based sample of treatment-seeking smokers, faster nicotine metabolizers were significantly less likely to quit smoking and showed higher rates of anxiety symptoms during a smoking cessation treatment program, vs. slower nicotine metabolizers. These results provide further evidence that transdermal nicotine is less effective for faster nicotine metabolizers and suggest the need to address cessation-induced anxiety symptoms among these smokers to increase the chances for successful smoking cessation.

Long-term nicotine replacement therapy: a randomized clinical trial.

IMPORTANCE: The US Food and Drug Administration adopted labeling for nicotine patches to allow use beyond the standard 8 weeks. This decision was based in part on data showing increased efficacy for 24 weeks of treatment. Few studies have examined whether the use of nicotine patches beyond 24 weeks provides additional therapeutic benefit. OBJECTIVE: To compare 8 (standard), 24 (extended), and 52 (maintenance) weeks of nicotine patch treatment for promoting tobacco abstinence. DESIGN, SETTING, AND PARTICIPANTS: We recruited 525 treatment-seeking smokers for a randomized clinical trial conducted from June 22, 2009, through April 15, 2014, through 2 universities. INTERVENTIONS: Smokers received 12 smoking cessation behavioral counseling sessions and were randomized to 8, 24, or 52 weeks of nicotine patch treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was 7-day point prevalence abstinence, confirmed with breath levels of carbon monoxide at 6 and 12 months (intention to treat). RESULTS: At 24 weeks, 21.7% of participants in the standard treatment arm were abstinent, compared with 27.2% of participants in the extended and maintenance treatment arms (χ(2)(1) = 1.98; P = .17). In a multivariate model controlled for covariates, participants in the extended and maintenance treatment arms reported significantly greater abstinence rates at 24 weeks compared with participants in the standard treatment arm (odds ratio [OR], 1.70 [95% CI, 1.03-2.81]; P = .04), had a longer duration of abstinence until relapse (ß = 21.30 [95% CI, 10.30-32.25]; P < .001), reported smoking fewer cigarettes per day if not abstinent (mean [SD], 5.8 [5.3] vs 6.4 [5.1] cigarettes per day; ß = 0.43 [95% CI, 0.06-0.82]; P = .02), and reported more abstinent days (mean [SD], 80.5 [38.1] vs 68.2 [43.7] days; OR, 1.55 [95% CI, 1.06-2.26]; P = .02). At 52 weeks, participants in the maintenance treatment arm did not report significantly greater abstinence rates compared with participants in the standard and extended treatment arms (20.3% vs 23.8%; OR, 1.17 [95% CI, 0.69-1.98]; P = .57). Similarly, we found no difference in week 52 abstinence rates between participants in the extended and standard treatment arms (26.0% vs 21.7%; OR, 1.33 [95% CI, 0.72-2.45]; P = .36). Treatment duration was not associated with any adverse effects or adherence to the counseling regimen, but participants in the maintenance treatment arm reported lower adherence to the nicotine patch regimen compared with those in the standard and extended treatment arms (mean [SD], 3.94 [2.5], 4.61 [2.0], and 4.7 [2.4] patches/wk, respectively; F2,522 = 6.03; P = .003). CONCLUSIONS AND RELEVANCE: The findings support the safety of long-term use of nicotine patch treatment, although they do not support efficacy beyond 24 weeks of treatment in a broad group of smokers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01047527.

The association between changes in alternative reinforcers and short-term smoking cessation.

BACKGROUND: While more than 50% of smokers make a serious quit attempt each year, less than 10% quit permanently. Evidence from studies of adolescent smoking and other substances of abuse suggest that alternative reinforcers, a construct of Behavioral Economic Theory, may contribute to the likelihood of smoking cessation in adults. This study examined the behavioral economics of smoking cessation within a smoking cessation clinical trial and evaluated how depressive symptoms and behavioral economic variables are associated with smoking cessation. METHODS: A sample of 469 smokers, enrolled in an effectiveness trial that provided counseling and 8 weeks of 21 mg nicotine patches, was analyzed. Alternative reinforcers (substitute and complementary reinforcers) and depressive symptoms were examined in relation to 7-day point prevalence abstinence, verified with breath carbon monoxide, 8 weeks after the quit date. RESULTS: Controlling for covariates associated with cessation (nicotine dependence, age of smoking initiation, patch adherence), participants who were abstinent at week 8 showed significantly higher substitute reinforcers at all time-points, compared to those who were smoking (p's<.05). Participants who were abstinent at week 8 showed lower complementary reinforcers and depressive symptoms at all time-points, compared to those who were smoking, but significant differences were confined to week 8 (p's<.01). There was no significant interaction between alternative reinforcers and depressive symptoms across the 8 weeks on week 8 abstinence. CONCLUSIONS: These results support continued examination of Behavioral Economic Theory in understanding adult smoking cessation in order to inform future treatments and guidelines.

Effects of tolcapone on working memory and brain activity in abstinent smokers: a proof-of-concept study.

BACKGROUND: Dopamine levels in the prefrontal cortex (PFC) are thought to play an important role in cognitive function and nicotine dependence. The catechol-O-methyltransferase (COMT) inhibitor tolcapone, an FDA-approved treatment for Parkinson's disease, increases prefrontal dopamine levels, with cognitive benefits that may vary by COMT genotype. We tested whether tolcapone alters working memory-related brain activity and performance in abstinent smokers. METHODS: In this double-blind crossover study, 20 smokers completed 8 days of treatment with tolcapone and placebo. In both medication periods, smokers completed blood oxygen level-dependent (BOLD) fMRI scans while performing a working memory N-back task after 24h of abstinence. Smokers were genotyped prospectively for the COMT val(158)met polymorphism for exploratory analysis. RESULTS: Compared to placebo, tolcapone modestly improved accuracy (p=0.017) and enhanced suppression of activation in the ventromedial prefrontal cortex (vmPFC) (p=0.002). There were no effects of medication in other a priori regions of interest (dorsolateral PFC, dorsal cingulate/medial prefrontal cortex, or posterior cingulate cortex). Exploratory analyses suggested that tolcapone led to a decrease in BOLD signal in several regions among smokers with val/val genotypes, but increased or remained unchanged among met allele carriers. Tolcapone did not attenuate craving, mood, or withdrawal symptoms compared to placebo. CONCLUSIONS: Data from this proof-of-concept study do not provide strong support for further evaluation of COMT inhibitors as smoking cessation aids.