Varenicline, an {alpha}4beta2 Nicotinic Acetylcholine Receptor Partial Agonist, vs Sustained-Release Bupropion and Placebo for Smoking Cessation: A Randomized Controlled Trial

Department of Medicine, Oregon Health and Science University, Portland, Oregon, United States
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 08/2006; 296(1):47-55. DOI: 10.1001/jama.296.1.47
Source: PubMed


The alpha4beta2 nicotinic acetylcholine receptors (nAChRs) are linked to the reinforcing effects of nicotine and maintaining smoking behavior. Varenicline, a novel alpha4beta2 nAChR partial agonist, may be beneficial for smoking cessation.
To assess efficacy and safety of varenicline for smoking cessation compared with sustained-release bupropion (bupropion SR) and placebo.
Randomized, double-blind, parallel-group, placebo- and active-treatment-controlled, phase 3 clinical trial conducted at 19 US centers from June 19, 2003, to April 22, 2005. Participants were 1025 generally healthy smokers (> or =10 cigarettes/d) with fewer than 3 months of smoking abstinence in the past year, 18 to 75 years old, recruited via advertising.
Participants were randomly assigned in a 1:1:1 ratio to receive brief counseling and varenicline titrated to 1 mg twice per day (n = 352), bupropion SR titrated to 150 mg twice per day (n = 329), or placebo (n = 344) orally for 12 weeks, with 40 weeks of nondrug follow-up.
Primary outcome was the exhaled carbon monoxide-confirmed 4-week rate of continuous abstinence from smoking for weeks 9 through 12. A secondary outcome was the continuous abstinence rate for weeks 9 through 24 and weeks 9 through 52.
For weeks 9 through 12, the 4-week continuous abstinence rates were 44.0% for varenicline vs 17.7% for placebo (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.70-5.50; P<.001) and vs 29.5% for bupropion SR (OR, 1.93; 95% CI, 1.40-2.68; P<.001). Bupropion SR was also significantly more efficacious than placebo (OR, 2.00; 95% CI, 1.38-2.89; P<.001). For weeks 9 through 52, the continuous abstinence rates were 21.9% for varenicline vs 8.4% for placebo (OR, 3.09; 95% CI, 1.95-4.91; P<.001) and vs 16.1% for bupropion SR (OR, 1.46; 95% CI, 0.99-2.17; P = .057). Varenicline reduced craving and withdrawal and, for those who smoked while receiving study drug, smoking satisfaction. No sex differences in efficacy for varenicline were observed. Varenicline was safe and generally well tolerated, with study drug discontinuation rates similar to those for placebo. The most common adverse events for participants receiving active-drug treatment were nausea (98 participants receiving varenicline [28.1%]) and insomnia (72 receiving bupropion SR [21.9%]).
Varenicline was significantly more efficacious than placebo for smoking cessation at all time points and significantly more efficacious than bupropion SR at the end of 12 weeks of drug treatment and at 24 weeks. Identifier: NCT00141206.

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Available from: Mitchell A Nides, Apr 04, 2014
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    • "Recall that nornicotine and varenicline produce partial extinction and at least partial generalization back to the nicotine training stimulus. Given that nornicotine and varenicline differ somewhat in receptor mechanisms (Coe et al. 2005a, b; Crooks and Dwoskin 1997; Damaj et al. 1998; Dwoskin et al. 1993; Gonzales et al. 2006; Middleton et al. 2007; Mihalak et al. 2006; Papke et al. 2007; Smith et al. 2007; Xu et al. 2001), we hypothesize that at least somewhat different stimulus elements are extinguished with the varenicline versus the nornicotine stimulus. What if we start extinction with one ligand, say nornicotine, and then switched to the other ligand partway through the extinction phase? "
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    ABSTRACT: Rationale: Pharmacotherapies are often utilized to aid in smoking cessation, and switching medication when treating nicotine dependence has become more commonplace. Although common, little is known about the impact of the initial therapy on the effects of the subsequent therapy. Objectives: To begin to fill this gap in our understanding, this project determined how switching compounds that share stimulus elements with nicotine during extinction altered extinction responding and generalization of this extinction back to nicotine. Methods: Rats were trained in a discriminated goal-tracking task where nicotine administration was followed by intermittent sucrose access; sucrose was withheld following saline administration. In experiment 1, nornicotine supplanted nicotine in extinction sessions 1-3 and then a switch to varenicline on extinction sessions 4-6 was examined. In experiment 2, the reverse was investigated; varenicline to start extinction and then a switch to nornicotine. Generalization of extinction back to the nicotine stimulus was then assessed by generating a cumulative dose-effect curve. Results: Generalization of extinction back to the training nicotine stimulus was greater if nornicotine had been received at any point in extinction compared to only receiving varenicline. Whereas, extinction with varenicline alone showed more generalization to lower doses of nicotine. Conclusions: A switch in cessation pharmacotherapy during extinction did not impede or enhance generalization back to the nicotine-training stimulus. The nornicotine stimulus appears to share more stimulus overlap with the 0.4 mg/kg nicotine stimulus and varenicline may share more overlap with lower nicotine doses.
    Psychopharmacology 09/2015; DOI:10.1007/s00213-015-4067-y · 3.88 Impact Factor
    • "Participants were eligible if they were 18–75 years of age, smoked 10 or more cigarettes per day, and had <3 months of abstinence in the past year (Gonzales et al., 2006; Jorenby et al., 2006). This trial was conducted at 19 centers in the US and the IRB at each site approved this trial. "
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    ABSTRACT: Recent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. In two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. For abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X(2)=8.15, df=2, omnibus-p=0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald=3.94, df=1, p=0.047), this non-replication can alter the interpretation of pharmacogenetic findings. Results from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Drug and alcohol dependence 06/2015; 154. DOI:10.1016/j.drugalcdep.2015.06.022 · 3.42 Impact Factor
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    • "However, clinical trial participation with an intention to quit smoking reduces the risk of confounding by health status. As is commonly seen in smoking cessation trials [40], [41], our study had a nontrivial drop out rate (32.5%) so we cannot exclude bias based on continuing participation; however, participants that do not return typlically are continuing smokers rather than successful abstainers. Because we did not serially measure glucose and insulin levels, we cannot describe the time course or pathophysiology of our observations. "
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    ABSTRACT: Weight gain after smoking cessation may increase diabetes mellitus and impaired fasting glucose (IFG) risk. This study evaluated associations between smoking cessation and continued smoking with incident diabetes and IFG three years after a quit attempt. The 1504 smokers (58% female) were mean (standard deviation) 44.7 (11.1) years old and smoked 21.4 (8.9) cigarettes/day. Of 914 participants with year 3 data, the 238 abstainers had greater weight gain, increase in waist circumference, and increase in fasting glucose levels than the 676 continuing smokers (p≤0.008). In univariate analyses, Year 3 abstinence was associated with incident diabetes (OR = 2.60, 95% CI 1.44–4.67, p = .002; 4.3% absolute excess) and IFG (OR = 2.43, 95% CI 1.74–3.41, p<0.0001; 15.6% absolute excess). In multivariate analyses, incident diabetes was associated independently with older age (p = 0.0002), higher baseline body weight (p = 0.021), weight gain (p = 0.023), baseline smoking rate (p = 0.008), baseline IFG (p<0.0001), and baseline hemoglobin A1C (all p<0.0001). Smoking more at baseline predicted incident diabetes among eventual abstainers (p<0.0001); weighing more at baseline predicted incident diabetes among continuing smokers (p = 0.0004). Quitting smoking is associated with increased diabetes and IFG risk. Independent risk factors include older age, baseline body weight, baseline glycemic status, and heavier pre-quit smoking. These findings may help target smokers for interventions to prevent dysglycemia. Trial Registration NCT00332644
    PLoS ONE 06/2014; 9(6):e98278. DOI:10.1371/journal.pone.0098278 · 3.23 Impact Factor
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