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
    • "Given that positive reactions to smoking have been shown to predict relapse (Strong et al, 2011), decreases in measures of positive reinforcement may provide an explanation as to the efficacy of varenicline (Gonzales et al, 2006; Jorenby et al, 2006). In addition, varenicline also decreased the negative reinforcement of withdrawal (Gonzales et al, 2006; Jorenby et al, 2006). However, changes in brain DA and subjective appraisals of smoking occurred in the absence of any changes in plasma cotinine or the number of cigarettes smoked per day from baseline. "
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    ABSTRACT: Background: Varenicline, a nicotinic partial agonist, is the most effective treatment for tobacco use disorder. However, its mechanism of action is still unclear and may involve stimulating dopaminergic transmission. Here, we used PET imaging with [(11)C]-(+)-PHNO to explore for the first time the impact of varenicline on dopamine transmission, in the D2-rich striatum and D3-rich extra-striatal regions and its relationship with craving, withdrawal and smoking. Methods: Eleven treatment-seeking smokers underwent two PET scans with [(11)C]-(+)-PHNO, each following 12 h overnight smoking abstinence both prior to receiving varenicline and following 10-11 days of varenicline treatment (i.e. at steady state drug levels). Subjective measures of craving and urges to smoke were also assessed on the days of the PET scans. Results: Varenicline treatment significantly reduced [(11)C]-(+)-PHNO binding in the dorsal caudate (p=0.008) and reduced some craving measures. Discussion: These findings provide the first evidence that varenicline is able to increase DA levels in the human brain, a factor that may contribute to its therapeutic efficacy.Neuropsychopharmacology accepted article preview online, 07 October 2015. doi:10.1038/npp.2015.305.
    No preview · Article · Oct 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
    • "). The FDA-approved smoking cessation agent varenicline is of potential interest for the treatment of alcohol dependence (Gonzales et al., 2006; Jorenby et al., 2006). Varenicline interferes with several nAChRs and is a partial agonist at a 4 b 2 nAChRs and therefore slightly increases mesolimbic dopamine by itself, while antagonizing further dopamine release produced by nicotine (Rollema et al., 2007). "
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    ABSTRACT: Background: Alcohol dependence is a devastating illness affecting a large population, and new pharmacological treatments with good efficacy are greatly needed. One potential candidate is varenicline, a smoking cessation agent with partial agonist action at α4 β2 nicotinic acetylcholine receptors. Methods: A total of 160 subjects, 30 to 70 years of age, fulfilling DSM-IV criteria for alcohol dependence without any serious physical or mental disorders, were recruited through advertisement at 3 university clinics in Sweden during March 2009 to January 2011. After a 2-week placebo run-in period, subjects received 2 mg varenicline daily (titrated from 0.5 mg during first week) or placebo for 12 weeks in a double-blind manner. Results: The primary outcome was the proportion of heavy drinking days, measured by self-reported alcohol consumption. Primary and secondary outcomes were calculated as a mean over the 10-week steady-state active treatment period. In the primary outcome analysis, no effect of varenicline over placebo was found (p = 0.73 for the intention to treat [ITT] and 0.92 for per protocol [PP]). Secondary outcome analysis found a significant reduction of specific alcohol marker phosphatidylethanol (PEth) in the blood in the varenicline group compared to placebo (p = 0.02 ITT). Craving (p = 0.048 PP) and Alcohol Use Disorders Identification Test (AUDIT) scores (p = 0.015 ITT) were also reduced in the active treatment group. PEth more strongly correlated with self-reported alcohol consumption than carbohydrate-deficient ttransferrin and γ-glutamyl transferase, and correlation coefficients were higher in the varenicline group than in the placebo group for all markers. Conclusions: Although the results of the main outcome of this study did not support an effect of varenicline in alcohol-dependent individuals, the secondary analyses of PEth, craving and AUDIT score support an effect of varenicline on alcohol consumption. The disclosure of a treatment effect and the lack of a clear placebo effect when using PEth as outcome variable, together with a nonsymmetric bias associated with self-reported data, strongly argue for using the specific biomarker PEth in studies of treatments of alcohol dependence.
    No preview · Article · Sep 2015 · Alcoholism Clinical and Experimental Research
    • "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.
    No preview · Article · Sep 2015 · Psychopharmacology
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