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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    • "On the day of testing, CO-level-assessed 12-h smoking abstinence was first determined. Participants who did not meet criteria (CO o10 ppm; Jorenby et al., 2006; Piper et al., 2009), were rescheduled. Those confirmed abstinent then provided baseline ratings for their amount of craving, intensity of craving, and control over craving. "
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    ABSTRACT: Given that the vast majority of functional magnetic resonance imaging (fMRI) studies of drug cue reactivity use unisensory visual cues, but that multisensory cues may elicit greater craving-related brain responses, the current study sought to compare the fMRI BOLD response to unisensory visual and multisensory, visual plus odor, smoking cues in 17 nicotine-dependent adult cigarette smokers. Brain activation to smoking-related, compared to neutral, pictures was assessed under cigarette smoke and odorless odor conditions. While smoking pictures elicited a pattern of activation consistent with the addiction literature, the multisensory (odor+picture) smoking cues elicited significantly greater and more widespread activation in mainly frontal and temporal regions. BOLD signal elicited by the multisensory, but not unisensory cues, was significantly related to participants' level of control over craving as well. Results demonstrated that the co-presentation of cigarette smoke odor with smoking-related visual cues, compared to the visual cues alone, elicited greater levels of craving-related brain activation in key regions implicated in reward. These preliminary findings support future research aimed at a better understanding of multisensory integration of drug cues and craving.
    10/2015; DOI:10.1016/j.pscychresns.2015.10.008
    • "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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2015; DOI:10.1038/npp.2015.305 · 7.05 Impact Factor
    • "). 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.
    Alcoholism Clinical and Experimental Research 09/2015; 39(11). DOI:10.1111/acer.12854 · 3.21 Impact Factor
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