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Varenicline, an α4β2 Nicotinic Acetylcholine Receptor Partial Agonist, vs Sustained-Release Bupropion and Placebo for Smoking Cessation<SUBTITLE>A Randomized Controlled Trial</SUBTITLE>
Abstract
CONTEXT: 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. OBJECTIVE: To assess efficacy and safety of varenicline for smoking cessation compared with sustained-release bupropion (bupropion SR) and placebo. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTION: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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%]). CONCLUSION: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00141206.
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In the citing paper
“Varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, is reported to increase continuous abstinence rates to ∼50% following 12 weeks of treatment, which is significantly better than bupropion (∼30%) or placebo (∼18%”
From Parallel Anxiolytic-Like Effects and Upregulation of Neuronal Nicotinic Acetylcholine Receptors Following Chronic Nicotine and Varenicline (2011) · cites this paper as Gonzales et al., 2006
In the citing paper
“Varenicline, a partial agonist at the α4β2 nAChRs, and a full agonist at the α7 nAChRs, is a new, efficacious treatment for nicotine dependence (4–6).”
From Varenicline improves mood and cognition during smoking abstinence (2009) · cites this paper as [4]
In the citing paper
“These trials document treatment-related reductions in smoking urges and withdrawal-related negative affect (4, 5, 9), as well as reduced smoking reward during a lapse (10).”
From Varenicline improves mood and cognition during smoking abstinence (2009) · cites this paper as [4]
In the citing paper
“The effects of varenicline on subjective abstinence symptoms were of a magnitude similar to those observed in clinical efficacy trials (4, 36).”
From Varenicline improves mood and cognition during smoking abstinence (2009) · cites this paper as [4]
In the citing paper
“Individuals who relapsed derived less enjoyment from smoking while taking varenicline [241].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [241]
In the citing paper
“Nearly one quarter (21–23%) of patients taking varenicline for a short period of time (12 weeks) maintained abstinence at 52 weeks of follow-up.”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [241]
In the citing paper
“Gonzales and colleagues [241] found a similar decrease in negative affect, but also found a significant decrease in restlessness in patients taking varenicline.”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [241]
In the citing paper
“This represents a significant improvement over sustained-release bupropion (14–16%) and placebo (8–10%).”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [241]
In the citing paper
“Two large, randomized, placebo-controlled studies released in 2006 related the efficacy of varenicline to that of bupropion in aided smoking cessation [233, 241].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [241]
In the citing paper
“numerous studies have shown that varenicline, a Food and Drug Administration-approved drug widely used to help people quit smoking, potently acts as a partial agonist at ␣42* nAChRs”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Gonzales et al., 2006
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Metadata
- Authors
- Gonzales, D.
- Affiliations
- Oregon Health & Science University (US)
- Corresponding author
- Gonzales, David
- ORCID
- Gonzales, David
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2006-07-05
- Volume
- 296
- Issue
- 1
- Pages
- 47
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2107200746
- Cited by
- 1,361
- References
- 29
- Citations by year
- 2026: 32 · 2025: 21 · 2024: 25 · 2023: 25 · 2022: 34 · 2021: 26 · 2020: 52 · 2019: 49 · 2018: 41 · 2017: 51 · 2016: 50 · 2015: 70 · 2014: 74 · 2013: 80 · 2012: 94
- FWCI
- 85.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Oregon Health and Science University
- Cardinal Health
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- varenicline, bupropion sustained release, smoking cessation, α4β2 nicotinic acetylcholine receptor, partial agonists, nicotine dependence, continuous abstinence, exhaled carbon monoxide, brief counseling, nicotine replacement therapy, drug safety, adverse events, relapse, nicotine withdrawal symptoms, nicotine self-administration
- MeSH terms
- Varenicline, Adult, Benzazepines, Delayed-Action Preparations, Double-Blind Method, Female, Humans, Male, Middle Aged, Quinoxalines, Receptors, Nicotinic, Smoking Cessation, Bupropion, Nicotinic Agonists, Dopamine Uptake Inhibitors
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