Efficacy and tolerability of varenicline, an alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist, in a 12-week, randomized, placebo-controlled, dose-response study with 40-week follow-up for smoking cessation in Japanese smokers
ABSTRACT Varenicline, a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist, has been developed specifically for smoking cessation. In Japan, 39.3% of men smoke and this is a major public health concern.
The primary objective of this study was to evaluate the efficacy and dose-response relationship of varenicline in Japanese smokers.
In this double-blind, placebo-controlled, randomized, parallel-group study, subjects were randomized to receive varenicline at 0.25 mg BID, 0.5 mg BID, 1 mg BID, or placebo for 12 weeks followed by a 40-week, nontreatment follow-up phase. The primary efficacy variable was the continuous abstinence rate (CAR), defined as no reported smoking (not even a puff) or other nicotine use and confirmed by end-expiratory carbon monoxide level <or=10 ppm, during the last 4 weeks of treatment (weeks 9-12). Secondary end points included CARs for weeks 9-24 and 9-52. Craving, withdrawal, and smoking satisfaction were determined by the Minnesota Nicotine Withdrawal Scale, the Brief Questionnaire on Smoking Urges, and the modified Cigarette Evaluation Questionnaire. The tolerability of varenicline was also evaluated.
Of 618 subjects who received treatment, 515 (83.3%) were classified as nicotine dependent (scoring >or=5 on the Tobacco Dependence Screener), and constituted the primary analysis group. Of these, 385 (74.8%) subjects were male, and the mean age was within the range of 39.0 to 40.2 years. Across treatment groups, subjects claimed to have smoked a mean of 23.1 to 24.9 cigarettes per day in the preceding 30 days, and the mean score on the Fagerström Test for Nicotine Dependence was within the range from 5.4 to 5.7. The CAR for weeks 9-12 was significantly higher for all doses of varenicline compared with placebo (39.5% [51/129]). The highest CAR of 65.4% (85/130) was achieved with varenicline 1 mg BID (odds ratio [OR] [95% CI] = 2.98 [1.78-4.99]; P < 0.001). The CAR for weeks 9-52 was significantly greater for varenicline 1 mg BID than placebo (34.6% [45/130] vs 23.3% [30/129]; OR [95% CI] = 1.81 [1.04-3.17]; P = 0.036). The CARs for weeks 9-24 at 0.25, 0.5, and 1 mg BID were 33.6% (43/128), 35.2% (45/128), 37.7% (49/130), and for weeks 9-52 at 0.25 and 0.5 mg BID were 27.3% (35/128) and 28.9% (37/128) but failed to reach significance versus the placebo (29.5% [38/129] for weeks 9-24 and 23.3% [30/129] for weeks 9-52). Treatment-emergent adverse events (AEs) were more prevalent among varenicline-treated subjects (79.1% [121/153] at 0.25 mg BID, 80.6% [125/155] at 0.5 mg BID, and 80.1% [125/156] at 1 mg BID) than placebo subjects (71.4% [110/154]). The 3 most prevalent AEs at varenicline 1 mg BID were nasopharyngitis (35.9% [56/156]), nausea (24.4% [38/156]), and headache (10.3% [16/156]), all of which were of mild or moderate intensity. Nausea was the only AE that appeared dose related (7.2% [11/153] at 0.25 mg BID, 9.7% [15/155] at 0.5 mg BID, and 24.4% [38/156] at 1 mg BID) versus placebo (7.8% [12/154]).
Varenicline was associated with dose-dependent improvement in smoking abstinence rates during the last 4 weeks of treatment and in the longer term over 40 weeks of nontreatment follow-up. The dose associated with the highest efficacy was varenicline 1 mg BID.
- SourceAvailable from: Mitsuhisa Koga[Show abstract] [Hide abstract]
ABSTRACT: Varenicline is one of the most widely used drugs for smoking cessation. However, whether an adverse effect of varenicline is associated with the risk of serious cardiovascular events remains controversial. In this study, we determined if varenicline increases the risk of cardiovascular events using apolipoprotein E knockout (ApoE KO) mice. ApoE KO mice (8 weeks old) were injected with varenicline 0.5 mg kg(-1) day(-1) for 3 weeks. Varenicline aggravated atherosclerotic plaque formation in whole aorta from ApoE KO mice compared with vehicle. Methyllycaconitine, an alpha 7 nicotinic acetylcholine receptor (nAChR) antagonist, inhibited varenicline-induced aggravated plaque formation. Our findings show that varenicline progresses atherosclerotic plaque formation through alpha 7 nAChR, and thereby increases the risk of cardiovascular events. (C) 2014 The Authors. Published by Elsevier Inc.Biochemical and Biophysical Research Communications 11/2014; 455(3-4). DOI:10.1016/j.bbrc.2014.10.150 · 2.28 Impact Factor
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ABSTRACT: Aim To evaluate the long-term efficacy and potential risk of psychiatric side effects of varenicline for smoking cessation compared with placebo or nicotine replacement therapy. Subject and methods Systematic search of electronic databases (MEDLINE, EMBASE, Cochrane Central Register, SCI) up to March 2011. Two reviewers independently determined the eligibility of randomized controlled trials comparing varenicline with placebo, or nicotine replacement therapy with follow-up of at least 12 months. Information was independently extracted by 2 reviewers. Results Ten trials involving 6,375 smokers were included in the meta-analysis. The pooled risk ratios (RR) for continuous abstinence was 2.83 (95% CI: 2.20–3.63) at 52 weeks for varenicline (1 mg, twice per day) versus placebo. Varenicline seemed to be more effective in smokers with chronic obstructive pulmonary disease (RR, 3.33) than smokers with cardiovascular diseases (RR, 2.64) or health smokers (RR, 2.52), non-Asian smokers than Asian smokers (2.98 vs. 1.94), elder smokers than younger smokers (2.87 vs. 2.52), female smokers than male smokers (2.98 vs. 1.94). The five predominant reported adverse events for varenicline compared to placebo were vomiting, nausea, abnormal dreams, constipation, and dysgeusia. There was no sufficient evidence that varenicline was associated with an increased risk of psychiatric side effects (RR, 1.45, 95% CI: 0.90–2.32). Conclusion Varenicline therapy compared with placebo is associated with a favorable effect on smoking cessation at the end of 52 weeks. However, the psychiatric adverse events related with varenicline should be further studied with larger qualified study. People with preexisting mental illnesses should be prudently treated with varenicline.Journal of Public Health 08/2012; 20(4). DOI:10.1007/s10389-011-0476-5 · 2.06 Impact Factor
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ABSTRACT: RATIONALE: Alterations in cost-benefit decision making accompany numerous neuropsychiatric conditions, including schizophrenia, attention deficit hyperactivity disorder, and addiction. Central cholinergic systems have been linked to the etiology and/or treatment of many of these conditions, but little is known about the role of cholinergic signaling in cost-benefit decision making. OBJECTIVES: The goal of these experiments was to determine how cholinergic signaling is involved in cost-benefit decision making, using a behavioral pharmacological approach. METHODS: Male Long-Evans rats were trained in either "probability discounting" or "delay discounting" tasks, in which rats made discrete-trial choices between a small food reward and a large food reward associated with either varying probabilities of omission or varying delays to delivery, respectively. The effects of acute administration of different doses of nicotinic and muscarinic acetylcholine receptor agonists and antagonists were assessed in each task. RESULTS: In the probability discounting task, acute nicotine administration (1.0 mg/kg) significantly increased choice of the large risky reward, and control experiments suggested that this was due to robust nicotine-induced impairments in behavioral flexibility. In the delay discounting task, the muscarinic antagonists scopolamine (0.03, 0.1, and 0.3 mg/kg) and atropine (0.3 mg/kg) both significantly increased choice of the small immediate reward. Neither mecamylamine nor oxotremorine produced reliable effects on either of the decision making tasks. CONCLUSIONS: These data suggest that cholinergic receptors play multiple roles in decision making contexts which include consideration of reward delay or probability. These roles should be considered when targeting these receptors for therapeutic purposes.Psychopharmacology 07/2012; 224(4). DOI:10.1007/s00213-012-2777-y · 3.99 Impact Factor