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Efficacy and tolerability of varenicline, an α4β2 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

Department of Health Promotion and Education, Osaka Medical Center for Health Science and Promotion, Osaka, Japan.
Clinical Therapeutics (Impact Factor: 2.59). 06/2007; 29(6):1040-56. DOI: 10.1016/j.clinthera.2007.06.012
Source: PubMed

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.

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    • "These trials had a sample size ranging from 320 to 1,027. Eight of the studies were multicenter studies undertaken in the US and Europe, and two were done in Asia (Nakamura et al. 2007; Rigotti et al. 2010). The reported mean age of the participants ranging from 39 to 57 years old, and the proportion of male ranging from 44% to 82% (Table 1). "
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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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    • "The results of these experiments indicate that cholinergic receptors play multiple, dissociable roles in different forms of cost–benefit decision making. The findings concerning nicotinic receptors are of particular interest, as these receptors are a clinical target in several conditions which prominently feature alterations in cost–benefit decision making, including ADHD and addiction (Nakamura et al. 2007; Potter et al. 2006). Given the diversity of nicotinic receptor subtypes, it will be important in future studies to determine the roles of these subtypes (and the brain systems in which they act) in different aspects of cost–benefit decision making . "
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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
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    • "However, discontinuation from study treatment due to nausea was rare and occurred in 3% of the varenicline participants, compared with 1% of the bupropion SR participants and less than 1% of the placebo group. Nausea has consistently been the most frequently reported AE by participants taking varenicline, although the majority of these nausea experiences were reported as mild to moderate in intensity (Gonzales et al 2006; Jorenby et al 2006; Nides et al 2006; Oncken et al 2006; Nakamura et al 2007; Tsai et al 2007; Williams et al 2007). Furthermore, the onset and incidence of nausea peaked in the second week of treatment and reduced thereafter (Nides et al 2008). "
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    ABSTRACT: Varenicline, a partial agonist of alpha(4)beta(2) nicotinic acetylcholine receptors, is the most recently approved drug for smoking cessation. This paper reviews the outcomes of Phase 2 and Phase 3 clinical trials that assess the efficacy of varenicline in comparison to placebo and other smoking cessation pharmacotherapies, ie, sustained-release bupropion (bupropion SR) and nicotine transdermal patch. Varenicline has higher abstinence rates than placebo and the alternative active treatments at the end of standard regimen treatment periods. Significantly higher abstinence rates were also found with varenicline in comparison to both placebo and bupropion SR at the end of a 40-week non-treatment follow-up period. Varenicline typically tripled the abstinence rates compared with placebo. In addition, varenicline reduced craving and withdrawal symptoms as well as some of the positive experiences associated with smoking to a greater extent than placebo, bupropion SR, and nicotine replacement therapy (NRT). These findings are consistent with the proposed agonist/antagonist effects of varenicline. Preliminary studies assessing individual variables such as smoking dependency level and smoking reinforcement types provide justification to examine further the effects of varenicline according to these individual factors. Outcomes from such research could improve our understanding of varenicline's mechanism of action and could ultimately help clinicians to develop individualized smoking cessation programs. Also, given varenicline's ability to reduce the reward from smoking, it might be helpful to use it before cessation to motivate or prepare smokers for a quit attempt.
    Neuropsychiatric Disease and Treatment 05/2008; 4(2):353-63. · 2.15 Impact Factor
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