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1.  Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial 
Thorax  2008;63(8):717-724.
Background:
Varenicline, a new treatment for smoking cessation, has demonstrated significantly greater efficacy over placebo and sustained release bupropion (bupropion SR). A study was undertaken to compare a 12-week standard regimen of varenicline with a 10-week standard regimen of transdermal nicotine replacement therapy (NRT) for smoking cessation.
Methods:
In this 52-week, open-label, randomised, multicentre, phase 3 trial conducted in Belgium, France, the Netherlands, UK and USA, participants were randomly assigned (1:1) to receive varenicline uptitrated to 1 mg twice daily for 12 weeks or transdermal NRT (21 mg/day reducing to 7 mg/day) for 10 weeks. Non-treatment follow-up continued to week 52. The primary outcome was the biochemically confirmed (exhaled carbon monoxide ⩽10 ppm) self-reported continuous abstinence rate (CAR) for the last 4 weeks of the treatment period in participants who had taken at least one dose of treatment. Secondary outcomes included CAR from the last 4 weeks of treatment through weeks 24 and 52, and measures of craving, withdrawal and smoking satisfaction.
Results:
A total of 376 and 370 participants assigned to varenicline and NRT, respectively, were eligible for analysis. The CAR for the last 4 weeks of treatment was significantly greater for varenicline (55.9%) than NRT (43.2%; OR 1.70, 95% CI 1.26 to 2.28, p<0.001). The week 52 CAR (NRT, weeks 8–52; varenicline, weeks 9–52) was 26.1% for varenicline and 20.3% for NRT (OR 1.40, 95% CI 0.99 to 1.99, p = 0.056). Varenicline significantly reduced craving (p<0.001), withdrawal symptoms (p<0.001) and smoking satisfaction (p<0.001) compared with NRT. The most frequent adverse event was nausea (varenicline, 37.2%; NRT, 9.7%).
Conclusions:
The outcomes of this trial established that abstinence from smoking was greater and craving, withdrawal symptoms and smoking satisfaction were less at the end of treatment with varenicline than with transdermal NRT.
Trial registration number:
NCT00143325.
doi:10.1136/thx.2007.090647
PMCID: PMC2569194  PMID: 18263663
2.  Varenicline, Smoking Cessation and Neuropsychiatric Adverse Events 
The American journal of psychiatry  2013;170(12):1460-1467.
Objective
In 2009 FDA issued a black box warning for varenicline and neuropsychiatric events. We studied efficacy (smoking cessation) of varenicline, and safety (neuropsychiatric events) in both randomized clinical trials (RCTs) and a large observational study. The observational study was included to determine the generalizability of the RCT findings to the general population.
Method
RCTs: Re-analysis of all 17 placebo controlled RCTs (n=8027) of varenicline conducted by Pfizer using complete intent-to-treat person-level longitudinal data.
Observational Study
Analysis of Department of Defense collected adverse neuropsychiatric adverse event data in inpatients and outpatients taking varenicline versus nicotine replacement therapy (NRT) (n=35,800). The primary endpoints for the RCTs were smoking abstinence and adverse event reports of suicidal thoughts and behavior, depression, aggression/agitation, and nausea. The effect of varenicline in patients with (n=1004) and without (n=7023) psychiatric disorders was examined. The primary endpoints for the observational study were anxiety, depression, drug induced mental disorder, episodic and mood disorder, other psychiatric disorder, post traumatic stress disorder, schizophrenia, suicide attempt, transient mental disorder.
Results
RCTs: Varenicline did not increase rates of suicidal events, depression, or aggression/agitation. Varenicline increased risk of nausea (OR=3.69, 95% CI = (3.03, 4.48), p<0.0001). Varenicline increased rate of abstinence by 124% compared to placebo (p<0.0001), and 22% compared to bupropion (p<0.0001). While having a current psychiatric disorder or history of psychiatric illness increased the risk of neuropsychiatric events, it did so equally in treated and control patients.
Observational Study
Following propensity score matching, overall rate of neuropsychiatric disorders was lower for varenicline versus NRT (2.28% versus 3.16%, p<0.0001).
Conclusions
In the RCTs, varenicline revealed no increased risk of neuropsychiatric adverse events relative to placebo. Varenicline provided greater benefit in terms of smoking cessation relative to both placebo and bupropion. The same results were observed in patients with and without a current psychiatric disorder or history of psychiatric illness. In the observational study, the overall rate of neuropsychiatric disorders was lower in patients treated with varenicline relative to NRT, revealing that the finding of no increased risk of neuropsychiatric adverse events in RCTs generalizes to the population of patients engaging in treatment with varenicline.
doi:10.1176/appi.ajp.2013.12121599
PMCID: PMC4238282  PMID: 24030388
3.  Stopping smokeless tobacco with varenicline: randomised double blind placebo controlled trial  
Objective To assess the efficacy and safety of varenicline (a licensed cigarette smoking cessation aid) in helping users of smokeless tobacco to quit.
Design Double blind, placebo controlled, parallel group, multicentre, randomised controlled trial.
Setting Medical clinics (mostly primary care) in Norway and Sweden.
Participants Men and women aged ≥18 who used smokeless tobacco at least eight times a day, with no abstinence period over three months within one year before screening, who wanted to quit all tobacco use. Participants were excluded if they used any other form of tobacco (except smokeless tobacco) or medication to stop smoking within three months of screening or had any pre-existing medical or psychiatric condition.
Interventions Varenicline 1 mg twice daily (titrated during the first week) or placebo for 12 weeks, with 14 weeks’ follow-up after treatment.
Main outcome measures The primary end point was the four week continuous abstinence rate at the end of treatment (weeks 9-12) confirmed with cotinine concentration. A secondary end point was continuous abstinence rate for weeks 9-26. Safety and tolerability were also evaluated.
Results 431 participants (213 varenicline; 218 placebo) were randomised and received at least one dose of study drug. Participants’ demographics and baseline use of smokeless tobacco were similar (89% (189) and 90% (196), respectively, were men; mean age in both groups was 43.9; participants used smokeless tobacco products about 15 times a day, and about 80% first used smokeless tobacco within 30 minutes after awakening). Continuous abstinence rate at week 9-12 was higher in the varenicline group than the placebo group (59% (125) v 39% (85); relative risk 1.60, 95% confidence interval 1.32 to 1.87, P<0.001; risk difference 20%; number needed to treat 5). The advantage of varenicline over placebo persisted through 14 weeks of follow-up (continuous abstinence rate at week 9-26 was 45% (95) v 34% (73); relative risk 1.42, 1.08 to 1.79, P=0.012; risk difference 11%; number needed to treat 9). The most common adverse events in the varenicline group compared with the placebo group were nausea (35% (74) v 6% (14)), fatigue (10% (22) v 7% (15)), headache (10% (22) v 9% (20)), and sleep disorder (10% (22) v 7% (15)). Few adverse events led to discontinuation of treatment (9% (19) and 4% (9), respectively), and serious adverse events occurred in two (1%) and three (1%) participants, respectively.
Conclusion Varenicline can help people to give up smokeless tobacco and has an acceptable safety profile. The response rate in the placebo group in this study was high, suggesting a population less resistant to treatment than smokers.
Trial Registration NCT00717093.
doi:10.1136/bmj.c6549
PMCID: PMC2997603  PMID: 21134997
4.  Safety and Tolerability of Varenicline Tartrate (Champix®/Chantix®) for Smoking Cessation in HIV-Infected Subjects: A Pilot Open-Label Study 
AIDS Patient Care and STDs  2012;26(1):12-19.
Abstract
The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix®, Pfizer, Saint-Laurent, QC, Canada or Chantix®, Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 (p=0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9–12 was 42% (95% confidence interval [CI]: 26–58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline.
doi:10.1089/apc.2011.0199
PMCID: PMC3242617  PMID: 22007690
5.  Varenicline as a smoking cessation aid in a Greek population: a subanalysis of an observational study 
Tobacco Induced Diseases  2012;10(1):1.
Background
Greece has the highest proportion of smokers in the European Union with 42% of Greeks admitting that they smoke, based on a 2009 survey. This post-hoc analysis of a prospective, observational study evaluated the effectiveness and safety profile of the smoking cessation aid varenicline, as well as potential predictors of quit success in a Greek population.
Methods
Participants were prescribed varenicline according to the recommendations of the European Summary of Product Characteristics (1 mg twice daily). The 7-day point prevalence of abstinence at Week 12 was determined based on verbal reporting using a nicotine use inventory. Abstinence was confirmed by carbon monoxide measurements of exhaled air at the last visit of the study. The safety profile of varenicline was also assessed.
Results
At baseline, the Greek subsample (n = 196) had a mean age of 42.6 years, with 54.6% of them being men. Participants had a smoking history of 23.5 years and a Fagerström Test for Nicotine Dependence total score of 6.6. After 12 weeks of varenicline therapy, 70.4% (95% CI, 64.0-76.7) of all participants had quit smoking. This increased to 86.2% among participants who had taken the study medication for 80% of the planned number of treatment days. Age was a significant predictor of quit success. The most frequently observed treatment-emergent adverse event was nausea, occurring in 13.3% of participants.
Conclusions
In this 'real-world' observational study, 70.4% of Greek smokers successfully quit smoking after 12 weeks of varenicline therapy, providing support that varenicline is an effective smoking cessation medication. Further studies with longer follow-up are warranted.
Trial Registration
ClinicalTrials.gov: NCT00669240
doi:10.1186/1617-9625-10-1
PMCID: PMC3395840  PMID: 22300423
smoking cessation; Greece; varenicline; real world; observational
6.  Does smoking cessation with varenicline worsen vascular endothelial function? 
BMJ Open  2013;3(6):e003052.
Objectives
A meta-analysis suggested that the use of varenicline, which is a partial agonist of nicotinic acetylcholine receptors and is effective in smoking cessation, increases the risk of cardiovascular events within 52 weeks of starting treatment. Defining these events as occurring during drug treatment (usually for 12 weeks) or within 30 days of discontinuation, another meta-analysis showed that the risk was statistically insignificant. In the present study, we aimed to clarify the effect of varenicline-assisted smoking cessation on vascular endothelial function assessed by flow-mediated vasodilation (FMD).
Design
Before–after and time-series.
Setting
Tochigi Prefecture, Japan.
Participants
Data of 85 participants who visited nicotine-dependent outpatient services were reviewed. FMD was repeatedly measured in 33 of the 85 participants. Inclusion criteria: 20 years and older, Brinkman index ≥200, Tobacco Dependence Screener ≥5 and stated motivation to quit smoking.
Interventions
Each participant was treated with varenicline titrated up to 1.0 mg twice daily (for 12 weeks in total).
Primary and secondary outcome measures
Participants were evaluated by FMD prior to, and 3 months after, complete smoking cessation. Follow-up FMD measurements were carried out every 3 months if possible. Changes in FMD during varenicline use were also evaluated.
Results
FMD was significantly increased from 4.0±1.8% to 5.5±2.2% (p<0.01, n=22) 3 months after complete cessation. Although the timecourse of FMD in most of the cases showed an increase with fluctuations, there was an exceptional case where FMD decreased over the 9 months following complete cessation. Although statistically insignificant, FMD also increased during varenicline use (from 3.7±2.7% to 4.3±2.8%, n=11).
Conclusions
Our observations suggest that in ceasing smokers, varenicline and smoking cessation do not lead to a worsening of the vascular endothelial function.
Trial registration
FK-79 (International University of Health and Welfare).
doi:10.1136/bmjopen-2013-003052
PMCID: PMC3693419  PMID: 23794597
varenicline; smoking cessation; endothelial function; FMD
7.  Adherence to Varenicline and Abstinence Rates for Quitting Smoking in a Private Health Promotion Center-Based Smoking Cessation Clinic 
Background
Varenicline is an effective smoking cessation aid. However, smokers prescribed with varenicline do not always receive varenicline for 12 weeks, as recommended. This study analyzed the subjects who received varenicline and investigated the effect of varenicline treatment duration on the success rate of 6-month smoking cessation.
Methods
This study retrospectively analyzed 78 subjects, who received varenicline, out of the 105 smokers that had visited the smoking cessation clinic after medical examination from September 2007 to December 2009.
Results
The subjects were all males. Twenty-two subjects (28.2%) had varenicline treatment for 12 weeks or longer; 18 subjects (23.1%) for 8~12 weeks; 22 subjects (28.2%) for 4~8 weeks; and 16 subjects (20.5%) for less than 4 weeks. The total success rate of the 6-month smoking cessation was 47.4%. The success rate of the 6-month smoking cessation was 63.6% in the group that received varenicline for 12 weeks or longer, which was higher than 41.1% of the group that early terminated the varenicline treatment (p=0.074). The period of varenicline treatment was extended for one more week, the odds ratio of the 6-month smoking cessation success increased to 1.172-folds (p=0.004; 95% confidence interval, 1.052~1.305). Adverse events occurred in 30.8% of the subjects who received varenicline, but no serious adverse events were found.
Conclusion
If varenicline treatment period is extended, the odds ratio of the success rate for the 6-month smoking cessation increases. Therefore, an effort to improve drug compliance for varenicline in clinical practices could be helpful for the long-term success of smoking cessation.
doi:10.4046/trd.2012.72.5.426
PMCID: PMC3475468  PMID: 23101007
Smoking Cessation; Varenicline; Medication Adherence
8.  Combining varenicline and nicotine patches: a randomized controlled trial study in smoking cessation 
BMC Medicine  2014;12(1):172.
Background
Some smokers may benefit from a therapy that combines different nicotine replacement therapies (NRT) or drugs with different mechanisms of action.
The aim of this study was to determine the efficacy of the combined therapy of varenicline and nicotine patches versus varenicline monotherapy.
Methods
Three hundred forty-one smokers who smoked 20 or more cigarettes per day were recruited from a smoking cessation clinic between February 2012 and June 2013. The participants were randomized to receive a varenicline plus nicotine patch of 21 mg every 24 hours (170) or varenicline plus a placebo patch (171). All of the smokers received a standard 12-week course of varenicline and an 11-week course of either the placebo patch or the active patch after the target quit day. Both groups received behavioral support. The primary outcome was continuous abstinence for weeks 2 through 12 confirmed by exhaled levels of carbon monoxide. Post hoc subgroup analyses were performed to evaluate the treatment effects for a specific endpoint in subgroups of smokers.
Results
The combination of the nicotine patch with varenicline was not associated with higher rates of continuous abstinence at 12 weeks (39.1% versus 31.8%; odds ratio (OR) 1.24; 95% confidence interval (CI) 0.8 to 2.6) and 24 weeks (32.8% versus 28.2%; OR 1.17; 95% CI 0.4 to 1.9). When participants were analyzed by subgroups according to cigarette consumption, the abstinence rates among smokers who smoked more than 29 cigarettes per day at 12 weeks (OR 1.39; 95% CI 1.2 to 2.5) and 24 weeks (OR 1.46; 95% CI 1.2 to 2.8) were significantly higher in the combination group. Other post hoc analyses based on level of dependence and previous quit attempts did not show subgroup differences. No differences between the groups for the reported adverse events were observed (χ2 value 0.07; P 0.79).
Conclusions
The combination of varenicline with the nicotine patch does not improve abstinence rates at 12 and 24 weeks compared with varenicline used as monotherapy when all smokers were analyzed as a whole, independent of consumption level.
Trial registration
This study is registered at clinicaltrial.gov (NCT01538394).
doi:10.1186/s12916-014-0172-8
PMCID: PMC4198796  PMID: 25296623
Smoking cessation; Varenicline; Nicotine patches; Combination therapy; Randomized trial
9.  Maintenance Treatment With Varenicline for Smoking Cessation in Patients With Schizophrenia and Bipolar Disorder 
Importance
It is estimated that more than half of those with serious mental illness smoke tobacco regularly. Standard courses of pharmacotherapeutic cessation aids improve short-term abstinence, but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy.
Objective
To determine whether smokers diagnosed with schizophrenia and bipolar disease have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with standard treatment.
Design, Setting, and Participants
Randomized, double-blind, placebo-controlled, parallel-group, relapse-prevention clinical trial conducted in 10 community mental-health centers. Of 247 smokers with schizophrenia or bipolar disease recruited from March 2008-April 2012, 203 received 12-weeks' open-label varenicline and cognitive behavioral therapy and 87 met abstinence criteria to enter the relapse prevention intervention.
Interventions
Participants who had 2 weeks or more of continuous abstinence at week 12 of open treatment were randomly assigned to receive cognitive behavioral therapy and double-blind varenicline (1 mg, 2 per day) or placebo from weeks 12 to 52. Participants then discontinued study treatment and were followed up to week 76.
Main Outcomes and Measures
Seven-day rate of continuous abstinence at study week 52, the end of the relapse-prevention phase, confirmed by exhaled carbon monoxide. Secondary outcomes were continuous abstinence rates for weeks 12 through 64 based on biochemically verified abstinence and weeks 12 through 76, based on self-reported smoking behavior.
Results
Sixty-one participants completed the relapse-prevention phase; 26 discontinued participation (7 varenicline, 19 placebo) and were considered to have relapsed for the analyses; 18 of these had relapsed prior to dropout. At week 52, point-prevalence abstinence rates were 60% in the varenicline group (24 of 40) vs 19% (9 of 47) in the placebo group (odds ratio [OR], 6.2; 95% CI, 2.2-19.2; P < .001). From weeks 12 through 64,45% (18 of 40) among those in the varenicline group vs 15% (7 of 47) in the placebo group were continuously abstinent (OR, 4.6; 95% CI, 1.5-15.7; P = .004), and from weeks 12 through 76,30% (12 of 40) in the varenicline group vs 11% (5 of 47) in the placebo group were continuously abstinent (OR, 3.4; 95% CI, 1.02-13.6; P = .03). There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events.
Conclusions and Relevance
Among smokers with serious mental illness who attained initial abstinence with standard treatment, maintenance pharmacotherapy with varenicline and cognitive behavioral therapy improved prolonged tobacco abstinence rates compared with cognitive behavioral therapy alone after 1 year of treatment and at 6 months after treatment discontinuation.
doi:10.1001/jama.2013.285113
PMCID: PMC4124884  PMID: 24399553
10.  Varenicline for Smoking Cessation in Schizophrenia: Safety and Effectiveness in a 12-Week, Open-Label Trial 
Journal of dual diagnosis  2012;8(2):117-125.
Objectives
Varenicline was approved by the FDA in 2006. In 2009, based largely on case reports, the FDA issued a warning of possible adverse neuropsychiatric effects including depression and suicidal thoughts and behavior for varenicline and bupropion. Prospective trials of varenicline have not reported increased incidence of psychiatric adverse events other than sleep disturbance, but smokers with major mental illness have been excluded from large prospective trials of varenicline to date. We sought to evaluate the effect of a standard open-label 12-week varenicline trial on prospectively assessed safety and smoking outcomes in stable, treated adults with schizophrenia spectrum disorder and nicotine dependence.
Methods
One-hundred-and-twelve stable outpatients who smoked >10 cigarettes/day participated in a 12-week, open-label, smoking cessation trial of varenicline and weekly group cognitive behavioral therapy. Participants took varenicline for 4 weeks before attempting cessation. Trained raters collected safety and smoking outcome data weekly.
Results
Participants demonstrated improved psychotic symptoms, depressive symptoms and nicotine withdrawal symptoms from baseline to week 12 or early termination. At the end of 12 weeks open label treatment, the 14- and 28-day continuous abstinence rates were 47.3 and 34%, respectively. Expired CO declined significantly during treatment in those who did not achieve abstinence.
Conclusions
This prospective study suggests that varenicline may be well-tolerated and effective for smoking cessation in combination with group CBT in stable outpatients with schizophrenia, a group with high rates of smoking and smoking-attributable morbidity and mortality.
doi:10.1080/15504263.2012.663675
PMCID: PMC3414422  PMID: 22888309
Schizophrenia; smoking cessation; varenicline; CBT; open label; adverse events
11.  Varenicline attenuates some of the subjective and physiological effects of intravenous nicotine in humans 
Psychopharmacology  2009;207(1):153-162.
Rationale
Varenicline, a partial nicotinic acetylcholine receptor (nAChR) agonist, is approved for smoking cessation. A few preclinical studies examined the pharmacological effects of varenicline, alone or in combination with nicotine. How varenicline affects the pharmacological effects of pure nicotine has not been examined in humans. The goal of this study was to characterize varenicline’s actions on nicotine’s dose-dependent effects in abstinent smokers.
Methods
Six male and 6 female smokers participated in a double-blind, placebo-controlled, crossover study. Smokers had two, 4-day treatment periods, assigned in random sequence, to varenicline (1 mg/day) or placebo treatment. On day 4 of each treatment phase, smokers had an experimental session, where they received 3 escalating doses of intravenous (IV) nicotine (0.1, 0.4, and 0.7 mg/70 kg), in 30 minute intervals. Varenicline’s effects were assessed through subjective, physiological and cognitive performance outcomes to nicotine administered via IV route.
Results
In response to IV nicotine, varenicline treatment attenuated the rating of drug strength, high, head rush, and stimulated. Varenicline also attenuated nicotine-induced increases in heart rate. Varenicline had mixed effects on cognitive performance. Smokers under varenicline treatment, compared with placebo, reported enhanced positive mood measured with the Positive and Negative Affect Schedule (PANAS).
Conclusions
These findings provide new insights into the mechanisms of action of varenicline in smoking cessation.
doi:10.1007/s00213-009-1643-z
PMCID: PMC2796376  PMID: 19693492
varenicline; nicotine dependence; intravenous nicotine; nicotine abstinence
12.  Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Cardiovascular Disease 
Circulation  2010;121(2):221-229.
Background
Smoking cessation is a key component of secondary cardiovascular disease prevention. Varenicline, a partial α4β2 nicotinic acetylcholine receptor agonist, is effective for smoking cessation in healthy smokers, but its efficacy and safety in smokers with cardiovascular disease are unknown.
Methods and Results
A multicenter, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of varenicline with placebo for smoking cessation in 714 smokers with stable cardiovascular disease. Participants received varenicline (1 mg twice daily) or placebo, along with smoking-cessation counseling, for 12 weeks. Follow-up lasted 52 weeks. The primary end point was carbon monoxide–confirmed continuous abstinence rate for weeks 9 through 12 (last 4 weeks of treatment). The continuous abstinence rate was higher for varenicline than placebo during weeks 9 through 12 (47.0% versus 13.9%; odds ratio, 6.11; 95% confidence interval [CI], 4.18 to 8.93) and weeks 9 through 52 (19.2% versus 7.2%; odds ratio, 3.14; 95% CI, 1.93 to 5.11). The varenicline and placebo groups did not differ significantly in cardiovascular mortality (0.3% versus 0.6%; difference, −0.3%; 95% CI, −1.3 to 0.7), all-cause mortality (0.6% versus 1.4%; difference, −0.8%; 95% CI, −2.3 to 0.6), cardiovascular events (7.1% versus 5.7%; difference, 1.4%; 95% CI, −2.3 to 5.0), or serious adverse events (6.5% and 6.0%; difference, 0.5%; 95% CI, −3.1 to 4.1). As a result of adverse events, 9.6% of varenicline and 4.3% of placebo participants discontinued study drug.
Conclusions
Varenicline is effective for smoking cessation in smokers with cardiovascular disease. It was well tolerated and did not increase cardiovascular events or mortality; however, trial size and duration limit definitive conclusions about safety.
Clinical Trial Registration Information
URL: http://www.clinicaltrials.gov/ct2/show/NCT00282984. Unique identifier: NCT00282984
doi:10.1161/CIRCULATIONAHA.109.869008
PMCID: PMC4096941  PMID: 20048210
cardiovascular diseases; cerebrovascular disorders; peripheral vascular diseases; smoking; trials
13.  Safety of Varenicline Among Smokers Enrolled in the Lung HIV Study 
Nicotine & Tobacco Research  2012;15(1):247-254.
Introduction:
The prevalence of smoking is high among the human immunodeficiency virus (HIV)-infected population, yet there are few studies of tobacco dependence treatment in this population. This paper reports the safety of varenicline versus nicotine replacement therapy (NRT) and describes preliminary results about the effectiveness of varenicline versus NRT in HIV-infected smokers.
Methods:
Participants completed 12 weeks of telephone counseling and either varenicline or NRT. Varenicline was encouraged as the preferred intervention; NRT was used for those unable/unwilling to take varenicline. Adverse events (AEs), related to pharmacotherapy, were monitored. Biochemically confirmed abstinence at 3 months was examined. Inverse probability of treatment weighted logistic regression models was fit to compare participants on varenicline to those on NRT.
Results:
Among participants on varenicline (n = 118), the most common AEs were nausea, sleep problems, and mood disturbances. One person reported suicidal ideation; there were no cardiovascular complications. There were no differences in the varenicline AE profile between participants on combination antiretroviral therapy (ART) and those not on ART. The percentages of confirmed abstainers were 11.8% in the NRT group and 25.6% in the varenicline group. The odds of being abstinent were 2.54 times as great in the varenicline group compared with the NRT group in the propensity weighted model (95% CI 1.43–4.49).
Conclusions:
In this preliminary study, the safety profile of varenicline among HIV-infected smokers resembles findings among smokers without HIV. In addition, varenicline may be more effective at promoting abstinence in this population. Future randomized clinical trials are warranted.
doi:10.1093/ntr/nts121
PMCID: PMC3524069  PMID: 22589421
14.  Varenicline for smoking cessation: A review of the literature 
Background: Smoking is the leading preventable risk to human health. Various agents have been used to promote smoking cessation, but none has had long-term efficacy. Varenicline, a new nicotinic ligand based on the structure of cytosine, was approved by the US Food amd Drug Administration for use as a smoking cessation aid.
Objectives: The aims of this review were to provide an overview on the mechanism of action and preclinical and clinical data of the new drug, varenicline, and to discuss the current and future impact of varenicline as a treatment for smoking cessation.
Methods: MEDLINE, BIOSIS, and Google scholar databases were searched (March 1, 2007–July 1, 2008) using the terms varenicline, smoking cessation, and nicotinic receptors. Full-text articles in English were selected for reference, and articles presenting the mechanism of action, pharmacokinetics, and data from preclinical and clinical trials were included.
Results: The initial literature search yielded 70 papers. A total of 20 articles fulfilled the inclusion criteria. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, inhibits dopaminergic activation produced by smoking and decreases the craving and withdrawal syndrome that accompanies cessation attempts. In Phase III clinical trials, the carbon monoxide-confirmed 4-week continuous abstinence rates were significantly higher with varenicline than with buproprion sustained release or placebo for weeks 9 through 12. Varenicline has been found to be well tolerated, with nausea being the most commonly reported (28.1%) adverse event.
Conclusions: Varenicline is the first drug for smoking cessation that has been found to have significant effectiveness in long-term relapse prevention (up to 52 weeks). Varenicline, with its unique profile of agonist and antagonist properties, increased cessation rates (both short- and long-term) compared with both placebo and bupropion sustained release.
doi:10.1016/j.curtheres.2009.02.004
PMCID: PMC3969980  PMID: 24692831
varenicline; smoking cessation; nicotinic receptors; review
15.  A Double-Blind, Placebo-Controlled Trial Assessing the Efficacy of Varenicline Tartrate for Alcohol Dependence 
Journal of addiction medicine  2013;7(4):277-286.
Objectives
To assess the efficacy and safety of varenicline (Chantix®) for the treatment of alcohol use disorders. Varenicline is a partial α4β2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation. It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers. This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol use disorders.
Methods
Men and women (n=200) meeting the criteria for alcohol dependence were recruited across 5 clinical sites. Patients received double-blind varenicline or placebo and a computerized behavioral intervention. Varenicline was titrated during the first week to 2 mg/day, which was maintained during weeks 2–13.
Results
The varenicline group had significantly lower weekly percent heavy drinking days (primary outcome) (adjusted mean difference=10.4), drinks per day, drinks per drinking day, and alcohol craving compared with the placebo group (p values < 0.05). The average treatment effect on alcohol use was similar for smokers and nonsmokers. Varenicline was well-tolerated; adverse events were expected and mild.
Conclusions
Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol use disorders.
doi:10.1097/ADM.0b013e31829623f4
PMCID: PMC3914416  PMID: 23728065
Alcohol Dependence; varenicline; Chantix®; Champix®; Alcohol Use Disorder; randomized placebo-controlled clinical trial
16.  A Randomized Placebo-Controlled Trial of Varenicline for Smoking Cessation Allowing Flexible Quit Dates 
Nicotine & Tobacco Research  2011;14(3):343-350.
Introduction:
Current smoking cessation guidelines recommend setting a quit date prior to starting pharmacotherapy. However, providing flexibility in the date of quitting may be more acceptable to some smokers. The objective of this study was to compare varenicline 1 mg twice daily (b.i.d.) with placebo in subjects using a flexible quit date paradigm after starting medication.
Methods:
In this double-blind, randomized, placebo-controlled international study, smokers of ≥10 cigarettes/day, aged 18–75 years, and who were motivated to quit were randomized (3:1) to receive varenicline 1 mg b.i.d. or placebo for 12 weeks. Subjects were followed up through Week 24. Subjects were instructed to quit between Days 8 and 35 after starting medication. The primary endpoint was carbon monoxide–confirmed continuous abstinence during Weeks 9–12, and a key secondary endpoint was continuous abstinence during Weeks 9–24.
Results:
Overall, 493 subjects were randomized to varenicline and 166 to placebo. Continuous abstinence was higher for varenicline than for placebo subjects at the end of treatment (Weeks 9–12: 53.1% vs. 19.3%; odds ratio [OR] 5.9; 95% CI, 3.7–9.4; p < .0001) and through 24 weeks follow-up (Weeks 9–24: 34.7% vs. 12.7%; OR 4.4; 95% CI, 2.6–7.5; p < .0001). Serious adverse events occurred in 1.2% varenicline (none were psychiatric) and 0.6% placebo subjects. Fewer varenicline than placebo subjects reported depression-related adverse events (2.3% vs. 6.7%, respectively).
Conclusions:
Varenicline 1 mg b.i.d. using a flexible quit date paradigm had similar efficacy and safety compared with previous fixed quit date studies.
doi:10.1093/ntr/ntr220
PMCID: PMC3281242  PMID: 22080588
17.  Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis 
Background:
There have been postmarketing reports of adverse cardiovascular events associated with the use of varenicline, a widely used smoking cessation drug. We conducted a systematic review and meta-analysis of randomized controlled trials to ascertain the serious adverse cardiovascular effects of varenicline compared with placebo among tobacco users.
Methods:
We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, websites of regulatory authorities and registries of clinical trials, with no date or language restrictions, through September 2010 (updated March 2011) for published and unpublished studies. We selected double-blind randomized controlled trials of at least one week’s duration involving smokers or people who used smokeless tobacco that reported on cardiovascular events (ischemia, arrhythmia, congestive heart failure, sudden death or cardiovascular-related death) as serious adverse events asociated with the use of varenicline.
Results:
We analyzed data from 14 double-blind randomized controlled trials involving 8216 participants. The trials ranged in duration from 7 to 52 weeks. Varenicline was associated with a significantly increased risk of serious adverse cardiovascular events compared with placebo (1.06% [52/4908] in varenicline group v. 0.82% [27/3308] in placebo group; Peto odds ratio [OR] 1.72, 95% confidence interval [CI] 1.09–2.71; I2 = 0%). The results of various sensitivity analyses were consistent with those of the main analysis, and a funnel plot showed no publication bias. There were too few deaths to allow meaningful comparisons of mortality.
Interpretation:
Our meta-analysis raises safety concerns about the potential for an increased risk of serious adverse cardiovascular events associated with the use of varenicline among tobacco users.
doi:10.1503/cmaj.110218
PMCID: PMC3168618  PMID: 21727225
18.  Low incidence of adverse events following varenicline initiation among opioid dependent smokers with comorbid psychiatric illness 
Drug and alcohol dependence  2013;132(0):47-52.
Background
Most drug treatment patients smoke cigarettes, yet few data exist on the prevalence and outcomes of varenicline treatment among smokers with comorbid substance use and psychiatric disorders.
Methods
We reviewed all patient charts of opioid-dependent smokers prescribed varenicline between May 2006 and December 2009 in two urban methadone clinics that also provide on-site medical and psychiatric care. We assessed prevalence, adverse events, and effectiveness of varenicline treatment in this cohort.
Results
We identified 575 smokers among 690 patients (83.3%), and assessed 82 courses of varenicline treatment prescribed to 70 smokers. Both cardiovascular risk factors and psychiatric illness were highly prevalent among those prescribed varenicline: hypertension, 51%; hyperlipidemia, 23%; diabetes, 20%; depression, 53%; anxiety, 30%; psychotic disorders, 10%; bipolar disorder, 8.6%. Of 82 varenicline courses, nine (11%) were discontinued due to adverse events and two due to depressive symptoms. One patient initiated new psychiatric medications within six months of initiating varenicline, but did not discontinue varenicline. There were no reports of suicidal ideation, agitation prompting clinical intervention, or psychiatric hospitalization. There were no incident cardiac or vascular events within six months of varenicline prescription. Some (8.6%) varenicline-treated smokers quit smoking, and cessation was significantly associated with varenicline treatment duration.
Conclusions
Despite substantial comorbidity, opioid-dependent smokers receiving integrated substance abuse, medical and psychiatric care had few documented adverse events with varenicline treatment. Methadone patients will likely experience little harm and a great deal of benefit from treatment with varenicline for smoking cessation.
doi:10.1016/j.drugalcdep.2012.12.026
PMCID: PMC3762456  PMID: 23332438
Opioid dependence; Smoking cessation; Varenicline; Adverse events
19.  Efficacy of Varenicline to Prompt Quit Attempts in Smokers Not Currently Trying to Quit: A Randomized Placebo-Controlled Trial 
Nicotine & Tobacco Research  2011;13(10):955-964.
Introduction:
Nicotine replacement therapy to aid smoking reduction increases the probability of a future quit attempt among smokers not currently planning to quit smoking. We tested whether varenicline, a partial nicotine agonist, would also increase future quit attempts.
Methods:
This randomized, placebo-controlled trial recruited 218 smokers who were interested in quitting but had no plans to quit in the next month. Participants used varenicline (2 mg/day) or placebo for 2–8 weeks plus received brief counseling on methods to reduce cigarettes/day. The primary measure was the incidence of a quit attempt within 6 months of study entry. Secondary measures were point prevalence abstinence, motivation to stop smoking, and reduction in cigarettes/day.
Results:
Varenicline increased the incidence of a quit attempt more than placebo at the Nebraska site (73% vs. 41%; p < .001) but not at the Vermont site (45% vs. 51%; p = .45). Varenicline increased most other measures of quit attempts, motivation and abstinence, independent of site. The beneficial effects of varenicline in quit attempts appeared to be mediated by greater reductions in cigarettes/day, dependence, craving, and cigarette satisfaction. Varenicline had a greater effect on quit attempts in less-dependent smokers, in minority smokers, and in those who had less prior cessation or reduction activity. Adverse events were minimal.
Conclusions:
Varenicline increased quit attempts in smokers who are not currently trying to quit at one of the two study sites and improved most all secondary outcomes independent of site. This appeared to be due to decreasing cigarettes/day and level of dependence.
doi:10.1093/ntr/ntr103
PMCID: PMC3218639  PMID: 21652735
20.  Varenicline potentiates alcohol-induced negative subjective responses and offsets impaired eye movements 
Background
Varenicline is a partial nicotinic receptor agonist that is an effective smoking cessation medication. Preliminary evidence indicates that it may also reduce alcohol consumption but the underlying mechanism is not clear. For example, varenicline may reduce alcohol consumption by attenuating its subjectively rewarding properties or by enhancing its aversive effects. In this study, we examined the effects of an acute dose of varenicline upon subjective, physiological and objective responses to low and moderate doses of alcohol in healthy social drinkers.
Methods
Healthy men and women (N=15) participated in six randomized sessions; three sessions each with 2mg varenicline and placebo followed 3 hours later by a beverage containing placebo, low dose alcohol (0.4g/kg), or high dose alcohol (0.8g/kg). Subjective mood and drug effects (i.e., stimulation, drug liking), physiological measures (heart rate, blood pressure), and eye tracking tasks were administered at various intervals before and after drug and alcohol administration.
Results
Varenicline acutely increased blood pressure, heart rate, ratings of dysphoria and nausea, and also improved eye tracking performance. After alcohol drinking (vs placebo), varenicline increased dysphoria and tended to reduce alcohol liking ratings. It also attenuated alcohol-induced eye-tracking impairments. These effects were independent of the drug’s effects on nausea before drinking.
Conclusions
Our data support the theory that varenicline may reduce drinking by potentiating aversive effects of alcohol. Varenicline also offsets alcohol-induced eye movement impairment. The evidence suggests that varenicline may decrease alcohol consumption by producing effects which oppose the rewarding efficacy of alcohol.
doi:10.1111/j.1530-0277.2011.01675.x
PMCID: PMC3342420  PMID: 22339626
Varenicline; Alcohol; Subjective effects; Eye-tracking
21.  Effectiveness of smoking cessation therapies: a systematic review and meta-analysis 
BMC Public Health  2006;6:300.
Background
Smoking remains the leading preventable cause of premature deaths. Several pharmacological interventions now exist to aid smokers in cessation. These include Nicotine Replacement Therapy [NRT], bupropion, and varenicline. We aimed to assess their relative efficacy in smoking cessation by conducting a systematic review and meta-analysis.
Methods
We searched 10 electronic medical databases (inception to Sept. 2006) and bibliographies of published reviews. We selected randomized controlled trials [RCTs] evaluating interventions for smoking cessation at 1 year, through chemical confirmation. Our primary endpoint was smoking cessation at 1 year. Secondary endpoints included short-term smoking cessation (~3 months) and adverse events. We conducted random-effects meta-analysis and meta-regression. We compared treatment effects across interventions using head-to-head trials and when these did not exist, we calculated indirect comparisons.
Results
We identified 70 trials of NRT versus control at 1 year, Odds Ratio [OR] 1.71, 95% Confidence Interval [CI], 1.55–1.88, P =< 0.0001). This was consistent when examining all placebo-controlled trials (49 RCTs, OR 1.78, 95% CI, 1.60–1.99), NRT gum (OR 1.60, 95% CI, 1.37–1.86) or patch (OR 1.63, 95% CI, 1.41–1.89). NRT also reduced smoking at 3 months (OR 1.98, 95% CI, 1.77–2.21). Bupropion trials were superior to controls at 1 year (12 RCTs, OR1.56, 95% CI, 1.10–2.21, P = 0.01) and at 3 months (OR 2.13, 95% CI, 1.72–2.64). Two RCTs evaluated the superiority of bupropion versus NRT at 1 year (OR 1.14, 95% CI, 0.20–6.42).
Varenicline was superior to placebo at 1 year (4 RCTs, OR 2.96, 95% CI, 2.12–4.12, P =< 0.0001) and also at approximately 3 months (OR 3.75, 95% CI, 2.65–5.30). Three RCTs evaluated the effectiveness of varenicline versus bupropion at 1 year (OR 1.58, 95% CI, 1.22–2.05) and at approximately 3 months (OR 1.61, 95% CI, 1.16–2.21). Using indirect comparisons, varenicline was superior to NRT when compared to placebo controls (OR 1.66, 95% CI 1.17–2.36, P = 0.004) or to all controls at 1 year (OR 1.73, 95% CI 1.22–2.45, P = 0.001). This was also the case for 3-month data. Adverse events were not systematically different across studies.
Conclusion
NRT, bupropion and varenicline all provide therapeutic effects in assisting with smoking cessation. Direct and indirect comparisons identify a hierarchy of effectiveness.
doi:10.1186/1471-2458-6-300
PMCID: PMC1764891  PMID: 17156479
22.  Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis 
Objective To examine the risk of treatment emergent, cardiovascular serious adverse events associated with varenicline use for tobacco cessation.
Design Meta-analysis comparing study effects using four summary estimates.
Data sources Medline, Cochrane Library, online clinical trials registries, and reference lists of identified articles.
Review methods We included randomised controlled trials of current tobacco users of adult age comparing use of varenicline with an inactive control and reporting adverse events. We defined treatment emergent, cardiovascular serious adverse events as occurring during drug treatment or within 30 days of discontinuation, and included any ischaemic or arrhythmic adverse cardiovascular event (myocardial infarction, unstable angina, coronary revascularisation, coronary artery disease, arrhythmias, transient ischaemic attacks, stroke, sudden death or cardiovascular related death, or congestive heart failure).
Results We identified 22 trials; all were double blinded and placebo controlled; two included participants with active cardiovascular disease and 11 enrolled participants with a history of cardiovascular disease. Rates of treatment emergent, cardiovascular serious adverse events were 0.63% (34/5431) in the varenicline groups and 0.47% (18/3801) in the placebo groups. The summary estimate for the risk difference, 0.27% (95% confidence interval −0.10 to 0.63; P=0.15), based on all 22 trials, was neither clinically nor statistically significant. For comparison, the relative risk (1.40, 0.82 to 2.39; P=0.22), Mantel-Haenszel odds ratio (1.41, 0.82 to 2.42; P=0.22), and Peto odds ratio (1.58, 0.90 to 2.76; P=0.11), all based on 14 trials with at least one event, also indicated a non-significant difference between varenicline and placebo groups.
Conclusions This meta-analysis—which included all trials published to date, focused on events occurring during drug exposure, and analysed findings using four summary estimates—found no significant increase in cardiovascular serious adverse events associated with varenicline use. For rare outcomes, summary estimates based on absolute effects are recommended and estimates based on the Peto odds ratio should be avoided.
doi:10.1136/bmj.e2856
PMCID: PMC3344735  PMID: 22563098
23.  The Safety and Efficacy of Varenicline in Cocaine Using Smokers Maintained on Methadone: A Pilot Study 
In this double-blind, placebo-controlled trial, we compared varenicline (2 mg) to placebo for treatment for cocaine and tobacco dependence in 31 methadone-maintained subjects. Subjects received weekly counseling during the 12-week study participation. Our results indicate that varenicline is safe to give to this subject population, as there were no adverse events related to medication during this study. Varenicline was no more effective than placebo for abstinence from cocaine. Treatment with varenicline was associated with a reduced number of cigarettes smoked per day, even though subjects received only a brief education for smoking cessation. The self-report reduction in smoking was corroborated by CO levels and the Fagerström Test of Nicotine Dependence. However, self-ratings of positive mood on the Positive Affect Negative Affect Schedule did significantly decrease in the varenicline group as compared to the placebo group, although this appears to be due to randomization differences related to lifetime depression diagnosis. These preliminary findings may point to potential therapeutic value of varenicline for smoking cessation in cocaine users maintained on methadone.
doi:10.1111/j.1521-0391.2010.00066.x
PMCID: PMC2966972  PMID: 20716302
24.  Varenicline Ameliorates Nicotine Withdrawal-Induced Learning Deficits in C57BL/6 Mice 
Behavioral neuroscience  2008;122(5):1166-1171.
Varenicline a partial agonist for α4β2 nicotinic acetylcholine receptors (nAChRs) and full agonist for α7 nAChRs, has been approved for the treatment of smoking cessation. While recent clinical trials support the efficacy of varenicline for managing global nicotine withdrawal symptoms and for smoking cessation, varenicline effects on specific withdrawal-associated behaviors in animal models have not been tested. In mice and humans, withdrawal from chronic nicotine disrupts cognitive processing; in mice, this can be measured by changes in contextual fear conditioning. To elucidate potential mechanisms underlying the clinical efficacy of varenicline, the present study evaluated the effects of varenicline on contextual fear conditioning when administered alone and when administered 24 hours after withdrawal from chronic nicotine administration (6.3 mg/kg/day). Varenicline (0.01, 0.1, 1.0 mg/kg) had no effect on contextual fear conditioning when administered alone. However, varenicline dose-dependently prevented nicotine withdrawal-associated deficits in contextual fear conditioning. These data demonstrate that varenicline reverses nicotine withdrawal-induced deficits in an animal model and suggest that varenicline may be effective at treating nicotine withdrawal-associated deficits in learning and memory.
doi:10.1037/a0012601
PMCID: PMC2683368  PMID: 18823172
Nicotine; Withdrawal; Hippocampus; Fear Conditioning; Addiction; Acetylcholine; Cognition
25.  Varenicline Reduces Alcohol Self-Administration in Heavy-Drinking Smokers 
Biological psychiatry  2009;66(2):185-190.
Background
Alcohol and tobacco dependence are highly comorbid disorders, with preclinical evidence suggesting a role for nicotinic acetylcholine receptors (nAChRs) in alcohol consumption. Varenicline, a partial nicotinic agonist with high affinity for the α4β2 nAChR receptor, reduced ethanol intake in rodents. We aimed to test whether varenicline would reduce alcohol consumption and alcohol craving in humans.
Methods
This double-blind, placebo-controlled investigation examined the effect of varenicline (2 mg/day vs. placebo) on alcohol self-administration using an established laboratory paradigm in non-alcohol-dependent heavy drinkers (n = 20) who were daily smokers. Following 7 days of medication pretreatment, participants were first administered a priming dose of alcohol (.3 g/kg) and subjective, and physiologic responses were assessed. A 2-hour alcohol self-administration period followed during which participants could choose to consume up to 8 additional drinks (each .15 g/kg).
Results
Varenicline (.5 ± SE = .40) significantly reduced the number of drinks consumed compared to placebo (2.60 ± SE = .93) and increased the likelihood of abstaining from any drinking during the self-administration period. Following the priming drink, varenicline attenuated alcohol craving and reduced subjective reinforcing alcohol effects (high, like, rush, feel good, intoxicated). Adverse events associated with varenicline were minimal and, when combined with alcohol, produced no significant effects on physiologic reactivity, mood, or nausea.
Conclusions
This preliminary investigation demonstrated that varenicline significantly reduced alcohol self-administration and was well tolerated, alone and in combination with alcohol in heavy-drinking smokers. Varenicline should be investigated as a potential treatment for alcohol use disorders.
doi:10.1016/j.biopsych.2009.01.029
PMCID: PMC2863311  PMID: 19249750
Alcohol; craving; heavy drinkers; human laboratory; nicotinic acetylcholine receptors; self-administration; smokers; varenicline

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