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1.  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
2.  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
3.  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
4.  A Pilot Study of the Efficacy of Varenicline for the Treatment of Smokeless Tobacco Users in Midwestern United States 
Nicotine & Tobacco Research  2011;13(9):820-826.
Introduction:
Long-term smokeless tobacco (ST) use is known to increase the risk for oropharyngeal cancer, heart attack, and stroke. Varenicline has recently been demonstrated to increase ST abstinence rates among Swedish snus users. We have conducted a pilot study to obtain preliminary evidence of efficacy of varenicline for the treatment of ST users in Midwestern United States.
Methods:
We conducted a randomized, placebo-controlled Phase II clinical trial to evaluate the potential efficacy of 12 weeks of varenicline for the treatment of ST users with an a priori decision rule that a 1-tailed p < .20 for the comparison of the primary endpoint was evidence to conclude that future studies were warranted. Subjects were followed for 6 months after randomization.
Results:
We randomized 76 subjects (38 varenicline and 38 placebo). Subjects were similar at baseline with a mean age of 41 years, and all were male. The biochemically confirmed point prevalence tobacco abstinence rates at end of treatment were 55.3% for varenicline and 42.1% for placebo (p = .126) and 47.4% and 31.6% (p = .080), respectively, at 6 months. Point prevalence ST abstinence rates at end of treatment for varenicline were 57.9% and 42.1% for placebo (p = .084) and 57.9% and 31.6% (p = .011), respectively, at 6 months. Varenicline was associated with significantly less craving compared with placebo. Varenicline was well tolerated with nausea and sleep disturbance being the most common side effects.
Conclusions:
Varenicline decreases craving and may be effective for increasing tobacco abstinence rates among ST users. Larger trials may be warranted to confirm these results.
doi:10.1093/ntr/ntr078
PMCID: PMC3168243  PMID: 21504885
5.  Bupropion SR for the Treatment of Smokeless Tobacco Use 
Drug and alcohol dependence  2007;90(1):56-63.
Background:
No pharmacotherapies have been shown to increase long-term (≥ 6 month) tobacco abstinence rates among smokeless tobacco (ST) users. Bupropion SR has demonstrated potential efficacy for ST users in pilot studies. We conducted a multicenter, randomized, double-blind, placebo-controlled, clinical trial to assess the efficacy and safety of bupropion SR for tobacco abstinence among ST users.
Methods:
Adult ST users were randomized to bupropion SR titrated to 150 mg twice daily (N = 113) or placebo (N = 112) for 12 weeks plus behavioral intervention. The primary endpoint was the 7-day point-prevalence tobacco abstinence rate at week 12. Secondary outcomes included prolonged and continuous tobacco abstinence rates, craving and nicotine withdrawal, and weight gain.
Results:
The 7-day point-prevalence tobacco abstinence rates did not differ between bupropion SR and placebo at the end treatment (53.1% vs 46.4%; odds ratio (OR) 1.3; p = 0.301). The 7-day point prevalence abstinence did not differ at weeks 24 and 52. The prolonged and continuous tobacco abstinence rates did not differ at weeks 12, 24, and 52. A time-by-treatment interaction was observed in craving over time with greater decreases in the bupropion SR group. At 12 weeks, the mean (±SD) weight change from baseline among abstinent subjects was an increase of 1.7 (±2.9) kg for the bupropion SR group compared to 3.2 (±2.7) kg for placebo (p = 0.005).
Conclusions:
Bupropion SR did not significantly increase tobacco abstinence rates among ST users, but it significantly decreased craving and weight gain over the treatment period.
doi:10.1016/j.drugalcdep.2007.02.008
PMCID: PMC1994655  PMID: 17353101
tobacco, smokeless; tobacco use cessation; bupropion
6.  Tobacco Use Harm Reduction, Elimination, and Escalation in a Large Military Cohort 
American journal of public health  2010;100(12):2487-2492.
Objectives
We evaluated changing patterns of tobacco use following a period of forced tobacco abstinence in a US military cohort to determine rates of harm elimination (e.g., tobacco cessation), harm reduction (e.g., from smoking to smokeless tobacco use), and harm escalation (e.g., from smoking to dual use or from smokeless tobacco use to smoking or dual use).
Methods
Participants were 5225 Air Force airmen assigned to the health education control condition in a smoking cessation and prevention trial. Tobacco use was assessed by self-report at baseline and 12 months.
Results
Among 114 baseline smokers initiating smokeless tobacco use after basic military training, most demonstrated harm escalation (87%), which was 5.4 times more likely than harm reduction (e.g., smoking to smokeless tobacco use). Harm reduction was predicted, in part, by higher family income and belief that switching from cigarettes to smokeless tobacco is beneficial to health. Harm escalation predictors included younger age, alcohol use, longer smoking history, and risk-taking.
Conclusions
When considering a harm reduction strategy with ST, the tobacco control community should balance anticipated benefits of harm reduction with the risk of harm escalation and the potential for adversely affecting public health.
doi:10.2105/AJPH.2009.175091
PMCID: PMC2978188  PMID: 21068420
7.  Effectiveness of Stop-Smoking Medications: Findings from the International Tobacco Control (ITC) Four Country Survey 
Addiction (Abingdon, England)  2012;108(1):193-202.
Aim
To evaluate the population effectiveness of stop-smoking medications while accounting for potential recall bias by controlling for quit attempt recency.
Design
Prospective cohort survey.
Setting
United Kingdom, Canada, Australia, and the United States.
Participants
7,436 adult smokers (18+ years), selected via random digit dialling and interviewed as part of the International Tobacco Control Four Country Survey (ITC-4) between 2002 and 2009. Primary analyses utilized the subset of respondents who participated in 2006 or later (N = 2,550).
Measurements
Continuous abstinence from smoking for one month/six months.
Findings
Among participants who recalled making a quit attempt within one month of interview, those who reported using varenicline, bupropion, or the nicotine patch were more likely to maintain six-month continuous abstinence from smoking compared to those who attempted to quit without medication (adjusted OR (95% CI): 5.84 (2.12 – 16.12), 3.94 (0.87 – 17.80), 4.09 (1.72 – 9.74), respectively); there were no clear effects for oral NRT use. Those who did not use any medication when attempting to quit tended to be younger, to be racial/ethnic minorities, to have lower incomes, and to believe that medications do not make quitting easier.
Conclusions
Consistent with evidence from randomized controlled trials, smokers in the UK, Canada, Australia, and the US are more likely to succeed in quit attempts if they use varenicline, bupropion or nicotine patch. Previous population studies that failed to find an effect failed to adjust adequately for important sources of bias.
doi:10.1111/j.1360-0443.2012.04009.x
PMCID: PMC3500450  PMID: 22891869
8.  Randomized, placebo-controlled, double-blind trial of Swedish snus for smoking reduction and cessation 
Background
Epidemiological studies suggest that smokeless tobacco in the form of Swedish snus has been used by many smokers in Scandinavia to quit smoking, but the efficacy of snus has so far not been evaluated in controlled clinical trials.
Methods
We conducted a randomized, double-blind, placebo-controlled, clinical trial aimed at assessing the efficacy of snus to help adult cigarette smokers in Serbia to substantially reduce, and, eventually, completely stop smoking. The study enrolled 319 healthy smokers aged 20-65 years at two occupational health centers in Belgrade, Serbia. Most of them (81%) expressed an interest to quit rather than just reduce their smoking. Study products were used ad libitum throughout the 48-week study period. The main study objective during the first 24 weeks was smoking reduction. The primary end-point was defined as a biologically verified reduction of ≥ 50% in the average number of smoked cigarettes per day during week 21-24 compared to baseline. During week 25-48 participants were actively instructed to stop smoking completely. Outcome measures of biologically verified, complete smoking cessation included 1-week point prevalence rates at clinical visits after 12, 24, 36, and 48 weeks, as well as 4-, 12- and 24-week continued cessation rates at the week 36 and 48 visits.
Results
At the week 24 visit, the proportion of participants who achieved the protocol definition of a ≥ 50% smoking reduction was similar in the two treatment groups. However, the proportion that reported more extreme reductions (≥ 75%) was statistically significantly higher in the snus group than in the placebo group (p < 0.01). The results for biologically verified complete cessation suggested that participants in the snus group were more likely to quit smoking completely than the controls; the odds ratio (snus versus placebo) for the protocol estimates of cessation varied between 1.9 to 3.4, but these ratios were of borderline significance with p-values ranging from 0.04-0.10. Snus was well tolerated and only 2/158 (1.3%) participants in the snus group discontinued treatment due to an adverse event (in both cases unrelated to snus).
Conclusions
Swedish snus could promote smoking cessation among smokers in Serbia, that is, in a cultural setting without traditional use of oral, smokeless tobacco.
Trial registration
www.clinicaltrials.gov, identifier: NCT00601042
doi:10.1186/1477-7517-8-25
PMCID: PMC3186733  PMID: 21914165
Randomized trial; double-blind; placebo-controlled; Swedish snus; smoking reduction; smoking cessation
9.  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
10.  Varenicline’s effects on acute smoking behavior and reward and their association with subsequent abstinence 
Psychopharmacology  2010;210(1):45-51.
Rationale
Varenicline may aid smoking cessation by attenuating smoking behavior and reward. We compared the effects of varenicline versus placebo on smoking behavior and reward, assessed both prospectively and retrospectively, and related these effects to subsequent success in a brief simulated quit attempt with medication.
Materials and methods
Smokers (n=124) with high or low interest in quitting smoking participated in a double-blind crossover study of varenicline versus placebo effects on smoking behavior and reward. In each of two phases, subjects received a week of medication run-up with varenicline (0.5 mg, b.i.d.) or placebo while continuing to smoke, followed the next week by an attempt to quit while on medication. At the end of each run-up week, subjects completed retrospective measures of smoking reward (liking) and number of cigarettes over the prior 24 hrs, and they provided an expired air carbon monoxide (CO) measure. They then completed a prospective session in which they ad lib smoked and rated the rewarding effects of one of their preferred cigarettes while blind to brand.
Results
Varenicline decreased smoking reward significantly in the prospective assessment, but only marginally in the retrospective assessment. Varenicline did not alter smoking behavior prospectively, but did reduce CO and retrospective report of smoking amount. None of these effects of varenicline predicted subsequent days of abstinence due to varenicline.
Conclusions
During medication run-up, varenicline decreases acute smoking reward and may attenuate smoking behavior, but these effects do not appear to directly predict varenicline’s influence on smoking abstinence in a short-term test.
doi:10.1007/s00213-010-1816-9
PMCID: PMC2863002  PMID: 20306175
Smoking; Varenicline; Reward; Smoking cessation; Nicotine dependence
11.  Results of an initial clinical trial of varenicline for the treatment of cocaine dependence 
Drug and Alcohol Dependence  2011;121(1-2):163-166.
Background
Cocaine use, abuse and dependence remains a pressing public health problem. Based on its mechanism of action, varenicline, an alpha4 beta2 partial agonist seemed to be a likely candidate for treating cocaine dependence.
Methods
Cocaine dependent participants (n = 37) were enrolled in a 9-week double-blind placebo controlled clinical trial. Varenicline was titrated up to a target dose of 1 mg BID during the first week of medication.
Results
Varenicline was associated with lower odds of cocaine use than placebo (OR = 2.02, p=0.08), as measured by thrice-weekly urinalysis results. Compared to placebo-treated participants, varenicline treated participants had significantly decreased rates of cocaine reward, as measured by the Multiple Choice Procedure (MCP) (p = .02).
Conclusions
Varenicline appears to decrease cocaine use and reward, suggesting that further investigation of varenicline may be warranted.
doi:10.1016/j.drugalcdep.2011.08.025
PMCID: PMC3262950  PMID: 21925806
cocaine; treatment; pharmacotherapy; contingency management
12.  A pilot study to assess smokeless tobacco use reduction with varenicline 
Nicotine & Tobacco Research  2010;12(10):1037-1040.
Introduction:
Long-term smokeless tobacco (ST) use is known to increase the risk for oropharyngeal cancer, heart attack, and stroke. Extant literature on cigarette smokers suggests that smoking reduction increases smoking abstinence among smokers not interested in quitting. Similarly, a reduction strategy may reduce ST exposure and increase ST abstinence rates among ST users not interested in quitting.
Methods:
We conducted a pilot study to obtain preliminary data on the use of 12 weeks of varenicline as a tobacco reduction strategy among ST users not interested in quitting.
Results:
We enrolled 20 male ST users with a mean age of 42.8 ± 11.7 years who used an average of 3.9 ± 1.7 cans/pouches per week for 18.6 ± 8.6 years. At end of treatment (12 weeks), 60% (12/20) of subjects reduced their ST use by ≥50% and 15% (3/20) were biochemically confirmed abstinent from tobacco. At end of study (6 months), 50% (10/20) reduced by ≥50% of baseline use and 10% (2/20) were biochemically confirmed abstinent from tobacco. Varenicline reduced ST satisfaction, reward, and craving. Among subjects able to reduce ST, all subjects reported that reduction increased motivation and confidence in being able to maintain reduction and quit. The most common side effects were sleep disturbance (25%) and nausea (15%).
Discussion:
Varenicline may be effective in reducing ST use and achieving ST abstinence among ST users with no plans to quit but who are interested in reducing their ST use.
doi:10.1093/ntr/ntq134
PMCID: PMC2948050  PMID: 20724382
13.  Smoking cessation or reduction with nicotine replacement therapy: a placebo-controlled double blind trial with nicotine gum and inhaler 
BMC Public Health  2009;9:433.
Background
Even with effective smoking cessation medications, many smokers are unable to abruptly stop using tobacco. This finding has increased interest in smoking reduction as an interim step towards complete cessation.
Methods
This multi-center, double-blind placebo-controlled study evaluated the efficacy and safety of nicotine 4 mg gum or nicotine 10 mg inhaler in helping smokers (N = 314) to reduce or quit smoking. It included smokers willing to control their smoking, and participants could set individual goals, to reduce or quit. The study was placebo-controlled, randomized in a ratio of 2:1 (Active:Placebo), and subjects could choose inhaler or gum after randomization. Outcome was short-term (from Week 6 to Month 4) and long-term (from Month 6 to Month 12) abstinence or reduction. Abstinence was defined as not a single cigarette smoked and expired CO readings of <10 ppm. Smoking reduction was defined as a reduction in number of cigarettes per day by 50% or more versus baseline, verified by a lower-than-baseline CO reading at each visit during the same periods.
Results
Significantly more smokers managed to quit in the Active group than in the Placebo group. Sustained abstinence rates at 4 months were 42/209 (20.1%) subjects in the Active group and 9/105 (8.6%) subjects in the Placebo group (p = 0.009). Sustained abstinence rates at 12 months were 39/209 (18.7%) and 9/105 (8.6%), respectively (p = 0.019). Smoking reduction did not differ between the groups, either at short-term or long-term. Twelve-month reduction results were 17.2% vs. 18.1%, respectively. No serious adverse events were reported.
Conclusion
In conclusion, treatment with 10 mg nicotine inhaler or 4 mg nicotine chewing gum resulted in a significantly higher abstinence rate than placebo. In addition a large number of smokers managed to reduce their cigarette consumption by more than 50% compared to baseline.
doi:10.1186/1471-2458-9-433
PMCID: PMC2792228  PMID: 19943947
14.  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
15.  Pharmacotherapies for smoking cessation: a meta-analysis of randomized controlled trials 
Background
Many placebo-controlled trials have demonstrated the efficacy of individual pharmacotherapies approved for smoking cessation. However, few direct or indirect comparisons of such interventions have been conducted. We performed a meta-analysis to compare the treatment effects of 7 approved pharmacologic interventions for smoking cessation.
Methods
We searched the US Centers for Disease Control and Prevention's Tobacco Information and Prevention database as well as MEDLINE, EMBASE and the Cochrane Library for published reports of placebo-controlled, double-blind randomized controlled trials of pharmacotherapies for smoking cessation. We included studies that reported biochemically validated measures of abstinence at 6 and 12 months. We used a hierarchical Bayesian random-effects model to summarize the results for each intervention.
Results
We identified 70 published reports of 69 trials involving a total of 32 908 patients. Six of the 7 pharmacotherapies studied were found to be more efficacious than placebo: varenicline (odds ratio [OR] 2.41, 95% credible interval [CrI] 1.91–3.12), nicotine nasal spray (OR 2.37, 95% CrI 1.12–5.13), bupropion (OR 2.07, 95% CrI 1.73–2.55), transdermal nicotine (OR 2.07, 95% CrI 1.69–2.62), nicotine tablet (OR 2.06, 95% CrI 1.12–5.13) and nicotine gum (OR 1.71, 95% CrI 1.35–2.21). Similar results were obtained regardless of which measure of abstinence was used. Although the point estimate favoured nicotine inhaler over placebo (OR 2.17), these results were not conclusive because the credible interval included unity (95% CrI 0.95–5.43). When all 7 interventions were included in the same model, all were more efficacious than placebo. In our analysis of data from the varenicline trials that included bupropion control arms, we found that varenicline was superior to bupropion (OR 2.18, 95% CrI 1.09–4.08).
Interpretation
Varenicline, bupropion and the 5 nicotine replacement therapies were all more efficacious than placebo at promoting smoking abstinence at 6 and 12 months.
doi:10.1503/cmaj.070256
PMCID: PMC2443223  PMID: 18625984
16.  Adjunctive Varenicline Treatment with Antipsychotic Medications for Cognitive Impairments in People with Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial 
Neuropsychopharmacology  2011;37(3):660-668.
The aim of this study is to examine the effects of treatment with varenicline, a partial agonist at the α4β2 and full agonist at the α7 nicotine acetylcholine receptor, on cognitive impairments in people with schizophrenia. In all, 120 clinically stable people with schizophrenia participated in randomized, double-blind, placebo-controlled 8-week trial. Antipsychotic and concomitant medication doses remained fixed throughout the study. Varenicline was titrated up to 1 mg twice daily for weeks 2–8. Neuropsychological, clinical, and safety assessments were administered at baseline and weeks 1, 2, 4, and 8. In the primary analyses of neurocognitive differences at week 8, no varenicline–placebo differences were significant. In secondary longitudinal analyses, varenicline improved compared with placebo on the Digital Symbol Substitution Test (p=0.013) and the Wisconsin Card Sorting Test non-perseverative errors (p=0.043). Some treatment effects were different between smokers and non-smokers. In smokers, Continuous Performance Test hit reaction time (p=0.008) and Stroop Interference (p=0.004) were reduced for varenicline compared with placebo, while there were no treatment differences in non-smokers. No significant treatment main effects or interactions were noted for total scores on the Positive and Negative Syndrome Scale or the Scale for the Assessment for Negative Symptoms. Our findings suggest beneficial effects of adjunctive varenicline treatment with antipsychotics for some cognitive impairments in people with schizophrenia. In some cases, effects of treatment varied between smokers and non-smokers. Further study is required to assess the functional significance of these changes.
doi:10.1038/npp.2011.238
PMCID: PMC3260973  PMID: 22048460
schizophrenia; cognition; varenicline; antipsychotics; smoking; schizophrenia/antipsychotics; cognition; psychopharmacology; clinical pharmacology/clinical trials; valenicline; adjunctive treatment; antipsychotics; smoking
17.  Project IMPACT: A pharmacotherapy pilot trial investigating the abstinence and treatment adherence of Latino light smokers 
Light smoking is particularly prevalent among Latino smokers. Nicotine replacement (NRT) and varenicline are effective medications for smoking cessation for moderate-heavy smokers, but have not been tested in light smokers and thus there are no treatment guidelines for use with light smokers. This pilot trial tested the efficacy of NRT and varenicline in increasing smoking abstinence among Latino light smokers. A 3-group (NRT, varenicline, varenicline-placebo) randomized design was used and Latino light smokers (≤10 cpd) received 12 weeks of treatment which included a culturally-informed behavioral health session and ongoing medication management visits. At follow-up, there were no abstinent participants in the placebo and NRT groups. However, 30% of participants in the varenicline group were abstinent at the 3, 4, and 6 month follow-up. This study represents the only investigation that specifically targets Latino light smokers using these treatments and characterizing their treatment adherence.
doi:10.1016/j.jsat.2012.01.004
PMCID: PMC3762477  PMID: 22377389
Latinos; Hispanics; light smokers; varenicline; adherence; NRT
18.  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
19.  Smoking Cessation Pharmacogenetics: Analysis of Varenicline and Bupropion in Placebo-Controlled Clinical Trials 
Neuropsychopharmacology  2011;37(3):641-650.
Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23–2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27–2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36–0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45–2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.
doi:10.1038/npp.2011.232
PMCID: PMC3260990  PMID: 22048466
varenicline; bupropion; pharmacogenetics; nicotine; nicotinic receptor; CYP2B6; pharmacogenetics/pharmacogenomics; addiction and substance abuse; clinical pharmacology/clinical trials; neuropharmacology; varenicline; bupropion; nicotine; smoking cessation; nicotinic receptors
20.  A Pilot Clinical Trial of Varenicline for Smoking Cessation in Black Smokers 
Nicotine & Tobacco Research  2011;13(9):868-873.
Introduction:
Varenicline, a first-line non-nicotine medication, has not been evaluated in Black smokers, and limited attention has been paid to pharmacotherapy adherence in smoking cessation trials. This pilot study estimated quit rates for Black smokers treated with varenicline and tested a behavioral intervention to aid varenicline adherence.
Methods:
Seventy-two Black smokers (>10 cigarettes per day; cpd) were randomly assigned to adherence support (AS; n = 36) or standard care (n = 36). All participants received 3 months of varenicline and a single counseling session focused on making a quit plan. AS participants received 5 additional counseling sessions to encourage medication use. Outcome measures included salivary cotinine, and carbon monoxide confirmed smoking abstinence, reductions in self-reported cpd, and pill counts of varenicline adherence at Months 1, 2, and 3.
Results:
Sixty-one participants (84.7%) completed follow-up at Month 3. Participants were female (62.5%), 46.8 years of age, and smoked 16.3 cpd. No treatment group differences were found on the smoking or adherence outcome measures (p > .05). Collapsing across treatment, varenicline adherence was adequate (86.1%), yet despite a reduction of 12.2 (6.5) cpd from baseline to Month 3 (p < 0.001), only 23.6% were confirmed quit at Month 3. Participants who were quit at Month 3 had higher varenicline adherence rates (95.8%) than those who continued to smoke (80.8%, p ≤ .05).
Conclusions:
Studies are needed to examine the efficacy of varenicline among Black smokers. Interventions to facilitate adherence to pharmacotherapy warrant further attention as adherence is linked to improved tobacco abstinence.
doi:10.1093/ntr/ntr063
PMCID: PMC3203399  PMID: 21498427
21.  The Effects of Extended Pre-Quit Varenicline Treatment on Smoking Behavior and Short-Term Abstinence: A Randomized Clinical Trial 
Preclinical research and learning theory suggest that a longer duration of varenicline treatment prior to the target quit date (TQD) should reduce smoking rates before cessation and improve abstinence outcomes. A double-blind RCT tested this hypothesis among 60 smokers randomized to either Extended (4 weeks of pre-TQD varenicline) or standard run-in (3 weeks of placebo, 1 week of pre-TQD varenicline); everyone received 11 weeks of post-TQD varenicline and brief counseling. During the pre-quit run-in, the reduction in smoking rates was greater among the Extended group (42% vs. 24%, p<0.01) and this effect was greater among women (57% vs. 26%, p=0.001). Continuous abstinence during the final four weeks of treatment was enhanced among women in the Extended group (67% vs. 35%). While these data suggest that extending pre-quit varenicline reduces smoking during the pre-quit period and may further enhance cessation rates, confirmatory evidence is needed from larger clinical trials.
Trial Registration: www.clinicaltrials.gov identifier: NCT00835900
doi:10.1038/clpt.2011.317
PMCID: PMC3325094  PMID: 22130118
smoking cessation; varenicline; reinforcement; extinction
22.  Gastrointestinal adverse effects of varenicline at maintenance dose: a meta-analysis 
Background
Tobacco smoking remains the leading modifiable health hazard and varenicline is amongst the most popular pharmacological options for smoking cessation. The purpose of this study is to critically evaluate the extent of gastrointestinal adverse effects of varenicline when used at maintenance dose (1 mg twice a day) for smoking cessation.
Methods
We conducted a meta-analysis of randomised controlled trials published in PUBMED and EMBASE according to the PRISMA guidelines. Selected studies satisfied the following criteria: (i) duration of at least 6 weeks, (ii) titrated dose of varenicline for 7 days then a maintenance dose of 1 mg twice-per-day, (iii) randomized placebo-controlled design, (iv) extractable data on adverse event - nausea, constipation or flatulence. Data was synthesized into pooled odd ratios (OR) basing on random effects model. Quality of studies was also rated as per Cochrane risk-of-bias assessment. Number need to harm (NNH) was calculated for each adverse effect.
Results
98 potentially relevant studies were identified, 12 of which met the final inclusion criteria (n = 5114). All 12 studies reported adverse events on nausea, which led to an OR of 4.45 (95% CI = 3.79-5.23, p < 0.001; I2 = 0.06%, CI = 0%-58.34%) and a NNH of 5. Eight studies (n = 3539) contain data on constipation pooled into an OR of 2.45 (95% CI = 1.61-3.72, p < 0.001; I2 = 34.09%, CI = 0%-70.81%) with a NNH of 24. Finally, five studies (n = 2516) reported adverse events of flatulence, which pooled an OR of 1.74 (95% CI = 1.23-2.48, p = 0.002; I2 = 0%, CI = 0%- 79.2%) with a NNH of 35.
Conclusions
Use of varenicline at maintenance dose of 1 mg twice a day for longer than 6 weeks is associated with adverse gastrointestinal effects. In realistic terms, for every 5 treated subjects, there will be an event of nausea, and for every 24 and 35 treated subjects, we will expect an event of constipation and flatulence respectively. Family physicians should counsel patients of such risks accordingly during their maintenance therapy with varenicline.
doi:10.1186/1472-6904-11-15
PMCID: PMC3192741  PMID: 21955317
23.  A randomized placebo-controlled clinical trial of five smoking cessation pharmacotherapies 
Archives of general psychiatry  2009;66(11):1253-1262.
Context
Little direct evidence exists on the relative efficacies of different smoking cessation pharmacotherapies, yet such evidence is needed to make informed decisions about their clinical use.
Objective
The primary objective of this research was to assess the relative efficacies of five smoking cessation pharmacotherapy interventions using placebo-controlled, head-to-head comparisons.
Design
This was a randomized double-blind, placebo-controlled clinical trial.
Setting
Smokers were recruited from the community at two urban research sites.
Patients
Participants were 1504 adult smokers who smoked at least 10 cigarettes per day during the past 6 months and reported being motivated to quit smoking. Participants were excluded if they reported: using any form of tobacco other than cigarettes; current use of bupropion; having a current psychosis or schizophrenia diagnosis; or having medical contraindications for any of the study medications.
Interventions
Participants were randomized to one of six treatment conditions: nicotine lozenge, nicotine patch, bupropion SR, nicotine patch + nicotine lozenge, bupropion + nicotine lozenge or placebo. In addition, all participants received six individual counseling sessions.
Main Outcome Measures
The main outcome measures were biochemically-confirmed 7-day point-prevalence abstinence assessed at 1 week post-quit, end of treatment (8 weeks post-quit) and 6 months post-quit. Other outcomes were initial cessation, number of days to lapse, number of days to relapse, and latency to relapse after the first lapse.
Results
All pharmacotherapies differed from placebo when examined without protection for multiple comparisons (OR’s = 1.63–2.34). With such protection, only the nicotine patch + nicotine lozenge (OR = 2.34, p < .001) produced significantly higher abstinence rates at 6-months post-quit than did placebo.
Conclusions
While the nicotine lozenge, bupropion, and bupropion + lozenge produced effects that were comparable to those reported in previous research, the nicotine patch + lozenge produced the greatest benefit relative to placebo for smoking cessation.
doi:10.1001/archgenpsychiatry.2009.142
PMCID: PMC2933113  PMID: 19884613
24.  Evaluation of factors influencing intention to quit smokeless and cigarette tobacco use among Nigerian adolescents 
Background:
Smokeless and cigarette tobacco use is becoming increasingly popular among Nigerian adolescents. This study aimed to evaluate predictors of intention to quit tobacco use among adolescents that currently use tobacco products in Nigeria.
Materials and Methods:
A total of 536 male and female high school students in senior classes in Benue State, Nigeria were enrolled into the cross-sectional study. The survey instrument was adapted from the Global Youth Tobacco Survey (GYTS) questionnaire.
Results:
Among adolescents with tobacco habits, 80.5% of smokeless tobacco users and 82.8% of cigarette smokers intended to quit tobacco use within 12 months. After adjustment, significant predictors of intention to quit cigarette smoking were parents’ smoking status (P<0.01), peers’ smokeless use status (P<0.01) and perception that smoking made one comfortable at social events (P<0.01). For intention to quit smokeless tobacco use, significant predictors after adjustment were parents’ smokeless use status, (P=0.03) perception that smokeless tobacco use made one more comfortable at social events (P=0.04) and perception of harm from smokeless use (P=0.02).
Conclusion:
This study demonstrates that the intention to quit smokeless and cigarette tobacco use is significantly predicted by perception about the societal acceptance of tobacco use at social events, parents and peers’ tobacco use status as well as the perception of harm from use of tobacco products. Providing social support may increase quit attempts among youth smokers.
doi:10.4103/0300-1652.99829
PMCID: PMC3530241  PMID: 23271842
Adolescents; cigarettes; intention to quit; interventions; smokeless-tobacco; smoking; tobacco
25.  Tobacco use and associated factors among adolescent students in Dharan, Eastern Nepal: a cross-sectional questionnaire survey 
BMJ Open  2013;3(2):e002123.
Introduction
The tobacco use among the youth, in both smoking and smokeless forms, is quite high in the South East Asian region. Tobacco use is a major proven risk factor and contributes substantially to the rising epidemic of non-communicable diseases.
Objectives
To estimate the prevalence of tobacco use and determine associated factors among adolescent students of Dharan municipality.
Design
Cross-sectional study.
Setting
Secondary and higher secondary schools of Dharan municipality in Sunsari district of Nepal.
Participants
Students in middle (14–15 years) and late adolescence (16–19 years) from grades 9, 10, 11 and 12 were included.
Primary outcome measure
Ever tobacco use which was defined as one who had not used any form of tobacco in the past 1 month but had tried in the past.
Methodology
Self-administered questionnaire adapted from Global Youth Tobacco Survey was used to assess tobacco use among the representative sample of 1312 adolescent students selected by stratified random sampling from July 2011 to July 2012.
Results
Out of 1454 students, 1312 students completed the questionnaires with a response rate of 90.23%. Prevalence of ever use of any tobacco product was 19.7% (95% CI 17.7 to 21.6). More than half of the tobacco users (51.9%) consumed tobacco in public places whereas almost a third (75.6%) of the consumers purchased tobacco from shops. Multivariate analysis showed that tobacco use was associated with late adolescence (OR: 1.64; 95% CI 1.17 to 2.28), male gender (OR: 12.20; 95% CI 7.78 to 19.14), type of school (OR=1.72; 95% CI 1.01 to 2.94), Janajati ethnicity (OR: 2.05; 95% CI 1.39 to 3.01) and receiving pocket money ≥Nepalese rupees 500/month (OR: 1.45; 95% CI 1.04 to 2.03).
Conclusions
Tobacco-focused interventions are required for school/college going students to promote cessation among users and prevent initiation, focussing on late adolescence, male gender, government schools, Janajati ethnicity and higher amount of pocket money.
doi:10.1136/bmjopen-2012-002123
PMCID: PMC3585970  PMID: 23418297
Public Health; Preventive Medicine

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