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Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders. We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1:1:1:1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9–12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed. 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1·3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2·2%) of 989 in the bupropion group, 25 (2·5%) of 1006 in the nicotine patch group, and 24 (2·4%) of 999 in the placebo group. The varenicline–placebo and bupropion–placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were −1·28 (95% CI −2·40 to −0·15) and −0·08 (−1·37 to 1·21), respectively; the RDs for comparisons with nicotine patch were −1·07 (−2·21 to 0·08) and 0·13 (−1·19 to 1·45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6·5%) of 1026 participants in the varenicline group, 68 (6·7%) of 1017 in the bupropion group, 53 (5·2%) of 1016 in the nicotine patch group, and 50 (4·9%) of 1015 in the placebo group. The varenicline–placebo and bupropion–placebo RDs were 1·59 (95% CI −0·42 to 3·59) and 1·78 (−0·24 to 3·81), respectively; the RDs versus nicotine patch were 1·22 (−0·81 to 3·25) and 1·42 (−0·63 to 3·46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3·61, 95% CI 3·07 to 4·24), nicotine patch (1·68, 1·46 to 1·93), and bupropion (1·75, 1·52 to 2·01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2·07 [1·75 to 2·45] and 2·15 [1·82 to 2·54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort. The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo. Pfizer and GlaxoSmithKline.

Patients who continue to smoke after acute coronary syndrome are at increased risk of reinfarction and death. We previously found use of varenicline to increase abstinence 24 weeks after acute coronary syndrome; here we report results through 52 weeks. The EVITA trial was a multicentre, double-blind, randomized, placebo-controlled trial of varenicline for smoking cessation in patients admitted to hospital with acute coronary syndrome. Participants were randomly assigned (1:1) to receive varenicline or placebo for 12 weeks, in conjunction with low-intensity counselling. Smoking abstinence was assessed via 7-day recall, with biochemical validation using exhaled carbon monoxide. Participants lost to follow-up or withdrawn were assumed to have returned to smoking. Among the 302 participants, abstinence declined over the course of the trial, with 34.4% abstinent 52 weeks after acute coronary syndrome. Compared with placebo, point estimates suggest use of varenicline increased point-prevalence abstinence (39.9% v. 29.1%, difference 10.7%, 95% confidence interval [CI] 0.01% to 21.44%; number needed to treat 10), continuous abstinence (31.1% v. 21.2%, difference 9.9%, 95% CI −0.01% to 19.8%) and reduction in daily cigarette smoking by 50% or greater (57.8% v. 49.7%, difference 8.1%, 95% CI −3.1% to 19.4%). Varenicline and placebo groups had similar occurrence of serious adverse events (24.5% v. 21.9%, risk difference 2.7%, 95% CI −7.3% to 12.6%) and major adverse cardiovascular events (8.6% v. 9.3%, risk difference −0.7%, 95% CI −7.8% to 6.5%). Varenicline was efficacious for smoking cessation in this high-risk patient population. However, 60% of patients who received treatment with varenicline still returned to smoking. Trial registration: ClinicalTrials.gov, no. NCT00794573

Nonadherence to pharmacotherapies complicates studies of comparative pharmacotherapy effectiveness. Modeling adherence and abstinence simultaneously may facilitate analysis of both treatment acceptability and effectiveness. Secondary analyses of a three-arm randomized comparative trial of nicotine patch, varenicline, and combination nicotine patch and lozenge among adult daily smokers (N = 1086) were conducted. Adherence rates collected via interactive voice response systems during the first 27 days of quitting were compared across treatment conditions. Repeated measures latent class analyses of adherence and abstinence in 3-day parcels through 27 days of a quit attempt were conducted with treatment, demographic, and smoking history covariates. Adherence varied across treatments and was lowest for nicotine lozenge use in combination nicotine replacement therapy (NRT). Five latent classes that differed significantly in 6-month abstinence rates were retained, including three subgroups of adherent participants varying in treatment response and two nonadherent groups varying in abstinence probabilities. Nonadherence was more likely among those receiving varenicline and combination NRT, relative to patch monotherapy. Varenicline and combination NRT did not promote abstinence among adherent latent classes but did promote abstinence among those partially adherent, relative to patch alone. Combination therapy attenuated increased risk of treatment disengagement with more years smoking. Minority smokers, those high in dependence, and those with shorter past abstinence were at increased risk for low-adherence and low-abstinence latent classes. Varenicline and combination nicotine patch and lozenge are less likely to be used as directed and may not increase first-month abstinence better than patch alone when taken adherently. This secondary analysis of adherence and abstinence in a comparative effectiveness trial shows that adherence is highest for the nicotine patch, next highest for varenicline, and lowest for combination nicotine patch and lozenge therapy due to low lozenge use. Distinct latent classes were found that varied in both first-month abstinence and adherence. Varenicline and combination NRT may not enhance abstinence over patch alone among smokers who take medication adherently. Adherent use of medication especially benefits those who are low in dependence and have positive quitting histories; it is less beneficial to at-risk smokers and members of racial minorities.

Rationale Cigarette demand is a behavioral economic measure of the relative value of cigarettes. Decreasing the value of cigarette reinforcement may help with quitting smoking. Objectives This study aimed to evaluate the effects of initial use of varenicline (VAR) versus nicotine replacement therapy (NRT) on demand for cigarettes on quit day among smokers with substance use disorders (SUD) and to determine whether reduced demand was associated with subsequent abstinence from smoking at 1 and 3 months. Methods Participants ( N  = 110) were randomized to double-blind, double-placebo conditions: VAR with placebo NRT or NRT with placebo capsules. The cigarette purchase task (CPT) was used to assess demand for cigarettes at baseline and on quit day, following a 1-week medication dose run-up/placebo capsule lead-in and first day use of the patch. Results Demand for cigarettes decreased from baseline to quit day without significant differences between medications. Reductions in CPT intensity (number of cigarettes that would be smoked if they were free) and CPT breakpoint (lowest price at which no cigarettes would be purchased) predicted greater likelihood of abstaining on quit day. Reduced intensity predicted length of abstinence at 1 and 3 months while reduced breakpoint predicted only 1 month length of abstinence. Conclusions Initial therapeutic doses of VAR and NRT resulted in similar reductions in cigarette reinforcement. Larger initial reductions in demand on quit day were associated with early success with abstaining from cigarettes. Behavioral economic approaches may be useful for identifying individuals who benefit less from pharmacotherapy and may need additional treatment resources. Trial registration https://clinicaltrials.gov/ct2/show/NCT00756275

This study replicated and extended results of a previous trial, which found that combination varenicline/bupropion treatment increased smoking abstinence in smokers who were male, highly dependent, and who did not respond to prequit nicotine patch treatment with a >50% reduction in expired-air carbon monoxide in the first week. One hundred and twenty-two male nicotine patch nonresponders and 52 responders were identified. Smokers in each group were randomized to receive 12 weeks of varenicline plus bupropion treatment versus varenicline plus placebo. The primary outcome was continuous smoking abstinence at weeks 8-11 after the target quit date. For smokers with a high level of dependence, judged by having a baseline Fagerstrom Test for Nicotine Dependence (FTND) score ≥ 6 and cigarette consumption ≥ 20/d, combination varenicline/bupropion treatment increased the abstinence rate relative to varenicline alone: 71.0% versus 43.8% (odds ratio = 3.14; 95% confidence interval = 1.11-8.92, p [one tailed] = .016). In contrast, less dependent smokers did not show a benefit of combination treatment relative to varenicline (abstinence rates of 32.1% vs. 45.6%, respectively); there was a significant interaction of treatment and dependence level. Patch nonresponders tended to benefit the most from combination treatment, which was well tolerated overall. Combination varenicline/bupropion treatment proved significantly more efficacious than varenicline alone among highly dependent male smokers. These results, together with prior studies, support an adaptive treatment paradigm that assigns smoking cessation treatment according to baseline smoker characteristics and initial response to nicotine patch treatment. This study replicated, in a prospective manner, an important and surprising retrospective finding from a previous clinical trial, which showed that a specific subpopulation of smokers benefited substantially from receiving a combination treatment of varenicline plus bupropion, relative to varenicline plus placebo. Specifically, male smokers having high baseline nicotine dependence (FTND score ≥ 6 and cigarette consumption ≥ 20/d), showed a marked increase in smoking abstinence rate on combination pharmacotherapy. The present study likewise found an enhancement in end-of-treatment abstinence rate in this subgroup, from 43.8% to 71.0%. The adaptive treatment paradigm, which classifies smokers based on initial dependence level and response to prequit nicotine patch treatment, may be used to identify target populations of smokers whose success can be enhanced by intervening with combination pharmacotherapy before the quit-smoking date. ClinicalTrials.gov identifier: NCT01806779.

Abstract Background Postmenopausal smokers have difficulty quitting smoking and experience considerable weight gain with smoking cessation. We examined whether adjunctive smoking treatment with exercise, compared to a relaxation control condition, could improve cigarette abstinence, decrease cigarettes smoked per day (CPD), and ameliorate changes in body mass index (BMI) in postmenopausal smokers. Methods Women (N = 301) signed informed consent and were randomized to treatment at two sites (Universities of Connecticut and Minnesota). We randomized groups of participants to a comprehensive group treatment program that included 12 weeks of varenicline and either a moderate exercise or relaxation component for 6 months. Participants were followed for a year after medication treatment. Results Overall, 17.3% of patients reported carbon monoxide-verified continuous abstinence for the 9- to 12-week period, and 11.6% reported prolonged abstinence at 1 year, with no significant differences between treatment conditions. CPD reported at study visits showed significant main effects for time in weeks, for site, and for treatment. The Exercise condition reported smoking fewer CPD over time, and that advantage widened over time. In terms of BMI, significant effects for time in weeks, and for the interaction of Week × Treatment condition, reflected gradually increasing BMI in these women over time, but with the increase in BMI slower in the Exercise condition. Conclusions Exercise, compared to relaxation, was associated with a reduced BMI and CPD in postmenopausal women, but did not increase end of treatment or prolonged abstinence. Further research is needed to devise exercise programs that increase smoking cessation rates in postmenopausal women. Implications This study adds to the literature on the effectiveness of a moderate exercise intervention compared to a relaxation control condition as an adjunctive treatment for smoking cessation in postmenopausal women. Our exercise program did not increase end of treatment or prolonged abstinence rates in postmenopausal women; however, there was a beneficial effect on smoking reduction and reduced body mass index. Additional research is needed to devise exercise programs that increase smoking cessation rates in postmenopausal women.

Cognitive deficits during nicotine withdrawal may contribute to smoking relapse. However, interacting effects of chronic nicotine dependence and acute nicotine withdrawal on cognitive control are poorly understood. Here we examine the effects of nicotine dependence (trait; smokers (n = 24) vs. non-smoking controls; n = 20) and acute nicotinic stimulation (state; administration of nicotine and varenicline, two FDA-approved smoking cessation aids, during abstinence), on two well-established tests of inhibitory control, the Go–Nogo task and the Flanker task, during fMRI scanning. We compared performance and neural responses between these four pharmacological manipulations in a double-blind, placebo-controlled crossover design. As expected, performance in both tasks was modulated by nicotine dependence, abstinence, and pharmacological manipulation. However, effects were driven entirely by conditions that required less inhibitory control. When demand for inhibitory control was high, abstinent smokers showed no deficits. By contrast, acutely abstinent smokers showed performance deficits in easier conditions and missed more trials. Go–Nogo fMRI results showed decreased inhibition-related neural activity in right anterior insula and right putamen in smokers and decreased dorsal anterior cingulate cortex activity on nicotine across groups. No effects were found on inhibition-related activity during the Flanker task or on error-related activity in either task. Given robust nicotinic effects on physiology and behavioral deficits in attention, we are confident that pharmacological manipulations were effective. Thus findings fit a recent proposal that abstinent smokers show decreased ability to divert cognitive resources at low or intermediate cognitive demand, while performance at high cognitive demand remains relatively unaffected, suggesting a primary attentional deficit during acute abstinence.

Varenicline tartrate is superior for smoking cessation to other tobacco cessation therapies by 52 weeks, in the outpatient setting. We aimed to evaluate the long-term (104 week) efficacy following a standard course of inpatient-initiated varenicline tartrate plus Quitline-counselling compared to Quitline-counselling alone. Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to one of three hospitals, were randomised to receive either 12-weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice-daily) plus Quitline-counselling, (n = 196) or Quitline-counselling alone, (n = 196), with continuous abstinence from smoking assessed at 104 weeks. A total of 1959 potential participants were screened for eligibility between August 2008 and December 2011. The proportion of participants who remained continuously abstinent (intention-to-treat) at 104 weeks were significantly greater in the varenicline tartrate plus counselling arm (29.2% n = 56) compared to counselling alone (18.8% n = 36; p = 0.02; odds ratio 1.78; 95%CI 1.10 to 2.86, p = 0.02). Twenty-two deaths occurred during the 104 week study (n = 10 for varenicline tartrate plus counselling and n = 12 for Quitline-counselling alone). All of these participants had known or developed underlying co-morbidities. This is the first study to examine the efficacy and safety of varenicline tartrate over 104 weeks within any setting. Varenicline tartrate plus Quitline-counselling was found to be an effective opportunistic treatment when initiated for inpatient smokers who had been admitted with tobacco-related disease.

Low rates of adherence to smoking cessation pharmacotherapy may limit the effectiveness of treatment. However, few studies have examined adherence in smoking cessation trials thus, there is a limited understanding of factors that influence adherence behaviors. This brief report analyzes correlates of adherence to varenicline among people living with HIV/AIDS. Study participants were recruited from three HIV care centers in New York City and enrolled in a three-arm randomized controlled pilot study in which all subjects received varenicline. At the 1-month study visit, there were no significant differences in adherence by study condition, therefore we combined treatment arms to examine correlates of adherence (n = 127). We used pill counts to assess varenicline adherence, defined as taking at least 80% of the prescribed dose. We conducted a multivariate path analysis to assess factors proposed by the information-motivation-behavioral skills model to predict adherence. Only 56% of smokers were at least 80% adherent to varenicline at 1 month. Adherence-related information, self-efficacy, a college degree, and non-Hispanic white race/ethnicity were associated with increased varenicline adherence. In path analysis, information and motivation were associated with increased adherence self-efficacy, and adherence self-efficacy was associated with increased adherence, but with marginal significance. These associations with adherence were no longer significant after controlling for race/ethnicity and education. Further exploration of the role of a modifiable correlates of adherence, such as adherence-related information, motivation and self-efficacy is warranted. Interventions are needed that can address disparities in these and other psychosocial factors that may mediate poor medication adherence.

As the prevalence of cigarette smoking has declined, the proportion of smokers who smoke less than 10 cigarettes/day (cpd) has increased. Varenicline may provide an effective pharmacotherapeutic treatment option for increasing smoking abstinence rates among light smokers. We conducted a randomized, placebo-controlled clinical trial evaluating the efficacy of varenicline for increasing smoking abstinence rates among light smokers (5-10 cpd). Participants received varenicline or placebo for 12 weeks. Outcomes were assessed at 3 and 6 months. Ninety-three participants were randomized. Fifty-two percent of participants terminated the study early. At end-of-treatment (3 months), the point prevalence smoking abstinence rate was 53.3% in the varenicline group compared to 14.5% in placebo (odds ratio [OR]: 6.69, 95% confidence interval [CI]: 2.48-18.06, P < .001), and the prolonged smoking abstinence rate was 40.0% and 8.3%, respectively (OR: 7.33, 95% CI: 2.24-23.98, P = .001). At end-of-study (6 months), the point prevalence smoking abstinence rate was 40.0% in the varenicline group compared to 20.8% in placebo (OR: 2.53, 95% CI: 1.01-6.34, P = .047), and the prolonged smoking abstinence rate was 31.1% and 8.3%, respectively (OR: 4.97, 95% CI: 1.49-16.53, P = .009). The estimated magnitude of the treatment effect remained consistent across the various missing data assumptions and in analyses that adjusted for gender. Nausea and sleep disturbance were more commonly reported in the varenicline group. Varenicline was safe and effective for increasing long-term smoking abstinence rates in a population of predominantly White light cigarette smoker. The efficacy of varenicline in this study was comparable to that observed in heavier smokers. Our findings demonstrate that varenicline is effective for increasing smoking cessation in light smokers. Our findings have implications for advancing the treatment of light smokers in clinical practice.