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Addiction Biology Jul 2019Tobacco and cannabis co-users (T+CUs) have poor cannabis cessation outcomes, but the mechanisms underlying this are not well understood. This laboratory study examined...
Tobacco and cannabis co-users (T+CUs) have poor cannabis cessation outcomes, but the mechanisms underlying this are not well understood. This laboratory study examined the effects of (1) the partial nicotinic agonist, varenicline, on tobacco cessation among T+CUs, and (2) varenicline, alone, and when combined with the cannabinoid agonist nabilone, on cannabis withdrawal and a laboratory model of cannabis relapse. Non-treatment-seeking T+CUs were randomized to active-varenicline or placebo-varenicline, and completed a 15-day outpatient phase; varenicline was titrated to 1 mg BID during days 1-8, and participants were instructed to abstain from tobacco during days 9-15. Participants then moved inpatient for 16 days, where they continued their outpatient medication and tobacco abstinence. Inpatient testing included two, 8-day medication periods, where active-nabilone and placebo-nabilone were administered in counterbalanced order, and measures of acute cannabis effects (days 1-2), withdrawal (days 4-5) and 'relapse' (days 6-8) were collected. Participants in the active-varenicline group were more likely to achieve cotinine-verified tobacco abstinence during the outpatient period versus placebo-varenicline group (46 percent versus 24 percent, respectively), and also reported less mood disturbance and cigarette craving while inpatient. Active-nabilone attenuated cannabis withdrawal in both groups but did not affect cannabis relapse. Regression analyses revealed that two tobacco-related variables, i.e. age of first cigarette use, and cigarette craving while inpatient, were independent predictors of cannabis relapse outcomes. Thus, varenicline holds promise in this population, as a tool to examine the effects of tobacco abstinence on cannabis use outcomes, and as a component of smoking cessation treatments targeting T+CUs.
Topics: Adult; Cigarette Smoking; Comorbidity; Dronabinol; Female; Humans; Male; Marijuana Abuse; Nicotine; Nicotinic Agonists; Smoking Cessation; Smoking Cessation Agents; Substance Withdrawal Syndrome; Varenicline; Young Adult
PubMed: 30378231
DOI: 10.1111/adb.12664 -
Addiction (Abingdon, England) May 2019It is useful, for theoretical and practical reasons, to be able to specify functions for continuous abstinence over time in smoking cessation attempts. This study aimed... (Comparative Study)
Comparative Study Review
BACKGROUND AND AIM
It is useful, for theoretical and practical reasons, to be able to specify functions for continuous abstinence over time in smoking cessation attempts. This study aimed to find the best-fitting models of mean proportion abstinent with different smoking cessation pharmacotherapies up to 52 weeks from the quit date.
METHODS
We searched the Cochrane Database of Systematic Reviews to identify randomized controlled trials (RCTs) of pharmacological treatments to aid smoking cessation. For comparability, we selected trials that provided 12 weeks of treatment. Continuous abstinence rates for each treatment at each follow-up point in trials were extracted along with methodological details of the trial. Data points for each pharmacotherapy at each follow-up point were aggregated where the total across contributing studies included at least 1000 participants per data point. Continuous abstinence curves were modelled using a range of different functions from the quit date to 52-week follow-up. Models were compared for fit using R and Bayesian information criterion (BIC).
RESULTS
Studies meeting our selection criteria covered three pharmacotherapies [varenicline, nicotine replacement therapy (NRT) and bupropion] and placebo. Power functions provided the best fit (R > 0.99, BIC < 17.0) to continuous abstinence curves from the target quit date in all cases except for varenicline, where a logarithmic function described the curve best (R = 0.99, BIC = 21.2). At 52 weeks, abstinence rates were 22.5% (23.0% modelled) for varenicline, 16.7% (16.0% modelled) for bupropion, 13.0% (12.4% modelled) for NRT and 8.3% (8.9% modelled) for placebo. For varenicline, bupropion, NRT and placebo, respectively, 55.9, 65.0, 62.3 and 56.5% of participants who were abstinent at the end of treatment were still abstinent at 52 weeks.
CONCLUSIONS
Mean continuous abstinence rates up to 52 weeks from initiation of smoking cessation attempts in clinical trials can be modelled using simple power functions for placebo, nicotine replacement therapy and bupropion and a logarithmic function for varenicline. This allows accurate prediction of abstinence rates from any time point to any other time point up to 52 weeks.
Topics: Biobehavioral Sciences; Bupropion; Follow-Up Studies; Humans; Randomized Controlled Trials as Topic; Recurrence; Smoking Cessation; Smoking Cessation Agents; Tobacco Use Cessation Devices; Varenicline
PubMed: 30614586
DOI: 10.1111/add.14549 -
Psychopharmacology Apr 2020Barriers to smoking cessation, including negative affect and cognitive dysfunction, may contribute to high smoking rates among people living with HIV/AIDS (PLWH).... (Clinical Trial)
Clinical Trial
RATIONALE
Barriers to smoking cessation, including negative affect and cognitive dysfunction, may contribute to high smoking rates among people living with HIV/AIDS (PLWH). Varenicline may help PLWH quit smoking by improving mood and cognition, yet this has not been explored.
OBJECTIVES
The goal of this study was to evaluate the effect of varenicline on mood and cognition among PLWH enrolled in a smoking cessation clinical trial.
METHODS
In this secondary analysis of a varenicline trial (NCT01710137), we assessed mood (depression, anxiety) and cognition (attention, working memory) at weeks 0 (baseline), 1, 3, and 12 (end-of-treatment, EOT). Primary outcomes were changes in mood and cognition from baseline to EOT. Secondarily, mood and cognition were evaluated as predictors of biochemically confirmed 7-day point-prevalence abstinence at EOT.
RESULTS
Overall, 173 subjects (87 varenicline, 86 placebo) were included. At EOT, varenicline reduced anxiety (P < 0.001), vs. placebo (P = 0.31; interaction P = 0.05). Across both treatment arms, reductions in anxiety from baseline to EOT were associated with a higher likelihood of abstinence (OR = 1.3, 95% CI 1.1 to 1.6, P = 0.01). There were no significant treatment by time interactions for cognition or depression.
CONCLUSIONS
These data suggest that varenicline operates, at least in part, by reducing anxiety. Anxiety should be an intervention target for smokers with HIV interested in quitting.
Topics: Adult; Affect; Anxiety; Cigarette Smoking; Cognition; Female; Follow-Up Studies; HIV Infections; Humans; Male; Middle Aged; Smokers; Smoking Cessation; Smoking Cessation Agents; Varenicline; Young Adult
PubMed: 31938877
DOI: 10.1007/s00213-020-05451-w -
PloS One 2024Alcohol Use Disorder (AUD) is a major cause of premature death, disability and suffering. Available treatments are of modest efficacy and under-prescribed so there is a...
A randomized, double-blind, placebo-controlled, multicentre trial on the efficacy of varenicline and bupropion in combination and alone for treatment of alcohol use disorder: Protocol for the COMB study.
BACKGROUND
Alcohol Use Disorder (AUD) is a major cause of premature death, disability and suffering. Available treatments are of modest efficacy and under-prescribed so there is a pressing need for a well-tolerated and effective treatment option for AUD. Dopamine is hypothesized to be involved in the development of alcohol dependence. To challenge the low-dopamine hypothesis of addiction, this randomized, double-blind, placebo-controlled, 13-week, multicentre clinical trial with four parallel arms is designed to evaluate the efficacy of two substances raising dopamine levels, varenicline and bupropion, alone and in combination vs. placebo on alcohol consumption in AUD. Varenicline, a partial agonist at brain nicotinic acetylcholine receptors increases dopamine release, whereas bupropion is a centrally-acting, norepinephrine-dopamine reuptake inhibitor. Varenicline is previously shown to reduce alcohol intake in individuals with AUD. We hypothesize that the effect size of a combination of two drugs affecting dopamine levels in the brain will exceed that of approved AUD therapies.
METHODS
Consenting individuals with AUD will be recruited via media advertisements. Those fulfilling the eligibility criteria (N = 380) will be randomized to one of four interventions (n = 95 per arm). Treatment will comprise one week of titration (varenicline 0.5‒2 mg; bupropion SR 150‒300 mg) plus 12 weeks at steady state. Efficacy will be evaluated using two primary endpoints of alcohol consumption: Heavy Drinking Days and blood levels of phosphatidylethanol. Secondary objectives, exploratory and subgroup analyses will be also performed. The modified Intention-to-Treat and Per Protocol datasets will be evaluated using Analysis of Covariance. Last patient out is estimated to occur in December, 2022.
DISCUSSION
The COMB Study aims to evaluate the efficacy of the combination of varenicline and bupropion, two drugs affecting dopamine, on alcohol consumption, and to challenge the low-dopamine hypothesis of addiction. Study Code COMB-BO8, EudraCT 2018-000048-24, Version 3.2, Lidö & deBejczy, 2020-06-16; https://clinicaltrials.gov identifier NCT04167306.
Topics: Humans; Varenicline; Bupropion; Alcoholism; Nicotinic Agonists; Dopamine; Smoking Cessation; Benzazepines; Quinoxalines; Treatment Outcome; Alcohol Drinking; Double-Blind Method; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 38206930
DOI: 10.1371/journal.pone.0296118 -
JAMA Network Open Sep 2019Drug safety communications released by the US Food and Drug Administration (FDA) are often based on limited evidence on safety signals after approval. Varenicline may... (Observational Study)
Observational Study
IMPORTANCE
Drug safety communications released by the US Food and Drug Administration (FDA) are often based on limited evidence on safety signals after approval. Varenicline may serve as a relevant case study because it was the target of several FDA communications in 2008 and 2009; ultimately, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) dismissed safety concerns on increased suicidal thoughts and aggressive and erratic behavior on December 16, 2016.
OBJECTIVE
To examine the association between FDA drug safety communications and the use of varenicline.
DESIGN, SETTING, AND PARTICIPANTS
Retrospective, longitudinal, cross-sectional study of Veterans Health Administration (VHA) outpatient data from October 1, 2001, through December 31, 2018, and Medicaid drug state use data from July 1, 2006, through September 30, 2018, on varenicline prescribing.
MAIN OUTCOMES AND MEASURES
Prescribing records for varenicline and nicotine replacement therapy (NRT) in the VHA were extracted, and the number of unique varenicline and NRT users in the VHA per quarter was measured. An interrupted time series analysis was performed to describe the association between FDA safety warnings and the use of varenicline and NRT. To test the generalizability of the findings, similar analyses were conducted using the number of prescriptions reimbursed for varenicline by Medicaid every quarter in 2006-2018.
RESULTS
After its addition to the VHA national drug formulary in January 2007, varenicline use presented a steady increase, reaching a peak of 32 581 quarterly unique users in the first quarter of 2008. Within 12 months of the February 1, 2008, public health advisory, quarterly varenicline use in VHA patients decreased by 68.7% (from 32 581 to 10 182 patients; P < .001 for slope change), and NRT use increased by 32.1% (from 55 728 to 73 629 patients; P < .001 for slope change). In Medicaid prescriptions, varenicline use decreased by 38.0% (from 109 308 to 67 761 prescriptions; P < .001 for slope change) within 12 months of the 2008 public health advisory. Twelve months after the publication of the EAGLES trial, which showed no significant increase in psychiatric/behavioral effects with varenicline relative to NRT, use of varenicline increased by 42.7% in VHA patients (from 9251 to 13 199 patients; P = .01 for slope change) and by 26.0% in Medicaid prescriptions (112 063 to 141 122; P = .26 for slope change ).
CONCLUSIONS AND RELEVANCE
With use of varenicline as a case study, early communications from the FDA and VHA followed by a labeling change appeared to be associated with a considerable decrease in drug use, which may have been associated with negative public health consequences.
Topics: Epidemiologic Studies; Humans; Interrupted Time Series Analysis; Medicaid; Mental Disorders; Nicotinic Agonists; United States; United States Food and Drug Administration; Varenicline
PubMed: 31483473
DOI: 10.1001/jamanetworkopen.2019.10626 -
Sleep May 2015To assess adverse drug reaction reports of "abnormal sleep related events" associated with varenicline, a partial agonist to the α4β2 subtype of nicotinic...
STUDY OBJECTIVES
To assess adverse drug reaction reports of "abnormal sleep related events" associated with varenicline, a partial agonist to the α4β2 subtype of nicotinic acetylcholine receptors on neurones, indicated for smoking cessation.
DESIGN
Twenty-seven reports of "abnormal sleep related events" often associated with abnormal dreams, nightmares, or somnambulism, which are known to be associated with varenicline use, were identified in the World Health Organisation (WHO) Global Individual Case Safety Reports Database. Original anonymous reports were obtained from the four national pharmacovigilance centers that submitted these reports and assessed for reaction description and causality.
MEASUREMENTS AND RESULTS
These 27 reports include 10 of aggressive activity occurring during sleep and seven of other sleep related harmful or potentially harmful activities, such as apparently deliberate self-harm, moving a child or a car, or lighting a stove or a cigarette. Assessment of these 17 reports of aggression or other actual or potential harm showed that nine patients recovered or were recovering on varenicline withdrawal and there were no consistent alternative explanations. Thirteen patients experienced single events, and two had multiple events. Frequency was not stated for the remaining two patients.
CONCLUSIONS
The descriptions of the reports of aggression during sleep with violent dreaming are similar to those of rapid eye movement sleep behavior disorder and also nonrapid eye movement (NREM) sleep parasomnias in some adults. Patients who experience somnambulism or dreams of a violent nature while taking varenicline should be advised to consult their health providers. Consideration should be given to clarifying the term sleep disorders in varenicline product information and including sleep related harmful and potentially harmful events.
Topics: Adult; Aggression; Benzazepines; Dreams; Drug Labeling; Female; Humans; Male; Middle Aged; Nicotinic Agonists; Parasomnias; Pharmacovigilance; Quinoxalines; Sleep Wake Disorders; Smoking Cessation; Somnambulism; Varenicline; World Health Organization
PubMed: 25409105
DOI: 10.5665/sleep.4686 -
BMJ (Clinical Research Ed.) Mar 2015To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials.
DESIGN
Systematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models, risk differences, and Peto odds ratios.
DATA SOURCES
Medline, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised controlled trials with a placebo comparison group that reported on neuropsychiatric adverse events (depression, suicidal ideation, suicide attempt, suicide, insomnia, sleep disorders, abnormal dreams, somnolence, fatigue, anxiety) and death. Studies that did not involve human participants, did not use the maximum recommended dose of varenicline (1 mg twice daily), and were cross over trials were excluded.
RESULTS
In the 39 randomised controlled trials (10,761 participants), there was no evidence of an increased risk of suicide or attempted suicide (odds ratio 1.67, 95% confidence interval 0.33 to 8.57), suicidal ideation (0.58, 0.28 to 1.20), depression (0.96, 0.75 to 1.22), irritability (0.98, 0.81 to 1.17), aggression (0.91, 0.52 to 1.59), or death (1.05, 0.47 to 2.38) in the varenicline users compared with placebo users. Varenicline was associated with an increased risk of sleep disorders (1.63, 1.29 to 2.07), insomnia (1.56, 1.36 to 1.78), abnormal dreams (2.38, 2.05 to 2.77), and fatigue (1.28, 1.06 to 1.55) but a reduced risk of anxiety (0.75, 0.61 to 0.93). Similar findings were observed when risk differences were reported. There was no evidence for a variation in depression and suicidal ideation by age group, sex, ethnicity, smoking status, presence or absence of psychiatric illness, and type of study sponsor (that is, pharmaceutical industry or other).
CONCLUSIONS
This meta-analysis found no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression, or death with varenicline. These findings provide some reassurance for users and prescribers regarding the neuropsychiatric safety of varenicline. There was evidence that varenicline was associated with a higher risk of sleep problems such as insomnia and abnormal dreams. These side effects, however, are already well recognised.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO 2014:CRD42014009224.
Topics: Aggression; Benzazepines; Depression; Humans; Mental Disorders; Quinoxalines; Risk Factors; Sleep Wake Disorders; Suicide; Suicide, Attempted; Tobacco Use Cessation Devices; Varenicline
PubMed: 25767129
DOI: 10.1136/bmj.h1109 -
Addiction (Abingdon, England) Apr 2022To determine how varenicline, bupropion, nicotine replacement therapy (NRT) and electronic cigarettes compare with respect to their clinical effectiveness and safety. (Meta-Analysis)
Meta-Analysis Review
Comparative clinical effectiveness and safety of tobacco cessation pharmacotherapies and electronic cigarettes: a systematic review and network meta-analysis of randomized controlled trials.
AIM
To determine how varenicline, bupropion, nicotine replacement therapy (NRT) and electronic cigarettes compare with respect to their clinical effectiveness and safety.
METHOD
Systematic reviews and Bayesian network meta-analyses of randomized controlled trials, in any setting, of varenicline, bupropion, NRT and e-cigarettes (in high, standard and low doses, alone or in combination) in adult smokers and smokeless tobacco users with follow-up duration of 24 weeks or greater (effectiveness) or any duration (safety). Nine databases were searched until 19 February 2019. Primary outcomes were sustained tobacco abstinence and serious adverse events (SAEs). We estimated odds ratios (ORs) and treatment rankings and conducted meta-regression to explore covariates.
RESULTS
We identified 363 trials for effectiveness and 355 for safety. Most monotherapies and combination therapies were more effective than placebo at helping participants to achieve sustained abstinence; the most effective of these, estimated with some imprecision, were varenicline standard [OR = 2.83, 95% credible interval (CrI) = 2.34-3.39] and varenicline standard + NRT standard (OR = 5.75, 95% CrI = 2.27-14.88). Estimates were higher in smokers receiving counselling than in those without and in studies with higher baseline nicotine dependence scores than in those with lower scores. Varenicline standard + NRT standard showed a high probability of being ranked best or second-best. For safety, only bupropion at standard dose increased the odds of experiencing SAEs compared with placebo (OR = 1.27, 95% CrI = 1.04-1.58), and we found no evidence of effect modification.
CONCLUSIONS
Most tobacco cessation monotherapies and combination therapies are more effective than placebo at helping participants to achieve sustained abstinence, with varenicline appearing to be most effective based on current evidence. There does not appear to be strong evidence of associations between most tobacco cessation pharmacotherapies and adverse events; however, the data are limited and there is a need for improved reporting of safety data.
Topics: Adult; Bayes Theorem; Bupropion; Electronic Nicotine Delivery Systems; Humans; Network Meta-Analysis; Randomized Controlled Trials as Topic; Smoking Cessation; Tobacco Use Cessation; Tobacco Use Cessation Devices; Treatment Outcome; Varenicline
PubMed: 34636108
DOI: 10.1111/add.15675 -
International Journal of Environmental... Sep 2021We aimed to investigate the effectiveness of the Korean national five-day residential smoking cessation program and the factors affecting the long-term smoking cessation...
We aimed to investigate the effectiveness of the Korean national five-day residential smoking cessation program and the factors affecting the long-term smoking cessation of participants. The residential smoking cessation program (2017-2018) recruited smokers with a smoking duration ≥ 20 years and who have attempted to quit smoking more than twice and/or smokers with chronic morbidities. Participants underwent an intensive intervention, including individual psychological therapy, group therapy, medical counseling, and pharmacotherapy. The 6-month continuous abstinence rate (CAR) was assessed via self-reports, the urine cotinine levels, and/or expired-air carbon monoxide levels. Logistic regression was used to analyze the adjusted odds ratio (aOR) to assess factors related to smoking cessation. Overall, 484 participants who completed the residential program and questionnaire were evaluated. The 3- and 6-month CAR were 81.82% and 63.22%, respectively. The aOR of 6-month continuous abstinence was lower among participants with severe nicotine dependence (aOR: 0.46, 95% confidence interval [CI]: 0.26-0.81) and higher among participants with combination therapy of varenicline with short-term nicotine replacement therapy (NRT) (aOR: 1.64, 95% CI: 1.07-2.51), with higher self-efficacy (aOR: 1.97, 95% CI: 1.15-3.37). The residential smoking cessation program was effective. High self-efficacy, combination therapy of varenicline with short-term NRT, and low nicotine dependence were associated with a high 6-month CAR.
Topics: Humans; Smoking; Smoking Cessation; Tobacco Use Cessation Devices; Tobacco Use Disorder; Varenicline
PubMed: 34574823
DOI: 10.3390/ijerph18189901 -
Archivos de Bronconeumologia Oct 2023There are multiple systematic reviews and meta-analyses on the efficacy and safety of pharmacological treatments against nicotine dependence. However, there are few...
INTRODUCTION
There are multiple systematic reviews and meta-analyses on the efficacy and safety of pharmacological treatments against nicotine dependence. However, there are few guidelines to answer frequent questions asked by a clinician treating a smoker. Therefore, the aim of this paper is to facilitate the treatment of tobacco addiction.
MATERIAL AND METHODS
12 PICO questions are formulated from a GLOBAL PICO question: "Efficacy and safety of pharmacological treatment of tobacco dependence". A systematic review was carried out to answer each of the questions and recommendations were made. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system was used to grade the certainty of the estimated effects and the strength of the recommendations.
RESULTS
Varenicline, nicotine replacement therapy (NRT), bupropion and cytisine are more effective than placebo. Varenicline and combined nicotine therapy are superior to the other therapies. In smokers with high dependence, a combination of drugs is recommended, being more effective those associations containing varenicline. Other optimization strategies with lower efficacy consist of increasing the doses, the duration, or retreat with varenicline. In specific populations varenicline or NRT is recommended. In hospitalized, the treatment of choice is NRT. In pregnancy it is indicated to prioritize behavioral treatment. The financing of smoking cessation treatments increases the number of smokers who quit smoking. There is no scientific evidence of the efficacy of pharmacological treatment of smoking cessation in adolescents.
CONCLUSIONS
The answers to the 12 questions allow us to extract recommendations and algorithms for the pharmacological treatment of tobacco dependence.
Topics: Pregnancy; Female; Humans; Adolescent; Tobacco Use Disorder; Varenicline; Smoking Cessation; Nicotinic Agonists; Thoracic Surgery; Pulmonary Medicine; Tobacco Use Cessation Devices; Bupropion; Alcoholism
PubMed: 37567792
DOI: 10.1016/j.arbres.2023.07.024