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Journal of the American College of... Dec 2018Tobacco use is the leading preventable cause of death worldwide and is a major risk factor for cardiovascular disease (CVD). Both prevention of smoking initiation among... (Review)
Review
Tobacco use is the leading preventable cause of death worldwide and is a major risk factor for cardiovascular disease (CVD). Both prevention of smoking initiation among youth and smoking cessation among established smokers are key for reducing smoking prevalence and the associated negative health consequences. Proven tobacco cessation treatment includes pharmacotherapy and behavioral support, which are most effective when provided together. First-line medications (varenicline, bupropion, and nicotine replacement) are effective and safe for patients with CVD. Clinicians who care for patients with CVD should give as high a priority to treating tobacco use as to managing other CVD risk factors. Broader tobacco control efforts to raise tobacco taxes, adopt smoke-free laws, conduct mass media campaigns, and restrict tobacco marketing enhance clinicians' actions working with individual smokers.
Topics: Bupropion; Cigarette Smoking; Health Promotion; Humans; Smoking Cessation; Tobacco Use; Tobacco Use Cessation; Tobacco Use Cessation Devices; Treatment Outcome; Varenicline
PubMed: 30522631
DOI: 10.1016/j.jacc.2018.10.020 -
British Journal of Clinical Pharmacology Feb 2014Strategies for assisting smoking cessation include behavioural counselling to enhance motivation and to support attempts to quit and pharmacological intervention to... (Review)
Review
Strategies for assisting smoking cessation include behavioural counselling to enhance motivation and to support attempts to quit and pharmacological intervention to reduce nicotine reinforcement and withdrawal from nicotine. Three drugs are currently used as first line pharmacotherapy for smoking cessation, nicotine replacement therapy, bupropion and varenicline. Compared with placebo, the drug effect varies from 2.27 (95% CI 2.02, 2.55) for varenicline, 1.69 (95% CI 1.53, 1.85) for bupropion and 1.60 (95% CI 1.53, 1.68) for any form of nicotine replacement therapy. Despite some controversy regarding the safety of bupropion and varenicline, regulatory agencies consider these drugs as having a favourable benefit/risk profile. However, given the high rate of psychiatric comorbidity in dependent smokers, practitioners should closely monitor patients for neuropsychiatric symptoms. Second-line pharmacotherapies include nortriptyline and clonidine. This review also offers an overview of pipeline developments and issues related to smoking cessation in special populations such as persons with psychiatric comorbidity and pregnant and adolescent smokers.
Topics: Adolescent; Benzazepines; Bupropion; Counseling; Drug Design; Female; Humans; Molecular Sequence Data; Pregnancy; Quinoxalines; Smoking Cessation; Tobacco Use Cessation Devices; Tobacco Use Disorder; Varenicline
PubMed: 23488726
DOI: 10.1111/bcp.12116 -
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 -
Preventive Cardiology 2008Varenicline is a partial agonist of alpha4beta2 nicotinic receptors. It was recently approved for smoking cessation in the United States. It is administered at a dosage... (Review)
Review
Varenicline is a partial agonist of alpha4beta2 nicotinic receptors. It was recently approved for smoking cessation in the United States. It is administered at a dosage of 0.5 mg once a day for an initial period of 3 days followed by 0.5 mg twice a day for the next 4 days. Following this, the drug is administered at a dosage of 1.0 mg twice a day. The total duration of therapy is 12 weeks. Common adverse effects include nausea, headache, and insomnia. Recent studies show that varenicline is almost twice as effective as bupropion SR in smoking cessation. Given the increased risk of cardiovascular morbidity secondary to smoking, especially in the elderly, varenicline is a major therapeutic tool in the fight against smoking.
Topics: Benzazepines; Humans; Quinoxalines; Smoking Cessation; Treatment Outcome; Varenicline
PubMed: 18607153
DOI: 10.1111/j.1751-7141.2008.08258.x -
AIDS and Behavior Jul 2017Smoking represents an important health risk for people living with HIV (PLHIV). Low adherence to smoking cessation pharmacotherapy may limit treatment effectiveness. In... (Randomized Controlled Trial)
Randomized Controlled Trial
Combining Text Messaging and Telephone Counseling to Increase Varenicline Adherence and Smoking Abstinence Among Cigarette Smokers Living with HIV: A Randomized Controlled Study.
Smoking represents an important health risk for people living with HIV (PLHIV). Low adherence to smoking cessation pharmacotherapy may limit treatment effectiveness. In this study, 158 participants recruited from three HIV care centers in New York City were randomized to receive 12-weeks of varenicline (Chantix) either alone as standard care (SC) or in combination with text message (TM) support or TM plus cell phone-delivered adherence-focused motivational and behavioral therapy (ABT). Generalized linear mixed-effect models found a significant decline in varenicline adherence from week 1-12 across treatment groups. At 12-weeks, the probability of smoking abstinence was significantly higher in SC+TM+ABT than in SC. The study demonstrates the feasibility of delivering adherence-focused interventions to PLHIV who smoke. Findings suggest intensive behavioral support is an important component of an effective smoking cessation intervention for this population, and a focus on improving adherence self-efficacy may lead to more consistent adherence and higher smoking abstinence.
Topics: Adult; Behavior Therapy; Cell Phone; Counseling; Female; HIV Infections; Humans; Male; Medication Adherence; Middle Aged; Motivational Interviewing; New York City; Nicotinic Agonists; Research Design; Smoking; Smoking Cessation; Telephone; Text Messaging; Treatment Outcome; Varenicline
PubMed: 27605365
DOI: 10.1007/s10461-016-1538-z -
American Family Physician Sep 2017
Review
Topics: Adult; Drug Labeling; Humans; Smoking Cessation; Smoking Cessation Agents; Varenicline
PubMed: 28925657
DOI: No ID Found -
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 -
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 -
The Journal of Pharmacology and... Mar 2021Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs).... (Comparative Study)
Comparative Study
Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs). Nicotine supports self-administration in rodents. However, it remains undetermined whether cotinine can be self-administered. This study aimed to characterize cotinine self-administration in rats, to compare effects of cotinine to those of nicotine, and to determine potential involvement of nAChRs in cotinine's effects. Adult Wistar rats were trained to self-administer cotinine or nicotine (0.0075, 0.015, 0.03, or 0.06 mg/kg per infusion) under fixed-ratio (FR) and progressive-ratio (PR) schedules. Blood nicotine and cotinine levels were determined after the last FR session. Effects of mecamylamine, a nonselective nAChR antagonist, and varenicline, a partial agonist for 42* nAChRs, on cotinine and nicotine self-administration were determined. Rats readily acquired cotinine self-administration, responded more on active lever, and increased motivation to self-administer cotinine when the reinforcement requirement increased. Blood cotinine levels ranged from 77 to 792 ng/ml. Nicotine induced more infusions at lower doses during FR schedules and greater breakpoints at higher doses during the PR schedule than cotinine. There was no difference in cotinine self-administration between male and female rats. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results indicate that cotinine was self-administered by rats. These effects of cotinine were less robust than nicotine and exhibited no sex difference. nAChRs appeared to be differentially involved in self-administration of nicotine and cotinine. These results suggest cotinine may play a role in the development of nicotine use and misuse. SIGNIFICANCE STATEMENT: Nicotine addiction is a serious public health problem. Cotinine is the major metabolite of nicotine, but its involvement in nicotine reinforcement remains elusive. Our findings indicate that cotinine, at doses producing clinically relevant blood cotinine levels, supported intravenous self-administration in rats. Cotinine self-administration was less robust than nicotine. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results suggest cotinine may play a role in the development of nicotine use and misuse.
Topics: Animals; Cotinine; Dose-Response Relationship, Drug; Drug Interactions; Female; Male; Mecamylamine; Nicotine; Rats; Rats, Wistar; Receptors, Nicotinic; Self Administration; Varenicline
PubMed: 33361363
DOI: 10.1124/jpet.120.000367 -
Neuropharmacology Nov 2020The landscape of worldwide tobacco use is changing, with a decrease in traditional smoking and an exponential rise in electronic cigarette use. No new nicotine cessation... (Review)
Review
The landscape of worldwide tobacco use is changing, with a decrease in traditional smoking and an exponential rise in electronic cigarette use. No new nicotine cessation pharmacotherapies have come to market in the last 10 years. The current therapies that have been approved by the United States Food and Drug Administration for nicotine cessation include nicotine replacement therapy, varenicline, a nicotinic acetylcholine receptor partial agonist, and the atypical antidepressant bupropion. Nicotine replacement therapy and varenicline both act on nicotinic acetylcholine receptors. Bupropion inhibits the dopamine transporter, the norepinephrine transporter, and the nicotinic acetylcholine receptors to inhibit smoking behavior. Notwithstanding these treatments, rates of successful nicotine cessation in clinical trials remain low. Recent pharmacological approaches to improve nicotine cessation rates in animal models have turned their focus away from activating nicotinic acetylcholine receptors. The present review focuses on such pharmacological approaches, including nicotine vaccines, anti-nicotine antibodies, nicotine-degrading enzymes, cannabinoids, and metformin. Both immunopharmacological and enzymatic approaches rely on restricting and degrading nicotine within the periphery, thus preventing psychoactive effects of nicotine on the central nervous system. In contrast, pharmacologic inhibition of the enzymes which degrade nicotine could affect smoking behavior. Cannabinoid receptor agonists and antagonists interact with the dopamine reward pathway and show efficacy in reducing nicotine addiction-like behaviors in preclinical studies. Metformin is currently approved by the Food and Drug Administration for the treatment of diabetes. It activates specific intracellular kinases that may protect against the lower metabolism, higher oxidation, and inflammation that are associated with nicotine withdrawal. Further studies are needed to investigate non-nicotinic targets to improve the treatment of tobacco use disorder. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
Topics: Animals; Antidepressive Agents; Bupropion; Disease Models, Animal; Electronic Nicotine Delivery Systems; Humans; Nicotinic Agonists; Receptors, Nicotinic; Smoking Cessation; Smoking Cessation Agents; Tobacco Use Cessation Devices; Tobacco Use Disorder; Varenicline
PubMed: 32758566
DOI: 10.1016/j.neuropharm.2020.108225