-
The Medical Letter on Drugs and... Jan 2024
Topics: Humans; Dry Eye Syndromes; Cyclosporine; Ophthalmic Solutions; Fluorocarbons
PubMed: 38212258
DOI: 10.58347/tml.2024.1694c -
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 -
Addictive Behaviors Apr 2024Little is known about the mechanisms by which medication adherence promotes smoking cessation among adults with MDD. We tested the hypothesis that early adherence...
SIGNIFICANCE
Little is known about the mechanisms by which medication adherence promotes smoking cessation among adults with MDD. We tested the hypothesis that early adherence promotes abstinence by increasing behavioral treatment (BT) utilization.
METHODS
Data for this post-hoc analysis were from a randomized trial of 149 adults with current or past MDD treated with BT and either varenicline (n = 81) or placebo (n = 68). Arms were matched on medication regimen. Early medication adherence was measured by the number of days in which medication was taken at the prescribed dose during the first six of 12 weeks of pharmacological treatment (weeks 2-7). BT consisted of eight 45-minute sessions (weeks 1-12). Bioverified abstinence was assessed at end-of-treatment (week 14). A regression-based approach was used to test whether the effect of early medication adherence on abstinence was mediated by BT utilization.
RESULTS
Among 141 participants who initiated the medication regimen, BT utilization mediated the effect of early medication adherence on abstinencea) an interquartile increase in early medication days from 20 to 42 predicted a 4.2 times increase in abstinence (Total Risk Ratio (RR) = 4.24, 95% CI = 2.32-13.37; p <.001); b) increases in BT sessions predicted by such an increase in early medication days were associated with a 2.7 times increase in abstinence (Indirect RR = 2.73, 95% CI = 1.54-7.58; p <.001); and c) early medication adherence effects on abstinence were attenuated, controlling for BT (Direct RR = 1.55, 95% CI = 0.83-4.23, p =.17).
CONCLUSIONS
The effect of early medication adherence on abstinence in individuals with current or past MDD is mediated by intensive BT utilization.
Topics: Adult; Humans; Depressive Disorder, Major; Medication Adherence; Nicotinic Agonists; Smoking Cessation; Varenicline; Randomized Controlled Trials as Topic
PubMed: 38199093
DOI: 10.1016/j.addbeh.2024.107952 -
Journal of Addiction MedicineThe high prevalence of tobacco/nicotine use among youth, including e-cigarettes, is a public health problem in the United States. Early exposure leads to an increased... (Review)
Review
The high prevalence of tobacco/nicotine use among youth, including e-cigarettes, is a public health problem in the United States. Early exposure leads to an increased risk of dependence and health consequences in adulthood. We reviewed the literature on current treatment approaches for nicotine/tobacco use in adolescents/young adults and highlighted underexplored areas of treatment research. There are no current Food and Drug Administration-approved medications for treatment of nicotine/tobacco use disorders in adolescents. However, in research settings and on a case-to-case basis, clinical practice medications (including nicotine replacement therapy, bupropion, and varenicline) have been prescribed to this population with consideration of risk-benefit analysis when behavioral treatments are not sufficient to address dependence. Among the nonpharmacological interventions, there is evidence to support the potential for expanded use of contingency management in youth. Neural differences predisposing adolescents to substance use, along with higher attentiveness to value of options in decision making (flexible reward system) may enhance the effectiveness of reward-based approaches for treatment of substance use disorders in this population. The overall high rates of nonresponders across psychosocial and pharmacological treatments highlight the importance of considering novel strategies to improve existing interventions. We suggest that future research be done that considers unique characteristics of today's adolescents, such as high social activism and engagement with digital rewards to tailor contingency management for this age group and assess its effectiveness. Adolescents could potentially benefit from rewards administered through digital media (eg, video games, computer-based apps, and social media influencers).
Topics: Young Adult; Adolescent; Humans; Nicotine; Smoking Cessation; Nicotinic Agonists; Electronic Nicotine Delivery Systems; Internet; Tobacco Use Cessation Devices; Tobacco Use Disorder; Bupropion; Varenicline; Tobacco Use
PubMed: 38197859
DOI: 10.1097/ADM.0000000000001249 -
EClinicalMedicine Dec 2023The efficacy and safety of varenicline for smoking cessation among individuals who smoke tobacco cigarettes and also use electronic cigarettes (known e-cigarettes or...
BACKGROUND
The efficacy and safety of varenicline for smoking cessation among individuals who smoke tobacco cigarettes and also use electronic cigarettes (known e-cigarettes or vapes) have not been studied. We aimed to address this knowledge gap and examine predictors for smoking abstinence.
METHODS
In this double-blind, placebo-controlled, single-centre randomised trial in Italy, we enrolled adults who had used an e-cigarette daily for at least 12 months and who also smoked at least one tobacco cigarette per day and had a willingness to quit smoking. 155 participants were randomly assigned to receive either varenicline (n = 78) or matched placebo (n = 77). Varenicline (1 mg, administered twice daily for 12 weeks) was given in combination with smoking cessation counseling in dual users with an intention to quit smoking. Participants in both treatment groups received the same smoking cessation counselling throughout the whole duration of the study. The trial consisted of a 12-week treatment phase followed by a 12-week follow-up. The primary efficacy endpoint was continuous abstinence rate (CAR) in weeks 4-12. Secondary efficacy endpoints were the CAR in weeks 4-24 and 7-day point prevalence of smoking abstinence at weeks 12 and 24. This study is registered in EUDRACT, 2016-000339-42.
FINDINGS
Between November 2018, and February 2020, 114 participants (61 in the varenicline group and 53 in the placebo group) completed the intervention phase at week 12 and 88 participants (52 in the varenicline group and 36 in the placebo group) completed the follow-up phase at week 24. CARs were significantly higher for the varenicline vs placebo at each time-point: 50.0% vs 16.9% (OR = 4.9; 95% CI, 2.3-10.4; P < 0.0001) between weeks 4 and 12; and 48.7% vs 14.3% (OR = 5.7; 95% CI, 2.6-12.3; P < 0.0001) between weeks 4 and 24. The 7-day point prevalence of smoking abstinence was also higher for the varenicline than placebo at each time point. Adverse events were rated as mild or moderate and rarely led to treatment discontinuation.
INTERPRETATION
Our findings indicate that inclusion of varenicline in a cessation programme for adults who smoke and use e-cigarettes with an intention to quit smoking could result in smoking abstinence without serious adverse events. In the absence of evidence from other smoking cessation methods, it could be useful to suggest the use of varenicline in cessation programmes specifically designed to help dual users stop smoking. Further research in larger and more generalisable populations is required to strengthen such a suggestion.
FUNDING
Global Research Award for Nicotine Dependence, an independently reviewed competitive grants programmeme funded by Pfizer.
PubMed: 38192585
DOI: 10.1016/j.eclinm.2023.102316 -
Addiction (Abingdon, England) Apr 2024Smoking is considered the main cause of preventable death world-wide. This study aimed to review the efficacy and safety of cytisine for smoking cessation. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
Smoking is considered the main cause of preventable death world-wide. This study aimed to review the efficacy and safety of cytisine for smoking cessation.
METHODS
This review included an exhaustive search of databases to identify randomized controlled trials (RCTs) in health centers of any level with smokers of any age or gender investigating the effects of cytisine at standard dosage versus placebo, varenicline or nicotine replacement therapy (NRT).
RESULTS
We identified 12 RCTs. Eight RCTs compared cytisine with placebo at the standard dose covering 5922 patients, 2996 of whom took cytisine, delivering a risk ratio (RR) of 2.25 [95% confidence interval (CI) = 1.42-3.56; I = 88%; moderate-quality evidence]. The greater intensity of behavioral therapy was associated directly with the efficacy findings (moderate-quality evidence). The confirmed efficacy of cytisine was not evidenced in trials conducted in low- and middle-income countries. We estimate a number needed to treat (NNT) of 11. Two trials compared the efficacy of cytisine versus NRT, and the combination of both studies yields modest results in favor of cytisine. Three trials compared cytisine with varenicline, without a clear benefit for cytisine. Meta-analyses of all non-serious adverse events in the cytisine group versus placebo groups yielded a RR of 1.24 (95% CI = 1.11-1.39; participants = 5895; studies = 8; I = 0%; high-quality evidence).
CONCLUSIONS
Cytisine increases the chances of successful smoking cessation by more than twofold compared with placebo and has a benign safety profile, with no evidence of serious safety concerns. Limited evidence suggests that cytisine may be more effective than nicotine replacement therapy, with modest cessation rates.
Topics: Humans; Smoking Cessation; Varenicline; Nicotine; Nicotinic Agonists; Bupropion; Benzazepines; Quinoxalines; Alkaloids; Azocines; Quinolizines; Quinolizidine Alkaloids
PubMed: 38161271
DOI: 10.1111/add.16399 -
European Journal of Pharmaceutics and... Feb 2024Current strategies for smoking withdrawal conditions involve monotherapy of nicotine and combinational therapy of nicotine with varenicline or bupropion as per the CDC...
Current strategies for smoking withdrawal conditions involve monotherapy of nicotine and combinational therapy of nicotine with varenicline or bupropion as per the CDC and FDA. The available dosage forms for nicotine are patches, gums, inhalers and nasal sprays, bupropion and varenicline are available in tablet form. This research work focused on developing a microneedle delivery system to deliver combination drug for overcoming the obstacles encountered by oral route of administration of varenicline such as severe side effects (mood swings, agitation, depressed behaviour, seizures, etc), and nicotine therapy challenges such as short half-life, repeated dosing, nausea, and vomiting. The nanoparticles of nicotine prepared by nanoprecipitation method showed particle size PTZ (356.6 ± 65.98), percentage entrapment efficiency (35.55 % ± 0.007), in-vitro drug release (47.89 % ± 0.7) for 72 h. Microneedles showed height (600 μm), width (350 μm), and tip diameter (10 μm). The nanoparticles encapsulated in microneedles showed in-vitro sustained delivery of nicotine (67.00 % ± 4.92) and varenicline (79.78 % ± 1.09) in 48 h. Nicotine released in a sustained manner attaches to the nicotine acetylcholine receptors (nAchR) to release dopamine for controlling the withdrawal challenges such as anxiety, irritability, cravings, disturbed sleep pattern, etc. The varenicline released from microneedles binds to the nAchR and inhibits dopamine release responsible for the euphoric effect induced by nicotine, and thus assists in curbing the nicotine withdrawal symptoms. This combination microneedle system offers prolonged treatment in a single application for smoking withdrawal conditions wherein patients are not in stage of oral dosing because of repeated dosing resulting in adverse effects like seizures, hypertension, sleep disturbances, insomnia, and nausea.
Topics: Humans; Nicotine; Varenicline; Bupropion; Receptors, Nicotinic; Nicotinic Agonists; Dopamine; Smoking Cessation; Benzazepines; Substance Withdrawal Syndrome; Quinoxalines; Smoking; Seizures; Nausea
PubMed: 38159871
DOI: 10.1016/j.ejpb.2023.114171 -
Pharmacology, Biochemistry, and Behavior Feb 2024Smoking is the leading cause of preventable death worldwide, with <7 % of smoking cessation attempts being met with success. Nicotine, the main addictive agent in...
Smoking is the leading cause of preventable death worldwide, with <7 % of smoking cessation attempts being met with success. Nicotine, the main addictive agent in cigarettes, enhances the reinforcing value of other environmental rewards. Under some circumstances, this reward enhancement maintains nicotine consumption. Varenicline (i.e., cessation aid Chantix™) also has reward-enhancement effects via nicotinic acetylcholine receptor agonism (nAChRs) - albeit less robust than nicotine. Cotinine is the major metabolite of nicotine. Recent studies suggest that cotinine is a positive allosteric modulator (PAM) and/or a weak agonist at nAChRs. Thus, cotinine may enhance the behavioral effects of nAChR compounds such as varenicline and/or exert some behavioral effects alone. We used 20 (10M, 10F) Sprague-Dawley rats to assess reward-enhancement within-subjects by examining responding maintained by a reinforcing visual stimulus on a Variable Ratio 2 schedule of reinforcement. To assess the reward-enhancing effects of cotinine, rats received one injection of cotinine (saline, 0.1, 0.3, 1.0, 3.0, 6.0 mg/kg) before each 1 h session. To assess cotinine and varenicline interactions, rats received an injection of cotinine (saline, 0.1, 1.0, or 6.0 mg/kg) and of varenicline (saline, 0.1, 0.3, 1.0, or 3.0 mg/kg) before the session. While we replicated prior work identifying reward-enhancement by 0.1, 0.3, and 1.0 mg/kg varenicline, cotinine alone did not produce reward-enhancement nor augment the reward-enhancing effects of varenicline. Future studies may consider examining the reward-enhancing effects of cotinine with other reinforcers or co-administered with other smoking cessation aids such as bupropion.
Topics: Humans; Rats; Animals; Varenicline; Nicotine; Cotinine; Rats, Sprague-Dawley; Nicotinic Agonists; Receptors, Nicotinic; Benzazepines; Quinoxalines
PubMed: 38154590
DOI: 10.1016/j.pbb.2023.173702 -
Tumori Apr 2024Cigarette smoke accounts for over 90,000 deaths each year in Italy. Tobacco dependence treatment guidelines suggest adopting an integrated pharmacological-behavioral... (Observational Study)
Observational Study
INTRODUCTION
Cigarette smoke accounts for over 90,000 deaths each year in Italy. Tobacco dependence treatment guidelines suggest adopting an integrated pharmacological-behavioral model of intervention. Cytisine is a partial agonist of nicotinic receptors. Trials conducted to date have demonstrated its good efficacy in promoting smoking cessation. The cytisine scheme of treatment consists of 25 days of treatment. A 40-day regimen, with an escalating dose and an extended duration of the treatment, has been in use in many anti-smoking centers in Italy for several years, but to date there are no reports on the use of cytisine with this scheme.
METHODS
A retrospective, real-life, observational study was conducted between January 2016 and September 2022. The 300 patients who had received at least one dose of study medication were selected. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. Univariate and multivariate logistic regression models were implemented for self-reported seven-day point prevalence for abstinence at three, six and 12 months.
RESULTS
The median age of the patients was 59 years, 57% were women. The median smoking exposure was 33.8 pack-years. Self-reported smoking abstinence at three, six and 12 months was 68.7%, 56.3% and 47.3% respectively. 84% completed the cytisine treatment, 31.3% reported adverse events and in 8.3% these led to dropping out of the treatment.
CONCLUSION
Cytisine, administered with a novel therapeutic scheme in the real-life setting of a specialized anti-smoking center, significantly promotes smoking abstinence. However, more studies are needed to assess the tolerability and efficacy of this new regimen.
Topics: Humans; Female; Middle Aged; Male; Smoking Cessation; Varenicline; Nicotinic Agonists; Benzazepines; Retrospective Studies; Quinoxalines; Alkaloids; Azocines; Quinolizines; Quinolizidine Alkaloids
PubMed: 38149659
DOI: 10.1177/03008916231216906 -
Journal of Clinical Medicine Dec 2023Tobacco smoking has been a recognized risk factor for cardiovascular diseases (CVD). Smoking is a chronic relapsing disease and pharmacotherapy is a main component of... (Review)
Review
Tobacco smoking has been a recognized risk factor for cardiovascular diseases (CVD). Smoking is a chronic relapsing disease and pharmacotherapy is a main component of smoking cessation. Obstructive sleep apnea (OSA) and smoking both increase the risk of CVD and are associated with significant morbidity and mortality. There are few existing data examining how pharmacological treatment, such as nicotine replacement therapy (NRT), bupropion, and varenicline, affect smokers suffering with OSA and especially their cardiovascular effects. The aim of this review was to evaluate the effects of smoking cessation pharmacotherapy on OSA with a special emphasis on the cardiovascular system. Results: Only small studies have assessed the effect of NRTs on OSA. Nicotine gum administration showed an improvement in respiratory events but with no permanent results. No specific studies were found on the effect of bupropion on OSA, and a limited number evaluated varenicline's effects on sleep and specifically OSA. Varenicline administration in smokers suffering from OSA reduced the obstructive respiratory events, especially during REM. Studies on second-line medication (nortriptyline, clonidine, cytisine) are even more limited. There are still no studies evaluating the cardiovascular effects of smoking cessation medications on OSA patients. Conclusions: Sleep disturbances are common withdrawal effects during smoking cessation but could be also attributed to pharmacotherapy. Smokers should receive personalized treatment during their quitting attempts according to their individual needs and problems, including OSA. Future studies are needed in order to evaluate the efficacy and safety of smoking cessation medications in OSA patients.
PubMed: 38137639
DOI: 10.3390/jcm12247570