-
The Journal of Pharmacology and... Apr 2021Nicotine has previously been shown to augment the antinociceptive effects of -opioid agonists in squirrel monkeys without producing a concomitant increase in behavioral...
Nicotine has previously been shown to augment the antinociceptive effects of -opioid agonists in squirrel monkeys without producing a concomitant increase in behavioral disruption. The present studies were conducted to extend these findings by determining the ability of the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial 42 nAChR agonist varenicline to selectively augment the antinociceptive effects of the -opioid receptor (MOR) full agonist fentanyl, the MOR partial agonist nalbuphine, and the -opioid receptor (KOR) agonist U69,593 in male squirrel monkeys. Results indicate that both nAChR ligands selectively increased the antinociceptive effects of nalbuphine and that epibatidine increased the antinociceptive effects of U69,593 without altering effects on operant behavior. However, neither epibatidine nor varenicline enhanced the antinociceptive effects of fentanyl, perhaps due to its high efficacy. The enhancement of nalbuphine's antinociceptive effects by epibatidine, but not varenicline, could be antagonized by either mecamylamine or dihydro--erythroidine, consistent with 42 mediation of epibatidine's effects but suggesting the involvement of non-nAChR mechanisms in the effects of varenicline. The present results support previous findings showing that an nAChR agonist can serve as an adjuvant for MOR antinociception and, based on results with U69,593, further indicate that the adjuvant effects of nAChR drugs may also apply to antinociception produced by KOR. Our findings support the further evaluation of nAChR agonists as adjuvants of opioid pharmacotherapy for pain management and point out the need for further investigation into the mechanisms by which they produce opioid-adjuvant effects. SIGNIFICANCE STATEMENT: Nicotine has been shown to augment the antinociceptive effects of -opioid receptor analgesics without exacerbating their effects on operant performance. The present study demonstrates that the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial α4β2 nAChR agonist varenicline can also augment the antinociceptive effects of nalbuphine, as well as those of a -opioid receptor agonist, without concomitantly exacerbating their behaviorally disruptive effects. These findings support the view that nAChR agonists and partial agonists may have potential as adjuvant therapies for opioid-based analgesics.
Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Conditioning, Operant; Drug Synergism; Fentanyl; Male; Nalbuphine; Nicotinic Agonists; Nociception; Pyridines; Saimiri; Varenicline
PubMed: 33441370
DOI: 10.1124/jpet.120.000423 -
Pharmacology, Biochemistry, and Behavior Mar 2015Varenicline and bupropion each have been shown to significantly improve cessation of tobacco addiction in humans. They act through different mechanisms and the question...
Varenicline and bupropion each have been shown to significantly improve cessation of tobacco addiction in humans. They act through different mechanisms and the question about the potential added efficacy with their combined used has arisen. Preclinical animal models of nicotine addiction can help with the evaluation of this combined approach and what dose combinations of varenicline and bupropion may be useful for enhancing tobacco cessation. In this study, we investigated the interacting dose-effect functions of varenicline and bupropion in a rat model of nicotine self-administration. Young adult female Sprague-Dawley rats were allowed to self-administer nicotine in 1-h sessions under an FR1 reinforcement schedule. Varenicline (0.3, 1. 3 mg/kg) and bupropion (8.33, 25, 75 mg/kg) were administered alone or together 15 min before each session. The vehicle saline was the control. Higher doses of each drug alone reduced nicotine self-administration compared to control with reductions of 62% and 75% with 3 mg/kg varenicline and 75 mg/kg bupropion respectively. Lower dose varenicline which does not by itself reduce nicotine self-administration, significantly augmented bupropion effects. The 0.3 mg/kg varenicline dose combined with the 25 and 75 mg/kg bupropion doses caused greater reductions of nicotine self-administration than either dose of bupropion given alone. However, higher dose varenicline did not have this effect. Lower dose bupropion did not augment varenicline effects. Only the high bupropion dose significantly enhanced the varenicline effect. Likewise, combining 1 mg/kg varenicline with 75 mg/kg bupropion reduced self-administration to a greater extent than either dose alone. These results demonstrate that combination therapy with varenicline and bupropion may be more beneficial than monotherapy with either drug alone.
Topics: Animals; Bupropion; Dose-Response Relationship, Drug; Drug Synergism; Female; Nicotine; Rats; Self Administration; Varenicline
PubMed: 25616031
DOI: 10.1016/j.pbb.2015.01.009 -
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 -
Experimental and Clinical... Oct 2017Nicotine is metabolized into cotinine and then into trans-3'-hydroxycotinine, mainly by cytochrome P450 2A6. Recent studies reported better effectiveness of varenicline...
Nicotine is metabolized into cotinine and then into trans-3'-hydroxycotinine, mainly by cytochrome P450 2A6. Recent studies reported better effectiveness of varenicline in women and in nicotine normal metabolizers phenotypically determined by nicotine-metabolite ratio. Our objective was to study the influence of nicotine-metabolite ratio, CYP2A6 genotype and sex on the response to nicotine replacement therapy and varenicline. Data were extracted from a longitudinal study which included smokers participating in a smoking cessation program. Response to treatment was defined by the absence of relapse when a set threshold of reduction in cigarettes per day relative to the week before the study was no more reached. The analysis considered total and partial reduction defined by a diminution of 100% and of 90% in cigarettes per day, respectively. The hazard ratio of relapsing was estimated in multivariate Cox regression models including the sex and the nicotine metabolism determined by the phenotype or by CYP2A6 genotyping (rs1801272 and rs28399433). In the normal metabolizers determined by phenotyping and in women, the hazard ratio for relapsing was significantly lower with varenicline for a partial decrease (HR = 0.33, 95% CI [0.12, 0.89] and HR = 0.20, 95% CI [0.04, 0.91], respectively) and nonsignificantly lower for a total cessation (HR = 0.45, 95% CI [0.20, 1.0] and HR = 0.38, 95% CI [0.14, 1.0]). When compared with the normal metabolizers determined by phenotyping, the hazard ratio for a partial decrease was similar in the normal metabolizers determined by genotyping (HR = 0.42, 95% CI [0.18, 0.94]) while it was significantly lower with varenicline for a total cessation (HR = 0.50, 95% CI [0.26, 0.98]). Women and normal nicotine metabolizers may benefit more from varenicline over nicotine replacement therapy. (PsycINFO Database Record
Topics: Adult; Cotinine; Cytochrome P-450 CYP2A6; Female; Genotype; Humans; Longitudinal Studies; Male; Middle Aged; Nicotine; Recurrence; Smoking; Smoking Cessation; Tobacco Products; Varenicline
PubMed: 29048184
DOI: 10.1037/pha0000141 -
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 -
Nicotine & Tobacco Research : Official... Aug 2017Post-cessation weight gain (PCWG) is a major barrier to maintaining abstinence, especially in weight-concerned smokers. Varenicline is the most effective medication for...
INTRODUCTION
Post-cessation weight gain (PCWG) is a major barrier to maintaining abstinence, especially in weight-concerned smokers. Varenicline is the most effective medication for smoking cessation but has minimal impact on PCWG. Lorcaserin is an FDA-approved medication for weight management in overweight or obese patients which also provides a noticeable benefit in treating drug dependence. We hypothesized that combining varenicline with lorcaserin may help prevent PCWG. We conducted an open-label, single arm, Phase II clinical pilot study to obtain preliminary data on the safety and effectiveness of combination varenicline and lorcaserin in preventing PCWG in overweight and obese smokers.
METHODS
Twenty overweight or obese (body mass index 27-40 kg/m2) cigarette smokers were enrolled. The primary outcomes were weight and waist circumference (WC) changes at 12 and 26 weeks in smokers meeting criteria for prolonged smoking abstinence. All participants received open-label varenicline (1 mg twice a day) and lorcaserin (10 mg twice a day) for 12 weeks with follow-up at 26 weeks.
RESULTS
Ten subjects met criteria for prolonged smoking abstinence at 12 weeks (50%) and 6 at 26 weeks (30%). Among those achieving prolonged smoking abstinence at 12 weeks, WC was +0.2 ± 6.0 cm (90% CI; -2.9, +3.4) and weight gain was +1.1 ± 3.9 kg (90% CI; -0.9, +3.1).
CONCLUSIONS
Weight gain and WC increases following prolonged smoking abstinence may be reduced among overweight and obese smokers using combination varenicline and lorcaserin. This combinatory treatment warrants further research in the obese and weight-concerned smoking population.
IMPLICATIONS
This is the first published prospective pilot study to evaluate lorcaserin for use in reducing PCWG in overweight and obese smokers. When combined with varenicline, lorcaserin minimized PCWG and increases in WC. In addition to the benefit on PCWG reduction, lorcaserin may be a potential new pharmacological treatment for smoking cessation and warrants further larger studies.
Topics: Adult; Benzazepines; Female; Humans; Male; Middle Aged; Nicotinic Agonists; Obesity; Overweight; Pilot Projects; Tobacco Use Disorder; Varenicline; Weight Gain; Young Adult
PubMed: 27852796
DOI: 10.1093/ntr/ntw304 -
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 -
Neuroscience Feb 2022The mesolimbic dopamine (DA) system reinforces behaviors that are critical for survival. However, drug dependence can occur when drugs of abuse, such as nicotine,...
The mesolimbic dopamine (DA) system reinforces behaviors that are critical for survival. However, drug dependence can occur when drugs of abuse, such as nicotine, highjack this reinforcement system. Pharmacologically targeting the DA system to selectively block drug reinforcement requires a detailed understanding of the neural circuits and molecular pathways that lead to the reward-based activation of mesolimbic circuits. Varenicline is an approved smoking cessation drug that has been shown to block nicotine-evoked DA increases in the nucleus accumbens (NAc) through action on nicotinic acetylcholine receptors. Because these receptors have been implicated in the reinforcement of other addictive substances, we explored the possibility that varenicline could broadly affect reward processing. We used in vivo fiber photometry to monitor midbrain DA neuron activity and striatal DA levels following either natural or drug rewards in mice treated with varenicline. We demonstrate that varenicline pretreatment enhances the suppression of nicotine-evoked DA release by attenuating DA neuron activity in the VTA. Varenicline's ability to attenuate DA release is highly specific to nicotine, and varenicline slightly elevates DA release when co-administered with morphine or ethanol. Furthermore, varenicline has no effect on DA release in response to naturally rewarding behavior such as food intake or exercise. These results demonstrate the exquisite specificity with which varenicline blocks nicotine reward and highlight the complexity with which different rewards activate the mesolimbic DA system.
Topics: Animals; Dopamine; Mice; Nicotinic Agonists; Nucleus Accumbens; Pharmaceutical Preparations; Reward; Varenicline
PubMed: 34923039
DOI: 10.1016/j.neuroscience.2021.12.016 -
Addictive Behaviors Nov 2021Varenicline is an FDA-approved medication for smoking cessation and has demonstrated promise in reducing alcohol use. This study sought to compare the efficacy of...
The effect of varenicline on smoking and drinking outcomes among Black and White adults with alcohol use disorder and co-occurring cigarette smoking: A secondary analysis of two clinical trials.
INTRODUCTION
Varenicline is an FDA-approved medication for smoking cessation and has demonstrated promise in reducing alcohol use. This study sought to compare the efficacy of varenicline in reducing smoking and drinking among Black and White people seeking alcohol treatment.
METHODS
Linear mixed modeling was conducted using data from two multi-site placebo-controlled randomized clinical trials examining the effects of varenicline for treatment of Alcohol Use Disorder (AUD; O'Malley et al., 2018; Litten et al., 2013) among Black and White adults with AUD and co-occurring cigarette smoking. The primary analyses were conducted in a sample of 117 adults (O'Malley trial: 29.1% female, 55.2% Black), and replicated in an independent sample of 73 adults (Litten trial: 23.3% female, 45.2% Black).
RESULTS
Black participants smoked fewer cigarettes per day compared to White participants (O'Malley trial: F = 8.95, p = .003; Litten trial: F = 4.74p = .03). Linear mixed models revealed a marginal effect of varenicline on reducing cigarettes smoked per day regardless of race in the O'Malley trial (F = 3.34, p = .07), which was replicated in the Litten trial (F = 20.77p < .0001). Participants reduced the number of drinks consumed regardless of treatment condition or race in both trials (O'Malley trial: F = 131.69, p < .0001; Litten trial:F = 60.36, p < .0001).
CONCLUSIONS
Our adjusted model findings suggest varenicline reduced smoking among Black and White people with AUD and co-occurring cigarette smoking. However, these findings should be replicated in a larger sample.
Topics: Adult; Alcoholism; Cigarette Smoking; Double-Blind Method; Female; Humans; Male; Smoking; Smoking Cessation; Treatment Outcome; Varenicline
PubMed: 34216871
DOI: 10.1016/j.addbeh.2021.106970 -
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