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Individual differences in responding to bupropion or varenicline in a preclinical model of nicotine self-administration vary according to individual demand for nicotine.

ABSTRACT: Bupropion and varenicline are the top two smoking cessation interventions that are marginally successful in increasing abstinence rates when compared to placebo. Although smokers vary in their history and pattern of tobacco use, there is a significant gap in addressing this individual variability with individually targeted treatments. The present study takes the initial step towards a better understanding of individual differences in treatment outcomes by assessing the effect of bupropion or varenicline on nicotine self-administration in rats. Rats were first assessed for their individual economic demand for sucrose and then for self-administered nicotine (0.03?mg/kg/inf; 2?h sessions). We then examined the effect of bupropion (0, 10, 30, 60?mg/kg) or varenicline (0, 0.1, 1.0, 3.0?mg/kg) pretreatment on individual rates of nicotine self-administration using progressive ratio schedule of reinforcement. Thereafter, rats were subjected to four rounds of extinction and reinstatement tests. We found that individual demand for sucrose did not predict individual demand for nicotine. Acute pretreatments with bupropion or varenicline were most effective at decreasing nicotine self-administration in rats that had a higher demand for nicotine. Rats with higher demand for nicotine also showed higher magnitude of responding in extinction and during nicotine-triggered reinstatement tests. Although the acute treatment protocol employed in this study is an important initial step towards a better understanding of individual treatment effects, future research modeling chronic treatment approaches will be needed to further extend our findings.

SUBMITTER: Kazan T

PROVIDER: S-EPMC6457454 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Individual differences in responding to bupropion or varenicline in a preclinical model of nicotine self-administration vary according to individual demand for nicotine.

Kazan Theodore T Charntikov Sergios S

Neuropharmacology 20190103

Bupropion and varenicline are the top two smoking cessation interventions that are marginally successful in increasing abstinence rates when compared to placebo. Although smokers vary in their history and pattern of tobacco use, there is a significant gap in addressing this individual variability with individually targeted treatments. The present study takes the initial step towards a better understanding of individual differences in treatment outcomes by assessing the effect of bupropion or var ...[more]

PMID: 30611697

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Project description:ImportanceQuitting smoking is enhanced by the use of pharmacotherapies, but concerns have been raised regarding the cardiovascular safety of such medications.ObjectiveTo compare the relative cardiovascular safety risk of smoking cessation treatments.Design, setting, and participantsA double-blind, randomized, triple-dummy, placebo- and active-controlled trial (Evaluating Adverse Events in a Global Smoking Cessation Study [EAGLES]) and its nontreatment extension trial was conducted at 140 multinational centers. Smokers, with or without established psychiatric diagnoses, who received at least 1 dose of study medication (n = 8058), as well as a subset of those who completed 12 weeks of treatment plus 12 weeks of follow up and agreed to be followed up for an additional 28 weeks (n = 4595), were included.InterventionsVarenicline, 1 mg twice daily; bupropion hydrochloride, 150 mg twice daily; and nicotine replacement therapy, 21-mg/d patch with tapering.Main outcomes and measuresThe primary end point was the time to development of a major adverse cardiovascular event (MACE: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) during treatment; secondary end points were the occurrence of MACE and other pertinent cardiovascular events (MACE+: MACE or new-onset or worsening peripheral vascular disease requiring intervention, coronary revascularization, or hospitalization for unstable angina).ResultsOf the 8058 participants, 3553 (44.1%) were male (mean [SD] age, 46.5 [12.3] years). The incidence of cardiovascular events during treatment and follow-up was low (<0.5% for MACE; <0.8% for MACE+) and did not differ significantly by treatment. No significant treatment differences were observed in time to cardiovascular events, blood pressure, or heart rate. There was no significant difference in time to onset of MACE for either varenicline or bupropion treatment vs placebo (varenicline: hazard ratio, 0.29; 95% CI, 0.05-1.68 and bupropion: hazard ratio, 0.50; 95% CI, 0.10-2.50).Conclusions and relevanceNo evidence that the use of smoking cessation pharmacotherapies increased the risk of serious cardiovascular adverse events during or after treatment was observed. The findings of EAGLES and its extension trial provide further evidence that smoking cessation medications do not increase the risk of serious cardiovascular events in the general population of smokers.Trial registrationclinicaltrials.gov Identifier: NCT01574703.

Project description:Background and aimsAnalysed using classical frequentist hypothesis testing with alpha set to 0.05, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) did not find enough evidence to reject the hypothesis of no difference in neuropsychiatric adverse events (NPSAEs) attributable to varenicline, bupropion, or nicotine patch compared with placebo. This might be because the null hypothesis was true or because the data were insensitive. The present study aimed to test the hypothesis more directly using Bayes factors.DesignEAGLES was a randomised, double-blind, triple-dummy, controlled trial.SettingGlobal (16 countries across five continents), between November 2011 and January 2015.ParticipantsParticipants were smokers with (n = 4116) and without (n = 4028) psychiatric disorders.InterventionsVarenicline (1 mg twice daily), bupropion (150 mg twice daily), nicotine patch (21 mg once daily with taper) and matched placebos.MeasurementsThe outcomes included: (i) a composite measure of moderate/severe NPSAEs; and (ii) a composite measure of severe NPSAEs. The relative evidence for there being no difference in NPSAEs versus data insensitivity for the medications was calculated in the full and sub-samples using Bayes factors and corresponding robustness regions.FindingsFor all but two comparisons, Bayes factors were <1/3, indicating moderate to strong evidence for no difference in risk of NPSAEs between active medications and placebo (Bayes factor = 0.02-0.23). In the psychiatric cohort versus placebo, the data were suggestive, but not conclusive of no increase in NPSAEs with varenicline (Bayes factor = 0.52) and bupropion (Bayes factor = 0.71). Here, the robustness regions ruled out a ≥7% and ≥8% risk increase with varenicline and bupropion, respectively.ConclusionsSecondary analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study trial using Bayes factors provides moderate to strong evidence that use of varenicline, bupropion or nicotine patches for smoking cessation does not increase the risk of neuropsychiatric adverse events relative to use of placebo in smokers without a history of psychiatric disorder. For smokers with a history of psychiatric disorder the evidence also points to no increased risk but with less confidence.

Project description: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.

Project description:Learning processes associated with nicotine influence the development of addiction to tobacco products. In the present report, we are interested in the interoceptive stimulus effects of nicotine acquiring control over appetitive behaviors - specifically, reward seeking. Also of interest is the current smoking cessation drug, varenicline (Chantix®). Varenicline, with its nicotine-like stimulus effects, can decrease withdrawal and cravings for a subset of individuals addicted to nicotine, though relapse is still common. We trained rats (N?=?48) with nicotine (0.4?mg/kg, SC) as an excitatory stimulus (i.e., paired with sucrose) in a drug-discriminated goal-tracking (DGT) task. There was no access to sucrose on interspersed saline days. After acquisition of the initial nicotine-saline discrimination, rats were separated into four groups to test discrimination reversal and drug substitution. The control group maintained nicotine as the excitatory stimulus (NIC+). The substitution group had varenicline (1?mg/kg) replace nicotine as the stimulus paired with sucrose (VAR+). One reversal group had nicotine signal the absence of sucrose (i.e., now available on intermixed saline sessions; NIC-). The last group was similar to the NIC- group except varenicline replaced nicotine on non-reinforced sessions (VAR-). We found that varenicline fully substituted as the training stimulus when the drug-sucrose relation remained in place (VAR+). Both reversal groups acquired the new discrimination, albeit slowly and more variable for the VAR- group in comparison to NIC-. There was an effect of group during substitution testing. Specifically, nicotine fully substituted for varenicline regardless of condition. However, varenicline only partially substituted for the nicotine stimulus. At the start of extinction, responding mimicked that of the rats training condition. However, by extinction session 12, all groups maintained similarly low levels of responding. These findings show nicotine and varenicline share stimulus elements, yet the conclusion of partial to full substitution depends on the nature of the testing protocol.

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Individual differences in responding to bupropion or varenicline in a preclinical model of nicotine self-administration vary according to individual demand for nicotine.

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Individual differences in responding to bupropion or varenicline in a preclinical model of nicotine self-administration vary according to individual demand for nicotine.

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