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Zonisamide Reduces Withdrawal Symptoms But Does Not Enhance Varenicline-Induced Smoking Cessation.

ABSTRACT: Varenicline (Chantix) is a first-line treatment for smoking cessation but does not produce cessation in many individuals. It may be possible to improve abstinence by co-administering varenicline with other medications. Zonisamide (Zonegran) has a similar pharmacologic profile to topiramate, which has been shown to reduce smoking, but is better tolerated. This study evaluated whether combined zonisamide and varenicline reduced tobacco withdrawal and increased abstinence among smokers trying to quit, relative to varenicline and placebo.This was a double-blind, randomized, placebo-controlled pilot trial of zonisamide + varenicline versus placebo + varenicline for smoking cessation. Smokers received brief counseling and study medications, and completed weekly assessments for 10 consecutive weeks. The primary outcome was continuous abstinence rates (biochemically verified) during the final 4 weeks of treatment.Results are presented as intent-to-treat and completer analyses. Seventy-four individuals were enrolled; 45 completed the study. Overall, 14.9% (intent-to-treat) and 25.0% (completer) of participants maintained sustained abstinence during the final 4 weeks of treatment. There were no differences between groups for biochemically-verified smoking, but zonisamide + varenicline reduced self-reported smoking, nicotine withdrawal, and craving compared to placebo + varenicline.Zonisamide decreased nicotine withdrawal and craving, though not of sufficient magnitude to modify smoking behavior. The sample size was small and low rates of abstinence across groups suggest the study population was difficult to treat. Additional evaluation of zonisamide or other medications that increase GABA or decrease glutamate in larger or more diverse populations may yield positive clinical benefit for nicotine/tobacco cessation.This study provides support for layering novel medications with varenicline for smoking cessation, for investigating medications that target the GABA and glutamate system, and for assessing the contribution that reductions in nicotine withdrawal have on ultimate cessation outcomes.

SUBMITTER: Dunn KE

PROVIDER: S-EPMC5942620 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Zonisamide Reduces Withdrawal Symptoms But Does Not Enhance Varenicline-Induced Smoking Cessation.

Dunn Kelly E KE Marcus Taylor F TF Kim Cynthia C Schroeder Jennifer R JR Vandrey Ryan R Umbricht Annie A

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 20151017 5

<h4>Introduction</h4>Varenicline (Chantix) is a first-line treatment for smoking cessation but does not produce cessation in many individuals. It may be possible to improve abstinence by co-administering varenicline with other medications. Zonisamide (Zonegran) has a similar pharmacologic profile to topiramate, which has been shown to reduce smoking, but is better tolerated. This study evaluated whether combined zonisamide and varenicline reduced tobacco withdrawal and increased abstinence among ...[more]

PMID: 26476459

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Project description:ImportanceGiven the actions of varenicline tartrate and bupropion hydrochloride sustained-release (SR) on neurobiological targets related to affect and reward, it is thought that the modulation of nicotine withdrawal symptoms may contribute to their effectiveness.ObjectiveTo assess the relative efficacy of varenicline and bupropion SR plus intensive counseling on smoking cessation and emotional functioning.Design and settingPlacebo-controlled randomized clinical trial at a university medical center.ParticipantsIn total, 294 community volunteers who wanted to quit smoking.InterventionsTwelve weeks of varenicline, bupropion SR, or placebo plus intensive smoking cessation counseling (10 sessions, for a total of approximately 240 minutes of counseling).Main outcome measuresProlonged abstinence from smoking and weekly measures of depression, negative affect, and other symptoms of nicotine withdrawal.ResultsSignificant differences were found in abstinence at the end of treatment and through the 3-month postquit follow-up visit, favoring both active medications compared with placebo. At the 6-month postquit follow-up visit, only the varenicline vs placebo comparison remained significant. Varenicline use was also associated with a generalized suppression of depression and reduced smoking reward compared with the other treatments, while both active medications improved concentration, reduced craving, and decreased negative affect and sadness compared with placebo, while having little effect (increase or decrease) on anxiety and anger. No differences were noted in self-reported rates of neuropsychiatric adverse events.Conclusions and relevanceIn a community sample, varenicline exerts a robust and favorable effect on smoking cessation relative to placebo and may have a favorable (suppressive) effect on symptoms of depression and other affective measures, with no clear unfavorable effect on neuropsychiatric adverse events.Trial registrationclinicaltrials.gov Identifier: NCT00507728.

Project description:Background and aimsVarenicline effectiveness may be related to the level of adherence, which might be reduced by adverse effects such as nausea. The aim of the study was to test a possible effect of nausea on smoking cessation outcomes mediated by adherence.DesignMediation path analysis.SettingMultiple sites within Canada and the United States.ParticipantsTreatment-seeking smokers receiving varenicline from two smoking cessation clinical trials: Quit2Live (NCT01836276; n = 449) and Pharmacogenetics of Nicotine Addiction Treatment (PNAT) (NCT01314001; n = 421).MeasurementsNausea severity was collected through self-report and adherence was biologically assessed using varenicline concentrations (Quit2Live, plasma sample at week 4; PNAT, saliva sample at week 2). In Quit2Live, the end-points were cotinine-verified abstinence at weeks 4, 12 and 26. In PNAT, the end-points were carbon monoxide-verified abstinence at weeks 2, 12 and 26.FindingsEarly nausea was not directly associated with abstinence [odds ratio (OR) ranging from 0.73-1.28; P ? 0.26]. However early nausea was indirectly associated with lower cessation rates at multiple timepoints (ORs ranging from 0.92-0.94; 95% CI between 0.83-0.99) in a relationship mediated by reduced varenicline adherence (assessed by plasma varenicline concentrations) in the primary trial (Quit2Live). This relationship between nausea, adherence and cessation was similar in direction but weaker in effect size (ORs ranging from 0.98-0.99; 95% CI between 0.90-1.03) in a secondary trial (PNAT), where adherence was assessed using salivary varenicline concentrations.ConclusionsThese data suggest that early nausea during varenicline treatment may be indirectly associated with lower likelihood of smoking cessation through reducing varenicline adherence. Differences in robustness between the trials may be due to the different biological matrices (plasma vs. saliva) and/or timing used to assess varenicline adherence. The results of the first study suggest that improved management of early nausea during varenicline treatment may positively impact smoking cessation success through increasing varenicline adherence.

Project description:ImportanceSome cigarette smokers may not be ready to quit immediately but may be willing to reduce cigarette consumption with the goal of quitting.ObjectiveTo determine the efficacy and safety of varenicline for increasing smoking abstinence rates through smoking reduction.Design, setting, and participantsRandomized, double-blind, placebo-controlled, multinational clinical trial with a 24-week treatment period and 28-week follow-up conducted between July 2011 and July 2013 at 61 centers in 10 countries. The 1510 participants were cigarette smokers who were not willing or able to quit smoking within the next month but willing to reduce smoking and make a quit attempt within the next 3 months. Participants were recruited through advertising.InterventionsTwenty-four weeks of varenicline titrated to 1 mg twice daily or placebo with a reduction target of 50% or more in number of cigarettes smoked by 4 weeks, 75% or more by 8 weeks, and a quit attempt by 12 weeks.Main outcomes and measuresPrimary efficacy end point was carbon monoxide-confirmed self-reported abstinence during weeks 15 through 24. Secondary outcomes were carbon monoxide-confirmed self-reported abstinence for weeks 21 through 24 and weeks 21 through 52.ResultsThe varenicline group (n = 760) had significantly higher continuous abstinence rates during weeks 15 through 24 vs the placebo group (n = 750) (32.1% for the varenicline group vs 6.9% for the placebo group; risk difference (RD), 25.2% [95% CI, 21.4%-29.0%]; relative risk (RR), 4.6 [95% CI, 3.5-6.1]). The varenicline group had significantly higher continuous abstinence rates vs the placebo group during weeks 21 through 24 (37.8% for the varenicline group vs 12.5% for the placebo group; RD, 25.2% [95% CI, 21.1%-29.4%]; RR, 3.0 [95% CI, 2.4-3.7]) and weeks 21 through 52 (27.0% for the varenicline group vs 9.9% for the placebo group; RD, 17.1% [95% CI, 13.3%-20.9%]; RR, 2.7 [95% CI, 2.1-3.5]). Serious adverse events occurred in 3.7% of the varenicline group and 2.2% of the placebo group (P = .07).Conclusions and relevanceAmong cigarette smokers not willing or able to quit within the next month but willing to reduce cigarette consumption and make a quit attempt at 3 months, use of varenicline for 24 weeks compared with placebo significantly increased smoking cessation rates at the end of treatment, and also at 1 year. Varenicline offers a treatment option for smokers whose needs are not addressed by clinical guidelines recommending abrupt smoking cessation.Trial registrationclinicaltrials.gov Identifier: NCT01370356.

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Zonisamide Reduces Withdrawal Symptoms But Does Not Enhance Varenicline-Induced Smoking Cessation.

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Zonisamide Reduces Withdrawal Symptoms But Does Not Enhance Varenicline-Induced Smoking Cessation.

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