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Phase IIb Trial of an ?7 Nicotinic Receptor Partial Agonist With and Without Nicotine Patch for Withdrawal-Associated Cognitive Deficits and Tobacco Abstinence.

ABSTRACT: PURPOSE/BACKGROUND:The objective of this study was to determine whether a novel ?7 nicotinic acetylcholine receptor partial agonist improves cognition during nicotine withdrawal and improves abstinence rates. To do so, the effect of the ?7 nicotinic acetylcholine receptor partial agonist, encenicline, on cognition and abstinence was evaluated when given as monotherapy and when combined with transdermal nicotine patch (nicotine replacement therapy [NRT]). METHODS:Adult daily smokers, n = 160, who were motivated to quit smoking completed cognitive testing at satiated baseline and after overnight abstinence and then were randomized to receive a 12-week trial of encenicline 1 mg twice daily or identical placebo the day of the overnight abstinent cognitive testing. In the first 6 weeks of the 12-week encenicline administration, participants were also randomized to 6 weeks of NRT patch or placebo patch. Primary outcomes were cognition during abstinence and 7-day point-prevalence abstinence at week 12. RESULTS:No beneficial effects of encenicline were observed on cognition or abstinence when compared with placebo or when combined with NRT compared with placebo capsule + NRT. Of the 4 conditions, abstinence rates were lowest among those assigned to encenicline alone. CONCLUSIONS:Beneficial effects of NRT were observed on cognitive and abstinence outcomes when combined with encenicline compared with encenicline plus placebo patch. Addition of NRT to encenicline improved odds of abstinence approximately 3-fold compared with encenicline plus placebo patch. We conclude that encenicline, 1 mg/d, did not improve abstinence-associated cognitive impairment or abstinence rates as monotherapy or adjunctive therapy to NRT patch.

SUBMITTER: Schuster RM

PROVIDER: S-EPMC6019566 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Phase IIb Trial of an α7 Nicotinic Receptor Partial Agonist With and Without Nicotine Patch for Withdrawal-Associated Cognitive Deficits and Tobacco Abstinence.

Schuster Randi Melissa RM Pachas Gladys N GN Stoeckel Luke L Cather Corinne C Nadal Mireya M Mischoulon David D Schoenfeld David A DA Zhang Haiyue H Ulysse Christine C Dodds Elisabeth B EB Sobolewski Sara S Hudziak Vicenta V Hanly Ailish A Fava Maurizio M Evins A Eden AE

Journal of clinical psychopharmacology 20180801 4

<h4>Purpose/background</h4>The objective of this study was to determine whether a novel α7 nicotinic acetylcholine receptor partial agonist improves cognition during nicotine withdrawal and improves abstinence rates. To do so, the effect of the α7 nicotinic acetylcholine receptor partial agonist, encenicline, on cognition and abstinence was evaluated when given as monotherapy and when combined with transdermal nicotine patch (nicotine replacement therapy [NRT]).<h4>Methods</h4>Adult daily smoker ...[more]

PMID: 29912798

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Project description:IntroductionNetwork theories of psychopathology highlight that, rather than being indicators of a latent disorder, symptoms of disorders can causally interact with one another in a network. This study examined tobacco withdrawal from a network perspective.MethodsParticipants (n = 525, 50.67% female) completed the Minnesota Tobacco Withdrawal Scale four times (2 weeks prior to a target quit day, on the target quit day, and 4 and 8 weeks after the target quit day) over the course of 8 weeks of treatment with nicotine patch and behavioral counseling within a randomized clinical trial testing long-term nicotine patch therapy in treatment-seeking smokers. The conditional dependence among seven withdrawal symptoms was estimated at each of the four measurement occasions. Influential symptoms of withdrawal were identified using centrality indices. Changes in network structure were examined using the Network Comparison Test.ResultsFindings indicated many associations among the individual symptoms of withdrawal. The strongest associations that emerged were between sleep problems and restlessness, and associations among affective symptoms. Restlessness and affective symptoms emerged as the most central symptoms in the withdrawal networks. Minimal differences in the structure of the withdrawal networks emerged across time.ConclusionsThe cooccurrence of withdrawal symptoms may result from interactions among symptoms of withdrawal rather than simply reflecting passive indicators of a latent disorder. Findings encourage greater consideration of individual withdrawal symptoms and their potential interactions and may be used to generate hypotheses that may be tested in future intensive longitudinal studies.ImplicationsThis study provides a novel, network perspective on tobacco withdrawal. Drawing on network theories of psychopathology, we suggest that the cooccurrence of withdrawal symptoms may result from interactions among symptoms of withdrawal over time, rather than simply reflecting passive indicators of a latent disorder. Results indicating many associations among individual symptoms of withdrawal are consistent with a network perspective. Other results of interest include minimal changes in the network structure of withdrawal across four measurement occasions prior to and during treatment with nicotine patch and behavioral counseling.

Project description:IntroductionAlthough exogenous progesterone may hold promise as a treatment for nicotine use disorders, it is unclear whether it is similarly effective in males and females. This study examined the effects of progesterone on nicotine use disorder comprehensively using behavioral, psychological, and neural measures in male and female smokers exposed to brief abstinence.Aims and methodsThirty-three male and 33 female non-treatment-seeking smokers participated in a double-blind, randomized, placebo-controlled crossover study of 200 mg of progesterone or placebo daily over a four-day abstinence period. Smoking behavior and subjective effects of nicotine were assessed at baseline and after final drug administration. Nicotine withdrawal, smoking urges, mood states, and neural response to smoking cues were measured at baseline, after the first drug administration, and after the final drug administration.ResultsNo main effect of drug (progesterone vs. placebo) emerged for any outcome. Significant sex by drug interactions emerged for nicotine withdrawal (p = .020), perceived strength of nicotine (p = .040), and perceived bad effects of nicotine (p = .029). Males receiving progesterone reported worse nicotine withdrawal (p = .046) and a trend towards decreased bad effects of nicotine (p = .070). Males on progesterone also reported greater tension and anxiety relative to placebo (p = .021). Females on progesterone perceived nicotine's effects as being stronger relative to placebo (p = .046).ConclusionsProgesterone causes sex-dependent effects on smoking-related outcomes during brief abstinence. Specifically, progesterone in males may increase rather than decrease nicotine withdrawal and negative affect during abstinence, potentially hindering efforts to quit smoking.ImplicationsIn male and female smokers undergoing a brief period of abstinence, we examined the effects of progesterone on smoking outcomes. While progesterone had limited effects in female smokers, in males, it worsened nicotine withdrawal and negative affect. Our findings emphasize the importance of analyzing sex differences in future studies examining progesterone as a potential treatment and suggest that progesterone in males could potentially exacerbate aspects of nicotine dependence.Clinicaltrials.gov registrationNCT01954966. https://clinicaltrials.gov/ct2/show/NCT01954966.

Project description:ObjectiveTo examine the effectiveness of a nicotine patch worn for four weeks before a quit attempt.DesignRandomised controlled open label trial.SettingPrimary care and smoking cessation clinics in England, 2012-15.Participants1792 adults who were daily smokers with tobacco dependence. 899 were allocated to the preloading arm and 893 to the control arm.InterventionsParticipants were randomised 1:1, using concealed randomly permuted blocks stratified by centre, to either standard smoking cessation pharmacotherapy and behavioural support or the same treatment supplemented by four weeks of 21 mg nicotine patch use before quitting: "preloading."Main outcome measuresThe primary outcome was biochemically confirmed prolonged abstinence at six months. Secondary outcomes were prolonged abstinence at four weeks and 12 months.ResultsBiochemically validated abstinence at six months was achieved by 157/899 (17.5%) participants in the preloading arm and 129/893 (14.4%) in the control arm: difference 3.0% (95% confidence interval -0.4% to 6.4%), odds ratio 1.25 (95% confidence interval 0.97 to 1.62), P=0.08 in the primary analysis. There was an imbalance between arms in the frequency of varenicline use as post-cessation treatment, and planned adjustment for this gave an odds ratio for the effect of preloading of 1.34 (95% confidence interval 1.03 to 1.73), P=0.03: difference 3.8% (0.4% to 7.2%). At four weeks, the difference in prolonged abstinence unadjusted for varenicline use was odds ratio 1.21 (1.00 to 1.48), difference 4.3% (0.0% to 8.7%), P=0.05, and adjusted for varenicline use was 1.32 (1.08 to 1.62) P=0.007. At 12 months the odds ratio was 1.28 (0.97 to 1.69), difference 2.7% (-0.4% to 5.8%), P=0.09 unadjusted for varenicline use and after adjustment was 1.36 (1.02 to 1.80) P=0.04. 5.9% of participants discontinued preloading owing to intolerance. Gastrointestinal symptoms-chiefly nausea-occurred in 4.0% (2.2% to 5.9%) more people in the preloading arm than control arm. Eight serious adverse events occurred in the preloading arm and eight in the control arm (odds ratio 0.99, 0.36 to 2.75).ConclusionsEvidence was insufficient to confidently show that nicotine preloading increases subsequent smoking abstinence. The beneficial effect seems to have been masked by a concurrent reduction in the use of varenicline in people using nicotine preloading, and future studies should explore ways to mitigate this unintended effect.Trial registrationCurrent Controlled Trials ISRCTN33031001.

Dataset Information

Phase IIb Trial of an ?7 Nicotinic Receptor Partial Agonist With and Without Nicotine Patch for Withdrawal-Associated Cognitive Deficits and Tobacco Abstinence.

Publications

Phase IIb Trial of an α7 Nicotinic Receptor Partial Agonist With and Without Nicotine Patch for Withdrawal-Associated Cognitive Deficits and Tobacco Abstinence.

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