A Double-Blind Randomized Placebo-Controlled Trial of Oral Naltrexone for Heavy-Drinking Smokers Seeking Smoking Cessation Treatment.
ABSTRACT: Post hoc analyses of 2 randomized controlled trials suggest naltrexone may reduce alcohol use and improve smoking cessation outcomes among heavy drinkers receiving smoking cessation treatment. However, no studies have been conducted specifically to examine naltrexone for this purpose or to test whether naltrexone has benefit when added to smoking cessation counseling that explicitly addresses heavy drinking.We recruited heavy-drinking smokers from the community and randomized them to receive 10 weeks of either (i) 50 mg naltrexone (n = 75) or (ii) placebo (n = 75) daily. Participants received 6 weeks of transdermal nicotine patch and 6 sessions of counseling that addressed both heavy drinking and smoking. Participants were followed for 26 weeks after their target quit smoking date.Across medication conditions, there were substantial reductions at follow-up in percent heavy drinking days (primary outcome) and average drinks per week (secondary outcome). However, participants receiving naltrexone did not differ significantly from those receiving placebo on percent heavy drinking days (effect size d = -0.04, 95% CI [-0.30, 0.22], p = 0.76) or average drinks per week (d = -0.09, 95% CI [-0.35, 0.18], p = 0.54) during follow-up. Naltrexone compared to placebo was not associated with a significant increase in smoking abstinence rates during follow-up, odds ratio = 0.93, 95% CI [0.46, 1.86], p = 0.83. The effect of naltrexone on these outcomes was not significantly moderated by current alcohol dependence or gender.Results indicate that heavy-drinking smokers, including those with current alcohol dependence, can make substantial reductions in drinking in the context of smoking cessation treatment. However, this study provided no evidence that naltrexone is efficacious for enhancing reductions in drinking or improving smoking cessation in this population. Limitations of this study included lower-than-desired sample size and modest adherence to study medication.
Project description:OBJECTIVES:Heavy-drinking tobacco users are less likely to successfully quit smoking than their moderate-drinking counterparts, even when they are prescribed smoking cessation medication. One strategy for improving treatment outcomes in this subgroup of tobacco users may be to combine medication therapies to target both alcohol and tobacco use simultaneously. Adding naltrexone to frontline smoking cessation treatments may improve treatment outcomes in this group. METHOD:This double-blind, placebo-controlled human laboratory study examined the effects of varenicline (2?mg/d) and varenicline (2?mg/d), combined with a low dose of naltrexone (25?mg/d) on alcohol-primed smoking behavior in a laboratory model of smoking relapse in heavy-drinking tobacco users (n?=?30). Participants attended a laboratory session and received an alcohol challenge (target breath alcohol concentration?=?0.030?g/dL). They completed a smoking delay task that assessed their ability to resist smoking followed by an ad libitum smoking phase (primary outcomes). They also provided ratings of subjective drug effects and craving, and carbon monoxide levels were measured after smoking (secondary outcomes). RESULTS:Participants receiving varenicline monotherapy delayed smoking longer and smoked fewer cigarettes than those on placebo. Participants receiving varenicline?+?low-dose naltrexone did not delay smoking longer than those receiving varenicline alone. Participants in both active medication arms smoked fewer cigarettes ad libitum than those receiving placebo. CONCLUSIONS:Varenicline can improve smoking outcomes even after an alcohol prime, supporting its use in heavy drinkers who wish to quit smoking. Findings did not support increased efficacy of combined varenicline?+?low-dose naltrexone relative to varenicline monotherapy.
Project description:Naltrexone, an efficacious medication for alcohol dependence, does not work for everyone. Symptoms such as insomnia and mood instability that are most evident during early abstinence might respond better to a different pharmacotherapy. Gabapentin may reduce these symptoms and help prevent early relapse. This clinical trial evaluated whether the combination of naltrexone and gabapentin was better than naltrexone alone and/or placebo during the early drinking cessation phase (first 6 weeks), and if so, whether this effect persisted.A total of 150 alcohol-dependent individuals were randomly assigned to a 16-week course of naltrexone alone (50 mg/day [N=50]), naltrexone (50 mg/day) with gabapentin (up to 1,200 mg/day [N=50]) added for the first 6 weeks, or double placebo (N=50). All participants received medical management.During the first 6 weeks, the naltrexone-gabapentin group had a longer interval to heavy drinking than the naltrexone-alone group, which had an interval similar to that of the placebo group; had fewer heavy drinking days than the naltrexone-alone group, which in turn had more than the placebo group; and had fewer drinks per drinking day than the naltrexone-alone group and the placebo group. These differences faded over the remaining weeks of the study. Poor sleep was associated with more drinking in the naltrexone-alone group but not in the naltrexone-gabapentin group, while a history of alcohol withdrawal was associated with better response in the naltrexone-gabapentin group.The addition of gabapentin to naltrexone improved drinking outcomes over naltrexone alone during the first 6 weeks after cessation of drinking. This effect did not endure after gabapentin was discontinued.
Project description:BACKGROUND:The opioid antagonist naltrexone is not efficacious for every alcohol treatment seeker. However, various individual factors, such as genetic differences and nicotine-use/smoking status, have been suggested as predictors of naltrexone response. In a randomized clinical trial, we previously reported that nicotine-use/smoking status might be a stronger predictor of naltrexone efficacy than OPRM1 A118G single nucleotide polymorphism (SNP) genotype. In this report, we further characterize the nicotine-users in that trial, examine other drinking outcomes, examine the influence of smoking change on naltrexone effects on drinking, and validate the result in smokers with disialo carbohydrate-deficient transferrin (%dCDT) change as an independent biomarker of response. METHODS:Individuals (n = 146) meeting DSM-IV criteria for alcohol dependence who were genotyped for the OPRM1 A118G SNP and who did, or did not, use nicotine/cigarettes were randomized, in a balanced fashion, to naltrexone (50 mg/d) or placebo and provided medical management (MM) over a 16-week clinical trial. Alcohol use and smoking during the trial were assessed and analyzed. RESULTS:Nicotine-use/smoking status significantly interacted with medication in reducing percent heavy drinking days (PHDD) during the trial (p = 0.003), such that nicotine-users/smokers showed significantly lower PHDD on naltrexone versus placebo (p = 0.0001, Cohen's d = 0.89), while nonusers showed no significant difference between naltrexone and placebo (p = 0.95, Cohen's d = 0.02). Similar effects were shown for drinks per day and percent days drinking. The superiority of naltrexone over placebo on PHDD reduction in nicotine-users/smokers was confirmed with %dCDT (Cohen's d range 0.3 to 0.9 over the study). Naltrexone did not significantly change cigarette use in smokers, and change in use did not influence naltrexone's effect on PHDD. CONCLUSIONS:These data confirm past findings that naltrexone is more efficacious in those who use nicotine/cigarettes. Compared to previous work on the OPRM1 A118G SNP, it appears that nicotine-use might be a more salient predictor of naltrexone treatment response. While naltrexone did not change cigarette use during the study, and smoking change was not related to alcohol reduction, it should be noted that participants were not seeking smoking cessation and MM did not address this issue.
Project description:Naltrexone, an opioid antagonist, may facilitate reduction in drinking among young adults. We compared the efficacy and safety of naltrexone administered daily plus targeted dosing with placebo to reduce drinking in young adults who engage in heavy drinking.A randomized, double-blind, placebo-controlled study was conducted in an outpatient research center in March 2008-January 2012. Participants were aged 18-25 years and reported ? 4 heavy drinking days in the prior 4 weeks. Interventions included naltrexone 25 mg daily plus 25 mg targeted (at most daily) in anticipation of drinking (n = 61) or daily/targeted placebo (n = 67). All participants received a personalized feedback session and brief counseling every other week. Primary outcomes were percent heavy drinking days and percent days abstinent over the 8-week treatment period. Secondary outcomes included number of drinks per drinking day and percentage of days with estimated blood alcohol concentration (BAC) levels ? 0.08 g/dL.Of 140 randomized patients, 128 began treatment, comprising the evaluable sample. During treatment, percent heavy drinking days (naltrexone: mean = 21.60, SD = 16.05; placebo: mean = 22.90, SD = 13.20) (P = .58) and percent days abstinent (naltrexone: mean = 56.60, SD = 22.52; placebo: mean = 62.50, SD = 15.75) (P = .39) did not differ by group. Naltrexone significantly reduced the number of drinks per drinking day (naltrexone: mean = 4.90, SD = 2.28; placebo: mean = 5.90, SD = 2.51) (P = .009) and percentage of drinking days with estimated BAC ? 0.08 g/dL (naltrexone: mean = 35.4, SD = 28.40; placebo: mean = 45.7, SD = 26.80) (P = .042). There were no serious adverse events. Sleepiness was more common with naltrexone.Naltrexone did not reduce frequency of drinking or heavy drinking days, but reduced secondary measures of drinking intensity. While effects were modest, the risk-benefit ratio favors offering naltrexone to help young adult heavy drinkers reduce the amount of alcohol they drink.ClinicalTrials.gov identifier: NCT00568958.
Project description:Naltrexone reduces drinking among individuals with alcohol use disorders (AUDs), but it is not effective for everyone. Variability in its effects on reward-related brain activation, genetic variation, and/or cigarette smoking may account for this mixed response profile. This randomized clinical trial tested the effects of naltrexone on drinking and alcohol cue-elicited brain activation, evaluated whether OPRM1 A118G genotype or smoking moderated these effects, and explored whether the effects of medication on cue-elicited activation predicted subsequent drinking. One hundred and fifty-two treatment-seeking individuals with alcohol dependence, half preselected to carry at least one A118G G (Asp) allele, were randomized to naltrexone (50?mg) or placebo for 16 weeks and administered an fMRI alcohol cue reactivity task at baseline and after 2 weeks of treatment. Naltrexone, relative to placebo, significantly reduced alcohol cue-elicited activation of the right ventral striatum (VS) between baseline and week 2 and reduced heavy drinking over 16 weeks. OPRM1 genotype did not significantly moderate these effects, but G-allele carriers who received naltrexone had an accelerated return to heavy drinking after medication was stopped. Smoking moderated the effects of medication on drinking, such that naltrexone was superior to placebo only among smokers. The degree of reduction in right VS activation between scans interacted with medication in predicting subsequent drinking, such that individuals with greater reduction in activation who received naltrexone, but not placebo, experienced the least heavy drinking during the following 14 weeks. These data replicate previous findings that naltrexone reduces heavy drinking and reward-related brain activation among treatment-seeking individuals with AUDs, and indicate that smoking and the magnitude of reduction in cue-elicited brain activation may predict treatment response.
Project description:Heavy-drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available.The present study used a double-blind, randomized, 2?×?2 medication design, testing varenicline alone (VAR; 1 mg twice daily), low dose naltrexone alone (L-NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on cigarette craving and subjective response to alcohol and cigarettes in a sample (n?=?130) of heavy-drinking daily smokers (?10 cigarettes/day).All participants were tested after a 9-day titration period designed to reach a steady state on the target medication. Testing was completed at 12 h of nicotine abstinence, after consuming a standard dose of alcohol (target breath alcohol concentration?=?0.06 g/dl) and after smoking the first cigarette of the day.The combination of VAR?+?L-NTX was superior to placebo, and at times superior to monotherapy, in attenuating cigarette craving, cigarette and alcohol "high," and in reducing ad-lib consumption of both cigarettes and alcohol during the 9-day medication titration period.These preliminary findings indicate that clinical studies of the combination of VAR?+?L-NTX for heavy drinkers trying to quit smoking are warranted and may ultimately improve clinical care for this sizeable and treatment-resistant subgroup of smokers.
Project description:This study evaluated whether tobacco quitline telephone coaches can be trained to counsel hazardous-drinking smokers to improve smoking cessation success and to limit or abstain from alcohol use.Smokers (N = 1,948) who called the New York State Smokers' Quitline and reported hazardous drinking (exceeding sex-specific weekly limits [14 drinks for men, 7 drinks for women] or meeting/exceeding daily drinking limits [5 drinks for men, 4 drinks for women] at least once in the past year) were randomized to receive either brief motivational counseling to limit or abstain from alcohol plus an alcohol reduction booklet added to standard care (Alcohol + Tobacco Counseling; ATC), or only smoking cessation counseling plus a smoking cessation booklet added to standard care (Tobacco-Only Counseling; TOC).Acceptable coach adherence was achieved. The intention-to-treat (ITT) analysis showed that ATC was associated with a significantly higher rate of smoking abstinence at 7-month follow-up (13.5%) compared with TOC (10.3%; p = .03). The respondent analysis (ATC= 26.2%; TOC = 20.4%) paralleled the ITT findings. When controlling for treatment condition, participants who did not report any heavy drinking were significantly more likely to quit smoking than those who reported any heavy drinking (OR = 1.87, 95% CI [1.29, 2.71]; p = .001).A brief alcohol intervention plus standard care via a telephone quitline resulted in significantly higher smoking cessation rates for hazardous-drinking callers. Given that quitline coaches were trained to provide the intervention with acceptable adherence, the potential to extend this intervention for wide-scale implementation and impact is promising.
Project description:BACKGROUND:Precision medicine aims to identify those patients who will benefit the most from specific treatments. Recent work found large effects of naltrexone among "reward drinkers," defined as individuals who drink primarily for the rewarding effects of alcohol. This study sought to replicate and extend these recent findings by examining whether the desire to drink mediated the effect of naltrexone among reward drinkers. METHODS:We conducted a secondary analysis of a 12-week randomized clinical trial of daily or targeted naltrexone among problem drinkers (n = 163), with a focus on 86 individuals (n = 45 naltrexone and n = 41 placebo) who received daily medication. Interactive voice response technology was used to collect daily reports of drinking and desire to drink. Factor mixture models were used to derive reward and relief phenotypes. Moderation analyses were used to evaluate naltrexone effects, with phenotype as a moderator variable. Multilevel mediation tested average desire to drink as a mediator. RESULTS:Results indicated 4 phenotypes: low reward/low relief; low reward/high relief; high reward/low relief; and high reward/high relief. There was an interaction between the high reward/low relief subgroup (n = 10) and daily naltrexone versus placebo on drinks per drinking day (DPDD; p = 0.03), percent heavy drinking days (p = 0.004), and daily drinking (p = 0.02). As compared to placebo, individuals in the high reward/low relief phenotype who received daily naltrexone had significantly fewer DPDD (Cohen's d = 2.05) and had a lower proportion of heavy drinking days (Cohen's d = 1.75). As hypothesized, reductions in average desire to drink mediated the effect of naltrexone on average daily drinking among the high reward/low relief drinkers (moderated mediation effect: p = 0.029). CONCLUSIONS:This theory-driven study replicates the empirical finding that naltrexone is particularly efficacious among high reward/low relief drinkers. Our study brings the field a step closer to the potential of using a precision medicine approach to treating alcohol use disorder.
Project description:Women living with HIV/AIDS who drink alcohol are at increased risk for adverse health outcomes, but there is little evidence on best methods for reducing alcohol consumption in this population. We conducted a pilot study to determine the acceptability and feasibility of conducting a larger randomized clinical trial of naltrexone vs. placebo to reduce alcohol consumption in women living with HIV/AIDS.We designed the trial with input from community and scientific review. Women with HIV who reported current hazardous drinking (>7 drinks/week or ?4 drinks per occasion) were randomly assigned to daily oral naltrexone (50mg) or placebo for 4months. We evaluated willingness to enroll, adherence to study medication, treatment side effects, and drinking and HIV-related outcomes.From 2010 to 2012, 17 women enrolled (mean age 49years, 94% African American). Study participation was higher among women recruited from an existing HIV cohort study compared to women recruited from an outpatient HIV clinic. Participants took 73% of their study medication; 82% completed the final assessment (7-months). Among all participants, mean alcohol consumption declined substantially from baseline to month 4 (39.2 vs. 12.8 drinks/week, p<0.01) with continued reduction maintained at 7-months. Drinking reductions were similar in both naltrexone and placebo groups.A pharmacologic alcohol intervention was acceptable and feasible in women with HIV, with reduced alcohol consumption noted in women assigned to both treatment and placebo groups. However, several recruitment challenges were identified that should be addressed to enhance recruitment in future alcohol treatment trials.
Project description:To assess the efficacy and safety of varenicline (Chantix) for the treatment of alcohol dependence. Varenicline is a partial ?4?2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation. It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers. This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol dependence.Men and women (n = 200) meeting the criteria for alcohol dependence were recruited across 5 clinical sites. Patients received double-blind varenicline or placebo and a computerized behavioral intervention. Varenicline was titrated during the first week to 2 mg/d, which was maintained during weeks 2 to 13.The varenicline group had significantly lower weekly percent heavy drinking days (primary outcome) (adjusted mean difference = 10.4), drinks per day, drinks per drinking day, and alcohol craving compared with the placebo group (P < 0.05). The average treatment effect on alcohol use was similar for smokers and nonsmokers. Varenicline was well-tolerated; adverse events were expected and mild.Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol dependence.