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Gabapentin combined with naltrexone for the treatment of alcohol dependence.

ABSTRACT: 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.

SUBMITTER: Anton RF

PROVIDER: S-EPMC3204582 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Gabapentin combined with naltrexone for the treatment of alcohol dependence.

Anton Raymond F RF Myrick Hugh H Wright Tara M TM Latham Patricia K PK Baros Alicia M AM Waid L Randolph LR Randall Patrick K PK

The American journal of psychiatry 20110331 7

<h4>Objective</h4>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 (fir ...[more]

PMID: 21454917

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Project description:ImportanceApproved medications for alcohol dependence are prescribed for less than 9% of US alcoholics.ObjectiveTo determine if gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid-modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner.Design, participants and settingA 12-week, double-blind, placebo-controlled, randomized dose-ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single-site, outpatient clinical research facility adjoining a general medical hospital.InterventionsOral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual-guided counseling.Main outcomes and measuresRates of complete abstinence and no heavy drinking (coprimary) and changes in mood, sleep, and craving (secondary) over the 12-week study. RESULTS Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P < .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups.Conclusions and relevanceGabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence.Trial registrationclinicaltrials.gov Identifier: NCT00391716.

Project description:ContextNaltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict naltrexone response.ObjectiveTo evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone.DesignPharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004.SettingEleven academic sites in the COMBINE Study.ParticipantsRecently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA.InterventionsAlcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI).Main outcome measuresTime trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome.ResultsAlcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P = .07) and a decreased percentage of heavy drinking days (P = .04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P = .005). No gene x medication interactions were observed in those treated with both MM and CBI.ConclusionsThese results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 genotyping in alcoholic individuals might be useful to assist in selecting treatment options.Trial registrationclinicaltrials.gov Identifier: NCT00006206.

Project description:BackgroundThe 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.MethodsIndividuals (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.ResultsNicotine-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.ConclusionsThese 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:Glutamate and opioid systems play important roles in alcohol drinking behaviors. We examined if combined treatment with the NMDA antagonist memantine and the opioid antagonist naltrexone, when compared with naltrexone alone, would have a greater influence on alcohol drinking behaviors. Fifty-six, non-treatment-seeking heavy drinkers, with alcohol dependence and a positive family history (FHP) of alcoholism, participated in a randomized, double-blind, crossover trial, including two 6-8 days treatment periods, separated by a 6-day washout, and 3 alcohol drinking paradigm (ADP) sessions. After the first baseline (BAS) ADP1 session, participants were randomized to receive either naltrexone (NTX; 50 mg/day) + placebo memantine, or NTX (50 mg/day) + memantine (MEM; 20 mg/day), during the first treatment period, following which they completed ADP2. After a 6-day washout, participants were crossed over to the treatment they did not receive during the first treatment period, following which they completed ADP3. During each ADP, participants received a priming drink of alcohol followed by 3 1-hour, self-administration periods during which they had ad-lib access to 12 drinks. Individually, both NTX and NTX + MEM, when compared to BAS ADP1, significantly reduced the number of drinks consumed (p's < 0.001) and craving (p's < 0.001). When comparing NTX + MEM vs. NTX on number of drinks consumed, there was a significant treatment* sequence interaction (p = 0.004). Specifically, when NTX + MEM followed NTX alone, NTX + MEM resulted in a further reduction in drinking (mean: -1.94; 95% CI: -2.6, -0.8, p = 0.0005). However, when NTX alone followed NTX + MEM, NTX alone did not lead to further reduction in drinking (mean: 0.59; 95% CI: -0.67, 1.43, p = 0.47). Similar patterns were observed for alcohol craving; specifically, a significant reduction in craving was observed when NTX + MEM followed NTX alone (p = 0.009), but craving reduction was maintained when NTX + MEM was followed by NTX alone. Neither treatment condition significantly influenced alcohol-induced stimulation or sedation. Memantine (at a dose of 20 mg/day) enhances the efficacy of naltrexone (50 mg/day) in reducing alcohol drinking and craving among FHP drinkers with beneficial effects that appear to carryover after discontinuation of memantine treatment.

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Gabapentin combined with naltrexone for the treatment of alcohol dependence.

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Gabapentin combined with naltrexone for the treatment of alcohol dependence.

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