The dopamine receptor D2 (DRD2) SNP rs1076560 is associated with opioid addiction.

The risk for drug addiction is partially heritable. Genes of the dopamine system are likely candidates to harbour risk variants, as dopamine neurotransmission is involved in mediating the rewarding effects of drugs of abuse. One functional single nucleotide polymorphism in dopamine receptor D2 (DRD2), rs1076560, is involved in regulating splicing of the gene and alters the ratio of DRD2 isoforms located pre- and postsynaptically. rs1076560 has been previously associated with cocaine abuse and we set out to confirm this association in a sample of European American (EA) (n = 336) and African American (AA) (n = 1034) cocaine addicts and EA (n = 656) and AA (n = 668) controls. We also analysed the role of rs1076560 in opioid dependence by genotyping EA (n = 1041) and AA (n = 284) opioid addicts. rs1076560 was found to be nominally associated with opioid dependence in EAs (p = 0.02, OR = 1.27) and AAs (p = 0.03, OR = 1.43). When both opioid-addicted ancestral samples were combined, rs1076560 was significantly associated with increased risk for drug dependence (p = 0.0038, OR = 1.29). This association remained significant after correction for multiple testing. No association was found with cocaine dependence. These data demonstrate the importance of dopamine gene variants in the risk for opioid dependence and highlight a functional polymorphism that warrants further study.

A pilot trial of injectable, extended-release naltrexone for the treatment of co-occurring cocaine and alcohol dependence.

BACKGROUND: There is a high co-occurrence of cocaine and alcohol use disorders, and patients with both of these problems are difficult to treat. There is a reasonable rationale and some empirical data to justify a pilot trial of an injectable, extended-release formulation of naltrexone for treating co-occurring cocaine and alcohol addiction. METHODS: Eighty cocaine (n = 80) and alcohol dependent, treatment-seeking subjects were randomly assigned to receive either two monthly extended-release injections of naltrexone or two matching placebo injections in an 8-week clinical trial, with weekly medical management plus cognitive behavioral therapy visits. RESULTS: No differences in reduction in cocaine or alcohol use were observed between the injectable naltrexone and placebo groups during the 8-week trial. CONCLUSIONS: Injectable extended-release naltrexone, while an ideal method for ensuring medication adherence in these traditionally hard-to-treat patients, did not result in any measurable reduction in cocaine or alcohol use over the course of 8 weeks of treatment.

Further evidence for association of polymorphisms in the CNR1 gene with cocaine addiction: confirmation in an independent sample and meta-analysis.

Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide insights for effective treatment. As endocannabinoid signaling and dopamine neurotransmission have been shown to be involved in drug reward, genes related to these systems are plausible candidates for susceptibility to CD. The cannabinoid receptor 1 protein regulates both the endocannabinoid and dopaminergic neurobiological systems, and polymorphisms in the cannabinoid receptor gene, CNR1, have been associated previously with substance dependence. In this study, we attempt to replicate findings associating CNR1 with CD in African Americans. Cocaine-addicted individuals (n=860) and unaffected controls (n=334) of African descent were genotyped for two single nucleotide polymorphisms (SNPs) in CNR1 (rs6454674, rs806368). We observed a significant difference in genotype frequencies between cases and controls for both SNPs (P≤0.042). A meta-analysis was also performed combining our data with that of Zuo et al. who also studied these polymorphisms in African American cocaine addicts (total n=1253 cases versus 543 controls). When our data were combined, rs6454674 increased in significance to P=0.027; however, rs806368 was no longer significant. This study confirms the association between rs6454674 and CD. However, because there is considerable co-morbidity of CD with other drugs of abuse, additional studies are necessary to determine whether polymorphisms in CNR1 induce a general susceptibility to substance dependence or are specific to cocaine addiction. Furthermore, as this population consists of American individuals of African descent, the possibility of population stratification should not be excluded.

A double-blind, placebo-controlled trial to assess the efficacy of quetiapine fumarate XR in very heavy-drinking alcohol-dependent patients.

BACKGROUND: Despite advances in developing medications to treat alcohol dependence, few such medications have been approved by the Food and Drug Administration. Identified molecular targets are encouraging and can lead to the development and testing of new compounds. Atypical antipsychotic medications have been explored with varying results. Prior research suggests that the antipsychotic quetiapine may be beneficial in an alcohol-dependent population of very heavy drinkers. METHODS: In this double-blind, placebo-controlled trial, 224 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetiapine or placebo and Medical Management behavioral intervention. Patients were stratified on gender, clinical site, and reduction in drinking prior to randomization. RESULTS: No differences between the quetiapine and placebo groups were detected in the primary outcome, percentage heavy-drinking days, or other drinking outcomes. Quetiapine significantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking prior to randomization had significantly better drinking outcomes during the maintenance phase (p < 0.0001). No significant interactions, however, were observed between reducer status and treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%), and somnolence (34 vs. 9%). CONCLUSIONS: This multisite clinical trial showed no efficacy for quetiapine compared with placebo at reducing alcohol consumption in heavy-drinking alcohol-dependent patients.

A double-blind, placebo-controlled trial assessing the efficacy of levetiracetam extended-release in very heavy drinking alcohol-dependent patients.

BACKGROUND: Despite advances in the development of medications to treat alcohol dependence, few medications have been approved by the U.S. Food and Drug Administration. The use of certain anticonvulsant medications has demonstrated potential efficacy in treating alcohol dependence. Previous research suggests that the anticonvulsant levetiracetam may be beneficial in an alcohol-dependent population of very heavy drinkers. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, 130 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either levetiracetam extended-release (XR) or placebo and a Brief Behavioral Compliance Enhancement Treatment intervention. Levetiracetam XR was titrated during the first 4 weeks to 2,000 mg/d. This target dose was maintained during weeks 5 through 14 and was tapered during weeks 15 and 16. RESULTS: No significant differences were detected between the levetiracetam XR and placebo groups in either the primary outcomes (percent heavy drinking days and percent subjects with no heavy drinking days) or in other secondary drinking outcomes. Treatment groups did not differ on a number of nondrinking outcomes, including depression, anxiety, mood, and quality of life. The only difference observed was in alcohol-related consequences. The levetiracetam XR treatment group showed significantly fewer consequences than did the placebo group during the maintenance period (p = 0.02). Levetiracetam XR was well tolerated, with fatigue being the only significantly elevated adverse event, compared with placebo (53% vs. 24%, respectively; p = 0.001). CONCLUSIONS: This multisite clinical trial showed no efficacy for levetiracetam XR compared with placebo in reducing alcohol consumption in heavy drinking alcohol-dependent patients.

A double-blind, randomized trial of sertraline for alcohol dependence: moderation by age of onset [corrected] and 5-hydroxytryptamine transporter-linked promoter region genotype.

Late-onset/low-vulnerability alcoholics (LOAs) appear to drink less when treated with a selective serotonin reuptake inhibitor than placebo, whereas early-onset/high-vulnerability alcoholics (EOAs) show the opposite effect. We conducted a 12-week, parallel-group, placebo-controlled trial of the efficacy of sertraline in alcohol dependence (AD). We compared the effects in LOAs versus EOAs and examined the moderating effects of a functional polymorphism in the serotonin transporter gene. Patients (N = 134, 80.6% male, 34.3% EOAs) with Diagnostic and Statistical Manual of Mental Disorders-IV AD received up to 200 mg of sertraline (n = 63) or placebo (n = 71) daily. We used urn randomization, and patients were genotyped for the tri-allelic 5-hydroxytryptamine transporter protein linked promoter region polymorphism. Planned analyses included main and interaction effects of medication group, age of onset (≤ 25 years vs >25 years), and genotype (L'/L' vs S' carriers) on drinking outcomes. Results showed that the moderating effect of age of onset on the response to sertraline was conditional on genotype. There were no main or interaction effects among S' allele carriers. However, in L' homozygotes, the effects of medication group varied by age of onset (P = 0.002). At the end of treatment, LOAs reported fewer drinking and heavy drinking days when treated with sertraline (P = 0.011), whereas EOAs had fewer drinking and heavy drinking days when treated with placebo (P < 0.001). The small cell sizes and high rate of attrition, particularly for L' homozygotes, render these findings preliminary and their replication in larger samples necessary. Because AD is common, particularly in medical settings, and selective serotonin reuptake inhibitors are widely prescribed by practitioners, these findings have potential public health significance and warrant further evaluation.

Efficacy of extended-release naltrexone in patients with relatively higher severity of alcohol dependence.

BACKGROUND: Because some literature reviews have suggested that naltrexone's benefit may be limited to less-severe alcohol dependence, and exclusively to reduction in heavy drinking rather than abstinence, we examined the efficacy of once per month, injectable extended-release naltrexone (XR-NTX 380 mg) in patients with relatively higher severity alcohol dependence. METHODS: Post hoc analyses examined data from a multicenter, placebo-controlled, 24-week randomized trial of XR-NTX for alcohol dependence (N = 624). We analyzed treatment effects in alcohol-dependent patients who had higher baseline severity, as measured by: (i) the Alcohol Dependence Scale (ADS) or (ii) having been medically detoxified in the week before randomization. Efficacy was also examined via the relationship between pretreatment severity indices and reporting at least 4 days of lead-in abstinence prior to treatment-a major predictor of good outcome in the original study. RESULTS: Higher severity alcohol-dependent patients, defined by the ADS, when receiving XR-NTX 380 mg (n = 50) compared with placebo (n = 47), had significantly fewer heavy-drinking days in-trial (hazard ratio=0.583; p = 0.0049) and showed an average reduction of 37.3% in heavy-drinking days compared with 27.4% for placebo-treated patients (p = 0.039). Among those who had a detoxification just prior to randomization, these reductions were 48.9% (XR-NTX 380 mg; n = 11) and 30.9% (placebo; n = 15) (p = 0.004). Subjects with at least 4 days of pretreatment abstinence (n = 82) versus those without (n = 542) had significantly higher pretreatment ADS scores (p = 0.002) and were more likely to require detoxification prior to randomization (p < 0.001). Patients with lead-in abstinence experienced significantly better maintenance of initial and 6-month abstinence. CONCLUSIONS: These secondary analyses support the efficacy of XR-NTX 380 mg in relatively higher severity alcohol dependence for both reduction in heavy drinking and maintenance of abstinence, with implications for the role of adherence pharmacotherapy.

Long-term opioid blockade and hedonic response: preliminary data from two open-label extension studies with extended-release naltrexone.

The emergence of extended-release naltrexone (XR-NTX) raises the opportunity to explore the role of endorphin blockade on hedonic response during long-term alcohol dependence treatment. A hedonic survey was administered to 74 alcohol dependent patients treated for an average of 3.5 years with nearly continuous month-long intramuscular XR-NTX. The paper-and-pencil, one-time survey asked patients about the degree of pleasure they experienced in the past 90 days with drinking alcohol, sex, exercise and other daily activities. The data revealed lower pleasure ratings for alcohol than for sex, exercise and 10 other common activities. Mean responses to drinking alcohol and gambling were significantly lower than to listening to music, sex, reading, being with friends, eating good food, eating spicy food, and playing video/card games. This effect was independent of XR-NTX dose or duration. Although this exploratory study lacked baseline data, a comparison group or control for the impact of patient discontinuation, the data indicate the feasibility of examining long-term hedonic response in recovery. The differential hedonic ratings suggest that, in patients who persist with long-term continuous therapy, XR-NTX may selectively inhibit the pleasure associated with drinking alcohol, compared to a variety of other activities.

Gender differences in alcohol treatment: an analysis of outcome from the COMBINE study.

BACKGROUND: Relatively few studies have examined gender differences in the effectiveness of specific behavioral or pharmacologic treatment of alcohol dependence. The aim of this study is to assess whether there were gender differences in treatment outcomes for specific behavioral and medication treatments singly or in combination by conducting a secondary analysis of public access data from the national, multisite NIAAA-sponsored COMBINE study. METHODS: The COMBINE study investigated alcohol treatment among 8 groups of patients (378 women, 848 men) who received medical management (MM) with 16 weeks of placebo, naltrexone (100 mg/day), acamprosate (3 g/day), or their combination with or without a specialist-delivered combined behavioral intervention. We examined efficacy measures separately for men and women, followed by an overall analysis that included gender and its interaction with treatment condition in the analyses. These analyses were performed to confirm whether the findings reported in the parent trial were also relevant to women, and to more closely examine secondary outcome variables that were not analyzed previously for gender effects. RESULTS: Compared to men, women reported a later age of onset of alcohol dependence by approximately 3 years, were significantly less likely to have had previous alcohol treatment, and drank fewer drinks per drinking day. Otherwise, there were no baseline gender differences in drinking measures. Outcome analyses of 2 primary (percent days abstinent and time to first heavy drinking day) and 2 secondary (good clinical response and percent heavy drinking days) drinking measures yielded the same overall pattern in each gender as that observed in the parent COMBINE study report. That is, only the naltrexone by behavioral intervention interaction reached or approached significance in women as well as in men. There was a naltrexone main effect that was significant in both men and women in reduction in alcohol craving scores with naltrexone-treated subjects reporting lower craving than placebo-treated subjects. CONCLUSIONS: This gender-focused analysis found that alcohol-dependent women responded to naltrexone with COMBINE's Medical Management, similar to the alcohol-dependent men, on a wide range of outcome measures. These results suggest that clinicians can feel comfortable prescribing naltrexone for alcohol dependence in both men and women. In this study, it is also notable that fewer women than men reported receiving any alcohol treatment prior to entry into the COMBINE study. Of note, women tend to go to primary health care more frequently than to specialty substance abuse programs for treatment, and so the benefit we confirm for women of the naltrexone and MM combination has practical implications for treating alcohol-dependent women.

A double-blind, placebo-controlled study with quetiapine as adjunct therapy with lithium or divalproex in bipolar I patients with coexisting alcohol dependence.

BACKGROUND: This study evaluated the efficacy of quetiapine versus placebo as an adjunct to lithium or divalproex in reducing alcohol consumption in patients with bipolar I disorder and coexisting alcohol dependence. METHODS: Male and female outpatients (21 to 60 years) with a history of bipolar I disorder and alcohol dependence were included in this 12-week, placebo-controlled study. Patients treated with lithium or divalproex (ongoing or assigned at screening) were randomized to receive quetiapine (dosed up to 400 mg/d over 7 days, followed by 300 to 800 mg/d flexible dosing until study end) or placebo. The primary outcome measure was the change in the proportion of heavy drinking days from baseline to Week 12 (as derived from the Timeline Followback method). Secondary outcome measures included time to the first consecutive 2 weeks of abstinence, changes from baseline to Week 12 in the proportion of nondrinking days, mean number of standardized drinks per day, and Clinical Global Impressions-Severity of Illness score. RESULTS: Of 362 enrolled patients (mean 38.6 years), 176 were randomized to receive quetiapine and 186 to placebo. The mean proportion of heavy drinking days at baseline was 0.66 in the quetiapine group and 0.67 in the placebo group. At Week 12, the mean change in the proportion of heavy drinking days was -0.36 with quetiapine and -0.36 with placebo (p = 0.93). No statistically significant differences in any of the secondary outcome measures were noted between the quetiapine and placebo groups. The incidence of adverse events was consistent with the previously known tolerability profile of quetiapine. CONCLUSIONS: The efficacy of quetiapine in the treatment of bipolar disorder is already well established. In this study, however, quetiapine added to lithium or divalproex did not result in significantly greater improvement compared with placebo in measures of alcohol use and dependence in patients with bipolar I disorder and alcohol dependence.

Effects of alcoholism typology on response to naltrexone in the COMBINE study.

BACKGROUND: This study investigated whether subgroups of alcohol-dependent patients responded differently to naltrexone versus placebo in the NIAAA COMBINE study. In particular, the A versus B and the Early Onset versus Late Onset typologies were examined. Relative to Type A alcoholics, Type B alcoholics are characterized by greater severity, earlier onset, stronger family history, more childhood risk factors (e.g., conduct disorder), and greater frequency of comorbid psychiatric and substance use disorders. METHODS: COMBINE study participants were categorized as Type A or Type B using k-means cluster analysis and variables from 5 domains that have been shown to replicate the original Babor typology efficiently. Early Onset was defined as alcohol dependence beginning before age 25. For the planned analyses, the sample was reduced to the 618 participants receiving naltrexone alone or placebo, either with medical management (MM) alone or with MM plus the Combined Behavioral Intervention (CBI). The a priori primary outcome was percent heavy drinking days during treatment in the groups receiving MM without CBI. RESULTS: Among those receiving MM without CBI, Type A alcoholics had better drinking outcomes with naltrexone than placebo, whereas medication condition did not influence outcomes significantly in the Type Bs. Age of onset was not significantly related to outcome. For those receiving CBI, no significant effects were found for either typology. CONCLUSIONS: In this sample, the beneficial effects of opioid antagonism were limited to Type A alcoholics receiving treatment in a MM model. Future studies should investigate the relationship between clinically relevant genotypes, phenotypes such as typologies, and treatment response. More work is also needed to develop practical algorithms for phenotypic assignment.

OPRM1 Asn40Asp predicts response to naltrexone treatment: a haplotype-based approach.

BACKGROUND: Individualized pharmacotherapy requires identification of genetic variants predictive of treatment response. In OPRM1, Asn40Asp has been reported to be predictive of response to naltrexone treatment. Nevertheless, the in vitro function of the polymorphism remains elusive and over 300 OPRM1 sequence variants have been identified to date. Therefore we used a haplotype-based approach to capture information of other genetic variants that might predict treatment response to naltrexone in the COMBINE Study. METHODS: 5' nuclease genotyping assays (TaqMan) were applied for 10 SNPs. Five-locus haplotypes in 2 OPRM1 haplotype blocks were assigned to Caucasian participants. The relationship of the haplotypes to medication reflected by "good clinical outcome" was analyzed in 306 Caucasians treated without Combined Behavioral Intervention and with either naltrexone or placebo. RESULTS: A significant haplotype by medication interaction (p = 0.03) was found in OPRM1 block 1. Naltrexone-treated alcoholics with haplotype AGCCC, the single haplotype carrying the Asp40 allele had the highest percent of good clinical outcome. When interaction of genotypes at each of the 5 loci comprising block 1 with medication was examined, only the Asn40/Asp40 and Asp40/Asp40 genotypes were found to significantly interact with naltrexone treatment. No haplotype by medication interaction was documented in OPRM1 block 2. CONCLUSIONS: Our haplotype-based approach confirms that the single OPRM1 locus predictive of response to naltrexone treatment is Asn40Asp in exon 1. A substantial contribution of any other OPRM1 genetic variant to interindividual variations in response to naltrexone treatment (at least in terms of good clinical outcome) is not supported by our findings.

Effect of extended-release naltrexone (XR-NTX) on quality of life in alcohol-dependent patients.

BACKGROUND: Extended-release naltrexone (XR-NTX) is a once-a-month injectable formulation for the treatment of alcohol dependence previously shown to reduce drinking and heavy drinking relative to placebo (Garbutt et al., 2005). A 24-week, randomized, double-blind, placebo-controlled study established the efficacy and safety of XR-NTX in this patient population. In this report, the effect of XR-NTX on quality of life (QOL) was examined. METHODS: Alcohol-dependent patients were randomly assigned to receive XR-NTX 380 mg (N = 205), XR-NTX 190 mg (N = 210), or placebo (N = 209), combined with a standardized psychosocial intervention. QOL was assessed using the Medical Outcomes Study 36-item short-form health survey, administered at baseline and at 4-week intervals during 24 weeks of treatment. RESULTS: Compared with U.S. population norms, patients showed initial impairment in the health-related QOL domains of mental health, social functioning, and problems with work or other daily activities due to emotional problems. Adherence to all 6 injections was 65% for XR-NTX 190 mg, 63% for XR-NTX 380 mg, and 64% for placebo. Generalized estimating equations analyses using an intention-to-treat sample revealed that XR-NTX 380 mg was associated with significantly greater improvements from baseline in mental health (p = 0.0496), social functioning (p = 0.010), general health (p = 0.048), and physical functioning (p = 0.028), compared with placebo. Linear regression analyses revealed that reductions from baseline in drinking (percentage of drinking days and percentage of heavy drinking days in the last 30 days) were significantly (p < 0.05) correlated with improvements in quality of life. CONCLUSION: Extended-release naltrexone 380 mg in combination with psychosocial intervention was associated with improvements in QOL, specifically in the domains of mental health, social functioning, general health, and physical functioning.

Predictors of treatment outcome in outpatient cocaine and alcohol dependence treatment.

We examined the ability of several baseline variables to predict treatment outcome in a pharmacotherapy trial that included 164 participants who were both cocaine- and alcohol-dependent and were selected for a randomized, double-blind, placebo-controlled study. Predictor variables included results from the baseline Addiction Severity Index (ASI), initial Urine Drug Screen results, cocaine and alcohol craving and cocaine and alcohol withdrawal symptoms at the start of treatment. Successful treatment was defined as four continuous weeks of self-reported cocaine abstinence verified by urine drug screens. In respect to demographic characteristics, there were no significant differences between patients who achieved four weeks of abstinence from cocaine and those who did not. Baseline variables that most consistently predicted cocaine abstinence included initial urine drug screen (UDS) results, the initial Cocaine Selective Severity Assessment (CSSA) scores, and initial self-reported cocaine use in past 30 days, whereas cocaine craving, cocaine composite scores, alcohol craving, alcohol withdrawal symptoms, and alcohol composite scores did not. The results of this study suggest that cocaine dependence severity in general, and initial UDS results, the CSSA scores and frequency of recent cocaine use in particular, have a significant impact on treatment outcome in the treatment of cocaine-dependent patients with comorbid alcoholism. Initial UDS results and CSSA scores are very useful predictors of treatment outcome and could be used as stratifying variables in outpatient cocaine and alcohol medication trials.

Genetic variants in the cocaine- and amphetamine-regulated transcript gene (CARTPT) and cocaine dependence.

Dopaminergic brain systems have been implicated to play a major role in drug reward, thus making genes involved in these circuits plausible candidates for susceptibility to substance use disorders. The cocaine- and amphetamine-regulated transcript peptide (CARTPT) is involved in reward and feeding behavior and has functional characteristics of an endogenous psychostimulant. In this study we tested the hypothesis that variation in the CARTPT gene increases susceptibility to cocaine dependence in individuals of African descent. Genotypes of three HapMap tagging SNPs (rs6894758; rs11575893; rs17358300) across the CARTPT gene region were obtained in cocaine dependent individuals (n=348) and normal controls (n=256). All subjects were of African descent. There were no significant differences in allele, genotype or haplotype frequencies between cases and controls for any of the tested SNPs. Our results do not support an association of the CARTPT gene with cocaine dependence; however, additional studies using larger samples, comprehensive SNP coverage, and different populations are necessary to conclusively rule out CARTPT as a contributing factor in the etiology of cocaine dependence.

Relationship between medication adherence and treatment outcomes: the COMBINE study.

BACKGROUND: Within the alcoholism field, there is mounting evidence supporting an important relationship between medication adherence and drinking outcomes. Little is known however, about the complex relationships between medication and treatment variables and drinking outcomes. The present paper reports on the differential impact of medication adherence and treatment factors on drinking outcomes. Data derived from the COMBINE Study was used to investigate the interrelationships between medication adherence, combination treatments and drinking outcomes. METHODS: Twelve hundred and twenty-six patients were randomized to 1 of 8 different combination treatments involving 2 medications--naltrexone and acamprosate and placebo, and 2 behavioral treatments--medical management (MM) and combined behavioral intervention (CBI). Two primary drinking outcomes were percent days abstinent (PDA) and time to first heavy drinking day. Medication adherence was defined as a proportion that reflects the number of pills taken by the maximum number of pills expected to be taken over the course of the trial. A generalized linear mixed model was used to estimate the effects of adherence on PDA while proportional hazards model was used to examine similar co-variate effects on time to first heavy drinking day. RESULTS: Concerning time to first heavy drinking day, a significant three-way interaction was found between medication adherence, CBI and naltrexone (p = 0.0160). Within the MM only plus placebo group (no CBI), significant differences were found in "recovery" (i.e., no heavy drinking days) rates between adherers and nonadherers (40% vs. 10%, p < 0.0001). Such differences became nonsignificant (p = 0.12) when CBI was introduced into the relationship. CBI did not add any such advantage to naltrexone-treated patients. CONCLUSIONS: CBI might serve a protective function for nonadherers in the placebo group; the median relapse time was reduced when these nonadherers were exposed to the alcohol specialty intervention. CBI offered little additional benefit to nonadherers in the naltrexone group. Among nonadherers in the naltrexone group, relapse rates appear to be more a function of inadequate exposure to the active medication and less influenced by CBI.

A placebo-controlled randomized clinical trial of naltrexone in the context of different levels of psychosocial intervention.

BACKGROUND: Naltrexone is approved for the treatment of alcohol dependence when used in conjunction with a psychosocial intervention. This study was undertaken to examine the impact of 3 types of psychosocial treatment combined with either naltrexone or placebo treatment on alcohol dependency over 24 weeks of treatment: (1) Cognitive-Behavioral Therapy (CBT) + medication clinic, (2) BRENDA (an intervention promoting pharmacotherapy) + medication clinic, and (3) a medication clinic model with limited therapeutic content. METHODS: Two hundred and forty alcohol-dependent subjects were enrolled in a 24-week double-blind placebo-controlled study of naltrexone (100 mg/d). Subjects were also randomly assigned to 1 of 3 psychosocial interventions. All patients were assessed for alcohol use, medication adherence, and adverse events at regularly scheduled research visits. RESULTS: There was a modest main treatment effect for the psychosocial condition favoring those subjects randomized to CBT. Intent-to-treat analyses suggested that there was no overall efficacy of naltrexone and no medication by psychosocial intervention interaction. There was a relatively low level of medication adherence (50% adhered) across conditions, and this was associated with poor outcome. CONCLUSIONS: Results from this 24-week treatment study demonstrate the importance of the psychosocial component in the treatment of alcohol dependence. Moreover, results demonstrate a substantial association between medication adherence and treatment outcomes. The findings suggest that further research is needed to determine the appropriate use of pharmacotherapy in maximizing treatment response.

An intervention for treating alcohol dependence: relating elements of Medical Management to patient outcomes with implications for primary care.

PURPOSE: Alcohol dependence, frequently seen in medical settings, is a major problem that affects the health and well-being of many individuals and their families. The purpose of this study was to examine the relationship between treatment outcomes and patient and clinician factors specifically associated with a medically oriented intervention given for the treatment of alcohol dependence. The intervention was developed for the National Institute on Alcohol Abuse and Alcoholism-sponsored COMBINE Study, a randomized controlled trial combining 2 medications, naltrexone and acamprosate, with Medical Management, with or without specialty alcohol treatment. METHODS: We examined the effect of patient adherence to treatment (number of Medical Management visits, total minutes in treatment, alliance or therapeutic relationship with the clinician, patient satisfaction with treatment, and clinician adherence to the Medical Management protocol) on abstinence from alcohol, amount of heavy drinking, and clinical improvement during treatment. RESULTS: More Medical Management visits attended and less total time spent in Medical Management treatment was associated with more days of abstinence from alcohol, reductions in heavy alcohol drinking, and a higher likelihood of clinical improvement. The patients' positive perceptions of their alliance with their clinician and their satisfaction with treatment was significantly associated with more days of abstinence from alcohol during treatment. Two clinician factors clinician confidence in the Medical Management treatment and flexibility in delivering Medical Management were also associated with better patient outcomes. CONCLUSIONS: Medically trained clinicians with minimal specialty training in alcohol dependence treatments were able to deliver a brief and effective medication management intervention that was designed to be consistent with primary care practice.

Gender differences in predictors of treatment attrition with high dose naltrexone in cocaine and alcohol dependence.

Recently, we reported that naltrexone at 150 mg/day significantly decreased cocaine and alcohol use for men but not women with co-occurring cocaine and alcohol dependence. The present study is an exploratory investigation of predictors that explain the different gender responses to naltrexone, with a particular focus on differential predictors of treatment attrition. No significant predictors were associated with treatment discontinuation in men. Women, however, were more likely to discontinue treatment when reporting severe pre-treatment psychiatric problems or nausea while in treatment. Further research on the impact of pre-treatment and in-treatment gender differences with naltrexone is warranted.

Gender differences with high-dose naltrexone in patients with co-occurring cocaine and alcohol dependence.

This is a randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy of a higher-than-typical daily dose of naltrexone (150 mg/day), taken for 12 weeks, in 164 patients (n = 116 men and n = 48 women) with co-occurring cocaine and alcohol dependence. Patients were stratified by gender and then randomly assigned to either naltrexone or placebo, and to either cognitive-behavioral therapy or a type of medical management. The two primary outcomes were cocaine use and alcohol use. Significant Gender x Medication interactions were found for cocaine use via urine drug screens (three way, with time) and self-reports (two way) for drug severity (two way) and alcohol use (two way). The type of psychosocial treatment did not affect outcomes. Thus, 150 mg/day naltrexone added to a psychosocial treatment resulted in reductions in cocaine and alcohol use and drug severity in men, compared to higher rates of cocaine and alcohol use and drug severity in women.