A double blind, placebo-controlled trial that combines disulfiram and naltrexone for treating co-occurring cocaine and alcohol dependence

BACKGROUND: This is a double blind, placebo-controlled trial that evaluated the efficacy of disulfiram, naltrexone and their combination in patients with co-occurring cocaine and alcohol dependence. METHODS: 208 patients were randomized to disulfiram (250 mg/day), naltrexone (100 mg/day), the combination, or placebo for 11 weeks. Outcomes were in-trial abstinence from cocaine and/or alcohol. RESULTS: Few safety concerns were reported, although medication adherence was low in a number of patients for both medications, alone or in combination. In the primary analyses (GEE modeling), abstinence from cocaine as measured by cocaine-negative urines and days of self-reported abstinence from cocaine or alcohol did not differ between placebo and any of the medication groups. However, patients taking disulfiram (alone or in combination) were most likely to achieve combined abstinence from cocaine and alcohol. Secondary analyses revealed that patients taking the disulfiram-naltrexone combination were most likely to achieve 3 consecutive weeks of abstinence from cocaine and alcohol. CONCLUSION: There was an association between disulfiram treatment and abstinence from cocaine and alcohol. More patients taking the disulfiram-naltrexone combination achieved 3 consecutive weeks of abstinence in treatment than placebo-treated patients.     

Acamprosate and naltrexone treatment for alcohol dependence: an evidence-based risk-benefits assessment

This paper provides an evidence-based risk-benefit assessment of acamprosate and naltrexone in the treatment of alcohol dependence. A risk-benefit assessment is based on the premise that the choice of treatment depends on a number of factors, notably the adverse event profile and efficacy. An evidence-based approach attempts to operationalize how such risk-benefit assessments are made to inform physician choices. This approach involves a systematic assessment of all published double-blind, placebo-controlled trials. Based on this review, we conclude acamprosate and naltrexone are both useful in the treatment of alcohol dependence. However, the two drugs act in different ways in the brain, and their clinical profiles are different. Treatment effects seem to be more reliable for acamprosate, and this drug is better tolerated. The safety of the two drugs in combination has been supported by two independent double-blind studies, and combination treatment may offer an advantage for some patients.     

Extended-release naltrexone for alcohol and opioid dependence: A meta-analysis of healthcare utilization studies

Through improved adherence, once-monthly injectable extended-release naltrexone (XR-NTX) may provide an advantage over other oral agents approved for alcohol and opioid dependence treatment. The objective of this study was to evaluate cost and utilization outcomes between XR-NTX and other pharmacotherapies for treatment of alcohol and opioid dependence. Published studies were identified through comprehensive search of two electronic databases. Studies were included if they compared XR-NTX to other approved medicines and reported economic and healthcare utilization outcomes in patients with opioid or alcohol dependence. We identified five observational studies comparing 1,565 patients using XR-NTX to other therapies over 6 months. Alcohol dependent XR-NTX patients had longer medication refill persistence versus acamprosate and oral naltrexone. Healthcare utilization and costs was generally lower or as low for XR-NTX-treated patients relative to other alcohol dependence agents. Opioid dependent XR-NTX patients had lower inpatient substance abuse-related utilization versus other agents and $8170 lower total cost versus methadone.     

Naltrexone treatment of comorbid alcohol and cocaine use disorders

 Naltrexone (NTX) has been shown to be efficacious for the treatment of alcohol dependence. Since alcohol and cocaine use disorders commonly co-occur, we conducted a randomized, double-blind, placebo-controlled trial of NTX 50 mg/day in 64 subjects with comorbid alcohol and cocaine use disorders. Although subjects in both groups reduced their consumption of both alcohol and cocaine during the 8-week trial, there was no consistent advantage to NTX over placebo treatment. We conclude that, due to behavioral, neurochemical, or other factors, individuals with both alcohol and cocaine use disorders are distinct from those dependent on alcohol alone, and that NTX at a dosage of 50 mg/day is not efficacious in this patient population. Several factors, including medication dosage, length of treatment, sample size and attrition rate, limit the interpretation of these findings. Consequently, we recommend that subsequent trials of NTX to reduce the risk of relapse in patients with comorbid alcohol and cocaine use disorders take these issues into account. Received: 15 November 1997 / Final version: 9 May 1998     

Use of naltrexone in ketamine dependence

Ketamine is used as a cheap alternative to anaesthetic agents in developing countries. It is also misused as a rave drug because of its psychedelic effect. There are no guidelines for effective management of ketamine withdrawal effects or dependence. Herein we report a case of ketamine dependence and its successful treatment with opioid receptor antagonist naltrexone.     

Chronic pretreatment with naltrexone facilitates acquisition of intravenous cocaine self-administration in rats

Opioid systems may be involved in the reinforcing effects of drugs of abuse. It has been shown that the opioid antagonist naltrexone attenuates acquisition of intravenous cocaine self-administration behaviour in rats. Using a similar experimental set-up the effect of chronic blockade of opioid systems prior to cocaine exposure was examined. Rats were tested for acquisition of self-administration of one of 3 graded unit doses of cocaine (0.08, 0.16 and 0.32 mg.kg-1 per infusion) or saline. Chronic pretreatment with naltrexone (10 mg.kg-1 per day for 12 days) enhanced acquisition of intravenous cocaine self-administration but only in rats tested with the medium cocaine unit dose. It is concluded that chronic blockade of opioid systems facilitates acquisition of cocaine self-administration, probably by enhancing the reinforcing effect of cocaine.     

Divalproex utility in bipolar disorder with co-occurring cocaine dependence: a pilot study

OBJECTIVE: The aim of this open-label pilot study was to evaluate the utility of divalproex in decreasing cocaine use and stabilizing mood symptoms among patients with bipolar disorder with comorbid cocaine dependence. METHOD: Fifteen patients enrolled in the study and seven met final inclusion criteria of DSM-IV/SCID diagnoses of bipolar I disorder and comorbid cocaine dependence with active cocaine use. Patients were started on open-label divalproex. After stabilization on divalproex sodium, weekly assessments were undertaken for 8weeks. Subjects also attended dual recovery counseling. RESULTS: The results revealed significant improvement on % cocaine abstinent days, dollars spent on cocaine, ASI's drug use severity index, % alcohol abstinent days, drinks per drinking day, marijuana use and cigarettes smoking. They also had significant improvement on manic, depressive, and sleep symptoms and on functioning. There were no reported adverse events or increases in liver function tests. CONCLUSION: The results of this open-label study point to the potential utility of divalproex in patients with bipolar disorder and primary cocaine dependence. Double-blind, placebo-controlled studies to fully evaluate the efficacy of divalproex in this high risk clinical population are warranted.     

Quality of life in veterans with alcohol dependence and co-occurring mental illness

Quality of life is negatively impacted by diagnosis of mental illness. Those with mental illness report problems in physical, psychological, cognitive, social, and occupational functioning. This study was designed to examine changes in quality of life in veterans with dual diagnoses. All veterans participated in a treatment study designed to treat alcohol dependence with naltrexone, disulfiram, and the combination of naltrexone/disulfiram or placebo for 12 weeks. Quality of life was assessed before treatment and at the end of treatment. Quality of life improved for all veterans and the improvement was more significant for those who abstained from alcohol throughout treatment. Severity of psychiatric symptom was associated with worse quality of life. This study demonstrates the importance of addressing social functioning in veterans with dual diagnosis.     

Effect of naltrexone on subjective alcohol response in subjects at high and low risk for future alcohol dependence

We investigated specific subjective effects of naltrexone pretreatment or placebo during various intervals on the breath alcohol level (BAL) curve in nonalcoholic volunteers. Fifteen high-risk (social drinkers with an alcoholic father) and 14 low-risk (no alcoholic relatives in at least two generations) subjects were tested in a double-blind, placebo-controlled study of the effects of 50 mg oral naltrexone on response to a moderate dose of alcohol. Dependent measures included subjective stimulation and sedation subscales from the Biphasic Alcohol Effects Scale (BAES) and mood subscales from the Profile of Mood States (POMS). At rising BALs, high-risk subjects showed a naltrexone-related attenuation of BAES stimulation. This effect was not evident in low-risk subjects, who directionally showed the opposite effect, although nonsignificant. For both groups, there were no significant naltrexone-related effects for BAES sedation; however, naltrexone did affect several POMS scales on alcohol response, such as decreased vigor, and increased fatigue, tension, and confusion. Confusion was significantly elevated for the high-risk group during rising BALs of the naltrexone session. The results suggest a differential response to naltrexone, based on paternal history of alcoholism and level of stimulation experienced during alcohol drinking. Received: 22 August 1995 / Final version: 25 July 1996     

Intracerebroventricular naltrexone treatment attenuates acquisition of intravenous cocaine self-administration in rats

The influence of centrally administered naltrexone, an opiate antagonist, on acquisition of intravenous cocaine self-administration behaviour in rats was examined. On five consecutive days, three hours per day, they could self-administer a cocaine solution (30 μg per infusion) through an indwelling cannula. Treatment consisted of daily injections of naltrexone (2 or 5 μg) or placebo into the lateral ventricle 30 minutes before testing. Naltrexone treatment dose dependently attenuated the rate of cocaine self-infusion. Both self-infusion rate and rate of responding on the reinforcement lever in the group treated with 5 μg naltrexone differed from placebo, whereas rate of responding on a dummy lever did not. These findings a) support the notion that opioid systems play a role in cocaine reinforcement, and b) suggest that naltrexone exerts its effect on cocaine reinforcement through action in the central nervous system.     

Associations between behavioral disinhibition and cocaine use history in individuals with cocaine dependence

Background

Behavioral disinhibition has been suggested as both a cause and consequence of substance use disorders. Many studies examining associations between behavioral disinhibition and substance use history have focused on individuals with alcohol dependence or non-dependent college students. In the present study, the relationship between behavioral disinhibition and cocaine use history in individuals with cocaine dependence is examined.

Methods

Forty-six non-treatment-seeking cocaine-dependent men and women completed impulsivity (Barratt Impulsiveness Scale; BIS) and novelty seeking (Temperament and Character Inventory; TCI) questionnaires at the baseline visit of an ongoing study. Unadjusted, and adjusted for gender and age, Pearson correlations were calculated between BIS, TCI, and cocaine use variables from the Structured Clinical Interview for DSM-IV and Timeline Follow-back (age of onset, quantity/frequency of past 30 day cocaine use).

Results

As expected, elevated motor impulsivity and novelty seeking were each associated with younger age of dependence onset. Also, individuals with lower levels of persistence on the TCI reported more days of cocaine use over the previous month. Unexpectedly, increased novelty seeking and attentional impulsivity were associated with fewer days of cocaine use and less money spent on cocaine, respectively. Controlling for age and gender did not substantially change the pattern of observed associations.

Conclusions

The present study provides preliminary evidence for associations between behavioral disinhibition and cocaine use history in cocaine-dependent individuals. Given our relatively small sample size and the correlational nature of our findings, further research is needed to replicate and extend our results.     

Differences between adult non-drug users versus alcohol,cocaine and concurrent alcohol and cocaine problem users

Concurrent drug use is a serious public health concern with significant morbidity and mortality associated with the combined use of alcohol and cocaine. Multinomial logistic regression was used to assess differences between non-drug users and alcohol, cocaine and concurrent problem users incorporating data from the 2005 National Survey on Drug Use and Health. Results demonstrated that alcohol and cocaine use is associated with mental health disturbance, other drug use and adverse social consequences. Furthermore, concurrent users were more likely to report cigarette and marijuana use as well as lifetime STDs and arrest for breaking the law. Study results have implications for planning prevention and treatment services differentially for alcohol, cocaine and concurrent users and support the need for more intense resources allocated to the prevention and treatment of the concurrent use of alcohol and cocaine.     

Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients

Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, we recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingency management (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications we designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25–29%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement.     

A double-blind,placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence

Background

Topiramate increases GABAergic activity and antagonizes the AMPA/kainate subtype of glutamate receptors. Through these mechanisms of action, topiramate may reduce alcohol and cocaine reward and may reduce alcohol and cocaine craving. Topiramate has been shown to reduce drinking in persons with alcohol dependence, and reduce relapse in stimulant-dependent patients. The current trial was intended to test the ability of topiramate to promote cocaine and alcohol abstinence among patients addicted to both drugs.

Methods

The study was a double-blind, placebo-controlled, 13-week trial involving 170 cocaine and alcohol dependent subjects. After achieving a period of cocaine and alcohol abstinence, subjects were randomized to topiramate, 300 mg daily, or identical placebo capsules. In addition, subjects received weekly individual psychotherapy. Primary outcome measures included self-reported alcohol and cocaine use, and thrice weekly urine drug screens. Secondary outcome measures included cocaine and alcohol craving, Addiction Severity Index results, cocaine withdrawal symptoms, and clinical global improvement ratings.

Results

Topiramate was not better than placebo in reducing cocaine use on the a priori primary outcome measure, or in reducing alcohol use. Topiramate was not better than placebo in reducing cocaine craving. Topiramate-treated subjects, compared to placebo-treated subjects, were more likely to be retained in treatment and more likely to be abstinent from cocaine during the last three weeks of the trial. Subjects who entered treatment with more severe cocaine withdrawal symptoms responded better to topiramate.

Discussion

Topiramate plus cognitive behavioral therapy may reduce cocaine use for some patients with comorbid cocaine and alcohol dependence.     

Preliminary evaluation of extended-release naltrexone in Michigan and Missouri drug courts

This pilot study, a retrospective case series analysis, examined the feasibility and effectiveness of treating alcohol dependence with extended-release naltrexone (XR-NTX) in the drug court setting. In two Michigan courts and in one Missouri court, 32 clients were treated with XR-NTX and were matched with 32 clients with standard care in an open-label, voluntary recruitment design. Treatment with XR-NTX was associated with relative risk reductions (RRRs; p = ns) of 57% fewer missed drug court sessions, a 35% reduction in the monthly ratio of positive drug and alcohol tests to total tests, and 35% fewer individuals with greater than 25% overall positive alcohol or drug tests. In the principal end-point analysis of annualized number of new arrests, 26% of standard-care clients were rearrested versus 8% on XR-NTX (RRR = 69%; p < .05). Treatment with XR-NTX appeared to be feasible and was associated with a consistently large treatment effect across multiple outcomes relevant to the drug court setting.     

Extended-release naltrexone for treatment of alcohol dependence in primary care

The feasibility of using extended-release injectable naltrexone (XR-NTX) to treat alcohol dependence in routine primary care settings is unknown. An open-label, observational cohort study evaluated 3-month treatment retention, patient satisfaction, and alcohol use among alcohol-dependent patients in two urban public hospital medical clinics. Adults seeking treatment were offered monthly medical management (MM) and three XR-NTX injections (380 mg, intramuscular). Physician-delivered MM emphasized alcohol abstinence, medication effects, and accessing mutual help and counseling resources. Seventy-two alcohol-dependent patients were enrolled; 90% (65 of 72) of eligible subjects received the first XR-NTX injection; 75% (49 of 65) initiating treatment received the second XR-NTX injection; 62% (40 of 65), the third. Among the 56% (n = 40) receiving three injections, median drinks per day decreased from 4.1 (95% confidence interval = 2.9–6) at baseline to 0.5 (0–1.7) during Month 3. Extended-release naltrexone delivered in a primary care MM model appears a feasible and acceptable treatment for alcohol dependence.     

Factors in sustained recovery from cocaine dependence

The goal was to identify factors that predicted sustained cocaine abstinence and transitions from cocaine use to abstinence over 24 months. Data from baseline assessments and multiple follow-ups were obtained from three studies of continuing care for patients in intensive outpatient programs (IOPs). In the combined sample, remaining cocaine abstinent and transitioning into abstinence at the next follow-up were predicted by older age, less education, and less cocaine and alcohol use at baseline, and by higher self-efficacy, commitment to abstinence, better social support, lower depression, and lower scores on other problem severity measures assessed during the follow-up. In addition, higher self-help participation, self-help beliefs, readiness to change, and coping assessed during the follow-up predicted transitions from cocaine use to abstinence. These results were stable over 24 months. Commitment to abstinence, self-help behaviors and beliefs, and self-efficacy contributed independently to the prediction of cocaine use transitions. Implications for treatment are discussed.     

Correlates of health-related quality of life in Thai patients with alcohol dependence

This study aimed to examine the correlates of health related quality of life in Thai patients with alcohol dependence. The amount of alcohol intake was calculated by timeline followback chart and the health related quality of life was determined by Short Form–36 Health Survey. The means of the Short Form–36 Physical Component and Mental Component Summary were 67.43 (18.74) and 64.45 (20.90), respectively. Stepwise linear regression models showed the number of heavy drinking days was significantly correlated with the Physical Component Summary and Mental Component Summary. Such moderate correlations suggest that drinking and health related quality of life measures might tap different aspects of alcohol outcomes and should be concurrently administered.     

Perpetration of partner violence: effects of cocaine and alcohol dependence and posttraumatic stress disorder

The present study examined the effects of substance dependence and posttraumatic stress disorder (PTSD) on perpetration of partner violence. Participants were 72 men and 124 women diagnosed with and/or without PTSD and cocaine or alcohol dependence. Participants were interviewed with the Structured Clinical Interview for the DSM-IV (SCID-IV) and completed the Conflict Tactics Scale-2 (CTS-2). Analyses indicated that participants with comorbid cocaine dependence and PTSD reported the highest frequency of partner violence relative to all other groups. Main effects were also detected for drug dependence and PTSD. Results suggest that substance dependence and PTSD alone are associated with increased violence in couples, and most importantly, the presence of PTSD serves to further potentiate the perpetration of partner violence among cocaine-dependent individuals.     

酒依赖者“醒悟”的内涵及其产生背景分析

目的：分析酒依赖者所说的“醒悟”的内涵及产生背景。方法：对自述体验“醒悟”后戒酒且实际戒酒时间超过3年以上的男性酒依赖者12例及其家属进行详细的精神科面谈和既往病历分析。结果：体验“醒悟”的时点为自从酒量剧增起第20.25±5.46年。即将体验“醒悟”时，他们正因饮酒问题处在家庭破坏或下岗或身体衰弱的危机，本人痛感人生失败或生命危险，束手无策，而盼望获救。这时，恰有人忠告他们只要戒酒有望解决问题，他们忽然间感到希望、和平、宽容、无限感激等不同的情感变化的同时，都毫无抵制地接受自己是酒依赖者的事实。结论：酒依赖者所说的“醒悟”的内涵可归纳为“伴有解放感的情绪性共鸣”。求生欲望达到极限是“醒悟”产生的内因，而周围人及时的忠告是“醒悟”产生的外因。