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.     

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 × 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.     

Effect of early and late compliance on the effectiveness of acamprosate in the treatment of alcohol dependence

Background

The aim of this study is to assess the influence of early and late compliance of acamprosate on attendance and abstinence duration in the treatment of alcohol dependence.

Methods

Individual patient data of 2,305 patients from 11 randomized controlled trials comparing acamprosate (n = 1,128) with placebo (n = 1,177) were used to predict early and late compliance and to study the effect of early and late compliance on attendance and abstinence duration using regression analysis and structural equation modeling.

Results

Early compliance was predicted by baseline motivation to become fully abstinent and baseline abstinence (R² = .26); late compliance was predicted by early compliance (R² = .13); treatment discontinuation was predicted by young age, marital status, compliance, and treatment condition (R² = .26); and abstinence duration was predicted by motivation to become fully abstinent early compliance and the interaction of early compliance and treatment condition (R² = .27). Structural equation modeling showed that abstinence duration was significantly associated with motivation at baseline, late compliance, and treatment condition (Goodness of Fit Index [GFI] χ²/df = 1.56; Parsimonious Goodness of Fit Index [PGFI] = 0.69).

Conclusions

Motivation to become fully abstinent and abstinence at the start of treatment are important for early compliance. Early compliance in turn predicts late compliance. Late compliance, in combination with motivation to become fully abstinent, and treatment condition (acamprosate vs. placebo) predict duration of abstinence. This suggests that motivational interventions directed toward full abstinence motivation and abstinence at the start of treatment are crucial for both compliance with acamprosate and successful treatment outcome.     

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.     

Behavioral naltrexone therapy: an integrated treatment for opiate dependence

Treatment of opiate dependence with naltrexone has been limited by poor compliance. Behavioral Naltrexone Therapy (BNT) was developed to promote adherence to naltrexone and lifestyle changes supportive of abstinence, by incorporating components from empirically validated treatments, including Network Therapy with a significant other to monitor medication compliance, the Community Reinforcement Approach, and voucher incentives. An overview is presented of the BNT treatment manual. In an uncontrolled Stage I trial (N = 47), 19% completed the 6-month course of treatment. Retention was especially poor in the subsample of patients who were using methadone at baseline (N = 18; 39% completed 1 month, none completed 6 months), and more encouraging among heroin-dependent patients (N = 29; 65% completed 1 month, 31% completed 6 months). Thus, attrition continues to be a serious problem for naltrexone maintenance, although further efforts to develop interventions such as BNT are warranted.     

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.     

Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings

The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.     

Acamprosate in the treatment of alcohol dependence

Acamprosate is indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation in combination with psychosocial support. Acamprosate is a synthetic taurine analogue that seems to act centrally to restore the normal activity of glutamatergic neurotransmission altered by chronic alcohol exposure. Over the past 15 years, the safety and efficacy of acamprosate for alcohol dependence have been well established in multiple double-blind, placebo-controlled trials. Overall, acamprosate has been consistently associated with greater beneficial effects on measures of alcohol abstinence compared with placebo. Specifically, patients treated with acamprosate achieve greater rates of complete abstinence, longer times to first drink and/or increased duration of cumulative abstinence when compared with placebo. Acamprosate received approval by the US FDA for the treatment of alcohol dependence in July 2004 and is currently prescribed in 28 countries.     

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     

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     

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, but not naltrexone, inhibits conditioned abstinence behaviour associated with repeated ethanol administration and exposure to a plus-maze

Rationale: Drugs that reduce relapse in alcoholics are thought to inhibit either positive reinforcement for drinking (e.g. naltrexone) or negative reinforcement (e.g. acamprosate), and may reduce the impact of conditioned stimuli associated with previous alcohol use. We have developed a model for such conditioning by repeatedly pairing ethanol administration with plus-maze exposure. Substitution of saline for ethanol greatly increased stretched-attend postures and time in the central square, conditioned to the environment. Objective: To test the hypothesis that if this behaviour indicates a negative affective state caused by the expectation of ethanol, it should be inhibited by drugs that reduce negative, but not positive, reinforcement. Methods: The effects of naltrexone and acamprosate on alcohol-conditioned abstinence behaviour were compared. Results: Acute administration of either drug alone produced no significant effects on plus-maze behaviour in naive mice. Naltrexone had no significant effect on the alcohol-conditioned abstinence behaviour, but acamprosate reduced the incidence of stretched-attend postures. Conclusions: The experiments replicated previous findings for alcohol/environment conditioned behaviour, and demonstrated, as predicted, that this was decreased by acamprosate but not by naltrexone. Effects of acamprosate on conditioned negative reinforcement may be the cause of this effect, but more work is required to establish the usefulness of this model in evaluation of anti-relapse drugs. Received: 4 May 1999 / Final version: 21 July 1999     

A placebo-controlled trial of memantine as an adjunct to injectable extended-release naltrexone for opioid dependence

There is preclinical support for using NMDA receptor glutamatergic antagonists to aid in naltrexone-based treatment of opioid dependence. We hypothesized that adding memantine will improve efficacy of extended-release (XR) naltrexone to prevent relapse. In this double blind study opioid-dependent participants (N = 82) underwent inpatient detoxification and naltrexone induction. During naltrexone initiation participants were randomized to receive memantine 40 mg or placebo and continued treatment for 12-weeks with XR naltrexone and relapse-prevention therapy. Sixty eight percent of participants completed detoxification and received the first dose of XR naltrexone. Rates of trial completion were significantly greater in participants receiving placebo than memantine (70% vs. 43%, p < 0.05). Severity of opioid withdrawal symptoms during the first 3 weeks of the trial appeared to be lower in the group receiving memantine (p = 0.07). Adding memantine does not appear to increase the effectiveness of injectable XR naltrexone as a relapse prevention strategy in opioid dependence and may lead to an increase in treatment drop-out.     

The effects of acamprosate on alcohol-cue reactivity and alcohol priming in dependent patients: a randomized controlled trial

Rationale  Acamprosate is a widely utilized, efficacious treatment for relapse prevention in alcohol-dependent patients; yet, little is known regarding its therapeutic mechanism of action. Objectives  The aim of the present study was to examine the effect of acamprosate on cue reactivity and alcohol priming in alcohol-dependent patients. Methods  In a double-blind design, 56 treatment seeking patients were randomized to 21 days of either acamprosate or placebo treatment and then participated in a series of cue- and alcohol-priming sessions. Alcohol cues consisted of a mixture of alcohol related visual, tactile, olfactory, and auditory stimuli. Non-alcohol-related cues were contextually similar but had no connection to alcohol. In the alcohol-priming procedure, patients were provided with an alcohol drink of their own choice at a dose corresponding to 0.20 gr. EtOH/kg bodyweight. Subjective, physiological, and biological measurements were recorded before and after each test session. Following study completion, all patients were referred to formal treatment. Results  The results showed that acamprosate attenuated the subjective craving induced by alcohol priming in comparison to placebo-treated patients. Furthermore, acamprosate reduced alcohol-induced elevation in blood-cortisol levels. Lastly, there was a negative correlation between acamprosate plasma levels and alcohol craving following a priming drink. No effects of acamprosate on cue reactivity, or on the acute rewarding and sedating effects of the priming drink, were observed. Conclusion  These results suggest a potential mechanism by which acamprosate mediates its therapeutic effect in the treatment of alcoholism, by attenuating the urge to drink following an alcohol slip.     

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.     

Past year treatment status and alcohol abuse symptoms among US adults with alcohol dependence

Objective

We tested whether the number and type of alcohol abuse symptoms were associated with an increased likelihood of treatment seeking among respondents with alcohol dependence.

Methods

Data from 4027 adult respondents from 2006 and 2007 National Survey on Drug Use and Health (NSDUH) who met DSM-IV criteria for the past year alcohol dependence were used. Respondents were classified according to the number of past year alcohol abuse symptoms endorsed, as well as type of abuse symptom. Associations were estimated using weighted multivariate logistic regressions that controlled for severity of alcohol dependence, other drug use disorders and other characteristics.

Results

Twenty-eight percent of individuals with alcohol dependence had one alcohol abuse symptom, 20% had two and 19% had three or four. Individuals with more alcohol abuse symptoms differed from those without alcohol abuse symptoms in a number of sociodemographic characteristics and severity of alcohol and drug dependence. Even after adjusting for these factors, individuals with three or four alcohol abuse symptoms had 2.67 times increased odds of treatment seeking, as compared to those without alcohol abuse symptoms [95% CI = 1.65–4.30]. However, individuals with one or two alcohol abuse symptoms were no more likely to seek treatment than those without alcohol abuse symptoms. Majority of those with one or two alcohol abuse symptoms endorsed the hazardous abuse symptom.

Conclusion

Alcohol abuse symptoms are important factors for treatment seeking in individuals with alcohol dependence, but only among certain subset of individuals with three or four alcohol abuse symptoms. Examining structural and psychosocial differences across these subgroups may help inform and reduce barriers to treatment seeking among this population.     

注射用纳曲酮微球预防阿片类药物依赖复吸的临床研究

目的：评估注射纳曲酮微球预防阿片类药物依赖复吸的疗效和安全性。方法：筛选符合海洛因依赖且无其他躯体疾病,年龄18~45岁,至少有3次复吸史,自愿接受戒毒治疗的患者24例。随机纳入研究组及对照组,研究组注射纳曲酮微球,对照组服用盐酸纳曲酮片;疗程均为20周,停药后随访4周。在第0、2、4、8、12、16、20、24周时观察疗效和安全性。结果：研究组和对照组各纳入12名海洛因依赖患者,1名患者未参加随访,2名患者中途退出,共有21名患者（研究组11人,对照组10人）顺利完成实验。自给药后4~24周,研究组尿检阴性率均高于对照组,其差异在接受治疗后8周时有统计学意义（P =0.035）。研究组5人（45.5%）及对照组中2人（20.0%）完成全部访视。研究组与对照组的平均脱落时间分别为18.55周与11.40周,差异有统计学意义（P=0.033）。自用药后4周,研究组用药1 h后渴求评分均低于对照组,在访视5（用药后4周）和访视7（用药后12周）时有显著性差异（P=0.028;P=0.042）。在整个研究过程中,没有出现严重的治疗相关不良事件。结论：与口服纳曲酮片相比,注射用纳曲酮微球能降低患者复吸风险,减轻患者戒毒期间对毒品的渴求程度,提高患者服药依从性,增加其自愿接受治疗的时间,无不良事件发生风险,可以考虑作为海洛因依赖防复吸治疗的有效手段。     

Which treatment for alcohol dependence: naltrexone,acamprosate and/or behavioural intervention?

Alcoholism is the third leading cause of preventable mortality and morbidity in the US. In the COMBINE (Combined Pharmacotherapies and Behavioural Interventions) study, the co-primary end points were the percentage of days abstinent and the time to first heavy drinking day after 16 weeks, and 1 year. The biggest difference observed in COMBINE was that seen between combined behavioural intervention (CBI; percentage of abstinent days = 66.6%) and CBI and medical management with placebos (79.8%). This illustrated a major effect of the medical management of nine sessions and/or the placebo pills. Acamprosate had no effect alone or in combination with naltrexone. At 16 weeks with medical management, there were 75.1% of the patients who were abstinent for placebos, and this was improved by naltrexone, CBI, and naltrexone with CBI (80.6, 78.2 and 77.1%, respectively). There was a follow up after 1 year, which showed that, with medical management, the amount of those who were abstinent for placebos was 61.4%, and this was improved by naltrexone, CBI, and naltrexone with CBI (66.2, 66.6 and 67.3%, respectively), but this improvement no longer reached statistical significance. After 1 year, there was no difference between groups in the overall frequency of hospitalisation, emergency treatment for alcohol problems, use of medication for drinking or emotional problems and detoxification. Being part of a study for alcohol dependence is known to increase the percentage of abstinent days. In COMBINE, this percentage was high in the group having medical management and placebo pills, and naltrexone or additional behavioural therapy only had modest additional effects.     

帕罗西汀治疗酒依赖临床疗效研究

目的：探讨帕罗西汀治疗酒依赖患者的疗效与安全性。方法：采用临床开放研究,将68例酒依赖患者随机入组,治疗24周,在不同治疗时段采用密执根酒精依赖调查表（MAST）、饮酒渴求度、饮酒量调查表、17项汉密尔顿抑郁量表（Hamilton Depression Scale,HAMD-17）、汉密尔顿焦虑量表（Hamdton Anxieg Scale,HAMA）进行测试。结果：观察期内帕罗西汀组的饮酒渴求度,在治疗的第8、16、24周,明显低于对照组,比较差异有显著性fP值均〈0,05）;帕罗西汀组的酒精消耗量在治疗的第8、16、24周,较对照组显著减少,差异有统计学意A（P值均〈0．05）;帕罗西汀组HAMD-17评分,在治疗的第6、8、16、24周比较差异有显著性（P值均〈O．05）;帕罗西汀组的FLAMA评分,在治疗的第2、4、8周,明显低于对照组,比较差异有显著性（P值均〈0．05）;复饮患者纳曲酮组和对照组分别有6／31例、12／29例,差异有显著性（P值〈0．05）;不良事件记录显示帕罗西汀比较常见的不良反应主要为消化道反应（30／34）和乏力、嗜睡、头疼等神经系统副作用（3／34）。结论：帕罗西汀能有效降低酒依赖患者的心理渴求、酒精消耗和复饮风险,同时也能缓解酗酒导致的抑郁、焦虑症状。帕罗西汀的不良反应程度较轻,患者多可耐受,是一种安全有效的酒依赖治疗药物。     

Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence

Background

Alcohol use, abuse and dependence remain a pressing public health problem. Based on its mechanism of action, varenicline seemed to be a likely candidate for treating alcohol dependence.

Methods

Alcohol dependent subjects (n = 40) were enrolled in a 13-week double-blind placebo controlled clinical trial. Subject visits were once per week. At each visit, subjects were tested for breath alcohol levels, provided self-report data on alcohol and nicotine use, and on mood and craving. In addition, subjects received once a week medical management (MM).

Results

There was no difference between varenicline and placebo treated groups on any of the drinking outcomes. Compared to placebo-treated subjects, varenicline treated subjects had decreased rates of alcohol craving and cigarette smoking, as well as greater mood improvements during the later part of the study (weeks 6–13). In addition, among subjects who were cigarette smokers, those treated with varenicline were significantly less likely to report heavy drinking during the trial.

Conclusions

Although varenicline was not significantly more effective than placebo at reducing drinking during the trial, its effects on alcohol craving and mood suggest that future investigation of the mechanism of action of varenicline, as well as additional clinical studies may be warranted. In particular, the findings regarding the influence of smoking status on heavy drinking among varenicline-treated subjects should be investigated in future studies.