Naltrexone with or without fluoxetine for preventing relapse to heroin addiction in St. Petersburg, Russia

This randomized placebo-controlled trial tested the efficacy of oral naltrexone with or without fluoxetine for preventing relapse to heroin addiction and for reducing HIV risk, psychiatric symptoms, and outcome. All patients received drug counseling with parental or significant-other involvement to encourage adherence. Patients totaling 414 were approached, 343 gave informed consent, and 280 were randomized (mean age, 23.6 ± 0.4 years). At 6 months, two to three times as many naltrexone patients as naltrexone placebo patients remained in treatment and had not relapsed, odds ratio (OR) = 3.5 (1.96–6.12), p < .0001. Overall, adding fluoxetine did not improve outcomes, OR = 1.35 (0.68–2.66), p = .49; however, women receiving naltrexone and fluoxetine showed a trend toward a statistically significant advantage when compared to women receiving naltrexone and fluoxetine placebo, OR = 2.4 (0.88–6.59), p = .08. HIV risk, psychiatric symptoms, and overall adjustment were markedly improved among all patients who remained on treatment and did not relapse, regardless of group assignment. More widespread use of naltrexone could be an important addition to addiction treatment and HIV prevention in Russia.     

Reassessing naltrexone maintenance as a treatment for illicit heroin users

Most studies investigating the efficacy of naltrexone maintenance as a treatment for illicit heroin users have reported poor outcomes. Many of these studies, however, classify patients who periodically return to heroin use while receiving naltrexone maintenance as treatment failures. This study investigated 6-month outcome status in 100 illicit heroin users who commenced naltrexone maintenance in a community-based out-patient treatment programme. The study aimed to assess patient status at 6 months using contrasting outcome criteria. In the first analysis periodic heroin use was not considered to constitute treatment failure (hence naltrexone was continued and they remained under observation). In the second analysis, return to heroin use was considered to represent treatment failure. Using the first approach, we found that 60% of patients were still on naltrexone maintenance at 6 months, with only a small number (28%) having returned to heroin use. In contrast, when return to heroin use for 7 or more consecutive days was regarded as a treatment failure, only 31% of patients were "retained in treatment" with the majority (62%) having returned to heroin use. It is argued that since periods of heroin use are commonly associated with attempting to manage heroin dependence, the analysis that allowed periodic heroin use during treatment, and produced positive outcome data, represented a more valid assessment of naltrexone maintenance as a treatment for illicit heroin users. It is suggested that this outcome criterion should therefore be employed in future research. Poor outcomes reported in many previous studies may be an artefact of using inappropriate outcome criteria to assess illicit heroin use.     

Depot naltrexone: long-lasting antagonism of the effects of heroin in humans

RATIONALE: Naltrexone, an opioid antagonist, is currently approved as a treatment for heroin dependence. However, naltrexone is generally not well accepted by patients, and medication non-compliance is a difficult obstacle to treatment. A sustained-release form of naltrexone may improve compliance. OBJECTIVE: The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex). METHODS: Twelve heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, six participants received 192 mg naltrexone base and six participants received 384 mg naltrexone base. For safety, the low dose of depot naltrexone was tested before the high dose. The effects of heroin (0, 6.25, 12.5, 18.75, 25 mg, i.v.) were evaluated for the next 6 weeks. One dose of heroin was tested per day on Mondays through Fridays, and the entire dose range was tested each week. Active heroin doses were administered in ascending order during the week, while placebo could be administered on any day. Subjective, performance, and physiological effects were measured both before and after heroin administration. The hypotheses were that depot naltrexone would antagonize the effects of heroin, and that the high dose of depot naltrexone would produce a more effective and longer-lasting antagonism than the low dose. RESULTS: The low and high doses of depot naltrexone antagonized heroin-induced subjective ratings for 3 and 5 weeks, respectively. Plasma levels of naltrexone remained above 1 ng/ml for approximately 3 and 4 weeks after administration of 192 mg and 384 mg naltrexone. Other than the initial discomfort associated with the injection of depot naltrexone, there were no untoward side-effects. CONCLUSIONS: These results suggest that this depot formulation of naltrexone provides a safe, effective, long-lasting antagonism of the effects of heroin.     

The association between naltrexone compliance and daily supervision

Most studies investigating the efficacy of naltrexone maintenance as a treatment for illicit heroin use have reported poor patient compliance in taking naltrexone. A number of studies have, however, reported better compliance when patients receive family therapy, or when patients resided in a supportive family environment. These studies suggest that patient outcomes on naltrexone maintenance may be better if there is ongoing family support to continue naltrexone use. The current study investigated 6-month outcome status in 300 illicit heroin users who commenced naltrexone maintenance in a community-based out-patient treatment programme. The study aimed to assess the relationship between vigilance of naltrexone supervision by salient others over the first 6 weeks of treatment and patient status at 6 months. Supervision of naltrexone at week 6 was a predictor of a patient's status at 6 months, with those receiving less supervision of 3-4 days more likely to have returned to heroin use or be assessed as 'heroin use undetermined'. In contrast, patients who still received naltrexone supervision for 6 or 7 days per week at week 6 were more likely to be taking naltrexone or were naltrexone- and heroin-free at 6 months. It is argued that since relapse to heroin use is a common occurrence, vigilant supervision of naltrexone dosing in a supportive environment may improve patient retention and reduce relapse. It is suggested that poor outcomes reported in many previous studies may reflect use of inadequate supportive frameworks that encourage naltrexone compliance.     

美沙酮、丁丙诺啡、可乐定、纳曲酮“阶梯式”疗法治疗海洛因依赖脱毒后复吸患者33例

采用美沙酮、丁丙诺啡、可乐定、纳曲酮为主药的“阶梯式戒毒疗法”，治疗３３例戒毒后屡次复吸的海洛因依赖者。成功戒断８例，已操守０．５ａ以上，停服纳曲酮２个月以上；仍在服纳曲酮１６例，已分别服用１－４个月，操守率７２．７％；失败９例，其中服纳曲酮１－２个月后又复吸海洛因４例，治疗中失去联系而脱试３例，服纳曲酮１次后，戒断症状重而中止，改为自然康复２例，失败率２７．３％；配合心理疏导，有显著抗复吸作用，心理依赖降低，戒毒效果良好。     

A comparison of antagonist-precipitated withdrawal under anesthesia to standard inpatient withdrawal as a precursor to maintenance naltrexone treatment in heroin users: outcomes at 6 and 12 months

To compare two methods of heroin withdrawal, 51 heroin users were randomised to undergo a 1 day precipitated withdrawal procedure using naloxone under anaesthetic. About 50 participants were randomised to receive the current standard inpatient withdrawal treatment using clonidine plus symptomatic medication. Following withdrawal, both groups were offered 9 months of naltrexone treatment and supportive counselling. Outcome measures were: commencement of naltrexone, retention in treatment and heroin use at 6 and 12 months. Significantly more of the precipitated withdrawal group completed withdrawal, commenced naltrexone and stayed in treatment for the first 3 months. Overall, there was a significant reduction in both self-reported heroin use and morphine concentration in hair over the 12 month study period, with participants in the precipitated withdrawal group showing significantly lower morphine concentration at 6 months. Being younger and having a lower level of dependence were predictors of abstinence at 6 and 12 months. The advantage of precipitated withdrawal under anesthesia did not persist beyond 3 months with respect to retention in naltrexone treatment or beyond 6 months with respect to heroin use. Long-term follow-up is crucial in assessing the effects of treatment interventions for heroin dependence.     

Improving naltrexone response: an intervention for medical practitioners to enhance medication compliance in alcohol dependent patients

The effectiveness of naltrexone, a FDA-approved medication for alcohol dependence, can be improved if we support and help patients to consistently take their medication. We illustrate how patient noncompliance with treatment negatively affects outcome, and, we describe a new intervention to enhance medication compliance. Outcome was evaluated for 196 alcohol dependent outpatients who were treated with 50 mg/day naltrexone or placebo for 12 weeks. For patients who adhered to the prescribed treatment, relapse rates were lower with naltrexone than placebo (10% vs. 38.6%, p < 0.001). For noncompliant patients, relapse rates were high and comparable between naltrexone- and placebo-treated patients (42.9% vs. 40%). In a second study of 100 alcohol dependent outpatients, we introduced an intervention that resulted in better medication compliance rates compared to a previous naltrexone study of patients who did not receive the intervention (77.0% vs. 60.8%, p < 0.01). This provided some support for the use of an intervention that targets medication compliance when prescribing naltrexone.     

Extended-release intramuscular naltrexone

An extended-release intramuscular formulation of naltrexone that provides sustained release of the drug over a 28-day period has been developed with the aim of improving treatment adherence in patients treated with naltrexone for alcohol dependence. Biodegradable polylactide-co-glycolide polymer microspheres containing 34% w/w naltrexone are reconstituted in an aqueous suspension just prior to intramuscular administration. Extended-release intramuscular naltrexone 380 mg administered once every 4 weeks, in combination with psychosocial therapy, demonstrated superior efficacy to placebo plus psychosocial therapy in reducing the heavy drinking event rate (primary endpoint) in adult patients with alcohol dependence in a 6-month well controlled trial. Among the subset of patients who abstained completely from drinking during the 7 days prior to the first dose of medication (n = 53; 8% of the total study population), those treated with extended-release intramuscular naltrexone 380 mg had greater reductions in the number of drinking days and the number of heavy drinking days compared with placebo recipients. Treatment with extended-release intramuscular naltrexone 380 mg once every 4 weeks for up to 18 months was generally well tolerated, with infrequent treatment-related serious adverse events. The most common treatment-emergent adverse events leading to treatment discontinuation were nausea, injection site reaction and headache. The proportion of patients with clinically significant plasma transaminase elevations was not different between patients receiving extended-release intramuscular naltrexone and those receiving placebo.     

快速脱毒加纳曲酮栓植入治疗海洛因依赖疗效观察

目的:寻找一种安全、有效、可靠、病人能够接受的治疗方法,以降低海洛因依赖病人的复吸率。方法:使用全麻下快速药物拮抗脱毒加纳曲酮栓植入方法,治疗海洛因依赖69例,并通过随访的方式跟踪治疗效果。结果:植入长效纳曲酮缓释栓6个月后,患者对海洛因渴求程度分值从植入前2.21±s0.58降至0.21±s0.14,再尝试海洛因率从81.25%降至5.00%。肝功能与植入前相比无明显变化。结论:全麻快速脱毒加长效纳曲酮缓释栓植入的治疗方法安全、有效、可靠,值得推广使用。     

Single versus repeated sessions of ketamine-assisted psychotherapy for people with heroin dependence

A prior study found that one ketamine-assisted psychotherapy session was significantly more effective than active placebo in promoting abstinence (Krupitsky et al. 2002). In this study of the efficacy of single versus repeated sessions of ketamine-assisted psychotherapy in promoting abstinence in people with heroin dependence, 59 detoxified inpatients with heroin dependence received a ketamine-assisted psychotherapy (KPT) session prior to their discharge from an addiction treatment hospital, and were then randomized into two treatment groups. Participants in the first group received two addiction counseling sessions followed by two KPT sessions, with sessions scheduled on a monthly interval (multiple KPT group). Participants in the second group received two addiction counseling sessions on a monthly interval, but no additional ketamine therapy sessions (single KPT group). At one-year follow-up, survival analysis demonstrated a significantly higher rate of abstinence in the multiple KPT group. Thirteen out of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 out of 27 subjects (22.2%) in the single KPT group (p < 0.05). No differences between groups were found in depression, anxiety, craving for heroin, or their understanding of the meaning of their lives. It was concluded that three sessions of ketamine-assisted psychotherapy are more effective than a single session for the treatment of heroin addiction.     

盐酸纳曲酮用于阿片类依赖者脱毒后预防复发的效能研究

采用开放与双盲试验的多中心性随访观察，对于３０２例海洛因依赖者脱毒治疗后服用纳曲酮进行的为期６个月观察，就纳曲酮对阿片类依赖者预防复吸的效能进行了研究。双盲组纳曲酮的服用剂量为５０ｍｇ·ｄ－１，开放试验的药物剂量随用药者的反应进行调整。双盲试验中，纳曲酮组和安慰剂组第６个月的保持率分别为２８．５７％和７．１４％。开放组第６个月的纳曲酮保持率及平均保持时间分别为２３．６％和３．１６月，而该组人群既往脱毒后第６个月的操守率及平均操守时间分别为１．２％和０．５个月。双盲试验中服用纳曲酮组再吸海洛因后无舒适体验者占６８．１８％，安慰剂组为３３．３％；纳曲酮组尿吗啡检测阳性率（２４．３８％）低于安慰剂组（４０．４８％）。服药后出现的反应包括睡眠障碍、焦虑、食欲减退、无力、易激惹、腹痛和骨肌肉痛、发冷、恶心呕吐、紧张、腹泻、头晕、头痛、便秘和皮疹。这些症状中包括纳曲酮促发的稽延性戒断症状。少部分受试者出现肝脏功能异常及心电图异常。为达到充分阻断海洛因的作用，服用剂量以４０－５０ｍｇ·ｄ－１为宜。本研究显示，纳曲酮对阿片类依赖者脱毒后预防复吸有一定的辅助作用，药物毒副作用较小，适于长期服用。     

Efficacy of extended-release naltrexone in alcohol-dependent patients who are abstinent before treatment

Extended-release naltrexone (XR-NTX) is a once-a-month injectable formulation that is Food and Drug Administration-approved for the treatment of alcohol dependence in patients able to abstain from alcohol before treatment initiation. This paper presents the results of an analysis of efficacy data from a subgroup of patients with 4 days or more of voluntary abstinence before treatment initiation (n = 82) on a wide range of drinking-related outcomes. In these patients, all of whom received counseling, the rate of abstinence was severalfold higher for XR-NTX 380 mg compared with placebo: median time to first drink was 41 days versus 12 days, respectively; rate of continuous abstinence at end of the study was 32% versus 11% (P = 0.02). Extended-release naltrexone 380 mg, compared with placebo, substantially increased time to first heavy drinking event (>180 days vs 20 days; P = 0.04) and decreased the median number of any drinking days per month by 90% (0.7 vs 7.2; P = 0.005) and heavy drinking days per month by 93% (0.2 days vs 2.9 days; P = 0.007). The XR-NTX 380 mg group also had more than twice as many responders compared with placebo (70% vs 30%; P = 0.006; responder defined as having no more than 2 heavy drinking days in any consecutive 28-day period) and experienced greater improvement in gamma-glutamyl transpeptidase levels (P = 0.03). Outcomes for XR-NTX 190 mg (n = 26) were generally intermediate, demonstrating a dose-response effect. In conclusion, XR-NTX 380 mg prolonged abstinence and reduced the number of heavy drinking days and drinking days in patients who were abstinent for as few as 4 days before treatment initiation.     

海洛因瘾康复期使用纳曲酮防止复吸100例

目的：观察盐酸纳曲酮防止海洛因依赖者戒毒后复吸疗效。方法：ｍｏ１～２每日口服纳曲酮片１５～２０ｍｇ，ｍｏ３～４服１０～１５ｍｇ，ｍｏ５～６服５～１０ｍｇ，６ｍｏ为一个疗程。结果：３ｍｏ复吸率为４２％，６ｍｏ复吸率为７２％，显效率为４５％，有效率为７４％。结论：服药后可明显减轻海洛因依赖者对毒品渴求感和焦虑症状，降低复吸率。纳曲酮本身无依赖性，副作用轻微。     

Naltrexone treatment of heroin addiction: one-year follow-up

Pre-treatment characteristics and post-treatment outcome measures were compared for 40 patients who began naltrexone maintenance and 77 who did not after a 6-month period of temporary maintenance on L-alpha-acetylmethadol (methadyl acetate LAAM). Patients who chose to begin naltrexone were younger, had fewer incarcerations and fewer months incarcerated prior to LAAM treatment, had fewer opiate-free months following previous treatments, and were more likely to be of Caucasian ethnicity. One year later, significantly more patients who had received any naltrexone than those who had not were no longer in any treatment program and were opiate-free. We found no significant correlations between total duration of naltrexone-treatment and post-treatment outcome variables such as heroin use, arrests, incarcerations or enrollment in a treatment program.     

Efficacy of naltrexone treatment with combined crack and opiate users: A descriptive study of a new treatment service in Bristol,UK

Naltrexone has been shown to be clinically effective in treating opioid dependence, although there are reports that it may be unsafe in treatment of unselected cases. Although there are no generally accepted pharmacological treatments for crack cocaine addiction alone, there is evidence that naltrexone can be useful in cases of concurrent cocaine and heroin use. In 2005 Bristol Specialist Drug Service initiated a naltrexone treatment programme targeted at pre-release offenders using both crack cocaine and heroin. Of 172 referrals, only 51 (30%) were inducted into treatment, and only 16% of these were retained at 3 months, and 4% at 9 months. There was evidence to support induction in prison, as 90% of those who were inducted there continued treatment on release. An integrated approach between criminal justice and community services is of primary importance in getting users into treatment. Interviews highlighted that the environment outside of prison can trigger relapse, and that community clinics need to separate clients on an abstinence programme from those who continue to use. Of clients interviewed, 52% reported that they use heroin to mitigate severe come down from crack, and it is suggested that naltrexone may be of use for these specialized combined users.     

The Cost Effectiveness of Naltrexone Added to Cognitive-Behavioral Therapy in the Treatment of Alcohol Dependence

ABSTRACT

The purpose of this study was to evaluate the comparative cost of treating alcohol dependence with either cognitive behavioral therapy (CBT) alone or CBT combined with naltrexone (CBT+naltrexone). Two hundred ninety-eight outpatients dependent on alcohol who were consecutively treated for alcohol dependence participated in this study. One hundred seven (36%) patients received adjunctive pharmacotherapy (CBT+naltrexone). The Drug Abuse Treatment Cost Analysis Program was used to estimate treatment costs. Adjunctive pharmacotherapy (CBT+naltrexone) introduced an additional treatment cost and was 54% more expensive than CBT alone. When treatment abstinence rates (36.1% CBT; 62.6% CBT+naltrexone) were applied to cost effectiveness ratios, CBT+naltrexone demonstrated an advantage over CBT alone. There were no differences between groups on a preference-based health measure (SF-6D). In this treatment center, to achieve 100 abstainers over a 12-week program, 280 patients require CBT compared with 160 CBT+naltrexone. The dominant choice was CBT+naltrexone based on modest economic advantages and significant efficiencies in the numbers needed to treat.     

Efficacy of naltrexone treatment with combined crack and opiate users: A descriptive study of a new treatment service in Bristol, UK

Naltrexone has been shown to be clinically effective in treating opioid dependence, although there are reports that it may be unsafe in treatment of unselected cases. Although there are no generally accepted pharmacological treatments for crack cocaine addiction alone, there is evidence that naltrexone can be useful in cases of concurrent cocaine and heroin use. In 2005 Bristol Specialist Drug Service initiated a naltrexone treatment programme targeted at pre-release offenders using both crack cocaine and heroin. Of 172 referrals, only 51 (30%) were inducted into treatment, and only 16% of these were retained at 3 months, and 4% at 9 months. There was evidence to support induction in prison, as 90% of those who were inducted there continued treatment on release. An integrated approach between criminal justice and community services is of primary importance in getting users into treatment. Interviews highlighted that the environment outside of prison can trigger relapse, and that community clinics need to separate clients on an abstinence programme from those who continue to use. Of clients interviewed, 52% reported that they use heroin to mitigate severe come down from crack, and it is suggested that naltrexone may be of use for these specialized combined users.     

Effects of naltrexone on smoking cessation outcomes and weight gain in nicotine-dependent men and women

ABSTRACT: This study examined whether the opioid receptor antagonist naltrexone is efficacious in smoking cessation and whether sex moderates the response. We assessed smoking quit rates and weight gain in a double-blind randomized trial comparing oral naltrexone (n = 162) with placebo (n = 154) in nicotine-dependent participants who wanted to quit smoking. The medication was gradually titrated up to 50 mg during the week before the quit date and then maintained at this dose for 12 weeks. For the first 4 weeks after the quit date, all participants received a nicotine patch to mitigate tobacco withdrawal and attended weekly individual cognitive-behavioral smoking cessation counseling sessions. After this time, participants continued with naltrexone or placebo through 12 weeks. Follow-up assessments were conducted at 26 and 52 weeks. During treatment, naltrexone (vs placebo) increased quit rates, attenuated smoking urge, and reduced weight gain. At follow-up, after medication discontinuation, the effect of naltrexone on improving quit rates was no longer evident. Men and women experienced different benefits from naltrexone; men showed greater reductions in smoking, whereas women showed greater reductions in weight gain. In sum, naltrexone showed acute efficacy in treating nicotine dependence, but after the medication was discontinued, the effect on quit rate was not maintained. Further study of naltrexone in smoking cessation treatment and reduction of cessation-related weight gain, as well as preclinical investigation of mechanisms underlying sex differences, is warranted.     

Antagonist-precipitated heroin withdrawal under anaesthetic prior to maintenance naltrexone treatment: determinants of withdrawal severity

This study sought to characterize antagonist-precipitated heroin withdrawal during and immediately following anaesthesia and to identify the determinants of withdrawal severity and duration in 48 dependent heroin users. Objective withdrawal signs decreased significantly with each naloxone bolus administered under anaesthetic. The cost (amount) of the final heroin administration and the number of hours between last heroin use and commencement of anaesthesia were significant, independent predictors of the severity of withdrawal symptomatology. While 83% (40/48) of participants completed withdrawal according to objective criteria and commenced maintenance naltrexone treatment, almost half (22/48) were unable to commence naltrexone on the day of the procedure due to residual withdrawal signs. Fourteen of these 22 participants subsequently commenced naltrexone (median number of days between admission and commencement of naltrexone was 2, range 1 - 6) while eight left treatment prior to initiation of naltrexone. Significantly fewer of those with more severe withdrawal signs during anaesthesia commenced naltrexone (40% vs. 60%). While the severity and duration of withdrawal symptomatology may be moderated by encouraging participants to reduce (or cease) heroin use close to the time of withdrawal, for a substantial proportion of participants in this study, heroin withdrawal by this antagonist-precipitated procedure was neither rapid nor painless. [Ali R, Thomas P, White J, McGregor C, Danz,C, Gowing L, Stegink A, Athanasos P. Antagonist-precipitated heroin withdrawal under anaesthetic prior to maintenance naltrexone treatment: determinants of withdrawal severity. Drug Alcohol Rev 2003;22:425 - 431]     

盐酸纳曲酮对阿片类成瘾脱毒后防止复发效能的再评价──1088例纳曲酮维持治疗临床研究

目的··:就盐酸纳曲酮防止阿片类成瘾脱毒后复发的效能进行再评价。方法··:1088例完成脱毒治疗的海洛因依赖者给予纳曲酮治疗。药物剂量相对固定在40-50mg·d-1,并随患者反应调整。治疗期间定期门诊或出诊随访。结·果·:服用纳曲酮6个月的保持率为33.4%,与自身同期操守率(2.4%)比较具有显著性差异。服用纳曲酮后,再吸海洛因的欣快感、渴求程度及偶吸海洛因的发生率均降低。纳曲酮的不良反应轻,包括:睡眠障碍、消化系统症状和乏力,少数患者转氨酶呈一过性增高。在纳曲酮治疗的同时给予积极的家庭支持和社会帮教,提供生活和就业技能的指导,减少偶吸的机会等措施,有助于提高服药保持时间。结论··:进一步证实了纳曲酮对预防我国阿片类依赖者脱毒后复吸具有肯定的辅助治疗作用。