Recent advances in the treatment of opioid use disorders–focus on long-acting buprenorphine formulations

Oral methadone or sublingual buprenorphine are first-line medications for pharmacotherapy of opioid use disorders (OUDs). Three long-acting buprenorphine depot or implant formulations are currently available for the treatment of OUDs: (1) CAM 2038 (Buvidal) for subcutaneous weekly and monthly application; (2) RBP-6000 (Sublocade™) as a monthly depot formulation; and (3) A six-month buprenorphine implant [Probuphine™]. The pharmacology, clinical efficacy and prospects of these medications are discussed.     

A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial

OBJECTIVE: Both methadone and buprenorphine are effective therapy for heroin dependence. Efficacy is best documented for methadone maintenance therapy, but safety concerns limit its use. Buprenorphine offers lower overdose risk and improved access, but efficacy may be lower. The authors compared adaptive, buprenorphine-based stepped care to optimal methadone maintenance treatment. METHOD: This randomized controlled trial was undertaken 2004-2006. It consisted of a 24-day uniform double-blind induction phase followed by single-blind flexible dosing based on structured clinical criteria, for a total of 6 months. Ninety-six self-referred subjects with heroin dependence were randomly assigned to methadone or to stepped treatment initiated with buprenorphine/naloxone and escalated to methadone if needed. All subjects received intensive behavioral treatment. Primary outcome was retention in treatment. Secondary outcomes were completer analyses of problem severity (Addiction Severity Index) and proportion of urine samples free of illicit drugs. RESULTS: Overall, 6-month retention was 78%. Stepped treatment and methadone maintenance therapy outcomes were virtually identical. Among completers of stepped therapy, 46% remained on buprenorphine/naloxone. Proportion of urine samples free of illicit opiates increased over time and ultimately reached approximately 80% in both arms. Problem severity decreased significantly and uniformly in both arms. CONCLUSIONS: A stepped treatment of heroin dependence as described here appears equally efficacious compared to optimally delivered methadone maintenance therapy. Together with prior data on the advantageous safety of buprenorphine, this suggests that broad implementation of strategies using buprenorphine as first-line treatment should be considered.     

Higher methadone doses are associated with lower mortality in patients of opioid dependence in Taiwan

Optimal methadone dosage and service profile is challenging in treatment of opioid dependence. This study explores the impact of methadone dosage on the mortality of opioid-dependent patients in methadone maintenance therapy by using a large-scale and continual supervised dosing registry information system. Database of nationwide enrolled opioid-dependent patients at methadone clinics in Taiwan during 2006–2008 was assessed. The relative risk of age, sex, marital status, HIV infection and methadone dosage were analyzed by Cox regression analysis. Among all of the 33,549 recruited patients, the crude mortality rate was 134.78/10,000 person-years, and the standardized mortality ratio was 4.68. A dose–response relationship of higher- vs. lower-dosage groups on the risk of mortality risk was observed (adjusted HR = 0.68, P = 0.016). In further sub-grouping analysis, this trend was more significant in HIV positive patients, in subgroup of patients who continuously staying in MMT, and in subgroup of patients who re-enter MMT. This dosage effect is not significantly seen in patients receiving MMT more than 365 days. Further exploration of other treatment-related factors may be important for understanding the long-term treatment outcome of opioid addiction patients.     

Cognitive rehabilitation for individuals with opioid use disorder: A randomized controlled trial*

Aim: To examine the efficacy of cognitive rehabilitation treatment (CRT) for people with opioid use disorder who were recruited into a methadone maintenance treatment (MMT) programme.

Method: 120 male subjects were randomly assigned to (1) MMT plus CRT in two months or (2) MMT plus a control intervention. Subjects were assessed at the beginning, mid-point and post-intervention as well as at 1-, 3- and 6-month follow-up time points.

Results: Analysis with repeated measure ANOVA showed that the CRT group performed significantly better in tests of learning, switching, processing speed, working memory and memory span. Moreover, the CRT group had significantly lower opiate use over the control group during 3-months follow-up. Analysis including only those with a history of methamphetamine use showed that the CRT group had significantly lower amphetamine use. No group differences were observed for treatment retention.

Conclusions: Our findings provide evidence that adding CRT as an adjunct intervention to MMT can improve cognitive performance as well as abstinence from both opiates and stimulants.     

行为列联管理在美沙酮维持治疗者中的疗效:一项随机对照研究(英文)

背景为了应对海洛因依赖的严重后果,我国开展了美沙酮维持治疗(methadone maintenance treatment,MMT)项目,但是MMT依从性差。目的评估在美沙酮维持治疗中行为列联管理(contingency management,CM)对阿片类药物依赖者的作用。假设在上海市常规MMT项目基础上结合以奖励机制为基础的CM干预共12周,可提高MMT治疗依从性和增加操守程度。方法来自于3个自愿戒毒MMT门诊的160名海洛因依赖者被随机分入常规治疗组(MMT,n=80)和干预组(MMT+CM,n=80),在前12周每周评估患者的服药行为并进行尿液的毒品检测,随后在第16、20和24周分别进行上述评估检测。结果干预组和常规治疗组完成12周治疗的比例都很高,分别为87.5%和86.2%。12周中,两组服用美沙酮的平均天数差异无统计学意义[70(2.9)d与71(2.7)d],两组未吸海洛因的最长时间(分别为7.4周与6.5周)以及尿检阴性的次数(分别为7.9次与7.6次)也没有明显差异。同样,根据24周的分析提示两组间差异也无统计学意义。用成瘾严重程度指数评估成瘾程度,24周内两组完成随访者的成瘾严重程度都显著下降,但是两组间比较同样无明显差异。结论在我国上海的MMT门诊,以奖励机制为基础的行为列联管理干预并未起到提高治疗依从性和促进保持操守的作用。这与西方研究结果不同。究其原因,一是基线依从性高(86%),二是CM项目提供的奖励相对少。在CM项目中奖励是与场景相关的,因而需要对场景进行仔细的分析,了解在特定场景采用什么特定的奖励措施,以便鼓励目标人群改变行为。     

Opioid maintenance therapy suppresses alcohol intake in heroin addicts with alcohol dependence: preliminary results of an open randomized study

An open randomized study lasting 12 months was performed to evaluate the efficacy of methadone or buprenorphine to suppress alcohol use in two hundred and eighteen heroin addicts with alcohol dependence. Daily maintenance doses of methadone were 80, 120, 160, and 200 mg/day, while doses of buprenorphine were 8, 16, 24, and 32 mg/day.As expected, both treatments were able to reduce both heroin use and addiction severity (measured with ASI interview). However, although both medications were able to suppress alcohol use, the highest dose of buprenorphine was better than the highest dose of methadone, in reducing alcohol craving, ethanol intake (measured as daily number of drinks), and the ASI subscale of alcohol use.The mechanism underlying the effects of the opioid maintenance therapy on the reduction of alcohol intake is still unclear.The results of the present study may represent the first clinical evidence of the potential effective use of the highest doses of buprenorphine for the suppression of ethanol intake in heroin addicts with alcohol dependence.     

Naltrexone depot formulations for opioid and alcohol dependence: a systematic review

Naltrexone is an opioid receptor antagonist that blocks the reinforcing effects of opioids and reduces alcohol consumption and craving. It has no abuse potential, mild and transient side effects, and thus appears an ideal pharmacotherapy for opioid dependence. Its effectiveness in alcohol dependence is less evident, but compliance with naltrexone combined with psychosocial support has been repeatedly shown to improve drinking outcomes. Limited compliance with oral naltrexone treatment is a known drawback. Several naltrexone implant and injectable depot formulations are being investigated and provide naltrexone release for at least 1 month. Studies among opioid-dependent patients indicate significant reductions in heroin use, but sample sizes are usually small. In alcohol dependence, two large multicenter trials report alcohol and craving reductions for naltrexone and placebo groups, indicating a significant but moderate effect. The pharmacokinetic profile of the injectable formulation indicates reliable naltrexone release over 1 month at therapeutic levels. Implant formulations releasing naltrexone up to 7 months are reported. Findings on safety and tolerability confirm the generally mild adverse effects described for naltrexone tablets. However, further research on therapeutic levels (i.e., opioid blocking) is warranted. The majority of naltrexone implants lacks approval for regular clinical use and larger longitudinal studies are needed. The available naltrexone depot formulations have the potential to significantly improve medication compliance in opioid and alcohol dependence. In certain circumstances, they may constitute a promising new treatment option.     

美沙酮联用丁丙诺啡对海洛因依赖重度药瘾戒毒治疗临床研究

目的　探索对海洛因依赖重度药瘾较理想的戒毒治疗方法。　　方法　采用美沙酮与丁丙诺啡联合用药方案 ,对海洛因依赖重度药瘾 41例行戒毒治疗 ,1 2天为一疗程 ,并与单用美沙酮组 2 0例进行比较。　　结果　联合用药组控制症状较彻底 ,鸦片类药物戒断症状量表 (OWS)总分平稳下降 ,症状波动小 ,减药顺利 ,两药替换平稳 ,戒毒成功率 73 2 %。　　结论　我们认为美沙酮联用丁丙诺啡是一种值得推荐的戒毒治疗方法。     

Fluoxetine vs placebo for depressive symptoms after stroke: failed randomised controlled trial

BACKGROUND: Growth in antidepressant prescribing is a well-recognised phenomenon in developed countries. In stroke care, the evidence of effectiveness from systematic reviews is surprisingly weak. We therefore decided to undertake a randomised controlled trial comparing fluoxetine to placebo. METHODS: Double blind placebo-controlled trial. Cases were high-scorers on the GHQ-28 and we applied minimal exclusion criteria. RESULTS: Despite screening 614 patients we were able to randomise only one into the trial. High rates of refusal to participate and exclusions due to physical ill health were coupled with high rates of prescribing among stroke clinicians, to cause this recruitment problem. CONCLUSIONS: In addition to the predicted practical problems of conducting an RCT in an elderly frail population, it became clear that most clinicians are not in equipoise about the value of antidepressant medication despite the lack of strong evidence for its effectiveness.     

Beta endorphin levels during heroin, methadone, buprenorphine, and naloxone challenges: preliminary findings.

Beta endorphin (BE) is a polypeptide agonist for the brain's endogenous opioid system. Levels of BE are elevated by opioid antagonists such as naloxone and depressed by short-acting agonists such as heroin and morphine; they become normalized during steady-state methadone. Buprenorphine (BUP) is a partial opioid agonist whose effects on BE levels were examined in six former heroin addicts and 14 methadone-maintained patients before and after being switched to sublingual BUP 2 mg daily for 1 month. In six former methadone-treated subjects BE levels also were measured after stopping BUP and after naloxone challenge. Levels of BE were not significantly lower in subjects started on BUP after stopping heroin (n = 6) (8.0 versus 8.1 ng/ml) or in subjects started on BUP after stopping methadone (n = 14) (11.6 vs 15.6 ng/ml). However, BE levels were lower on BUP than after naloxone challenge (n = 6) (7.0 versus 34.9 ng/ml). Levels of BE did not significantly change between the first 2 weeks ("early") and "later," although BE levels on methadone significantly correlated with BE levels on BUP in the "early" but not the "later" phase. The BE levels on BUP also did not differ from BE levels of unmedicated normals.     

Buprenorphine and methadone in the treatment of opioid dependence: methods and design of the COBRA study

Buprenorphine and methadone are the two established substitution drugs licensed in many countries for the treatment of opioid dependence. Little is known, however, about how these two drugs are applied and how they work in clinical practice. In this paper we present the aims, methods, design and sampling issues of a collaborative multi-stage epidemiological study (COBRA) to address these issues. Based on a nationally representative sample of substitution physicians, the study is designed as an observational, naturalistic study, consisting of three major parts. The first part was a national survey of substitution doctors (prestudy, n = 379 doctors). The second part was a cross-sectional study (n = 223 doctors), which consisted of a target-week assessment of 2,694 consecutive patients to determine (a) the severity and problem profiles and treatment targets; (b) the choice and dosage scheme of the substitution drug; (c) past and current interventions, including treatment of comorbid hepatitis C; and (d) cross-sectional differences between the two drugs with regard to comorbidity, clinical course, acceptance/compliance and social integration. The third part consists of a prospective-longitudinal cohort study of 48 methadone-treated and 48 buprenorphine-treated patients. The cohort is followed up over a period of 12 months to investigate whether course and outcome of the patients differ by type or treatment received in terms of clinical, psychosocial, pharmaco-economic and other related measures. The response rate among substitution doctors was 57.1%; that among eligible patients was 71.7%. Comparisons with the federal registers reveal that the final samples of doctors and patients may be considered nationally representative with regard to regional distribution, training, type of setting as well as the frequency of patients treated with buprenorphine or methadone. The COBRA study provides a unique comprehensive database, informing about the natural allocation and intervention processes in routine care and about the course and outcome of patients treated with buprenorphine or methadone.     

Megavitamin and dietary treatment in schizophrenia: a randomised, controlled trial

OBJECTIVE: The aim of this study was to assess the efficacy of adjunctive megavitamin and dietary treatment in schizophrenia. METHOD: A random allocation double-blind, controlled comparison of dietary supplement and megavitamin treatment, and an alternative procedure was given for 5 months to 19 outpatients with a diagnosis of schizophrenia. In addition to usual follow-up, the experimental group received amounts of megavitamins based on their individual serum vitamin levels plus dietary restriction based on Radioallergosorbent (RAST) tests. The control group received 25 mg vitamin C and were prescribed substances considered allergenic from the RAST test. RESULTS: Five months of treatment showed marked differences in serum levels of vitamins but no consistent self-reported symptomatic or behavioural differences between groups. CONCLUSIONS: This study does not provide evidence supporting a positive relationship between regulation of levels of serum vitamins and clinical outcome in schizophrenia over 5 months.     

Buprenorphine augmentation improved symptoms of OCD,compared to placebo - Results from a randomized,double-blind and placebo-controlled clinical trial

BackgroundIn the search for new psychopharmacologic options in the treatment of obsessive-compulsive disorders (OCD), some findings suggested that augmentation with buprenorphine, a partial-opioid agonist used to treat opioid addiction, moderate acute pain and moderate chronic pain, is worthy of consideration. Accordingly, to explore this possibility further, a double-blinded, placebo-controlled clinical trial was performed.MethodA total of 43 patients (mean age: 34.41 years; SD = 6.58; 53.5% males) with refractory OCD and treated with SSRIs or clomipramine at therapeutic dosages were randomly assigned either to an adjuvant buprenorphine or to an adjuvant placebo condition. Patients completed the Yale-Brown-Obsessive-Compulsive Scale (Y-BOCS) at baseline, weeks 3, 9 and 12 (study completion). Buprenorphine (2–4 mg; sublingual) and placebo (tablets with identical shape, color, consistency, and scent) were given daily.ResultsSymptoms of obsessive-compulsive disorders decreased over time, but more so in the buprenorphine than in the placebo condition. Substantial improvements were observed up to week 3 and then 9. Response and partial response were observed in the buprenorphine at week 9 more than in the placebo condition. The advantage had disappeared by week 12.ConclusionsThe pattern of results suggests that adjuvant buprenorphine augmentation can reduce symptoms of obsessive-compulsive disorders after only three weeks, compared to a placebo. Adjuvant buprenorphine seems to accelerate symptom improvement.     

Effects of a classroom-based educational resource on adolescent mental health literacy: A cluster randomised controlled trial

Evidence suggests that poor mental health literacy is a key barrier to help-seeking for mental health difficulties in adolescence. Educational programs have shown positive effects on literacy, however, the evidence base remains limited and available studies have many methodological limitations. Using cluster Randomised Control Trial (RCT) methodology, the current study examines the impact of ‘HeadStrong’, a school-based educational intervention, on mental health literacy, stigma, help-seeking, psychological distress and suicidal ideation. A total of 380 students in 22 classes (clusters) from 10 non-government secondary schools was randomised to receive either HeadStrong or Personal Development, Health and Physical Education (PDHPE) classes. Participants were assessed pre- and post-intervention, and at 6-month follow-up. Literacy improved and stigma reduced in both groups at post-intervention and follow-up, relative to baseline. However, these effects were significantly greater in the HeadStrong condition. The study demonstrates the potential of HeadStrong to improve mental health literacy and reduce stigma.     

Cholera toxin-B subunit blocks excitatory opioid receptor-mediated hyperalgesic effects in mice, thereby unmasking potent opioid analgesia and attenuating opioid tolerance/dependence

In a previous study we demonstrated that injection (i.p.) of low doses of GM1 ganglioside in mice rapidly attenuates morphine’s analgesic effects. This result is consonant with our electrophysiologic studies in nociceptive types of dorsal root ganglion (DRG) neurons in culture, which showed that exogenous GM1 rapidly increased the efficacy of excitatory (Gs-coupled) opioid receptor functions. By contrast, treatment of DRG neurons with the non-toxic B-subunit of cholera toxin (CTX-B) which binds selectively to GM1, blocked the excitatory, but not inhibitory, effects of morphine and other bimodally-acting opioid agonists, thereby resulting in a net increase in inhibitory opioid potency. The present study provides more direct evidence that endogenous GM1 plays a physiologic role in regulating excitatory opioid receptor functions in vivo by demonstrating that cotreatment with remarkably low doses of CTX-B (10 ng/kg, s.c.) selectively blocks hyperalgesic effects elicited by morphine or by a kappa opioid agonist, thereby unmasking potent opioid analgesia. These results are comparable to the effects of cotreatment of mice with morphine plus an ultra-low dose of the opioid antagonist, naltrexone (NTX) which blocks opioid-induced hyperalgesic effects, unmasking potent opioid analgesia. Low-dose NTX selectively blocks excitatory opioid receptors at their recognition site, whereas CTX-B binds to, and interferes with, a putative allosteric GM1 regulatory site on excitatory opioid receptors. Furthermore, chronic cotreatment of mice with morphine plus CTX-B attenuates development of opioid tolerance and physical dependence, as previously shown to occur during cotreatment with low-dose NTX.     

帕罗西汀治疗抑郁症的双盲对照研究

评估帕罗西汀和阿米替林治疗抑郁症病人的临床疗效。　　方法　采用随机、双盲对照的研究方法 ,帕罗西汀组和阿米替林组各 1 6例 ,治疗 6周。　　结果　帕罗西汀与阿米替林疗效相似 ,帕罗西汀的植物神经、心血管、神经系统及其它副作用显著少于阿米替林 ;帕罗西汀主要副作用为轻度口干、便秘。　　结论　帕罗西汀是一种安全而有效的抗抑郁剂