Background

Opioid dependence is associated with substantial health and social burdens, and opioid agonist treatment (OAT) is highly effective in improving multiple outcomes for people who receive this treatment. Methadone and buprenorphine are common medications provided as OAT. We aimed to examine buprenorphine compared with methadone in the treatment of opioid dependence across a wide range of primary and secondary outcomes.

Methods

We did a systematic review and meta-analysis in accordance with GATHER and PRISMA guidelines. We searched Embase, MEDLINE, CENTRAL, and PsycINFO from database inception to Aug 1, 2022; clinical trial registries and previous relevant Cochrane reviews were also reviewed. We included all RCTs and observational studies of adults (aged ≥18 years) with opioid dependence comparing treatment with buprenorphine or methadone. Primary outcomes were retention in treatment at 1, 3, 6, 12, and 24 months, treatment adherence (measured through doses taken as prescribed, dosing visits attended, and biological measures), or extra-medical opioid use (measured by urinalysis and self-report). Secondary outcomes were use of benzodiazepines, cannabis, cocaine, amphetamines, and alcohol; withdrawal; craving; criminal activity and engagement with the criminal justice system; overdose; mental and physical health; sleep; pain; global functioning; suicidality and self-harm; and adverse events. Single-arm cohort studies and RCTs that collected data on buprenorphine retention alone were also reviewed. Data on study, participant, and treatment characteristics were extracted. Study authors were contacted to obtain additional data when required. Comparative estimates were pooled with use of random-effects meta-analyses. The proportion of individuals retained in treatment across multiple timepoints was pooled for each drug. This study is registered with PROSPERO (CRD42020205109).

Findings

We identified 32 eligible RCTs (N=5808 participants) and 69 observational studies (N=323 340) comparing buprenorphine and methadone, in addition to 51 RCTs (N=11 644) and 124 observational studies (N=700 035) that reported on treatment retention with buprenorphine. Overall, 61 studies were done in western Europe, 162 in North America, 14 in north Africa and the Middle East, 20 in Australasia, five in southeast Asia, seven in south Asia, two in eastern Europe, three in central Europe, one in east Asia, and one in central Asia. 1 040 827 participants were included in these primary studies; however, gender was only reported for 572 111 participants, of whom 377 991 (66·1%) were male and 194 120 (33·9%) were female. Mean age was 37·1 years (SD 6·0). At timepoints beyond 1 month, retention was better for methadone than for buprenorphine: for example, at 6 months, the pooled effect favoured methadone in RCTs (risk ratio 0·76 [95% CI 0·67–0·85]; I·=74·2%; 16 studies, N=3151) and in observational studies (0·77 [0·68–0·86]; I·=98·5%; 21 studies, N=155 111). Retention was generally higher in RCTs than observational studies. There was no evidence suggesting that adherence to treatment differed with buprenorphine compared with methadone. There was some evidence that extra-medical opioid use was lower in those receiving buprenorphine in RCTs that measured this outcome by urinalysis and reported proportion of positive urine samples (over various time frames; standardised mean difference –0·20 [–0·29 to –0·11]; I·=0·0%; three studies, N=841), but no differences were found when using other measures. Some statistically significant differences were found between buprenorphine and methadone among secondary outcomes. There was evidence of reduced cocaine use, cravings, anxiety, and cardiac dysfunction, as well as increased treatment satisfaction among people receiving buprenorphine compared with methadone; and evidence of reduced hospitalisation and alcohol use in people receiving methadone. These differences in secondary outcomes were based on small numbers of studies (maximum five), and were often not consistent across study types or different measures of the same constructs (eg, cocaine use).

Interpretation

Evidence from trials and observational studies suggest that treatment retention is better for methadone than for sublingual buprenorphine. Comparative evidence on other outcomes examined showed few statistically significant differences and was generally based on small numbers of studies. These findings highlight the imperative for interventions to improve retention, consideration of client-centred factors (such as client preference) when selecting between methadone and buprenorphine, and harmonisation of data collection and reporting to strengthen future syntheses.

Funding

Australian National Health and Medical Research Council.

中文翻译：

---

丁丙诺啡与美沙酮治疗阿片类药物依赖：随机和观察性研究的系统回顾和荟萃分析

背景

阿片类药物依赖与巨大的健康和社会负担有关，阿片类药物激动剂治疗 (OAT) 对于改善接受这种治疗的人的多种结局非常有效。美沙酮和丁丙诺啡是以 OAT 形式提供的常见药物。我们的目的是比较丁丙诺啡与美沙酮治疗阿片类药物依赖的广泛主要和次要结果。

方法

我们根据 GATHER 和 PRISMA 指南进行了系统回顾和荟萃分析。我们检索了 Embase、MEDLINE、CENTRAL 和 PsycINFO，从数据库建立到 2022 年 8 月 1 日；还审查了临床试验注册和之前的相关 Cochrane 综述。我们纳入了所有对阿片类药物依赖的成年人（年龄≥18岁）进行的随机对照试验和观察性研究，比较了丁丙诺啡或美沙酮的治疗效果。主要结局是 1、3、6、12 和 24 个月时的治疗保留率、治疗依从性（通过按处方服用的剂量、参加的给药访视和生物测量来衡量）或医疗外阿片类药物的使用（通过尿液分析和自我评估来衡量） -报告）。次要结果是使用苯二氮卓类药物、大麻、可卡因、安非他明和酒精；退出; 渴望；犯罪活动和与刑事司法系统的接触；过量; 精神和身体健康；睡觉; 疼痛; 全球运作；自杀和自残；和不良事件。还回顾了单组队列研究和仅收集丁丙诺啡保留数据的随机对照试验。提取了有关研究、参与者和治疗特征的数据。需要时联系研究作者以获取更多数据。使用随机效应荟萃分析汇总比较估计值。每种药物在多个时间点保留接受治疗的个体比例被汇总。本研究已在 PROSPERO 注册（CRD42020205109）。

发现

我们确定了 32 项合格的随机对照试验（N=5808 名受试者）和 69 项比较丁丙诺啡和美沙酮的观察性研究（N=323 340），此外还有 51 项随机对照试验（N=11 644）和 124 项观察性研究（N=700 035）报告了丁丙诺啡保留治疗。总体而言，西欧开展了 61 项研究，北美开展了 162 项研究，北非和中东开展了 14 项研究，大洋洲开展了 20 项研究，东南亚开展了 5 项研究，南亚开展了 7 项研究，东欧开展了 2 项研究，中欧开展了 3 项研究，中欧开展了 1 项研究。东亚一个，中亚一个。这些初步研究纳入了 1 040 827 名参与者；然而，仅报告了 572 111 名参与者的性别，其中 377 991 名 (66·1%) 为男性，194 120 名 (33·9%) 为女性。平均年龄为 37·1 岁 (SD 6·0)。在超过 1 个月的时间点，美沙酮的保留率优于丁丙诺啡：例如，在 6 个月时，RCT 中的综合效应有利于美沙酮（风险比 0·76 [95% CI 0·67–0·85]；I · =74·2%；16 项研究，N=3151）和观察性研究（0·77 [0·68–0·86]；I ·=98·5%；21 项研究，N=155 111）。随机对照试验的保留率通常高于观察性研究。没有证据表明丁丙诺啡与美沙酮的治疗依从性存在差异。有一些证据表明，在随机对照试验中，接受丁丙诺啡治疗的患者的非医疗阿片类药物使用率较低，这些随机对照试验通过尿液分析测量这一结果，并报告阳性尿液样本的比例（在不同的时间范围内；标准化平均差 –0·20 [–0·29 至–0·11]；I ·=0·0%；三项研究，N=841），但使用其他措施时未发现差异。丁丙诺啡和美沙酮在次要结局方面存在一些统计学上的显着差异。有证据表明，与美沙酮相比，接受丁丙诺啡的人可卡因的使用、渴望、焦虑和心脏功能障碍有所减少，并且治疗满意度有所提高；以及接受美沙酮治疗的患者住院率和饮酒量减少的证据。次要结果的这些差异基于少量研究（最多五项），并且不同研究类型或相同结构的不同测量（例如可卡因使用）之间往往不一致。

解释

试验和观察性研究的证据表明，美沙酮的治疗保留效果优于舌下含服丁丙诺啡。其他检查结果的比较证据显示几乎没有统计学上的显着差异，并且通常基于少量研究。这些发现强调了采取干预措施提高保留率的必要性，在选择美沙酮和丁丙诺啡时考虑以客户为中心的因素（例如客户偏好），以及协调数据收集和报告以加强未来的综合。

资金

澳大利亚国家健康和医学研究委员会。