Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor R J, Fry-Smith A, Day E, Lintzeris N, Roberts T, Burls A, Taylor R S
Department of Public Health and Epidemiology, University of Birmingham, UK.
Health Technol Assess. 2007 Mar;11(9):1-171, iii-iv. doi: 10.3310/hta11090.
To assess the clinical effectiveness and cost-effectiveness of buprenorphine maintenance therapy (BMT) and methadone maintenance therapy (MMT) for the management of opioid-dependent individuals.
Major electronic databases were searched from inception to August 2005. Industry submissions to the National Institute for Health and Clinical Excellence were accessed.
The assessment of clinical effectiveness was based on a review of existing reviews plus an updated search for randomised controlled trials (RCTs). A decision tree with Monte Carlo simulation model was developed to assess the cost-effectiveness of BMT and MMT. Retention in treatment and opiate abuse parameters were sourced from the meta-analysis of RCTs directly comparing flexible MMT with flexible dose BMT. Utilities were derived from a panel representing a societal perspective.
Most of the included systematic reviews and RCTs were of moderate to good quality, and focused on short-term (up to 1-year follow-up) outcomes of retention in treatment and the level of opiate use (self-report or urinalysis). Most studies employed a trial design that compared a fixed-dose strategy (i.e. all individuals received a standard dose) of MMT or BMT and were conducted in predominantly young men who fulfilled criteria as opiate-dependent or heroin-dependent users, without significant co-morbidities. RCT meta-analyses have shown that a fixed dose of MMT or BMT has superior levels of retention in treatment and opiate use than placebo or no treatment, with higher fixed doses being more effective than lower fixed doses. There was evidence, primarily from non-randomised observational studies, that fixed-dose MMT reduces mortality, HIV risk behaviour and levels of crime compared with no therapy and one small RCT has shown the level of mortality with fixed-dose BMT to be significantly less than with placebo. Flexible dosing (i.e. individualised doses) of MMT and BMT is more reflective of real-world practice. Retention in treatment was superior for flexible MMT than flexible BMT dosing but there was no significant difference in opiate use. Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT. A pooled RCT analysis showed no significant difference in serious adverse events with MMT compared with BMT. Although treatment modifier evidence was limited, adjunct psychosocial and contingency interventions (e.g. financial incentives for opiate-free urine samples) appeared to enhance the effects of both MMT and BMT. Also, MMT and BMT appear to be similarly effective whether delivered in a primary care or outpatient clinic setting. Although most of the included economic evaluations were considered to be of high quality, none used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. One company (Schering-Plough) submitted cost-effectiveness evidence based on an economic model that had a 1-year time horizon and sourced data from a single RCT of flexible-dose MMT compared with flexible-dose BMT and utility values obtained from the literature; the results showed that for MMT vs no drug therapy, the incremental cost-effectiveness ratio (ICER) was pound 12,584/quality-adjusted life-year (QALY), for BMT versus no drug therapy, the ICER was pound 30,048/QALY and in a direct comparison, MMT was found to be slightly more effective and less costly than BMT. The assessment group model found for MMT versus no drug therapy that the ICER was pound 13,697/QALY, for BMT versus no drug therapy that the ICER was pound 26,429/QALY and, as with the industry model, in direct comparison, MMT was slightly more effective and less costly than BMT. When considering social costs, both MMT and BMT gave more health gain and were less costly than no drug treatment. These findings were robust to deterministic and probabilistic sensitivity analyses.
Both flexible-dose MMT and BMT are more clinically effective and more cost-effective than no drug therapy in dependent opiate users. In direct comparison, a flexible dosing strategy with MMT was found be somewhat more effective in maintaining individuals in treatment than flexible-dose BMT and therefore associated with a slightly higher health gain and lower costs. However, this needs to be balanced by the more recent experience of clinicians in the use of buprenorphine, the possible risk of higher mortality of MMT and individual opiate-dependent users' preferences. Future research should be directed towards the safety and effectiveness of MMT and BMT; potential safety concerns regarding methadone and buprenorphine, specifically mortality and key drug interactions; efficacy of substitution medications (in particular patient subgroups, such as within the criminal justice system, or within young people); and uncertainties in cost-effectiveness identified by current economic models.
评估丁丙诺啡维持治疗（BMT）和美沙酮维持治疗（MMT）用于管理阿片类药物依赖个体的临床有效性和成本效益。
检索了自数据库建立至2005年8月的主要电子数据库。获取了制药行业向英国国家卫生与临床优化研究所提交的材料。
临床有效性评估基于对现有综述的回顾以及对随机对照试验（RCT）的最新检索。开发了一个带有蒙特卡洛模拟模型的决策树，以评估BMT和MMT的成本效益。治疗保留率和阿片类药物滥用参数来自直接比较灵活MMT与灵活剂量BMT的RCT的荟萃分析。效用值来自一个代表社会视角的专家小组。
纳入的大多数系统综述和RCT质量中等或良好，且侧重于治疗保留率和阿片类药物使用水平（自我报告或尿液分析）的短期（长达1年随访）结果。大多数研究采用的试验设计是比较MMT或BMT的固定剂量策略（即所有个体接受标准剂量），且主要在符合阿片类药物依赖或海洛因依赖标准、无显著合并症的年轻男性中进行。RCT荟萃分析表明，固定剂量的MMT或BMT在治疗保留率和阿片类药物使用方面优于安慰剂或无治疗，较高的固定剂量比较低的固定剂量更有效。有证据表明，主要来自非随机观察性研究，与无治疗相比，固定剂量的MMT可降低死亡率、HIV风险行为和犯罪率，一项小型RCT表明固定剂量BMT的死亡率显著低于安慰剂。MMT和BMT的灵活给药（即个体化剂量）更能反映实际临床实践。灵活MMT的治疗保留率优于灵活BMT给药，但阿片类药物使用方面无显著差异。对人群横断面研究数据的间接比较表明，BMT的死亡率可能低于MMT。一项汇总RCT分析显示，MMT与BMT相比，严重不良事件无显著差异。尽管治疗修饰因素的证据有限，但辅助心理社会和应急干预措施（如对无阿片类药物尿液样本的经济激励）似乎可增强MMT和BMT的效果。此外，MMT和BMT在初级保健或门诊环境中实施时似乎同样有效。尽管纳入的大多数经济评估被认为质量较高，但没有一个使用了所有适当的参数、有效性数据、视角和比较对象，以使结果能够推广到英国国家医疗服务体系（NHS）背景。一家公司（先灵葆雅）基于一个经济模型提交了成本效益证据，该模型的时间跨度为1年，数据来自一项比较灵活剂量MMT与灵活剂量BMT的单一RCT以及从文献中获得的效用值；结果显示，对于MMT与无药物治疗相比，增量成本效益比（ICER）为12,584英镑/质量调整生命年（QALY），对于BMT与无药物治疗相比，ICER为30,048英镑/QALY，在直接比较中，发现MMT比BMT稍有效且成本更低。评估组模型发现，对于MMT与无药物治疗相比，ICER为13,697英镑/QALY，对于BMT与无药物治疗相比，ICER为26,429英镑/QALY，与行业模型一样，在直接比较中，MMT比BMT稍有效且成本更低。考虑社会成本时，MMT和BMT都比无药物治疗带来更多健康收益且成本更低。这些发现对于确定性和概率性敏感性分析具有稳健性。
灵活剂量的MMT和BMT在阿片类药物依赖使用者中比无药物治疗在临床和成本效益方面更具优势。在直接比较中，发现灵活剂量的MMT在维持个体治疗方面比灵活剂量的BMT稍有效，因此带来稍高的健康收益且成本更低。然而，这需要与临床医生最近使用丁丙诺啡的经验、MMT较高死亡率的可能风险以及个体阿片类药物依赖使用者的偏好相平衡。未来的研究应针对MMT和BMT的安全性和有效性；美沙酮和丁丙诺啡潜在的安全问题，特别是死亡率和关键药物相互作用；替代药物的疗效（特别是在刑事司法系统或年轻人等特定患者亚组中）；以及当前经济模型确定的成本效益方面的不确定性。
