FORWARDS; Facilitating Opiate Recovery: Withdrawal and Abstinence through Detoxification Support.

阿片类药物成瘾是一项重大的健康挑战。阿片替代治疗（如美沙酮或丁丙诺啡）和社会心理支持治疗在改善健康和社会功能方面非常有效。然而，现在越来越多的人关注禁欲，特别是老年阿片类成瘾者，他们的身心健康需求日益复杂；目前，40-49岁人群的死亡率最高。解毒通常包括逐渐减少OST，并使用支持性药物，包括安眠药或洛非昔定来治疗新出现的症状，但其疗效有限和/或只能短期使用。目前，洛非昔定已经缺货一年多了，目前还不清楚它何时会再次上市。几十年来都没有新药问世。我们需要开发适合社区环境的治疗方法，因为住院或住院治疗的可用性有限。基于证据，我们提出GABA-B激动剂巴氯芬具有促进阿片解毒和防止复发的理想特性，以满足这一未满足的需求。巴氯芬是一种通用药物，被许可用于治疗痉挛，目前用于治疗酒精中毒。尽管渴望戒断，但很少有鸦片成瘾者由于存在或害怕戒断症状（包括焦虑、失眠、肌肉疼痛、不宁腿和渴望）而成功地完成戒毒。巴氯芬可能会改善这些症状。虽然我们的临床经验和其他研究表明巴氯芬可以与美沙酮一起安全服用，但它们可能会相互作用，导致呼吸抑制等不良反应。此外，有可能成瘾者服用的剂量高于推荐剂量，因此我们的第一项研究将确定巴氯芬和美沙酮的安全剂量组合，并评估巴氯芬是否“受欢迎”。我们将只研究美沙酮，因为它是最常见的OST，并且由于其在大脑中的完全激动剂作用，比丁丙诺啡（部分激动剂）更有可能引起不良反应。我们将招募稳定剂量美沙酮的稳定阿片类成瘾者（DSM-5）。该研究将是一项安慰剂对照、单次上升剂量药代动力学-药效学研究，包括测量巴氯芬血浆水平及其客观效应（呼吸、心率、生长激素）和主观效应（焦虑、镇静、“喜欢”）。参与者将参加我们的临床研究机构，在那里他们将在基线和接下来的6小时内完成评估，包括身体（心血管、呼吸）、情绪（焦虑）和阿片类药物相关措施（渴望、戒断）。在服用常规的美沙酮药物一小时后，他们将服用巴氯芬或安慰剂。我们将增加巴氯芬的剂量（10mg、30mg、60mg、90mg），与使用美沙酮剂量范围的安慰剂患者进行比较；如果联合用药没有不良反应，我们将增加巴氯芬的剂量。来自酒精中毒研究的证据表明，巴氯芬90mg不太可能有效，所以我们不打算高于这个剂量。假设巴氯芬和美沙酮在临床相关剂量下可以安全地联合使用，我们将进行一项安慰剂对照、随机的概念验证试验，以确定巴氯芬是否有助于促进阿片类成瘾者从美沙酮中解毒。我们将只招募那些致力于我们的社区阿片类药物解毒途径的人，以便56人完成这项试验。我们的目的是观察巴氯芬是否能减少美沙酮的剂量并增加戒断率。数据将在试验期间使用有效的测量方法收集，如阿片类药物戒断、焦虑、睡眠、不宁腿。我们还将收集有关不良事件和招募和保留可行性的信息。我们将获得数据来设计最终试验，其主要结果将是参与者成功实现戒断的比例

Opiate addiction is a major health challenge. Treatment with opiate substitution treatment (OST; eg methadone or buprenorphine) and psychosocial support has been highly effective in improving health and social functioning. However there is now a growing focus on abstinence, particularly for older opiate addicts with increasingly complex physical and mental health needs; death rates are now the highest in those aged 40-49 years old. Detoxification generally involves tapering of OST with supportive medication including sleeping tablets or lofexidine to treat emerging symptoms, but their efficacy is limited and/or can only be used short-term. Currently lofexidine has been unavailable for over a year and it is unclear when it will become available again. There have been no new medications in decades. We need to develop treatments suitable for community settings since availability of inpatient or residential treatment is limited. Based on evidence, we propose that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse to meet this unmet need. Baclofen is generic, licensed for spasticity, and is currently used off-label to treat alcoholism. Despite desiring abstinence, few opiate addicts successfully complete detoxification due to presence or fear of withdrawal symptoms including anxiety, insomnia, muscle aches, restless legs and craving. Such symptoms are likely to be improved by baclofen.Whilst our clinical experience and other studies suggest baclofen can be taken safely with methadone, they could potentially interact causing adverse effects such as respiratory depression. In addition, there is a possibility of addicts taking higher than recommended doses, so our first study will therefore determine what are safe dose combinations of baclofen and methadone and to assess if baclofen is 'liked'. We will only study methadone as it is the most common OST and due to its full agonist effects in the brain, more likely than buprenorphine (a partial agonist) to cause adverse effects. We will recruit stable opiate addicts (DSM-5) on stable doses of methadone. The study will be a placebo controlled, single ascending dose pharmacokinetic-pharmacodynamic study that involves measuring baclofen plasma levels alongside its objective (respiration, heart rate, growth hormone) and subjective effects (anxiety, sedation, 'liking'). Participants will attend our clinical research facility where they will complete assessments at baseline and for the next 6hrs including physical (cardiovascular, respiratory), mood (anxiety), and opiate-related measures (craving, withdrawal). An hour after taking their usual methadone medication, they will take baclofen or placebo. We will give increasing doses of baclofen (10mg, 30mg, 60mg, 90mg) to compare with placebo to patients on a range of methadone doses; if a combination results in no adverse effects, we will increase the baclofen dose level. Evidence from studies in alcoholism suggests that baclofen >90mg is unlikely to be efficacious so we do not intend to go higher than this.Assuming we can safely combine baclofen and methadone at clinically relevant doses, we will then conduct a placebo-controlled, randomized proof-of-concept trial to determine if baclofen is useful for facilitating detoxification from methadone in opiate addicts. We will recruit only those who are committed to our community opiate detoxification pathway so that 56 complete this trial. Our aim is to see whether baclofen produces a clinically meaningful reduction in methadone dose and increases abstinence rates. Data will be collected during the trial using validated measures eg opiate withdrawal, anxiety, sleep, restless legs. We will also collect information about adverse events and feasibility of recruitment and retention. We will obtain data to design the definitive trial for which the primary outcome will be the proportion of participants successfully achieving abstinence