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

转发；

• 批准号: MR/T025557/1
• 负责人: Anne Lingford Hughes
• 金额: $ 207.52万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT025557%2F1
• 关键词: FORWARDS; Facilitating; Opiate; Recovery; Withdrawal

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

阿片成瘾是一项重大的健康挑战。阿片类替代疗法（OST；例如美沙酮或丁丙诺啡）和社会心理支持在改善健康和社会功能方面非常有效。然而，现在人们越来越关注戒断，特别是对于身心健康需求日益复杂的老年阿片类药物成瘾者；目前40-49岁人群的死亡率最高。排毒通常涉及使用支持性药物（包括安眠药或洛非西定）逐渐减少 OST 来治疗新出现的症状，但其疗效有限和/或只能短期使用。目前洛非西定已经停售一年多了，尚不清楚何时会再次上市。几十年来没有新药出现。由于住院或住院治疗的可用性有限，我们需要开发适合社区环境的治疗方法。基于证据，我们提出 GABA-B 激动剂巴氯芬具有促进阿片类药物解毒和防止复发的所需特性，以满足这一未满足的需求。巴氯芬是通用名，获批用于治疗痉挛，目前在标签外用于治疗酒精中毒。尽管希望戒毒，但由于存在或害怕戒断症状（包括焦虑、失眠、肌肉酸痛、腿不安和渴望），很少有阿片类成瘾者能够成功完成戒毒。巴氯芬可能会改善此类症状。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，成瘾者服用的剂量可能高于推荐剂量，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，并评估巴氯芬是否被“喜欢”。我们只会研究美沙酮，因为它是最常见的 OST，并且由于其在大脑中具有完全激动剂作用，比丁丙诺啡（部分激动剂）更有可能引起不良反应。我们将招募使用稳定剂量美沙酮的稳定阿片类药物成瘾者 (DSM-5)。该研究将是一项安慰剂对照、单剂量递增的药代动力学-药效学研究，涉及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设施，在那里他们将完成基线和接下来 6 小时的评估，包括身体（心血管、呼吸）、情绪（焦虑）和阿片类药物相关测量（渴望、戒断）。服用通常的美沙酮药物一小时后，他们将服用巴氯芬或安慰剂。我们将增加巴氯芬剂量（10毫克、30毫克、60毫克、90毫克），以与服用一系列美沙酮剂量的患者的安慰剂进行比较；如果联合用药没有产生不良反应，我们将增加巴氯芬的剂量水平。酗酒研究的证据表明，巴氯芬 >90 毫克不太可能有效，因此我们不打算高于此水平。假设我们可以以临床相关剂量安全地将巴氯芬和美沙酮联合使用，然后我们将进行安慰剂对照、随机证明确定巴氯芬是否有助于促进阿片类成瘾者美沙酮戒毒的概念试验。我们将只招募那些致力于我们社区鸦片戒毒途径的人，以便 56 人完成这项试验。我们的目的是了解巴氯芬是否能减少美沙酮剂量并提高戒断率，从而具有临床意义。试验期间将使用经过验证的措施收集数据，例如阿片戒断、焦虑、睡眠、不安腿。我们还将收集有关不良事件以及招聘和保留可行性的信息。我们将获取数据来设计最终试验，其主要结果将是成功戒烟的参与者的比例

项目成果

Additional file 1 of FORWARDS-1: an adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment-a pharmacokinetic-pharmacodynamic study

FORWARDS-1的附加文件1：一项适应性、单盲、安慰剂对照递增剂量研究，急性巴氯芬对美沙酮维持治疗期间阿片类药物依赖的安全参数 - 药代动力学-药效研究

• DOI: http://dx.10.6084/m9.figshare.21358107
• 发表时间: 2022
• 作者: Paterson L

FORWARDS-1: an adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment-a pharmacokinetic-pharmacodynamic study.

FORWARDS-1：一项针对美沙酮维持治疗期间阿片类药物依赖的安全参数的急性巴氯芬适应性、单盲、安慰剂对照递增剂量研究——药代动力学-药效学研究。

• DOI: http://dx.10.17863/cam.89755
• 发表时间: 2022
• 作者: Paterson L

A dose-finding design for dual-agent trials with patient-specific doses for one agent with application to an opiate detoxification trial.

双药试验的剂量探索设计，其中一种药物的患者特定剂量，适用于阿片戒毒试验。

• DOI: http://dx.10.17863/cam.79326
• 发表时间: 2022
• 作者: Mozgunov P

Additional file 2 of FORWARDS-1: an adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment-a pharmacokinetic-pharmacodynamic study

FORWARDS-1的附加文件2：一项适应性、单盲、安慰剂对照的剂量递增研究，急性巴氯芬对美沙酮维持治疗期间阿片类药物依赖的安全参数 - 药代动力学-药效研究

• DOI: http://dx.10.6084/m9.figshare.21358110
• 发表时间: 2022
• 作者: Paterson L

FORWARDS-1: an adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment-a pharmacokinetic-pharmacodynamic study.

FORWARDS-1：一项针对美沙酮维持治疗期间阿片类药物依赖的安全参数的急性巴氯芬适应性、单盲、安慰剂对照递增剂量研究——药代动力学-药效学研究。

• DOI: http://dx.10.17863/cam.90890
• 发表时间: 2022
• 作者: Paterson L