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: 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.
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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。
作者：
使用阿片类替代治疗（例如美沙酮）治疗阿片成瘾是有益的。然而，一些人渴望戒除且会从中受益，但缓解阿片戒断问题的选择有限。临床前和初步临床证据表明，γ - 氨基丁酸B型（GABA - B）受体激动剂巴氯芬具有促进阿片类戒毒和预防复吸的理想特性。本研究旨在了解对接受美沙酮治疗的阿片类药物依赖者使用巴氯芬是否存在任何安全问题。
从伦敦西北部的成瘾治疗服务机构（英国国家医疗服务体系和第三部门服务提供者）招募正在接受美沙酮维持治疗的阿片类药物依赖者（《精神障碍诊断与统计手册》第5版中的重度阿片类药物使用障碍）。参与者身体健康，无严重慢性阻塞性肺疾病或2型呼吸衰竭，目前无对其他物质（尼古丁除外）的依赖，无当前严重的《精神障碍诊断与统计手册》第5版中的精神障碍，且无巴氯芬或4800国际单位维生素D（安慰剂）的禁忌证。符合条件的参与者将按3∶1的比例随机分组，在适应性、单盲、递增剂量设计中接受巴氯芬或安慰剂。贝叶斯剂量递增模型将根据“剂量限制性毒性”（DLT）事件的发生率和参与者特定的美沙酮剂量来确定巴氯芬的剂量（10、30、60或90毫克）。一系列呼吸、心血管和镇静指标，包括英国国家早期预警评分（NEWS2）和格拉斯哥昏迷量表，将用于确定剂量限制性毒性。在实验当天，参与者将服用他们日常剂量的美沙酮，大约1小时后服用一剂巴氯芬或安慰剂（维生素D3）。在给药后的5小时内，将定期使用经过验证的问卷和检查来获取包括血氧饱和度、经皮二氧化碳分压、呼吸频率、QTc间期、主观感受（镇静、药物喜好、渴望）、血浆水平（巴氯芬、美沙酮）和不良事件等指标。
研究结果将确定对接受美沙酮治疗的患者开具多大剂量的巴氯芬是安全的，以便为后续巴氯芬促进阿片类戒毒疗效的概念验证试验提供依据。根据巴氯芬在酒精中毒治疗中的临床经验以及阿片类依赖管理指南，对于接受≤60毫克/天美沙酮治疗的患者，可继续进行研究的最低可接受剂量为30毫克巴氯芬。
临床试验注册号为Clinicaltrials.gov NCT05161351，于2021年12月16日注册。
在线版本包含补充材料，可在10.1186/s13063 - 022 - 06821 - 9获取。
Treatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone. Opiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of ‘dose-limiting toxicity’ (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO2, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodically for 5 h after dosing. Study outcomes will determine what dose of baclofen is safe to prescribe to those receiving methadone, to inform a subsequent proof-of-concept trial of the efficacy baclofen to facilitate opiate detoxification. To proceed, the minimum acceptable dose is 30 mg of baclofen in patients receiving ≤ 60 mg/day methadone based on the clinical experience of baclofen’s use in alcoholism and guidelines for the management of opiate dependence. Clinicaltrials.gov NCT05161351. Registered on 16 December 2021. The online version contains supplementary material available at 10.1186/s13063-022-06821-9.
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影响因子：
4.2
作者：
Darke, Shane;Mills, Katherine L.;Teesson, Maree
通讯作者：
Teesson, Maree
DOI：
10.1046/j.1365-2710.2000.00295.x
发表时间：
2000-10-01
影响因子：
2
作者：
Akhondzadeh, S;Ahmadi-Abhari, SA;Farzanehgan, ZM
通讯作者：
Farzanehgan, ZM
DOI：
10.1111/j.1530-0277.2008.00805.x
发表时间：
2009-01-01
影响因子：
3.2
作者：
Evans, Suzette M.;Bisaga, Adam
通讯作者：
Bisaga, Adam
影响因子：
2.9
作者：
Drake, RG;Davis, LL;Lowe, JS
通讯作者：
Lowe, JS
影响因子：
2.8
作者：
Addolorato, G;Caputo, F;Gasbarrini, G
通讯作者：
Gasbarrini, G