Sequential Trial of Adding Buprenorphine, Cognitive Behavioral Treatment, and Transcranial Magnetic Stimulation to Improve Outcomes of Long-Term Opioid Therapy for Chronic Pain (ACTION)

摘要 接受长期阿片类药物治疗(LTOT)的患者中，有相当比例的患者疼痛缓解效果不佳和/或效果不佳 尽管存在重大风险，但仍能正常工作。由于LTOT缩减会导致停用戒断症状，因此 决定缩减或过渡LTOT可能会令人望而生畏，并造成临床困境。新奇高效 在降低风险的同时改善LTOT患者疼痛和生活质量(QOL)的治疗方法是 这是必要的，但必须确保这些倡议是以患者为中心的。提供治疗试验，可以 增加到目前的LTOT管理，而不必前瞻性地承诺减少阿片类药物或经历 停用阿片类药物可显著提高安全、以患者为中心和有效的LTOT风险比率 减少，同时改善疼痛和生活质量。拟议的研究通过以下顺序满足了这一关键需求 评估三种可添加到LTOT的慢性疼痛循证治疗方法的试验 而不必经历阿片类药物的戒断或致力于缩减。在这项研究中，服用LTOT的个体 将首先试验为期7天的低剂量丁丙诺啡透皮吸收，以确定安全性和耐受性，以及 然后将进入一项随机盲法停药试验，以评估丁丙诺啡透皮吸收的疗效 服用LTOT的患者的疼痛严重程度。那些对丁丙诺啡试验有积极反应并希望 过渡到丁丙诺啡(和停用LTOT)将作为预期队列进行过渡和跟踪。那些 丁丙诺啡不起效将接受二次随机对照评价疗效 对疼痛的认知行为干预(CBI)结合为期3天的脑刺激加速疗程 (重复经颅刺激；rTMS)对疼痛严重程度的影响。拟议的研究旨在提高参与度 对服用LTOT的个人作出关于LTOT的知情治疗决定；提供急需的安全性和 小剂量丁丙诺啡诱导策略的耐受性数据；并评估一种新的有效性 联合非药物治疗，可以解决疼痛、阿片类药物风险和抑郁症 对丁丙诺啡过渡无反应。主要创新包括使用低承诺、以患者为中心 无强制戒断治疗的“试验”和更短的脑“加速”方案的评估 可以增强CBI的刺激，使这一新的干预措施可扩展、可推广和可持续。这 应用程序直接响应FOA(RFA-DA-23-041)，其中强调了参与的重要性 具有生活经验的个人，为旨在提高生活质量和减少 对那些服用LTOT的人造成伤害。这也符合Hear倡议的研究重点，以优化护理 适用于患有慢性疼痛和有阿片类药物相关伤害风险的个人。这项研究的发现将提供 新的和迫切需要的经验证据，为临床实践提供信息，并推动这一领域的科学。

ABSTRACT A significant proportion of patients on Long Term Opioid Therapy (LTOT) have suboptimal pain relief and/or poor functioning despite significant risks. Because LTOT tapering can cause disabling withdrawal symptoms, the decision to taper or transition from LTOT can be daunting and create a clinical dilemma. Novel and effective treatment approaches that improve pain and quality of life (QOL) for individuals on LTOT while reducing risk are needed, but it is essential to ensure these initiatives are patient-centered. Offering treatment trials that can be “added to” current LTOT management without having to prospectively commit to an opioid taper or experience opioid withdrawal could significantly enhance the rates of safe, patient-centered, and effective LTOT risk reduction while improving pain and QOL. The proposed study addresses this critical need by sequentially evaluating trials of three evidence-based treatments for chronic pain that can be “added to” LTOT without having to experience opioid withdrawal or commit to a taper. In this study, individuals on LTOT will first trial a 7-day initiation of low-dose transdermal buprenorphine to determine safety and tolerability, and then will enter a blinded randomized discontinuation trial to evaluate efficacy of transdermal buprenorphine on pain severity among those on LTOT. Those who respond positively to the buprenorphine trial and want to transition to buprenorphine (and off LTOT) will be transitioned and followed as a prospective cohort. Those who do not respond to buprenorphine will undergo a second randomization evaluating the effectiveness of a Brief Cognitive Behavioral Intervention (CBI) for Pain combined with a 3-day “accelerated” course of Brain Stimulation (repetitive Transcranial Stimulation; rTMS) on pain severity. The proposed study aims to improve engagement of individuals on LTOT to make informed treatment decisions about LTOT; provide much needed safety and tolerability data on low-dose buprenorphine induction strategies; and evaluate the effectiveness of a novel combined non-pharmacological treatment that can address pain, opioid risk, and depression among those who do not respond to buprenorphine transition. Key innovations include the use of low-commitment, patient-centered ”trials” of treatment without mandating withdrawal and the evaluation of shorter “accelerated” protocols of brain stimulation that can enhance CBI that make this novel intervention scalable, generalizable and sustainable. This application is directly responsive to the FOA (RFA-DA-23-041), which underscores the importance of engaging individuals with lived experience to inform multilevel interventions aimed at improving quality of life and reducing harm for those on LTOT. It is also consistent with the research priorities of the HEAL initiative to optimize care for individuals with chronic pain and those at risk for opioid-related harms. The findings from this study will provide novel and critically needed empirical evidence to inform clinical practice and advance the science in this area.