Discontinuation From Chronic Opioid Therapy For Pain Using a Buprenorphine Taper

 描述(申请人提供)：接受慢性阿片类药物疼痛治疗(COT-P)的患者中，有相当大一部分患者的疼痛缓解效果不佳和/或功能不佳，尽管阿片类药物治疗存在明显的风险，包括过量死亡。在如何管理COT-P患者，尤其是那些需要停用阿片类药物的患者方面，临床知识存在很大差距。当存在停止COT-P的指征时，没有经验证据表明如何处理阿片类药物的停止或阿片类药物停止后的结果。这项应用的长期目标是扩大目前对COT-P患者停用阿片类药物的了解。丁丙诺啡是一种部分阿片受体激动剂，非常适合用于阿片类药物逐渐减少/戒毒环境，但非常需要评估丁丙诺啡对COT-P患者的耐受性和有效性。初步证据表明，丁丙诺啡诱导对COT-P患者耐受性良好，但由于疼痛和戒断症状，逐渐减少是具有挑战性的。本申请的目的是评价丁丙诺啡辅助的COT-P停药，并确定N-型钙通道阻滞剂加巴喷丁作为辅助药物帮助阿片类药物停药的作用。这项研究的中心假设是，与接受丁丙诺啡/安慰剂治疗的患者相比，接受丁丙诺啡逐渐减少并辅以加巴喷丁的COT-P患者的阿片类药物停用率更高。第二个假设是，与安慰剂相比，接受丁丙诺啡治疗的患者疼痛减轻，服用加巴喷丁的患者戒断和疼痛评分较低。为了验证这些假设，将在150名有阿片类药物停用指征的COT-P患者中进行丁丙诺啡辅助阿片类药物停用的两阶段研究。这项研究的具体目的是：(1)确定COT-P受试者对丁丙诺啡的耐受率；(2)观察加巴喷丁在丁丙诺啡辅助的COT-P逐渐减少期间改善结局的有效性。主要的结果措施将是丁丙诺啡耐受性和阿片类药物的停止。拟议研究的基本原理是确定基础比率和效果大小，以便为更大的随机对照试验提供信息，说明加巴喷丁在丁丙诺啡辅助的COT-P逐渐减少期间对阿片类药物停止的影响。预计将有相当数量的受试者耐受丁丙诺啡，与安慰剂相比，随机服用加巴喷丁的受试者停用阿片类药物的比率将更高。此外，还假设与以下因素相关的疼痛程度在诱导前到诱导后和逐渐减少时会有显著差异 停用阿片类药物。将测量在缩减后1个月、3个月和6个月恢复使用阿片类止痛剂的情况。这些结果预计将产生积极影响，确定在有指示时促进阿片类药物戒断的方法，从而降低处方阿片类药物过量的风险。这项创新的研究将首次系统地探索丁丙诺啡和加巴喷丁在没有成瘾的COT-P患者的阿片类药物逐渐减少过程中的作用，并首次系统地评估阿片类药物停用前后的疼痛。

 DESCRIPTION (provided by applicant): A significant proportion of patients maintained on chronic opioid therapy for pain (COT-P) have suboptimal pain relief and/or poor functioning despite the appreciable risk of opioid treatment, including overdose death. There is a major gap in clinical knowledge regarding how to manage individuals on COT-P, especially those in need of opioid cessation. When an indication exists for discontinuation from COT-P, there is no empirical evidence as to how to approach opioid discontinuation or outcomes after opioid cessation. The long-term goal of this application is to expand the current knowledge about opioid discontinuation for those on COT-P. Buprenorphine, a partial mu-opioid receptor agonist, is well-suited for use in opioid tapering/detoxification settings, but there is a great need to evaluate the tolerability and effectiveness of buprenorphine for those on COT-P. Preliminary evidence suggests that buprenorphine induction is well-tolerated for those on COT-P, but tapering is challenging due to pain and withdrawal symptoms. The objectives of this application are to evaluate buprenorphine-assisted discontinuation from COT-P and to determine the role of gabapentin, an N-type calcium channel blocker, as an adjunctive agent to assist with opioid cessation. The central hypothesis of this study is that COT-P patients undergoing a buprenorphine taper with adjunctive gabapentin will have higher rates of opioid cessation when compared with those on buprenorphine/ placebo. Secondary hypotheses are that patients will have decreased pain after buprenorphine initiation and that those on adjunctive gabapentin will have lower withdrawal and pain scores when compared with placebo. To test these hypotheses, a two-phase study of buprenorphine-assisted opioid discontinuation will be conducted in 150 COT-P patients with an indication for opioid cessation. The specific aims of this study are: (1) To determine the base rate of buprenorphine tolerability among COT-P subjects, and (2) To examine the efficacy of gabapentin in improving outcomes during a buprenorphine-assisted taper from COT-P. The primary outcome measures will be buprenorphine tolerance and opioid cessation. The rationale for the proposed research is to determine base rates and effect sizes to inform a larger randomized- controlled trial of the effects of gabapentin on opioid cessation during buprenorphine-assisted taper from COT-P. It is expected that a significant number subjects will tolerate buprenorphine, and that those randomized to gabapentin will have higher rates of opioid cessation when compared with placebo. Additionally, it is hypothesized that there will be significant differences in pre- to post- induction and taper levels of pain associated with opioid cessation. Resumption of opioid analgesic use at 1-, 3- and 6-months post-taper will be measured. Such results are expected to have a positive impact by identifying approaches to facilitate opioid cessation when indicated, thereby decreasing risk for prescription opioid overdose. This innovative study will be the first to systematically explore both buprenorphine and gabapentin during opioid tapering in COT-P patients who do not have addiction and the first to systematically evaluate pain before and after opioid discontinuation.