Randomized Clinical Trial Intervention to Treat Chronic Pain Among Persons Maintained on Methadone for Opioid Use Disorder

摘要 此R01应用程序遵循成功完成的R34项目，并解决了我们的总体目标 优化美沙酮剂量作为治疗慢性疼痛和阿片类药物使用障碍(OUD)的方法 在接受美沙酮治疗的OUD患者中。高达62%的人在 美沙酮在临床上有显著的疼痛，而在普通人群中这一比例为31%。基质金属蛋白酶中的疼痛 与不良的治疗结果和严重的痛苦有关。没有有效的治疗并存疼痛的方法 尽管临床前和人类数据表明分开服用美沙酮可能是一种 对于疼痛的管理比每天一次剂量更优化的策略，这从来没有得到过经验检验。 这项研究将使用双盲、 每日服用一次美沙酮与两次美沙酮的随机安慰剂对照比较。这个项目是 得到我们最近成功完成的R34的大力支持，这表明了强大的可行性和 电子、自主、蜂窝支持的商用地堡(MedMinder)的可接受性 管理美沙酮带回家的剂量。那项研究的参与者表示，他们将再次使用地堡 (86%)并推荐给其他人(95%)，当地诊所将MedMinder盒子纳入他们日常的带回家的食物中 管理操作和初步的个人数据显示，在 两次给药周期与一次给药周期。来自两家美沙酮诊所的患者将参加第二阶段 组间研究，随机分为每日一次美沙酮与每日两次美沙酮，疗程均为12周。 美沙酮将通过R34中使用的相同电子弹药箱进行分配。主要结果是每周一次 对疼痛和OUD结果的评估，对服药前后疼痛的生态瞬时评估， 并采用穴位患病率的方法对实验室诱发疼痛的作用机制进行探讨。我们将评估 以下目标：(主要1)确定美沙酮剂量间隔(一次与两次)对疼痛严重程度的影响， (初级2)确定美沙酮剂量间隔(一次与两次)对疼痛相关功能的影响， (初级3)确定美沙酮剂量间隔(一次与两次)对OUD相关指标的影响，以及 (次级1)确定美沙酮给药间隔对实验室引起的疼痛反应的影响 定量感官测试。我们预计每天被分配两次剂量的参与者将在 疼痛严重程度，疼痛相关功能改善，以及与OUD相关的结果没有变化或改善 相对于接受每日一次剂量的标准护理的人。如果有效，这种方法可能会改变 对疼痛的基质金属蛋白酶的护理，因为它将是可行的实施在一个 美沙酮诊所，并将施加较低的提供者负担。结果可能提供一种高强度的治疗 有相当数量的基质金属蛋白酶患者每天都会感到疼痛，但没有可靠的治疗方法。

ABSTRACT This R01 application follows a successfully completed R34 project and addresses our overarching goal of optimizing methadone dosing as a method for managing comorbid chronic pain and opioid use disorder (OUD) among persons receiving methadone for the treatment of OUD. Up to 62% of persons maintained on methadone for OUD experience clinically significant pain, versus 31% in the general population. Pain in MMP is associated with poor OUD treatment outcomes and severe distress. No effective treatment for comorbid pain and OUD currently exists; though preclinical and human data suggest divided methadone dosing may be a more optimal strategy for managing pain than once daily dosing, this has never been empirically examined. This study will evaluate an intervention for comorbid chronic pain among MMP using a double-blind, randomized, placebo-controlled comparison of ONCE versus TWICE daily methadone dosing. This project is strongly supported by our recent successful completion of an R34, which demonstrated strong feasibility and acceptability of an electronic, autonomous, cellular-enabled commercially available pillbox (MedMinder) to manage methadone take-home dosing. Participants in that study indicated they would use the pillbox again (86%) and recommend it to others (95%), local clinics adopted the MedMinder box into their routine take-home management operations, and preliminary within-person data showed clear and orderly pain reductions during the TWICE vs. ONCE dosing periods. Patients from two methadone clinics will be enrolled into a Phase II between-group study and randomized to ONCE versus TWICE-daily methadone dosing for 12-weeks. Methadone will be dispensed via the same electronic pillbox used in the R34. Primary outcomes are weekly assessments of pain and OUD outcomes, ecological momentary assessment of pain before and after dosing, and point-prevalence measures of laboratory-induced pain to explore mechanism of effects. We will assess the following aims: (Primary 1) Determine impact of methadone dose interval (ONCE vs. TWICE) on pain severity, (Primary 2) Determine impact of methadone dose interval (ONCE vs. TWICE) on pain-related function, (Primary 3) Determine impact of methadone dose interval (ONCE vs. TWICE) on OUD-related metrics, and (Secondary 1) Determine impact of methadone dosing interval on response to laboratory-induced pain using quantitative sensory testing. We expect participants assigned to TWICE daily dosing will show decreases in pain severity, improved pain-related function, and no change or improvements in OUD-related outcomes relative to persons receiving standard-of-care ONCE daily dosing. If effective, this approach could transform the care of MMP with pain because it would be feasible to implement within the operational structure of a methadone clinic and would impose low provider burden. Results could provide a high magnitude treatment for the substantial number of MMP who experience daily pain with no reliable form of treatment.