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

摘要 此R 01应用程序遵循成功完成的R34项目，并满足我们的总体目标， 优化美沙酮剂量作为管理慢性疼痛和阿片类药物使用障碍（OUD）共病的方法 在接受美沙酮治疗OUD的人中。高达62%的人维持在 美沙酮治疗OUD的患者经历临床显著疼痛，而普通人群中为31%。MMP疼痛 与OUD治疗效果差和严重痛苦相关。无有效治疗共病疼痛的方法 和OUD目前存在;虽然临床前和人类数据表明，分开的美沙酮剂量可能是一个 虽然这是比每日一次给药更好的管理疼痛的最佳策略，但从未进行过经验检验。 本研究将使用双盲， 随机、安慰剂对照比较每日一次与每日两次美沙酮给药。这个项目是 我们最近成功完成的R34项目有力地支持了这一点，该项目证明了强大的可行性， 电子、自主、蜂窝式商用药盒（MedMinder）的可接受性 管理美沙酮带回家的剂量。该研究的参与者表示他们将再次使用药丸盒 (86%）并推荐给其他人（95%），当地诊所将MedMinder盒子纳入日常带回家 管理操作，初步的人内数据显示， 两次与一次给药期。两间美沙酮诊所的病人将被纳入第二阶段 组间研究，随机分为每日一次和每日两次美沙酮给药组，持续12周。 美沙酮将通过与R34相同的电子药盒分发。主要结果为每周一次 疼痛和OUD结局的评估，给药前后疼痛的生态学瞬时评估， 和实验室诱发疼痛的点患病率测量，以探讨其作用机制。我们将评估 以下目的：（主要1）确定美沙酮给药间隔（一次与两次）对疼痛严重程度的影响， （主要2）确定美沙酮给药间隔（一次与两次）对疼痛相关功能的影响， （初级3）确定美沙酮给药间隔（一次与两次）对OUD相关指标的影响，以及 （次要1）确定美沙酮给药间隔对实验室诱发疼痛反应的影响，使用 定量感官测试我们预计分配至每日两次给药的受试者将显示出 疼痛严重程度，疼痛相关功能改善，OUD相关结局无变化或改善 相对于接受标准治疗每日一次给药的患者。如果有效，这种方法可以改变 的MMP与疼痛的护理，因为它将是可行的，在一个业务结构内实施， 美沙酮诊所，并会造成低供应商的负担。结果可以提供高强度的治疗， 大量的MMP经历日常疼痛而没有可靠的治疗形式。

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.