Brain Mechanisms of Cognitive Response to Pharmacotherapy in Opioid Use Disorder

预防复发是阿片类药物使用障碍（OUD）治疗的最大挑战。我们 建议通过研究OUD的影响来阐明OUD的反应机制 药物治疗的神经认知领域有助于复发。我们将使用 先前验证的神经认知探针，功能性磁共振成像（fMRI）， 以及阿片样物质部分激动剂的新型缓释注射制剂（Brixadi ®）， 丁丙诺啡（XRBUP）和批准的拮抗剂纳洛酮（XRNTX）。 使用两种具有相反阿片受体作用的药物将允许全面的 评价对OUD复发预防药物的反应机制。R61 阶段（目标1）将在执行功能、激励、 显著性和情绪调节，以及将表明 两种药物。至少在两个领域存在差异，效应量至少很小 （Cohen's d>0.2），将作为推进到R33阶段（目标2）的里程碑。R33 阶段将测试在R61阶段中检查的相互作用的显著性以及 解释复发的大脑信号由阿片类药物阳性尿检的百分比和对 研究治疗。参与者将是寻求治疗的OUD患者，他们将接受 每月三次XRNTX或XRBUP注射，产生约100天的治疗， 每周进行尿液毒理学监测在R61期，40例寻求治疗的OUD患者 完成解毒的患者将被随机分配到XRNTX或XRBUP。如果 如果达到里程碑，R33阶段将随机分配160名受试者。Logistic回归将 用于测试大脑信号在建立复发脆弱性模型中的解释价值， 区分治疗组的变量，测试整合脑的解释价值， 复发脆弱性的行为模型，确定变量负荷之间的差异 治疗组，并探讨治疗个体差异的潜在机制 结果。该提案将是第一个神经系统层面的认知调查， 下一代丁丙诺啡纳洛酮缓释制剂的作用 解释OUD治疗反应和失败的个体异质性。这个项目可以 通过阐明OUD的脑机制，推进OUD的理论和个体化治疗 在一般的OUD和SUD中复发的脆弱性。

Relapse prevention is the greatest challenge in opioid use disorder (OUD) treatment. We propose to elucidate the mechanisms of response to OUD by investigating the effects of OUD pharmacotherapy on the neurocognitive domains instrumental to relapse. We shall use previously validated neurocognitive probes, functional Magnetic Resonance Imaging (fMRI), and the novel extended-release injectable preparation (Brixadi ®) of the opioid partial agonist buprenorphine (XRBUP) and approved antagonist naltrexone (XRNTX), in OUD patients. Using two medications with opposing opioid receptor action will allow a comprehensive evaluation of the response mechanisms to relapse prevention medications in OUD. The R61 phase (Aim 1) will search for treatment effects in the domains of executive function, incentive salience and emotion regulation and the interaction that will indicate a difference between the two medications. Differences in at least two domains, with an effect size that is at least small (Cohen's d>0.2), will serve as a milestone for advance to the R33 phase (Aim 2). The R33 phase will test the significance of the interactions examined in the R61 phase and the ability of the brain signal to explain relapse defined by % of opioid-positive urine tests and adherence to the study treatments. Participants will be treatment-seeking OUD patients who will receive three monthly XRNTX or XRBUP injections yielding approximately 100 days of treatment and have weekly urine toxicology monitoring. In the R61 phase, 40 treatment-seeking OUD patients who completed detoxification will be randomly assigned to XRNTX or XRBUP. If the milestone is met, the R33 phase will randomize 160 participants. Logistic regression will be used to test the explanatory value of the brain signal in modeling relapse vulnerability, identify variables that differentiate treatment groups, test the explanatory value of integrated brain- behavior models of relapse vulnerability, identify differences in variable loading between treatment groups, and explore the potential mechanism of individual variability in treatment outcomes. The proposal would be the first neural systems' level investigation of the cognitive effects of the next generation extended-release preparation of buprenorphine and naltrexone to explain the individual heterogeneity of OUD treatment response and failure. This project can advance the theory and personalized treatment of OUD by elucidating the brain mechanisms of vulnerability to relapse in OUD and SUD in general.