Brain Mechanisms of Cognitive Response to Pharmacotherapy in Opioid Use Disorder

阿片类药物使用障碍药物治疗认知反应的脑机制

• 批准号: 10494073
• 负责人: James W Loughead
• 金额: $ 39.81万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10494073
• 关键词: Adherence; Agonist; Amygdaloid structure; Anterior; Base of the Brain; Behavior assessment; Behavioral Mechanisms; Brain; Brain imaging; Buprenorphine; Classification; Clinical; Cognition; Cognitive; Complement; Drug Metabolic Detoxication; Emotions; Evaluation; Face; Failure; Functional Magnetic Resonance Imaging; Inferior; Inferior frontal gyrus; Injectable; Injection of therapeutic agent; Injections; Insula of Reil; Investigation; Logistic Regressions; Measures; Medial; Methadone; Modeling; Monitor; Motivation; Naltrexone; Neurocognitive; Opioid; Opioid Antagonist; Opioid Receptor; Opioid agonist; Oral; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacotherapy; Phase; Phenotype; Prefrontal Cortex; Preparation; Property; Randomized; Relapse; Rest; Sampling; Signal Transduction; Stimulus; System; Task Performances; Testing; Toxicology; Treatment Failure; Treatment outcome; Urine; Ventral Striatum; antagonist; brain behavior; cue reactivity; disorder later incidence prevention; emotion regulation; executive function; frontal lobe; improved; incentive salience; individual variation; innovation; insight; medication-assisted treatment; model building; neuroimaging; neuromechanism; next generation; novel; opioid overdose; opioid use disorder; personalized medicine; relating to nervous system; response; theories; treatment duration; treatment effect; treatment group; treatment response

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.

预防复发是阿片类药物使用障碍（OUD）治疗中最大的挑战。我们 提议通过研究OUD的影响来阐明对OUD的反应机制 神经认知领域的药物疗法有助于缓解。我们将使用 先前已验证的神经认知问题，功能磁共振成像（fMRI）， 和新型的延长释放的注射剂（Brixadi®）的阿片类药物部分激动剂 OUD患者的丁丙诺啡（XRBUP）和批准的拮抗剂纳曲酮（XRNTX）。 使用两种具有相反阿片受体动作的药物将允许全面 评估OUD救济预防药物的响应机制。 R61 阶段（AIM 1）将在执行功能领域中寻找治疗效果，激励 显着性和情感调节以及将表明差异的相互作用 两种药物。至少两个域的差异，其效果大小至少很小 （Cohen的D> 0.2）将成为前进到R33阶段的里程碑（AIM 2）。 R33 阶段将测试在R61阶段检查的相互作用的重要性以及 大脑信号解释继电器由阿片类药物阳性尿液测试的百分比定义并遵守 研究治疗。参与者将是寻求治疗的Oud患者 每月XRNTX或XRBUP注射约100天的治疗和 进行每周的尿液毒理学监测。在R61阶段，40个寻求治疗的Oud 完成排毒的患者将随机分配到XRNTX或XRBUP。如果是 达到了里程碑，R33阶段将随机分配160名参与者。逻辑回归将是 用于测试大脑信号在建模中继电器漏洞中的解释值，识别 区分治疗组的变量，测试综合大脑综合的剥夺价值 救济脆弱性的行为模型，确定可变加载之间的差异 治疗组，并探索治疗中个体变异性的潜在机制 结果。该提案将是对认知的第一个神经系统级别的调查 丁丙诺啡和纳曲酮的下一代延长释放准备的影响 解释OUD治疗反应和失败的个体异质性。这个项目可以 通过阐明大脑机制来推进OUD的理论和个性化处理 一般来说，OUD和SUD的易受救济。