A Clinical Laboratory with Integrated Neuroscience (CLIN) for Early Evaluation of Medications for Substance Use Disorders

美国严峻的阿片类药物危机仍在继续，芬太尼(高效合成阿片类药物)推动着 前所未有的死亡率。药物过量死亡现在是未成年人死亡的主要原因。 50人，2017年有超过4.7万美国人死于阿片类药物过量。截至2018年12月，费城 阿片类药物过量死亡率在全国排名第三(仅次于匹兹堡和巴尔的摩)。 在费城致命的阿片类药物过量中，芬太尼占84%。药物辅助治疗(MAT) 用于阿片使用障碍--无论是全阿片激动剂(美沙酮)、部分阿片激动剂(丁丙诺啡)，还是 完全拮抗剂(纳曲酮)-对于减少阿片类药物的使用和防止过量死亡至关重要。 不幸的是，这些救命药物的依从性往往很差，辅以非阿片类药物的使用。 (尤其是可卡因)是常见的罪魁祸首。年，几乎一半的阿片类药物过量死亡中发现了可卡因。 费城。 确定有前景的辅助药物，以减少在MAT期间可卡因和其他非法药物的使用 可以提高遵从性，每年拯救数千人的生命。此外，测量这些药物如何 “参与”预定的大脑靶点将加速合理的药物开发。为了实现这两个目标，我们 将结合当地重要的成瘾资源和研究优势(例如，在临床试验和人类 神经成像)建立综合神经科学(CLIN)临床实验室，用于评估 宾夕法尼亚大学成瘾研究中心的药物使用障碍。这个 UG1中最初为期两年的示范项目将测试候选抗复发药物卡里拉津的前景 具有高D3亲和力的药物，既有初步的临床疗效(减少非法药物使用，又有改善 坚持救命的纳曲酮)，以及靶向接触(例如，钝化药物线索触发的边缘 在阿片类药物使用障碍患者中)。该项目将招募戒毒的阿片类药物患者(最多75人)。 在一个由10个临床治疗地点组成的近端网络中。符合条件的患者将被随机分配(2：1比例)到 卡里普津(呋喃西林，每天1.5毫克)与安慰剂相比，所有人每月都将接受最多3次缓释注射 在12周的门诊试验中注射纳曲酮(Vivitrol，380 mg)(早期疗效)。成像的一个子群- 符合条件的患者还将接受住院目标参与措施(奖励和 抑制)，在开始门诊试验之前。我们还将检查(探索性目标)的影响 大脑和临床上假说驱动的遗传多态(例如，DA D3受体的rs6280) 对D3药物的反应。摘要：经验丰富的CLIN团队、创新的大脑工具和 对一种D3药物进行了新的测试，以改善对纳曲酮的依从性，这是最初的明显优势 示范项目，并增加它既提供新知识又拯救生命的可能性。出局- 多年的CLIN优势包括新候选药物的前景(例如，GABA B PAM、增食欲素 拮抗剂)和用于测量阿片受体和药物的新型高选择性PET示踪剂 入住率。

The nation’s grim opioid crisis surges on, with the fentanyls (high potency synthetic opioids) driving unprecedented mortality rates. Drug overdose deaths are now the leading cause of death in those under age 50, with more than 47,000 Americans dying of opioid overdose in 2017. As of December 2018, Philadelphia had the third highest rate of opioid overdose deaths in the country (out-ranked only by Pittsburgh and Baltimore). Fentanyl is present in 84% of the fatal opioid overdoses in Philadelphia. Medication-assisted treatment (MAT) for opioid use disorders – whether full opioid agonist (methadone), partial opioid agonist (buprenorphine), or a full antagonist (naltrexone) – is critical for reducing opioid use, and for preventing overdose deaths. Unfortunately, compliance with these life-saving medications is often poor, with ancillary use of non-opioid drugs (especially cocaine) as a common culprit. Cocaine is found in almost half of the opioid overdose deaths in Philadelphia. Identifying promising adjunctive medications that reduce cocaine and other illicit drug use during MAT could improve adherence and save thousands of lives each year. Further, measuring how these medications “engage” the intended brain targets will speed rational medication development. Toward both these goals, we will cohere significant local addiction resources and research strengths (e.g., in clinical trials and human neuroimaging) to establish a Clinical Laboratory with Integrated Neuroscience (CLIN) for Evaluation of Medications for Substance Use Disorders at the University of Pennsylvania Center for Studies of Addiction. The initial 2-year demonstration project in the UG1 will test the promise of cariprazine, a candidate anti-relapse medication with high D3-affinity, both for preliminary clinical efficacy (reduced illicit drug use, and improved adherence to life-saving naltrexone), and for target engagement (e.g., blunting of drug cue-triggered limbic activation) in patients with opioid use disorders. The project will recruit detoxified opioid patients (up to n=75) within a proximal network of 10 clinical treatment sites. Eligible patients will be randomly-assigned (2:1 ratio) to cariprazine (Vraylar, 1.5 mg daily) vs. placebo, and all will receive up to 3 monthly injections of extended release injectable naltrexone (Vivitrol, 380 mg) in a 12 week outpatient trial (Early Efficacy). A subgroup of imaging- eligible patients will also receive inpatient Target Engagement measures (brain imaging probes for reward and inhibition) prior to beginning the outpatient trial. We will also examine (Exploratory Aim) the impact of hypothesis- driven genetic polymorphisms (e.g., rs6280 for DA D3 receptor) on both the brain and clinical response to the D3 medication. Summary: The highly experienced CLIN team, innovative brain tools, and the novel testing of a D3 medication to improve adherence to naltrexone, are clear strengths of the initial demonstration project, and increase the likelihood that it will both provide new knowledge and save lives. Out- years CLIN strengths include the promise of new candidate medications (e.g., GABA B PAMs, orexin antagonists, cannabidiol) and new, highly-selective PET tracers for measuring opioid receptors and medication occupancy.