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这些人的主要死亡原因 50岁以下，2017年有超过4.7万美国人死于阿片类药物过量。截至12月 2018年，费城的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%。 阿片使用障碍的药物辅助治疗(MAT)--是否完全使用阿片激动剂 (美沙酮)、部分阿片激动剂(丁丙诺啡)或完全拮抗剂(纳曲酮)-对 减少阿片类药物的使用，防止过量死亡。不幸的是，遵守这些生活- 节约药物往往很差，辅助使用非阿片类药物(特别是可卡因)是一种 共同罪魁祸首。在费城，几乎一半的阿片类药物过量死亡中都发现了可卡因。 确定可减少可卡因和其他非法药物使用的有前景的辅助药物 在MAT期间，可以提高遵从性，每年拯救数千人的生命。进一步，测量 这些药物如何与预定的大脑靶点“接触”将加速合理的药物治疗 发展。为了实现这两个目标，我们建立了一个临床实验室， 神经科学(CLIN)，用于评估治疗物质使用障碍的药物 宾夕法尼亚州成瘾研究中心。 在UG1的初步演示项目中，我们将测试多巴胺D3的前景- 用于(目标1)初步试验的首选药物，卡里拉津(Vraylar，每天1.5毫克)与安慰剂(两者均为 临床疗效(减少非法药物使用，提高对挽救生命的丁丙诺啡的依从性)， 和(目标2)用于靶向参与(例如，阿片类药物和可卡因线索激活边缘)，在患者中 在8周的门诊试验中，同时患有阿片类药物使用障碍(OUD)和可卡因使用障碍(CocUD)。 最近，宾夕法尼亚大学和弗吉尼亚大学的UG1实验室拨款与NIDA合作， 建议筛选一种通过数据挖掘确定的药物，奥氮平，用于临床疗效 (主要目标：减少非法阿片类药物的使用)两个地点(每个地点24个)为期8周的观察性试验 用于丁丙诺啡稳定的有严重精神疾病(SMI)症状的患者。 次级目标是减少其他非法药物的使用和改善睡眠；探索性的 目标包括提高垫子的坚持性、学习的保持性以及思想和情绪 精神障碍症状。最初的示范项目(卡里普秦)和奥氮平 参与者还将收到一组表型探针(例如，用于奖励/抑制； 神经认知)，以捕捉复发的脆弱性，并可能在药物反应中的异质性。

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 have established 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. In the initial demonstration project for the UG1, we will test the promise of a dopamine D3- preferring agent, cariprazine (Vraylar, 1.5 mg daily), vs. placebo both for (Aim 1) preliminary clinical efficacy (reduced illicit drug use, and improved adherence to life-saving buprenorphine), and (Aim 2) for target engagement (e.g., limbic activation by opioid and cocaine cues), in patients with both opioid use disorder (OUD) and cocaine use disorder (CocUD), in an 8 week outpatient trial. Recently, the UG1 Laboratory grants at UPenn and VCU have, in collaboration with NIDA, proposed to screen a medication identified by data-mining, olanzapine, for clinical efficacy (Primary Aim: reduction in illicit opioid use) in a two-site (n=24 per site), 8-week observational trial for buprenorphine-stabilized OUD patients with symptoms of Serious Mental Illness (SMI). Secondary Aims feature reduction in other illicit drug use and improvement in sleep; Exploratory Aims include improvements in MAT adherence, in study retention, and in thought and mood disorder symptoms. Both the initial demonstration project (cariprazine) and the olanzapine participants will also receive a battery of phenotypic probes (e.g., for reward/inhibition; neurocognition) to capture relapse vulnerability, and likely heterogeneity in medication response.