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

综合神经科学 (CLIN) 临床实验室，用于药物滥用障碍药物的早期评估

• 批准号: 10395761
• 负责人: Anna Rose Childress
• 金额: $ 16.54万
• 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: 2021-07-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395761
• 关键词: Adherence; Adjuvant Analgesic; Administrative Supplement; Age; Alcohols; Ambulatory Care; American; Automobile Driving; Baltimore; Behavioral; Brain; Brain imaging; Buprenorphine; Cannabis; Cause of Death; Clinic; Clinical; Clinical Treatment; Clinical Trials; Cocaine; Collaborations; Country; Cues; Data Analyses; Development; Disease; Dopamine; Dose; Drug Screening; Drug usage; Enrollment; Ethanol; Evaluation; Fentanyl; Goals; Grant; Heterogeneity; Human; Image; Individual; Laboratories; Life; Literature; Measures; Medical; Methadone; Mood Disorders; Naltrexone; National Institute of Drug Abuse; Neurocognition; Neurosciences; Nicotine; Observational Study; Opioid; Opioid agonist; Outcome; Outpatients; Parents; Participant; Patients; Pennsylvania; Pharmaceutical Preparations; Phase; Phenotype; Philadelphia; Pittsburgh Sleep Quality Index; Placebos; Population; Randomized; Relapse; Research; Research Personnel; Resources; Rewards; Role; Savings; Site; Sleep; Specific qualifier value; Speed; Subgroup; Suboxone; Substance Use Disorder; Symptoms; Testing; Therapeutic; Universities; Urine; Withdrawal Symptom; Work; addiction; clinical efficacy; cocaine use; craving; data mining; diaries; experience; illicit drug use; illicit opioid; imaging probe; improved; improvement on sleep; indexing; medication compliance; medication-assisted treatment; mortality; neuroimaging; non-opioid analgesic; olanzapine; opioid epidemic; opioid mortality; opioid overdose; opioid use; opioid use disorder; overdose death; phase 2 study; prevent; recruit; response; screening; severe mental illness; synthetic opioid; treatment adherence; treatment site; week trial

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.

芬太尼（高效力合成阿片类药物）驾驶国家的严峻阿片类药物危机激增 空前的死亡率。药物过量死亡现在是那些人的主要死亡原因 50岁以下，2017年有超过47,000名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是该国的第三高（仅排名） 匹兹堡和巴尔的摩）。费城致命的阿片类药物过量的84％存在于芬太尼。 药物辅助治疗（MAT）用于卵类药物使用障碍 - 是否全蛋白激动剂 （美沙酮），部分阿片类药物激动剂（丁丙诺啡）或完整的拮抗剂（Naltrexone） - 对于 减少阿片类药物的使用，并防止过量死亡。不幸的是，遵守这些生活 - 保存药物通常很差，辅助使用非阿片类药物（尤其是可卡因）作为 常见的罪魁祸首。在费城几乎一半的阿片类药物过量死亡中发现了可卡因。 确定有希望减少可卡因和其他非法药物使用的有希望的辅助药物 在垫子中可以提高依从性并挽救数千人的生命。此外，测量 这些药物如何“参与”预期的大脑靶标将加快理性药物 发展。达到这两个目标，我们已经建立了一个综合的临床实验室 神经科学（CLIN）用于评估大学药物使用障碍的药物 宾夕法尼亚成瘾研究中心。 在UG1的最初演示项目中，我们将测试多巴胺D3-的承诺 优先特工仙兰津（Vraylar，每天1.5毫克），与安慰剂相比（AIM 1）初步 临床效率（降低非法药物使用，并提高遵守挽救生命的丁丙诺啡）， （目标2）用于目标参与（例如，阿片类药物和可卡因提示的边缘激活），患者 在8周的门诊试验中，与阿片类药物使用障碍（OUD）和可卡因使用障碍（Cocud）一起使用。 最近，UPenn和VCU的UG1实验室赠款与NIDA合作 提议筛选通过数据挖掘的奥氮平鉴定的药物，以提高临床效率 （主要目的：减少非法阿片类药物的使用）在两个站点（每个站点n = 24），8周观察试验中 丁丙诺啡稳定的OUD患者患有严重精神疾病症状（SMI）。 次要目的降低了其他非法药物使用和睡眠改善；探索性 目的包括改善垫子依从性，研究保留以及思想和情绪 疾病症状。最初的示范项目（Cariprazine）和Olanzapine 参与者还将收到一系列表型问题（例如，奖励/抑制； 神经认知）以捕获药物反应中的救济脆弱性和可能的​​异质性。