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: 9895139
• 负责人: Anna Rose Childress
• 金额: $ 52.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9895139
• 关键词: Adherence; Adjuvant Analgesic; Affective; Affinity; Age; Agonist; Alcohols; American; Amygdaloid structure; Attention; Automobile Driving; Baltimore; Behavioral; Brain; Brain imaging; Buprenorphine; Cannabidiol; Cannabis; Cause of Death; Clinical; Clinical Treatment; Clinical Trials; Cocaine; Country; Cues; Data; Development; Dopamine; Evaluation; Fentanyl; Genetic Polymorphism; Globus Pallidus; Goals; Human; Image; Injectable; Injections; Inpatients; Knowledge; Laboratories; Life; Measures; Medial; Methadone; Motivation; Naltrexone; Neurosciences; Nicotine; Opioid; Opioid Receptor; Opioid agonist; Outcome Measure; Outpatients; Patients; Pennsylvania; Pharmaceutical Preparations; Philadelphia; Placebos; Positron-Emission Tomography; Randomized; Relapse; Research; Research Personnel; Resources; Rewards; Risk-Taking; Savings; Signal Transduction; Speed; Subgroup; Substance Use Disorder; Testing; Tracer; Universities; Urine; Ventral Striatum; Ventral Tegmental Area; Withdrawal Symptom; Work; addiction; base; behavioral response; clinical efficacy; cocaine use; drug craving; experience; gamma-Aminobutyric Acid; hypocretin; illicit drug use; imaging probe; improved; innovation; medication compliance; medication-assisted treatment; mortality; neuroimaging; non-opioid analgesic; novel; opioid epidemic; opioid mortality; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; overdose death; pre-clinical; prescription opioid; prevent; primary endpoint; receptor; recruit; response; secondary endpoint; synthetic opioid; tool; treatment site

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.

国家严峻的阿片类药物危机激增，芬太尼（高效合成阿片类药物） 空前的死亡率。药物过量死亡现在是那些未成年人死亡的主要原因 50，2017年有超过47，000名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）。 费城84%的致命阿片类药物过量病例中含有芬太尼。药物辅助治疗（MAT） 对于阿片类药物使用障碍-无论是完全阿片类药物激动剂（美沙酮），部分阿片类药物激动剂（丁丙诺啡），或 完全拮抗剂（纳洛酮）-对于减少阿片类药物的使用和预防过量死亡至关重要。 不幸的是，这些救命药物的依从性往往很差，辅助使用非阿片类药物 （特别是可卡因）作为一个共同的罪魁祸首。可卡因被发现在近一半的阿片类药物过量死亡， 费城 确定减少MAT期间可卡因和其他非法药物使用的有希望的替代药物 可以提高依从性，每年挽救数千人的生命。此外，测量这些药物 “参与”预期的大脑目标将加速合理的药物开发。为了实现这两个目标，我们 将凝聚重要的当地成瘾资源和研究力量（例如，在临床试验和人类 神经影像学），以建立一个临床实验室与综合神经科学（CLIN）的评价 宾夕法尼亚大学成瘾研究中心的物质使用障碍药物。的 UG 1的初始2年示范项目将测试卡利拉嗪（一种候选抗复发药物）的前景 具有高D3亲和性的药物，既用于初步临床疗效（减少非法药物使用， 坚持使用救命的纳洛酮），以及用于目标接合（例如，药物线索触发的边缘系统钝化 激活）在阿片类药物使用障碍的患者中。该项目将招募阿片类药物脱毒患者（最多n=75） 在10个临床治疗点的近端网络内。合格患者将随机分配（2：1比例）至 卡利拉嗪（Vraylar，1.5 mg/天）与安慰剂，所有患者将接受长达3个月的缓释注射 注射纳洛酮（Vivitrol，380 mg）在12周的门诊试验（早期疗效）。影像学的一个亚组- 符合条件的患者还将接受住院目标参与措施（脑成像探头奖励， 在开始门诊试验之前进行抑制。我们还将研究（探索性目标）的影响， 假设驱动的遗传多态性（例如，rs6280用于DA D3受体）对脑和临床 对D3药物的反应。总结：经验丰富的CLIN团队，创新的大脑工具， D3药物的新测试，以提高对纳洛酮的依从性，是最初研究的明显优势。 这将是一个示范项目，并增加提供新知识和拯救生命的可能性。出去- 多年来CLIN的优势包括新候选药物的前景（例如，GABA B PAM，食欲素 拮抗剂，大麻二酚）和新的高选择性PET示踪剂，用于测量阿片受体和药物 占用率