Pre-clinical assessments of dose-sparing and anti-addictive adjuvants to prevent the future abuse of opioid analgesics

对节省剂量和抗成瘾佐剂进行临床前评估，以防止未来阿片类镇痛药的滥用

基本信息

批准号：
10269894
负责人：
Allison White
金额：
$ 5.4万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2023-01-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269894
关键词：
Acoustics Acute Acute Pain Adjuvant American Analgesics Anxiety Behavior Behavioral Assay Biological Assay Clinic Clinical Clinical Trials Data Doctor of Philosophy Dose Drug Combinations Drug Targeting Drug abuse Epidemic Equilibrium Ethers Euphoria Exhibits Future GTP-Binding Proteins Goals Human Hydrocodone Hydromorphone Japan Lead Locomotion Measures Mental Depression Morphine Motor Mouse Strains Mus National Institute of Drug Abuse Nociception Opioid Analgesics Opioid agonist Oxycodone Pain Pathway interactions Persons Pharmaceutical Preparations Pilot Projects Population Preclinical Testing Property Pruritus Psychoses Publishing Rattus Receptor Signaling Recording of previous events Reporting Research Research Project Grants Rewards Safety Signal Pathway Signal Transduction Sucrose Tail Testing Therapeutic Therapeutic Effect Treatment Efficacy Validation Withdrawal addiction base clinically relevant conditioned place preference drug abuse prevention drug induced behavior dysphoria economic cost feeding health economics heroin use in vivo interest kappa opioid receptors mu opioid receptors novel opioid abuse opioid overdose opioid use opioid use disorder pre-clinical pre-clinical assessment preference prepulse inhibition prescription opioid preservation prevent public health relevance research clinical testing salvinorin A side effect socioeconomics

项目摘要

Project Abstract Treating acute pain with highly addictive mu opioid receptor (MOR)-targeting analgesic drugs, such as oxycodone, hydrocodone, and hydromorphone, has contributed greatly to the present American opioid overdose epidemic, owing to the inherent euphoria-inducing (“rewarding”) effects of these opioid analgesic drugs. Compounds that activate the kappa opioid receptor (KOR), when co-administered with MOR-targeting opioid analgesic drugs, can not only reduce these rewarding properties, but can also enhance of their painkilling properties. However, conventional (“unbiased”) KOR activators have failed in the clinic due to poor tolerance. Many of the negative side effects that follow the use of unbiased KOR agonists are thought to be associated with engaging G protein-independent signaling pathways. It has therefore been proposed that newer G protein- biased KOR agonists might retain their therapeutic benefits without creating negative side effects by reducing the extent to which they signal through these G protein-independent pathways. My long-term goal is therefore to provide an appropriate level of pre-clinical validation to support future clinical trials of the G protein-biased KOR agonist nalfurafine as an anti-addictive / dose-sparing adjuvant to be administered alongside MOR-targeting opioid analgesic drugs. Nalfurafine is an immediately tangible adjuvant candidate given its current use in Japan for uremic pruritus and its decade-long history of safety and tolerability. In this way, successful pre-clinical testing of the use of nalfurafine as an adjuvant will materially advance a novel (and quickly tractable) strategy to reduce the addictive liability of treating acute pain with conventional opioid analgesic drugs. In the short-term, I will perform key mouse-based effect, side effect, and in vivo signaling studies, pairing nalfurafine with the clinically relevant MOR-targeting analgesic drugs morphine, oxycodone, hydrocodone, and hydromorphone, to support this long-term goal. Aim 1 is to determine, via mouse behavioral assays, the therapeutic efficacy of nalfurafine as an adjuvant that reduces the addictive potential of MOR-targeting analgesic drugs without compromising their anti-nociceptive effects. Aim 2 is to determine the anti-therapeutic liabilities associated with co-administration of nalfurafine with MOR-targeting opioid analgesic drugs via mouse behavioral assays that inform on known side effects of unbiased KOR agonists (namely dysphoria, depression, anxiety, and psychotomimesis). Pre-clinical evidence establishing nalfurafine as an addiction-reducing additive to opioid analgesic drugs should lead to future human trials of such a drug combination in acute pain indications. In this way, my proposal is responsive to NIDA’s Notice of Special Interest NOT-19-048 “Research to Prevent Drug Use, Misuse and Addiction”.

项目摘要使用高度成瘾的 mu 阿片受体 (MOR) 靶向镇痛药物治疗急性疼痛，例如羟考酮、氢可酮和氢吗啡酮，在很大程度上导致了美国目前阿片类药物的过量使用流行病，归因于这些阿片类镇痛药物固有的欣快感（“奖励”）作用。与 MOR 靶向阿片类药物联合给药时，可激活 kappa 阿片受体 (KOR) 的化合物镇痛药不仅可以减少这些有益特性，还可以增强其止痛作用然而，传统的（“无偏见的”）KOR 激活剂由于耐受性差而在临床上失败。使用无偏 KOR 激动剂后产生的许多负面副作用被认为与因此，有人提出，新的 G 蛋白- 偏向的 KOR 激动剂可能会通过减少因此，我的长期目标是通过这些不依赖于 G 蛋白的途径发出信号。提供适当水平的临床前验证，以支持 G 蛋白偏向的 KOR 的未来临床试验激动剂纳芙拉芬作为抗成瘾/剂量节省佐剂，与 MOR 靶向药物一起给药鉴于目前在日本的使用，阿片类镇痛药纳芙拉芬是一种立即可行的辅助候选药物。针对尿毒症瘙痒症及其长达十年的安全性和耐受性历史，成功地进行了临床前测试。使用纳芙拉芬作为佐剂将实质性地推进一种新颖的（且易于处理的）策略来减少使用传统阿片类镇痛药治疗急性疼痛的成瘾倾向在短期内，我会。进行基于小鼠的关键效应、副作用和体内信号传导研究，将纳芙拉芬与临床药物配对相关的 MOR 靶向镇痛药物吗啡、羟考酮、氢可酮和氢吗啡酮，以支持该长期目标 1 是通过小鼠行为测定确定纳芙拉芬的治疗效果。作为佐剂可降低 MOR 靶向镇痛药物的成瘾潜力，同时又不影响其作用目标 2 是确定与联合用药相关的抗治疗责任。纳芙拉芬与 MOR 靶向阿片类镇痛药物通过小鼠行为测定得出已知的信息无偏 KOR 激动剂的影响（即烦躁、抑郁、焦虑和临床前拟精神病）。有证据表明纳芙拉芬是阿片类镇痛药的一种减少成瘾的添加剂，这应该会导致未来对这种药物组合治疗急性疼痛适应症的人体试验这样，我的建议是有效的。 NIDA 的特别关注通知 NOT-19-048“预防药物使用、误用和成瘾的研究”。