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Reverse Translation of Patient Controlled Analgesia: a New Measure of Rodent Pain

患者自控镇痛的逆向翻译：啮齿类动物疼痛的新测量方法

基本信息

批准号：
8850923
负责人：
Joseph Paul Garner
金额：
$ 20.17万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850923
关键词：
3D Print Absence of pain sensation Acute Pain Adult Adverse effects Affect American Analgesics Animals Arthritis Awareness Basic Science Behavior Behavioral Paradigm Biological Biological Assay Caring Chronic Clinic Clinical Computer software Cues Data Disease Dose Drug Costs Electronics Emotional Environment Equipment Esthesia Failure Feeling suicidal Flare Goals Healed Health Home environment Homologous Gene Hospitals House mice Human Ibuprofen Individual Injury Intractable Pain Invaded Language Left Life Light Marketing Measures Meniscus structure of joint Methods Modeling Monitor Mus Neuropathy Nipples Nociception Opiates Outcome Pain Pain management Patient-Controlled Analgesia Patients Pharmaceutical Preparations Physiology Population Problem Solving Public Health Recovery Reflex action Reporting Research Personnel Resort Risk Rodent Rodent Model Self Administration Severities Signal Transduction Societies Solutions Specificity Stimulus Suicide attempt Symptoms Tail Techniques Technology Testing Time Toxic effect Translating Translations Ursidae Family Water Work behavior measurement chronic pain cost design drinking drug development drug discovery emotional experience experience feeding gabapentin healing killings mouse model new technology novel strategies open source painful neuropathy patient safety pressure prevent receptor research study response success trend unprofitable drug development

项目摘要

DESCRIPTION (provided by applicant): Approximately 30% of American adults suffer some kind of chronic pain. This profound public health issue is compounded by the serious side effects and abuse potential of the opiate painkillers (analgesics) used to help manage chronic pain. Thus new kinds of analgesics are desperately needed. Recently, an entire new class of analgesics (NK1-receptor antagonists) turned out to be ineffective in humans despite widespread success in rodents. These failures are part of a wider trend - FDA data shows that 85% of analgesics fail in human trials, while the average failure rate of all new drugs is roughly 89%. Few of these failures are due to side effects or toxicity. Instead in about 80% of cases, they simply don't work. These failures represent roughly 75% of the cost of drug development, creating financial pressures that drive widespread negative impacts on society (including the cost of drugs, and the lack of drug development for unprofitable diseases or populations). Recent failed analgesics ('pain killers') provide useful lessons for solving this broader problem. Every drug that fails in human trials appeared to work in animals - simply put; analgesic drug discovery in animals is very prone to false positives. One reason for this is that the measures of pain in mice which are used to discover new analgesics bear little correspondence to human clinical symptoms. For instance in mice we measure the suppression of reflex responses rather than the suppression of the sensation of pain itself; but in humans, we want to find drugs that blunt the sensation of pain and leave essential injury-preventing reflexes intact. Thus, in mice we are actually measuring exactly the wrong things if we want to discover a useful analgesic in humans. To solve this problem we ideally need to ask a mouse to rate the severity and type of pain it is experiencing in exactly the same way that we ask humans in a hospital recovery suite, but without the benefit of language. In fact, we already covertly monitor a human patient's pain in a way that is easily converted for use in mice - by giving the patient control over their own analgesia, and observing their self-dosing behavior. In humans this technique is called 'Patient Controlled Analgesia'. Animals can also selectively consume analgesics to control pain - a phenomenon called 'Analgesic Self Administration'. However, current Analgesic Self Administration techniques in animals are crude and poorly suited to drug discovery and translation. Therefore, this project will refine these techniques to develop a mouse equivalent of Patient Controlled Analgesia, so that pain in mice can be measured in the same way it is in humans. We will develop equipment that allows the use of this technique in the home cage of group-housed mice. We will test whether it can ask mice to report the severity and type of pain they are in, and whether it would have correctly identified as failures the very drugs which recently failed in humans. The resulting technology will be made publically available as open source software and 3D printing files, so that any researcher can build this new equipment. The impacts will be profound: for researchers we will deliver a translational predictive measure of pain in the mouse; and for patients this will mean the faster delivery of more effective and cheaper drugs.

描述（由申请人提供）：大约30%的美国成年人患有某种慢性疼痛。这一深刻的公共卫生问题由于用于帮助管理慢性疼痛的阿片类止痛药（镇痛药）的严重副作用和滥用潜力而变得更加复杂。因此，迫切需要新的止痛药。最近，一种全新的镇痛药（NK 1受体拮抗剂）被证明对人类无效，尽管在啮齿动物中取得了广泛的成功。这些失败是更广泛趋势的一部分- FDA数据显示，85%的镇痛药在人体试验中失败，而所有新药的平均失败率约为89%。这些失败很少是由于副作用或毒性。相反，在大约80%的情况下，它们根本不起作用。这些失败约占药物开发成本的75%，造成的财务压力对社会产生了广泛的负面影响（包括药物成本，以及缺乏针对无利可图疾病或人群的药物开发）。最近失败的止痛药（“止痛药”）为解决这个更广泛的问题提供了有用的教训。每一种在人体试验中失败的药物似乎都在动物身上起作用--简单地说，在动物身上发现止痛药很容易出现假阳性。其中一个原因是，用于发现新镇痛药的小鼠疼痛测量与人类临床症状几乎没有对应性。例如，在小鼠中，我们测量的是反射反应的抑制，而不是疼痛感觉本身的抑制;但在人类中，我们希望找到减弱疼痛感觉的药物，并保持基本的损伤预防反射完好无损。因此，如果我们想在人类身上发现一种有用的止痛药，我们实际上在老鼠身上测量的是错误的东西。为了解决这个问题，我们需要让一只老鼠评估它所经历的疼痛的严重程度和类型，就像我们在医院康复室里问人类一样，但没有语言的好处。事实上，我们已经秘密地监测了人类患者的疼痛，这种方式很容易转换为用于小鼠-通过让患者控制自己的镇痛，并观察他们的自我给药行为。在人类中，这种技术被称为“病人自控镇痛”。动物也可以选择性地服用止痛药来控制疼痛-这种现象称为“自我止痛”。然而，目前的动物镇痛自我管理技术是粗糙的，不适合药物的发现和翻译。因此，本项目将完善这些技术，以开发一种相当于病人自控镇痛，这样老鼠的疼痛就可以像人类一样测量。我们将开发设备，允许使用这种技术在家庭笼组圈养小鼠。我们将测试它是否能要求小鼠报告它们所处的疼痛的严重程度和类型，以及它是否能正确地将最近在人类身上失败的药物识别为失败。由此产生的技术将以开源软件和3D打印文件的形式提供，以便任何研究人员都可以构建这种新设备。影响将是深远的：对研究人员来说，我们将提供一种小鼠疼痛的翻译预测方法;对患者来说，这将意味着更快地提供更有效、更便宜的药物。