Opiate-Induced Tolerance & Hyperalgesia in Pain Patients

描述（由申请人提供）： 本研究提案描述了一个5年计划，以发展以患者为导向的临床疼痛研究的学术生涯。该职业发展计划的目标是通过疼痛，临床药理学和流行病学研究方面的指导培训来扩展申请人的科学技能，以便成为一名成功的独立资助的临床科学家。 饰演角色：Larry F Chu博士是斯坦福大学医学院麻醉系的助理教授（任命待定）。他的短期职业目标是通过密切的研究指导和临床流行病学的正式培训，获得临床疼痛研究的原则和实践方面的额外培训。他的长期职业目标是开发一个以患者为导向的研究计划，重点是表征与慢性疼痛的药物治疗相关的神经可塑性变化。研究环境：朱博士将由帕洛阿尔托VA疼痛服务中心助理教授兼主任大卫克拉克博士指导，他将提供临床疼痛管理和疼痛研究技术方面的专业知识。为了加强培训，Steven Shafer博士将提供临床药理学原理方面的专业知识。Shafer博士是国际公认的临床药理学研究者，在培养博士后研究员和指导初级临床科学家方面有着悠久而富有成效的历史。通过完成斯坦福大学的K30临床研究培训计划，将提供临床研究原则方面的正式教学培训。朱博士已被接受进入45个单位的计划，这将是两年多完成，并在临床流行病学硕士学位的结果。此外，一个由有成就的科学家和临床研究人员组成的跨学科咨询委员会将提供额外的科学和职业指导。 研究计划：申请人的研究将集中在表征与慢性疼痛患者的慢性阿片类药物治疗相关的神经可塑性变化。吗啡等阿片类药物是治疗中度至重度疼痛的基础药物。最近的证据表明，长期阿片类药物治疗的疼痛患者随着时间的推移对疼痛（痛觉过敏）变得更加敏感。还有一个长期存在的概念，即对阿片类药物的镇痛耐受性（习惯化）在长期使用过程中发展，尽管这种现象从未进行过前瞻性研究。我们的具体目标是前瞻性地测试假设，1）接受长期阿片类药物治疗的疼痛患者随着时间的推移对这些药物产生剂量依赖性耐受性和/或痛觉过敏，2）阿片类药物诱导的耐受性和痛觉过敏相对于各种类型的疼痛不同地产生，3）阿片类药物诱导的痛觉过敏独立于戒断现象发生，和4）阿片样物质诱导的耐受性和痛觉过敏基于性别和/或种族而不同地发展。这项拟议的研究将是疼痛患者耐受性和痛觉过敏的第一个定量和前瞻性研究，并将对阿片类药物治疗慢性疼痛的合理使用产生重要影响。

DESCRIPTION (provided by applicant): This research proposal describes a 5-year plan for the development of an academic career in patient-oriented clinical pain research. The goal of this career development proposal is to expand the applicant' s scientific skills through mentored training in pain, clinical pharmacology, and epidemiologic research in order to become a successful independently-funded clinical scientist. The Candidate: Larry F. Chu, MD, MS is an Assistant Professor (appointment pending) in the Department of Anesthesia at the Stanford University School of Medicine. His short-term career goal is to obtain additional training in the principles and practice of clinical pain research through close research mentorship and formal training in clinical epidemiology. His long-term career goal is to develop a patient-oriented research program that focuses on characterizing neuroplastic changes associated with the pharmacologic treatment of chronic pain. Research Environment: Dr. Chu will be mentored by Dr. David Clark, Assistant Professor and Chief of the Palo Alto VA Pain Service, who will provide expertise in clinical pain management and pain research techniques. To enhance the training, Dr. Steven Shafer will provide expertise in the principles of clinical pharmacology. Dr. Shafer is an internationally-recognized investigator in clinical pharmacology who has a long and productive history of training postdoctoral fellows and mentoring junior clinical scientists. Formal didactic training in the principles of clinical research will be provided through completion of Stanford's K30 Clinical Research Training Program. Dr. Chu has been accepted into the 45-unit program, which will be completed over two years and result in a Master's Degree in Clinical Epidemiology. In addition, an interdisciplinary advisory committee of accomplished scientists and clinical researchers will provide additional scientific and career guidance. Research Plan: The applicant's research will focus on characterizing neuroplastic changes associated with chronic opioid therapy in patients with chronic pain. Opiates such as morphine are the cornerstone medications for the treatment of moderate to severe pain. Recent evidence suggests that pain patients on chronic opioid therapy become more sensitive to pain (hyperalgesia) over time. There is also a long-standing notion that analgesic tolerance to opioids (habituation) develops during chronic use even though this phenomenon has never been prospectively studied. Our specific aims propose to prospectively test the hypotheses that; 1) Pain patients on chronic opioid therapy develop dose-dependent tolerance and/or hyperalgesia to these medications over time, 2) Opioid-induced tolerance and hyperalgesia develop differently with respect to various types of pain, 3) Opioid-induced hyperalgesia occurs independently of withdrawal phenomena, and 4) Opioid-induced tolerance and hyperalgesia develop differently based on gender and/or ethnicity. This proposed study will be the first quantitative and prospective study of tolerance and hyperalgesia in pain patients and will have important implications for the rational use of opioids in the treatment of chronic pain.