Predicting Post-Operative Pain and Analgesic Use: The Role of Endogenous Opioids

描述(由申请者提供)：该职业发展奖(K23)将为应聘者提供必要的培训，以建立一个与了解关键神经行为风险因素(即，不规则的中枢疼痛处理、睡眠障碍和消极思维)如何影响神经生物学机制(即，内源性阿片类药物功能)的研究计划，从而导致疼痛结果的个体差异。慢性疼痛是一个主要的健康问题，影响着相当一部分美国人，并与巨大的痛苦和经济负担有关。睡眠障碍、情绪和异常的中枢疼痛处理被认为是慢性疼痛和残疾的重要预测因子，并与内源性阿片类药物功能受损间接相关。这项拟议的研究计划将系统地解决通过纳洛酮挑战对内源性阿片类药物功能的手术前直接测试在预测膝关节骨关节炎(OA)患者全膝关节置换(TKA)后疼痛和阿片类止痛剂使用方面的作用。膝关节骨关节炎是最常见的慢性疼痛疾病之一，预计随着美国人口的老龄化，这种情况将急剧增加。K23的具体培训目标包括指导、授课和经验，旨在发展疼痛、阿片类药物阻断和睡眠评估方法的神经生物学专业知识，并在生物统计分析方面奠定坚实的基础。到目前为止，还没有研究探讨异常的中枢疼痛处理、睡眠障碍和情绪与内源性阿片类药物功能受损的关系。因此，拟议的研究计划旨在调查这些危险因素是否具有共同的神经生物学底物，将它们与TKA后的重要临床疼痛结局联系起来，包括TKA后的持续性疼痛和阿片类药物的增加使用。特别是，这项拟议的研究将系统地评估通过纳洛酮挑战直接在手术前测试内源性阿片类药物功能在预测TKA术后疼痛和阿片类药物使用方面的有效性。其他工作将检查内源性阿片功能是否与异常的中枢疼痛处理、睡眠障碍和疼痛相关的对疼痛的负面思维有关。了解风险因素及其影响TKA术后结果的潜在机制，将对选择手术患者、告知术后疼痛管理、改善慢性疼痛患者的健康相关生活质量，以及协助制定旨在减少本提案中研究的风险因素的影响的干预措施具有重要意义。候选人的长期目标是完善疼痛的生物、心理和社会模型，促进术后疼痛治疗干预措施的发展或加强，并防止慢性化。 公共卫生相关性：骨关节炎(OA)影响着2000万美国老年人，随着美国人口老龄化，膝骨性关节炎的患病率预计将大幅增加。疼痛是与退行性关节疾病相关的最常见的症状，中枢疼痛调节系统的异常功能、睡眠障碍和消极思维会加剧疼痛。这项拟议的研究将增加对这些因素影响全膝关节置换(TKA)后疼痛相关结果的机制的理解。这项研究的结果将被用来改变与慢性疼痛发展相关的可改变的危险因素，并开发和改进对术后疼痛的心理社会干预。

DESCRIPTION (provided by applicant): This Career Development Award (K23) will provide the candidate the necessary training to establish a program of research related to understanding how key neurobehavioral risk factors (i.e., irregular central pain processing, sleep disturbance, and negative thinking) impact neurobiological mechanisms (i.e., endogenous opioid function) that contribute to individual differences in pain outcomes. Chronic pain is a major health problem affecting a significant proportion of the American population and is associated with substantial suffering and economic burden. Sleep disturbance, mood, and aberrant central pain processing have been identified as important predictors of chronic pain and disability, and have been indirectly associated with impaired endogenous opioid function. The proposed research plan will systematically address the utility of a direct pre-surgical test of endogenous opioid function via naloxone challenge in predicting pain and opioid analgesic use following total knee arthroplasty (TKA) in patients with knee osteoarthritis (OA), one of the most prevalent chronic pain conditions and predicted to drastically increase as the U.S. population ages. Specific training aims of this K23 include mentorship, didactics, and experiences designed to develop expertise in the neurobiology of pain, opioid blockade and sleep assessment methods as well as develop a solid foundation in biostatistical analyses. No research to date has examined the relationship between abnormal central pain processing, sleep disturbance, and mood with impaired endogenous opioid function. Consequently, the proposed research plan intends to investigate whether these risk factors share a neurobiological substrate that links them to important clinical pain outcomes following TKA, including persistent post-TKA pain, and increased opioid use. In particular, the proposed study will systematically evaluate the effectiveness of a direct pre- surgical test of endogenous opioid function via naloxone challenge in predicting post-operative pain and opioid use following TKA. Additional work will examine whether endogenous opioid function is associated with abnormal central pain processing, sleep disturbance, and pain related negative thinking on pain. Understanding the risk factors and underlying mechanisms whereby they exert their influence on outcomes following TKA, will have important implications for the selection of surgical patients, inform the management of post-operative pain, improve the health-related quality of life of individuals with chronic pain, and assist in the development of interventions designed to reduce the impact of the risk factors studied in this proposal. The candidate's long term goal is to refine biopsychosocial models of pain and facilitate the development or enhancement of therapeutic interventions for post-operative pain and to prevent chronicity. PUBLIC HEALTH RELEVANCE: Osteoarthritis (OA) affects 20 million older Americans and the prevalence of knee OA is projected to dramatically increase as the U.S. population ages. Pain is the most common symptom associated with degenerative joint disease and is aggravated by abnormal functioning of central pain modulatory systems, sleep disturbance, and negative thinking. The proposed study will increase understanding of the mechanisms by which these factors impact pain related outcomes following total knee arthroplasty (TKA). Findings from this study will be used to alter modifiable risk factors associated with the development of chronic pain and to develop and refine psychosocial interventions for post-operative pain.