Recovery from Pain and Disability after Surgery

 描述（由申请人提供）：手术后慢性疼痛已经引起了相当大的关注，但它只是对患者重要的手术后慢性功能障碍的一个方面。其他包括认知和身体功能障碍，对疼痛和运动的恐惧，以及冲动，这与处方阿片类药物滥用的风险有关。这些问题发生在全膝关节置换术（TKA）后的大多数患者（10-40%）中，具体取决于结局指标。 本P01旨在解决在理解、预防和治疗术后慢性疼痛和残疾方面取得进展的障碍，这些障碍是如此重要，以至于单独的研究者无法对其产生有意义的影响。1)临床前和临床研究都被任意时间点功能障碍的发生率作为主要结局所阻碍;我们展示了手术后个体动物和人类恢复时间过程建模的能力增加及其在检查干预措施和机制方面的实用性。2)恢复通常在一个领域进行检查：我们在动物中检查了TKA后以患者为中心的几个领域及其机制。3)通过未知机制的术前认知情感（C-A）状态预测患者术后恢复，临床前研究仅在正常动物中进行恢复：我们提供了一个统一的、机械的和临床上可行的假设，将C-A状态与蓝斑（LC）功能联系起来，并将其用于测试加速TKA术后恢复的新靶向治疗。 在过去的4年里，这组独立资助的研究人员共同努力，产生新的动物模型，开发概念，并证明解决这些关键障碍的可行性。在创新的行政和研究核心的支持下，P01作为一个整体将通过研究一个中心假设和3个有凝聚力的互动目标在该领域产生重大影响： 1.中心假设：LC在手术损伤时的活动和对手术损伤的反应是疼痛和其他以患者为中心的领域恢复速度的关键决定因素 2.项目1：LC →脊髓信号传导对于手术后超敏反应和残疾的正常恢复至关重要，并且被实验诱导的强直性LC活性增加所破坏 3.项目二：LC →脊髓，向脊髓上区域发出信号对于术后疼痛、冲动和注意力分散的恢复至关重要，并受到术前增强的强直性LC活动的干扰 4.项目3：LC紧张性活动与灾难性参与乐观认知风格连续体相互作用，以解释多个患者领域恢复时间过程的新差异，并确定将从预防性加巴喷丁治疗中受益或受到伤害的患者

 DESCRIPTION (provided by applicant): Chronic pain after surgery has garnered considerable attention, but it is but one facet of chronic dysfunction after surgery important to patients. Othes include cognitive and physical dysfunction, fear of pain and movement, and impulsivity, which is tied to risk of prescription opioid misuse. These problems occur in a large minority of patients (10-40%), depending on the outcome measure, after total knee arthroplasty (TKA). This P01 seeks to address barriers to progress in understanding, preventing, and treating chronic pain and disability after surgery which are so fundamental that they cannot be meaningfully impacted by individual investigators acting in isolation. 1) Both preclinical and clinical research is stymid by use of point incidences of dysfunction at arbitrary times as primary outcomes; we show the increased power of modeling time course of recovery in individual animals and humans after surgery and its utility to examine interventions and mechanisms. 2) Recovery is typically examined in one domain: we examine several patient-centered domains after TKA and their mechanisms in animals. 3) Recovery after surgery in patients is predicted by preoperative cognitive-affective (C-A) state by unknown mechanisms and preclinical research studies recovery in normal animals only: we provide a unifying, mechanistic, and clinically actionable hypothesis relating C-A state and locus coeruleus (LC) function and use it to test novel targeting of therapies to speed recovery after TKA. Over the past 4 years this group of independently funded investigators has worked together to generate new animal models, develop concepts, and demonstrate feasibility of addressing each of these critical barriers. As supported by innovative Administrative and Research Cores, this P01 as a whole will have a major impact in the field by examining a central hypothesis and 3 cohesive, interactive aims: 1. CENTRAL HYPOTHESIS: Activity of the LC at the time of and in response to surgical injury is a key determinant of speed of recovery across pain and other patient-centered domains 2. PROJECT 1: LC → spinal cord signaling is essential to normal recovery from hypersensitivity and disability after surgery and is disrupted by experimentally induced increased tonic LC activity 3. PROJECT 2: LC → spinal cord, signaling to supraspinal regions is essential to recovery from pain, impulsivity, and distraction after surgery and is disturbed by pre-surgery increased tonic LC activity 4. PROJECT 3: LC tonic activity interacts with a catastrophizing ↔ optimism cognitive style continuum to explain novel variance in time course of recovery across multiple patient domains and identifies patients who will benefit from or be harmed by preventative gabapentin treatment