Recovery from Pain and Disability after Surgery

 描述(申请人提供)：手术后慢性疼痛已经引起了相当大的关注，但这只是手术后慢性功能障碍的一个方面，对患者来说很重要。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。这些问题发生在极少数患者(10%-40%)，这取决于全膝关节置换术(TKA)后的结果。本P01寻求解决在理解、预防和治疗手术后慢性疼痛和残疾方面取得进展的障碍，这些障碍是如此根本，以至于单独行动的调查人员不能对其产生有意义的影响。1)临床前和临床研究都是通过使用任意时间的功能障碍的点发生率作为主要结果来阻碍的；我们展示了在单个动物和人类手术后的恢复时间过程的建模的增加的能力以及它在检查干预和机制方面的有效性。2)恢复通常是在一个领域内研究的：我们在动物TKA后研究了几个以患者为中心的领域及其机制。3)术前认知-情感(C-A)状态通过未知的机制和临床前研究仅在正常动物中预测患者术后的恢复：我们提出了C-A状态和蓝斑(LC)功能的统一的、机械的和临床上可操作的假说，并用它来测试新的靶向治疗以加速TKA后的恢复。在过去的4年里，这组独立资助的研究人员共同努力，创造了新的动物模型，开发了概念，并展示了解决这些关键障碍的可行性。在创新管理和研究核心的支持下，P01作为一个整体将通过审查一个中心假设和三个连贯的互动目标在该领域产生重大影响： 1.中心假设：在手术损伤时和对手术损伤的反应中，LC的活动是跨越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→脊髓信号是手术后从过敏和残疾中正常恢复所必需的，并被实验诱导的紧张性LC活动增加所干扰 3.项目2：LC→脊髓，向脊髓上区域发出信号对于术后从疼痛、冲动和分心中恢复至关重要，并因术前增强的紧张性LC活动而受到干扰 4.项目3：LC紧张性活动与灾难性的↔乐观主义认知风格连续体相互作用，以解释跨多个患者领域的康复时间进程的新差异，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