Integrating brain and behavioral measures of central pain inhibition to personalize treatment in chronic pain management

虽然中枢神经系统（CNS）的疼痛抑制在实验室中强烈调节急性疼痛，但其 对患者结果的相关性知之甚少。动物模型研究，人类行为范例， 和神经影像学已经暗示了慢性疼痛的病理生理学中的中枢疼痛抑制。但 最常用的对患者中枢疼痛抑制的评估受到技术方面的限制， 费用和可获得性，阻碍了它们的广泛使用，并导致在如何发挥核心作用方面存在知识差距。 疼痛抑制影响患者结果和治疗反应。当前项目的目标是定义 使用新的大脑和行为工具研究慢性疼痛患者中枢疼痛抑制的变化，包括 功能性近红外光谱（fNIRS）和抵消镇痛。FNIRS允许经济有效的测量 活动依赖性皮质血流动力学变化的动态，临床为基础的设置。抵消镇痛， 定义为如果在有害刺激之前有更强的刺激，则主观疼痛强度降低， 在机制上不同于最常用的中枢疼痛抑制措施，条件性疼痛 调变中心假设是，抵消镇痛受损，其神经相关改变， 慢性疼痛患者。此外，我们假设，在基线时中枢疼痛抑制的损失更大， 与度洛西汀的更大疼痛缓解相关，这可能会挽救疼痛抑制不足。该提案 基本原理是疼痛抑制的测量将确定患者亚组，这将改善未来的RCT 通过集中研究不同的表型人群，并最终改善患者护理， 个性化的疼痛治疗在这个职业发展奖，提出了三个目标。一是 将在一项横断面研究中评价抵消镇痛与慢性疼痛强度的关系 比较高或低慢性膝关节疼痛强度但 相同程度的关节退化其次，在同一研究中，fNIRS将用于定义皮质相关性 抵消镇痛，扩大申请人的初步数据，在年轻，健康的志愿者。三是 将在慢性膝关节疼痛患者中进行前瞻性试验，作为研究 对度洛沙汀治疗反应的疼痛抑制。这些研究为申请人提供实践培训 在发展与脑成像和临床试验相关的研究技能，并将辅之以指导 和评估会议，正式的教学法课程，研讨会和会议。该项目将在 在匹兹堡大学，这对临床和转化研究有杰出的支持， 发展独立的物理学家和科学家。总之，这个项目将定位申请人以及 在慢性疼痛患者为导向的研究中实现独立，并允许随后的研究严格 检查中枢疼痛抑制作为治疗反应的预测生物标志物。

Although pain inhibition by the central nervous system (CNS) strongly modulates acute pain in the lab, its relevance for patient outcomes is less well known. Studies with animal models, human behavioral paradigms, and neuroimaging have implicated central pain inhibition in the pathophysiology of chronic pain. However, the most commonly used assessments of central pain inhibition in patients are limited by technical aspects, expense, and accessibility, preventing their widespread use and resulting in a knowledge gap in how central pain inhibition impacts patient outcomes and treatment response. The goal of the current project is to define changes in central pain inhibition in patients with chronic pain using novel brain and behavioral tools, including functional near-infrared spectroscopy (fNIRS) and offset analgesia. FNIRS allows cost-effective measurement of activity-dependent cortical hemodynamic changes in an ambulatory, clinic based setting. Offset analgesia, defined as a reduction in subjective pain intensity if a noxious stimulus is preceded by a stronger stimulus, is mechanistically distinct from the most commonly used measure of central pain inhibition, conditioned pain modulation. The central hypothesis is that offset analgesia is impaired and its neural correlates altered in patients with chronic pain. Additionally, we hypothesize that greater loss of central pain inhibition at baseline is associated with greater pain relief with duloxetine, which may rescue deficient pain inhibition. The proposal rationale is that measures of pain inhibition will identify subgroups of patients which will improve future RCTs by focusing studies on phenotypically-distinct populations and, ultimately, improving patient care by personalizing pain treatment. In this career development award, three aims are proposed. First, the relationship of offset analgesia and chronic pain intensity will be evaluated in a cross-sectional study comparing offset analgesia magnitude across patients with high or low chronic knee pain intensity but the same degree of joint degeneration. Second, in this same study, fNIRS will be used to define cortical correlates of offset analgesia, extending the applicant’s preliminary data in young, healthy volunteers. Third, a prospective trial will be performed in patients with chronic knee pain as a first step in investigating the impact of pain inhibition on treatment response to duloxetine. These studies provide hands-on training for the applicant in developing research skills related to brain imaging and clinical trials and will be complemented by mentoring and evaluation meetings, formal didactics coursework, seminars, and meetings. The project will be conducted at the University of Pittsburgh, which has outstanding support for clinical and translational research and a long history of developing independent physician-scientists. Together, this project will position the applicant well to achieve independence in chronic pain patient-oriented research and allow subsequent studies rigorously examining central pain inhibition as a predictive biomarker of treatment response.