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

尽管中枢神经系统(CNS)的疼痛抑制强烈地调节了实验室中的急性疼痛，但其 与患者预后的相关性则不太为人所知。对动物模型、人类行为模式的研究， 神经影像研究表明，中枢性疼痛抑制与慢性疼痛的病理生理机制有关。然而， 最常用的对患者中枢性疼痛抑制的评估受到技术方面的限制， 费用和可获得性，阻止了它们的广泛使用，并导致了关于如何集中的知识鸿沟 疼痛抑制影响患者的结果和治疗反应。当前项目的目标是定义 使用新的大脑和行为工具对慢性疼痛患者中枢疼痛抑制的改变，包括 功能性近红外光谱(FNIRS)和抵消镇痛。FNIRS支持经济高效的测量 以临床为基础的非卧床环境中依赖活动的皮质血流动力学变化的研究。抵消止痛， 被定义为如果在有害刺激之前有更强的刺激，主观疼痛强度的降低，是 在机制上与最常用的中枢疼痛抑制措施--条件性疼痛--截然不同 调制。中心假说是抵消止痛受损，其神经关联在... 患有慢性疼痛的患者。此外，我们假设，在基线时，中枢疼痛抑制的更大损失是 与度洛西汀更好的止痛有关，这可能会挽救缺乏疼痛抑制的情况。这项建议 基本原理是，疼痛抑制措施将确定患者的亚群，这将改善未来的RCT 通过将研究集中在表型不同的人群上，并最终通过以下方式改善患者护理 个性化的疼痛治疗。在这个职业发展奖中，提出了三个目标。首先， 抵消止痛和慢性疼痛强度的关系将在一项横断面研究中进行评估 比较慢性膝关节疼痛强度高或低的患者的止痛幅度，但 关节退变程度相同。其次，在这项研究中，fNIRS将用于定义大脑皮层的相关性 对抵消止痛的研究，扩大了申请者在年轻、健康的志愿者中的初步数据。第三，a 将在慢性膝部疼痛患者中进行前瞻性试验，作为调查 度洛西汀治疗反应中的疼痛抑制。这些研究为申请者提供实践培训。 发展与脑成像和临床试验相关的研究技能，并将得到指导的补充 以及评估会议、正式的教学课程、研讨会和会议。该项目将被实施 在匹兹堡大学，该校对临床和转化性研究有着杰出的支持，并拥有长期的 培养独立内科医生-科学家的历史。总而言之，该项目将使申请者很好地 在面向慢性疼痛患者的研究中实现独立，并允许严格进行后续研究 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.