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

点击翻译按钮获取中文摘要

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.