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 pat