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

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.

Grant Number: 5K23NS123429-05
NIH Institute/Center: NIH
Principal Investigator: Benedict Alter