Chronic postsurgical pain (CPSP) is a major healthcare burden, affecting nearly 20% of patients undergoing major surgery. CPSP is associated with diminished quality of life, mood disturbances, functional impairment, and increases the risk of opioid use disorder. Considerable research suggests that a combination of somatosensory, immune, affective and cognitive mechanisms contribute to CPSP, and that CPSP phenotypes are highly heterogeneous, even after identical surgical procedures. However, most prior research has explored peripheral or central mechanisms in isolation, preventing an integrated insight into underlying biological factors that drive these distinct clinical phenotypes. Preclinical models of CSPS have also failed to capture this phenotypic heterogeneity or meaningful clinical outcome measures, significantly limiting forward translation of basic discoveries. As a result, current strategies for predicting, preventing and treating CPSP are extremely limited. To address this need, we have developed the IMPETUS program that draws expertise from pain neurobiology, clinical pain research, clinical psychology, cognitive neuroscience, immunology, proteomics, genomics, transcriptomics, bioinformatics, machine learning, and pain medicine. Our goal is to gain integrated mechanistic insights into peripheral and central biological processes that contribute to CPSP, and to understand how these processes contribute to CPSP heterogeneity. Aim 1. Characterize peripheral neural and immune mechanisms contributing to CPSP. In patients with CPSP subsequent to abdominal or genitourinary surgery (n=220) and contemporaneous controls (n=100), we will characterize somatosensory profiles of mechanical and thermal sensitivity, the neural and immune milieu at the cutaneous site of injury, and circulating immune host profiles, and compare them with correlates across the same domains in a mouse model of laparotomy. Aim 2. Characterize cognitive and affective mechanisms contributing to CPSP. In patients with CPSP and controls, we will use granular longitudinal data collection methods to characterize affective, cognitive, and activity/sleep measures of CPSP, and compare them with animal model correlates across these domains, using translational outputs of amotivation, punishment-sensitivity, reversal learning task, and actigraphy. Aim 3. Identify and back-translate mechanism-based CPSP phenotypes. Using state-of-the-art machine learning approaches applied to multidimensional data generated in Aims 1 and 2, we will identify discrete CPSP phenotypes, and recapitulate them in animal models for improved translatability. We expect the IMPETUS program to 1) identify distinct somatosensory, neural, immune, affective and cognitive mechanisms that contribute to distinct CPSP phenotypes and explain inter-patient heterogeneity, with cross-species validation; 2) Characterize distinct phenotypic clusters within CPSP to inform personalized patient care and stratified clinical trials for CPSP interventions; and 3) Develop animal models that recapitulate specific clinical phenotypes of CPSP to accelerate for mechanistic exploration and novel therapeutic development.
