Biopsychosocial determinants of pediatric-onset chronic musculoskeletal pain

About This Grant

Abstract Pediatric-onset chronic musculoskeletal pain disorders are common, but the mechanisms underlying their pathophysiology are poorly understood. Current best practices in pediatric pain management focus on symptom management and restoration of function. Absent a more mechanistic understanding of the drivers of pediatric chronic pain and potential sub-types of chronic pain based on underlying pathophysiology (as opposed to phenotypic classifications), pain providers are unable to target treatments to the root causes of patients’ symptoms. There is no cure for pediatric-onset chronic pain, and many children and adolescents continue to have pain in adulthood, highlighting the need for greater research into the development of novel treatment strategies. At Cincinnati Children’s Hospital Medical Center, we have a large and well-established multidisciplinary team of investigators who are already working to unravel the complex biopsychosocial contributors to chronic musculoskeletal (MSK) pain in children. Our multiple ongoing registries and cohorts have more than 2400 patients with pediatric-onset primary MSK pain disorders, pediatric rheumatic diseases, and surgical interventions for whom we have rich medical history, pain-related and psychosocial data. The proposed research would leverage these existing registries and cohorts to enroll a heterogeneous sample of N=600 adolescents and young adults (ages 16-26); N= 400 with primary chronic MSK pain, or chronic MSK pain secondary to rheumatic disease or major MSK surgery, and N=200 with a rheumatic disease or history of major MSK surgery, but no chronic pain. Using a mixed retrospective-prospective cohort study design, we first propose to combine and harmonize retrospective data from patients’ past clinical registry and research records. We then will acquire prospective data regarding pain characteristics, quantitative sensory testing and cytokine profiling and apply a model-based unsupervised clustering analytic approach to define mechanistically distinct chronic MSK pain subgroups. Further, we will use serum samples from patients to conduct in vitro experiments to identify neuro-immune signaling pathways impacting sensory transduction using an innovative induced Pluripotent Stem Cell (iPSC) model. This mechanistic examination will be further augmented by analysis of how psychosocial, behavioral and lifestyle factors mediate pain-related outcomes among participants. In pursuing an analysis of patients that extends from the level of community characteristics to single-cell assays, this research will result in the construction of a robust biopsychosocial model in which patients across multiple pain sub-groups may be classified according to genetic and cellular mechanisms as well as psychological, behavioral, and social features promoting risk and resilience. Through collaboration across disciplines along with patient advisory partners, this study will reveal mechanistically driven treatment targets for future therapeutic trials as well as novel insights into the relationship between painful MSK conditions of childhood and the biopsychosocial factors that contribute to patient outcomes.