ABSTRACT Endometriosis is a debilitating gynecologic disease presenting with severe pelvic pain and is characterized by the growth of endometrial-like tissue outside of the uterus impacting 10% of reproductive aged women or an estimated 200 million women and adolescents worldwide. Compared to women without endometriosis, women with endometriosis, especially adolescents and young adults with endometriosis, are at an increased risk of chronic opioid use, dependence, and overdose. Therefore, optimal pain management in endometriosis patients, especially starting in adolescence, is critical and will have significant positive impact on resolving the opioid health crisis. Currently, primary treatment options for endometriosis focus on hormonal suppression and/or excision of the endometriotic lesions, although response to these conventional treatments is variable and as a result, many of those with endometriosis are plagued with persistent pelvic pain. Emerging evidence suggests that endometriosis patients who develop persistent pelvic pain have developed centralized pain, and therefore surgical removal of endometriotic tissue does not fully improve their pain. Since many women with diagnosed endometriosis report their symptoms started during adolescence, this transition from acute to chronic pain is likely happening during adolescence and young adulthood. Thus, studying adolescents and young adults with endometriosis, who are in the early stages of their disease trajectory, is critical to fully understanding who is at higher risk of developing chronic pain. However, data on longitudinal changes in biomarkers and endometriosis- associated pain in adolescents is lacking, resulting in lost opportunity for early interventions. The overarching goal of this innovative application is to improve and optimize pain management for endometriosis through identifying plasma protein biomarkers of chronic pain development in adolescents and young adults with endometriosis. Specifically, we propose to conduct a longitudinal analysis of endometriosis cases diagnosed in adolescence with follow-up data and paired blood samples collected 10 years apart from adolescence to adulthood and apply a state of the art 7000-plex proteomics assay to identify plasma protein biomarkers of centralized, chronic pain development. In addition, we will examine change in plasma proteomic biomarkers in paired blood samples drawn 10 years apart (i.e. at adolescence and adulthood), and together these unique resources will allow prospective investigation of predictors and biological factors related to transitioning from acute to chronic pain or chronification of pain. Results from this study will generate important novel data identifying adolescents and young women with endometriosis who are at greater risk of developing chronic pain despite receiving current standard of care, leading to development of novel pain interventions targeted to a younger population to prevent chronification of pain, which will be a critical step forward to resolving the ongoing opioid crisis.

NARRATIVE Adolescents and young women with endometriosis, a gynecologic disease causing severe pelvic pain, are at an increased risk of becoming chronic opioid users. This innovative application aims to improve and optimize pain management for endometriosis by evaluating biomarkers in endometriosis cases diagnosed in adolescence with follow-up data and paired blood samples collected 10 years apart from adolescence to adulthood to identify plasma protein biomarkers of centralized, chronic pain development. Results from this study will ultimately lead to development of novel strategies to prevent and treat chronification of pain optimized for adolescents and young adults with endometriosis, significantly contributing to ending the current opioid pandemic.