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Chronic posttraumatic musculoskeletal pain (CPMP) is common posttraumatic stress exposure (TSE) that disproportionately burdens women. We previously showed across three independent longitudinal cohort studies that, in women only, increased peritraumatic 17β-estradiol (E2) levels were associated with substantially lower CPMP over a year. Here, we aimed to validate this finding in a fourth longitudinal cohort and determine whether exogenous E2 administration protects against CPMP-like behavior in a well-validated animal model of TSE. Using nested participant samples and data from the AURORA study (n=549), an emergency department-(ED) based longitudinal study of TSE survivors, we assessed the relationship between circulating E2 levels and CPMP in women and men using repeated measures mixed modeling of E2/CPMP measured immediately, 2-weeks, and 6-months post-TSE. Ovariectomized-(OVX) female and male Sprague Dawley rats were exposed to TSE (single prolonged stress) and administered E2 (45μg/kg) subcutaneously immediately or 3 days post-TSE. Consistent with previous results, we observed an inverse relationship between peritraumatic E2 and longitudinal CPMP only in women (β=-0.137, p=0.033). No statistically significant relationships were identified between E2 and pain at 2-weeks or 6-months. E2 protected against CPMP-like behavior in female animals only if administered immediately post-TSE. In conclusion, peritraumatic E2 levels predict CPMP recovery in women TSE survivors and administration of E2 immediately post-TSE protects against CPMP-like behavior in female animals. Together with previous findings, this data suggests that immediate post-TSE administration of E2 in women could be a promising therapeutic strategy for the prevention of CPMP. Funding Source: U01MH110925, K01AR071504, Rita Allen Foundation Award in Pain U01MH110925, K01AR071504, Rita Allen Foundation Award in Pain.

Chronic pain and serious mental illness increase risk of opioid use, and opioid use can exacerbate both conditions. Substance use disorder (SUD) treatment can be lifesaving, but chronic pain and serious mental illness may make recovery challenging. We evaluated the association between current chronic pain and prior hospitalization for mental illness and 90-day SUD treatment engagement, among emergency department (ED) patients at high risk of opioid overdose.