Exposome Signatures of Prescription Medication and Mild Traumatic Brain Injury Sequelae

Mild traumatic brain injury (mTBI) has been termed the signature wound of active duty service members (ADSM) returning from Operation Iraqi Freedom and Operation Enduring Freedom with estimated incidence rates between 19.5% and 23%, respectively. Locally, mTBI accounted for 9% of all diagnoses at Fort Bragg, NC, between 2016 and 2022. Our study examines long-term effects of medications prescribed to reduce or prevent mTBI complications that may lead to postconcussive syndrome (PCS).

The Medical Assessment and Readiness System (MARS) housed at Womack Army Medical Center, Fort Bragg, NC was used to capture unique health care encounters including ICD-10 codes for concussion or mTBI from 2016-2022. The overarching MARS protocol (17-02683) was approved by the Naval Medical Center Portsmouth Institutional Review Board in compliance with all applicable Federal regulations governing the protection of human subjects. We identified ADSMs receiving initial outpatient treatment for concussion. Each SM had a concurrent active prescription before the initial injury diagnosis or received a prescription for one or more prophylactic drug candidates on the day of mTBI diagnosis. Our analysis included therapeutics prescribed at the time of injury used to treat conditions unrelated to TBI. We stratified to include concurrent prescription data and assess prevalence of primary (short term) and secondary (long term) mTBI symptoms and sequelae including PCS constellation symptoms associated with prescription use.

We analyzed 46,691 unique outpatient encounters for ADSMs initially receiving outpatient treatment for concussion from 2016 to 2022 generating a convenience sample of 2,638 SMs with an existing prescription, or who were prescribed PDC at the time of mTBI diagnosis. Our convenience sample experienced triple the rate of migraine diagnosis (ICD10: G43, 33% and 31%) and sleep disorders (ICD10: G47; 57% and 62%) within 2 years post mTBI when compared to controls with no PDC prescription. Post-traumatic headache (ICD10: G443) rates doubled from 15.5% in controls with no prescription to 30% and 31% in ADSMs with prescriptions.

Secondary injury mechanisms may expand mTBI, leading to increased neuronal death and injury expansion. However, clinical attempts to mitigate tissue damage may result in long-term effects that increase PCS symptom severity, resulting in a reduction of ADSMs' overall health, well-being, and readiness. Our findings suggest increased negative health risks following use of specific prescription drugs for mTBI. Additional prospective trials are required to identify viable mitigation strategies.