Evaluating Sex Differences in Biomarkers of Chronic Pain Among Active-Duty Personnel: An Exploratory Analysis of a Pragmatic Clinical Trial With a SMART Design

Chronic pain affects approximately one-third of active-duty service members (ADSMs), yet effective treatment remains challenging. Salivary cortisol and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) are established non-invasive biomarkers of stress and oxidative DNA damage and may provide reliable unbiased indicators of treatment efficacy in chronic pain. However, their associations with pain outcomes and potential sex differences remain unclear. It was hypothesized that interdisciplinary pain treatment would result in decreased levels of stress and oxidative DNA damage biomarkers, as well as decreased pain intensity, and that the magnitude of challenge might vary by sex. Our objective was to compare longitudinal changes in salivary cortisol and urinary 8-OHdG in relation to pain outcomes and sex. A total of 190 ADSMs who referred for chronic pain treatment completed data collection on the Patient-Reported Outcomes Measurement Information System (PROMIS) measures and urine and saliva samples at baseline and post-treatment. Multivariable regression models were used to predict changes in PROMIS scores relative to changes in cortisol and 8-OHdG, while adjusting for baseline levels. Interaction terms between participants' sex and changes in biomarkers were added to each model. Given the study's exploratory nature, a significance threshold of <i>p</i> < .10 was used for all analyses. Five statistically significant sex-by-cortisol interactions were identified for pain measures (pain impact, pain interference, physical functioning, sleep impairment, and social functioning), but none for 8-OHdG. Future work is needed to replicate these findings in larger samples. The research protocol was registered in ClinicalTrials.gov (NCT03297905; https://clinicaltrials.gov/study/NCT03297905).