Speakers - 2026

Title: Allostatic Load and Pain-Depression Comorbidity: A Mediation Analysis of Bilirubin

Abstract

Objective: Pain-depression comorbidity, characterized by the concurrent presence of chronic pain and depressive symptoms, represents a clinically challenging condition associated with poorer prognosis, higher healthcare costs, and increased treatment resistance compared to either condition alone. Chronic stress-induced oxidative stress has been increasingly recognized as a common biological pathway underlying both pain and depression. Allostatic load index (ALI), a composite measure of chronic stress-induced multisystem physiological dysregulation, captures the cumulative biological burden of repeated stress exposure. Bilirubin, traditionally viewed as a metabolic waste product, has recently been identified as one of the most potent endogenous antioxidants, capable of eliminating reactive oxygen species and modulating neuroinflammatory responses. However, the association between ALI and pain-depression comorbidity, as well as the potential mediating role of bilirubin in this relationship, remains poorly understood. This study aimed to investigate the association between ALI and pain-depression comorbidity and to examine whether bilirubin mediates this relationship.

Methods: This study included 3,891 U.S. adults from the National Health and Nutrition Examination Survey (NHANES) 2009–2010 cycle. Participants were categorized into four groups: healthy, pain without depression, depression without pain, and pain-depression comorbidity. Weighted multinomial logistic regression, restricted cubic splines (RCS), mediation analyses, and XGBoost machine learning were conducted.

Results: (1) ALI significantly increased the risk of pain-depression comorbidity and, to a lesser extent, pain without depression. RCS analyses revealed linear positive associations for both groups with no evidence of nonlinearity. In contrast, no significant association was observed between ALI and depression without pain. (2) Bilirubin partially mediated the ALI-comorbidity association, accounting for 11.8% (95% CI: 2.3%–25.5%) of the total effect. (3) XGBoost identified poverty-income ratio, age, and ALI as the top predictors of comorbidity.

Conclusion: This study highlights the independent effect of ALI on pain-depression comorbidity and the mediating role of bilirubin. ALI may serve as a practical clinical risk assessment indicator. Interventions targeting stress management and oxidative balance may alleviate the comorbidity burden.

What will the audience take away from presentation?

• Understand the role of allostatic load in pain-depression comorbidity. Attendees will learn how chronic stress-induced multisystem dysregulation (ALI) contributes to the co-occurrence of pain and depression.
• Recognize bilirubin as a novel therapeutic target. Bilirubin, an endogenous antioxidant, partially mediates the ALI-comorbidity pathway, highlighting its potential for intervention.
• Apply routine clinical biomarkers for risk stratification. ALI components (blood pressure, blood tests) and bilirubin are routinely collected, providing a simple, low-cost tool for identifying high-risk individuals.
• Translate findings into practice. Clinicians can use ALI for early risk detection; researchers can explore oxidative stress interventions; policymakers can target socioeconomic vulnerabilities in prevention strategies.