Background: Chronic pain is the leading cause of disability worldwide and is strongly associated with the epidemic of opioid overdosing events. However, the causal links between chronic pain, opioid prescriptions, and mortality remain unclear. Methods: This study included 13,884 US adults aged ≥20 years who provided data on chronic pain in the National Health and Nutrition Examination Survey 1999–2004 with linkage to mortality databases through 2015. We employed the generalized form of the front-door formula within the structural causal model framework to investigate the causal effect of chronic pain on all-cause mortality mediated by opioid prescriptions. Results: We identified a total of 718 participants at 3 years of follow-up and 1260 participants at 5 years as having died from all causes. Opioid prescriptions increased the risk of all-cause mortality with an estimated odds ratio (OR) (95% confidence interval) = 1.5 (1.1, 1.9) at 3 years and 1.3 (1.1, 1.6) at 5 years. The front-door formula revealed that chronic pain increased the risk of all-cause mortality through opioid prescriptions; OR = 1.06 (1.01, 1.11) at 3 years and 1.03 (1.01, 1.06) at 5 years. Our bias analysis showed that our findings based on the front-door formula were likely robust to plausible sources of bias from uncontrolled exposure–mediator or mediator–outcome confounding. Conclusions: Chronic pain increased the risk of all-cause mortality through opioid prescriptions. Our findings highlight the importance of careful guideline-based chronic pain management to prevent death from possibly inappropriate opioid prescriptions driven by chronic pain.
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