Association Between Long-Term ACEI/ARB Use and Postoperative Pain in Hypertensive Patients: A Retrospective Cohort Study and Genetic Validation

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used for hypertension management. Emerging evidence suggests that these agents may influence pain perception through neuroinflammatory and hormonal pathways. However, their impact on acute postoperative pain has not been well characterized. Aim: This study aimed to explore the hypothesis that long-term ACEI/ARB use is associated with reduced acute postoperative pain in hypertensive patients undergoing non-cardiac surgery. Methods: We conducted a hybrid study combining a retrospective cohort analysis with a drug-target Mendelian randomization approach. A total of 1206 hypertensive patients who underwent general anesthesia and received patient-controlled intravenous analgesia were included. The primary outcome was the presence of moderate-to-severe postoperative pain, which was defined as a numerical rating scale (NRS) score ≥ 4 on postoperative days (PODs) 1 and 3. Secondary outcomes included opioid consumption measured in morphine milligram equivalents. Confounders were adjusted using inverse probability of treatment weighting. Missing data was treated by multiple imputation with chained equation, as 37.3% of POD3 NRS missing. Genetic validation was performed using expression quantitative trait loci for ACEI/ARB target genes and genome-wide association data on multisite chronic pain. Results: Patients receiving ACEIs/ARBs had significantly lower rates of moderate-to-severe pain on postoperative day 1 (OR 0.74, 95% CI 0.57– 0.94; ARR 6.87%; NNT 14.6) but had no significance on day 3 (OR 0.77, 95% CI 0.57– 1.04), despite similar opioid consumption on both days. Genetic validation found associations between several ACEI/ARB target genes and reduced chronic pain risk, directionally consistent with our clinical observations. Conclusion: Long-term ACEI/ARB use may offer potential analgesic benefits for surgical patients with hypertension. These preliminary findings provide a foundation for future research to explore their potential role in perioperative pain management. Keywords: ACE inhibitors, angiotensin receptor blockers, postoperative pain, hypertension, Mendelian randomization, perioperative analgesia