¹National Institute of Neurology and Psychiatry, Department of Neuropsychopharmacology, Tokyo, Japan, ²Tokyo Metropolitan Institute of Medical Science, Department of Clinical Medical Sciences, Tokyo, Japan, ³Tokyo Dental College, Department of Oral Health and Clinical Science, Tokyo, Japan, ⁴Tokyo Dental College, Department of Dental Anesthesiology, Tokyo, Japan, ⁵Toho University Sakura Medical Center, Chiba, Japan, Department of Surgery, Chiba, Japan, ⁶Saitama Medical University International Medical Center, Department of Anesthesiology, Saitama, Japan, ⁷Juntendo University School of Medicine, Department of Anesthesiology and Pain Medicine, Tokyo, Japan, ⁸University of Calgary, Faculty of Veterinary Medicine, Alberta, Canada, ⁹Cumming School of Medicine, University of Calgary, Department of Physiology & Pharmacology, Alberta, Canada

Background: Postoperative pain management often requires opioid analgesics, but patients show large variability in the doses needed for adequate pain relief. These inter-individual differences hinder effective pain control and may increase the risk of opioid-related adverse outcomes. Genetic factors are estimated to contribute up to 60% of the variability in opioid analgesic response. RUNX1, a transcription factor implicated in pain regulation, has emerged as a potential genetic contributor. However, its role in human opioid analgesic requirements has not been established.

Aims & Objectives: We aimed to determine whether genetic variation in RUNX1 is associated with postoperative opioid analgesic requirements. Specifically, we focused on the RUNX1 single nucleotide polymorphism (SNP) rs2236431 and sought to replicate any association in two independent cohorts of surgical patients.

Method: Two cohorts of postoperative patients were analyzed. In the discovery cohort (n = 355, patients undergoing orthognathic surgery), genotype data from a prior whole genome genotyping were extracted for variants in the RUNX1 gene region. Tagging SNPs were tested for association with total perioperative opioid consumption (converted to fentanyl equivalent dose). In the second cohort (n = 112, patients undergoing major abdominal surgery), the top candidate SNP from the discovery cohort was genotyped by the TaqMan allelic discrimination assay to validate its association with opioid analgesia. Pain scores and analgesic requirements were recorded, and analyses were conducted to investigate the association between the rs2236431 SNP and total dose of rescue analgesics (converted to fentanyl dose) required during the first 24-h postoperative period.

Results: In the discovery cohort, RUNX1 SNP rs2236431 showed a significant association with 24-h total postoperative opioid analgesic requirements. Patients homozygous for the major allele (A/A) required higher total opioid doses for pain relief compared to those carrying the minor C allele (A/C or C/C). Notably, rs2236431 was not associated with patients’ reported pain intensity, suggesting the genotype affects opioid efficacy rather than pain perception. In the independent validation cohort, the same SNP effect was replicated. A/A homozygotes had significantly greater 24-h total postoperative rescue opioid needs than minor allele carriers, whereas none of the few patients homozygous for the C/C genotype required any rescue analgesia. The association between rs2236431 and opioid requirements was significant in both cohorts, indicating that this RUNX1 variant contributes to opioid analgesia regardress of types of surgery.

Discussion & Conclusions: This study identifies RUNX1 rs2236431 as a novel genetic determinant of opioid analgesic requirement in acute postoperative pain management. The consistent findings across two different surgical cohorts underscore the clinical relevance and robustness of this association. Patients with the A/A genotype at rs2236431 may experience reduced opioid analgesic efficacy, necessitating higher doses to achieve pain relief. This genetic marker, if validated in further studies, could be used to personalize postoperative pain management by identifying individuals who might benefit from adjusted analgesic strategies to optimize pain control and minimize opioid exposure. In conclusion, our results highlight a previously unrecognized role for RUNX1 in human analgesic response, offering a potential avenue for improving pain management through precision medicine.