Impact of CYP2E1 Polymorphisms on Preoperative Paracetamol Analgesic Response in Patients with Lower Extremity Fractures

Background: Paracetamol is widely used for acute pain management in orthopedic trauma; however, interindividual variability in analgesic response remains insufficiently understood. Cytochrome P450 2E1 (CYP2E1), a key enzyme involved in paracetamol metabolism and the formation of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), may contribute to this variability. This study aimed to investigate the relationship between CYP2E1 gene polymorphisms and the analgesic efficacy of paracetamol in patients with lower extremity fractures. Methods: A total of 127 patients with lower extremity fractures and 100 healthy controls were included. All patients received 1000 mg of intravenous paracetamol. Pain intensity was assessed using the Visual Analog Scale (VAS) at baseline and at 30, 60, and 120 min after administration. Genotyping of CYP2E1 polymorphisms (*1A, *5B, *6, and *7B) was performed using PCR-RFLP. Differences in the VAS scores and analgesic response were analyzed according to genotype. Results: Paracetamol administration resulted in a significant reduction in pain scores at all time points (p < 0.001). Patients carrying the CYP2E15B variant exhibited significantly higher VAS scores and a weaker early analgesic response compared to non-carriers (p ≤ 0.001). Similarly, CYP2E11A carriers demonstrated higher pain scores across all time points (p < 0.05), although the magnitude of effect was less pronounced. No significant differences were observed for the CYP2E16 variant. Due to low frequency, CYP2E17B could not be reliably analyzed. Conclusions: Paracetamol is an effective analgesic in patients with lower extremity fractures; however, CYP2E1 polymorphisms may modulate individual pain perception and early analgesic response. In particular, the *5B and, to a lesser extent, *1A variants are associated with higher pain scores. These findings support the potential role of pharmacogenetic approaches in personalized pain management.