Relationship between paracetamol effectiveness and CYP2E1 gene polymorphism in the treatment of pain in the pre-operative period of patients with lower extremity fractures

The primary enzyme responsible for the metabolic conversion of paracetamol into N-acetyl-p-benzoquinone imine (NAPQI) is cytochrome P450 CYP2E1. Although the relationship between paracetamol efficacy and the polymorphisms of various genes has been investigated, no study has specifically examined its association with this gene. Therefore, this study aimed to evaluate the efficacy of paracetamol and its relationship with cytochrome P450 CYP2E1 gene polymorphism in the preoperative period in patients presenting with lower extremity trauma and scheduled for surgery, with the objective of developing personalized pharmacotherapy strategies. This study was conducted at Pamukkale University Faculty of Medicine, Department of Orthopedics, and included 127 patients treated for lower extremity fractures and a control group of 100 healthy individuals without pain complaints. Each patient received an intravenous dose of 1000 mg of paracetamol (Parol). Visual Analog Scale (VAS) pain scores were recorded before and at 30 minutes after paracetamol administration. Blood samples were collected in 5 ml anticoagulant vacuum tubes, and genomic DNA isolation was performed using the standard phenol-chloroform method. Among the patients, 62.2% (n=79) had isolated tibial fractures, 22.8% (n=29) had isolated femoral fractures, and 15% had fractures in other regions (acetabulum, fibula, patella, calcaneus). Paracetamol was found to be effective as an analgesic in all patients. The frequency of the CYP2E11A heterozygous genotype was significantly higher in the patient group compared to the control group (p=0.041). The frequency of CYP2E17B heterozygous alleles was significantly lower in the patient group than in the control group (p<0.001). No significant difference was observed between the patient and control groups regarding the CYP2E15B and CYP2E16 alleles (p>0.05). In the CYP2E11A and CYP2E15B heterozygous genotypes, VAS scores before and after Parol administration were significantly higher (p<0.05). However, in the CYP2E16 and CYP2E17B genotypes, no significant difference was found in VAS scores between normal and heterozygous alleles before and after Parol administration (p>0.05). Across all gene polymorphisms, VAS scores significantly decreased after Parol administration compared to pre-treatment scores (p<0.001). In conclusion, the absence of a significant difference in paracetamol efficacy across all gene polymorphisms suggests that pain management may be similarly effective regardless of genetic variations. However, CYP2E11A and CYP2E15B polymorphisms may play a more prominent role in the therapeutic efficacy of Parol. This study demonstrates that genetic variations can lead to interindividual differences in the therapeutic effects of Parol. These findings emphasize the importance of personalized approaches in pain management and highlight the impact of genetic factors on pharmacotherapy. Keywords: Lower Extremity Fractures, Paracetamol, Cytochrome P450, CYP2E1