Abstract: BACKGROUND: Pain management after joint replacement in elderly patients is the focus of clinical attention. Sufentanil is often used for postoperative analgesia due to its strong analgesic effect. There are individual differences in pain threshold among patients, which may be related to drug metabolism. CYP3A4 is a key enzyme in the metabolism of sufentanil, and its genetic polymorphism can affect enzyme activity. 
OBJECTIVE: To explore the effect of CYP3A4*1G polymorphism on the pharmacokinetics and pain threshold of sufentanil in elderly patients undergoing joint replacement to provide a basis for the formulation of individualized analgesic regimens.
METHODS: A total of 150 elderly patients who underwent joint replacement in Xiantao First People's Hospital from January 2020 to January 2025 were selected as the study objects. The clinical data, pharmacokinetic parameters and post-administration pain threshold of patients with different genotypes were compared. Multiple linear regression was used to analyze the association between CYP3A4*1G and pain threshold under different genotypes. The effects of different genotypes and pharmacokinetic parameters on pain threshold were observed by two-factor analysis of variance. Pearson correlation was used to analyze the correlation between the blood concentration of sufentanil and the pain threshold under different genotypes. 
RESULTS AND CONCLUSION: (1) Of the 150 patients enrolled, 88 were in the wild homozygote group, 54 were in the mutant heterozygote group, and 8 were in the mutant homozygote group. (2) CYP3A4*1G allele mutation rate was 23.33%. The distribution of CYP3A4*1G alleles was consistent with Hardy-Weinberg genetic balance test (χ2=0.102, P=0.950). (3) Compared with wild homozygote group, terminal elimination half-life, area under the curve, and pain threshold at each time point in mutant heterozygote group and mutant homozygote group were significantly increased (P < 0.05), and clearance rate was significantly decreased (P < 0.05). Compared with mutant heterozygote group, terminal elimination half-life, area under the curve, and pain threshold at each time point in mutant homozygote group were significantly increased (P < 0.05), and clearance rate was significantly decreased (P < 0.05). (4) Multiple linear regression analysis showed that CYP3A4*1G gene polymorphism was significantly associated with pain threshold in mutant homozygotes and mutant heterozygotes (P < 0.05). (5) The results of two-factor analysis of variance showed that regardless of pharmacokinetic parameters, the difference of pain threshold among different genotypes was statistically significant (P < 0.001), the pain threshold of mutant homozygote > mutant heterozygote > wild homozygote. (6) The pain threshold of electrical stimulation in patients with different genotypes increased after injection of sufentanil compared with before administration, and decreased with the decrease of blood concentration of sufentanil, showing a good correlation (r=0.81, 0.89, 0.86, all P < 0.05). (7) It is indicated that in elderly patients undergoing joint replacement, the pain threshold increased after sufentanil injection, while CYP3A4*1G allele mutation would slow down sufentanil metabolism, and the pain threshold was significantly positively correlated with sufentanil blood concentration.

Key words: CYP3A4*1G, gene polymorphism, joint replacement, elderly patients, sufentanil, pharmacokinetics, pain threshold