Key Takeaways & Executive Findings
- •• CYP3A4*1G gene polymorphism significantly affects sufentanil pharmacokinetics in elderly joint replacement patients, with mutant genotypes showing prolonged elimination half-life and reduced clearance. • Patients with CYP3A4*1G mutations exhibit higher pain thresholds after sufentanil administration, indicating altered analgesic response. • Pain threshold is positively correlated with sufentanil plasma concentration, and this correlation is stronger in mutant genotype groups. • Genotype-guided dosing of sufentanil may improve individualized pain management in elderly patients undergoing joint replacement.
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-way ANOVA. Pearson correlation analysis was used to analyze the correlation between sufentanil plasma concentration and pain threshold under different genotypes. RESULTS AND CONCLUSION: Among the 150 patients, 88 were wild-type homozygotes, 54 were mutant heterozygotes, and 8 were mutant homozygotes. The allele mutation rate of CYP3A4*1G was 23.33%, and the distribution of CYP3A4*1G alleles conformed to the Hardy-Weinberg genetic equilibrium test (χ2=0.102, P=0.950). Compared with the wild-type homozygote group, the mutant heterozygote and mutant homozygote groups had significantly increased terminal elimination half-life, area under the curve, and pain threshold at each time point (P < 0.05), and significantly decreased clearance rate (P < 0.05). Compared with the mutant heterozygote group, the mutant homozygote group had significantly increased terminal elimination half-life, area under the curve, and pain threshold at each time point (P < 0.05), and significantly decreased clearance rate (P < 0.05). 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). Two-way ANOVA showed that regardless of pharmacokinetic parameters, the difference in pain threshold among different genotype groups was significant (P < 0.001), with mutant homozygotes > mutant heterozygotes > wild-type homozygotes. The electrical stimulation pain threshold of patients with different genotypes increased after sufentanil injection compared with before administration, and decreased with the decrease of sufentanil plasma concentration, with good correlation (r=0.81, 0.89, 0.86, all P < 0.05). It is suggested that the pain threshold of elderly patients undergoing joint replacement increases after sufentanil injection, and the CYP3A4*1G allele mutation slows down the metabolism of sufentanil, and the pain threshold is significantly positively correlated with the plasma concentration of sufentanil.
1. Introduction
Severe pain after joint replacement in elderly patients requires effective analgesic drugs, but traditional empirical medication often leads to insufficient or excessive doses, causing adverse reactions such as respiratory depression. Due to organ function decline and reduced drug metabolism capacity, postoperative analgesia in elderly patients needs precise regulation [1-3]. Sufentanil is widely used for postoperative analgesia after joint replacement in elderly patients, but individual responses to sufentanil vary significantly, mainly related to its metabolic rate, which not only affects analgesic efficacy but may also lead to adverse reactions [4-6]. Cytochrome P450 (CYP) 3A4 is involved in the metabolism of many commonly used clinical drugs in the human liver and intestine, and sufentanil is one of its substrates [7-9].
Variations at the CYP3A4*1G locus can alter CYP3A4 enzyme activity, affecting the metabolism of sufentanil, ultimately influencing its pharmacokinetic characteristics in the body and its regulatory effect on pain threshold [10-12]. Currently, research on CYP3A4*1G gene polymorphism in the application of sufentanil after joint replacement in elderly patients is still relatively scarce, and the specific mechanism of CYP3A4*1G polymorphism on sufentanil metabolism has not been revealed, nor has it been linked to the multidimensional mechanism of pain threshold regulation. Therefore, this study takes elderly patients undergoing joint replacement as the research object to explore the effect of CYP3A4*1G gene polymorphism on the pharmacokinetics and pain threshold of sufentanil after surgery, aiming to improve the theoretical system of pharmacogenomics in the field of perioperative analgesia in elderly patients.
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PENG Changsheng, ZHOU Jianjun, HU Xuhua, JIN Ming, XIE Wenlong (2026). Effect of CYP3A4*1G gene polymorphism on pharmacokinetics and pain threshold of sufentanil after joint replacement in elderly patients. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21622
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Frequently Asked Questions
What is the significance of CYP3A4*1G gene polymorphism in elderly patients undergoing joint replacement?
CYP3A4*1G gene polymorphism affects the activity of CYP3A4 enzyme, which is crucial for the metabolism of sufentanil. This polymorphism leads to inter-individual variability in drug metabolism, influencing both pharmacokinetics and analgesic effects. In elderly patients, this can result in different pain thresholds and potential adverse effects, highlighting the need for genotype-guided dosing.
How does CYP3A4*1G polymorphism affect sufentanil pharmacokinetics?
In this study, patients with mutant genotypes (heterozygotes and homozygotes) showed significantly increased terminal elimination half-life and area under the curve, and decreased clearance rate compared to wild-type homozygotes. This indicates slower metabolism and higher drug exposure in carriers of the mutation.
What is the relationship between CYP3A4*1G polymorphism and pain threshold?
The study found that pain threshold was significantly higher in patients with mutant genotypes compared to wild-type, with mutant homozygotes having the highest pain threshold. This suggests that the polymorphism influences analgesic response, possibly due to altered sufentanil metabolism and concentration.
Can CYP3A4*1G genotyping be used to personalize sufentanil dosing in elderly patients?
Yes, genotyping for CYP3A4*1G can help predict sufentanil metabolism and analgesic response. This information can guide dose adjustments to achieve optimal pain control while minimizing adverse effects, especially in elderly patients who are more vulnerable to drug-related complications.
What are the clinical implications of this study for postoperative pain management?
The study emphasizes the importance of considering genetic factors in postoperative pain management. By identifying patients with CYP3A4*1G mutations, clinicians can tailor sufentanil dosing to improve analgesic efficacy and safety, potentially reducing the risk of under- or over-dosing.
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