Pharmacokinetics of Sufentanil After Epidural Administration During the Course of Extensive Abdominal Surgery.

BACKGROUND AND OBJECTIVE: Epidural sufentanil is widely used for intraoperative analgesia and is recognized as a safe and effective route of administration when carefully monitored and administered at the lowest effective doses. Optimizing drug dosing requires a precise understanding of its pharmacokinetics. While it is known that sufentanil concentrations in the blood decline more slowly after epidural administration compared with intravenous administration, and the flip-flop phenomenon has been observed in this context, a pharmacokinetic model accounting for this phenomenon has not yet been described. METHODS: This study aimed to develop a pharmacokinetic model of sufentanil following epidural administration, with a focus on its absorption from the epidural space. The study was performed in 23 patients, aged 30-83 years with an American Society of Anesthesiologists (ASA) classification of 2-3, undergoing major abdominal (oncologic and non-oncologic) surgery under general anesthesia and epidural analgesia. Blood samples were collected, and sufentanil concentrations were measured at time points ensuring coverage of the absorption phase. Population analysis was performed using a full Bayesian approach implemented in Stan/Torsten programs with the "cmdstanr" and "bbr.bayes" packages in RStudio. RESULTS: The Bayesian approach helped incorporate prior information about sufentanil disposition. A two-compartment disposition model with two-compartmental absorption best described the data, featuring a fast absorption rate constant into plasma and the peripheral compartment, and a slow redistribution process from the epidural fat compartment. CONCLUSIONS: This study mechanistically describes the flip-flop pharmacokinetics of sufentanil and allows for more precise dosing of epidural sufentanil (NCT06069219).