Impact of environmentally induced hypothermia on fentanyl and norfentanyl pharmacokinetics following intravenous administration to Wistar rats

Critically ill patients frequently develop hypothermia from sepsis, trauma, or environmental exposure, which can alter drug disposition, yet the effect on fentanyl pharmacokinetics has not been well defined. This study compared fentanyl and norfentanyl pharmacokinetics in Wistar rats exposed to moderate (30°C) or severe (27°C) environmentally induced hypothermia versus normothermic controls following intravenous fentanyl administration, with concentrations measured by LC-ESI-MS/MS and parameters calculated using Phoenix WinNonlin. Severe hypothermia significantly increased fentanyl Cmax and AUC while reducing clearance by 44% and decreasing volume of distribution, with norfentanyl exposure also increased across all measured parameters; moderate hypothermia produced smaller, more limited changes. The results demonstrate that hypothermia alters fentanyl and norfentanyl pharmacokinetics in a temperature-dependent manner, which may have implications for opioid dosing in hypothermic critically ill patients.