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Background <p>Fentanyl, a synthetic opioid with potent analgesic and sedative properties, is widely administered in intensive care. Many critically ill patients present with, or develop, hypothermia driven by multifactorial disturbances such as sepsis, trauma, circulatory shock, or environmental exposure. Because reduced core temperature affects perfusion, metabolism, and clearance, hypothermia may meaningfully alter fentanyl disposition, although these effects remain insufficiently defined. Given these uncertainties, this study investigates how moderate hypothermia (MH) and severe hypothermia (SH) alter the pharmacokinetics of fentanyl and its primary metabolite, norfentanyl, compared with normothermic controls.</p> Methods <p>Male Wistar rats were divided into three groups and subjected to different environmental temperatures: normothermic controls (37&#xa0;°C), MH (30&#xa0;°C), and SH (27&#xa0;°C). Fentanyl (10&#xa0;µg/kg) was administered via a short intravenous infusion, and serial blood samples were collected over 60&#xa0;min. Serum fentanyl and norfentanyl concentrations were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin software.</p> Results <p>Maximum fentanyl concentration increased in both MH and SH groups, reaching statistical significance only under severe hypothermia (<i>p &lt;</i> 0.001). The area under the concentration-time curve (AUC) increased markedly (<i>p</i> = 0.009) in SH group, indicating increased overall drug exposure. Clearance decreased by 44% (<i>p</i> = 0.010), and volume of distribution in steady state (V<sub>ss</sub>) was reduced in both groups (SH: <i>p &lt;</i> 0.001, MH: <i>p</i> = 0.029), reflecting impaired drug elimination under severe hypothermic conditions. For norfentanyl, exposure increased significantly in the SH group across all parameters, whereas in the MH group increases were limited to C<sub>max</sub> and AUC<sub>0–t</sub>.</p> Conclusions <p>Hypothermia significantly alters fentanyl and norfentanyl pharmacokinetics in a temperature-dependent manner.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2026年1月23日

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  • Paulina Stach,
  • Kamil Skowron,
  • Sebastian Rojek,
  • Agnieszka Cios,
  • Anna Wesołowska,
  • Marilyn A. Huestis,
  • Krzysztof Gil

摘要

Background

Fentanyl, a synthetic opioid with potent analgesic and sedative properties, is widely administered in intensive care. Many critically ill patients present with, or develop, hypothermia driven by multifactorial disturbances such as sepsis, trauma, circulatory shock, or environmental exposure. Because reduced core temperature affects perfusion, metabolism, and clearance, hypothermia may meaningfully alter fentanyl disposition, although these effects remain insufficiently defined. Given these uncertainties, this study investigates how moderate hypothermia (MH) and severe hypothermia (SH) alter the pharmacokinetics of fentanyl and its primary metabolite, norfentanyl, compared with normothermic controls.

Methods

Male Wistar rats were divided into three groups and subjected to different environmental temperatures: normothermic controls (37 °C), MH (30 °C), and SH (27 °C). Fentanyl (10 µg/kg) was administered via a short intravenous infusion, and serial blood samples were collected over 60 min. Serum fentanyl and norfentanyl concentrations were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin software.

Results

Maximum fentanyl concentration increased in both MH and SH groups, reaching statistical significance only under severe hypothermia (p < 0.001). The area under the concentration-time curve (AUC) increased markedly (p = 0.009) in SH group, indicating increased overall drug exposure. Clearance decreased by 44% (p = 0.010), and volume of distribution in steady state (Vss) was reduced in both groups (SH: p < 0.001, MH: p = 0.029), reflecting impaired drug elimination under severe hypothermic conditions. For norfentanyl, exposure increased significantly in the SH group across all parameters, whereas in the MH group increases were limited to Cmax and AUC0–t.

Conclusions

Hypothermia significantly alters fentanyl and norfentanyl pharmacokinetics in a temperature-dependent manner.

Graphical Abstract