Author: van Lemmen, Maarten et al.
Anesthesiology. August 2025. doi:10.1097/ALN.0000000000005710
This exploratory study examined the ventilatory effects of fentanyl in healthy volunteers using a pharmacokinetic–pharmacodynamic modeling approach. Twelve subjects received five sequential clinical doses of fentanyl (totaling 350 µg over two hours), with ventilatory parameters and end-tidal CO₂ monitored. Three models were tested: one describing ventilation alone, one describing CO₂ alone, and a combined physiological model incorporating CO₂ kinetics and ventilatory control.
The combined physiological model produced a markedly lower fentanyl potency estimate (C50 of 2.3 ng/mL) compared with the simpler ventilation-only model (7.5 ng/mL). The physiological model also yielded unique parameters describing ventilatory controller gain, time constant, and tissue CO₂ volume. These findings suggest that models accounting for CO₂ kinetics provide more pharmacologically realistic and clinically relevant assessments of opioid-induced ventilatory depression.
What you should know:
-
Fentanyl can significantly depress ventilation at lower concentrations than simpler models predict.
-
Traditional models may overestimate the concentration needed to cause ventilatory depression.
-
A more realistic potency estimate (C50 ~2.3 ng/mL) was derived when CO₂ feedback was included.
-
This suggests clinical opioid safety assessments may need to integrate ventilatory control mechanisms rather than relying on simplified pharmacodynamic models.
Thank you to Anesthesiology for allowing me to use this article.