ArticleFrontiers in pharmacology2026
Naloxone reversal of fentanyl-induced respiratory depression versus naloxone-induced precipitated withdrawal: an
Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Naloxone reverses opioid-induced respiratory depression (RD) but may precipitate withdrawal in opioid-dependent individuals. Although both have been studied separately, their concentration-response relationships have not been described within a single model. We developed a mechanistic pharmacokinetic/pharmacodynamic simulation model combining an established model of naloxone-induced reversal of fentanyl-induced RD with a novel mechanistic model of precipitated withdrawal based on normalized μ-opioid receptor activation. Methods: Utility was defined as the probability (P) of respiratory reversal minus the weighted probability of precipitated withdrawal, P(reversal) - k·P(withdrawal), where k denotes the relative weight assigned to withdrawal. A withdrawal threshold parameter Results: The model reproduced the expected concentration-response relationships for respiratory depression, withdrawal, and their combined utility. Utility increased with higher withdrawal thresholds and decreased with greater withdrawal weight. Calibration against clinical data yielded a preliminary Conclusion: The proposed model quantitatively links two pharmacodynamic consequences of competitive μ-opioid receptor antagonism and generates testable hypotheses regarding the receptor activation threshold underlying precipitated withdrawal. The presented utility function is an experimental modeling exercise. In life-threatening opioid overdoses, restoration of ventilation, prevention of hypoxic injury and survival take priority over avoidance of withdrawal (
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