{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:07:31Z","timestamp":1789020451472,"version":"build-2803163510"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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 \u03bc-opioid receptor activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Utility was defined as the probability (P) of respiratory reversal minus the weighted probability of precipitated withdrawal, P(reversal) \u2212 k\u00b7P(withdrawal), where k denotes the relative weight assigned to withdrawal. A withdrawal threshold parameter\n                      <jats:italic>w<\/jats:italic>\n                      was introduced to reflect the fractional decrease in \u03bc-opioid receptor activation required to precipitate withdrawal.\n                      <jats:italic>w<\/jats:italic>\n                      was calibrated using published naloxone-withdrawal data. Simulations allowed evaluations across varying naloxone concentrations, overdose severities, withdrawal thresholds and weighting factors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>w<\/jats:italic>\n                      estimate = 0.30 (95%CI 0.16\u20130.40). At this value of\n                      <jats:italic>w<\/jats:italic>\n                      at k = 1 (a neutral model reference of equal weight to reversal and withdrawal), the utility was negative over the naloxone concentration range of 10\u201330\u00a0ng\/mL, indicating that modeled probability of precipitated withdrawal exceeded that of model-defined respiratory reversal over this range. At k &amp;lt; 1, the utility became positive.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The proposed model quantitatively links two pharmacodynamic consequences of competitive \u03bc-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 (\n                      <jats:italic>i.e.,<\/jats:italic>\n                      set k &amp;lt; 1).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1944044","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:33:15Z","timestamp":1789018395000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Naloxone reversal of fentanyl-induced respiratory depression versus naloxone-induced precipitated withdrawal: an in silico utility model"],"prefix":"10.3389","volume":"17","author":[{"given":"Albert","family":"Dahan","sequence":"first","affiliation":[{"name":"MediD Consultancy Group","place":["Amsterdam, Netherlands"]},{"name":"Centre for Human Drug Research","place":["Leiden, Netherlands"]},{"name":"Enalare Therapeutics Inc.","place":["Mullica Hill, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack D. 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