{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:48:03Z","timestamp":1789055283934,"version":"build-2803163510"},"reference-count":31,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:00:00Z","timestamp":1768003200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:00:00Z","timestamp":1768003200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:p>Few studies have quantified the effects of non\u2010pharmacological interventions (e.g., rescue breathing) in the setting of community opioid overdose. We extended a previously validated model for opioid antagonists by incorporating the mechanism of rescue breathing, and quantified combinatorial effects between rescue breathing and various formulations of naloxone under different fentanyl overdose scenarios in a virtual patient population suffering from opioid\u2010induced respiratory failure. We defined successful reversal of an overdose as fewer than 5% of the virtual population experiencing cardiac arrest after intervention. Our model showed that timely rescue breathing reduced the naloxone dose needed for successful overdose reversal from greater than 8\u2009mg (intranasal) to less than 2\u2009mg (intramuscular) and extended the naloxone rescue window to 10\u2009minutes under a median fentanyl intravenous overdose scenario. Administration of 4\u2009mg naloxone intranasally reduced the duration of rescue breathing needed from 11\u2009hours to 5\u2009minutes under a median fentanyl transmucosal overdose scenario. High\u2010quality (as delivered by well\u2010trained rescuers), but not low\u2010quality (as delivered by laypersons), rescue breathing could successfully rescue severe opioid overdose scenarios. Even in cases where virtual subjects survived without naloxone, 4\u2009mg intranasal naloxone provided benefit by shortening the time to recovery of spontaneous. Our results highlight the importance of utilizing both pharmacological and non\u2010pharmacological interventions in reversal of overdose.<\/jats:p>","DOI":"10.1002\/cpt.70186","type":"journal-article","created":{"date-parts":[[2026,1,11]],"date-time":"2026-01-11T07:35:52Z","timestamp":1768116952000},"page":"1466-1475","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Modeling Supports Combinatorial Effects Between Pharmacological and Non\u2010Pharmacological Interventions to Prevent Opioid\u2010Induced Cardiac Arrest"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5877-7419","authenticated-orcid":false,"given":"Bradlee","family":"Thrasher","sequence":"first","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Mann","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8114-5820","authenticated-orcid":false,"given":"Anik","family":"Chaturbedi","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1664-0977","authenticated-orcid":false,"given":"Shilpa","family":"Chakravartula","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7269-4687","authenticated-orcid":false,"given":"Hamed","family":"Meshkin","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0666-7696","authenticated-orcid":false,"given":"Affan","family":"Affan","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0788-4166","authenticated-orcid":false,"given":"Alexander","family":"Galluppi","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4062-8040","authenticated-orcid":false,"given":"Ji Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8644-067X","authenticated-orcid":false,"given":"Nigar","family":"Karimli","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7372-6724","authenticated-orcid":false,"given":"Yue","family":"Han","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6405-724X","authenticated-orcid":false,"given":"Zachary","family":"Dezman","sequence":"additional","affiliation":[{"name":"Division of Anesthesiology, Addiction Medicine, and Pain Medicine, Office of Neuroscience, Office of New Drugs, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1984-8026","authenticated-orcid":false,"given":"Jeffry","family":"Florian","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2772-0839","authenticated-orcid":false,"given":"Zhihua","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,10]]},"reference":[{"issue":"2","key":"e_1_2_11_1_1","first-page":"S366","article-title":"Part 3: adult basic and advanced life support: 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care","volume":"142","author":"Panchal A.R.","year":"2020","journal-title":"Circulation"},{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs\u20105519093\/v1"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.51839"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm7305a4"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/add.15806"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3527"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2696"},{"key":"e_1_2_11_8_1","unstructured":"SAMHSA.Overdose Prevention and Response Toolkit<https:\/\/library.samhsa.gov\/sites\/default\/files\/overdose\u2010prevention\u2010response\u2010kit\u2010pep23\u201003\u201000\u2010001.pdf>."},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resuscitation.2005.03.024"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000539-200111000-00046"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2281.2001.00349.x"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.106.6.1806"},{"key":"e_1_2_11_13_1","unstructured":"USFDA.E14 Clinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Non\u2010Antiarrhythmic Drugs<https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/e14\u2010clinical\u2010evaluation\u2010qtqtc\u2010interval\u2010prolongation\u2010and\u2010proarrhythmic\u2010potential\u2010non\u2010antiarrhythmic\u20100>."},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chas.0c00096"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-199108000-00009"},{"key":"e_1_2_11_16_1","unstructured":"USFDA.KLOXXADO\u2122 (naloxone hydrochloride) nasal spray<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/212045s000lbl.pdf>."},{"key":"e_1_2_11_17_1","unstructured":"USFDA.Naloxone Hydrochloride Injection Updated December 2024<https:\/\/dailymed.nlm.nih.gov\/dailymed\/fda\/fdaDrugXsl.cfm?setid=236349ef\u20102cb5\u201047ca\u2010a3a5\u201099534c3a4996&type=display>."},{"key":"e_1_2_11_18_1","unstructured":"USFDA.NARCAN\u00ae (naloxone hydrochloride) nasal spray<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2015\/208411lbl.pdf>."},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2027"},{"key":"e_1_2_11_20_1","unstructured":"USFDA.Actiq\u00ae (oral transmucosal fentanyl citrate)<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/1998\/20747lbl.pdf>."},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/2042098617744161"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM195405062501801"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm7416a2"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm7348a2"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-200208000-00001"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6935a1"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadr.2024.100223"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.1464"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2018-025567"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugpo.2021.103457"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugpo.2024.104323"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70186","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70186","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70186","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T03:29:07Z","timestamp":1778297347000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70186"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,10]]},"references-count":31,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/cpt.70186"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70186","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,10]]},"assertion":[{"value":"2025-10-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}