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We explored the physiological implications of both drugs on ventilation and airway patency in anaesthetized mice. Our results revealed a similar reduction in respiratory frequency with equivalent scaled dosages of fentanyl and morphine, though the onset of suppression was more rapid with fentanyl. Additionally, fentanyl resulted in transient airflow obstructions during the inspiratory cycle, which were absent following morphine administration. Notably, these fentanyl\u2010specific obstructions were eliminated with tracheostomy, implicating the upper airways as a major factor contributing to fentanyl\u2010induced respiratory depression. We further demonstrate that bronchodilators salbutamol and adrenaline effectively reversed these obstructions, highlighting the bronchi's contribution to fentanyl\u2010induced airflow obstruction. Our study also uncovered a significant reduction in sighs during OIRD, which were eliminated by fentanyl and markedly reduced by morphine. Finally, we found that fentanyl\u2010exposed mice had reduced survival under hypoxic conditions compared to mice given morphine, demonstrating that fentanyl becomes more lethal in the context of hypoxaemia. Our findings shed light on the distinct and profound impacts of these opioids on respiration and airway stability and lay the foundation for improved opioid use guidelines and more effective OIRD prevention strategies.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15728-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Both morphine and fentanyl significantly suppressed respiratory frequency, but the onset of suppression was faster with fentanyl. Also, while both drugs increased tidal volume, this effect was more pronounced with fentanyl.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Fentanyl administration resulted in transient obstructions during the inspiratory phase, suggesting its unique impact on airway stability. This obstruction was not observed with morphine.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The fentanyl\u2010induced obstructions were reversed by administering bronchodilators such as salbutamol and adrenaline. This suggests a possible therapeutic strategy for mitigating the adverse airway effects of fentanyl.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Both drugs reduced the frequency of physiological sighs, a key mechanism to prevent alveolar collapse. However, fentanyl administration led to a complete cessation of sighs, while morphine only reduced their occurrence.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Fentanyl\u2010treated mice showed a significantly reduced ability to survive under hypoxic conditions compared to those administered morphine. This indicates that the impacts of hypoxaemia during opioid\u2010induced respiratory depression can vary based on the opioid used.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp285163","type":"journal-article","created":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T17:23:40Z","timestamp":1696181020000},"page":"4625-4642","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["A comparative examination of morphine and fentanyl: unravelling the differential impacts on breathing and airway stability"],"prefix":"10.1113","volume":"601","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7986-4247","authenticated-orcid":false,"given":"Nicholas J.","family":"Burgraff","sequence":"first","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan A.","family":"Baertsch","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle WA USA"},{"name":"Department of Pediatrics University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5626-3999","authenticated-orcid":false,"given":"Jan\u2010Marino","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle WA USA"},{"name":"Department of Pediatrics University of Washington  Seattle WA USA"},{"name":"Department of Neurological Surgery University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature18944"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.67523"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-022-03300-7"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.4103\/ija.ija_171_22"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15580"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201511654"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1329-21.2021"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00150.2022"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-011-2239-8"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.5664\/jcsm.3954"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181c38c25"},{"issue":"5","key":"e_1_2_5_13_1","first-page":"449","article-title":"Fentanyl\u2010induced cough\u2013pathophysiology and prevention","volume":"22","author":"El Baissari M. 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