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Subjects were administered a hypercapnic gas mixture which produces an elevation in minute ventilation (MV), a result of the ventilatory response to hypercapnia. Subjects breathed a hypercapnic gas mixture through a tight\u2010fitting mask for an initial period of 46 min prior to a series of mask \u201cholidays\u201d introduced to reduce subject discomfort and encourage study completion. Ten minutes after initiating the hypercapnic gas mixture, a remifentanil bolus was administered, and an infusion continued for the study duration. Subjects were administered either naloxone or nalmefene 15 min after initiating the remifentanil infusion and MV monitored for 21 min followed by a mask holiday. Both nalmefene and naloxone produced a time\u2010dependent reversal of remifentanil\u2010induced reductions in MV measured 2.5\u201320 min post administration. At the primary endpoint (5 min post administration), nalmefene increases in MV (5.75 L\/min) were nearly twice that produced by naloxone (3.01 L\/min) (<jats:italic>P<\/jats:italic> &lt; .0009); the point estimate favors nalmefene, demonstrating non\u2010inferiority and superiority. In this model of opioid\u2010induced respiratory depression, nalmefene has a more rapid onset of action than naloxone, which required 20 min to achieve a comparable reversal of respiratory depression. Both nalmefene and naloxone were well tolerated by healthy volunteers. This rapid onset of action may prove particularly valuable in an era when over 90% of fatalities are linked to synthetic opioid overdose.<\/jats:p>","DOI":"10.1002\/jcph.2421","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T11:18:42Z","timestamp":1709551122000},"page":"828-839","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Reversal of Opioid\u2010Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone"],"prefix":"10.1002","volume":"64","author":[{"given":"Mark","family":"Ellison","sequence":"first","affiliation":[{"name":"Phax Pharma  Watford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Hutton","sequence":"additional","affiliation":[{"name":"Indivior, Inc., N  Chesterfield VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Webster","sequence":"additional","affiliation":[{"name":"Dr. Vince Clinical Research  Overland Park KS USA"},{"name":"Center for U.S. Policy  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2646-815X","authenticated-orcid":false,"given":"Phil","family":"Skolnick","sequence":"additional","affiliation":[{"name":"Indivior, Inc., N  Chesterfield VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,4]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"AhmadFB CisewskiJA RossenLM SuttonP.Provisional drug overdose death counts. 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