{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:09:56Z","timestamp":1790197796909,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T00:00:00Z","timestamp":1754956800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T00:00:00Z","timestamp":1754956800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    As illegally made fentanyl and congeners continue to drive overdose deaths in the US, experts have called for stronger and longer\u2010lasting antagonists. A randomized, 4\u2010period, 2\u2010treatment crossover replicate\u2010design study in healthy moderately\u2010experienced opioid users (n = 24) evaluated the reversal of opioid\u2010induced respiratory depression (OIRD) by intramuscular (IM) nalmefene 1.5 mg administered by auto\u2010injector delivering a formulation developed for faster onset, compared to intranasal (IN) naloxone 4 mg. Fentanyl infusions were administered to induce a 50% reduction in minute ventilation (MV). Reversal of OIRD, pharmacokinetics, and safety were investigated under steady\u2010state fentanyl agonism. For the primary endpoint, nalmefene demonstrated superiority at 5 min with an MV increase of 4.59 L\/min, more than twice the 1.99 L\/min increase for naloxone (\n                    <jats:italic>P<\/jats:italic>\n                    \u00a0&lt;\u00a0.0001). Nalmefene superiority was also demonstrated at 10, 15, 20, and 30 min, while non\u2010inferiority was demonstrated at 2.5 and 90 min. The time\u2010course of mean antagonist concentrations correlated with increases in mean MV, peaking at approximately 5\u201010 min following nalmefene compared to 20\u201030 min following naloxone. Decreases in transcutaneous CO\n                    <jats:sub>2<\/jats:sub>\n                    (TCO\n                    <jats:sub>2<\/jats:sub>\n                    ) followed a similar time\u2010course with a slight delay. At each threshold of percent reversal (25%\u2010100%), nalmefene consistently showed a faster time to onset than naloxone. Both antagonist treatments were tolerated with no serious adverse events. This study shows that nalmefene 1.5 mg IM administered by auto\u2010injector achieved a faster onset, higher magnitude, and longer duration of reversal of OIRD compared to naloxone 4 mg IN and represents another option for the treatment of opioid overdose.\n                  <\/jats:p>","DOI":"10.1002\/jcph.70088","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T02:55:04Z","timestamp":1755053704000},"page":"1661-1675","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Reversal of Fentanyl\u2010Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene Administered by Auto\u2010Injector Versus Intranasal Naloxone"],"prefix":"10.1002","volume":"65","author":[{"given":"Alessandra","family":"Cipriano","sequence":"first","affiliation":[{"name":"Imbrium Therapeutics L.P., a subsidiary of Purdue Pharma L.P.  Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellie","family":"He","sequence":"additional","affiliation":[{"name":"Imbrium Therapeutics L.P., a subsidiary of Purdue Pharma L.P.  Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manjunath","family":"Shet","sequence":"additional","affiliation":[{"name":"Imbrium Therapeutics L.P., a subsidiary of Purdue Pharma L.P.  Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glen","family":"Apseloff","sequence":"additional","affiliation":[{"name":"Ohio Clinical Trials, LLC  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C.","family":"Harris","sequence":"additional","affiliation":[{"name":"Imbrium Therapeutics L.P., a subsidiary of Purdue Pharma L.P.  Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,12]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"AhmadFB RossenLM SuttonP.Provisional Drug Overdose Death Counts.National Center for Health Statistics. Accessed March 28 2025.https:\/\/www.cdc.gov\/nchs\/nvss\/vsrr\/drug\u2010overdose\u2010data.htm"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/yco.0000000000000717"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugpo.2017.06.010"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12630\u2010019\u201001294\u2010y"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6905a2"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2016.11.033"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.40736"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2024.1399803"},{"key":"e_1_2_10_10_1","volume-title":"Provisional drug overdose death counts","author":"Ahmad FB","year":"2024"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2022.05.013"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.114293"},{"key":"e_1_2_10_13_1","unstructured":"NallaniS SmithLT UppoorRS MehtaMU.Reversal of high potency synthetic opioid overdose: literature review [poster]. Presented at: 2021 FDA Science Forum; May 26 2021; virtual.https:\/\/www.fda.gov\/science\u2010research\/fda\u2010science\u2010forum\/reversal\u2010high\u2010potency\u2010synthetic\u2010opioid\u2010overdose\u2010literature\u2010review."},{"key":"e_1_2_10_14_1","unstructured":"FDA approves naloxone injection to counteract opioid overdoses [press release].U.S. Food & Drug Administration. Accessed March 14 2025.https:\/\/www.fda.gov\/drugs\/news\u2010events\u2010human\u2010drugs\/fda\u2010approves\u2010naloxone\u2010injection\u2010counteract\u2010opioid\u2010overdoses"},{"key":"e_1_2_10_15_1","unstructured":"FDA approves higher dosage of naloxone nasal spray to treat opioid overdose [press release].U.S. Food & Drug Administration. Accessed March 14 2025.https:\/\/www.fda.gov\/news\u2010events\/press\u2010announcements\/fda\u2010approves\u2010higher\u2010dosage\u2010naloxone\u2010nasal\u2010spray\u2010treat\u2010opioid\u2010overdose"},{"key":"e_1_2_10_16_1","unstructured":"Data from: State Unintentional Drug Overdose Reporting System (SUDORS).Centers for Disease Control and Prevention.2024. Accessed March 14 2025.https:\/\/www.cdc.gov\/drugoverdose\/fatal\/dashboard"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2021.108019"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsr1706626"},{"key":"e_1_2_10_19_1","unstructured":"US Food and Drug Administration.Determination that REVEX (nalmefene hydrochloride injection) 0.1 milligram base\/milliliter and 1.0 milligram base\/milliliter was not withdrawn from sale for reasons of safety or effectiveness.Federal Regist. 2017;82(212):51282\u201151283.https:\/\/www.federalregister.gov\/documents\/2017\/11\/03\/2017\u201023952\/determination\u2010that\u2010revex\u2010nalmefene\u2010hydrochloride\u2010injection\u201001\u2010milligram\u2010basemilliliter\u2010and\u201010"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.118.256115"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.759"},{"key":"e_1_2_10_22_1","unstructured":"IndiviorI.OPVEE\u00ae (nalmefene) nasal spray: full prescribing information[package insert]. 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