{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T13:29:00Z","timestamp":1790342940939,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2004,3,9]],"date-time":"2004-03-09T00:00:00Z","timestamp":1078790400000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2004,3]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The etiology of acute chest syndrome, the most severe complication of the sickle cell crisis, is unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>Our objective was to assess exposure to morphine as an etiologic factor for acute chest syndrome in sickle cell disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A post hoc analysis of a randomized controlled trial comparing oral with continuous infusion of morphine was performed. Children (aged 5\u201317 years) with sickle cell crisis were randomized to receive oral sustained\u2010release morphine, 1.9 mg \u00b7 kg<jats:sup>\u22121<\/jats:sup> \u00b7 12 h<jats:sup>\u22121<\/jats:sup>, or a continuous intravenous infusion of morphine at 0.04 mg \u00b7 kg<jats:sup>\u22121<\/jats:sup> \u00b7 h<jats:sup>\u22121<\/jats:sup> by use of a double\u2010blind, placebo\u2010controlled design. In a subgroup of 15 patients, the pharmacokinetics of morphine and its active metabolite morphine\u20106\u2010glucuronide were also studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At baseline, demographic and physiologic characteristics were similar between groups. There were no differences in the number of previous rescue doses per day, painful sites per episode, physician contacts per year, and hospitalizations per year between treatment arms. There was a 2\u2010fold higher morphine area under the concentration\u2010time curve at steady state (AUC<jats:sub>ss<\/jats:sub>) and a 3\u2010fold higher morphine\u20106\u2010glucuronide AUC<jats:sub>ss<\/jats:sub> with oral morphine than with a continuous intravenous infusion of morphine (<jats:italic>P<\/jats:italic> &lt; .001 and <jats:italic>P<\/jats:italic> &lt; .006, respectively). New onset of acute chest syndrome was 3\u2010fold more prevalent in the oral group (57%) versus the continuous intravenous infusion group (17%) (<jats:italic>P<\/jats:italic> &lt; .001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The risk of acute chest syndrome is significantly associated with high systemic exposure to morphine and its active metabolite morphine\u20106\u2010glucuronide after oral administration of slow\u2010release morphine. Morphine may facilitate respiratory deterioration by eliciting a decrease in oxygen saturation, by inducing histamine release, or through an as\u2010yet\u2010unidentified mechanism. The safe systemic exposure to morphine in terms of area under the concentration\u2010time curve should be further studied in children with sickle cell disease.<\/jats:p><jats:p><jats:italic>Clinical Pharmacology &amp; Therapeutics<\/jats:italic> (2004) <jats:bold>75<\/jats:bold>, 140\u2013146; doi: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1016\/j.clpt.2003.10.007\">10.1016\/j.clpt.2003.10.007<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1016\/j.clpt.2003.10.007","type":"journal-article","created":{"date-parts":[[2004,3,6]],"date-time":"2004-03-06T10:39:24Z","timestamp":1078569564000},"page":"140-146","source":"Crossref","is-referenced-by-count":81,"title":["Systemic Exposure to Morphine and the Risk of Acute Chest Syndrome in Sickle Cell Disease"],"prefix":"10.1111","volume":"75","author":[{"given":"Ernest A.","family":"Kopecky","sequence":"first","affiliation":[{"name":"Divisions of Clinical Pharmacology and Toxicology and Pediatric Medicine The Hospital for Sick Children  Toronto"},{"name":"Faculty of Pharmacy University of Toronto  Toronto"},{"name":"Purdue Pharma  Stamford"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Divisions of Clinical Pharmacology and Toxicology and Pediatric Medicine The Hospital for Sick Children  Toronto"},{"name":"Faculty of Pharmacy University of Toronto  Toronto"},{"name":"Purdue Pharma  Stamford"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant","family":"Joshi","sequence":"additional","affiliation":[{"name":"Divisions of Clinical Pharmacology and Toxicology and Pediatric Medicine The Hospital for Sick Children  Toronto"},{"name":"Faculty of Pharmacy University of Toronto  Toronto"},{"name":"Purdue Pharma  Stamford"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Koren","sequence":"additional","affiliation":[{"name":"Divisions of Clinical Pharmacology and Toxicology and Pediatric Medicine The Hospital for Sick Children  Toronto"},{"name":"Faculty of Pharmacy University of Toronto  Toronto"},{"name":"Purdue Pharma  Stamford"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,3,9]]},"reference":[{"key":"e_1_2_5_2_1","first-page":"2503","article-title":"Hydroxyurea: specific therapy for sickle cell anemia","volume":"79","author":"Kaufman R. 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