{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T20:05:10Z","timestamp":1780603510683,"version":"3.54.1"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2017,1,1]],"date-time":"2017-01-01T00:00:00Z","timestamp":1483228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Klinikum f\u00fcr Anaesthesiologie"},{"name":"Klinikum rechts der Isar"},{"DOI":"10.13039\/501100005713","name":"Technische Universit\u00e4t, Munich, Germany","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005713","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Chronic administration of morphine and midazolam, alone or in combination, can induce tolerance to their effects. Data showed that co-administration of morphine and midazolam increased effective dose requirement of morphine, exceeding that observed with morphine alone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To elucidate the pharmacokinetic component to the tolerance, we administered midazolam (2 mg\/kg) and morphine (10 mg\/kg) alone or their combination daily to rats for 12 days followed by a pharmacokinetic study on day 13. On the study day, each animal received a single bolus dose of 5 mg\/kg morphine, and 2 mg\/kg of midazolam 30 s later. Multiple blood samples were obtained for 6 h. Plasma drug concentrations were assayed by mass spectrometry optimized for small samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key findings<\/jats:title><jats:p>Mean morphine clearance was as follows: 22.2, 27.2, 26.0 and 23.4 l\/h per kg in the saline\u2013saline, saline\u2013midazolam, saline\u2013morphine and midazolam\u2013morphine groups, respectively. Corresponding midazolam clearances were 32.8, 23.0, 22.2 and 31.1 l\/h per kg. ANOVA indicated no significant differences among the four groups in the clearances, half-lives, and volumes of distribution. Morphine and midazolam clearances were significantly correlated (R2 = 0.48, P &amp;lt; 0.001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This animal model suggests that altered pharmacokinetics cannot explain tolerance evidenced as increased dose requirement for morphine or midazolam, when administered alone or combination, for extended periods.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jphp.12663","type":"journal-article","created":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T08:56:49Z","timestamp":1480323409000},"page":"82-88","source":"Crossref","is-referenced-by-count":8,"title":["Pharmacokinetics cannot explain the increased effective dose requirement for morphine and midazolam in rats during their extended administration alone or in combination"],"prefix":"10.1093","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6683-9584","authenticated-orcid":false,"given":"Stefan J","family":"Schaller","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children \u2013 Boston , Boston, MA,","place":["USA"]},{"name":"Harvard Medical School , Boston, MA,","place":["USA"]},{"name":"Klinik f\u0171r Anaesthesiologie, Klinikum rechts der Isar, Technische Universit\u00e4t M\u0171nchen , Munich,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saad M","family":"Alam","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children \u2013 Boston , Boston, MA,","place":["USA"]},{"name":"Harvard Medical School , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianren","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children \u2013 Boston , Boston, MA,","place":["USA"]},{"name":"Harvard Medical School , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Zhao","sequence":"additional","affiliation":[{"name":"Program in Pharmacology and Experimental Therapeutics, Tufts University School of Medicine , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Blobner","sequence":"additional","affiliation":[{"name":"Klinik f\u0171r Anaesthesiologie, Klinikum rechts der Isar, Technische Universit\u00e4t M\u0171nchen , Munich,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J","family":"Greenblatt","sequence":"additional","affiliation":[{"name":"Program in Pharmacology and Experimental Therapeutics, Tufts University School of Medicine , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J A Jeevendra","family":"Martyn","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children \u2013 Boston , Boston, MA,","place":["USA"]},{"name":"Harvard Medical School , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,1,1]]},"reference":[{"key":"2024103012562141400_jphp12663-cit-0001","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1097\/CCM.0b013e3182783b72","article-title":"Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit","volume":"41","author":"Barr","year":"2013","journal-title":"Crit Care 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