{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T15:18:49Z","timestamp":1747149529046,"version":"3.40.5"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T00:00:00Z","timestamp":1631836800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration\u2010effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic\/pharmacodynamic analysis of COMFORT\u2010Behavior (COMFORT\u2010B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up\u2010titration). In responders to morphine up\u2010titration, the COMFORT\u2010B score slowly decreases with increasing morphine concentrations at morphine concentrations &gt;20 ng\/mL. In nonresponding children, no decrease in COMFORT\u2010B score is expected. In general, lower baseline COMFORT\u2010B scores (2.1 points on average) in younger children (postnatal age &lt;10.3 days) were found. Based on the model, we conclude that the percentage of children at a desirable COMFORT\u2010B score is maximized at a morphine concentration between 5 and 30 ng\/mL for children aged &lt;10 days, and between 5 and 40 ng\/mL for children &gt;10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put &gt;95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children.<\/jats:p>","DOI":"10.1002\/jcph.1952","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T18:28:46Z","timestamp":1628792926000},"page":"99-109","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Quantifying the Pharmacodynamics of Morphine in the Treatment of Postoperative Pain in Preverbal Children"],"prefix":"10.1002","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3369-6107","authenticated-orcid":false,"given":"Sebastiaan C.","family":"Goulooze","sequence":"first","affiliation":[{"name":"Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research Leiden University  Leiden The Netherlands"},{"name":"LAP&amp;P Consultants BV  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tirsa","family":"de Kluis","sequence":"additional","affiliation":[{"name":"Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research Leiden University  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monique","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Erasmus University MC\u2013Sophia Children's Hospital  Rotterdam The Netherlands"},{"name":"Section Nursing Science Department of Internal Medicine Erasmus University MC  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilse","family":"Ceelie","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University MC Utrecht\u2013Wilhelmina Children's Hospital  Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saskia N.","family":"de Wildt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Erasmus University MC\u2013Sophia Children's Hospital  Rotterdam The Netherlands"},{"name":"Department of Pharmacology and Toxicology Research Institute Health Sciences Radboud University MC  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dick","family":"Tibboel","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Erasmus University MC\u2013Sophia Children's Hospital  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elke H.J.","family":"Krekels","sequence":"additional","affiliation":[{"name":"Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research Leiden University  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherijne A.J.","family":"Knibbe","sequence":"additional","affiliation":[{"name":"Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research Leiden University  Leiden The Netherlands"},{"name":"Department of Clinical Pharmacy St. Antonius Hospital  Nieuwegein The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,9,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9592.2007.02213.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-010-0333-1"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2016.06.026"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-013-0097-6"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-014-0135-4"},{"key":"e_1_2_8_7_1","first-page":"1","article-title":"Paracetamol and morphine for infant and neonatal pain; still a long way to go?","author":"Baarslag MA","year":"2016","journal-title":"Expert Rev Clin Pharmacol"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/pan.12361"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2017.05.022"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1988.127"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-003-1899-4"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12156"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aen248"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2017.05.027"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/jpepsy\/17.1.95"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(99)00239-0"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002508-199603000-00004"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12280"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-014-1315-5"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2012.148050"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(02)00031-3"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejp.569"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.PCC.0000149318.40279.1A"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200948060-00003"},{"volume-title":"NONMEM Users Guides","year":"2015","author":"Beal SL","key":"e_1_2_8_25_1"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000485"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.2165\/11536750-000000000-00000"},{"issue":"199","key":"e_1_2_8_28_1","article-title":"PII\u2010108\u2010\u201cTruncated Sigmoid Emax Models\u201d: a reparameterization of the sigmoid Emax model for use with truncated PK\/PD data","volume":"63","author":"Bachman W.R. WJ. G","year":"1998","journal-title":"Clin Pharmacol Ther"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-009-9093-4"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1552-6909.1999.tb02167.x"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001425"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/AJP.0b013e3181a5b52a"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejp.921"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.01.042"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1952","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcph.1952","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1952","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T17:08:22Z","timestamp":1693242502000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.1952"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,17]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["10.1002\/jcph.1952"],"URL":"https:\/\/doi.org\/10.1002\/jcph.1952","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"type":"print","value":"0091-2700"},{"type":"electronic","value":"1552-4604"}],"subject":[],"published":{"date-parts":[[2021,9,17]]},"assertion":[{"value":"2021-02-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}