{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:51:00Z","timestamp":1790661060522,"version":"4.1.0"},"reference-count":30,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T00:00:00Z","timestamp":1677024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:p>The widely prescribed opioid oxycodone may cause lethal respiratory depression. We compared the effects of oxycodone on breathing and antinociception in healthy young volunteers. After pharmacokinetic\/pharmacodynamic (PK\/PD) modeling, we constructed utility functions to combine the wanted and unwanted end points into a single function. We hypothesized that the function would be predominantly negative over the tested oxycodone concentration range. Twenty\u2010four male and female volunteers received 20 (n\u00a0=\u00a012) or 40 (n\u00a0=\u00a012) mg oral oxycodone immediate\u2010release tablets. Hypercapnic ventilatory responses (visit 1) or responses to 3 nociceptive assays (pain pressure, electrical, and thermal tests; visit 2) were measured at regular intervals for 7\u2009hours. the PK\/PD analyses, that included carbon dioxide kinetics, stood at the basis of the utility function: probability of antinociception minus probability of respiratory depression. Oxycodone had rapid onset\/offset times (30\u201340\u2009minutes) with potency values (effect\u2010site concentration causing 50% of effect) ranging from 0.05 to 0.13\u2009ng\/mL for respiratory variables obtained at hypercapnia and antinociceptive responses. Ventilation at an extrapolated end\u2010tidal carbon dioxide partial pressure of 55\u2009mmHg, was used for creation of 3 utility functions, one for each of the nociceptive tests. Contrary to expectation, the utility functions were close to zero or positive over the clinical oxycodone concentration range. The similar or better likelihood for antinociception relative to respiratory depression may be related to oxycodone's receptor activation profile or to is high likeability that possibly alters the modulation of nociceptive input. Oxycodone differs from other \u03bc\u2010opioids, such as fentanyl, that have a consistent negative utility.<\/jats:p>","DOI":"10.1002\/cpt.2863","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T11:39:31Z","timestamp":1675683571000},"page":"1080-1088","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Oral Oxycodone\u2010Induced Respiratory Depression During Normocapnia and Hypercapnia: A Pharmacokinetic\u2010Pharmacodynamic Modeling Study"],"prefix":"10.1111","volume":"113","author":[{"given":"Marieke","family":"Hellinga","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marijke Hyke","family":"Algera","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Olofsen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rutger","family":"van der Schrier","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Sarton","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0289-6432","authenticated-orcid":false,"given":"Monique","family":"van Velzen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3161-3945","authenticated-orcid":false,"given":"Albert","family":"Dahan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden The Netherlands"},{"name":"PainLess Foundation  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke","family":"Niesters","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,22]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2012.04317.x"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e31829ce4cb"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000001529"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000002138"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000002991"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000003441"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.21037\/apm.2019.10.09"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181d69087"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000001505"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.17735"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aex295"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/ftox.2022.1001709"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000539-200110000-00028"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.01.009"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270008314465"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-012-0786-5"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13330"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-020-00980-1"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2058"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/ael051"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-007-9440-z"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2017.14"},{"key":"e_1_2_9_23_1","first-page":"631","article-title":"The kappa opioid agonist U\u201050,488H antagonizes respiratory effects of mu opioid receptor agonists in conscious rats","volume":"264","author":"Dosaka\u2010Akita K.","year":"1993","journal-title":"J. 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