{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:21:18Z","timestamp":1786123278774,"version":"build-2736575974"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:p>\n                    Morphine is a potent analgesic used for treating surgical and cancer pain. Despite being the drug of choice for the management of severe pain in children, the high interindividual variability in morphine pharmacokinetics limits its clinical utility to effectively relieve pain without adverse effects. This review was conducted to identify and describe all studies that have assessed the effect of genetic factors on the pharmacokinetics of morphine and its main metabolites in children. Embase and Medline databases were used to conduct the literature search, and the systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Of the 188 articles screened and after the application of specific inclusion and exclusion criteria, the review identified 8 studies. These studies suggest that genetic variants of selected metabolic enzymes and transporters may play a role in the observed interindividual variability in morphine plasma concentrations. Variants of the genes\n                    <jats:italic toggle=\"yes\">SLC22A1<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">ABCC3<\/jats:italic>\n                    had the most supporting evidence for genetic variants that influence morphine and morphine metabolites pharmacokinetics. Although the available evidence suggests a potential genetic contribution to the variability in morphine concentration, the heterogeneity of the included studies in terms of experimental design and small sample sizes in some studies makes it challenging to propose the use of genetic biomarkers to personalize morphine dosing. This underscores the need to conduct more comprehensive and large-scale pharmacokinetic-pharmacogenetic studies to determine how or if genetic testing can optimize morphine safety and effectiveness in children.\n                  <\/jats:p>","DOI":"10.1213\/ane.0000000000007349","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T13:54:30Z","timestamp":1733925270000},"page":"550-559","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":1,"title":["The Influence of Pharmacogenetic Factors on the Pharmacokinetics of Morphine and Its Metabolites in Pediatric Patients: A Systematic Review"],"prefix":"10.1213","volume":"141","author":[{"given":"Kheireddin","family":"Mufti","sequence":"first","affiliation":[{"name":"From the BC Children\u2019s Hospital Research Institute, Vancouver, British Columbia, Canada"},{"name":"Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Eduardo","family":"Ju\u00e1rez-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"From the BC Children\u2019s Hospital Research Institute, Vancouver, British Columbia, Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niloofar","family":"Gheshlaghi","sequence":"additional","affiliation":[{"name":"From the BC Children\u2019s Hospital Research Institute, Vancouver, British Columbia, Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"Pharmaceutical Outcomes Program, British Columbia Children\u2019s Hospital, Vancouver, British Columbia, Canada"},{"name":"Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Lovnicki","sequence":"additional","affiliation":[{"name":"From the BC Children\u2019s Hospital Research Institute, Vancouver, British Columbia, Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"Pharmaceutical Outcomes Program, British Columbia Children\u2019s Hospital, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Rod","family":"Rassekh","sequence":"additional","affiliation":[{"name":"From the BC Children\u2019s Hospital Research Institute, Vancouver, British Columbia, Canada"},{"name":"Division of Oncology, Hematology & Bone Marrow Transplant, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin J. D.","family":"Ross","sequence":"additional","affiliation":[{"name":"From the BC Children\u2019s Hospital Research Institute, Vancouver, British Columbia, Canada"},{"name":"Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce C.","family":"Carleton","sequence":"additional","affiliation":[{"name":"From the BC Children\u2019s Hospital Research Institute, Vancouver, British Columbia, Canada"},{"name":"Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"Pharmaceutical Outcomes Program, British Columbia Children\u2019s Hospital, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catrina M.","family":"Loucks","sequence":"additional","affiliation":[{"name":"From the BC Children\u2019s Hospital Research Institute, Vancouver, British Columbia, Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada"},{"name":"Department of Anesthesiology, Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2024,12,11]]},"reference":[{"key":"R1-20250815","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.clinthera.2012.01.016","article-title":"Morphine use in hospitalized children in the United States: a descriptive analysis of data from pediatric hospitalizations in 2008.","volume":"34","author":"Lasky","year":"2012","journal-title":"Clin Ther"},{"key":"R2-20250815","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1111\/pan.13639","article-title":"The Society for Pediatric Anesthesia recommendations for the use of opioids in children during the perioperative period.","volume":"29","author":"Cravero","year":"2019","journal-title":"Paediatr Anaesth"},{"key":"R3-20250815","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/tpj.2014.56","article-title":"Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics.","volume":"15","author":"Sadhasivam","year":"2015","journal-title":"Pharmacogenomics J"},{"key":"R4-20250815","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.jpain.2017.06.001","article-title":"Opioid analgesics administered for pain in the inpatient pediatric setting.","volume":"18","author":"Walco","year":"2017","journal-title":"J Pain"},{"key":"R5-20250815","doi-asserted-by":"crossref","first-page":"474","DOI":"10.6061\/clinics\/2016(08)11","article-title":"Metabolism and pharmacokinetics of morphine in neonates: a review.","volume":"71","author":"Pacifici","year":"2016","journal-title":"Clinics"},{"key":"R6-20250815","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1046\/j.1365-2044.2002.02624_2.x","article-title":"Unwanted effects of morphine-6-glucuronide and morphine.","volume":"57","author":"Cann","year":"2002","journal-title":"Anaesthesia"},{"key":"R7-20250815","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1097\/FTD.0000000000000009","article-title":"Clinical pharmacokinetics of morphine and its metabolites during morphine dose titration for chronic cancer pain.","volume":"36","author":"De Gregori","year":"2014","journal-title":"Ther Drug Monit"},{"key":"R8-20250815","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1093\/bja\/aer232","article-title":"Comparative clinical effects of hydromorphone and morphine: a meta-analysis.","volume":"107","author":"Felden","year":"2011","journal-title":"Br J Anaesth"},{"key":"R9-20250815","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.ejpain.2010.09.007","article-title":"A randomised controlled trial on the efficacy and side-effect profile (nausea\/vomiting\/sedation) of morphine-6-glucuronide versus morphine for post-operative pain relief after major abdominal surgery.","volume":"15","author":"Binning","year":"2011","journal-title":"Eur J Pain"},{"key":"R10-20250815","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ejps.2015.03.020","article-title":"A review of morphine and morphine-6-glucuronide\u2019s pharmacokinetic\u2013pharmacodynamic relationships in experimental and clinical pain.","volume":"74","author":"Sverrisd\u00f3ttir","year":"2015","journal-title":"Eur J Pharm Sci"},{"key":"R11-20250815","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s40262-016-0471-7","article-title":"A prospective population pharmacokinetic study on morphine metabolism in cancer patients.","volume":"56","author":"Oosten","year":"2017","journal-title":"Clin Pharmacokinet"},{"key":"R12-20250815","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/bcp.12305","article-title":"Clinical trials in children.","volume":"79","author":"Joseph","year":"2015","journal-title":"Br J Clin Pharmacol"},{"key":"R13-20250815","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1155\/2014\/614784","article-title":"Hospitalized children continue to report undertreated and preventable pain.","volume":"19","author":"Birnie","year":"2014","journal-title":"Pain Res Manag"},{"key":"R14-20250815","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1124\/jpet.300.2.355","article-title":"The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes.","volume":"300","author":"Hines","year":"2002","journal-title":"J Pharmacol Exp Ther"},{"key":"R15-20250815","first-page":"262","article-title":"Developmental pharmacokinetics in pediatric populations.","volume":"19","author":"Lu","year":"2014","journal-title":"J ped pharmacol therap"},{"key":"R16-20250815","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1002\/jcph.1284","article-title":"Developmental changes in pharmacokinetics and pharmacodynamics.","volume":"58","author":"van den Anker","year":"2018","journal-title":"J Clin Pharmacol"},{"key":"R17-20250815","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.2217\/pgs.13.94","article-title":"OCT1 genetic variants influence the pharmacokinetics of morphine in children.","volume":"14","author":"Fukuda","year":"2013","journal-title":"Pharmacogenomics"},{"key":"R18-20250815","doi-asserted-by":"crossref","first-page":"621","DOI":"10.2217\/pgs-2017-0002","article-title":"OCT1 genetic variants are associated with postoperative morphine-related adverse effects in children.","volume":"18","author":"Balyan","year":"2017","journal-title":"Pharmacogenomics"},{"key":"R20-20250815","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/cpt.2350","article-title":"An evidence-based framework for evaluating pharmacogenomics knowledge for personalized medicine.","volume":"110","author":"Whirl-Carrillo","year":"2021","journal-title":"Clin Pharmacol Therap"},{"key":"R21-20250815","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1097\/j.pain.0000000000001135","article-title":"Human pain genetics database: a resource dedicated to human pain genetics research.","volume":"159","author":"Meloto","year":"2018","journal-title":"Pain"},{"key":"R22-20250815","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13643-021-01626-4","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.","volume":"10","author":"Page","year":"2021","journal-title":"Syst Rev"},{"key":"R23-20250815","article-title":"Covidence systematic review software VHI, Melbourne, Australia."},{"key":"R24-20250815","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12863-015-0211-2","article-title":"Assessing the quality of published genetic association studies in meta-analyses: the quality of genetic studies (Q-Genie) tool.","volume":"16","author":"Sohani","year":"2015","journal-title":"BMC Genet"},{"key":"R25-20250815","article-title":"NIH style guide, age."},{"key":"R26-20250815","doi-asserted-by":"crossref","first-page":"217","DOI":"10.5055\/jom.2012.0119","article-title":"Morphine clearance in children: does race or genetics matter?","volume":"8","author":"Sadhasivam","year":"2012","journal-title":"J Opioid Manag"},{"key":"R27-20250815","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.2217\/pgs.14.99","article-title":"ABCC3 and OCT1 genotypes influence pharmacokinetics of morphine in children.","volume":"15","author":"Venkatasubramanian","year":"2014","journal-title":"Pharmacogenomics"},{"key":"R28-20250815","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/tpj.2015.98","article-title":"ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children.","volume":"17","author":"Chidambaran","year":"2017","journal-title":"Pharmacogenomics J"},{"key":"R29-20250815","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1002\/cpt.1249","article-title":"Influence of OCT 1 ontogeny and genetic variation on morphine disposition in critically ill neonates: lessons from PBPK modeling and clinical study.","volume":"105","author":"Hahn","year":"2019","journal-title":"Clin Pharmacol Therap"},{"key":"R30-20250815","doi-asserted-by":"crossref","first-page":"e485","DOI":"10.1097\/CCM.0000000000003741","article-title":"Morphine dose optimization in critically ill pediatric patients with acute respiratory failure: a population pharmacokinetic-pharmacogenomic study.","volume":"47","author":"Zuppa","year":"2019","journal-title":"Crit Care Med"},{"key":"R31-20250815","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1002\/jcph.1592","article-title":"Influence of MRP3 genetics and hepatic expression ontogeny for morphine disposition in neonatal and pediatric patients.","volume":"60","author":"Hahn","year":"2020","journal-title":"J Clin Pharmacol"},{"key":"R32-20250815","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.2217\/pgs.14.115","article-title":"Effect of UGT2B7-900G > A (-842G > A; rs7438135) on morphine glucuronidation in preterm newborns: results from a pilot cohort.","volume":"15","author":"Matic","year":"2014","journal-title":"Pharmacogenomics"},{"key":"R33-20250815","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1542\/peds.2011-2607","article-title":"Race and unequal burden of perioperative pain and opioid related adverse effects in children.","volume":"129","author":"Sadhasivam","year":"2012","journal-title":"Pediatrics"},{"key":"R34-20250815","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.bcp.2013.06.019","article-title":"Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration.","volume":"86","author":"Tzvetkov","year":"2013","journal-title":"Biochem Pharmacol"},{"key":"R35-20250815","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/00008571-200403000-00003","article-title":"Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver.","volume":"14","author":"Lang","year":"2004","journal-title":"Pharmacogenetics"},{"key":"R36-20250815","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1101\/gr.137323.112","article-title":"Annotation of functional variation in personal genomes using RegulomeDB.","volume":"22","author":"Boyle","year":"2012","journal-title":"Genome Res"},{"key":"R37-20250815","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans.","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"R38-20250815","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1353\/hpu.0.0236","article-title":"Perioperative analgesic treatment in Latino and non-Latino pediatric patients.","volume":"21","author":"Jimenez","year":"2010","journal-title":"J Health Care Poor Underserved"},{"key":"R39-20250815","doi-asserted-by":"crossref","first-page":"5902","DOI":"10.1073\/pnas.0730858100","article-title":"Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1.","volume":"100","author":"Shu","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"R40-20250815","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/tpj.2015.78","article-title":"Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug\u2013drug interactions.","volume":"15","author":"Arimany-Nardi","year":"2015","journal-title":"Pharmacogenomics J"},{"key":"R41-20250815","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans.","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"R43-20250815","doi-asserted-by":"crossref","first-page":"e0269379","DOI":"10.1371\/journal.pone.0269379","article-title":"Changes in the development of opioid tolerance on re-exposure among people who use heroin: A qualitative study.","volume":"17","author":"Kesten","year":"2022","journal-title":"PLoS One"},{"key":"R45-20250815","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1046\/j.1472-8206.2003.00140.x","article-title":"Drug metabolism and disposition in children.","volume":"17","author":"Strolin Benedetti","year":"2003","journal-title":"Fundament Clin Pharmacol"},{"key":"R46-20250815","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1016\/S0140-6736(88)91691-1","article-title":"Analgesic activity of morphine-6-glucuronide.","volume":"331","author":"Osborne","year":"1988","journal-title":"Lancet"},{"key":"R47-20250815","doi-asserted-by":"crossref","first-page":"842454","DOI":"10.3389\/fped.2022.842454","article-title":"Hydromorphone prescription for pain in children\u2014what place in clinical practice?","volume":"10","author":"Rodieux","year":"2022","journal-title":"Front Pediatr"},{"key":"R48-20250815","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1136\/archdischild-2020-319059","article-title":"Morphine or hydromorphone: which should be preferred? A systematic review.","volume":"106","author":"Sp\u00e9nard","year":"2021","journal-title":"Arch Dis Child"}],"container-title":["Anesthesia &amp; Analgesia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1213\/ANE.0000000000007349","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:36:41Z","timestamp":1786113401000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1213\/ANE.0000000000007349"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,11]]},"references-count":45,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025]]}},"URL":"https:\/\/doi.org\/10.1213\/ane.0000000000007349","relation":{},"ISSN":["0003-2999","1526-7598"],"issn-type":[{"value":"0003-2999","type":"print"},{"value":"1526-7598","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,11]]}}}