{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:05:20Z","timestamp":1790229920204,"version":"4.1.0"},"reference-count":73,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Off\u2010label use of gabapentin for the treatment of chronic pain in children has increased over the last decade, with multiple clinical trials evaluating its role pain management and potential opioid\u2010sparing effects. To date, however, these studies appear to rely on empirical evidence without further consideration of pharmacokinetic\u2010pharmacodynamic principles. Here, we use clinical trial simulations and apply extrapolation concepts to identify dosing regimens of morphine and gabapentin in children that correlate with effective analgesia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Simulation scenarios were based on a clinical study (NCT03275012) aimed at the evaluation of the efficacy of gabapentin\u2010morphine combination\n                      <jats:italic>vs<\/jats:italic>\n                      . morphine alone in a paediatric cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200966, aged 3\u2009months to 18\u2009years). Concentration\n                      <jats:italic>vs<\/jats:italic>\n                      . time profiles of morphine and gabapentin in the target paediatric population were derived using established population pharmacokinetic models. AUC, Cmax and Css were used as metrics of exposure across the titration and maintenance phases of therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Morphine doses titrated from 0.6 to 1.2\u00a0mg\/kg\/day resulted in concentrations within established analgesic ranges (Cmax: 36.3\u201382.0\u00a0ng\/mL; Css: 8.5\u201319.5\u00a0ng\/mL). Add\u2010on gabapentin can be titrated in a stepwise manner from 5 up to a maximum of 63\u2009mg\/kg. At the maximum dose, median exposure (AUC\n                      <jats:sub>0\u20138<\/jats:sub>\n                      ) corresponded to approximately 35\u2009mg\/L\u00b7h (i.e., 1200\u2009mg\/day adult dose equivalent).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A weight\u2010banded dosing regimen results in consistent exposure to gabapentin and morphine across different age groups while ensuring acceptable safety margins. In addition, these results offer a rational basis for future clinical trials aiming to reduce opioid burden and optimize pain control in children.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70803","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:53:27Z","timestamp":1790229207000},"source":"Crossref","is-referenced-by-count":0,"title":["Gabapentin as an add\u2010on analgesic to morphine in paediatric patients with chronic pain"],"prefix":"10.1002","author":[{"given":"Paul","family":"Healy","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Therapeutics Group, School of Pharmacy University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariagrazia","family":"Felisi","sequence":"additional","affiliation":[{"name":"CVBF\u2010Consorzio per le Valutazioni Biologiche e Farmacologiche  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Ceci","sequence":"additional","affiliation":[{"name":"Fondazione per la Ricerca Farmacologica Gianni Benzi onlus  Valenzano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6211-1430","authenticated-orcid":false,"given":"Oscar","family":"Della Pasqua","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Therapeutics Group, School of Pharmacy University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the GAPP Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurol.2018.08.005"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2018.07.007"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1213\/ANE.0000000000002500","article-title":"Opioids for the treatment of chronic pain","volume":"125","author":"Ballantyne JC","year":"2017","journal-title":"Anesth Analg"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/01410768221089015"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2023.100763"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.d5142"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpainsymman.2007.03.015"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar1782"},{"issue":"5","key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"e1169","DOI":"10.1542\/peds.2015-1364","article-title":"Prescription opioids in adolescence and future opioid misuse","volume":"136","author":"Miech R","year":"2015","journal-title":"Pediatrics"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2020.2539"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2021.12.009"},{"issue":"4","key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s00482-011-1051-2","article-title":"Schmerztherapie bei Chronisch Schmerzkranken, Schwer Beeintr\u00e4chtigten Kindern und Jugendlichen: Langzeiterfolge einer 3\u2010W\u00f6chigen Station\u00e4ren Schmerztherapie","volume":"25","author":"Dobe M","year":"2011","journal-title":"Schmerz"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1542\/hpeds.2023\u2010007376"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa042580"},{"key":"e_1_2_10_16_1","volume-title":"Guidelines on the management of chronic pain in children","author":"World Health Organization (WHO)","year":"2020"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1213\/00000539\u2010200007000\u201000035"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010016\u20101988\u2010z"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010017\u20100140\u20102"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228\u2010013\u20101545\u20101"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2014.10.015"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13063\u2010018\u20103169\u20103"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.297"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.298"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.12637"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13809"},{"key":"e_1_2_10_27_1","unstructured":"International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.ICH 11 A Guideline on Pediatric Extrapolation. 24 August2024.https:\/\/database.ich.org\/sites\/default\/files\/ICH_E11A_Guideline_Step4_2024_0821.pdf"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12674"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen\u20102018\u2010023296"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.1138"},{"key":"e_1_2_10_31_1","volume-title":"Persisting pain in children package: WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses","author":"World Health Organization (WHO)","year":"2012"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/pan.12361"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088\u2010198207030\u201000006"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010016\u20100398\u2010z"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0920\u20101211(01)00311\u20104"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2016.06.026"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010015\u20100256\u20104"},{"key":"e_1_2_10_38_1","unstructured":"Center for Drug Evaluation and Research Food and Drug Administration.Clinical Pharmacology and Biopharmaceutics Review.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2008\/022195s000_022207s000_ClinPharmR.pdf. (last accessed 21 May 2023)."},{"key":"e_1_2_10_39_1","unstructured":"Centers for Disease Control and Prevention (CDC) National Center for Health Statistics (NCHS).National Health and Nutrition Examination Survey Data. Hyattsville MD: U.S. Department of Health and Human Services Centers for Disease Control and Prevention (2011\u20102012). Available at:wwwn.cdc.gov\/nchs\/nhanes\/continuousnhanes\/default.aspx?BeginYear=2011(last accessed 21 May 2023)."},{"key":"e_1_2_10_40_1","unstructured":"Caliper Project.CALIPER Pediatric Reference Interval Database. Available athttps:\/\/caliper.research.sickkids.ca\/#\/. (last accessed 21 May 2023)."},{"issue":"3","key":"e_1_2_10_41_1","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1097\/00000542-198603000-00004","article-title":"A double\u2010blind comparison of the efficacy of methadone and morphine in postoperative pain control","volume":"64","author":"Gourlay GK","year":"1986","journal-title":"Anesthesiology"},{"issue":"1","key":"e_1_2_10_42_1","first-page":"D1091","article-title":"The IUPHAR\/BPS guide to pharmacology in 2019: updates and expansion to encompass the new guide to immunopharmacology","volume":"46","author":"Harding SD","year":"2019","journal-title":"Nucleic Acids Res"},{"issue":"2","key":"e_1_2_10_43_1","first-page":"S1","article-title":"The concise guide to PHARMACOLOGY 2023\/24: introduction and other protein targets","volume":"180","author":"Alexander SPH","year":"2023","journal-title":"Br J Pharmacol"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S195788"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000003267"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1177\/2042098620958910"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.16201"},{"issue":"2","key":"e_1_2_10_48_1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1097\/01.j.pain.0000460303.63948.8e","article-title":"The pain and opioids in: treatment study: characteristics of a cohort using opioids to manage chronic non\u2010cancer pain","volume":"156","author":"Campbell G","year":"2015","journal-title":"Pain"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keh627"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1586\/ecp.11.59"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2015.1061505"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1542\/hpeds.2020\u2010003582"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpain.2009.03.002"},{"key":"e_1_2_10_54_1","volume-title":"Chronic pain assessment toolbox for children with disabilities: section 3.0: chronic pain assessment tools","author":"Kingsnorth S","year":"2014"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2022.09.025"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2025.1642279"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1111\/papr.12741"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs\u20107793877\/v1"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2010.526106"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1055\/a\u20101690\u20105637"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010015\u20101853\u20105"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1111\/aas.12766"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000005144"},{"issue":"12","key":"e_1_2_10_64_1","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1007\/s00431-016-2781-z","article-title":"Moving toward a paradigm shift in the regulatory requirements for paediatric medicines","volume":"175","author":"Chin WW","year":"2016","journal-title":"Eur J Pediatr"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40272\u2010017\u20100261\u20101"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.6"},{"issue":"2","key":"e_1_2_10_67_1","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1542\/peds.2013-3225","article-title":"Paediatric drug formulations: a review of challenges and progress","volume":"134","author":"Ivanovska V","year":"2014","journal-title":"Pediatrics"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.3928\/19382359\u201020170921\u201003"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70139"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228\u2010010\u20100974\u20103"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41746\u2010025\u201001910\u2010w"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1213\/00000539\u2010199310000\u201000007"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1177\/0310057X1204000516"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sempedsurg.2024.151458"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70803","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bcp.70803","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70803","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:53:31Z","timestamp":1790229211000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/bcp.70803"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":73,"alternative-id":["10.1002\/bcp.70803"],"URL":"https:\/\/doi.org\/10.1002\/bcp.70803","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]},"article-number":"bcp.70803"}}