{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T19:10:50Z","timestamp":1793387450126,"version":"4.5.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T00:00:00Z","timestamp":1704240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The survival of preterm infants continues to improve, along with an increased in neonatal intensive care unit (NICU) management of chronic infants who are medically complex infants who have prolonged hospital stays, sometimes up until 2\u00a0years of age. Despite advances in neonatal and infant care, the management of pain and sedation in chronic NICU patients continues to be a challenge. Challenges such as development of appropriate pain, sedation, and withdrawal scales along with unfamiliarity of the NICU care team with pediatric disease states and pharmacotherapy complicate management of these patients. Opioid induced hyperalgesia (OIH) and delirium may play a large role in these refractory cases, yet are often not considered in the NICU population. Drug therapy interventions such as gabapentin, ketamine, risperidone, and others have limited data for safety and efficacy in this population. This article summarizes the available literature regarding the evidence for diagnosis and management of infants with refractory pain and sedation along with the challenges that clinicians face when managing these patients.<\/jats:p>","DOI":"10.3389\/fphar.2023.1259064","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T04:29:07Z","timestamp":1704256147000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Challenges in management of refractory pain and sedation in infants"],"prefix":"10.3389","volume":"14","author":[{"given":"Alexandra","family":"Oschman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karishma","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s44158-022-00036-9","article-title":"Recommendations for analgesia and sedation in critically ill children admitted to intensive care unit","volume":"2","author":"Amigoni","year":"2022","journal-title":"J. Anesth. Analg. Crit. Care"},{"key":"B2","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1001\/archpedi.153.4.331","article-title":"Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates","volume":"153","author":"Anand","year":"1999","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1016\/S0140-6736(04)16251-X","article-title":"Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial","volume":"363","author":"Anand","year":"2004","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1056\/NEJM198711193172105","article-title":"Pain and its effects in the human neonate and fetus","volume":"317","author":"Anand","year":"1987","journal-title":"N. Engl. J. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000475928","article-title":"Effect of anesthesia on the developing brain: infant and fetus","volume":"43","author":"Andropoulos","year":"2018","journal-title":"Fetal Diagn Ther."},{"key":"B6","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1097\/00000542-200603000-00025","article-title":"Opioid-induced hyperalgesia: a qualitative systematic review","volume":"104","author":"Angst","year":"2006","journal-title":"Anesthesiology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"F47","DOI":"10.1136\/fn.72.1.f47","article-title":"Exposure to invasive procedures in neonatal intensive care unit admissions","volume":"72","author":"Barker","year":"1995","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e20151940","DOI":"10.1542\/peds.2015-1940","article-title":"Diagnosis and management of delirium in critically ill infants: case report and review","volume":"137","author":"Brahmbhatt","year":"2016","journal-title":"Pediatrics"},{"key":"B9","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1111\/dmcn.14324","article-title":"Gabapentin for pain, movement disorders, and irritability in neonates and infants","volume":"62","author":"Burnsed","year":"2020","journal-title":"Dev. Med. Child. Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1177\/1060028019891969","article-title":"An evaluation of risperidone dosing for pediatric delirium in children less than or equal to 2 Years of age","volume":"54","author":"Campbell","year":"2020","journal-title":"Ann. Pharmacother."},{"key":"B11","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1001\/jama.300.1.60","article-title":"Epidemiology and treatment of painful procedures in neonates in intensive care units","volume":"300","author":"Carbajal","year":"2008","journal-title":"JAMA"},{"key":"B12","doi-asserted-by":"publisher","first-page":"138","DOI":"10.3389\/fnins.2019.00138","article-title":"Effects of perinatal exposure to ketamine on the developing brain","volume":"13","author":"Cheung","year":"2019","journal-title":"Front. Neurosci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e20154271","DOI":"10.1542\/peds.2015-4271","article-title":"Prevention and management of procedural pain in the neonate: an update","volume":"137","year":"2016","journal-title":"Pediatrics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.jpainsymman.2004.02.021","article-title":"Opioids in renal failure and dialysis patients","volume":"28","author":"Dean","year":"2004","journal-title":"J. Pain Symptom Manage"},{"key":"B15","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/j.clp.2019.08.004","article-title":"Pharmacology of common analgesic and sedative drugs used in the neonatal intensive care unit","volume":"46","author":"Donato","year":"2019","journal-title":"Clin. Perinatol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1124\/jpet.120.000004","article-title":"Chronic morphine-induced changes in signaling at the A3 adenosine receptor contribute to morphine-induced hyperalgesia, tolerance, and withdrawal","volume":"374","author":"Doyle","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1001\/jama.291.14.1753","article-title":"Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit","volume":"291","author":"Ely","year":"2004","journal-title":"JAMA"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e804","DOI":"10.1097\/PR9.0000000000000804","article-title":"Pediatric pain treatment and prevention for hospitalized children","volume":"5","author":"Friedrichsdorf","year":"2020","journal-title":"Pain Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e20153369","DOI":"10.1542\/peds.2015-3369","article-title":"Detection and management of delirium in the neonatal unit: a case series","volume":"137","author":"Groves","year":"2016","journal-title":"Pediatrics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1016\/j.clp.2014.08.010","article-title":"Pain management in newborns","volume":"41","author":"Hall","year":"2014","journal-title":"Clin. Perinatol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/sj.jp.7211861","article-title":"Clinical reliability and validity of the N-PASS: neonatal pain, agitation and sedation scale with prolonged pain","volume":"28","author":"Hummel","year":"2008","journal-title":"J. Perinatol."},{"key":"B22","article-title":"Psychometric evaluation of the neonatal pain, agitation, and sedation scale (n-Pass) tool in infants and children age one to thirty-six months in the post-anesthesia care unit","volume":"900","author":"Hummel","year":"2014","journal-title":"Dissertations"},{"key":"B23","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1055\/s-0039-3400458","article-title":"Management of hyperactive delirium in the pediatric intensive care unit: case series of three young children","volume":"9","author":"Jesus","year":"2020","journal-title":"J. Pediatr. Intensive Care"},{"key":"B24","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1097\/ALN.0000000000003752","article-title":"Methadone and ketamine: boosting benefits and still more to learn","volume":"134","author":"Kharasch","year":"2021","journal-title":"Anesthesiology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1001\/jama.258.13.1789","article-title":"Delirium (acute confusional states)","volume":"258","author":"Lipowski","year":"1987","journal-title":"JAMA"},{"key":"B26","doi-asserted-by":"publisher","first-page":"262","DOI":"10.5863\/1551-6776-19.4.262","article-title":"Developmental pharmacokinetics in pediatric populations","volume":"19","author":"Lu","year":"2014","journal-title":"J. Pediatr. Pharmacol. Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.clp.2019.08.005","article-title":"Assessment of pain in the newborn: an update","volume":"46","author":"Maxwell","year":"2019","journal-title":"Clin. Perinatol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.clp.2019.08.006","article-title":"Nonpharmacologic management of pain during common needle puncture procedures in infants: current research evidence and practical considerations: an update","volume":"46","author":"McNair","year":"2019","journal-title":"Clin. Perinatol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/s41372-020-00878-7","article-title":"Practical approaches to sedation and analgesia in the newborn","volume":"41","author":"McPherson","year":"2021","journal-title":"J. Perinatol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.1097\/CCM.0000000000003194","article-title":"Benzodiazepines and development of delirium in critically ill children: estimating the causal effect","volume":"46","author":"Mody","year":"2018","journal-title":"Crit. Care Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1038\/s41372-020-00840-7","article-title":"Neonatal Pain, Agitation, and Sedation Scale's use, reliability, and validity: a systematic review","volume":"40","author":"Morgan","year":"2020","journal-title":"J. Perinatol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1097\/ALN.0000000000003743","article-title":"Perioperative methadone and ketamine for postoperative pain control in spinal surgical patients: a randomized, double-blind, placebo-controlled trial","volume":"134","author":"Murphy","year":"2021","journal-title":"Anesthesiology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1055\/s-0036-1586202","article-title":"Analgesia and sedation protocol for mechanically ventilated postsurgical children reduces benzodiazepines and withdrawal symptoms-but not in all patients","volume":"27","author":"Neunhoeffer","year":"2017","journal-title":"Eur. J. Pediatr. Surg."},{"key":"B34","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1097\/j.pain.0000000000002046","article-title":"The use and reporting of neonatal pain scales: a systematic review of randomized trials","volume":"162","author":"Olsson","year":"2021","journal-title":"Pain"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1016\/j.pcl.2017.06.009","article-title":"Delirium in pediatric critical care","volume":"64","author":"Patel","year":"2017","journal-title":"Pediatr. Clin. North Am."},{"key":"B36","doi-asserted-by":"publisher","first-page":"705","DOI":"10.2165\/00003088-200645070-00005","article-title":"Morphine metabolite pharmacokinetics during venoarterial extra corporeal membrane oxygenation in neonates","volume":"45","author":"Peters","year":"2006","journal-title":"Clin. Pharmacokinet."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1213\/01.ANE.0000081061.12235.55","article-title":"The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review","volume":"97","author":"Petrenko","year":"2003","journal-title":"Anesth. Analg."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e2115998","DOI":"10.1001\/jamanetworkopen.2021.15998","article-title":"Assessment of 2-year neurodevelopmental outcomes in extremely preterm infants receiving opioids and benzodiazepines","volume":"4","author":"Puia-Dumitrescu","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"B39","doi-asserted-by":"publisher","first-page":"207","DOI":"10.5863\/1551-6776-22.3.207","article-title":"The use of gabapentin for pain and agitation in neonates and infants in a neonatal ICU","volume":"22","author":"Sacha","year":"2017","journal-title":"J. Pediatr. Pharmacol. Ther."},{"key":"B40","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1097\/PCC.0000000000000356","article-title":"Pediatric delirium and associated risk factors: a single-center prospective observational study","volume":"16","author":"Silver","year":"2015","journal-title":"Pediatr. Crit. Care Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1176\/appi.ajp.2010.09111606","article-title":"Infant delirium in pediatric critical care settings","volume":"167","author":"Silver","year":"2010","journal-title":"Am. J. Psychiatry"},{"key":"B42","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1097\/PCC.0000000000001127","article-title":"Implementation of an ICU bundle: an interprofessional quality improvement project to enhance delirium management and monitor delirium prevalence in a single PICU","volume":"18","author":"Simone","year":"2017","journal-title":"Pediatr. Crit. Care Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"e74","DOI":"10.1097\/PCC.0000000000002873","article-title":"2022 society of critical care medicine clinical practice guidelines on prevention and management of pain, agitation, neuromuscular blockade, and delirium in critically ill pediatric patients with consideration of the ICU environment and early mobility","volume":"23","author":"Smith","year":"2022","journal-title":"Pediatr. Crit. Care Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1097\/CCM.0000000000002515","article-title":"Delirium and benzodiazepines associated with prolonged ICU stay in critically ill infants and young children","volume":"45","author":"Smith","year":"2017","journal-title":"Crit. Care Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e2022056415K","DOI":"10.1542\/peds.2022-056415K","article-title":"Analgesia, sedation, and anesthesia for neonates with cardiac disease","volume":"150","author":"Smith-Parrish","year":"2022","journal-title":"Pediatrics"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.2119\/molmed.2012.00244","article-title":"Morphine induces hyperalgesia without involvement of \u03bc-opioid receptor or morphine-3-glucuronide","volume":"18","author":"Swartjes","year":"2012","journal-title":"Mol. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/s11916-010-0171-1","article-title":"Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon?","volume":"15","author":"Tompkins","year":"2011","journal-title":"Curr. Pain Headache Rep."},{"key":"B48","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1097\/CCM.0000000000002324","article-title":"Delirium and mortality in critically ill children: epidemiology and outcomes of pediatric delirium","volume":"45","author":"Traube","year":"2017","journal-title":"Crit. Care Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"169","DOI":"10.3233\/PIC-13070","article-title":"Review of delirium in the pediatric intensive care unit","volume":"2","author":"Turkel","year":"","journal-title":"J. Pediatr. Intensive Care"},{"key":"B50","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1089\/cap.2013.0001","article-title":"The diagnosis and management of delirium in infancy","volume":"23","author":"Turkel","year":"","journal-title":"J. Child. Adolesc. Psychopharmacol."},{"key":"B51","unstructured":"Overview of pain. Merck Manual. Professional edition\n            WatsonJ. C.\n          2020"},{"key":"B52","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/s41572-020-00223-4","volume":"6","author":"Wilson","year":"2020","journal-title":"Delirium. Nat. Rev. Dis. Prim."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1177\/0883073813517508","article-title":"Repeated exposure to anesthetic ketamine can negatively impact neurodevelopment in infants: a prospective preliminary clinical study","volume":"29","author":"Yan","year":"2014","journal-title":"J. Child. Neurol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1259064\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T04:29:12Z","timestamp":1704256152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1259064\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,3]]},"references-count":53,"alternative-id":["10.3389\/fphar.2023.1259064"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1259064","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,3]]},"article-number":"1259064"}}