Developmental pharmacokinetics of opioids in neonates

Karel Allegaert, MD, PhD, Sinno H. Simons, MD, PhD, Christine Vanhole, MD, PhD, Dick Tibboel, MD, PhD


Recognition and treatment of pain are now important indicators of the quality of care being delivered to neonates. However, population-specific characteristics have to be considered, necessitating an integrated, population-specific approach. Such an approach starts with a systematic evaluation of pain, using a validated pain-assessment instrument, and should be followed by effec-tive interventions, mainly based on appropriate, i.e, safe and effective, administration of analgesics. We will illustrate the impact of age on the pharmacokinetics and metabolism of opioids using recently collected and reported observations of tramadol disposition in early neonatal life. Although distribution volume and clearance display age-dependent maturation, it is important to recognize that important, unexplained interindividual variability in drug metabolism is still observed. Research questions in the field of developmental pharmacokinetics of opioids should focus on covariables of relevance in the interindividual variability of both pharmacokinetics and pharmacodynamics of opioids in neonates and on long-term outcomes in preterm and term neonates to whom opioids were administered, with regard to behavioral consequences and effects on pain thresholds.


opioids, neonates, pharmacokinetics, interindividual variability

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Anand KJ, Hickey PR: Pain and its effects in the human neonate and fetus. N Engl J Med. 1987; 317(21): 1321-1329.

Anand KJ, Sippell WG, Aynsly-Green A: Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: Effects on the stress response. Lancet. 1987; 1(8524): 62-66.

Anand KJ: Clinical importance of pain and stress in preterm neonates. Biol Neonate. 1998; 73(1): 1-9.

Winberg J: Do neonatal pain and stress program the brain’s response to future stimuli? Acta Paediatr. 1998; 87(7): 723-725.

Van Dijk M, Peters JW, Bouwmeester NJ, et al.: Are postoperative pain instruments useful for specific groups of vulnerable infants? Clin Perinatol. 2002; 29(3): 469-491.

Berde CB, Sethna NF: Analgesics for the treatment of pain in children. N Engl J Med. 2002; 347(14): 1094-1103.

Peters JW, Schouw R, Anand KJ, et al.: Does neonatal surgery lead to increased pain sensitivity in later childhood? Pain. 2005; 114(3): 444-454.

Nandi R, Fitzgerald M: Opioid analgesia in the newborn. Eur J Pain. 2005; 9(2): 105-108.

Allegaert K, de Hoon J, van Overmeire B, et al.: Clinical phar-macology of non opioid analgesics in neonates. Verh K Acad GeneeskdBelg. 2005; 67(5-6): 289-315.

Kearns GL, Abdel-Rahman SM, Alander SW, et al.: Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med. 2003; 349(12): 1157-1167.

Berde CB, Jaksic T, Lynn AM, et al.: Anesthesia and analgesia during and after surgery in neonates. Clin Ther. 2005; 27(6): 900-921.

Van den Anker JN: Pharmacokinetics and renal function in preterm infants. Acta Paediatr. 1996; 85(12): 1393-1399.

Alcorn J, McNamara PJ: Ontogeny of hepatic and renal systemic clearance pathways in infants: Part 1. Clin Pharmacokinet. 2002; 41(12): 959-998.

Simons S, Anderson BJ, Tibboel D: Analgesic agents. In Yaffe SJ, Aranda JV (eds.): Neonatal and Pediatric Pharmacology: Therapeutic Principles in Practice. Philadelphia: Lippincott, Williams and Wilkins, 2005, pp. 638-662.

Yaster M, Maxwell LG: Opioid agonists and antagonists. In Schechter N, Berde CB, Yaster M (eds.): Pain in Infants, Children and Adolescents. Philadelphia: Lippincott, Williams and Wilkins, 2003, pp. 181-224.

Murthy BV, Pandya KS, Booker PD, et al.: Pharmacokinetics of tramadol in children after i.v. or caudal epidural administration. BrJAnaesth. 2000; 84(3): 346-349.

Allegaert K, Anderson BJ, Verbesselt R, et al.: Tramadol disposition in the very young: An attempt to assess in vivo cytochrome P-450 2D6 activity. Br J Anaesth. 2005; 95(2): 231239.

Allegaert K, van den Anker JN, Verbesselt R, et al.: O-demethylation of tramadol in the first months of life. Eur J Clin Pharmacol. 2005; 61(11): 837-842.

Allegaert K, Rayyan M, de Hoon J, et al.: Contribution of glucuronidation to tramadol elimination in early neonatal life. Basic Clin Pharmacol Toxicol. 2006; 98: 110-112.

Bouwmeester NJ, Anderson BJ, Tibboel D, et al.: Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth. 2004; 92(2): 208-217.

Krumbiegel P, Domke S, Morseburg B, et al.: Maturation of hepatosomal mono-oxygenation and glucuronidation activities in pre- and full-term infants as studied using the [15N]methacetin urine test. Acta Paediatr. 1997; 86(11): 1236-1240.

Wells PG, Mackenzie PI, Chowdhury JR, et al.: Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metab Dispos. 2004; 32(3): 281-290.

Lynn A, Nespeca MK, Bratton SL, et al.: Clearance of morphine in postoperative infants during intravenous infusion: The influence of age and surgery. Anesth Analg. 1998; 86(5): 958-963.

Carcillo JA, Doughty L, Kofos D, et al.: Cytochrome P450-mediated drug metabolism is reduced in children with sepsis-induced multiple organ failure. Intensive Care Med. 2003; 29(6): 980-984.

Blake MJ, Abdel-Rahman SM, Pearce RE, et al.: Effect of diet on the ontogeny of caffeine and dextromethorphan metabolism. Presented at the 2006 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics. Baltimore: March 9, 2006.

Palmer SN, Giesecke NM, Body SC, et al.: Pharmacogenetics of anesthetic and analgesic agents. Anesthesiology. 2005; 102(3): 663-671.

Leeder JS: Translating pharmacogenetics and pharmacogenomics into drug development for clinical pediatrics and beyond. Drug Discov Today. 2004; 9(13): 567-573.

Bjorkman S: Prediction of cytochrome p450-mediated hepatic drug clearance in neonates, infants and children: How accurate are available scaling methods? Clin Pharmacokinet. 2006; 45(1): 1-11.

Anderson BJ, Hansen TG: Getting the best from pediatric pharmacokinetic data. Paediatr Anaesth. 2004; 14(9): 713-714.

Anderson BJ, Allegaert K, Holford NH: Population clinical pharmacology of children: Modelling covariate effects. Eur J Pediatr (online only). June 29, 2006. Available at,17,56;journal,1,857;Un kingpublicationresults,1:100415,1. Accessed August 1, 2006.

van Dijk M, Tibboel D, van den Anker JN, et al.: Analgesic trials in neonates: Observations, pitfalls and recommendations. PaediatrPerinatDrug Ther. 2005; 6(4): 203-210.



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