From Benchmark to Bedside, Use of Opioids in Neonates and Infants Undergoing Major Surgical Interventions: Essence for a Sufficient Nociceptive Blockade

  • Enno Freye Universitätsklinikum Duesseldorf (UKD) Heinrich-Heine-University Duesseldorf, Germany.
Keywords: Neonate, descending inhibitory noceptive system, ontogenisis opioid-subreceptors, tolerance development, type of opioid


While for a long time it has been perceived that neonates and young children do not perceive pain as the adult, this notion had to be corrected on the basis of neurophysiological data and the ontogenisis of the nociceptive system. Also, it has been demonstrated conclusively that neonates and the young infant perceive pain at a much lower nociceptive input which is largely due to a still immature inhibitory descending neuronal pathway. Minor inflictions are threfore perceived as a strong painful input, resulting in  a greater size of the receptive field,  long lasting pain sensations at high intensity, all which may have an impact on a lowering of the pain threshold,  a change of behavioral patterns and a lesser performance at school at later life.Pain as being induced during surgery makes administration of potent opioids mandatory. One, however, has to take into consideration that because of the immature development of the opioid subreceptor system, before reaching a max. analgsic level, respiratory depression and muscular rigidity become apparent. In addition, because of the immaturity of liver enzymes, the age-related rapid change in the volume of distribution and the elimination half-life, the duration action of an opioid cannot be predicted. It is therefore is advisable to titrate the dose to effect and not on a mg/kg-basis.


Craig KD, Whitfield MF, Grunau RV, Linton J, Hadjistavropoulos HD. Pain in the preterm neonate: behavioral and physiological indices. Pain. 1993; 52(3):287-99.

DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and berhavioral disorders in a sibling birth cohort. Anesth Analg. 2011; 113(5):1143-51.

Sprung J, Flick RP, Katusic SK, Colligan RC, Barbaresi WJ, Bojanić K, et al. Attention-Deficit/Hyperactivity Disorder After Early Exposure to Procedures Requiring General Anesthesia. Mayo Clin Proc. 2012; 87(2):120-129.

DiMaggio C, Sun LS, Ing C, Li G. Pediatric Anesthesia and Neurodevelopmental Impairments: A Bayesian Meta-Analysis. J Neurosurg Anesthesiol. 2012; 24(4):376–81.

Backeljauw B, Holland SK, Altaye M, Loepke AW. Cognition and Brain Structure Following Early Childhood Surgery With Anesthesia. Pediatrics. 2015; 136(1).

Fitzgerald M, Butcher T, Shortland P. Developmental changes in the laminar termination of a fibre cutaneous sensory afferents in the rat spinal cord dorsal horn. J CVomp Neurol, 1994; 348(2):225-33.

Schade, J.P. and H. Ford, Basic neurology. Vol. 2nd edition. 1972, Amsteredam, London, New York: Elsevier. pp 31.

Anand KJ, Hansen DD, Hickey PR. Hormonal-metabolic stress response in neonates undergoing cardiac surgery. Anesthesiology. 1990; 73(4):661-70.

Anand KJ, Brown MJ, Causon RC, Christofides ND, Bloom SR, Aynsley-Green A. Can the human neonate mount an endocrine and metabolic response to surgery? J Pediatr Surg. 1985; 20(1):41-8.

Hickey PR, Hansen DD, Wessel DL, Lang P, Jonas RA. Pulmonary and systemic hemodynamic responses to fentanyl in infants. Anesth Analg. 1985; 64(5):483-6.

Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet. 1987; 1(8524):62-6.

Zeller K, Vogel J, Kuschinsky W. Postnatal distribution of Glut 1 glucose transporter and circumventricular organs duruing development. Brain Res Dev Brain Res. 1996; 91(2):200-8.

Jensen TS, Yaksh TL. The antinociveptive activity of excitatory anmio acids in the rat brainstem: An anatomical and pharmacological analysis. Brain Res. 1992; 569(2):255-67.

Baranauskas G, Nistri A. Sensitization of pain pathways in the spinal cord: cellular mechanism. Prog Neurobiol. 1998; 54(3):349-65.

Chiang CY, Hu JW, Sessle BJ. NMDA receptor involvement in neuroplastic changes induced by neonatal capsaicin treatment in trigeminal nociceptive neurons. J Neurophysiol. 1997; 78(5):2799-803.

Kitchen I, Kelly M, Viveros MP. Ontogenesis of kappa opioid-receptors in the rat brain using [3H] U69593 as a binding ligand. Eur J Pharmacol. 1990; 175(1):93-6.

Colwell CS, Cepeda C, Crawford C, Levine MS. Postnatal development of glutamate-receptor mediated responses in the neostriatum. Dev Neurosci. 1998; 20(2-3):154-63.

Goldman A, Lloyd-Thomas AR. Pain management in children. Br Med Bull. 1991; 47(3):676-89.

Jaffe JH, MartinWR. Opioid analgesics and antagonists, in The Pharmacological Basis of Therapeutics, A.F. Gilman, et al., Editors. 1990, Pergamon Press: New York. p. 485-531.

Kuhar MJ, Pert CB, Snyder SH. Regional distribution of opiate receptor binding in monkey and human brain. Nature. 1973; 245(5426), 447-50.

Lipartiti M, Lazzaro A, Zanoni R, Mazzari S, Toffano G, Leon A. Monosialoganglioside GM1 reduces NMDA neurotoxicity in neonatal rat brain. Exp Neurol. 1991; 113(3):301-5.

Mather LE. Clinical pharmacokinetics of fentanyl and its newer derivatives. Clin Pharmacokinet. 1983; 8(5):422-446.

Meldrum B, Garthwaite J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci. 1990; 11(9):379-87.

Tobias JD. Postoperative pain management. Pediatric Annals. 1997; 26(8):490-500.

Chahal H, D'Souza SW, Barson AJ, Slater P. Modulation by magnesium of N-methyl-D-aspartate receptor in developing human brain. Arch Dis Child Fetal Neonatal Ed. 1998; 78(2):F116-20.

Ghosh A, Greenberg ME. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science. 1995; 268(5208):239-47.

Quiding H, Olsson GL, Boreus LO, Bondesson U. Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration. Br J Clin Pharmacol. 1992; 33(1):45-9.

Rakic P, Bourgeois JP, Eckenhoff MF, Zecevic N, Goldman-Rakic PS. Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science. 1986; 232(4747):232-5.

Sarrieau A, Sharma S, Meaney MJ. Postnatal development and environmental regulation of hippocampal glucocorticoid and mineralocoticoid receptors. Brain Res. 1988; 471(1):158-62.

Jacobson B, Eklund G, Hamberger L, Linnarsson D, Sedvall G, Valverius M. Perinatal origin of adult self-destructive behavior. Acta psychiat Scand. 1987; 76(4):364-71.

Coyle JT, Pert CB. Ontogenetic development of (3H)-naloxone binding in rat brain. Neuropharmacology. 1976; 15(9):555-60.

Jacobsen M. Developmental neurobiology. 1970, New York: Holt, Rinehard &Winston.

Leysen JE, Gommeren W, Niemegeers CJ. [3H]Sufentanil, a superior ligand for the mu-opiate receptor: Binding properties and regional distribution in rat brain and spinal cord. Eur J Pharmacol. 1983; 87(2-3):209-25.

Freye E, Opioide in der Medizin. 3. Edition ed. Vol. 8. Auflage. 2009, Berlin, Heidelberg, New York: Springer. 331.

Stahl KD, van Bever W, Janssen P, Simon EJ. Receptor affinity and pharmacological potency of a series of narcotic analgesics, anti-diarrheal and neuroleptic drugs. Eur J Pharmacol. 1977; 46(3):199-205.

Rosenbaum JS, Holford NHG, Sadee W. Opiate receptor binding-effect relationship: Sufentanil and etorphine produce analgesia at the µ-site with low fractional receptor occupancy. Brain Res. 1984; 291(2):317-24.

Zhang AZ, Pasternak GW. Ontogeny of opioid pharmacology and receptors: high and low affinity site differences. Eur J Pharmacol. 1981; 73(1):29-40.

Purcell-Jones G, Dormon F, Sumner E. The use of opioids in neonates. A retrospective study of 933 cases. Anaesthesia. 1987; 42(12):1316-20.

Wohltmann M, Roth BL, Coscia CJ. Differential postnatal development of mu and delta opiate receptores. Brain Res. 1982; 255(4):679-84.

Ling GS, Pasternak GW. Spinal and supraspinal opioid analgesia in the mouse: the role of subpopulations of opioid binding sites. Brain Res. 1983; 271(1):152-6.

Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The effects of morphine and nalorphine-like drugs in the non-dependant and morphine-dependant chronic spinal dog. J Pharmacol Exp Ther. 1976; 197(3):517-32.

Rosenbaum JS, Holford NH, Sadée W. In vivo receptor binding of opioid drugs at the mu site. J Pharmacol Exp Ther. 1985; 233(3):735-40.

Holaday JW, Porreca F, Rothmann RB. Functional coupling among opioid receptor types, in Opioids in Anesthesia, F.G. Estafanous, Editor. 1990, Butterworth-Heinemann: Boston, London, Singapore. p. 50-71.

Vaught JL, Rothman RB, Westfall TC. Mu and delta receptors: their role in analgesia and in the differential effects of opioid peptides on analgesia. Life Sci. 1982; 30(17):1443-55.

Engelhard B, Risua B. Development of the blood-brain barrier, in New Concepts of a Blood-Brain-Barrier, G.J.e. al, Editor. 1995, Plenum Press: New York. p. pp 11-31.

Leslie FM, Tso S, Hurlbut DE. Differential appearance of opiate receptor subtypes in neonatal rat brain. Life Sci. 1982; 31(12-13):1393-6.

Freye E. Die postoperative Schmerzbehandlung. Anaesthesiol Reanimat, 1991. 16: p. 379-392.

Romagnoli A, Keats AS. Ceiling effect for respiratory depression by nalbuphine. Clin Pharmacol Ther. 1980; 27(4):478-85.

Gal TJ, DiFazio CA, Moscicki J. Analgesic and respiratory depressant activity of nalbuphine: a comparison with morphine. Anesthesiology. 1982; 57(5):367-74.

Pasternak GW, Zhang A, Tecott L. Developmential differences between high and low affinity opiate binding sites: their relationship to analgesia and respiratory depression. Life Sci. 1980; 27(13):1185-90.

Freye, E. and J.V. Levy, Opioids in Medicine - A Comprehensive Review on the Mode of Action and the Use of Analgesics in Different Clinical Pain States. 2008, Dordrecht/NL: Springer Science + Business Media BV. 465.

Spiegel K, Pasternak GW. Meptazinol: a novel mu-1 selective opioid analgesic. J Pharmacol Expt Ther. 1984; 228(2):414-9.

Sheikh A, Tunstall ME. Comparative study of meptazinol and pethidine for the relief of pain in labour. Br J Obstet Gynaecol. 1986; 93(3):264-9.

Navarro, G. and S. Garcia-Flores, The use of nalbuphine versus pethidine in women with labour pain. Mex J Gyn Obst, 1984. 5: p. 20-25.

Sircar R, Zukin SR. Ontogenety of sigma opiate/phencyclidine-binding sites in rat brain. Life Sci. 1983; 33 Suppl 1: 255-8.

Fitzgerald, M. and K.J.S. Anand, Developmental neuroanatomy and neurophysiology of pain., in Pain in infants, children and adolescents, N.L. Schechter, C.B. Berde, and M. Yaster, Editors. 1994, Williams and Wilkins: Baltimore. p. 11-31.

Fitzgerald M, Koltzenburg M. The functional development of descending inhibitory pathways in the dorsolateral funiculus of the newborn rat spinal cord. Brain Res. 1986; 389(1-2):261-70.

Fitzgerald M, Reynolds ML, Benowitz LI. GAP-43 expression in the developing rat lumbar spinal cord. Neuroschioence. 1991; 41(1):187-99.

Fitzgerald M, Shaw A, MacIntosh N. Postnatal development of the cutaneous flexor reflex: a comparative study in premature infants and newborn rat pups. Dev Child Neurol, 1988; 30(4):520-6.

Johnston CC, Stevens B, Craig KD, Grunau RV. Developmental changes in pain expression in preterm, full-term, two- and four-month-old infants. Pain. 1993; 52(2):201-8.

Bicknell HR Jr, Beal JA. Axonal and dentritic development of substantia gelatinosa neurons in the lumbosacral spinal cord of the rat. J Comp Neurol, 1984; 226(4):508-22.

Fitzgerald M. Developmental biology of inflammatory pain. Br J Anaesth, 1995; 75(2):177-85.

Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia. Pain. 1989; 39(1):31-6.

Jennings E, Fitzgerald M. Postnatal changes in response of rat dorsal horn cells to afferent stimulation: a fibre-induced sensitization. J Physiol. 1998; 509 (Pt 3): 859-68.

Lawrence AJ, Michalkiewicz A, Morley JS, MacKinnon K, Billington D. Differential inhibition of hepatic morphine UDP-glucoronosyltransferases by metal ions. Biochem Pharmacol. 1992; 43(11):2335-40.

Armstrong-James M. The functional status and the columnal organization of single cells responding to cutaneous stimulation in neonatal rat somatosensory cortex SI. J Physiol, 1975; 246(3):501-38.

McEwen BS. The plasticity of the hippocampus is the reason for its vulnerability. Neurosciences, 1994; 6(4):239-246.

Taddio A, Goldbach M, Ipp M, Stevens B, Koren G. Effect of neonatal circumcision on pain responses during vaccination of boys. Lancet. 1995; 345(8945):291-2.

Reynolds ML, Fitzgerald M. Long-term sensory hyperinnervation following neonatal skin wounds. J Comp Neurol. 1995; 358(4):487-98.

Grunau RV, Whitfield MF, Petrie JH, Fryer EL. Early pain experience, child and family factors as precorsors of somatization: a prospective study of extremely premature and fullterm children. Pain. 1994; 56(3):353-9.

McGrath, P.A., Pain in children: Nature, assessment and management. 1990, New York: Guilford Press.

Caspi A, Henry B, McGee RO, Moffitt TE, Silva PA. Temperamental origins of child and adolescent behavior problems: from age three to age fifteen. Child Dev. 1995; 66(1):55-68.

Plotsky PM, Meaney MJ. Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF), mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res. 1993; 18(3):195-200.

Landfield PW, McEwan BS, Sapolsky RM, Meaney MJ. Hippocampal cell death. Science, 1996; 272(5266):1249-51.

Anand KS. Relationships between stress responses and clinical outcome in newborns, infants, and children. Crit Care Med. 1993; 21(9 Suppl):S358-9.

Greeley WJ, de Bruijn NP, Davis DP. Sufentanil pharmacokinetics in pediatric cardiovascular patients. Anesth Analg. 1987; 66(11):1067-1072.

Greeley, W.J., N.P. de Bruijn, and D.P. Davis, Pharmacokinetics of sufentanil in pediatric patients. Anesthesiology, 1986. 65: p. A 422.

Hanna MH, Peat SJ, Woodham M, Knibb A, Fung C. Analgesic efficacy and CSF pharmacokinetics of intrathecal morphine-6-glucoronide: comparison with morphine. Br J Anaesth. 1990; 64(5):547-50.

Sullivan AF, Dickenson AH. Electrophysiologic studies on the spinal antinociceptive action of kappa opioid agonists in the adult and the 21 day old rat. J Pharmacol Exp Ther. 1991; 256(3):1119-25.

Akil H, Watson SJ, Young E. Endogenous opioids. Biology and function. Ann Rev Neurosci. 1984; 7:223-55.

Wood M. Plasma drug binding: implications for anesthesiologists. Anesth Analg. 1986; 65(7):786-804.

Simantov R, Snowman AM, Snyder SH. A morphine-like factor "enkephalin" in rat brain: subcellular localization. Brain Res. 1976; 107(3):650-7.

Boerner U. The metabolism of morphine and heroine in man. Drug Metab Rev. 1975; 4(1): 39-73.

McKenzie JS, Beechy NR. The effects of morphine and pethidine on somatic evoked responses in the midbrain of the cat, and their relevance to analgesia. Electroenceph Clin Neurophysiol, 1962; 14(4):501-519.

Smith MT, Watt JA, Cramond T. Morphine-3-glucoronide - a potent antagonist of morphine analgesia. Life Sci. 1990; 47(6):579-585.

Kupferberg HJ, Way EL. Pharmacological basis for the increased sensitivity of the newborn rat to morphine. J Pharmacol Expt Ther, 1963; 141:105-12.

Hartley R, Green M, Quinn MW, Rushforth JA, Levene MI. Development of morphine glucoronidation in premature neonates. Bol Neonate. 1994; 66(1):1-9.

Lynn AM, Nespeca MK, Opheim KE, Slattery JT. Respiratory effects of intravenous moprhine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg. 1993; 77(4):695-701.

Quiding H, Anderson P, Bondesson U, Boréus LO, Hynning PA. Plasma concentrations of codeine and its metabolite morphine, after single and repeated oral administration. Eur J Clin Pharmacol. 1986; 30(6):673-7.

Shanahan EC, Marshall AG, Garrett CP. Adverse reactions to intravenous codeine phosphate in children. Anaesthesia. 1983; 38(1):40-3.

Roth B, Schlünder C, Houben F, Günther M, Theisohn M. Analgesia and sedation in neonatal intensive care using fentanyl by continuous infusion. Dev Pharmacol Ther. 1991; 17(3-4):121-7.

Arnold JH, Truog RD, Scavone JM, Fenton T. Changes in the pharmacodynamic response to fentanyl in neonates during continzuous infusion. J Pediatr. 1991; 119(4):639-43.

Pokela ML, Ryhänen PT, Koivisto ME, Olkkola KT, Saukkonen AL. Alfentanil-induced rigidity in newborn infants. Anesth Analg. 1992; 75(2):252-7.

Wells S, Williamson M, Hooker D. Fentanyl-indiced chest wall rigidity in a neonate: a case report. Heart Lung. 1994; 23(3):196-8.

Olkkola KT, Hamunen K, Maunuksela EL. Clinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children. Clin Pharmacikinet. 1995; 28(5):385-404.

Jaffe JH, Martin WR. Opioid Analgesics and Antagonists, in The pharmacological Basis of Therapeutics, A.G. Gilman, et al., Editors. 1993, McGraw Hill: New York. p. 485-531.

Petrat G, Klein U, Meissner W. On demand analgesia with piritramide in children. A study on dosage specification and safety. Eur J Pediatr Surg. 1997; 7(1):38-41.

Tobias JD. Postoperative pain management. Pediatr Ann. 1997; 26(8):490-500.

Büttner, W. Die Erfassung des postoperativen Schmerzes beim Kleinkind. 1998, München: Arcis verlag.

Büttner, W., et al., Erste Ergebnisse der Zuverlässigkeit und Gültigkeit einer deutschsprachigen Skala zur quantitativen Erfassung des postoperativen Schmerzes beim Kleinkind. Anaesthesist, 1990. 39: p. 593-602.

McGrath, P.J., et al., CHEOPS: A behavioral scale for rating postoperative pain in children. Adv Pain Res Ther, 1985: p. 395.

How to Cite
Freye E. From Benchmark to Bedside, Use of Opioids in Neonates and Infants Undergoing Major Surgical Interventions: Essence for a Sufficient Nociceptive Blockade. AACC. 1(3):88-.
Review Article(s)