Abstract
Preterm infants are exposed to frequent painful procedures and agitating stimuli over the many weeks of their hospitalization in the neonatal intensive care unit (NICU). The adverse neurobiological impact of pain and stress in the preterm infant has been well documented, including neuroimaging and neurobehavioral outcomes. Although many tools have been validated to assess acute pain, few methods are available to assess chronic pain or agitation (a clinical manifestation of neonatal stress). Both nonpharmacologic and pharmacologic approaches are used to reduce the negative impact of pain and agitation in the preterm infant, with concerns emerging over the adverse effects of analgesia and sedatives. Considering benefits and risks of available treatments, units must develop a stepwise algorithm to prevent, assess, and treat pain. Nonpharmacologic interventions should be consistently utilized prior to mild to moderately painful procedures. Sucrose may be utilized judiciously as an adjunctive therapy for minor painful procedures. Rapidly acting opioids (fentanyl or remifentanil) form the backbone of analgesia for moderately painful procedures. Chronic sedation during invasive mechanical ventilation represents an ongoing challenge; appropriate containment and an optimal environment should be standard; when indicated, low-dose morphine infusion may be utilized cautiously and dexmedetomidine infusion may be considered as an emerging adjunct.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Synnes, A. R. et al. School entry age outcomes for infants with birth weight </= 800 grams. J. Pediatr. 157, 989–994 (2010). e981.
Schmidt, B. et al. Prediction of late death or disability at age 5 years using a count of 3 neonatal morbidities in very low birth weight infants. J. Pediatr. 167, 982–986 (2015). e982.
Synnes, A. et al. Determinants of developmental outcomes in a very preterm Canadian cohort. Arch. Dis. Child Fetal Neonatal Ed. 102, F235–F234 (2017).
Guo, T. et al. Quantitative assessment of white matter injury in preterm neonates: association with outcomes. Neurology 88, 614–622 (2017).
Back, S. A. & Miller, S. P. Brain injury in premature neonates: a primary cerebral dysmaturation disorder? Ann. Neurol. 75, 469–486 (2014).
Anand, K. J. Clinical importance of pain and stress in preterm neonates. Biol. Neonate 73, 1–9 (1998).
Anand, K. J. & Craig, K. D. New perspectives on the definition of pain. Pain 67, 3–6 (1996). discussion 209–211.
Anand, K. J. & Hickey, P. R. Pain and its effects in the human neonate and fetus. N. Engl. J. Med. 317, 1321–1329 (1987).
Anand, K. J., Sippell, W. G. & Aynsley-Green, A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1, 62–66 (1987).
Fitzgerald, M., Shaw, A. & MacIntosh, N. Postnatal development of the cutaneous flexor reflex: comparative study of preterm infants and newborn rat pups. Dev. Med. Child Neurol. 30, 520–526 (1988).
Anand, K. J. Neonatal stress responses to anesthesia and surgery. Clin. Perinatol. 17, 207–214 (1990).
Fitzgerald, M., Millard, C. & McIntosh, N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia. Pain 39, 31–36 (1989).
Committee on Fetus and Newborn & Section on Anesthesiology and Pain Medicine. Prevention and management of procedural pain in the neonate: an update. Pediatrics 137, e20154271 (2016).
Disma, N. et al. Anesthesia and the developing brain: a way forward for laboratory and clinical research. Paediatr. Anaesth. 28, 758–763 (2018).
Durrmeyer, X. et al. Premedication for neonatal endotracheal intubation: results from the epidemiology of procedural pain in neonates study. Pediatr. Crit. Care Med. 14, e169–e175 (2013).
Hatfield, L. A., Murphy, N., Karp, K. & Polomano, R. C. A systematic review of behavioral and environmental interventions for procedural pain management in preterm infants. J. Pediatr. Nurs. 44, 22–30 (2019).
Ranger, M. et al. Adverse behavioral changes in adult mice following neonatal repeated exposure to pain and sucrose. Front. Psychol. 9, 2394 (2018).
Zimmerman, K. O. et al. Sedation, analgesia, and paralysis during mechanical ventilation of premature infants. J. Pediatr. 180, 99–104 (2017). e101.
Miller, S. P. & Ferriero, D. M. From selective vulnerability to connectivity: insights from newborn brain imaging. Trends Neurosci. 32, 496–505 (2009).
Woodward, L. J., Anderson, P. J., Austin, N. C., Howard, K. & Inder, T. E. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N. Engl. J. Med. 355, 685–694 (2006).
Buser, J. R. et al. Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants. Ann. Neurol. 71, 93–109 (2012).
Zwicker, J. G. et al. Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine. J. Pediatr. 172, 81–87 (2016). e82.
Schneider, J. et al. Procedural pain and oral glucose in preterm neonates: brain development and sex-specific effects. Pain 159, 515–525 (2018).
Duerden, E. G. et al. Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. Ann. Neurol. 79, 548–559 (2016).
Duerden, E. G. et al. Early procedural pain is associated with regionally-specific alterations in thalamic development in preterm neonates. J. Neurosci. 38, 878–886 (2018).
Thompson, D. K. et al. Neonate hippocampal volumes: prematurity, perinatal predictors, and 2-year outcome. Ann. Neurol. 63, 642–651 (2008).
Toulmin, H. et al. Specialization and integration of functional thalamocortical connectivity in the human infant. Proc. Natl Acad. Sci. USA 112, 6485–6490 (2015).
Brummelte, S. et al. Procedural pain and brain development in premature newborns. Ann. Neurol. 71, 385–396 (2012).
Zwicker, J. G. et al. Score for neonatal acute physiology-II and neonatal pain predict corticospinal tract development in premature newborns. Pediatr. Neurol. 48, 123–129 (2013). e121.
Smith, G. C. et al. Neonatal intensive care unit stress is associated with brain development in preterm infants. Ann. Neurol. 70, 541–549 (2011).
Ranger, M. et al. Neonatal pain-related stress predicts cortical thickness at age 7 years in children born very preterm. PLoS ONE 8, e76702 (2013).
Chau, C. M. Y. et al. Hippocampus, amygdala, and thalamus volumes in very preterm children at 8 years: neonatal pain and genetic variation. Front. Behav. Neurosci. 13, 51 (2019).
Vinall, J. et al. Invasive procedures in preterm children: brain and cognitive development at school age. Pediatrics 133, 412–421 (2014).
Doesburg, S. M. et al. Neonatal pain-related stress, functional cortical activity and visual–perceptual abilities in school-age children born at extremely low gestational age. Pain 154, 1946–1952 (2013).
Vinall, J. et al. Slower postnatal growth is associated with delayed cerebral cortical maturation in preterm newborns. Sci. Transl. Med. 5, 168ra8 (2013).
Grunau, R. E. & Craig, K. D. Neonatal Facial Coding System Revised: Training Manual (University of British Columbia, Vancouver, 2010).
Gibbins, S. et al. Validation of the premature infant pain profile-revised (PIPP-R). Early Hum. Dev. 90, 189–193 (2014).
Hummel, P., Puchalski, M., Creech, S. D. & Weiss, M. G. Clinical reliability and validity of the N-PASS: neonatal pain, agitation and sedation scale with prolonged pain. J. Perinatol. 28, 55–60 (2008).
Lawrence, J. et al. The development of a tool to assess neonatal pain. Neonatal Netw. 12, 59–66 (1993).
Cignacco, E., Mueller, R., Hamers, J. P. & Gessler, P. Pain assessment in the neonate using the Bernese Pain Scale for Neonates. Early Hum. Dev. 78, 125–131 (2004).
Kappesser, J. et al. Pain-specific reactions or indicators of a general stress response?: Investigating the discriminant validity of 5 well-established neonatal pain assessment tools. Clin. J. Pain 35, 101–110 (2019).
Benoit, B., Martin-Misener, R., Newman, A., Latimer, M. & Campbell-Yeo, M. Neurophysiological assessment of acute pain in infants: a scoping review of research methods. Acta Paediatr. 106, 1053–1066 (2017).
Fabrizi, L. et al. A shift in sensory processing that enables the developing human brain to discriminate touch from pain. Curr. Biol. 21, 1552–1558 (2011).
Slater, R. et al. Premature infants display increased noxious-evoked neuronal activity in the brain compared to healthy age-matched term-born infants. Neuroimage 52, 583–589 (2010).
Bartocci, M., Bergqvist, L. L., Lagercrantz, H. & Anand, K. J. Pain activates cortical areas in the preterm newborn brain. Pain 122, 109–117 (2006).
Munsters, J., Wallstrom, L., Agren, J., Norsted, T. & Sindelar, R. Skin conductance measurements as pain assessment in newborn infants born at 22–27 weeks gestational age at different postnatal age. Early Hum. Dev. 88, 21–26 (2012).
Jansen, J., Beijers, R., Riksen-Walraven, M. & de Weerth, C. Cortisol reactivity in young infants. Psychoneuroendocrinology 35, 329–338 (2010).
Roue, J. M. et al. Multi-modal pain assessment: are near-infrared spectroscopy, skin conductance, salivary cortisol, physiologic parameters, and Neonatal Facial Coding System interrelated during venepuncture in healthy, term neonates. J. Pain Res. 11, 2257–2267 (2018).
Pena-Bautista, C. et al. Non-invasive monitoring of stress biomarkers in the newborn period. Semin. Fetal Neonatal Med. 24, 101002 (2019).
Pillai Riddell, R. R. et al. Non-pharmacological management of infant and young child procedural pain. Cochrane Database Syst. Rev. CD006275 (2015). https://doi.org/10.1002/14651858.CD006275.pub2.
Carbajal, R. et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA 300, 60–70 (2008).
Bellieni, C. V. & Johnston, C. C. Analgesia, nil or placebo to babies, in trials that test new analgesic treatments for procedural pain. Acta Paediatr. 105, 129–136 (2016).
Stevens, B., Yamada, J., Ohlsson, A., Haliburton, S. & Shorkey, A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst. Rev. 7, CD001069 (2016).
de Freitas, R. L., Kubler, J. M., Elias-Filho, D. H. & Coimbra, N. C. Antinociception induced by acute oral administration of sweet substance in young and adult rodents: the role of endogenous opioid peptides chemical mediators and mu(1)-opioid receptors. Pharmacol. Biochem. Behav. 101, 265–270 (2012).
Blass, E., Fitzgerald, E. & Kehoe, P. Interactions between sucrose, pain and isolation distress. Pharmacol. Biochem. Behav. 26, 483–489 (1987).
Taddio, A., Shah, V., Shah, P. & Katz, J. Beta-endorphin concentration after administration of sucrose in preterm infants. Arch. Pediatr. Adolesc. Med. 157, 1071–1074 (2003).
Gradin, M. & Schollin, J. The role of endogenous opioids in mediating pain reduction by orally administered glucose among newborns. Pediatrics 115, 1004–1007 (2005).
Hajnal, A., Smith, G. P. & Norgren, R. Oral sucrose stimulation increases accumbens dopamine in the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R31–R37 (2004).
Jones, P. G. & Dunlop, J. Targeting the cholinergic system as a therapeutic strategy for the treatment of pain. Neuropharmacology 53, 197–206 (2007).
Reboucas, E. C. et al. Effect of the blockade of mu1-opioid and 5HT2A-serotonergic/alpha1-noradrenergic receptors on sweet-substance-induced analgesia. Psychopharmacology 179, 349–355 (2005).
Stevens, B. et al. The minimally effective dose of sucrose for procedural pain relief in neonates: a randomized controlled trial. BMC Pediatr. 18, 85 (2018).
Bauer, K., Ketteler, J., Hellwig, M., Laurenz, M. & Versmold, H. Oral glucose before venepuncture relieves neonates of pain, but stress is still evidenced by increase in oxygen consumption, energy expenditure, and heart rate. Pediatr. Res. 55, 695–700 (2004).
Slater, R. et al. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet 376, 1225–1232 (2010).
Taddio, A., Shah, V., Atenafu, E. & Katz, J. Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants. Pain 144, 43–48 (2009).
Durrmeyer, X., Vutskits, L., Anand, K. J. & Rimensberger, P. C. Use of analgesic and sedative drugs in the NICU: integrating clinical trials and laboratory data. Pediatr. Res. 67, 117–127 (2010).
Tremblay, S. et al. Repeated exposure to sucrose for procedural pain in mouse pups leads to long-term widespread brain alterations. Pain 158, 1586–1598 (2017).
Johnston, C. C. et al. Routine sucrose analgesia during the first week of life in neonates younger than 31 weeks’ postconceptional age. Pediatrics 110, 523–528 (2002).
Ranger, M., Johnston, C. C. & Anand, K. J. Current controversies regarding pain assessment in neonates. Semin. Perinatol. 31, 283–288 (2007).
McPherson, C. & Grunau, R. E. Neonatal pain control and neurologic effects of anesthetics and sedatives in preterm infants. Clin. Perinatol. 41, 209–227 (2014).
Berde, C. B. et al. Anesthesia and analgesia during and after surgery in neonates. Clin. Ther. 27, 900–921 (2005).
Kumar, P., Denson, S. E. & Mancuso, T. J., Committee on Fetus and Newborn Section on Anesthesiology and Pain Medicine. Premedication for nonemergency endotracheal intubation in the neonate. Pediatrics 125, 608–615 (2010).
Ancora, G. et al. Evidence-based clinical guidelines on analgesia and sedation in newborn infants undergoing assisted ventilation and endotracheal intubation. Acta Paediatr. 108, 208–217 (2019).
Anand, K. J. et al. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates. Arch. Pediatr. Adolesc. Med. 153, 331–338 (1999).
van Straaten, H. L., Rademaker, C. M. & de Vries, L. S. Comparison of the effect of midazolam or vecuronium on blood pressure and cerebral blood flow velocity in the premature newborn. Dev. Pharmacol. Ther. 19, 191–195 (1992).
Anand, K. J. et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet 363, 1673–1682 (2004).
Bhandari, V., Bergqvist, L. L., Kronsberg, S. S., Barton, B. A. & Anand, K. J. Morphine administration and short-term pulmonary outcomes among ventilated preterm infants. Pediatrics 116, 352–359 (2005).
Menon, G. et al. Morphine analgesia and gastrointestinal morbidity in preterm infants: secondary results from the NEOPAIN trial. Arch. Dis. Child Fetal Neonatal Ed. 93, F362–F367 (2008).
Rao, R. et al. Neurobehavior of preterm infants at 36 weeks postconception as a function of morphine analgesia. Am. J. Perinatol. 24, 511–517 (2007).
Ferguson, S. A., Ward, W. L., Paule, M. G., Hall, R. W. & Anand, K. J. A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood. Neurotoxicol. Teratol. 34, 47–55 (2012).
Simons, S. H. et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. J. Am. Med. Assoc. 290, 2419–2427 (2003).
de Graaf, J. et al. Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: five-year follow-up of a randomized controlled trial. Pain 152, 1391–1397 (2011).
de Graaf, J. et al. Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age? Pain 154, 449–458 (2013).
Steinhorn, R. et al. Neonatal morphine exposure in very preterm infants—cerebral development and outcomes. J. Pediatr. 166, 1200–1207 (2015). e1204.
Chau, C. M. Y. et al. Morphine biotransformation genes and neonatal clinical factors predicted behaviour problems in very preterm children at 18 months. EBioMedicine 40, 655–662 (2019).
Saarenmaa, E., Neuvonen, P. J. & Fellman, V. Gestational age and birth weight effects on plasma clearance of fentanyl in newborn infants. J. Pediatr. 136, 767–770 (2000).
Ancora, G. et al. Efficacy and safety of continuous infusion of fentanyl for pain control in preterm newborns on mechanical ventilation. J. Pediatr. 163, 645–651 (2013). e641.
Ancora, G. et al. Follow-up at the corrected age of 24 months of preterm newborns receiving continuous infusion of fentanyl for pain control during mechanical ventilation. Pain 158, 840–845 (2017).
McPherson, C. et al. Brain injury and development in preterm infants exposed to fentanyl. Ann. Pharmacother. 49, 1291–1297 (2015).
Völler, S. et al. Rapidly maturing fentanyl clearance in preterm neonates. Arch. Dis. Child-Fetal Neonatal Ed. https://doi.org/10.1136/archdischild-2018-315920 (2019).
O'Mara, K. et al. Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates. J. Pediatr. Pharm. Ther. 17, 252–262 (2012).
Chrysostomou, C. et al. A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates. J. Pediatr. 164, 276–282 (2014). e271-273.
Laudenbach, V. et al. Effects of alpha(2)-adrenoceptor agonists on perinatal excitotoxic brain injury: comparison of clonidine and dexmedetomidine. Anesthesiology 96, 134–141 (2002).
Author information
Authors and Affiliations
Contributions
C.M., T.E.I. and S.P.M. drafted sections of the article. M.E-D. and A.N.M. revised it critically, contributing important intellectual content to the final manuscript. All authors provided final approval of the version to be published.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
McPherson, C., Miller, S.P., El-Dib, M. et al. The influence of pain, agitation, and their management on the immature brain. Pediatr Res 88, 168–175 (2020). https://doi.org/10.1038/s41390-019-0744-6
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41390-019-0744-6
This article is cited by
-
The effect of tactile versus auditory stimulation on reducing pain associated with invasive procedures among preterm neonates at NICUs
BMC Pediatrics (2025)
-
Current practices in neonatal pain management: a decade after the last Italian survey
Italian Journal of Pediatrics (2025)
-
Prevalence of intraventricular hemorrhage and associated factors to in premature babies in selected teaching hospitals in Rwanda
BMC Pediatrics (2025)
-
Assessment of cortisol as a neonatal pain biomarker in the application of non-pharmacological analgesia therapies: systematic review and meta-analysis
BMC Pediatrics (2025)
-
Sequential direct bilirubin values in preterm infants
Journal of Perinatology (2025)
