NEONATAL PAIN DURING MEDICAL PROCEDURES AND ITS LONG-TERM EFFECTS ON THE NERVOUS SYSTEM
DOI:
https://doi.org/10.47390/ydif-y2026v2i18/n39Keywords:
neonatal pain; procedural pain; NICU; neurodevelopment; HPA axis; preterm infants.Abstract
Advances in neonatal intensive care have markedly improved survival among preterm and critically ill newborns, but survival is accompanied by repeated exposure to invasive, pain-inducing procedures during a period of rapid brain maturation. This narrative review synthesizes clinical and translational evidence on neonatal procedural pain and its long-term consequences for the developing nervous system. Findings indicate that neonates, including extremely preterm infants, possess the neural architecture required to perceive pain while lacking mature descending inhibitory control, leaving them disproportionately vulnerable to noxious stimulation. Cumulative procedural pain exposure in the neonatal intensive care unit (NICU) has been associated with altered brain microstructure, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, blunted or sensitized cortisol reactivity, and later alterations in pain sensitivity, attention, and socio-emotional development. Non-pharmacological interventions such as oral sucrose, non-nutritive sucking, kangaroo care, and breast milk show consistent short-term analgesic benefit, whereas pharmacological approaches carry a more complex risk-benefit profile. The review concludes that systematic pain assessment and multimodal, evidence-based analgesia should be considered standard components of neonatal care, while acknowledging that long-term causal pathways remain incompletely understood.
References
1. Anand, K. J. S., & Hickey, P. R. (1987). Pain and its effects in the human neonate and fetus. New England Journal of Medicine, 317(21), 1321-1329.
2. Cong, X., et al. (2024). Neonatal pain assessment and non-pharmacological analgesia: An integrative literature review. Frontiers in Pain Research.
3. Costa, T., et al. (2025). Neonatal pain assessment and non-pharmacological analgesia: An integrative literature review. Frontiers in Pain Research.
4. Duerden, E. G., Grunau, R. E., et al. (2018). Early procedural pain is associated with regionally-specific alterations in thalamic development in preterm neonates. Journal of Neuroscience, 38(4), 878-886.
5. Fitzgerald, M. (2005). The development of nociceptive circuits. Nature Reviews Neuroscience, 6(7), 507-520.
6. Grunau, R. E., Holsti, L., Haley, D. W., Oberlander, T., Weinberg, J., Solimano, A., Whitfield, M. F., Fitzgerald, C., & Yu, W. (2005). Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain, 113(3), 293-300.
7. Grunau, R. E., Weinberg, J., & Whitfield, M. F. (2004). Neonatal procedural pain and preterm infant cortisol response to novelty at 8 months. Pediatrics, 114(1), e77-e84.
8. Grunau, R. E., Cepeda, I. L., Chau, C. M. Y., Brummelte, S., Weinberg, J., Lavoie, P. M., Ladd, M., Hirschfeld, A. F., Russell, E., Koren, G., Grunau, E. V., Diamond, G., Turvey, S. E., & Isaac, S. (2013). Neonatal pain-related stress and NFKBIA genotype are associated with altered cortisol levels in preterm boys at school age. PLOS ONE, 8(9), e73926.
9. Mueller, M. E., Graz, M. B., Truttmann, A. C., Schneider, J., & Duerden, E. G. (2024). Neonatal amygdala volumes, procedural pain and the association with social-emotional development in children born very preterm. Brain Structure and Function.
10. Pillai Riddell, R. R., Racine, N. M., Turcotte, K., Uman, L. S., Horton, R. E., Din Osmun, L., Ahola Kohut, S., Hillgrove Stuart, J., Stevens, B., & Gerwitz-Stern, A. (2015). Non-pharmacological management of infant and young child procedural pain (Update). Cochrane Database of Systematic Reviews, (12), CD006275.
11. Ranger, M., & Grunau, R. E. (2015). Early repetitive pain in preterm infants in relation to the developing brain. Pain Management, 5(1), 57-67.
12. Schiller, R. M., et al. (2018). Preterm birth, neonatal pain, and their impact on brain development and neurodevelopmental outcomes. Developmental Medicine & Child Neurology, 60(3), 256-266.
13. Schwaller, F., & Fitzgerald, M. (2010). The consequences of pain in early life: Injury-induced plasticity in developing pain pathways. European Journal of Neuroscience, 39(3), 344-352.
14. Silva, A., et al. (2026). Neonatal pain in very preterm infants: Long-term effects on brain, neurodevelopment and pain reactivity. Pediatric Research.
15. Steinhorn, R., McPherson, C., Anderson, P. J., Neil, J., Doyle, L. W., & Inder, T. (2015). Neonatal morphine exposure in very preterm infants: Cerebral development and outcomes. Journal of Pediatrics, 166(5), 1200-1207.
16. Stevens, B., Yamada, J., Ohlsson, A., Haliburton, S., & Shorkey, A. (2016). Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database of Systematic Reviews, (7), CD001069.
17. Vinall, J., & Grunau, R. E. (2014). Impact of repeated procedural pain-related stress in infants born very preterm. Pediatric Research, 75(5), 584-587.
18. Walker, S. M. (2019). Long-term effects of neonatal pain. Seminars in Fetal and Neonatal Medicine, 24(4), 101005.
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