A Comprehensive Evidence-Based Review of Non-Pharmaceutical Interventions for Neonatal Pain.

This narrative evidence-based review examines current progress in non-pharmaceutical interventions (NPIs) for neonatal pain, a critical factor influencing neurodevelopment and long-term health. NPIs offer safer alternatives to pharmacologic treatments in this vulnerable population. This review summarises advances in auditory approaches (white noise, maternal voice), oral-tactile strategies (non-nutritive sucking, oral glucose/sucrose), tactile interventions (kangaroo care) Yongxue Cai and positional support. These methods alleviate pain by activating endogenous opioid pathways, reducing stress hormone responses and recreating intrauterine-like sensory environments that modulate nociception. Collectively, NPIs reduce behavioral and physiological indicators of pain, enhance sensory integration and promote autonomic stability. Despite their benefits, challenges remain, including heterogeneous study designs, limited sample sizes and clinical constraints such as inadequate provider training and resource limitations in neonatal intensive care units. Future work should focus on large, standardised trials to establish optimal intervention protocols. Integration of neuroimaging and molecular tools may clarify central mechanisms, while personalised approaches using real-time physiological data could support precision pain management. Strengthening the evidence base will enable NPIs to evolve from empirically used techniques into standardised, neuroprotective strategies that improve both immediate comfort and long-term outcomes for neonates.