PURPOSE: Pain and oxidative stress represent critical and frequently underrecognized challenges in neonatal and pediatric care. Their synergistic interaction may adversely affect neurodevelopmental outcomes and long-term quality of life. Melatonin, a neurohormone with well-established antioxidant properties, has also demonstrated analgesic and anti-inflammatory effects, making it an attractive therapeutic candidate in this vulnerable population. This narrative review critically evaluates the available preclinical and clinical evidence on the analgesic role of melatonin in neonates and children. By integrating mechanistic insights with updated clinical data, the review aims to provide a unified perspective on melatonin as a multi-target analgesic, with particular emphasis on pain-modulating pathways that extend beyond its antioxidant activity. METHODS: Comprehensive literature search was performed using electronic databases, including PubMed and MEDLINE. The review considered peer-reviewed articles published in English that investigated melatonin's interaction with pain-related pathways in neonatal and pediatric populations. Both preclinical and clinical studies were analyzed, with particular focus on mechanisms involving MT2 receptor activation, suppression of neuroinflammation, modulation of GABAergic and opioid systems, and interference with N-methyl-d-aspartate receptor-mediated nociceptive signaling. Clinical evidence was reviewed with attention to analgesic efficacy, sedative properties, and safety in neonates and children. Studies with favorable, neutral, or inconclusive findings were considered if they were relevant to the review scope. FINDINGS: Melatonin exerts significant antinociceptive effects through both central and peripheral mechanisms, which are synergistic with its antioxidant action. These effects are mediated by MT2 receptor activation, modulation of inflammatory pathways (including NOD-like receptor protein 3 inflammasome inhibition), and regulation of central neurotransmission. Clinical studies in neonates and children indicate that melatonin is effective in reducing pain during invasive procedures and may serve as a sedative alternative in diagnostic and procedural settings. Across studies, melatonin demonstrated a favorable safety profile, including in preterm infants. IMPLICATIONS: Melatonin emerges as a safe, pleiotropic, and multi-target analgesic in pediatric care. Further translational and clinical research is warranted to better define its role in condition-specific pain management, as well as to establish optimal dosing strategies and routes of administration in neonatal and pediatric populations.
Perrone et al. (Fri,) studied this question.