Neonatal pain is now recognized as a critical issue, with evidence showing that even extremely preterm infants have nociceptive pathways and that untreated pain causes both short- and long-term problems. Despite greater understanding and better assessment tools, practices vary worldwide, with differences in guidelines, pain evaluation, and access to effective treatments. Opioids are vital for severe pain but are limited by side effects and uncertain long-term impacts. Alternatives such as acetaminophen, ketamine, and dexmedetomidine offer benefits, although evidence in neonates remains limited. Propofol provides rapid hypnosis but carries neurotoxicity risks and hemodynamic instability; midazolam is often used for anxiolysis, though concerns exist about its effectiveness, lack of analgesia, and adverse neurological outcomes. Benzodiazepines other than midazolam, such as lorazepam and diazepam, are used less frequently due to accumulation risks and benzyl alcohol toxicity. Intranasal formulations of fentanyl, midazolam, dexmedetomidine, and ketamine are emerging as quick, practical options for procedural sedation and analgesia, but more research is needed. Overall, neonatal pain management and sedation encounter gaps in evidence and practice, emphasizing the need for standardization, improved personalized approaches based on pharmacokinetic and pharmacodynamic maturation, multimodal strategies to minimize opioid and benzodiazepine exposure, and rigorous studies of new therapies to ensure safe, effective, and equitable care for newborns.
Cavallaro et al. (2026) studied this question.