Intranasal fentanyl to reduce pain intensity associated with retinopathy of prematurity screening in preterm infants: study protocol for a randomized controlled trial

Background Preterm infants are frequently exposed to painful procedures associated with adverse short- and long-term neurodevelopmental outcomes. Retinopathy of prematurity (ROP) screening is a necessary examination that is associated with moderate-to-high pain intensity scores and physiologic instability, despite the use of non-pharmacologic comfort measures and topical anesthesia. Current strategies have not reliably reduced procedural pain to mild or no pain levels, highlighting an important gap in neonatal pain management. Intranasal fentanyl provides rapid analgesia without requiring intravenous access and may offer a feasible option for procedural pain management in this population. Methods This study is a single-center, randomized, double-blind, placebo-controlled trial conducted in a level III neonatal intensive care unit. Preterm infants born at ≤ 31 weeks’ gestational age and/or with birth weight < 1250 g who are scheduled for clinically indicated ROP screening will be randomly assigned (1:1) to receive intranasal fentanyl (2 µg/kg) or intranasal normal saline placebo, administered 10 min prior to the examination, in addition to topical anesthesia and standard comfort measures. The primary outcome is pain intensity measured using the Premature Infant Pain Profile–Revised (PIPP-R) during the first 30 s following speculum insertion. Secondary outcomes include ongoing pain response, pain recovery, cry duration, physiologic recovery, salivary cortisol response, exam duration, adequacy of retinal visualization, and adverse events. Outcomes will be assessed using synchronized video, audio, and physiologic monitoring, with analyses conducted under an intention-to-treat framework. Discussion This trial will provide high-quality evidence regarding the effectiveness and safety of intranasal fentanyl for procedural pain relief during ROP screening in preterm infants. Findings may inform future clinical guidelines and contribute to improved pain management practices for this population. Trial registration ClinicalTrials.gov, NCT07112430. https://clinicaltrials.gov/study/NCT07112430 Prospectively registered on August 8, 2025.