This double-blinded, randomized controlled trial will evaluate the effectiveness and safety of intranasal fentanyl (INF) in reducing procedural pain associated with retinopathy of prematurity (ROP) screening in preterm infants. ROP screening is a necessary but painful procedure routinely performed in neonatal intensive care units (NICUs), and there remains a lack of consistent and effective pharmacological strategies for managing associated pain, particularly in preterm infants.
Eligible participants will include preterm infants born at or before 32 weeks gestation and scheduled for their first ROP exam. Infants with congenital anomalies, hemodynamic instability, or contraindications to fentanyl will be excluded. Participants will be randomized in a 1:1 ratio to receive either intranasal fentanyl (2 mcg/kg) or an equivalent volume of intranasal saline placebo. Randomization will be stratified by gestational age (\<28 weeks vs. ≥28 weeks) to ensure balance between treatment arms.
The intervention will be administered 5-10 minutes prior to the ROP screening using a mucosal atomization device to optimize nasal absorption and bioavailability. Non-pharmacological comfort measures such as swaddling and non-nutritive sucking will be applied uniformly to all participants as standard of care. The ROP examination will be performed by a pediatric ophthalmologist using a standardized protocol including use of a speculum and scleral depression.
The primary outcome is pain intensity as measured by the Premature Infant Pain Profile-Revised (PIPP-R) at 30 seconds after speculum insertion. Secondary outcomes include additional PIPP-R scores at subsequent timepoints (e.g., speculum removal), changes in physiological parameters (heart rate, oxygen saturation), crying time, pain recovery trajectory, and the occurrence of any adverse events such as respiratory depression, apnea, or need for rescue dosing.
Vital signs and continuous cardiorespiratory monitoring will be conducted before, during, and after the procedure to identify any immediate adverse effects. Pain scoring will be conducted by trained, blinded assessors who are not involved in administering the intervention or performing the ROP exam.
Safety monitoring will include predefined criteria for adverse events and a data safety monitoring plan, including interim review by an independent neonatologist. Any infant experiencing a serious adverse event will be promptly evaluated, and unblinding may occur if necessary for clinical care.
This trial is designed to address a significant gap in neonatal pain management by generating high-quality evidence on the feasibility, safety, and efficacy of intranasal fentanyl in a vulnerable population. The use of a non-invasive, easily administered opioid analgesic could improve procedural pain control without introducing the risks associated with intravenous access. Findings from this study may inform neonatal pain management protocols and support the development of evidence-based guidelines for the use of intranasal fentanyl in NICU settings.
