AbstractBackgroundRetinopathy is frequently seen in the neonatal intensive care unit (NICU), and its examination is a painful procedure for infants.AimThis randomized active‐controlled trial aimed to investigate the impact of multisensory stimulation (MSS) on neonatal pain during retinopathy of prematurity (ROP) examinations, in comparison with a white noise (WN) and control group receiving standard care.Study DesignConducted as a three‐arm, randomized controlled trial, the study was implemented in the NICU of a local university hospital. Recruitment spanned from July 2023 to November 2023, with preterm infants (gestational age < 37 weeks) randomly assigned to either a MSS, WN or a control group. MSS components included visual, auditory, tactile, olfactory and gustatory stimuli, all designed to create a synergistic, comforting environment for the infant during the procedure. Procedural pain, heart rate and oxygen saturation were assessed at various stages before and after ROP examinations.ResultsAnalysis of 90 participants revealed that the MSS group exhibited lower Premature Infant Pain Profile (PIPP) scores than the WN and control groups (mean difference: −2.12, 95% confidence interval [CI]: −2.62 to −1.62; odds ratio [OR]: 0.004, 95% CI [0.001, 0.012], p < 0.001). Additionally, heart rates were significantly lower in the MSS group (mean difference: −15.3 beats/min, 95% CI: −20.5 to −10.1; OR: 0.025, 95% CI [0.008, 0.073], p < .001) and oxygen saturation levels were higher (mean difference: 3.2%, 95% CI: 1.8% to 4.6%; OR: 1.12, 95% CI [1.05, 1.20], p < .001) than in the other groups.ConclusionsMSS emerges as a favourable, safe and non‐pharmacological intervention for pain management in ROP and similar procedures.Relevance to Clinical PracticeMultisensory stimulation can be effectively integrated into the routine care provided by critical care nurses during retinopathy of prematurity examinations in preterm infants. This non‐pharmacological intervention offers a practical approach for critical care nurses to reduce procedural pain and improve physiological stability in this vulnerable population.