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OBJECTIVES To compare the efficacy of 25% dextrose with 24% sucrose for heel-lance analgesia in preterm infants admitted to the NICU. METHODS In this noninferiority, double-blind, randomized controlled trial, preterm infants born at 28 weeks and 0 days to 35 weeks and 6 days of gestation who were due for a scheduled heel-lance procedure were enrolled. Infants randomly assigned to the intervention arm received 0.5 mL 25% dextrose, whereas infants in the active control group received 0.5 mL 24% sucrose orally just 2 minutes before the heel-lance procedure. The primary outcome was Premature Infant Pain Profile (PIPP) score 30 seconds after the procedure. Secondary outcomes included PIPP scores at 60 and 120 seconds, PIPP-Revised scores at 30, 60, and 120 seconds, and any adverse events. RESULTS Sixty-four infants were enrolled (32 in each group). The mean (SD) PIPP score at 30 seconds was 6.41 (2.56) in the dextrose group and 7.03 (2.23) in the sucrose group (mean difference, -0.63 (95% confidence interval, -1.85 to 0.60; P = .31). The upper margin of the confidence interval did not cross the predefined noninferiority margin of 2. The mean PIPP scores at 60 (5.03 [2.18] vs 5.39 [1.48]) and 120 (4.75 [1.97] vs 4.94 [1.46]) seconds were also similar. The PIPP-Revised scores between the 2 groups at all time intervals were comparable. One infant in the intervention group had a transient coughing episode. CONCLUSIONS In preterm infants under intensive care, 25% dextrose is noninferior to 24% sucrose for heel-lance analgesia as assessed by PIPP score.