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Procedural pain management for very low birth weight (VLBW) neonates has been minimal or nonexistent in most neonatal intensive care units (NICUs).To compare the efficacy of developmentally sensitive behavioral interventions (nonnutritive sucking via a pacifier, positioning) and sucrose for relieving procedural pain in VLBW infants and to determine the influence of contextual factors (gestational age, postnatal age, birth weight, severity of illness, frequency of painful procedures) on pain response.In a prospective randomized crossover trial, pain was assessed in 122 VLBW neonates using the Premature Infant Pain Profile following four randomly ordered interventions during consecutive routine heel lance procedures.Significant differences in pain existed among treatment interventions (F = 16.20, p < .0001). The pacifier with sucrose (F = 24.09, p < .0001) and pacifier with sterile water (F = 9.00, p = .003) significantly reduced pain. Prone positioning did not decrease pain (F=2.24, p=.137). Frequency of painful procedures approached significance in influencing pain response (F = 3.59, p = .01).The most efficacious interventions for reducing pain from single painful events were the pacifier with sucrose and the pacifier with sterile water. Research on the efficacy and safety of implementing these interventions, alone and in combination, for repeated painful procedures is needed. In addition, research is needed on the influence of implementing these interventions on pain response and clinical outcomes (e.g., health status and neurodevelopmental status) in VLBW neonates in the NICU.