88 This finding was very unexpected given the prolonged pain/stress exposure in the NICU in infants born so early. In the same cohort at 8 months’ CA, the preterm infants displayed a greater facial pain response to a finger lance in the first few seconds, and more rapid dampening of behavior and heart rate, compared to full-term infants.89 These findings of differences in

responses emerging over time rather than disappearing appear to be consistent with rodent studies.90 Since the finger lance may have been too minor to elicit differences between the preterm and full-term children, we undertook a study of reactivity to immunization injections at 4 months’ CA in infants born at or Inhibitors,research,lifescience,medical below 32 weeks’ gestation, compared to full-term controls.91 Again, there were no significant differences in facial or cardiac responses. Inhibitors,research,lifescience,medical However, sex differences were evident in cortisol response to immunization, with preterm boys displaying a lower cortisol response, although facial behavior and heart rate reactivity did not differ between boys or girls. Later in childhood, there have been a number of experimental studies of pain threshold in children born

preterm, revealing complex effects. Adolescents Inhibitors,research,lifescience,medical born preterm had more tender points and lower pain threshold compared to their term-born peers.92 In school-age children born preterm, using quantitative sensory testing, both hypersensitivity and hyposensitivity Inhibitors,research,lifescience,medical to pain have been found, compared to children born full-term,

depending on the type of pain stimulus and duration.93,94 Increased sensitivity to brief heat and reduced sensitivity to prolonged heat were found at sites that were not injured in infancy. These findings are consistent with studies Inhibitors,research,lifescience,medical of long-term HDAC inhibitor effects of early pain in rat pups.90 Importantly, neonatal surgery accounted for differences in pain sensitivity in children born at or below 25 weeks’ gestation.94 Given the extent of pain exposure in infants born that early, the minimal difference in pain sensitivity between micropremies who had not undergone surgery and controls was very surprising many and re-assuring. In some other studies of long-term changes in pain sensitivity following early surgery, both preterm and full-term children have been included in samples. Pain threshold at school-age depended on type of surgery and whether threshold was tested in the region of surgery. For example, sensitivity among children who had chest surgery in infancy showed reduced sensitivity to touch, cold, and heat in the region of the surgery.95 In other studies, increased sensitivity was evident later in young children with a history of surgery.96,97 An important finding was the need for more intraoperative anesthesia and more postoperative analgesia in children who had surgery previously, compared to children having their first surgery.