Morphine does not alleviate acute pain in preterm neonates

Preterm neonates undergo many painful procedures as part of their standard care in the Neonatal Intensive Care Unit (NICU). Preterm babies are able to experience pain and indeed are highly sensitive to it. Therefore, there is an urgent need to find safe and effective treatments to relieve pain in these infants. Recent expert opinions have recommended the use of continuous morphine infusions for ongoing analgesia during routine NICU care and invasive procedures in ventilated preterm neonates, despite limited data and conflicting evidence on their efficacy during routine invasive procedures or their safety in this population.

This study, which investigated the analgesic efficacy of intravenous morphine on heel stick-induced acute pain in preterm neonates, was nested within a prospective, randomized, double-blind, multicenter, placebo-controlled trial (the NEOPAIN Trial). Neonates born at 23 to 32 weeks gestation were enrolled from the NICU of one hospital to examine the analgesic efficacy of morphine for the acute pain elicited by heel sticks. Ventilated preterm neonates were randomized to either morphine (loading dose 100 mcg/kg, followed by infusions of 10 to 30 mcg/kg/h according to gestation, N=21) or placebo (5% dextrose infusions, N=21) groups. Pain-related responses to 3 heelsticks were evaluated: T1 heelstick before the loading dose, T2 heelstick at 2 to 3 hours after the loading dose, and T3 heelstick at 20 to 28 hours after the loading dose. Heel stick pain was assessed with two validated pain measurement instruments: the DAN scale (behavioral pain scale) and the PIPP score (multidimensional pain scale); plasma morphine levels were measured at T3.

Infants in the placebo and morphine groups had similar gestational ages and birth weights. With regard to pain assessment, no differences occurred at T1, T2 and T3 heel sticks in the DAN scores compared between the placebo and morphine groups or the PIPP scores compared between the two groups at the same time points. Within group comparisons showed no significant changes in the DAN scale or PIPP scores within either the placebo or morphine groups, although a trend towards lower PIPP scores occurred between T1 and T3 in the morphine group. There was no correlation between plasma morphine levels and pain scores.

This study has shown that the administration of intravenous morphine as a loading dose followed by a continuous infusion does not alleviate heel stick-induced pain in ventilated preterm neonates. This finding is worrisome because morphine is used widely for ongoing analgesia during routine NICU care and procedures in ventilated preterm neonates. In critically ill neonates, despite the efficacy of morphine to reduce prolonged or surgery-induced pain, however, its analgesic effect on the acute pain caused by invasive procedures remains unclear. Although initial data was in favor of an analgesic effect of morphine for procedural pain in preterm neonates, recent evidence seems to refute the effectiveness of morphine during acute pain in preterm neonates. Possible explanations for the lack of analgesic effect of morphine in preterm neonates may include the immaturity of opioid receptors (decreased receptor concentrations and/or receptor affinity), a decreased production of active metabolites, or the uncoupling of opioid receptors from intracellular signals.

The authors conclude that morphine does not provide adequate analgesia for acute pain in ventilated preterm neonates, caused by invasive procedures such as heel sticks, and that the administration of continuous morphine to preterm neonates does not eliminate the need for other analgesic approaches (e.g. sucrose) that are effective against acute procedural pain.

Acknowledgements: This study was supported by grant funds from the Fondation pour la Santé CNP, France (to R. Carbajal and R. Lenclen) and the National Institute for Child Health and Human Development (HD36484 to K.J.S. Anand, HD36270 to B.A. Barton). The authors gratefully acknowledge the contributions of the physicians, nurses, pharmacists, ultrasonographers, occupational and physical therapists at the participating institutions, and the parents who gave consent for this study.

Corresponding author: Ricardo Carbajal. Centre National de Ressources de Lutte contre la Douleur. Hôpital d’enfants Armand Trousseau. 26, av du Dr Netter. 75012 Paris FRANCE