title: Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial.
abstract: BACKGROUND
  Opioid analgesia is commonly used during neonatal intensive care. We undertook the Neurologic Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial to investigate whether pre-emptive morphine analgesia decreases the rate of a composite primary outcome of neonatal death, severe intraventricular haemorrhage (IVH), and periventricular leucomalacia (PVL) in preterm neonates.
  
  
  METHODS
  Ventilated preterm neonates (n=898) from 16 centres were randomly assigned masked placebo (n=449) or morphine (n=449) infusions. After a loading dose (100 microg/kg), morphine infusions (23-26 weeks of gestation 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); 30-32 weeks 30 microg kg(-1) h(-1)) were continued as long as clinically justified (maximum 14 days). Open-label morphine could be given on clinical judgment (placebo group 242/443 [54.6%], morphine group 202/446 [45.3%]). Analyses were by intention to treat.
  
  
  RESULTS
  Baseline variables were similar in the randomised groups. The placebo and morphine groups had similar rates of the composite outcome (105/408 [26%] vs 115/419 [27%]), neonatal death (47/449 [11%] vs 58/449 [13%]), severe IVH (46/429 [11%] vs 55/411 [13%]), and PVL (34/367 [9%] vs 27/367 [7%]). For neonates who were not given open-label morphine, rates of the composite outcome (53/225 [24%] vs 27/179 [15%], p=0.0338) and severe IVH (19/219 [9%] vs 6/189 [3%], p=0.0209) were higher in the morphine group than the placebo group. Placebo-group neonates receiving open-label morphine had worse rates of the composite outcome than those not receiving open-label morphine (78/228 [34%] vs 27/179 [15%], p<0.0001). Morphine-group neonates receiving open-label morphine were more likely to develop severe IVH (36/190 [19%] vs 19/219 [9%], p=0.0024).
  
  
  CONCLUSIONS
  Pre-emptive morphine infusions did not reduce the frequency of severe IVH, PVL, or death in ventilated preterm neonates, but intermittent boluses of open-label morphine were associated with an increased rate of the composite outcome. The morphine doses used in this study decrease clinical signs of pain but can cause significant adverse effects in ventilated preterm neonates.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. anandsunny@uams.edu
authors.forename: K J S
authors.initials: KJ
authors.lastname: Anand
authors.forename: R Whit
authors.initials: RW
authors.lastname: Hall
authors.forename: Nirmala
authors.initials: N
authors.lastname: Desai
authors.forename: Barbara
authors.initials: B
authors.lastname: Shephard
authors.forename: Lena L
authors.initials: LL
authors.lastname: Bergqvist
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Young
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Boyle
authors.forename: Ricardo
authors.initials: R
authors.lastname: Carbajal
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Bhutani
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Moore
authors.forename: Shari S
authors.initials: SS
authors.lastname: Kronsberg
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Barton
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007226:Infant Mortality; D007231:Infant, Newborn; D007234:Infant, Premature; D007262:Infusions, Intravenous; D015931:Intensive Care, Neonatal; D020300:Intracranial Hemorrhages / Q000517:prevention & control; D007969:Leukomalacia, Periventricular / Q000517:prevention & control; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects; D012121:Respiration, Artificial; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine