title: Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates.
abstract: BACKGROUND
  Morphine alleviates prolonged pain, reduces behavioral and hormonal stress responses induced by surgery among term neonates, and improves ventilator synchrony and sedation among ventilated preterm neonates, but its analgesic effects on the acute pain caused by invasive procedures remain unclear.
  
  
  OBJECTIVE
  To investigate the analgesic efficacy of intravenously administered morphine on heel stick-induced acute pain among preterm neonates.
  
  
  METHODS
  This study was nested within a prospective, randomized, double-blind, multicenter, placebo-controlled trial (the NEOPAIN Trial).
  
  
  METHODS
  A tertiary-care NICU in a teaching hospital.
  
  
  METHODS
  Forty-two preterm neonates undergoing ventilation.
  
  
  METHODS
  Neonates were randomized to either the morphine (loading dose of 100 microg/kg, followed by infusions of 10-30 microg/kg per hour according to gestation, N = 21) or placebo (5% dextrose infusions, N = 21) group. Pain responses to 3 heel sticks were evaluated, ie, before the loading dose (T1), 2 to 3 hours after the loading dose (T2), and 20 to 28 hours after the loading dose (T3).
  
  
  METHODS
  Pain was assessed with the Douleur Aiguë Nouveau-né (DAN) scale (behavioral pain scale) and the Premature Infant Pain Profile (PIPP) (multidimensional pain scale); plasma morphine levels were measured at T3.
  
  
  RESULTS
  Infants in the placebo and morphine groups had similar gestational ages (mean +/- SD: 27.2 +/- 1.7 vs 27.3 +/- 1.8 weeks) and birth weights (972 +/- 270 vs 947 +/- 269 g). Mean +/- SD DAN pain scores at T1, T2, and T3 were 4.8 +/- 4.0, 4.6 +/- 2.9, and 4.7 +/- 3.6, respectively, for the placebo group and 4.5 +/- 3.8, 4.4 +/- 3.7, and 3.1 +/- 3.4 for the morphine group. The within-group factor (pain at T1, T2, and T3) was not statistically different over time. The between-group analysis (infants receiving placebo versus those receiving morphine) showed no significant differences. Mean +/- SD PIPP pain scores at T1, T2, and T3 were 11.5 +/- 4.8, 11.1 +/- 3.7, and 9.1 +/- 4.0, respectively, for the placebo group and 10.0 +/- 3.6, 8.8 +/- 4.9, and 7.8 +/- 3.6 for the morphine group. The within-group factor was statistically different over time. The between-group analysis showed no significant differences. Mean +/- SD plasma morphine levels at T3 were 0.44 +/- 1.79 ng/mL and 63.36 +/- 33.35 ng/mL for the placebo and morphine groups, respectively. There was no correlation between plasma morphine levels and pain scores at T3 (DAN, R = -0.05; PIPP, R = -0.02).
  
  
  CONCLUSIONS
  Despite its routine use in the NICU, morphine given as a loading dose followed by continuous intravenous infusions does not appear to provide adequate analgesia for the acute pain caused by invasive procedures among ventilated preterm neonates.
authors.affiliation: Neonatal Intensive Care Unit, Poissy Saint Germain Hospital, Poissy, France. ricardo.carbajal@trs.aphp.fr
authors.forename: Ricardo
authors.initials: R
authors.lastname: Carbajal
authors.forename: Richard
authors.initials: R
authors.lastname: Lenclen
authors.forename: Myriam
authors.initials: M
authors.lastname: Jugie
authors.forename: Alain
authors.initials: A
authors.lastname: Paupe
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Barton
authors.forename: Kanwaljeet J S
authors.initials: KJ
authors.lastname: Anand
mesh_terms: D000208:Acute Disease; D000701:Analgesics, Opioid / Q000097:blood / Q000627:therapeutic use*; D001800:Blood Specimen Collection / Q000009:adverse effects*; D004311:Double-Blind Method; D005260:Female; D005865:Gestational Age; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000627:therapeutic use; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000097:blood / Q000188:drug therapy*; D007262:Infusions, Intravenous; D008297:Male; D009020:Morphine / Q000097:blood / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D011446:Prospective Studies; D012121:Respiration, Artificial
chemical_list: D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D009020:Morphine