Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial

Background. Relationships between plasma morphine concentrations and neonatal responses to endotracheal tube (ETT) suctioning are unknown in preterm neonates. Methods. Ventilated preterm neonates (n=898) from 16 centres were randomly assigned to placebo (n=449) or morphine (n=449). After an i.v. loading dose (100 mg kg21), morphine infu-sions [23–26 weeks postmenstrual age (PMA) 10 mg kg21 h21; 27–29 weeks 20 mg kg21 h21; and 30–32 weeks 30 mg kg21 h21] were established for a maximum of 14 days. Open-label morphine (20–100 mg kg21) was given for pain or agitation. Morphine assay and neonatal response to ETT suctioning was measured at 20–28 and 70–76 h after starting the drug infu-sion and at 10–14 h after discontinuation of the study drug. The concentration–effect response was investigated using non-linear mixed effects models. Results. A total of 5119 data points (1598 measured morphine concentrations and 3521 effect measures) were available from 875 neonates for analysis. Clearance was 50 % that of the mature value at 54.2 weeks PMA (CLmat50) and increased from 2.05 litre h 21 70 kg21 at 24 weeks PMA to 6.04 litre h21 70 kg21 at 32 weeks PMA. The volume of distribution in preter