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

Abstract

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 microg kg(-1)), morphine infusions [23-26 weeks postmenstrual age (PMA) 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); and 30-32 weeks 30 microg kg(-1) h(-1)] were established for a maximum of 14 days. Open-label morphine (20-100 microg kg(-1)) 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 infusion 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 (CLmat(50)) and increased from 2.05 litre h(-1) 70 kg(-1) at 24 weeks PMA to 6.04 litre h(-1) 70 kg(-1) at 32 weeks PMA. The volume of distribution in preterm neonates was 190 litre 70 kg(-1) (CV 51%) and did not change with age. There was no relationship between morphine concentrations (range 0-440 microg litre(-1)) and heart rate changes associated with ETT suctioning or with the Premature Infant Pain Profile.

Conclusions: A sigmoid curve describing maturation of morphine clearance is moved to the right in preterm neonates and volume of distribution is increased compared with term neonates. Morphine does not alter the neonatal response to ETT suctioning.

Fig 1

Quality of fit of pharmacokinetic data. (a) Displays individual Bayesian concentration predictions based on values of the parameters for the specific individual. (b) Displays the predicted typical (population) concentrations, which are based on population parameters and covariate information. (c) The y-axis displays the ratio of measured concentrations to those predicted from NONMEM post hoc, step-based on values of parameters for the specific individual. (d) The y-axis displays the ratio of measured concentrations to those predicted from PK analysis. (e) The weighted residuals for each subject in the two populations with values for each subject joined by vertical lines.

Fig 2

(a) Individual predicted clearances (CL) for morphine, standardized to a 70 kg person, from the NONMEM post hoc step, are plotted against PMA. The dashed line represents the non-linear relation between clearance and age. (b) Magnification of (a) to reveal the shift to the right for maturation of clearance in preterm neonates (solid line).

Fig 3

(a) Individual predicted volumes of distribution (V) for morphine, standardized to a 70 kg person, from the NONMEM post hoc step, are plotted against PMA. The dashed line represents the non-linear relation between clearance and age. (b) Magnification of (a) to reveal increased V in ventilator-dependent preterm neonates with no relationship to PMA (solid line).

Fig 4

The relationship between volumes of distribution (V) for morphine and PNA reveals increased V in ventilator-dependent preterm neonates with no relationship to PNA (solid line).

Fig 5

The lack of relationship between morphine concentrations and heart rate changes occurring with ETT suctioning.

Fig 6

The lack of relationship between morphine concentrations and PIPP scores associated with ETT suctioning.