The paracetamol concentration-effect relation in neonates

Objectives We suggested a loading dose (20mg center dot kg-1) followed by 10mg center dot kg-1 q6h of intravenous (IV) paracetamol to achieve an effect compartment concentration of 11mg center dot l-1 in neonates. Since there are no pharmacodynamic data to support such an effect compartment concentration, pain scores collected in neonates treated with an IV paracetamol loading dose (20mg center dot kg-1) were used to validate this effect compartment concentration. Methods Pain scores (Leuven Neonatal Pain Score, LNPS, 014) before and 0.5, 1, 2, 3, 4, 5, and 6h after IV paracetamol loading dose administration in neonates to whom IV paracetamol was administered as single analgesic (PARANEO, www.clinicaltrials.gov, NCT00969176) were collected. Trends were analyzed using repeated measures anova. An Emax model with a delayed response compartment was fitted to data using population modeling. Results Nineteen of 60 neonates included in the PARANEO study received monotherapy with IV paracetamol to treat mild to moderate pain (e.g., alprostadil administration, delivery related trauma). Using repeated measures anova, there was a trend (P=0.02) for lower pain scores within 30min after administration, with a slight increase in pain scores from 5 to 6h. An Emax model had a maximum effect of 4.15 pain units, an EC50 of 2.07mg center dot l-1. Equilibration halftime (T1/2keo) was 1.58h. Conclusion Intravenous paracetamol is effective for moderate pain. An effect compartment concentration of 10mg center dot l-1 (loading dose of 20mg center dot kg-1) is associated with a pain score reduction of 3.4 LNPS units. This analysis suggests a similar paracetamol effect compartment concentration in neonates compared to children.