The paracetamol concentration-effect relation in neonates



Karel Allegaert, MD, PhD, Neonatal Intensive Care Unit, University Hospital, Herestraat 49, 3000 Leuven, Belgium




We suggested a loading dose (20 mg·kg−1) followed by 10 mg·kg−1 q6h of intravenous (IV) paracetamol to achieve an effect compartment concentration of 11 mg·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 (20 mg·kg−1) were used to validate this effect compartment concentration.


Pain scores (Leuven Neonatal Pain Score, LNPS, 0–14) before and 0.5, 1, 2, 3, 4, 5, and 6 h after IV paracetamol loading dose administration in neonates to whom IV paracetamol was administered as single analgesic (PARANEO,, 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.


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 (= 0.02) for lower pain scores within 30 min after administration, with a slight increase in pain scores from 5 to 6 h. An Emax model had a maximum effect of 4.15 pain units, an EC50 of 2.07 mg·l−1. Equilibration halftime (T1/2keo) was 1.58 h.


Intravenous paracetamol is effective for moderate pain. An effect compartment concentration of 10 mg·l−1 (loading dose of 20 mg·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.