Table 1.

Studies on the relevance of paracetamol on pain (opioid reduction) during major pain syndromes in neonates (25, 50, 52).

Reference	Study design, pain model	Paracetamol dosing	Results
Van der Marel et al. (50)	Double-blind RCT, morphine + paracetamol or placebo, 30/54 PMA <45 weeks. Visual analog Scale (VAS) and comfort score. Major thoracic (lung, esophageal) or abdominal surgery	Rectal paracetamol 30–40 mg/kg loading dose, 20–30 mg/kg, q6h or q8h, maintenance dose	Cases < PMA 45 weeks needed less add on morphine compared to infants, but without any difference between both study arms (paracetamol or placebo) (threshold for additional morphine, ≥VAS)
Ceelie et al. (25)	Double-blind RCT, 71 neonates and infants (35/71 <10 days post-natal). Major thoracic (lung, esophageal) or abdominal surgery. Nurse rating scale-11 + comfort-B, cumulative maintenance dose of morphine was assessed	Morphine loading dose, followed by either continuous morphine or paracetamol i.v. (48 h). Backup morphine	No differences in pain scores Clinical relevant lower (−66%) exposure to morphine for the continuous morphine when compared to the paracetamol group
Härmä et al. (52)	Retrospective, “unblended” analysis (two consecutive time intervals) on opioid prescription in 218 preterm neonates (<32 weeks) before or following the use of intravenous paracetamol in the clinical pain management protocol (Neonatal Infant Acute Pain Assessment Scale) of a single Finnish unit	20 mg/kg intravenous as loading dose, followed by 7.5 mg/kg, q6h (maintenance)	Paracetamol-exposed neonates needed significantly fewer morphine doses, 1.78 [(4.56) vs. 4.35 (11.53)] and had a lower total morphine exposure [0.17 (0.45) vs. 0.37 (0.96) mg/kg]. No differences in pain score, days on ventilation of incidence of apneas

RCT, randomized, controlled trial; PMA, post-menstrual age; LNPS, Leuven Neonatal Pain Scale; VAS, Visual Analog Scale.