[Paracetamol (acetaminophen) use in neonatology: a (re)appreciation of an old drug]

Abstract

In neonates, paracetamol is mainly used for its analgesic action. This drug is actually preferred by neonatologists because of its broad therapeutic index. Recently, it has been demonstrated that paracetamol is also an anti-cyclooxygenase (COX) medication through its inhibitory action on the peroxidase arm of central and peripheral COX (Boutaud et al., 2002; Toussaint et al., 2010; Graham et al., 2013; Hinz et al., 2008; Hinz and Brune, 2011). As such, this drug interferes with the synthesis of prostaglandins. This inhibition of peroxidase is, however, limited to a low concentration of arachidonic acid (AA) (around 2μM, in vitro) when the plasmatic concentration of paracetamol is experimentally 10μM, actually within the same range as compared to the therapeutic concentrations in vivo. This may partly explain its low anti-inflammatory effect as compared to ibuprofen and indomethacin, which exert their inhibition on COX whatever the AA concentrations are. This new well-demonstrated action of paracetamol on peripheral COX-2 of intact cells could explain recent observations making this drug a potential alternative in treating patent ductus arteriosus. However, the higher dosages that have been claimed by some authors in this indication still remain to be validated. This inhibition that paracetamol shows on the physiological synthesis of prostaglandins E2 (PGE2) could also explain some long-term immune deviations because the physiological concentration of PGE2 is a well-known actor in the genesis of immune homeostasis in the submucosal area. Indeed, recent epidemiology studies have pointed out immune deviations in children repeatedly exposed to paracetamol earlier in life. Consequently, this is actually the new discovery of an old drug. From these new data on paracetamol, a more focused pharmacovigilance on the long-term effects of paracetamol repeatedly given in the early stage should be urgently initiated.