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has not been confirmed (Palmer et al, 2008 Level III‐3). The volume of distribution of
paracetamol decreases and clearance increases from 28 weeks postconceptional age
resulting in a gradual fall in elimination half‐life. Suggested maximum oral or rectal doses are:
25 mg/kg/day at 30 weeks postconceptional age; 45 mg/kg/day at 34 weeks postconceptional
age; 60 mg/kg/day in term neonates and infants; and 90 mg/kg/day in children aged between
6 months and 12 years. These doses are suitable for acute administration for 2 to 3 days
(Anderson et al, 2002 Level III‐3). Following IV dosing in neonates aged 28 to 45 weeks
postmentrual age, volume of distribution was similar to the adult value, suggesting higher
IV doses may be tolerated in neonates (Palmer et al, 2008 Level III‐3), but current recommended
maximum doses of IV paracetamol are 30 mg/kg/day in neonates and infants, and 40 to
60 mg/kg/day in infants and children (Palmer et al, 2007; Howard et al, 2008).
Adverse effects
Paracetamol is metabolised in the liver, predominantly via glucuronidation and sulphation.
Increased production of a reactive oxidative product N‐acetyl‐p‐benzoquinoneimine occurs if
the usual metabolic enzyme systems become saturated (eg acute overdose) or if glutathione is
depleted (eg with prolonged fasting). An increased contribution of sulphation to metabolism
and reduced production of oxidative metabolites may reduce the risk of toxicity in neonates,
particularly in the presence of unconjugated hyperbilirubinaemia (Palmer et al, 2008), but as
overall clearance is reduced a lower dose is appropriate. Risk factors for paracetamol
hepatoxicity may include fasting, vomiting, dehydration, systemic sepsis, pre‐existing liver
disease and prior paracetamol intake, however the situation remains unclear (Kaplowitz, 2004).
10.5.2 Non-selective non-steroidal anti-inflammatory drugs

NsNSAIDs are effective analgesic agents for mild to moderate pain. Although the product
information states that safety in children less than 2 years is not established, nsNSAIDs have
been studied and used in all age groups including infants (Eustace & O'Hare, 2007 Level IV).
The choice between ibuprofen, diclofenac and ketorolac mainly depends on the available
formulation and convenience of administration.
Clinical studies suggest similar efficacy of nsNSAIDs and paracetamol (Tay & Tan, 2002 Level II;
Hiller et al, 2006 Level II; Riad & Moussa, 2007 Level II), as long as equieffective doses are being
given. Combining nsNSAIDs and paracetamol has been shown to improve analgesia and/or
CHAPTER 10 tonsillectomy (Pickering et al, 2002 Level II), inguinal surgery (Riad & Moussa, 2007 Level II),
decrease the need for additional analgesia after adenoidectomy (Viitanen et al, 2003 Level II),
multiple dental extractions (Gazal & Mackie, 2007 Level II), and orthopaedic surgery (Hiller et al,
2006 Level II). As a component of multimodal analgesia, nsNSAIDs decrease opioid
consumption (Antila et al, 2006 Level II; Rugyte & Kokki, 2007 Level II). A combination of
individually titrated intraoperative opioids and regularly administered perioperative mild
analgesics (NSAID and/or paracetamol) is recommended for management of pain following
tonsillectomy (Hamunen & Kontinen, 2005 Level I).
Pharmacokinetics and pharmacodynamics
The elimination half‐life of ketorolac (Lynn et al, 2007), ibuprofen (Kyllonen et al, 2005) and
diclofenac (Litalien & Jacqz‐Aigrain, 2001) is longest in neonates, with the value in toddlers
approaching that of adults. Rectal bioavailability of diclofenac is high in children (van der Marel
et al, 2004). Ibuprofen plasma concentrations of 10 to 25 mg/L have been suggested post
paediatric inguinal hernia repair (Kokki et al, 2007). Target analgesic concentrations for other
NSAIDs, developmental changes in pharmacodynamics, and the impact of different
stereoisomer forms on the differential pharmacokinetics, efficacy and side‐effect profile
of NSAIDs (Kyllonen et al, 2005) require further evaluation (Anderson & Palmer, 2006).

348 Acute Pain Management: Scientific Evidence