Comparison of Two Different Doses of Paracetamol for Post-Operative Pain Relief

A randomised, crossover dose-effect trial of paracetamol 60 and 90 mg/kg in third molar surgery

Background Paracetamol is the most widely used analgesic in New Zealand but relatively little is known about its dose effect and concentration effect relationships. It appears that there is greater effect above the currently recommended dose, but the maximal effect has not as yet been described.

Paracetamol is toxic in overdose but the dose at which toxicity becomes apparent is disputed. In the past, the dose at which toxicity may become apparent has been 125 mg/kg/day, but more recently this has been revised upwards to 150 mg/kg/day in children (1). In children it has been proposed that toxicity does not develop following single ingestions of up to 200 mg/kg/day (2).

Paracetamol is metabolised by multiple pathways: urinary excretion of an oral dose is 55% as glucuronide conjugates, 30% as cysteine conjugates, 4% as mercapturic acid and cysteine conjugates (3). The mercapturic and cysteine conjugates are derived from a toxic intermediary metabolite, produced by oxidative metabolism by CYP2E1, and to a lesser degree CYP3A4 and CYP1A2 (4). At doses of up to 1500 mg the metabolism appears to be unchanged but there is no data for doses at or above 90 mg/kg (5). It has been proposed that paracetamol metabolism becomes saturated at higher doses and saturation of sulfation has been observed in rats (6). However saturation of either sulfation or glucuronidation has not been observed in cultured human hepatocytes (6).

In overdose, paracetamol has been observed to inhibit the activity of vitamin-K dependent clotting factors, in particular functional factor VII (7). This may explain the interaction between paracetamol and warfarin.