No evidence for combination or alternating paracetamol and ibuprofen in febrile children

The PITCH study is a UK randomised controlled trial of paracetamol, ibuprofen, and a combination of the two drugs in 156 febrile children (axillary temperatures of at least 37.8°C and up to 41.0°C), aged 6 months to 6 years in primary care. Parents were given standardised verbal and written advice on the appropriate use of loose clothing and encouraging children to take cool fluids. They were also given advice on how to administer the analgesia for up to 48 hours: paracetamol every 4-6 hours (maximum of four doses in 24 hours) and ibuprofen every 6-8 hours (maximum of three doses in 24 hours). The dose was determined by the child’s weight: paracetamol 15 mg/kg per dose and ibuprofen 10 mg/kg per dose.

All parents received two medicine bottles; either both active or one containing the active drug and the other placebo. Given the differences in dosing, the parents were aware of which was paracetamol/placebo and which was ibuprofen/placebo.

The two primary outcomes were the time without fever (<37.2°C) in the first four hours after administration the first dose and the proportion of children reported as being normal on the discomfort scale at 48 hours.

The researchers reported the following results based on an intention to treat analysis:

• Paracetamol plus ibuprofen was superior to paracetamol in terms of less time with fever in the first four hours (adjusted difference 55 minutes, 95% CI 33 to 77; P<0.001) but not superior to ibuprofen alone (16 minutes, –7 to 39; P=0.2).
• For less time with fever over 24 hours, paracetamol plus ibuprofen was superior to paracetamol (4.4 hours, 2.4 to 6.3; P<0.001) and to ibuprofen (2.5 hours, 0.6 to 4.4; P=0.008).
• Combined therapy cleared fever 23 minutes (2 to 45; P=0.025) faster than paracetamol alone but no faster than ibuprofen alone (–3 minutes, 18 to –24; P=0.8).
• No benefit was found for discomfort or other symptoms, although power was low for these outcomes. Adverse effects did not differ between groups.

The authors concluded that, “parents, nurses, pharmacists, and doctors wanting to use medicines to supplement physical measures to maximise the time that children spend without fever should use ibuprofen first and consider the relative benefits and risks of using paracetamol plus ibuprofen over 24 hours”.

An accompanying editorial notes that there is no persuasive evidence for recommending a combination or an alternating regimen of paracetamol and ibuprofen. Other suggestions made include improving the precision of diagnosis in febrile children, the importance of fluid intake and sensible clothing and weighing the child to determine the most appropriate dose of antipyretic. The editorialist concludes that ibuprofen is the most suitable antipyretic to use because of its longer duration of action. 

Br Med J 2008; 337: a1302 (link to abstract); Br Med J 2008; 337: a1409 (Editorial; link to extract)