NPC Archive Item: No good evidence for combination antipyretics in children

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Hay AD, Costelloe C, Redmond NM, et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. BMJ 2008;337:a1302

A combination of paracetamol plus ibuprofen was more effective than paracetamol alone but no more effective than ibuprofen alone to relieve fever in children in the first 4 hours. However, as the combination regimen is more complex, the risk of unintentionally exceeding the maximum recommended dose may be increased compared with using either drug on its own.

Clinicians should follow NICE guidance on feverish illness in children. This states that antipyretic drugs should not routinely be given to children with fever who are otherwise well with the sole aim of reducing body temperature or preventing febrile convulsions. Either paracetamol or ibuprofen may be used if the child appears distressed or is unwell. The two drugs should not be administered at the same time. The alternative agent should be used if the child does not respond to the first drug.

What does this study claim?
In the first 4 hours after administration, a combination of paracetamol plus ibuprofen reduced time with fever by 55 minutes compared with paracetamol alone (adjusted difference 55.3 minutes, 95% confidence interval [CI] 33.1 to 77.5; P<0.001). However, the combination was not superior to ibuprofen alone (adjusted difference 16.2 minutes, 95% CI –7.0 to 39.4; P=0.2). For time without fever in the first 24 hours, paracetamol plus ibuprofen was significantly better than paracetamol (adjusted difference 4.4 hours, 95% CI 2.4 to 6.3; P<0.001) and ibuprofen alone (adjusted difference 2.5 hours, 95% CI 0.6 to 4.4; P=0.008). There was no significant difference in fever associated discomfort between the groups. However, the study had low power to detect such differences between the groups due to problems recruiting sufficient numbers of children. A trial with greater power is required to confirm this result. Adverse effects did not differ between the groups. An accompanying editorial points out that the most worrying aspect of the study is that even under clinical trial conditions, 31/156 children received an unintentional drug overdose.

So what?
The NICE guideline development group found no evidence for any specific indications for the administration of antipyretics. Consensus was that paracetamol and ibuprofen should not be given to all children with fever, as there is no evidence that they shorten the duration of illness or reduce complications, such as febrile convulsions. However, antipyretic drugs should be offered to children who are miserable with fever because they may make them feel better.

This study does not argue for a change in these recommendations. Although it shows that a combination of paracetamol and ibuprofen reduced fever in the first 24 hours significantly better than either drug alone, NICE advises that such drugs should not be given with the sole intention of reducing fever. The study did not show a difference between the three arms in terms of reducing discomfort.

NICE conclude that there is evidence that paracetamol and ibuprofen are equally effective antipyretics. There is no evidence of a significant difference in the incidence of adverse events between the two drugs but paracetamol has a longer established safety record. Physical methods of temperature reduction (e.g. tepid sponging or over- or under-dressing) offer little additional benefit and cause crying and shivering in some children.

Study details
Design: Randomised controlled trial in 35 primary care sites in Bristol.

Patients: 156 children aged between 6 months and 6 years who were unwell with axillary temperature > 37.8°C and < 41.0°C and who could be managed at home.

Intervention and comparison: The children were randomised to receive regular doses of paracetamol (maximum 4 doses in 24 hours), ibuprofen (maximum 3 doses in 24 hours) or a combination of paracetamol and ibuprofen. All parents were given two medicine bottles: either both containing an active drug or one containing an active drug and the other placebo. Due to the differences in dosing, parents were aware which was paracetamol/placebo and which was ibuprofen/placebo. All parents were given advice on appropriate use of loose clothing and encouraging children to drink cool fluids. An axillary temperature probe was used to measure temperature every 30 seconds and parents completed symptom diaries.

Outcomes: The two primary outcomes were the time without fever (<37.2°C) in the first 4 hours and the proportion of children reported as being normal on the discomfort scale at 48 hours.

Results: These were analysed on an intention to treat basis.

Time without fever in first 4 hours: adjusted minutes difference (95% CI)

No discomfort at 48 hours: adjusted odds ratio (95% CI)

Combination vs. paracetamol

55.3 (33.1 to 77.5) P<0.001

1.33 (0.49 to 3.56) P=0.7

Combination vs. ibuprofen

16.2 (–7.0 to 39.4) P=0.2

0.89 (0.32 to 2.43) P>0.8

Ibuprofen vs. paracetamol (secondary comparison)

39.0 (15.9 to 61.0) P<0.001

1.50 (0.53 to 4.26) P>0.5

– only the differences in bold are statistically significant.

For fever associated discomfort, the study had low power to detect differences between the groups because of the small number of children included in the trial. The most common adverse effects were diarrhoea and vomiting which were equally distributed between the groups

Sponsorship: National Institute for Health Research health technology assessment programme.

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