Paracetamol in childhood

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Editor, – I am writing about the use of paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) ('Paracetamol: overused in childhood fever' Aust Prescr 2000;23:60-1). For a while we have been bogged down with the controversy about the concurrent prescribing of paracetamol and ibuprofen to children who have fever which is not controlled by paracetamol alone.

The current practice here is not to give paracetamol four-hourly for more than one day, after which the patient is advised to switch to six-hourly. As such, if breakthrough fever occurs after one day on paracetamol, some doctors advise patients to stagger the paracetamol dose with ibuprofen three hours inbetween.

What would be the concern about nephrotoxicity/hepatotoxicity when giving the two preparations concurrently to children?

Hing Wee Chuan
Drug Information Pharmacist
KK Hospital
Singapore

Professor Ric Day and Dr Robert Graham, St Vincent's Hospital, Sydney, and Dr Noel Cranswick, Royal Children's Hospital, Melbourne, comment:

Mr Hing Wee Chuan enquires about the use of paracetamol in combination with ibuprofen in children whose pyrexia does not respond to paracetamol alone. Firstly, the question should be asked whether the temperature needs to be lowered at all. There is increasing evidence1 that routine fever reduction is unnecessary, with no evidence that the risk of febrile seizures is reduced2 and some viral illnesses may even be prolonged.3

Prolonged dosing of paracetamol needs to be kept below 60 mg/kg/day in children to minimise the risk of liver toxicity. The practice of dosing four-hourly on day 1 and six-hourly thereafter as is practised in Mr Hing's hospital is acceptable as long as the daily dose limits are not exceeded. However, there is no evidence that the practice has any safety advantage. A clear upper limit for ibuprofen dosage in children for antipyresis has not been established. However, some adverse effects may be dose related. Uncommon but potentially serious adverse effects include aspirin-like sensitivity, renal toxicity and gastrointestinal bleeding.

If it is decided to treat fever, there is no evidence that the combination of paracetamol and ibuprofen is more effective than either drug alone. However, there is evidence from adult studies that the dose of NSAIDs can be reduced without loss of analgesic efficacy when paracetamol is used concomitantly.4 In this study there were fewer minor adverse effects such as dyspepsia when naproxen was combined with paracetamol in the treatment of rheumatoid arthritis, probably related to the lower dose of NSAID employed in the combination regimen. There is a safety benefit in combining NSAIDs with paracetamol if the dose of NSAID used is less than would normally be the case. We know that the risk of serious supper gastrointestinal adverse reactions to NSAIDs increases with the dose rate of NSAID.5 This would be most pertinent in those at increased risk, particularly the elderly.

Ibuprofen, like all NSAIDs, can be hazardous in patients with hepatic or renal impairment or in hypovolaemic situations.6 Paracetamol in this context could theoretically increase the risk of further hepatic damage.

Whether there is any merit in using the combination to treat fever would need to be subject to controlled studies. In the interim, there seems little evidence either to support or to raise concerns about the practice.

References

  1. Kramer MS, Naimark LE, Roberts-Brauer R, McDougall A, Leduc DG. Risks and benefits of paracetamol antipyresis in young children with fever of presumed viral origin. Lancet 1991;337:591-4.
  2. Schnaiderman D, Lahat E, Sheefer T, Aladjem M. Antipyretic effectiveness of acetaminophen in febrile seizures: ongoing prophylaxis versus sporadic usage. Eur J Pediatr 1993;152:747-9.
  3. Graham NMH, Burrell CJ, Douglas RM, Debelle P, Davies L. Adverse effects of aspirin, acetaminophen and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis 1990;162:1277-82.
  4. Seideman P, Melander A. Equianalgesic effects of paracetamol and indomethacin in rheumatoid arthritis. Br J Rheumatol1988;27:117-22.
  5. Simon LS. Risk factors and current NSAID use [editorial]. J Rheumatol 1999;26:1429-31.
  6. Johnson AG, Day RO. The problems and pitfalls of NSAID therapy in the elderly (Parts I & II). Drugs Aging 1991;1:130-43,212-27.