A dose ranging study ofibuprofen suspension as an antipyretic 1041

100° the antipyretic properties of ibuprofen syrup versus ace-

tylsalicylic acid syrup in febrile children. Br J Clin Pract Arch Dis Child: first published as 10.1136/adc.66.9.1041 on 1 September 1991. Downloaded from 1988;42:245-7. 10 BMA and Pharmaceutical Society. Drugs used in rheumatic 82 diseases and gout. In: Prasad AB, ed. British national forinulaty. No 19. Lotdon: BMA and Pharmaceutical Society ofGreat Britain, 1990:338-0.

67 Commentary NEW DRUG FOR OLD? ~60-~~~~~ Fever is universal. We all experience it from 52 0 time to time and the average child in Britain is 4)50- given an antipyretic drug on four or five days a year.' Since the demise of aspirin for childhood fever in 1986, paracetamol has had the field to itself. Fever in itself is unlikely to be harmful. As a response to infection it almost never rises above 41°C and, provided dehydration is avoided and heat loss is not prevented by over- heating or overclothing, fever of that degree is not damaging.2 Even in those prone to febrile convulsions, treatment offever does not seem to 0-625 1-25 2.5 5 0 prevent attacks.3 The reasons for giving an anti- Dose of ibuprofen (mg/kg) pyretic drug are to relieve discomfort and to Figure 3 Percentage ofchildren showing a temperature reduction of or more at three hours relieve the anxiety felt particularly by parents 1°C by dose ofibuprofen. (and by medical and nursing attendants). Do we need a new drug for this purpose and what risk ing fever control than 10 mg/kg paracetamol.8 are we prepared to take to develop one? However, doses of 15 mg/kg paracetamol are Paracetamol was first used in 1893 and has commonly prescribed. been in regular use since 1949.4 It has so far not Although 39 children warranted 'rescue' been associated with serious toxicity in ther- treatment, only five of these children had apeutic dosage and, despite its ready availabil- received an initial 5 mg/kg dose of ibuprofen. ity, overdosage has not been a serious problem The 'rescue' medication was given if the child's in children.5 It is effective. 8 axillary temperature remained above 372°C What properties should a drug have in order three hours after the initial randomised dose for it to replace paracetamol as an antipyretic for and the apparent 'failure' of the 5 mg/kg dose in children? Laying aside considerations ofpresen- these five children must be viewed against this tation and expense, I suggest the following: (i) it very strict temperature criterion and in com- should be demonstrably more effective in reliev- parison with other antipyretic measures. The ing discomfort and (ii) it should be free of serious when to mean baseline axillary temperature was 39°C in toxicity given very large numbers (mil- http://adc.bmj.com/ the 5 mg/kg ibuprofen group ofour study. In an lions) of children. Therein lies the rub. Does a earlier study in which children had a mean base- possibly slightly greater temperature reduction line oral temperature of 39°C, the mean oral with ibuprofen translate into significantly temperature three hours later remained at greater comfort for children in practice? There 38-7°C if only nursing measures were used and seems to be little evidence on that point. The was 37T8°C if 10 mg/kg paracetamol had been second of these conditions is, of course, impos- sible to satisfy without taking the risk and

given. on September 25, 2021 by guest. Protected copyright. Finally, the 5 mg/kg ibuprofen dose did not whether the risk is worthwhile depends on the compare unfavourably in our study with the seriousness of the condition to be treated and weaker doses in acceptability or in the nature of the effectiveness of present treatment. If aspirin adverse events. were a certain cure for leukaemia, for instance, its association with Reye's syndrome would be disregarded in that context because the benefit 1 Hull D. Fever-the fire of life. Arch Dis Child 1989;64:. would far exceed the risk. The risk-benefit 1741-7. equation is very different for childhood fever. 2 Tarlow M. Reye's syndrome and aspirin. BMJ 1986;292: 1543-4. So far there is no known serious toxicity for 3 Adams SS, McCullough KF, Nicholson JS. The pharma- ibuprofen but it has not until very recently been cological properties of ibuprofen, an anti-inflammatory, analgesic and antipyretic agent. Arch Int Pharmacodyn Ther used in very large numbers of children. It has 1%9;18:1 15-29. been used in the treatment of juvenile chronic 4 Brooks CD, Schiagel CA, Sekhar NC, Sibota JT. Tolerance and pharmacology of ibuprofen. Current Therapeutic arthritis for 11 years but only recently been used Research 1973;15:180-90. as an antipyretic.9 Aspirin was in use for over 80 5 Wilson G, Guerra AJMS, Santos NT. Comparative study of the antipyretic effects of ibuprofen (oral suspension) and years before its use in children was discon- paracetamol (suppositories) in paediatrics. J Int Med Res tinued. Drug surveillance is now much 1984;12:250-4. 6 Simila S, Kouvalainen K, Keinanen S. Oral antipyretic improved but to recommend any drug for use in therapy: evaluation of ibuprofen. Scandj Rheumatol 1976; a condition that affects virtually all children 5:81-3. 7 Amdekar YK, Desai RZ. Antipyretic activity of ibuprofen several times a year is to suggest an experiment. and paracetamol in children with pyrexia. BrJ Clin Pract There are many other non-steroidal anti- 1985;39:140-3. 8 Walson PD, Galletta G, Branden NJ, Alexander L. inflammatory drugs, the manufacturers of at Ibuprofen, acetaminophen and placebo treatment offebrile least one of which have to my knowledge children. ClinPharmacol Ther 1989;46:9-17. 9 Heremans G, Dehaen F, Rom N, Ramet J, Verboven M, seriously considered promoting its use for child- Loeb H. A single-blind parallel group study investigating hood fever but have so far not done so, so the 1042 Marriott, Stephenson, Hull, Povnall, Smith, Butler

number of experiments can be expected to pro- stated that 'since the withdrawal of paediatric liferate. Such experiments should be driyen by aspirin formulations, the incidence of accidental Arch Dis Child: first published as 10.1136/adc.66.9.1041 on 1 September 1991. Downloaded from need. Do we need them? paracetamol poisoning in children appears to be increasing'.' Although hepatotoxicity and death are rare in children under the age of 5 years,2 1 Rylance GW, Woods CG, Cullen RE, Rylance ME. Use of this is probably because children ingest smaller drugs by children. BMJ 1988;297:445-7. 2 Done AK. The treatment of fever in 1982: a review. Am doses and present earlier for treatment than J Med 1983;74:suppl 27-35. adults. If an entire bottle of paediatric ibupro- 3 Camfield PR, Camfield CS, Shapiro SH, Cummings C. The first febrile seizure-antipyretic instruction plus either fen suspension were ingested by a child aged 1 phenobarbital or placebo to prevent recurrence. J Pediatr to 2 years, serious toxicity would be 1980;97: 16-2 1. unlikely.' 4 Goodman LS, Gilman A, eds. The pharmacological basis of The consideration that an antipyretic drug therapeutics. 5th Ed. New York: MacMillan, 1975. should relieve discomfort is an important one. 5 Volans GN. Antipyretic analgesic overdosage in children. Comparative risks. BrJ Clin Pract 1990;44(suppl 70):26-9. Analgesia for children has perhaps not always 6 Lovejoy FH Jr. Aspirin and acetaminophen: a comparative been given the attention that it deserves. Ibu- view of their antipyretic and analgesic activity. Pediatrics 1978;62:suppl 904-9. profen has been used as an analgesic and anti- 7 Yaffe SJ. Comparative efficacy of aspirin and acetaminophen inflammatory drug in childhood arthritis for in the reduction of fever in children. Arch Int Med 1981; 141:286-92. some time3 and at much larger doses than in our 8 Walson PD, Galletta G, Branden NJ, Alexander L. study. Although fever may be seen by doctors as Ibuprofen, acetaminophen and placebo treatment of febrile children. Clin Pharmacol Ther 1989;46:9-17. a trivial and common feature of childhood ill- 9 Marriott SC, Stephenson TJ, Hull D, Pownall R, Smith CM, ness, the discomfort which accompanies febrile Butler A. A dose ranging study of ibuprofen suspension as an antipyretic. Arch Dis Child 1991;66:1037-42. illnesses is very real to that child. It has been estimated that over 240 million doses of ibupro- D P ADDY Dudley Road Hospital, fen have been given to children. To try to Birmingham B18 7QH improve the relief of pain is not to experiment, provided we adhere to the principle of primum non nocere. It is surely better that drugs used for children are subjected to the same scrutiny as Reply to the commentary by the authors those introduced for adults, rather than these We are not proponents of any particular drug drugs being absorbed into the paediatric for children. We are, however, proponents of formulary on an ad hoc basis, as has been the choice in prescribing for children and this case with many other childhood treatments over choice should be well informed. The purpose of the last decades. Perhaps if aspirin had been our study was to determine the minimum effec- subjected to the same scrutiny, and the same tive dose of ibuprofen for childhood fever, and surveillance after it was marketed,4 the associa- the safety of this drug in this context, rather tion with Reye's syndrome would have been than to compare it directly with paracetamol, detected before 80 years had elapsed? which others have done. Whether ibuprofen should have been granted a product licence as a

1 Volans GN. Pyrexia today; a symposium report. Education in http://adc.bmj.com/ childhood antipyretic is a decision for the Medi- practice. London: Boots Company, 1989. cines Control Agency, which enforces the Medi- 2 Meredith TJ, Newman B, Goulding R. Paracetamol poison- ing in children. BMJ 1978;ii:478-9. cines Act 1968. 3 Ansell BM. Ibuprofen in the management of Still's disease. The commentary states that paracetamol Practitioner 1973;211:659. 4 Rawlins MD, Jefferys DB. Study of United Kingdom overdosage has not been a serious problem in product licence applications containing new active sub- children. However, in the reference quoted it is stances, 1987-9. BMJ 1991;302:223-5. on September 25, 2021 by guest. Protected copyright.