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Dose alteration
Unsubstantiated alarmist declarations need to be examined
From Ms S. Conroy, MRPharmS, and others
We were concerned to read your news
article (PJ, 3/10 January, p4) which
suggested that a common medication practice in both adults and children
could no longer be recommended as safe. The news article was based on
a review paper published in the American journal Pediatric Nursing.1 The review concluded that the practice of alternating doses of paracetamol
with ibuprofen to help control fever in children cannot be safely recommended.
Although we would agree that more research into this practice is needed
due to the lack of an evidence base to support it, we suggest that the
emphasis in the PJ news article was uncritical of the paper and unhelpful
to practitioners working with children. Research is indeed needed to
determine whether doses of paracetamol and ibuprofen should be given
at the same time, alternately, or not at all. However this is a practice
which has been widespread for many years and unsubstantiated alarmist
declarations of a serious drug interaction would seem unnecessary and
should be examined in detail as we have done below.
The paper1 suggests that there is a risk of renal toxicity and paracetamol
accumulation in the kidneys. It concentrates on children with fever while
ignoring the fact that such drug combinations are also commonly used
in pain management in children and in adults. Any clinically significant
interaction between paracetamol and ibuprofen would surely by now be
widely documented in the medical literature.
The PJ news article has stimulated many concerned and confused enquiries
to paediatric pharmacists from academic nursing schools, primary care
trust advisers, community pharmacists and NHS Direct. We therefore wished
to balance the story by examining the evidence that we do have. The Pediatric
Nursing article1 makes a statement relating to renal toxicity which is
examined in detail below.
The statement reads: “... while glutathione is needed to prevent
the accumulation of acetaminophen (paracetamol) in the renal medulla,
ibuprofen inhibits glutathione production and also blocks the production
of renal prostaglandins by reducing renal blood flow. As a result, significant
tubular necrosis and renal toxicity can occur,2 which
can be even more pronounced when children are dehydrated.”
We have examined the original work which the Pediatric Nursing review
article bases this statement on to find it is based on case reports of
two children aged 12 and 14, who presented with acute flank pain and
reversible renal dysfunction with the use of non-steroidal anti-inflammatory
drugs.2 The authors of the case reports postulate the factors responsible
for the symptoms which are attributed to the adverse effects of NSAIDs.
They also mention that concomitant acetaminophen was present in both
cases (dose/duration/ number of doses administered etc were not specified),
and state that acetaminophen accumulates in the renal medulla, particularly
in states of renal ischaemia (possibly induced by NSAID use) or hypovolaemia.
The resultant metabolites can lead to medullary cellular necrosis in
the absence of glutathione, the production of which is inhibited by NSAIDs.
They then state that tubular toxicity of NSAIDs and acetaminophen are
at least theoretically synergistic. They also say that there was a suggestion
of tubular toxicity/necrosis in one of the cases only and the information
was not available for the other. They conclude that the practice of alternating
acetaminophen and NSAIDs for fever control theoretically increases the
risk of nephrotoxicity.2
It has not been possible to find further information on this proposed
interaction between paracetamol and ibuprofen. The Micromedex Drugdex
monograph (volume 119, June 2003) states that “at steady state,
the pharmacokinetics of acetaminophen and ibuprofen are not changed when
administered concurrently”, although the monograph has highlighted
that the evidence base for this is poor.
In essence, the news article quote in the PJ is based on two case reports
which clearly have limitations and weaknesses as sources of evidence,
with the proposed interaction being
based on a theoretical mechanism rather than evidence of documented patient
examples of its occurrence.
In conclusion, it is important to stress that practitioners should always
recommend the use of appropriate and adequate doses of a single agent
when treating pain or fever in a child. This should be combined with
non-pharmacological measures. Reassurance should be given to parents
and carers of children that fevers in the main are usually harmless,
and are part of the body’s natural response to fight infection.
It is not essential to control them in response to a thermometer reading,
but more to provide comfort to a child who is uncomfortable or distressed
as a result of the fever. However, in the light of little evidence to
suggest that there are true safety issues, professional judgement should
continue to be used for recommending combination treatment of paracetamol
with ibuprofen for fevers which do not respond to these first-line measures
in a child who is still in discomfort.
Sharon Conroy
Chairman
Steve Tomlin
Professional Secretary
Neonatal and Paediatric Pharmacists Group
Satpal Soor
Medicines Information
Guy’s Hospital
London
References
1. Carson SM. Alternating acetaminophen and ibuprofen in the febrile
child: examination of the evidence regarding efficacy and safety. Pediatric
Nursing 2003;29:379–82.
2. McIntire SC, Rubenstein RC, Gartner JC, Gilboa N, Ellis D. Acute flank
pain and reversible renal dysfunction associated with nonsteroidal anti-inflammatory
drug use. Pediatrics 1993;92:459–60. |
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