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Departments of Pediatrics,
Pharmacology & Physiology,
The George Washington
University School of Medicine
and Health Sciences, and the
Division of Pediatric Clinical
Pharmacology, Childrens
National Medical Center, WA,
USA
Correspondence to:
John N van den Anker, MD,
PhD
Division of Pediatric Clinical
Pharmacology, Childrens
National Medical Center, 111
Michigan Avenue, NW, WA,
20010-2970, USA
Tel.: +1 202 4762893
Fax: +1 202 476 3425
Email: jvandena@
childrensnational.org
Disclosures
The author is a paid consultant
for Reckitt Benckiser and has
received honoraria from Reckitt
Benckiser for presenting at a
symposium.
SUMMARY
Fever and pain in children, especially associated with infections, such as otitis
media, are very common. In paediatric populations, ibuprofen and paracetamol
(acetaminophen) are both commonly used over-the-counter medicines for the management of fever or mild-to-moderate pain associated with sore throat, otitis
media, toothache, earache and headache. Widespread use of ibuprofen and paracetamol has shown that they are both effective and generally well tolerated in the
reduction in paediatric fever and pain. However, ibuprofen has the advantage of
less frequent dosing (every 68 h vs. every 4 h for paracetamol) and its longer
duration of action makes it a suitable alternative to paracetamol. In comparative
trials, ibuprofen has been shown to be at least as effective as paracetamol as an
analgesic and more effective as an antipyretic. The safety profile of ibuprofen is
comparable to that of paracetamol if both drugs are used appropriately with the
correct dosing regimens. However, in the overdose situation, the toxicity of paracetamol is not only reached much earlier, but is also more severe and more difficult
to manage as compared with an overdose of ibuprofen. There is clearly a need for
advanced studies to investigate the safety of these medications in paediatric populations of different ages and especially during prolonged use. Finally, the recently
reported association between frequency and severity of asthma and paracetamol
use needs urgent additional investigations.
Introduction
Fever and pain are common in children, especially as
a result of infections, such as otitis media (1). In paediatric populations, the over-the-counter (OTC) medicines ibuprofen and paracetamol (acetaminophen)
are both commonly used for the management of fever
or mild-to-moderate pain associated with sore throat,
otitis media, toothache, earache and headache. Children are most likely to experience acute pain as a
result of illness, injury or medical procedures. Fever
in a child is one of the most common clinical symptoms managed by paediatricians and other healthcare
26
Review criteria
The information for this manuscript was
gathered from the peer-reviewed literature
(PubMed and Embase), textbooks, published
guidelines from the World Health Organization (WHO) and the American Academy of
Pediatrics (AAP), symposia reports and
abstract books from learned society meetings, such as the American Society for Clinical Pharmacology and Therapeutics (ASCPT)
and the American College of Clinical Pharmacology (ACCP). Information specifically
relevant to the topic of this manuscript was
selected, analysed and referenced.
2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 2632
doi: 10.1111/ijcp.12056
Physiology of fever
It is important to emphasise that fever is not an illness, but a physiological mechanism that has beneficial effects in fighting infection. Fever slows the
growth and replication of bacteria and viruses,
Pathophysiology of fever
Body temperature is regulated by the preoptic anterior hypothalamus. Under normal circumstances, this
thermoregulatory centre maintains body temperature
in a narrow physiological range by balancing the heat
produced by muscle and liver metabolism with the
amount of heat primarily lost through the skin and
lungs.
Fever, a cytokine-mediated increase in core body
temperature, is one component of the febrile
response, a physiological reaction to disease that
involves activation of various physiological, endocrinological and immunological systems (22). Although
primarily a reaction to infection, the febrile response
is also seen in other inflammatory and immunological diseases including malignancy and autoimmune
disease.
Fever is initiated by the pyrogenic cytokines,
namely interleukin-1 (IL-1), interleukin-6 (IL-6),
tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). Cytokines are nonstructural proteins produced in response to cell stress.
Almost all nucleated cells are capable of producing
and responding to cytokines. Cytokines remain
undetectable in the serum of normal subjects under
basal conditions. IL-1, IL-6, TNF-alpha and IFNgamma are intrinsically pyrogenic in that they rapidly induce fever by acting on the hypothalamic thermoregulatory centre.
The fever pathway is initiated when exogenous
pyrogens, such as microbes and or their toxins (e.g.
lipopolysaccharide or LPS), enter the body through a
defect in host barriers, stimulating mononuclear
phagocytes to release the aforementioned pyrogenic
cytokines. These cytokines travel in the systemic circulation to the organum vasculosum laminae terminalis (OVLT), a rich vascular network abutting the
hypothalamus with a minimal bloodbrain barrier.
The importance of the OVLT has been demonstrated
in studies showing that fever does not ensue after
peripheral administration of pyrogenic cytokines to
2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 2632
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To understand the mechanisms of action of the antipyretic agents considered herein, it is necessary to
review the components of the arachidonic acid cascade. Following proper stimulation (e.g. by an exogenous pyrogen), the cascade begins with the release of
phospholipids from cell membranes. Once liberated,
the phospholipids are converted to arachidonic acid
by phospholipase A2. Arachidonic acid is then
converted to prostaglandin by cyclooxygenase-2
(COX-2). Prostaglandin synthetase acts on the prostaglandin to produce PGE2, a proinflammatory
mediator causing pain, fever, erythema and oedema.
It is important to note that arachidonic acid is a
substrate for both COX-2 and a second isoform of
the enzyme, COX-1. Although COX-2 is an inducible
form of the enzyme not normally detectable in cells,
COX-1 is constitutively expressed. COX-2 is the
principal mediator of the inflammatory response,
thus resulting ultimately in production of PGE2.
COX-1 products, on the other hand, function primarily in renal function, vascular homeostasis and
gastrointestinal cytoprotection.
Paracetamol
The mechanism of action of paracetamol is not
entirely understood, but it is thought that it acts
centrally to convert the active oxidised form of COX
Ibuprofen
2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 2632
effective as, and perhaps more effective than, paracetamol (15 mg kg per dose) in lowering body temperature when either drug is given as a single or
repetitive dose (28,29).
However, another study concluded that to maximise the time that children spend without fever, one
should use ibuprofen first and consider the relative
benefits and risks of using paracetamol plus ibuprofen over 24 h (30). Overall, there is no evidence to
indicate that there is a significant difference in the
safety of standard doses of ibuprofen vs. paracetamol
in generally healthy children between 6 months and
12 years of age with febrile illnesses (31).
2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 2632
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Elimination
Drug elimination in paediatric patients can occur via
multiple routes, which include exhalation, biliary
secretion and renal clearance. Of these, the kidney is
quantitatively the most important. The kidney is the
primary organ responsible for the excretion of drugs
and their metabolites. The development of renal
function begins during early fetal development and is
complete by early childhood. From a developmental
perspective, renal function is highly dependent on
gestational age and postnatal adaptations. Renal
function begins to mature early during fetal organogenesis and is complete by early childhood. Increases
in glomerular filtration rate (GFR) result from both
nephrogenesis, a process that is completed by
34 weeks of gestation, and changes in renal and
Conclusion
Ibuprofen is an effective analgesic and antipyretic
drug for the treatment of childhood pain and fever.
Ibuprofen has the advantage of less frequent dosing
(every 68 h vs. every 4 h for paracetamol) and its
longer duration of action makes it a suitable alternative to paracetamol. In comparative trials, ibuprofen
has been shown to be at least as effective as paracetamol as an analgesic and more effective as an antipyretic (46,47). The safety profile of ibuprofen is
comparable with that of paracetamol. However, there
is a need for additional studies to investigate the
safety of these medications in different paediatric
2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 2632
31
responsibility for this article, but is grateful to Elements Communications Ltd and Mash Health for
editorial and production assistance (supported by
Reckitt Benckiser).
Authors contribution
Acknowledgements
Funding for the development of this supplement was
provided by Reckitt Benckiser. The author takes full
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