REVIEW ARTICLE

Optimising the management of fever and pain in

children
J. N. van den Anker

Departments of Pediatrics,
Pharmacology & Physiology,
The George Washington
University School of Medicine
and Health Sciences, and the
Division of Pediatric Clinical
Pharmacology, Children’s
National Medical Center, WA,
USA
Correspondence to:
John N van den Anker, MD,
PhD
Division of Pediatric Clinical
Pharmacology, Children’s
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
Review criteria
Fever and pain in children, especially associated with infections, such as otitis
The information for this manuscript was
media, are very common. In paediatric populations, ibuprofen and paracetamol
gathered from the peer-reviewed literature
(acetaminophen) are both commonly used over-the-counter medicines for the man-
(PubMed and Embase), textbooks, published
agement of fever or mild-to-moderate pain associated with sore throat, otitis
guidelines from the World Health Organiza-
media, toothache, earache and headache. Widespread use of ibuprofen and parac-
tion (WHO) and the American Academy of
etamol has shown that they are both effective and generally well tolerated in the
Pediatrics (AAP), symposia reports and
reduction in paediatric fever and pain. However, ibuprofen has the advantage of
abstract books from learned society meet-
less frequent dosing (every 6–8 h vs. every 4 h for paracetamol) and its longer
ings, such as the American Society for Clini-
duration of action makes it a suitable alternative to paracetamol. In comparative
cal Pharmacology and Therapeutics (ASCPT)
trials, ibuprofen has been shown to be at least as effective as paracetamol as an
and the American College of Clinical Phar-
analgesic and more effective as an antipyretic. The safety profile of ibuprofen is
macology (ACCP). Information specifically
comparable to that of paracetamol if both drugs are used appropriately with the
relevant to the topic of this manuscript was
correct dosing regimens. However, in the overdose situation, the toxicity of parac-
selected, analysed and referenced.
etamol 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
Message for the clinic
advanced studies to investigate the safety of these medications in paediatric popu-
For the clinician, the take-home message of
lations of different ages and especially during prolonged use. Finally, the recently
this article is that ibuprofen and paraceta-
reported association between frequency and severity of asthma and paracetamol
mol, if used correctly, are both well toler-
use needs urgent additional investigations.
ated and effective in the treatment of fever
and pain in infants and children. However,
in overdose situations, ibuprofen is less
toxic compared with paracetamol. Further-
more, ibuprofen does not increase the fre-
quency or severity of aspirin-unrelated
asthma, whereas recent data suggest that
early exposure to paracetamol might be
linked to asthma in children and adoles-
cents.

providers and accounts for at least one third of all

Introduction
Fever and pain are common in children, especially as
a result of infections, such as otitis media (1). In pae-
diatric populations, the over-the-counter (OTC) med-
icines 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. Chil-
dren 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 symp-
toms managed by paediatricians and other healthcare
presenting conditions in children (2).
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 although, surprisingly, optimal doses, dosing
regimens and choice of medication are not clearly
described in the scientific literature (3,4). Despite the
extensive use of ibuprofen and paracetamol, adverse
events (AEs) with the therapeutic use of these drugs
seem to be uncommon.
Ibuprofen is better tolerated than other non-steroi-
dal anti-inflammatory drugs (NSAIDs), although it

ª 2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 26–32
26 doi: 10.1111/ijcp.12056

has been associated with renal toxicity, allergic
reactions and gastrointestinal adverse effects (5,6). It
has also been documented in the literature that
ibuprofen use could lead to exacerbation of symp-
toms in febrile children with a past medical history
of asthma (7). However, this association has been
investigated in clinical trials and has not been con-
firmed (8,9).
Hepatotoxicity appears to be the most serious and
well-documented AE associated with paracetamol use
in children. Case reports have suggested that liver
failure can occur with chronic treatment with doses
just above the recommended maximum dose (10).
Urticaria and maculopapular rashes have been attrib-
uted to paracetamol use (11). Recently, a strong epi-
demiological association between paracetamol use
and asthma has emerged in the literature (12). This
epidemiological association of asthma and paraceta-
mol has been confirmed in two publications from
Phase III of the International Study of Allergy and
Asthma in Childhood (13,14). That study included
data on 200,000 children aged 6–7 years and 320,000
children aged 13–14 years from more than 40 coun-
tries. In both age groups, there was a paracetamol
dose-dependent increase in the prevalence and sever-
ity of asthma. Children who took paracetamol at
least monthly were more than three times as likely to
report asthma at 6–7 years of age and more than
twice as likely at ages 12–14 years.
Unfortunately, as many as one half of parents
administer incorrect doses of either paracetamol or
ibuprofen, and approximately 15% of parents give
supratherapeutic doses of both these OTC medicines
(15). Clearly, antipyretic and analgesic therapy will
remain a common practice by parents and it is gen-
erally encouraged and supported by paediatricians.
From a practical standpoint the World Health
Organization (WHO) recommended dose of ibupro-
fen is 5–10 mg ⁄ kg orally every 6–8 h, to a maximum
of 500 mg ⁄ day (16). For paracetamol, the WHO rec-
ommended dose is 10–15 mg ⁄ kg every 4 h. Aspirin
is not recommended in children who are 16 years of
age or less owing to its implication in the develop-
ment of Reye’s syndrome (17).
This review will summarise the physiology of fever,
the pathophysiology of fever, antipyretic therapy, and
clinical pharmacology aspects of using medicines in
children.
Physiology of fever
It is important to emphasise that fever is not an ill-
ness, but a physiological mechanism that has benefi-
cial effects in fighting infection. Fever slows the
growth and replication of bacteria and viruses,
ª 2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 26–32
Management of fever and pain in children 27
enhances neutrophil production and T-lymphocyte
proliferation and aids in the body’s acute-phase reac-
tion (18). The degree of fever does not always corre-
late with the severity of illness. Most fevers are of
short duration, are benign, and may actually protect
the host (19). There are data showing beneficial
effects on the immune system and even some data
indicating that fever may actually help the body to
recover more rapidly from viral infections, although
the fever may result in discomfort in children (20).
There is no evidence that children with fever are at
an increased risk of adverse outcomes (21).
Pathophysiology of fever
Body temperature is regulated by the preoptic ante-
rior 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, endocri-
nological and immunological systems (22). Although
primarily a reaction to infection, the febrile response
is also seen in other inflammatory and immunologi-
cal 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 inter-
feron-gamma (IFN-gamma). Cytokines are nonstruc-
tural 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 IFN-
gamma are intrinsically pyrogenic in that they rap-
idly induce fever by acting on the hypothalamic ther-
moregulatory 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 cir-
culation to the organum vasculosum laminae termi-
nalis (OVLT), a rich vascular network abutting the
hypothalamus with a minimal blood–brain barrier.
The importance of the OVLT has been demonstrated
in studies showing that fever does not ensue after
peripheral administration of pyrogenic cytokines to
28 Management of fever and pain in children
rats with ablated OVLTs. However, when these same
cytokines are injected directly into the brain, ablation
of the OVLT does not prevent fever (23). Thus, it
seems that the OVLT is the gateway between the
peripheral systemic circulation and the protected
circulation within the brain itself.
The exact mechanism of interaction between the
pyrogenic cytokines and the OVLT remains unknown.
It is postulated that the pyrogenic cytokines trigger
the arachidonic acid cascade in the endothelial cells of
the OVLT and that prostaglandin E2 (PGE2), an end
product of the cascade, then induces cyclic adenosine
monophosphate (cAMP) to act on the thermoregula-
tory nuclei of the hypothalamus, causing an elevation
in the thermal set point (24).
With the set point as a reference, the hypothala-
mus then perceives the current body temperature as
inadequate and coordinates an elevation of tempera-
ture. This is accomplished by accelerated heat pro-
duction (shivering, increased muscle tone, increased
metabolism, etc.), restricted heat loss (cutaneous
vasoconstriction and cessation of sweating) and heat-
seeking behaviours (25).
Antipyretic therapy: mechanism of
action
To understand the mechanisms of action of the anti-
pyretic agents considered herein, it is necessary to
review the components of the arachidonic acid cas-
cade. Following proper stimulation (e.g. by an exoge-
nous 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 pros-
taglandin 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 pri-
marily 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
ª 2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 26–32
to the inactive reduced form and that this central
inhibition of COX is responsible for the antipyretic
effects of paracetamol. As paracetamol does not inhi-
bit COX in peripheral tissues, it lacks anti-inflamma-
tory activity and is, therefore, not an NSAID.
Paracetamol also lacks effect on peripheral COX-1
functions, including renal function, vascular homeo-
stasis and gastrointestinal cytoprotection. Paraceta-
mol doses of 10–15 mg ⁄ kg per dose given every
4–6 h orally are generally regarded as well tolerated
and effective. Typically, the onset of an antipyretic
effect is within 30–60 min. Approximately 80% of
children will experience a decreased temperature
within that time span. There is no consistent evi-
dence that the use of an initial loading dose by either
the oral (30 mg ⁄ kg per dose) or rectal (40 mg ⁄ kg
per dose) route improves antipyretic efficacy. The
use of higher loading doses in clinical practice would
add potential risks for dosing confusion leading
to hepatotoxicity. Therefore, such doses are not
recommended (26).
Ibuprofen
Ibuprofen is a competitive inhibitor of the COX
enzymes in that it competes with arachidonic acid for
binding to the catalytic site on COX, thereby prevent-
ing prostaglandin synthesis. This competitive binding
is reversible. Unlike paracetamol, ibuprofen acts
peripherally. Furthermore, ibuprofen lacks specificity
for either COX isomer. For these reasons, ibuprofen
inhibits COX-2, reducing fever and inflammation,
thus making it a non-steroidal anti-inflammatory
agent or NSAID. However, ibuprofen also has side
effects associated with its inhibition of COX-1,
including gastrointestinal upset. Concern has been
raised over the nephrotoxicity of ibuprofen. In
numerous case reports, children with febrile illnesses
developed renal insufficiency when treated with ibu-
profen or other NSAIDs. Thus, caution is encouraged
when using ibuprofen in children with dehydration
(27). However, there are not enough data to support
a specific recommendation for the use of ibuprofen
for fever or pain in young infants (< 6 months of
age). The use of ibuprofen to manage fever has been
increasing because it seems to have a longer clinical
effect related to the lowering of body temperature.
Paracetamol vs. ibuprofen
Studies in which the effectiveness of ibuprofen and
paracetamol were compared have shown variable
results. However, the consensus is that both drugs
are more effective than placebo in reducing fever and
that ibuprofen (10 mg ⁄ kg per dose) is as least as

effective as, and perhaps more effective than, paracet-
amol (15 mg ⁄ kg per dose) in lowering body temper-
ature when either drug is given as a single or
repetitive dose (28,29).
However, another study concluded that to maxi-
mise the time that children spend without fever, one
should use ibuprofen first and consider the relative
benefits and risks of using paracetamol plus ibupro-
fen 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).
Clinical pharmacology aspects
Children younger than 15 years old account for 28%
of the population worldwide. As one must undergo
the developmental trajectory of childhood to reach
adulthood, any discussion of optimising the manage-
ment of fever and pain in children would be incom-
plete without inclusion of how development, the
most dynamic period of human live, influences drug
disposition and action and creates unique therapeutic
scenarios that are not seen in adults.
Despite being a continuum of physiological events
that culminate in maturity, development is often
arbitrarily divided into the stages of infancy, child-
hood, adolescence and even early adulthood. Across
this period of time organ size and function change as
does body composition, protein expression and cellu-
lar function. Some tissues may be more sensitive to
pharmacological effects early in life, whereas later in
life function may decline. As these developmental
changes in function and form occur, their implica-
tions with respect to the clinical pharmacology of
drugs and their appropriate place in paediatric ther-
apy must be considered.
Developmental clinical pharmacology
Throughout development, the impact of ontogeny
on pharmacokinetics and pharmacodynamics is, to a
great degree, predictable and follows definable physi-
ological ‘patterns’. This study will only focus on
developmental changes in metabolism and elimina-
tion of drugs and, more specifically, issues relevant
to the metabolism and elimination of ibuprofen and
paracetamol.
Ontogeny of drug metabolism in
children
The cytochrome P450 family of enzymes is responsi-
ble for the biotransformation of both endogenous
ª 2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 26–32
Management of fever and pain in children 29
substrates and therapeutic agents used, such as
paracetamol and ibuprofen in infants, children and
adolescents. There are considerable differences in the
expression and activity of these enzymes along the
developmental spectrum. At birth, the total hepatic
cytochrome P450 concentration is approximately
30% of adults and there are variable rates of matura-
tion both quantitatively and functionally (32,33).
CYP2C9 is a polymorphically expressed enzyme,
which catalyses the biotransformation of several
important drugs used in paediatrics (e.g. phenytoin,
ibuprofen, indomethacin). CYP2C9 has been
detected at very low levels (1% of adult levels) in
early gestation (earliest at 8 weeks). At full term,
activity increases to approximately 10% of that
observed in adults and by 5–6 months of age, is
approximately 25% of adult levels. A similar pattern
of developmental expression is demonstrated for
CYP2C19, an enzyme which is also polymorphically
expressed and largely responsible for the biotransfor-
mation of proton pump inhibitors (e.g. lansoprazole,
omeprazole, pantoprazole, esomeprazole, rabepraz-
ole); a drug class used extensively in neonates and
infants with gastro-oesophageal reflux. CYP2C19
activity increases quickly after birth and reaches adult
levels at approximately 6 months of postnatal age
(34). It is at this point (which is the same for
CYP2C9) that genotype–phenotype concordance is
expected and predictive relationships between the
CYP2C19 genotype and the activity of the enzyme
are apparent. In examining the ontogeny of both
CYP2C9 and CYP2C19 (as is the case with most all
of the cytochrome P450 isoforms), significant inter-
subject variability is apparent across the developmen-
tal continuum. Also, when constitutive activity of the
enzyme is normally low shortly after birth, geno-
type–phenotype discordance is evident and thus
genotypic classification of metaboliser status can be
errant.
Of the cytochrome P450 isoforms quantitatively
important for drug metabolism in humans, all
studies to date appear to have a developmental pat-
tern with respect to the attainment of activity. How-
ever, it is beyond the scope of this review to provide
a detailed description for each enzyme, as this has
already been accomplished in recent reviews on the
topic (35).
In overdose, paracetamol produces a centrilobular
hepatic necrosis that can be fatal. The importance of
metabolism in paracetamol toxicity has been estab-
lished. Paracetamol is metabolically activated by cyto-
chrome P450 isoforms CYP2E1, CYP1A2, CYP3A4
and CYP2A6 (36–38) to form a reactive metabolite,
N-acetyl-p-benzoquinone imine that covalently binds
to protein, causing toxicity. At therapeutic doses, the
30 Management of fever and pain in children
reactive metabolite is quickly detoxified by combining
irreversibly with the sulfhydryl group of glutathione
to produce a non-toxic conjugate that is eventually
excreted by the kidneys (39).
In addition to the development of the cytochrome
P450 family of enzymes (Phase I), knowledge regard-
ing the ontogeny of Phase II drug metabolising
enzymes UDP-glucuronosyltransferases (UGT) is of
great importance when prescribing drugs, such as
chloramphenicol, morphine, paracetamol and zido-
vudine. These drugs are all UGT substrates that will
have a requirement for alteration of dosing regimen
to compensate for reduced enzyme activity in the
first weeks and months of life. In premature infants
(gestational age 24–37 weeks), the plasma clearance
of morphine was found to be five-fold lower relative
to older children. The clearance of morphine, a pre-
dominant UGT2B7 and UGT1A1 substrate, generally
reaches adult levels between 2 and 6 months of age.
However, considerable variability exists (40).
Paracetamol glucuronidation (a substrate for
UGT1A6 and UGT1A9) is present in the fetus and
newborn at very low levels (1–10% of adults). Fol-
lowing birth, activity steadily increases with levels
approaching (50%) by 6 months of age and full
maturation by puberty. A similar profile is seen for
zidovudine, a substrate for UGT2B7. Zidovudine
clearance is significantly reduced in children
< 2 years of age relative to older children, which also
leads to a developmental difference in haematological
toxicity (anaemia) caused by this drug (41).
Similar to what is seen for the UGT isoforms,
ontogenic profiles also exist for glutathione s-trans-
ferase (GST), N-acetyltransferase (NAT), epoxide
hydroxylase (EPHX) and the sulfotransferases
(SULT), but this is clearly beyond the scope of this
review.
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 organo-
genesis 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
ª 2012 Blackwell Publishing Ltd Int J Clin Pract, January 2013, 67 (Suppl. 178), 26–32
intrarenal blood flow. GFRs vary widely among
different postconceptional ages and range from
approximately 2–4 ml ⁄ min ⁄ 1.73 m2 in full-term neo-
nates to a low of 0.6–0.8 ml ⁄ min ⁄ 1.73 m2 in preterm
neonates. The GFR increases rapidly during the first
2 weeks of life and then more slowly until adult val-
ues are reached by 8–12 months of postnatal age
(42,43). Development impacts not only GFR, but
also tubular secretion, which is immature at birth
and reaches adult capacity during the first year of
life.
Developmental changes that occur in renal function
are better characterised than any other organ system.
For drugs that have substantial renal clearance, kidney
function serves as a major determinant of age-specific
drug dosing regimens. Failure to account for the
ontogeny of renal function and adjust dosing regi-
mens accordingly can result in a degree of systemic
exposure that can increase the risk of drug-associated
AEs. It is also important to note that use of some
medications concomitantly (i.e. betamethasone, ibu-
profen and indomethacin) may cause alteration of the
normal pattern of renal maturation in the neonate
(44). Therefore, both maturation and effects of treat-
ment with regard to renal function are important
considerations when determining appropriate drug
treatments in young infants.
As denoted above, development produces pro-
found differences in processes that, collectively, can
influence all facets of drug disposition (i.e. absorp-
tion, distribution, metabolism and excretion).
Knowledge of the impact of ontogeny on the physio-
logical determinants of drug disposition enables pre-
diction of how development per se can impact
pharmacokinetics and also, enables the clinician to
use this information as a tool for designing age
appropriate drug regimens. A recent review by van
den Anker et al. describes the implications of devel-
opmental pharmacokinetics on paediatric therapeu-
tics (45).
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 6–8 h vs. every 4 h for paracetamol) and its
longer duration of action makes it a suitable alterna-
tive to paracetamol. In comparative trials, ibuprofen
has been shown to be at least as effective as paraceta-
mol as an analgesic and more effective as an antipy-
retic (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
 Management of fever and pain in children 31

populations and determine the effects over prolonged
use. Most importantly, the recently reported associa-
tion between frequency and severity of asthma and
paracetamol use needs urgent additional investiga-
tions (12).
Acknowledgements
Funding for the development of this supplement was
provided by Reckitt Benckiser. The author takes full
responsibility for this article, but is grateful to Ele-
ments Communications Ltd and Mash Health for
editorial and production assistance (supported by
Reckitt Benckiser).
Author’s contribution
The author conducted the literature review, devel-
oped the manuscript and approved the final version
of the manuscript.

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