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Evid.-Based Child Health 9: 730732 (2014)

Published online in Wiley Online Library ( DOI: 10.1002/ebch.1979

Cochrane in context: Combined and alternating
paracetamol and ibuprofen therapy for febrile children
Cochrane Review: Combined and alternating paracetamol and ibuprofen therapy for febrile children Wong
T, Stang AS, Ganshorn H, Hartling L, Maconochie IK, Thomsen AM, Johnson DW. Combined and alternating
paracetamol and ibuprofen therapy for febrile children. Cochrane Database of Systematic Reviews 2013, Issue 10.
Art. No.: CD009572. DOI: 10.1002/14651858.CD009572.pub2
This companion piece to the review, Combined and alternating paracetamol and ibuprofen therapy for febrile
children, contains the following pieces:
The abstract of the review
A commentary from one or more of the review authors, explaining why the review team felt the review was
an important one to produce
A review of clinical practice guidelines
Some other recently published references on this topic

Evidence-Based Child Health: a Cochrane Review Journal is now indexed by MEDLINE (http://www.ncbi. and Scopus (


alternating therapy versus monotherapy and combined

therapy versus alternating therapy).

Background Health-care professionals frequently recommend fever treatment regimens for children who
either combine paracetamol and ibuprofen or alternate
them. However, there is uncertainty about whether these
regimens are better than using single agents and about
the adverse effect profile of combination regimens.

Main results Six studies, enrolling 915 participants, are

Compared to administering a single antipyretic alone,
administering combined paracetamol and ibuprofen to
febrile children can result in a lower mean temperature
at 1 hour after treatment (mean difference 0.27 C,
95% confidence interval 0.45 to 0.08, two trials,
163 participants, moderate quality evidence). If no further antipyretics are given, combined treatment probably also results in a lower mean temperature at 4 hours
(mean difference 0.70 C, 95% confidence interval
1.05 to 0.35, two trials, 196 participants, moderate
quality evidence), and in fewer children remaining or
becoming febrile for at least 4 hours after treatment
(relative risk 0.08, 95% confidence interval 0.02 to
0.42, two trials, 196 participants, moderate quality evidence). Only one trial assessed a measure of child
discomfort (fever, associated symptoms at 24 and 48
hours), but did not find a significant difference in this
measure between the treatment regimens (one trial, 156
participants, evidence quality not graded).
In practice, caregivers are often advised to initially
provide a single agent (paracetamol or ibuprofen), and
then provide a further dose of the alternative if the
childs fever fails to resolve or recurs. Giving alternating treatment in this manner may result in a lower
mean temperature at 1 hour after the second dose (mean
difference 0.60 C, 95% confidence interval 0.94

Objectives To assess the results and side effects of combining paracetamol and ibuprofen, or alternating them
in consecutive treatments, compared with monotherapy
for treating fever in children.
Search methods In September 2013, we searched
Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials
International Pharmaceutical Abstracts (20092011).
Selection criteria We included randomized controlled
trials that compared alternating or combined paracetamol and ibuprofen regimens with monotherapy in children with fever.
Data collection and analysis One review author and
two assistants independently screened the searches and
applied the inclusion criteria. Two authors assessed
risk of bias and graded the evidence independently.
We conducted various analyses for different comparison groups (combined therapy versus monotherapy,
Copyright 2014 John Wiley & Sons, Ltd.



to 0.26, two trials, 78 participants, low quality evidence), and may also result in fewer children remaining
or becoming febrile for up to 3 hours after it is given
(relative risk 0.25, 95% confidence interval 0.11 to 0.55,
two trials, 109 participants, low quality evidence). One
trial assessed child discomfort (mean pain scores at 24,
48 and 72 hours), finding that these mean scores were
lower, with alternating therapy, despite fewer doses of
antipyretic being given overall (one trial, 480 participants, low quality evidence)
Only one small trial compared alternating therapy
with combined therapy. No statistically significant differences were seen in mean temperature or in the number of febrile children at 1, 4 or 6 hours (one trial, 40
participants, very low quality evidence).
In all the trials, there were no serious adverse events
that were directly attributed to the medications used.
Authors conclusions There is some evidence that
both alternating and combined antipyretic therapies
may be more effective at reducing temperatures
than monotherapy alone. However, the evidence for
improvements in measures of child discomfort remains
inconclusive. There is insufficient evidence to decide
which of combined or alternating therapy might be
more beneficial. Future research needs to measure
child discomfort using standardized tools, and assess
the safety of combined and alternating antipyretic

Authors Commentary
Tiffany Wong*,1 Antonia S. Stang2 Heather Ganshorn3
Lisa Hartling4 Ian K. Maconochie5 Anna M. Thomsen6
and David W. Johnson7

1 Department of Pediatrics, University of British Columbia, BC

Childrens Hospital, Vancouver, Canada
2 Department of Pediatrics, Community Health Services, Calgary,
Libraries and Cultural Resources, University of Calgary, Calgary,
4 Department of Pediatrics, University of Alberta, Edmonton, Canada
5 Department of Paediatrics A&E, St Marys Hospital, London, UK
6 Alberta Childrens Hospital, Calgary, Canada
Department of Pediatrics, Faculty of Medicine, University of
Calgary, Alberta Childrens Hospital, Calgary, Canada

*Correspondence to: Antonia Stang, Department of Pediatrics, Community Health Services, Calgary, Canada. E-mail: antonia.stang@
Keywords: febrile children, combined and alternating therapy,

The use of antipyretics is extremely common in

paediatricshealth-care providers counsel families on
the use of these medications on a daily basis. There
have been increasing reports on the use of both alternating and combined antipyretic therapies in children
and a number of randomized controlled trials on the
topic. However, the trials have varied in methodology,
medication dosing and reporting of outcomes. This
review filled an important gap in the current literature
by providing a meta-analysis of the evidence available.
Guidelines on the use of antipyretics appropriately
recommend the use of medication to improve a childs
comfort, not to reduce temperature. Unfortunately,
the majority of existing studies on combined and
alternating antipyretic therapies in children focus on
temperature reduction. A key finding of this review is
the need for further research on alternating and combined antipyretic therapies in children, with comfort,
and not temperature reduction, as the primary outcome.

Society, 2013

Medication is not always needed to reduce a childs temperature. The best reason for giving
your child medicine is not to reduce the fever, but to relieve any aches and pains.
Acetaminophen is a suitable medication for fever. Unless your doctor says otherwise, you
can give the dose recommended on the package every 4 hours until your childs temperature
comes down.
Alternatively, you can give your child ibuprofen, which is found in products such as Advil
and Motrin. Ibuprofen can be given every 68 hours up to four times in a 24-hour period.
Ibuprofen should only be given if your child is drinking reasonably well. Do not give
ibuprofen to infants younger than 6 months without first consulting your doctor.
Do not alternate between using acetaminophen and ibuprofen as this can cause your child to
be at risk of liver failure.
Infants younger than 6 months should be seen by a doctor when they have a fever.

Copyright 2014 John Wiley & Sons, Ltd.

Evid.-Based Child Health 9: 730732 (2014)

DOI: 10.1002/ebch.1979



Academy of
2011 (2)

There is insufficient evidence to support or refute the routine use of combination treatment
with both acetaminophen and ibuprofen. Practitioners who follow this practice should counsel
parents carefully regarding proper formulation, dosing and dosing intervals, and emphasize
the childs comfort instead of reduction of fever.

Institute for
Health and
2013 (3)

There are medicines (known as antipyretics) that are commonly used to reduce fever.
Paracetamol and ibuprofen are antipyretics (check the label if you are not sure from the
brand name which one it contains). These medicines can help to lower your childs
temperature and make them feel more comfortable but they do not treat the cause of the
You should not use paracetamol or ibuprofen simply to lower your childs temperature or to
try and prevent a febrile convulsion (a fit, seizure, caused by fever), because studies have
shown that paracetamol and ibuprofen do not reduce the risk of convulsions. However, it is
okay to give children one of these medicines if they have a fever and are distressed or
Paracetamol and ibuprofen should not be given at the same time. If you give your child one
of these medicines and the child is still distressed before the next dose of this medicine is
due, you may want to consider using the other. Only use these medicines for as long as your
child feels unwell or distressed, and ask your health-care professional if you need more
information. Always check the instructions on the medicine bottle or packet.


Some other recent systematic

1. Canadian Paediatric Society, Community Paediatrics Committee..
Caring for kids: fever and temperature taking. Canadian Paediatric
1. Purssell E. Systematic review of studies comparing combined treatSociety; 2013 [updated September 2013]. Available at: http://www.
ment with paracetamol and ibuprofen, with either drug alone. Arch
Dis Child 2011; 96: 11751179.
[accessed on 2 July 2014].
2. Sullivan JE, Farrar HC, Section on Clinical Pharmacology and Therapeutics, Committee on Drugs. Fever and antipyretic use in children.
Pediatrics 2011; 127: 580587. DOI: 10.1542/peds.2010-3852.
3. Excellence NIfHaC. Feverish illness in children: assessment
than 5 years. NICE Guideline 2013. Available at:
[accessed on 2 July 2014].

If you would like to make a comment on the above article, you are invited to submit a letter to the Editor by
email ( Selected letters may be edited and published in future issues of the journal.

Copyright 2014 John Wiley & Sons, Ltd.

Evid.-Based Child Health 9: 730732 (2014)

DOI: 10.1002/ebch.1979