Clinical

Pediatrics
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Alternating Antipyretics: Antipyretic Efficacy of Acetaminophen Versus Acetaminophen Alternated

With Ibuprofen in Children
Lynne C. Kramer, Peaches A. Richards, Amy M. Thompson, David P. Harper and Mary P. Fairchok
CLIN PEDIATR 2008 47: 907 originally published online 6 June 2008
DOI: 10.1177/0009922808319967
The online version of this article can be found at:
http://cpj.sagepub.com/content/47/9/907

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Alternating Antipyretics: Antipyretic

Efficacy of Acetaminophen Versus
Acetaminophen Alternated With
Ibuprofen in Children

Clinical Pediatrics
Volume 47 Number 9
November 2008 907-911
2008 Sage Publications
10.1177/0009922808319967
http://clp.sagepub.com
hosted at
http://online.sagepub.com

Lynne C. Kramer, MD, Peaches A. Richards, MD, Amy M. Thompson, MD,

David P. Harper, MD, and Mary P. Fairchok, MD
Methods A prospective, randomized double-blind
placebo control study comparing the efficacy of acetaminophen to acetaminophen alternated with ibuprofen
in 38 healthy outpatient children 6 months to 6 years
presenting to the outpatient clinic with fever >38C was
conducted. Temperatures were recorded at 0, 3, 4, 5, and
6 hours. Side effect diaries and parental perception of
efficacy were filled out hourly by parents.
Results There were no significant differences in temperature between the 2 groups at times 0, 3, and 6 hours.

lthough fever assists the host in fighting infection, parents often hold misconceptions about
potential associated dangers.1-3 Unfortunately,
these fears are often magnified by health care
providers.4,5 Acetaminophen and ibuprofen are currently the most frequently used antipyretic medications in children due to their safety and efficacy.6-9
From the Department of Pediatrics, Madigan Army Medical
Center, Tacoma, Washington (LCK, AMT, MPF); Weed Army
Community Hospital, Fort Irwin, California (PAR); and
Department of Pediatric HematologyOncology, Walter Reed
Army Medical Center, Tacoma, Washington (DPH).
This research was supported by a Resident Research Grant from
the American Academy of Pediatrics.
None of the authors have any conflicts of interest to report.
The opinions or assertions contained herein are the private
views of the author(s) and are not to be construed as official or
as reflecting the views of the Department of Defense.
The investigators have adhered to the policies for protection of
human subjects as prescribed in 45 CFR 46.
Address correspondence to: Col (Ret) Mary P. Fairchok,
Department of Pediatrics, Madigan Army Medical Center,
Tacoma, WA 98431; e-mail: mary.fairchok@us.army.mil.

The alternating group had significantly lower mean temperatures at both 4 hours (38.0C vs 37.4C; P = .05) and
5 hours (37.1C vs 37.9C; P = .0032). Parents did not perceive any difference in fever control between the groups.
Conclusions An alternating regimen of acetaminophen
with ibuprofen significantly decreased fever at 4 and 5
hours compared with acetaminophen alone. However,
parents did not perceive a difference in efficacy.
Keywords:

fever; acetaminophen; ibuprofen; pediatric

Recently, alternating acetaminophen with ibuprofen

has become commonplace by both parents and
physicians. At a national meeting, 50% of pediatricians reported that they routinely advised parents to
alternate acetaminophen with ibuprofen.5
Although alternation is common, there is limited
evidence on the safety or efficacy of combination
treatments. Alternating these medications may be
harmful, given the combined toxicity and potential
parental confusion in timing and dosing.10-14 Although 2
recent studies have suggested that alternating acetaminophen with ibuprofen might be more effective in
fever control than using a single medication,15,16 neither study considered the role for parental education
about fever in fever management.
In our study, the first performed in the United
States, we evaluated the antipyretic efficacy of alternating acetaminophen with ibuprofen versus acetaminophen alone. We also assessed the safety of the
2 regimens. Finally, we evaluated caretaker perception of efficacy of the regimens in the setting of preceding education about fever myths and facts.
907

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908

Clinical Pediatrics / Vol. 47, No. 9, November 2008

Materials and Methods

Table 1.
Time (Hours)

Study Design
This study was a randomized, prospective, doubleblinded, placebo-controlled trial comparing the
response of fever to acetaminophen alternated with
placebo versus acetaminophen alternated with
ibuprofen in a population of healthy children aged 6
months to 6 years presenting to the Pediatric Clinic
at Madigan Army Medical Center (MAMC) in
Tacoma, Washington, from January 2004 to January
2006 with a chief complaint of fever. The study protocol was approved by the MAMC Institutional
Review Board. Power analysis determined that 16
subjects in each group would provide 80% power at
a 5% significance level to detect a difference of
0.6C between the 2 groups. Caretakers approached
study physicians for entrance into the study after
reading posted fliers listing the criteria for enrollment. Children were eligible for enrollment if they
had a fever in the clinic documented to be above
38C. Children were excluded from enrollment if
there was a history of any antipyretic use in the preceding 4 hours, or if they had an allergy or other
medical contraindication to the medications.
After obtaining informed consent, baseline temperatures were recorded orally for children older
than 2 years, and rectally for children less than 2
years of age using a standard thermometer (BD
Flexible Digital Thermometer, BD Consumer
Healthcare, Franklin Lakes, NJ). Caretakers were
instructed on how to appropriately record temperatures and then provided with the thermometer for
home use. Baseline demographic information including age, race, and sex were obtained, and baseline
symptoms were also recorded. One of 4 study investigators then educated the caretakers in detail about
fever facts and myths based on a handout produced
by Dr Barton Schmitt.17 Caretakers were also provided with a copy of the handout.
Each caretaker then received a sealed envelope
containing their randomization sequence. Children
were assigned to treatment group A or B using previously generated computer-based randomization
blocks performed by the Department of Clinical
Investigation. Subjects in each group received either
medication or placebo according to the schedule
detailed in Table 1. This dosing schedule was chosen
based on a regimen commonly recommended by

0
3
4

Intervention Between Groups

Group A

Group B

Acetaminophen
placebo
Acetaminophen

Acetaminophen
Ibuprofen
placebo

pediatricians.5 Acetaminophen (Childrens Tylenol,

McNeil Consumer & Specialty Pharmaceuticals,
160 mg/5 mL) was dosed at 15 mg/kg/dose and
ibuprofen (Childrens Motrin, McNeil Consumer &
Specialty Pharmaceuticals, 100 mg/5 mL) was
dosed at 10 mg/kg/dose. An unblinded study pharmacist opened the envelope containing the randomized group assignment and dispensed the medications
and placebo (formulated by McNeil Consumer &
Specialty Pharmaceuticals to match color and taste
of study medications) according to the subjects
weight, and provided an envelope to the caretaker to
be opened at the conclusion of the study. The envelope provided instructions to the caretaker as to the
next appropriate time to provide either ibuprofen or
acetaminophen based on the medications used during the study. Parents and investigators remained
blinded to the regimen each child had received.
Caretakers recorded temperatures using the
same procedure as enrollment at times 3, 4, 5, and
6 hours. Caretakers also completed a list of symptoms at these times. Additionally, caretakers reported
whether they believed that the child needed to take
any additional antipyretic medication at times 3 and
4 hours. A blinded study investigator called the caretakers within 24 hours of completion of the study
and, using a scripted form, recorded the temperature
results, symptom results, and caretaker opinions on
efficacy at 3 and 4 hours.

Statistical Methods
Data were collected and stored in Excel, and analyzed using Stat View 4.57 (SAS Institute Inc.)
Descriptive analysis was performed to evaluate
demographic characteristics of the study population.
Univariate analyses were performed to assess the
differences in mean temperature at the recorded
times between the 2 groups, and differences in
recorded symptoms, and caretaker perception of
efficacy. All comparisons were done using Fishers
exact test. A 2-sided P value of 0.05 was considered
significant.

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Alternating Antipyretics in Children / Kramer et al

Results

Demographic Characteristicsa

Table 2.

A total of 42 caretakers approached physicians for

enrollment, and 40 enrolled. Two declined enrollment after learning more about the time required.
Two children, one from each group, were dropped
from the study after the baseline temperatures were
recorded: one childs parent (alternation group)
never obtained the study medication, the other
childs parent (acetaminophen group) did not answer
follow-up phone calls, so no further information was
available. The remaining 38 children were included.
Two participants, both from the alternating group,
were missing temperature recordings at one data
point (at 4 and 5 hours, respectively).
There were no differences between the groups in
demographic characteristics as shown in Table 2.
There was no difference in antimicrobial prescriptions between the 2 groups, with 6/19 patients in the
acetaminophen group and 8/19 in the alternating
group receiving antibiotics. Parents were asked if
they used any over-the-counter (OTC) medications
during the study period. None of the parents in the
acetaminophen group gave their children OTC medications during the study, but 21% of the parents in
the alternating group did use these medications
(Robitussin and Benadryl; P = .04).
Table 3 displays temperature data for the 2
groups. There were no differences in temperature
between the groups at hour 0 and 3. However, the
alternating group just met statistical significance
when compared with the acetaminophen group at
hour 4. At hour 5 there was a significant difference
between the 2 groups with the alternating group
having a mean temperature 0.8 Celsius lower than
the acetaminophen group (37.1C vs 37.9C; P =
.003). This difference was not sustained at hour 6.
During the study period, 8 (21%) of all patients
had symptoms including diarrhea, flatulence, emesis,
decreased appetite, epigastric pain, nausea, headache,
and insomnia. These symptoms did not prevent any of
the patients from taking the study medications. There
were no differences between groups in the incidence
of any of these potential side effects.
Parental perception of efficacy was assessed by
asking parents if they felt that their child needed additional antipyretic medication at hours 3 and 4 of the
study. A total of 39% of parents in the acetaminophen
group (95% CI 16%-61%) versus 21% (95% CI 3%39%) of the parents in the alternating group felt that
more medicine was needed at hour 3 (P = .14). By

909

Valuec

Characteristicb
Race
Asian
African American
Caucasian
Hispanic
Other
Gender
Male
Female
Age (months)
Mean
Range
Diagnosis
Bacterial illness
Viral illness

All Patients
(N = 38)

Acetaminophen
(n = 19)

Acetaminophen
Alternated
With Ibuprofen
(n = 19)

2 (5.3)
7 (18.4)
22 (57.9)
6 (15.8)
1 (2.6)

2 (10.5)
3 (15.8)
10 (52.6)
3 (15.8)
1 (5.3)

0 (0.0)
4 (21.1)
12 (63.2)
3 (15.8)
0 (0.0)

18 (47.4)
20 (52.6)

9 (52.6)
10 (47.4)

9 (52.6)
10 (47.4)

32.8
8-83

33.6
9-83

32.0
8-74

13 (34.2)
25 (65.8)

6 (31.6)
13 (68.4)

7 (36.8)
12 (63.2)

a . 2 and Fishers exact test for dichotomous variables, unpaired t test for
continuous variables. P values were not significant for any of the variables.
b . Where applicable, when N not specified, assume 38.
c . Data are given as n (%) unless otherwise specified.

Table 3. Mean Temperaturea Between

Groups at Hour 0, 3, 4, 5, and 6

Hour
Hour
Hour
Hour
Hour

0
3
4
5
6

Acetaminophen

Acetaminophen
Alternated
With Ibuprofen

38.8
37.7
38.0
37.9
37.5

39.2
37.7
37.4
37.1
37.4

(38.6-39.0)
(37.5-37.9)
(37.5-38.5)
(37.5-38.3)
(37.1-37.9)

(38.8-39.6)
(37.4-38.0)
(37.0-37.8)
(36.8-37.4)
(37.0-37.8)

P Valueb
NS
NS
.05
.003
NS

a . Values are given in degrees Celsius (95% confidence interval)

b . Unpaired t test; NS, nonsignificant.

hour 4, 33% (95% CI 11%-55%) of the acetaminophen

group and 21% (95% CI 3%-39%) of the alternating
group felt more medication was needed (P = .20).
These differences were not statistically significant.

Comment
We found significant differences in fever reduction
in our alternation group compared with acetaminophen at hours 4 and 5, suggesting superior efficacy
of an alternation regimen. However, the difference
in fever reduction was transient and of questionable

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Clinical Pediatrics / Vol. 47, No. 9, November 2008

clinical significance. There have been 3 other studies

comparing alternating acetaminophenibuprofen
regimens to single drug regimens. Two have suggested superior efficacy for the combined treatment
versus monotherapy alone15,16 and the third failed to
find a difference.18 Nabulsi et al15 compared alternation of ibuprofen (10 mg/kg) with acetaminophen
(15 mg/kg) 4 hours later to ibuprofen alone in children aged 6 months to 14 years. They found that a
higher proportion of participants were afebrile in the
alternation group compared with the ibuprofen
group at 6 hours from baseline, and this was sustained at hours 7 and 8. Given that their control
group was administered monotherapy with ibuprofen instead of acetaminophen, their design is not
comparable with ours.
Sarrell et al16 compared acetaminophen monotherapy, ibuprofen monotherapy, and alternation of these
2 medications in Israeli children 6 to 36 months of
age. The participants were treated with antipyretic
medication for three days. Children in the alternation
group had lower mean temperatures, more rapid fever
reduction, and less discomfort. However, there was no
standardization of exact time of temperature recording
by the parents, and parents were allowed to discontinue medication at their discretion.
Although our study and 2 others do suggest
improved fever reduction with alternation of
antipyretics, safety concerns remain in endorsing
this regimen. Other authors have raised concerns
about the safety of ibuprofen and acetaminophen
use in children, especially in combination.10-14,19,20 In
our study, parents predominantly reported gastrointestinal symptoms. There was no difference in the
occurrence of these symptoms between the groups.
Additionally, there was no way to distinguish if the
reported symptoms were the direct result of the
medication or secondary to the illness itself. None of
the participants discontinued the study due to perceived side effects. However, our study only evaluated administration of the medications over 6 hours
under controlled conditions ensuring the correct
dosage and interval. In reality, even without the
added complication of combination therapy, parents
often underdose or overdose these medications.21,22
The addition of alternating schedules could increase
these errors.13 Physicians can also contribute to dosing errors: in one study 47% physicians instructed
patients to give a complex schedule of acetaminophen every 4 hours alternating with ibuprofen
every 6 hours and 9% recommended alternating

the medication every 2 hours, a practice that is

clearly outside the standard dosing guidelines.5
A unique aspect of our study was that parents
were given fever education prior to beginning the
medications and were asked their opinion of efficacy
at hours 3 and 4. Casey et al23 examined the impact
of education on parents understanding of fever over
a 4-month time frame. They implemented a standardized interview in which the management of
fever was discussed, demonstrated, and practiced
followed by an educational information sheet mailed
2 months later. Parents in the intervention group
were less likely to have inappropriate physician visits and phone calls and inappropriate use of
antipyretic medication. In our study, despite the
education given, approximately 33% in the acetaminophen group and almost 25% in the alternating
group believed that more medication was needed at
3 and 4 hours, even though the mean temperatures
at those times were not above 38C. Although not
significant, almost twice the number of caretakers
the acetaminophen group believed more medication
was needed at hour 3. However, at hour 3, both
groups had received the same medication (acetaminophen: Table 1). Thus the difference in perceived efficacy could not have been related to the
medication regimen. Our education may have been
less effective because we were prescribing antipyretic
medications to these children. Perhaps more effective education, without a concurrent emphasis on
antipyretics, would improve perception of efficacy
and decrease fever phobia.
Limitations of this study include its small sample size and short duration. It is possible that repetition of the regimen over time may show a difference
in fever trends beyond the 6-hour mark. Further
research in the United States with larger study populations and longer follow-up may be helpful.
Additionally, the patients in this study came from a
clinic population of children who were otherwise
healthy and who had only minor illness. Thus,
results may not be applicable to children with more
severe ailments and higher baseline temperatures.
In conclusion, an alternating regimen of acetaminophen with ibuprofen did significantly decrease
fever in children after receiving 1 dose of acetaminophen alternated with 1 dose of ibuprofen when
compared with an acetaminophen regimen alone at
both 4 and 5 hours. However, these differences were
modest and not sustained by hour 6. Both regimens
were well tolerated in our population. There was not

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Alternating Antipyretics in Children / Kramer et al

an association with perception of efficacy on behalf

of caretakers and regimen used. Increased education in an effort to decrease fever phobia in parents
may ultimately be of more value than prescribing
complicated drug alternation regimens that have little or no clinically significant difference in fever
control. Lack of difference in perceived efficacy and
lack of sustained differences between the 2 groups
lends support for not routinely advocating use of
alternating antipyretic schedules.

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