Current Medical Research and Opinion

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Acetaminophen and ibuprofen in the treatment of

pediatric fever: a narrative review

Ian M. Paul & Philip D. Walson

To cite this article: Ian M. Paul & Philip D. Walson (2021) Acetaminophen and ibuprofen in the
treatment of pediatric fever: a narrative review, Current Medical Research and Opinion, 37:8,
1363-1375, DOI: 10.1080/03007995.2021.1928617

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CURRENT MEDICAL RESEARCH AND OPINION
2021, VOL. 37, NO. 8, 1363–1375
https://doi.org/10.1080/03007995.2021.1928617
Article ST-0073.R1/1928617

REVIEW ARTICLE

Acetaminophen and ibuprofen in the treatment of pediatric fever: a

narrative review
Ian M. Paula and Philip D. Walsonb
a
Pediatrics and Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA; bDepartment of Clinical Pharmacology, University
Medical Center at Georg-August-Universit€at, G€ottingen, Germany

ABSTRACT ARTICLE HISTORY

Objective: A narrative review of randomized, blinded, controlled studies assessing the antipyretic Received 28 January 2021
effect of ibuprofen versus acetaminophen or combined or alternating treatment in children Revised 22 April 2021
was conducted. Accepted 7 May 2021
Methods: Searches of the PubMed and Embase literature databases were conducted to identify rele-
KEYWORDS
vant articles. Selected articles were limited to studies published in English that investigated OTC oral Acetaminophen; ibuprofen;
tablet and syrup formulations of acetaminophen and ibuprofen; there were no publication date limits. combination therapy;
Open-label studies, nonrandomized studies, and those evaluating intravenous or suppository formula- alternating therapy;
tions of acetaminophen or ibuprofen were excluded. Variations in designs, endpoints, methods, and paracetamol; pediatric fever;
patient populations precluded our ability to conduct a formal systematic review. antipyresis
Results: At physician-directed dosing (acetaminophen 15 mg/kg vs ibuprofen 10 mg/kg), no significant
differences in antipyretic effects from 0–6 h and between 0–6, –12, –24, or –48 h, with single or mul-
tiple-doses, respectively, were observed. Tolerability profiles at physician dosing were similar. In 14
over-the-counter dose comparisons (acetaminophen, 10–15 mg/kg; ibuprofen, 2.5–10 mg/kg), antipyre-
sis favored ibuprofen in 6, was similar between groups in 7, and favored acetaminophen (15 mg/kg vs
ibuprofen 5 mg/kg) in 1 comparison. Both medications were well tolerated. Efficacy favored combin-
ation over individual components in 3 of 4 studies; alternating use results were mixed. All combination
or alternating treatments were well tolerated.
Conclusions: Antipyretic effects of ibuprofen and acetaminophen are similar at physician-directed
doses; ibuprofen may be modestly superior at over-the-counter doses.

Introduction
Fever in children is generally a benign process that, in and of
itself, does not require treatment in the absence of underlying
disease that may reduce tolerance to fever1. However, when
fever causes discomfort and distress, it can lead to parental
concern1. In this setting, acetaminophen (paracetamol) and
ibuprofen are over-the-counter (OTC) antipyretics that are
commonly used for relief of fever and associated discomfort2.
Ibuprofen impacts a variety of inflammatory pathways and
cellular systems via nonselective and reversible inhibition of
cyclooxygenase (COX) isoenzymes3. COX-1 is a constitutive
enzyme that catalyzes the production of prostanoids and
thromboxane A2 from arachidonic acid, compounds involved
in a range of physiological functions that regulate vascular,
gastric, and renal function. COX-2 is an inducible isoenzyme
whose activity is increased in painful and inflammatory condi-
tions, leading to increased production of prostaglandin E2, the
key mediator of fever in humans3. In contrast, the mechanism
of action of acetaminophen is still unknown although preclin-
ical studies have provided evidence of COX inhibition
centrally4, and other data have shown that the antinociceptive
effects of acetaminophen involve activation of descending spi-
nal serotonergic pathways5.
The American Academy of Pediatrics clinical report on anti-
pyretic use in children summarizes the individual antipyretic
effects of acetaminophen and ibuprofen and makes recom-
mendations for pediatric dosing2. Both drugs are more effect-
ive than placebo in reducing fever at physician-directed doses
(acetaminophen, 15 mg/kg every 4 h; ibuprofen, 10 mg/kg
every 6 h), and there is no evidence suggesting a significant
difference in safety at these doses2. In addition, both medica-
tions are available OTC for use at 10–15 mg/kg doses for acet-
aminophen and 5–10 mg/kg doses for ibuprofen.
Ibuprofen has a favorable overall safety profile in a range
of acute and chronic pain and inflammatory conditions3,6.
However, ibuprofen has also been associated with renal and
hepatic adverse events, depending on the dose, concomitant
use of other medications, comorbidities, and patient popula-
tion3,6,7. In children, the most common ibuprofen-related
adverse events were gastrointestinal (nausea, vomiting,

CONTACT Ian M. Paul ipaul@psu.edu Pediatrics and Public Health Sciences, Penn State College of Medicine, 500 University Drive, Hershey, 17033-0850
PA, USA
ß 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
www.cmrojournal.com
1364 I. M. PAUL AND P. D. WALSON
abdominal pain, diarrhea, constipation, dyspepsia, and flatu-
lence)8. Rarer (<0.01%), potentially life-threatening gastro-
intestinal adverse events were peptic ulcers, gastric
hemorrhage, and gastric perforation8. Renal adverse events
associated with ibuprofen are rare (<0.01%) and include
acute kidney failure, interstitial nephritis, and, with long-term
use, papillary necrosis8. Acetaminophen has an established
record of safety when taken according to the recommended
therapeutic dose range9. However, the use of acetaminophen
at levels exceeding the maximum daily dose is a well-docu-
ment leading cause of hepatotoxicity and acute
liver failure7,10.
While acetaminophen and ibuprofen are effective as anti-
pyretics individually, they have also been used in combined
or alternating regimens, with some authors suggesting that
the combination is more effective than either agent alone11.
Indeed, combination use of acetaminophen and ibuprofen
has gained traction with pediatricians; caregivers commonly
coadminister acetaminophen and ibuprofen12,13. Their com-
bined use can be well tolerated when both are taken as
directed13. Unfortunately, concerns exist regarding potential
dosing errors that lead to unintentional overdose with these
more complicated regimens. A recent systematic literature
review and meta-analysis of 199 cases of repeated suprather-
apeutic acetaminophen ingestion found that liver failure
occurred in 127/199 (64%), and of these, 49 (39%) died, des-
pite the fact that the reported dose taken was below the
24-h total daily allowance in 28% of the cases14. In contrast,
ibuprofen overdose is associated with few significant clinical
sequelae, although severe side effects, including rare cases
of death, have been reported15–17.
While both acetaminophen and ibuprofen have been
extensively studied and have well-established efficacy and
safety profiles, there have been few studies comparing the
antipyretic efficacy of the 2 drugs for the management of
childhood fever. Here we review studies comparing acet-
aminophen versus ibuprofen at physician-directed doses
(acetaminophen, 15 mg/kg; ibuprofen, 10 mg/kg), as well as
comparative studies assessing approved OTC doses (acet-
aminophen, 10–15 mg/kg; ibuprofen, 5–10 mg/kg).
Additionally, the current state of evidence for both combined
and alternating use of acetaminophen and ibuprofen in the
treatment of pediatric fever is reviewed.
Methods
Searches of the PubMed and Embase literature databases
were conducted to identify relevant articles to include in this
narrative review. The following search terms were employed
individually and in combination: acetaminophen (including
APAP, paracetamol), alternating dosing, antipyretic, antipyr-
etic agents, antipyretic/analgesic agents, combined dosing,
comparative studies, efficacy, fever, ibuprofen, ibuprofen/
acetaminophen combination product, multiple/multi-dose,
over-the-counter, pediatric, randomized studies, safety, and
single dose. Selected articles were limited to studies pub-
lished in English that investigated OTC oral tablet and syrup
formulations of acetaminophen and ibuprofen; there were
no publication date limits. Open-label studies, nonrandom-
ized studies, and those evaluating intravenous or suppository
formulations of acetaminophen or ibuprofen were excluded.
Variations in designs, endpoints, methods, and patient popu-
lations precluded our ability to conduct a formal system-
atic review.
Results
Single-dose studies
A total of 9 publications detailing 10 single-dose pediatric
studies, including treatment at both physician-directed dos-
ing and OTC doses, were identified and are summarized in
Table 118–26. These included 1 single-dose pediatric study at
physician-directed doses and 9 studies comparing single-
dose treatment with acetaminophen and ibuprofen at OTC
doses (acetaminophen range of 9.8–15 mg/kg; ibuprofen
range of 5–10.3 mg/kg). These studies had variable designs,
endpoints, methods of temperature measurement, doses,
medication formulations, and patient populations. The spe-
cific doses and formulations of ibuprofen and acetamino-
phen employed in these studies are summarized in Table 1.
Physician-directed dosing
One study, by Autret-Leca and colleagues, compared single-
dose treatment with acetaminophen and ibuprofen when
administered according to physician-directed dosing18. This
randomized, double-blinded study was conducted in children
aged 3 months to 12 years with fever of non-serious origin
who were followed over 8 h after treatment administration.
Subsequent doses given over 3 additional days (acetamino-
phen up to 4 times daily or ibuprofen up to 3 times daily)
were administered by parents in an open-label manner. No
significant difference between the acetaminophen and ibu-
profen groups was observed for the area under the tempera-
ture reduction curve from 0
6 h (AUC0–6h; primary
endpoint), expressed as an absolute difference in tympanic
temperature from baseline; mean AUC0–6h was

7.77 ± 3.54  C minutes with ibuprofen and
7.66 ± 3.76  C
minutes with acetaminophen (p ¼ .82). At the end of the
double-blind phase, open-label first-dose efficacy was rated
as “very efficacious” by 59.2% of parents of children given
ibuprofen compared with 37.2% of the parents of children
given acetaminophen (p < .001 for the treatment difference).
OTC dosing
A total of 8 publications detailing 9 single-dose treatment
studies of acetaminophen versus ibuprofen at OTC doses
(acetaminophen range of 9.8–15 mg/kg; ibuprofen range of
5–10.3 mg/kg) were identified (Table 1) 19–26.
In 5 of the 9 studies identified, ibuprofen provided signifi-
cantly greater temperature reductions than acetamino-
phen19,23–26. In the first of 2 randomized, double-blind
studies reported by Jayawardena and Kellstein19 that
compared ibuprofen 7.5 mg/kg with acetaminophen
10
15 mg/kg in patients aged 6 months to 11 years with
Table 1. Summary of single-dose studies comparing acetaminophen versus ibuprofen at physician-directed and over-the-counter dosing strengths.
Author, year
temperature measurement
technique; study duration
Single-dose comparison of acetaminophen vs ibuprofen at physician-directed dosing
Autret-Leca et al. 200718
Single-dose comparisons of acetaminophen vs ibuprofen at over-the-counter dosing
Jayawardena and Kellstein19
Figueras Nadal et al.20
Study design; Dose; n Primary outcome result Key secondary outcome result Adverse events
Acetaminophen; N Ibuprofen; N
Randomized, double-blind, 15 mg/kg; n ¼ 150 10 mg/kg; n ¼ 151 Area under the temperature For (1) area under the Ibuprofen: 11.2% of patients
parallel-group; reduction curve from 0–6 h: temperature reduction curve Acetaminophen: 10.6% of patients
Tympanic; 8 h Acetaminophen ¼ ibuprofen from 0–4 and 0–8 h; (2)
individual temperature
readings at each time point
from 30 min to 8 h; (3) time to
recurrence of a temperature
> 38.5  C; (4) time to reach a
temperature of  38  C; (5)
time to maximal temperature
reduction and time to reach
apyrexia (37.4  C):
Acetaminophen ¼ ibuprofen
For parental global assessment:
Ibuprofen > acetaminophen
(p < .001 after double-blind
period and p < .01 after the
open-label period)
Randomized, double-blind, 10–15 mg/kg: 7.5 mg/kg: TWSTD0–8 : TWSTD0–2, 0–4, 0–6: Pooled AE rates: Ibuprofen, 7.5%
parallel-group; Study 1, n ¼ 82; Study 1, n ¼ 78; Study 1: Ibuprofen > Ibuprofen > acetaminophen of patients Acetaminophen,
Oral, rectal; 8 h for each study Study 2, n ¼ 74 Study 2, n ¼ 85 acetaminophen (p<.001) (Study 1, p ¼ .015 at 2 h; 7.5% of patients; Most
Study 2: Acetaminophen p<.001 at 4 and at 6 h) common AE was vomiting:
¼ ibuprofen Maximum temperature difference 6.3% with acetaminophen;
Studies 1 and 2 pooled: from baseline: 4.6% with ibuprofen; NS
Ibuprofen > acetaminophen Ibuprofen > acetaminophen,
(p<.001) (Study 1, p < .001)
Greater temperature reductions
1–8 h: Ibuprofen >
acetaminophen (Study 1,
p < .05 for each)
Faster onset of temperature
control: Ibuprofen >
acetaminophen (Study 1,
p¼.003; Study 2, p¼.007)
Longer duration of
temperature control:
Ibuprofen > acetaminophen
(Study 1, p < .001)
Treatment failures:
Ibuprofen > acetaminophen
(Study 1, p ¼ .018 at 8 h)
Longer time to treatment failure:
Ibuprofen > acetaminophen
(Study 1, p ¼ .015)
Faster onset temperature control:
Ibuprofen > acetaminophen
(pooled, p < .001)
Longer duration of temperature
control:
Ibuprofen > acetaminophen
CURRENT MEDICAL RESEARCH AND OPINION
(pooled, p ¼ .042)
10.7 mg/kg , n ¼ 87 6.7 mg/kg, n ¼ 88
(continued)
1365
Table 1. Continued.
Author, year Study design;
temperature measurement
technique; study duration
Double-blind, double-dummy;
Tympanic; 8 h
Wong et al.21 Randomized, double-blind,
parallel-group;
Tympanic; 6 h
Vauzelle-Kervro€edan et al.22 Randomized, double-blind;
Rectal; 6 h
Kauffman et al.23 Randomized, double-blind,
placebo-controlled (placebo,
n ¼ 9), double-dummy;
Oral; 8 h
Wilson et al.24 Randomized, double-blind,
placebo-controlled (placebo,
n ¼ 22);
Rectal; up to 12 h
Sidler et al.25 Randomized, double-blind,
parallel-group;
Rectal; up to 24 h
Dose; n Primary outcome result
Acetaminophen; N Ibuprofen; N
Mean temperature change at 4 h:
Acetaminophen ¼ ibuprofen
12 mg/kg, n ¼ 210 5 mg/kg for Percentage achieving  1.5  C
temperature < 39.2  C; reduction from baseline in
10 mg/kg for tympanic membrane
temperature  39.2  C; temperature:
n ¼ 209 total Acetaminophen ¼ ibuprofen
9.8 ± 1.9 mg/kg, n ¼ 56 10.3 ± 1.9 mg/kg, n ¼ 60 Time to the lowest observed
temperature between 0–6 h:
Acetaminophen ¼ ibuprofen
10 mg/kg, n ¼ 8 7.5 mg/kg, n ¼ 12; Antipyresis vs placebo: Significant
10 mg/kg, n ¼ 8 for acetaminophen at hours
3–5 (p  .05); significant for
both ibuprofen doses at hours
1–6 (p  .05): Ibuprofen
7.5 mg/kg > acetaminophen
10 mg/kg at hours
3–5 (p .05)
12.5 mg/kg, n ¼ 52 5 mg/kg, n ¼ 43; Temperature reduction at 4 h:
10 mg/kg, n ¼ 47 Ibuprofen 10 mg/kg > ibuprofen
5 mg/kg
and > acetaminophen (p .05)
10 mg/kg, n ¼ 30 7 mg/kg, n ¼ 30; Temperature reduction at 3 h:
10 mg/kg, n ¼ 29 Ibuprofen 10 mg/kg
> acetaminophen (p  0.01);
Ibuprofen 7 mg/kg
> acetaminophen (p.05)
Key secondary outcome result
For (1) percentage of patients
with temperature reduction at
4 h; (2) maximum temperature
decrease; (3) mean time to
apyrexia; (4) patients with
temperature reduction
of  1.5  C; and (5) percentage
of patients reaching normal
temperature: Acetaminophen
¼ ibuprofen
For temperature reduction
of  2  C: Ibuprofen >
acetaminophen
(p ¼ .043)
For 1) time to achieve 1.5  C
reduction or 2) time to
normalization of temperature:
Acetaminophen ¼ ibuprofen
For percentage
achieving  37.5  C (i.e.
temperature normalization):
Ibuprofen > acetaminophen
(p¼.004)
For (1) extent of temperature
decrease; (2) rate of
temperature decrease; (3)
duration of
temperature < 38.5  C;
4) percentage of children
whose temperature
fell < 38.5  C:
Acetaminophen ¼ ibuprofen
For (1) faster onset; (2) greater
maximum temperature
reduction; (3) longer duration
of action: Ibuprofen >
acetaminophen (p.05)
Ibuprofen 10 mg/kg had longest
duration of action than any
other group (p  .05);
For area under the curve
measures for (1) temperature;
(2) change in temperature;
and (3) Percentage achieving
antipyresis: Ibuprofen
10 mg/kg > ibuprofen 5 mg/kg
and acetaminophen 12.5 mg/
kg (p  .05)
Percentage achieving  1  C
reduction: Acetaminophen
¼ ibuprofen
Adverse events
1366
AEs occurred in 10.0% of patients
taking ibuprofen and 9.1% of
patients taking
acetaminophen.
Twelve patients vomited within
30 min of receiving medication
(acetaminophen, 5;
ibuprofen, 7)
I. M. PAUL AND P. D. WALSON
Ibuprofen, n ¼ 22;
Acetaminophen, n ¼ 19; NS
Vomiting:
Ibuprofen, 0%
acetaminophen, 3.6%
No AEs or laboratory
abnormalities were attributed
to either of the 2 treatments
Ibuprofen 10 mg/kg, n ¼ 1 event
(transient hypothermia without
sequelae in the context of
profuse night sweats from
pulmonary tuberculosis);
Ibuprofen 5 mg/kg, n ¼ 1 event
(transient hypothermia (<
97  F) that occurred 12 h after
dosing;
Acetaminophen, n ¼ 0 events;
Placebo, n ¼ 0 events.
Ibuprofen 7 mg/kg, n ¼ 3 (10%)
patients (vomiting, abdominal
pain, rash)
Ibuprofen 10 mg/kg, n ¼ 1 (3.4%)
patients (hypothermia)
Acetaminophen, 10 mg/kg, n ¼ 2
(6.7%) patients (vomiting
in both)
(continued)
 CURRENT MEDICAL RESEARCH AND OPINION 1367

fever, ibuprofen 7.5 mg/kg provided a significantly better

5 mg/kg, 21% of those treated

with ibuprofen 10 mg/kg, 18%

acetaminophen 10 mg/kg, and

Mild drug-related GI AEs in 31%
mean (standard deviation [SD]) time-weighted sum of tem-

6% of those treated with

perature differences from baseline to 8 h of
10.5 (7.3) ver-

treated with ibuprofen

Adverse events

of those treated with

sus
5.7 (7.3) with acetaminophen. Kauffman et al.23

Abbreviations. AE, adverse event; GI, gastrointestinal; NR, not reported; NS, not significant; q6h, every 6 h; TWSTD 0–2/4/6/8, time-weighted sum of temperature differences from baseline through 2/4/6/8 h.
conducted a randomized, double-blind, placebo-controlled

placebo; NS
study comparing the efficacy of suspensions of acetamino-
phen and ibuprofen in febrile children aged 2–12 years of
age. Temperature reductions versus placebo were significant
for acetaminophen 10 mg/kg at hours 3–5 and for ibuprofen
Key secondary outcome result

at hours 1–6 (p  .05), with ibuprofen 7.5 mg/kg treatment

For oral temperature > 102.5  F,
antipyretic efficacy ranking

producing a significantly (p  .05) greater oral temperature

was ibuprofen 10 mg/kg

reduction than acetaminophen at hours 3–5. Ibuprofen

> ibuprofen 5 mg/kg

10 mg/kg > placebo

> acetaminophen

10 mg/kg resulted in a temperature reduction that was

achieved significantly earlier, was of greater magnitude, and
lasted longer than with acetaminophen (all p  .05). A dou-
ble-blind, parallel-group study conducted by Sidler and col-
leagues25 compared the efficacy of acetaminophen syrup
with ibuprofen syrup over 12–24 h in febrile (rectal tempera-
ture 38.5  C) hospitalized children aged 5 months to
reduction time curve at 4, 6,
and 8 h: Ibuprofen 10 mg/kg

(p<.05 for each time point);

> acetaminophen 10 mg/kg
Primary outcome result

acetaminophen 10 mg/kg

13 years. The mean temperature reduction observed from

Area under the percentage

¼ ibuprofen 5 mg/kg

baseline to 3 h (the primary efficacy endpoint) was significant

for all groups but was significantly lower with ibuprofen
(either dose) compared with acetaminophen (p  .05 for ibu-
profen 7 mg/kg and p  .01 for ibuprofen 10 mg/kg, vs acet-
aminophen 10 mg/kg). There were no apparent differences
in the clinical condition of the patients at 3 h or over time
between the 2 treatments. However, more patients receiving
acetaminophen than ibuprofen 7 mg/kg or 10 mg/kg
required a second dose of antipyretic treatment (59% vs
Ibuprofen; N

38% vs 44%, respectively25. Wilson et al.24 evaluated the sin-

gle-dose efficacy of ibuprofen and acetaminophen in febrile
10 mg/kg, n ¼ 28
5 mg/kg, n ¼ 32;

children aged 3 months to 12 years in a placebo-controlled,

modified double-blind study. Although both acetaminophen
Dose; n

12.5 mg/kg and ibuprofen 5 mg/kg were significantly better

than placebo in terms of fever reduction, there was no differ-
ence between the 2 treatment arms. However, ibuprofen
Acetaminophen; N

10 mg/kg was associated with a significantly greater reduc-

10 mg/kg, n ¼ 33

tion in temperature versus both acetaminophen 12.5 mg/kg

and ibuprofen 5 mg/kg at 4 h (p  .05). Similarly, Walson
et al.26 compared the efficacy, tolerability, and dose-response
of acetaminophen and ibuprofen in febrile children aged
2–11 years in a double-blind, placebo-controlled study.
temperature measurement
technique; study duration

placebo-controlled (placebo,

Following single-dose administration, ibuprofen 10 mg/kg

Randomized, double-blind,

n ¼ 34), parallel-group;

lowered temperatures significantly more than acetamino-

Study design;

phen 10 mg/kg for the group as a whole (p < .05), as well as

in a subgroup of patients with higher temperatures (>
Oral, rectal; 8 h

102.5  F) at baseline. No significant differences between

treatments were observed in fever reduction after single-
dose acetaminophen 10 mg/kg compared with single-dose
ibuprofen 5 mg/kg.
No difference in antipyretic efficacy was observed in 4 of
9 studies comparing acetaminophen and ibuprofen19–22. In a
double-blind study by Figueras Nadal and colleagues20,
Table 1. Continued.

which compared single oral doses of acetaminophen and

ibuprofen in hospitalized children aged 6 months to 12 years,
26
Author, year

Walson et al.

there was no significant difference between groups for the

primary efficacy endpoint of mean (SD) change in tympanic
temperature at 4 h (acetaminophen, 1.2  C [0.96]; ibuprofen,
1368 I. M. PAUL AND P. D. WALSON
1.3  C [1.1]) or at any other time up to 8 h. More patients tak-
ing ibuprofen had a  2  C reduction in temperature com-
pared with the number achieving this outcome with
acetaminophen (p ¼ .043). No differences in irritability, som-
nolence, or food rejection were noted between treatment
groups, with all of these symptoms improving over the first
4 h in both groups20. In the prospective, randomized, dou-
ble-blind study by Wong et al.21 in febrile children aged
6 months to 6 years, the primary endpoint of a tympanic
temperature reduction of  1.5  C from baseline was
achieved by similar percentages of patients across treatment
groups (acetaminophen, 77%; ibuprofen, 83%). However,
more patients taking ibuprofen reached a temperature
<37.5  C (ibuprofen, 78%, acetaminophen, 68%; p ¼ 004)21.
Vauzelle-Kervro€edan et al.22 conducted a randomized, dou-
ble-blind study comparing the efficacy of acetaminophen
granules 9.8 ± 1.9 mg/kg versus ibuprofen granules
10.3 ± 1.9 mg/kg in children (N ¼ 116) aged 8 months to
12 years (average, 4.1 ± 2.6 years) with fever due to viral or
bacterial infection. Study medications were administered in a
spoonful of yogurt, cream cheese, or stewed fruit. The time
required to achieve the lowest observed rectal temperature
between 0 and 6 h (primary efficacy endpoint) was not differ-
ent between groups (acetaminophen, 3.65 ± 1.47 h; ibupro-
fen, 3.61 ± 1.34 h); in addition there were no significant
differences observed between treatments in the extent or
rate of temperature decrease, duration of time with tempera-
ture < 38.5  C, or the number of children with temperatures
< 38.5  C.
Multiple-dose studies
One multi-dose study compared physician-directed doses
and OTC doses of acetaminophen and ibuprofen27, and 4
others28–31 compared multiple doses of the 2 medications at
OTC doses (Table 2). As was the case in the single-dose stud-
ies, these studies utilized variable designs, endpoints, meth-
ods of temperature measurement, medication formulations,
and patient populations. OTC doses studied were 10–15 mg/
kg/dose for acetaminophen and 2.5–10 mg/kg/dose for ibu-
profen. The exact doses and formulations used in these trials
are summarized in Table 2. All 6 multiple-dose studies uti-
lized an every-6-h dosing interval.
Physician-directed dosing
Walson et al.27 reported the results of a block-randomized,
double-blind study comparing the efficacy and safety of
acetaminophen 15 mg/kg and ibuprofen 2.5 mg/kg, 5 mg/kg,
or 10 mg/kg administered every 6 h for 24–48 h in febrile
children aged 6 months to 11 years, 7 months. In the com-
parison of acetaminophen 15 mg/kg with ibuprofen 10 mg/
kg, there were no differences in mean oral or rectal tempera-
ture reduction at any time interval (0–6, 0–12, 0–24, or
0–48 h after treatment) tested27.
OTC dosing
Five multiple-dose comparisons of acetaminophen versus
ibuprofen in pediatric fever at OTC doses were found. In 3 of
the studies28,29,31, acetaminophen and ibuprofen showed
similar efficacy as antipyretics. Vinh et al.28 conducted a dou-
ble-blind comparison of acetaminophen syrup 12 mg/kg and
ibuprofen syrup 10 mg/kg administered every 6 h for up to
36 h after defervescence in children (N ¼ 80) aged 2–14 years
hospitalized with uncomplicated typhoid fever. On the pri-
mary efficacy measure, median axillary fever clearance time
was reduced by 35% with ibuprofen (68 h) versus with acet-
aminophen (104 h), but the difference did not reach statis-
tical significance (p ¼ .055). The duration/severity of fever as
measured by the area under the temperature-time curve was
reduced with ibuprofen by 42% compared with acetamino-
phen (74 h vs 127 h, respectively; p ¼ .013). Similarly,
McIntyre and Hull29 found no difference between ibuprofen
and acetaminophen in the change from baseline tempera-
ture at 4 h in hospitalized febrile children aged 2 months to
12 years. Likewise, there were no significant differences in
time to axillary temperature below 37.5  C or time until
second dose. Significantly more patients who received acet-
aminophen experienced improvements in irritability scores
than those who received ibuprofen (38% vs 18%, respect-
ively; p ¼ .047). A study by Autret et al.31 in children aged
6 months to 5 years hospitalized with fever associated with
infectious diseases and treated with antibiotics found no sig-
nificant difference between acetaminophen and ibuprofen in
the area under the temperature reduction curve during the
first 12 h after treatment (95% CI:
21.3, 115.7).
In the remaining 2 studies, results were mixed. In a
randomized, double-blind, crossover study in children aged
10 months to 4 years with febrile seizures, Van Esch et al.30
found that ibuprofen reduced rectal temperatures more than
acetaminophen at the primary endpoint of 4 h (p ¼ .05; p ¼
.04 after adjusting for covariates). Finally, in the study by
Walson and colleagues27 detailed above, OTC dose compari-
sons were also studied. Ibuprofen 10 mg/kg was associated
with a significantly greater percent temperature reduction at
0–6 h (p < .05) versus ibuprofen 2.5 mg/kg and ibuprofen
5 mg/kg. Acetaminophen 15 mg/kg was associated with sig-
nificantly greater fever reduction versus ibuprofen 2.5 mg
from hours 0–6 and versus ibuprofen 5 mg/kg during the 0-
to 12- and 0- to 24-h intervals (p < .05 for each) but not
over the interval of 0–48 h versus ibuprofen 5 mg/kg.
Combination studies
The possibility of drug-drug interactions between acetamino-
phen and ibuprofen has raised concerns regarding patient
safety. However, the likelihood of drug-drug interactions
when co-administered is low. Acetaminophen and ibuprofen
have different mechanisms of action3,5,32 and follow different
metabolic pathways33,34. Furthermore, pharmacokinetic stud-
ies have revealed no alterations in individual plasma drug
concentrations when the 2 agents were administered
together35–39. Given the potential for drug-drug interactions
involving acetaminophen or ibuprofen with other agents
(e.g. aspartame or diuretics), it is important that the
Table 2. Summary of multiple-dose studies comparing acetaminophen versus ibuprofen at physician-directed and over-the-counter dosing strengths.
Author, year Study design; Dose; n Primary outcome result Key secondary outcome result Adverse events
temperature measurement
technique; study duration
Acetaminophen; N Ibuprofen; N
Multiple-dose comparisons of acetaminophen vs ibuprofen at physician-directed dosing
Walson et al.27 Randomized, double-blind, 15 mg/kg q6h, n ¼ 16 10 mg/kg q6h, n ¼ 15 Temperature reduction 0–6 h: Temperature reduction at 0–12, Ibuprofen groups combined, most
parallel-group Ibuprofen 10 mg/ 0–24, and 0–48 h: Ibuprofen common AEs were
Oral, rectal; up to 48 h kg ¼ acetaminophen 15 mg/kg 10 mg/kg ¼ acetaminophen sweating (n ¼ 8); GI (n ¼ 7);
15 mg/kg Acetaminophen, most common
AEs were hypothermia (n ¼ 3);
abdominal pain (n ¼ 3);
agitation and/or
nervousness (n ¼ 3)
Multiple-dose comparisons of acetaminophen vs ibuprofen at over-the-counter dosing
Vinh et al.28 Randomized, double-blind; 12 mg/kg q6h, n ¼ 40 10 mg/kg q6h, n ¼ 40 Fever “clearance”: Temperature duration and Ibuprofen, n ¼ 13 (32.5%);
Axillary; until 36 h after Acetaminophen ¼ ibuprofen severity: Acetaminophen, n ¼ 7 (17.5%;
defervescence Ibuprofen > acetaminophen p ¼ .12; NS)
(p ¼ .013)
McIntyre and Hull,29 Double-blind, parallel-group; 50 mg/kg/24 h (i.e. 12.5 mg/kg 20 mg/kg/24 h (i.e. 5 mg/kg Change in temperature at 4 h: Distribution of times until Ibuprofen AE rate, 13% (when
Axillary; maximum of 3 days q6h), n ¼ 74 q6h); n ¼ 76 Acetaminophen ¼ ibuprofen temperature fell below 37.5  C administered at the minimal
and distribution of times to dosing level of 5 mg/kg);
second dose: Acetaminophen AE rate, 19%
Acetaminophen ¼ ibuprofen (when administered at full
over-the-counter dosing level;
p ¼ .34, NS)
8 acetaminophen- and 7
ibuprofen-treated patients
withdrew from the study due
to AEs or lack of efficacy
Van Esch et al.30 Randomized, double-blind, 10 mg/kg q6h, n ¼ 36 5 mg/kg q6h, n ¼ 34 Temperature at 4 h after first Mean and highest temperature 14 AEs recorded in 9 patients
crossover; dose: during treatment: overall; 8 occurred with
Rectal; 24 h Ibuprofen > acetaminophen Acetaminophen ¼ ibuprofen acetaminophen and 6
(p ¼ .05; p ¼ .04 after adjusting with ibuprofen
for covariates)
Autret et al.31 Randomized, double-blind, 10 mg/kg q6h, n ¼ 74 7.5 mg/kg q6h, n ¼ 77 Area under the percentage Percentage temperature reduction Ibuprofen, 9 patients (11.7%): 5
parallel-group reduction in temperature curve from 0–4 h: with GI symptoms 3 skin
Rectal; 72 h from 1–12 h: Ibuprofen > acetaminophen reactions, 1 epistaxis
Acetaminophen ¼ ibuprofen (p<.04) Acetaminophen, 5 (6.5%): 2
Mean temperature reduction from with GI symptoms, 2 skin
0–4 h and time to maximum reactions, 1 epistaxis
antipyresis:
Acetaminophen ¼ ibuprofen
Walson et al.27 Randomized, double-blind, 15 mg/kg q6h, n ¼ 16 2.5 mg/kg q6h, n ¼ 15; Temperature reduction 0–6 h: Temperature reduction at 0–12, Ibuprofen groups combined, most
parallel-group 5 mg/kg q6h, n ¼ 15 Ibuprofen 10 mg/kg > ibuprofen 0–24, and 0–48 h: common AEs were
Oral, rectal; up to 48 h 2.5 mg/kg and 5 mg/kg; Acetaminophen 15 mg/kg sweating (n ¼ 8); GI (n ¼ 7);
acetaminophen 15 mg/kg > ibuprofen 5 mg/kg at 0–12 Acetaminophen, most common
> ibuprofen 2.5 mg/kg (p<.05) and 0–24 h (p < .05 for each), AEs were hypothermia (n ¼ 3);
but not at 0–48 h abdominal pain (n ¼ 3);
agitation and/or
nervousness (n ¼ 3)
Abbreviations. AE, adverse event; GI, gastrointestinal; NR, not reported; NS, not significant; q6h, every 6 h.
CURRENT MEDICAL RESEARCH AND OPINION
1369
1370 I. M. PAUL AND P. D. WALSON
healthcare provider consider the patient’s medical history
and that caregivers communicate with the healthcare pro-
vider and pharmacist regarding the patient’s past or current
medical treatments, dietary restrictions, and conditions. Four
studies were identified in which the combined use of acet-
aminophen and ibuprofen in pediatric fever was reported;
the dosing and formulations of ibuprofen and acetamino-
phen used in these studies are summarized in Table 311,40–42.
Three of the 4 studies showed that the acetaminophen/
ibuprofen combination was superior to either agent alone.
Vyas et al.40 compared single-dose acetaminophen, ibupro-
fen, and their combination in febrile children aged 6 months
to 12 years. In a multivariate analysis, there was a significant
difference between groups in tympanic temperature reduc-
tion 4 h postdose (p ¼ .013), with the maximum reduction
being observed in the combination group. In a post hoc
multiple comparisons test, the combination was statistically
superior to acetaminophen alone (p ¼ .03), but not to ibu-
profen alone (p ¼ .17); there was no difference between
acetaminophen alone and ibuprofen alone (p ¼ .10).
Paul and colleagues11 conducted a 3-arm, randomized,
controlled study comparing the effectiveness of a single
dose of ibuprofen with the combined administration of ibu-
profen and acetaminophen, as well as an alternating regimen
of ibuprofen and acetaminophen (see below for results from
the alternating arm) in febrile children aged 6–84 months.
The combined use of ibuprofen and acetaminophen pro-
duced greater decreases in temporal artery temperature
compared with ibuprofen alone over the 6-h observation
period, with significant differences favoring the combination
treatment at hours 4 (p ¼ .002), 5 (p < .001), and 6 (p
< .001).
Hay et al.41 reported results of a randomized, blinded
comparison of either acetaminophen every 4–6 h, ibuprofen
suspension every 6–8 h, or a combination of the two in
febrile children aged 6 months to 6 years managed at home.
After 4 h, the combined treatment group and the ibuprofen
group had achieved 55 min and 39 min without fever (axil-
lary), respectively, which was significantly more than the
16 min observed with acetaminophen alone (p < .001 for
both comparisons). Children given both drugs spent less
time with fever over the first 24 h. Although the combined
treatment resulted in greater control of objective measures
of fever, there was some suggestion that more fever-associ-
ated symptoms were normalized in children given ibuprofen
alone than in those receiving acetaminophen alone or com-
bination treatment after 24 and 48 h.
Lal et al.42 conducted a randomized, double-blind com-
parison of acetaminophen, nimesulide, and ibuprofen plus
acetaminophen combination administered 3 times daily for
5 days in hospitalized children with acute respiratory tract
infections. In contrast to the other studies, no significant dif-
ferences in axillary temperature reduction were observed
between any of the treatment groups.
Alternating studies
Six studies evaluated the antipyretic efficacy of alternating
doses of acetaminophen (10
15 mg/kg) and ibuprofen
(5
10 mg/kg) in children11,43–47; dosing schedule and drug
formulation details from these studies are summarized in
Table 4.
Luo et al.43 compared the 24-h efficacy of alternating
acetaminophen and ibuprofen (shortest dosing intervals
were 4 h for acetaminophen and 6 h for ibuprofen; it was
stipulated that at least 2 h were to pass between doses of
acetaminophen and ibuprofen) versus monotherapy with
either ibuprofen or acetaminophen alone every 4 h in 474
febrile children aged 6 months to 5 years. The alternating
regimen began with acetaminophen. No significant clinical
or statistical differences were found in axillary temperatures
over 24 h across the 3 treatment groups. There was, how-
ever, a significantly lower percentage of children with per-
sistent fever for a duration of 4 or 6 h in the alternating
group versus in either monotherapy group (p  .003
for both).
In the study by Paul et al.11, the alternating regimen using
single-dose ibuprofen followed 3 h later by single-dose acet-
aminophen oral solution had a greater antipyretic effect than
single-dose ibuprofen alone at hours 4, 5, and 6 (p  .003
for all). All patients in the alternating group were afebrile
(< 38.0  C) at hours 4, 5, and 6 versus only 30%, 40%, and
50%, respectively, in the ibuprofen-alone group (p  .002 for
each hour vs alternating treatment). There was no significant
difference between the combined and alternating regimens.
Pashapour et al.44 compared the clinical effectiveness of
acetaminophen every 4 h with a regimen of acetaminophen
alternating with ibuprofen every 4 h in hospitalized infants
aged 9–24 months with fever of nonbacterial origin. There
was no significant difference in rectal temperature after 2 h.
However, temperatures were significantly lower with the
alternating regimen versus acetaminophen monotherapy at
hours 4, 5, 7, and 8 (p < .05 for all).
Kramer et al.45 conducted a randomized, prospective, dou-
ble-blinded, placebo-controlled study comparing the antipyr-
etic effects of acetaminophen alternating with either
ibuprofen or placebo in febrile, but otherwise healthy, chil-
dren aged 6 months to 6 years who presented at a pediatric
clinic. Alternating acetaminophen with ibuprofen significantly
decreased fever compared with alternating acetaminophen
with placebo at hour 4 (37.4  C vs 38.0  C; p ¼ .05) and hour
5 (37.1  C vs 37.9  C; p ¼ .003); however, there were no dif-
ferences in oral temperature between the groups at hours 0,
3, and 6. There were no differences between treatment
groups regarding parental perception of the need for addi-
tional fever medication at hours 3 or 4 (p ¼ .14 and p ¼ .20),
respectively, suggesting that the small differences in oral
temperature were not clinically important.
Nabulsi et al.46 performed a randomized, double-blind,
placebo-controlled comparison of the “efficacy and safety” of
a single dose of ibuprofen followed 4 h later by either acet-
aminophen or placebo in febrile children aged 6 months to
14 years. Alternating ibuprofen/acetaminophen was more
effective than ibuprofen/placebo, with significantly more
patients in the alternating group becoming afebrile at 6 h
compared with those in the ibuprofen/placebo group (83.3%
vs 57.6%; p ¼ .018); this difference was also significantly
Table 3. Studies of combination acetaminophen and ibuprofen administration.
Author, year Study design; Dose; n Primary outcome result Key secondary outcome result Adverse events
temperature measurement
technique; study duration Acetaminophen; N Ibuprofen; N Acetaminophen þ ibuprofen
combined or alternating; N
Vyas et al.40 Randomized, investigator-blind, 15 mg/kg, n ¼ 33 10 mg/kg, n ¼ 33 Acetaminophen 15 mg/kg Temperature reduction over 4 h: Post hoc multiple comparison test Ibuprofen, 3 (9.3%), abdominal
parallel-group þ Ibuprofen 10 mg/kg, n ¼ 33 Combination > ibuprofen or at 4 h: Combination pain, nausea, and
Tympanic; 4 h acetaminophen > acetaminophen (p¼.03); maculopapular skin rash;
alone (p ¼ .013) acetaminophen ¼ ibuprofen; Acetaminophen, 2 (6.7%),
ibuprofen ¼ combination abdominal pain and vomiting;
Combination, 4 (12.9%),
abdominal pain2, vomiting and
skin rash;
No serious or severe AEs were
reported in any group
Paul et al.11 Randomized, controlled NA Single dose of 10 mg/kg, n ¼ 20 Single-dose ibuprofen 10 mg/kg Antipyresis at 4–6 h: NR Not collected
Temporal artery; 6 h febrile episodes followed 3 h later by single- Combination > ibuprofen alone
dose acetaminophen 15 mg/ (4 h, p ¼ .002; 5 h and 6 h,
kg; n ¼ 20 febrile episodes p < .001 for each)
Hay et al.41 Randomized, blinded 15 mg/kg q4–6h (maximum 4 10 mg/kg q6–8h (maximum 3 Ibuprofen 10 mg/kg Time without fever 0–4 h: Temperature reduction at 24 h: Most common AEs:Diarrhea:
Axillary; 48 h doses/24 h) for 48 h, n ¼ 52 doses/24 h) for 48 h, n ¼ 52 þ acetaminophen 15 mg/kg Combination and Combination > ibuprofen ibuprofen, 9 (17.3%);
for 48 h, n ¼ 52 ibuprofen > acetaminophen (p ¼ .008) and acetaminophen acetaminophen, 10 (19.2%);
(p<.001 for both) (p ¼ .001) combination, 12 (23.1%);
Vomiting: ibuprofen, 3 (5.8%);
acetaminophen, 6 (11.5%);
combination, 2 (3.8%);
Rash: ibuprofen, 2 (3.8%);
acetaminophen, 2 (3.8%);
combination, 1 (1.9%)
Cough: ibuprofen, 0;
acetaminophen, 2 (3.8%);
combination, 1 (1.9%)
Cold to the touch: ibuprofen, 3
(5.8%);
acetaminophen, 0; combination, 2
(3.8%);
AEs were equally distributed
between groups.
Lal et al.42 Randomized, double-blind, 10 mg/kg thrice-daily for NA Acetaminophen 10 mg/kg Temperature reduction: NR “Only a few adverse effects
parallel-group 5 days, n ¼ 33 þ ibuprofen 10 mg/kg Acetaminophen ¼ combination namely, epigastric pain,
Axillary; 5 days thrice daily for 5 days, n ¼ 18 vomiting were encountered”;
there were no differences
between groups
Abbreviations. AE, adverse event; NA, not applicable; NR, not reported; q4–6h, every 4–6 h; q6h, every 6 h; q6–8h, every 6–8 h.
CURRENT MEDICAL RESEARCH AND OPINION
1371
Table 4. Studies of alternating acetaminophen and ibuprofen administration.
Author, year Study design/temperature measurement
technique; treatment duration
Luo et al.43 Randomized, controlled
Axillary; 24 h
Paul et al.11 Randomized, controlled
Temporal artery; 6 h
Pashapour et al.44 Randomized, controlled
Rectal; 8 h
Kramer et al.45 Randomized, double-blind, placebo-
controlled, prospective;
Oral; 6 h
Nabulsi et al.46 Randomized, double-blind, placebo-
controlled;
Rectal; 8 h
Sarrell et al.47 Randomized, double-blind, parallel- 12.5 mg/kg q6h for 3 days, n ¼ 154
group; Each treatment group
received a loading dose of either
ibuprofen 10 mg/kg (half of each
treatment group) or acetaminophen
25 mg/kg (half of each treatment
group); 3 days
Abbreviations. AE, adverse event; GI, gastrointestinal; NA, not applicable; NR, not reported; q4h, every 4 h; q6h, every 6 h; q8h, every 8 h.
Acetaminophen; N
10 mg/kg q4h, for 24 h; n ¼ 158
NA
15 mg/kg q4h for 2 doses, n ¼ 35
15 mg/kg alternating with placebo,
n ¼ 19; Acetaminophen at hour 0,
placebo at hour 3, then
acetaminophen at hour 4
NA
Dose; n
Ibuprofen; N Acetaminophen þ ibuprofen combined
or alternating; N
10 mg/kg q6h, for 24 h; n ¼ 158 Acetaminophen
Acetaminophen 10 mg/kg  q4h
alternating with ibuprofen 10 mg/
kg  q6h, for 24 h; n ¼ 158; shortest
interval between acetaminophen
and ibuprofen was  2 h
Single dose of 10 mg/kg, n ¼ 20 Single dose of ibuprofen 10 mg/kg
febrile episodes followed by single dose of
acetaminophen 15 mg/kg 3 h later,
n ¼ 20 febrile episodes
NA Acetaminophen 15 mg/kg alternating Antipyresis at 2 h:
with ibuprofen 10 mg/kg 4 h later;
patients received 1 dose of each
medication in the study; n ¼ 35
NA Acetaminophen 15 mg/kg alternating Temperature reduction between
with ibuprofen 10 mg/kg, n ¼ 19;
Acetaminophen at hour 0,
ibuprofen at hour 3, and placebo at
hour 4
Single dose of 10 mg/kg initial dose, Single dose of ibuprofen 10 mg/kg
with a single dose of placebo 4 h initially, then acetaminophen
later, n ¼ 33 15 mg/kg 4 h later, n ¼ 37
5 mg/kg q8h for 3 days, n ¼ 155 Study medication was administered
every 4 h; Administration began
with acetaminophen 12.5 mg/kg
and was followed with ibuprofen
5 mg/kg 4 h later; the drugs were
given in this alternating fashion for
3 days, n ¼ 155
Primary outcome result
Temperature or Non-Communicating
Children’s Pain Checklist:
Acetaminophen and
ibuprofen ¼ alternating treatment
Antipyresis at 4–6 h:
Ibuprofen alternating with
acetaminophen > ibuprofen alone
(4 h, p ¼ .003; 5 h and 6 h,
p < .001 for each)
Acetaminophen ¼ alternating
treatment
Antipyresis at 4, 5, 7, and 8 h:
Alternating treatment > acetaminophen
(4 h, p ¼ .048; 5 h, p ¼ .04; 7 h,
p ¼ .04; 8 h, p ¼ .02)
groups: Alternating
treatment > acetaminophen/placebo
at 4 h (p ¼ .05) and 5 h (p ¼ .003)
Alternating
treatment ¼ acetaminophen/placebo
at 0, 3, and 6 h
Percentage afebrile at 6 (primary
efficacy time point), 7, 8 h:
Ibuprofen alternating with
acetaminophen > ibuprofen
(6 h, p ¼ .018
Temperature reduction, less antipyretic Fever recurrence at day 5: Ibuprofen
medication use, less stress,
(regardless of initial loading dose):
Ibuprofen alternating with
acetaminophen > ibuprofen or
acetaminophen alone
(p < .001 for all measures)
Key secondary outcome result
Percentage with persistent fever at 4 No significant differences in rates of
and 6 h:
Alternating treatment > ibuprofen
and acetaminophen (4 h, p ¼ .003;
6 h, p<.001)
NR Not collected
NR
NR
Percentage afebrile at 7 or 8 h:
Ibuprofen alternating with
acetaminophen > ibuprofen at 7 h,
p < .001; 8 h, p < .001); Duration
of antipyresis:
Ibuprofen alternating with
acetaminophen > ibuprofen at 8 h
(p < .001)
alternating with
acetaminophen > ibuprofen or
acetaminophen alone (p ¼ .02)
Less absenteeism from day care:
Ibuprofen alternating with
acetaminophen > ibuprofen alone
or acetaminophen alone (p < .001)
1372
Adverse events
AEs between groups For the
combination, acetaminophen, and
ibuprofen groups, respectively, rates
of AEs were as follows: low body
temperature, 1.92%, 2.53%, and
1.91%; rash, 8.33%, 8.86%, and
8.28%; asthma, 0%, 0%, and 1.27%;
and GI AEs, 84.62%, 84.18%,
and 85.35%
I. M. PAUL AND P. D. WALSON
No “major complications” of treatment
were observed in any group
21% of patients had AEs including
diarrhea, flatulence, emesis,
decreased appetite, epigastric pain,
nausea, headache,
and insomnia; there were no
difference in the rates of any of
these AEs between groups
Low body temperature (i.e. < 36.5  C
rectally): ibuprofen alternating with
acetaminophen, 5 (13.9%);
ibuprofen, 6 (18.2%); (p ¼ .6, NS).
No serious AEs were observed. No
symptoms suggestive of GI, hepatic,
or renal toxicity
No drug-related AEs or serious illnesses
were reported

greater at 7 and 8 h (p < .001 for both time points). Patients
treated with alternating doses of ibuprofen and acetamino-
phen also had a significantly longer time to recurrence of
fever versus ibuprofen alone (mean ± SD: 7.4 ± 1.3 h vs
5.7 ± 2.3 h; p < .001) and a significantly greater decline in
rectal temperature at 7 (p ¼ .026) and 8 (p ¼ .002) hours.
Sarrell et al.47 conducted a randomized, double-blind, 3-
arm, parallel-group study in febrile children aged
6–36 months comparing acetaminophen alone versus ibupro-
fen alone versus an alternating regimen of ibuprofen and
acetaminophen. Prior to beginning randomized treatment,
patients in each treatment group received a loading dose of
either acetaminophen or ibuprofen. Alternating acetamino-
phen and ibuprofen, regardless of which medication was
given first, was significantly more effective than acetamino-
phen or ibuprofen monotherapy with respect to mean rectal
temperature, rate of fever reduction, additional antipyretic
medication needed (all p < .001), and fever recurrence at
day 5 (p ¼ .02). Measures of the child’s stress, as well as
absenteeism from daycare (and hence work absenteeism for
the parent), were also significantly reduced in the alternating
group (p < .001 for all measures).
Discussion
This review explored the antipyretic efficacy and tolerability
of acetaminophen versus ibuprofen, as well as treatment reg-
imens using both drugs reported in randomized studies in
children. The data indicate that physician-directed acet-
aminophen and ibuprofen dosing provide equivalent fever
reduction and that ibuprofen may be modestly superior at
OTC doses. Limited data suggest that combined or alternat-
ing use of acetaminophen and ibuprofen may provide
greater fever reduction compared with either agent alone.
Although our main focus was the comparative efficacy of
acetaminophen and ibuprofen in the treatment of pediatric
fever, antipyresis alone is not the most meaningful outcome,
as there is little evidence that fever itself is harmful48.
Indeed, according to the American Academy of Pediatrics,
improvement in the child’s overall comfort level should be
the goal of antipyretic treatment2. Despite this recommenda-
tion, very few studies in this review18,20,25,29,41,47 assessed
the clinical response of children, including measures of com-
fort or stress, or parental impression of the child’s well-being.
In recent years, the practice of alternating acetaminophen
with ibuprofen or combining the 2 drugs to reduce pediatric
fever has become increasingly common. The studies
reviewed here generally support the antipyretic advantages
of alternating and/or combining acetaminophen and ibupro-
fen versus the use of either antipyretic as monotherapy.
Studies evaluating the efficacy of alternating or combining
regimens of acetaminophen and ibuprofen showed superior-
ity versus either drug alone in some, but not all cases.
Additional studies are needed to investigate combined and
alternating strategies and to determine if one is more advan-
tageous than the other. The only study to investigate both
approaches found no difference between the 2 dosing strat-
egies11. Additional investigations should include assessments
CURRENT MEDICAL RESEARCH AND OPINION 1373
for school/work absenteeism, family stress, child discomfort,
sleep, and fluid intake, among others. Regardless of whether
acetaminophen and ibuprofen were administered in an alter-
nating or a combined manner, the regimens were well toler-
ated and the observed safety profiles were similar to those
seen with antipyretic monotherapy. Clinicians must weigh
these advantages against the additional costs and potential
risks of such therapy, including the possibility that such use,
with different dosing intervals, might lead to confusion and
result in accidental excessive dosing by parents or use where
contraindicated (e.g. ibuprofen use with renal dysfunction/
dehydration or accidental or intentional overdose of acet-
aminophen), contributing to “fever phobia” or failure to diag-
nose or monitor for signs of serious underlying diseases.
This review has some limitations. First, the studies
included in this review varied in design, for instance, in
terms of patient characteristics including age; method of
temperature measurement; efficacy and tolerability end-
points assessed; dosing regimens tested; and study duration;
these variations precluded our ability to conduct a formal
systematic review. Secondly, the review may be limited by
publication bias whereby studies having positive outcomes
are more likely to be reported. Further, most of the studies
were of short duration (often less than 8 h) with limited fol-
low-up, and not all included systematic assessment of toler-
ability, both of which may have limited the incidence of
adverse events reported.
Conclusions
Although the overall antipyretic efficacy of OTC oral tablet
and syrup formulations of acetaminophen and ibuprofen in
febrile children at physician-directed doses is similar, ibupro-
fen may have modest advantages over acetaminophen at
OTC doses in terms of faster onset of antipyresis, overall effi-
cacy, and duration of fever reduction, but provides only lim-
ited clinical benefit. Both acetaminophen and ibuprofen are
well tolerated and effective when caregivers follow the label-
ling information on dosing. Combining or alternating acet-
aminophen with ibuprofen, given their differential
mechanisms of action, metabolism, and end-organ toxicities,
appears to provide some antipyretic efficacy advantages in
children versus either agent alone and appears to be well
tolerated. Given that improvements in patient comfort or dis-
tress are arguably more meaningful outcomes than antipyre-
sis, per se, a systematic evaluation of these patient-centered
outcomes during treatment with acetaminophen or ibupro-
fen may prove helpful in determining the best course of
action in the management of pediatric fever.
Transparency
Declaration of funding
This manuscript was funded by Pfizer. The study sponsor had no role in
the conceptualization or drafting of this article.
1374 I. M. PAUL AND P. D. WALSON
Declaration of financial/other relationships
IMP has served as a paid consultant for the Consumer Healthcare
Products Association, Evidera, Johnson & Johnson, and Pfizer and as a
consultant for GlaxoSmithKline within the past 3 years. PDW has served
as a paid consultant on previous trials of acetaminophen and ibuprofen
and as an expert witness in FDA hearings involving manufacturers of
acetaminophen and ibuprofen. He has also served as a paid consultant
for the Consumer Healthcare Products Association.
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Author contributions
Both authors were responsible for project conceptualization, data cur-
ation and formal analysis, and manuscript review and editing. Both
authors approved the final manuscript as submitted and agree to be
accountable for all aspects of the work.
Acknowledgements
Medical writing support was provided by John H. Simmons, MD, and
Duprane Pedaci Young, PhD, of Peloton Advantage, LLC, an OPEN
Health company, and was funded by Pfizer.
ORCID
Ian M. Paul http://orcid.org/0000-0002-6344-8609
Philip D. Walson http://orcid.org/0000-0002-9566-8024
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