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Objective: To summarize studies testing the efficacy and after receiving the dose, and 1.11 (95% CI, 0.89-1.38) at
safety of single-dose acetaminophen and ibuprofen for 4 hours. Ibuprofen (5-10 mg/kg) reduced temperature more
treating children’s pain or fever. than acetaminophen (10-15 mg/kg) at 2, 4, and 6 hours
after treatment (respective weighted-effect sizes: 0.19 [95%
Data Sources: Reports were gathered by searching com- CI, 0.05-0.33], 0.31 [95% CI, 0.19-0.44], and 0.33 [95%
puterized databases (from their inception through May CI, 0.19-0.47]) (9 fever trials; 1078 children). For ibupro-
2002) and registries, relevant journals, and bibliogra- fen 10 mg/kg (acetaminophen, 10-15 mg/kg), correspond-
phies of key articles. ing effect sizes were 0.34 (95% CI, 0.12-0.56), 0.81 (95%
CI, 0.56-1.03), and 0.66 (95% CI, 0.44-0.87). There was
Study Selection: Seventeen blinded, randomized con- no evidence the drugs differed from each other (or pla-
trolled trials with children (⬍18 years) receiving either cebo) in incidence of minor or major harm (17 safety trials;
drug to treat fever or moderate to severe pain. 1820 children).
Data Extraction: Under a fixed-effects model, outcome Conclusions: In children, single doses of ibuprofen
measures for an initial single dose of ibuprofen vs acetami- (4-10 mg/kg) and acetaminophen (7-15 mg/kg) have
nophen were the risk ratio for achieving more than 50% similar efficacy for relieving moderate to severe pain,
of maximum pain relief, effect size for febrile temperature and similar safety as analgesics or antipyretics. Ibupro-
reduction, and risk ratio for minor and major harm. fen (5-10 mg/kg) was a more effective antipyretic than
acetaminophen (10-15 mg/kg) at 2, 4, and 6 hours post-
Data Synthesis: Ibuprofen (4-10 mg/kg) and acetami- treatment.
nophen (7-15 mg/kg) showed comparable efficacy (3 pain
relief trials; 186 children). The risk ratio point- estimates
was1.14(95%confidenceinterval[CI],0.82-1.58)at2hours Arch Pediatr Adolesc Med. 2004;158:521-526
A
CETAMINOPHEN AND IBU- studies before drawing conclusions,12-14
profen are widely pre- ideally by way of meta-analysis.15,16
scribed in children and are Heeding this call, we investigated by
the most frequently used way of meta-analysis the following 3 ques-
over-the-counter analge- tions about acetaminophen and ibupro-
sics and antipyretics, yet their relative ef-
ficacy and safety is uncertain. For adult an- For editorial comment
algesia, research has shown ibuprofen
From the Pain Research Unit,
treatment to be just as1,2 or more3,4 effec- see page 595
Sydney Children’s Hospital,
tive than acetaminophen. As the pharma-
Randwick, New South Wales, fen for single-dose, short-term use in chil-
Australia (Drs Perrott, codynamic profile of the drugs may vary
dren: (1) their relative efficacy for treating
Goodenough, and Champion, with patient age,5-7 generalization of these
pain, (2) their relative efficacy for treat-
and Ms Piira); Department of results to children may be inappropriate.
ing fever, and (3) their safety compared
Psychology, Northwestern A clear picture has not yet emerged
with each other and with placebo.
University, Evanston, Ill from studies with children comparing the
(Dr Perrott); School of 2 drugs. Although some studies have con-
Psychology, University of cluded ibuprofen to be the superior anal- METHODS
New South Wales (Ms Piira gesic8 and antipyretic,9 literature reviews
and Dr Goodenough), and
typically have concluded that the drugs DATA SOURCES
the Centre for Children’s
Cancer and Blood Disorders, were equally effective but that acetamino- We searched the following electronic data-
Sydney Children’s Hospital phen should be preferred because its safety bases from their inception through May 2002
(Dr Goodenough), Randwick. seemed more assured.5,6,10,11 Other com- to identify randomized controlled trials of ibu-
Dr Perrott is now with mentators have noted the importance of profen and acet aminophen for pediatric pain
TrialGraphix, Chicago, Ill. considering contextual variation across and fever: MEDLINE, EMBASE, Cochrane
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521
Abbreviations: CI, confidence interval; NA, not applicable; temp, fever outcome measure was between-drug difference in temperature at given time point;
trb, fever outcome was between-drug difference in temperature reduction from baseline.
*After attrition, at 4 hours (6 hours for Walson et al22).
†Risk ratio values greater than 1 indicate a greater likelihood of minor (major) harm for ibuprofen than for acetaminophen treatment.
‡For pain, the risk ratio values greater than 1 indicate a greater likelihood of achieving more than 50% of the maximum pain relief with ibuprofen than with
acetaminophen treatment. For fever, the values given are reported as febrile temperature reduction effect size (95% CI).
§The exact dosage was 240 mg/d for children younger than 8 years and 360 mg/d for children aged 8 years and older.
㛳The exact dosage was 200 mg/d.
¶Outcomes were estimated from a figure rather than a table.
#The exact dosage was 5 mg/kg if the initial temperature was less than 39.2°C; or 10 mg/kg otherwise.
**The mean effect size for analysis comparing 10 mg/kg of ibuprofen with 10 mg/kg or more of acetaminophen.
††Studies that examined safety that were not already included in the pain for fever analysis.
‡‡The number of patients included in the minor harm analysis. For the major harm analysis, there were 899 participants in the acetaminophen arm
and 914 in the ibuprofen arm.
Library, Biological Abstracts, Biological Abstracts/RRM, caine, codeine, and others), if the data were already included
CINAHL, Dissertation Abstracts International, EBM Reviews- in another study, or if insufficient data were provided to cal-
Best Evidence, EBM Reviews-Database of Abstracts of Reviews culate a value for the relevant outcome measures. The latter
of Effectiveness, ERIC, Expanded Academic ASAP, General criterion resulted in the exclusion of 3 studies from the pain
Science Abstracts, Health Reference Center Academic, Health analysis17-19 and 1 from the fever analysis20 (but did not pro-
Source Plus, HealthStar, Oxford Pain Relief Database, hibit their inclusion in the safety analysis), and in the exclu-
PsychInfo, and Web of Science. We used combinations of the sion of 1 study from the safety analysis.21
following search terms: “clinical trial,” “RCT,” “random*,” For multidose studies, we included only the data for the
“trial,” “study,” “ibuprofen,” “Brufen,” “proprionic acid,” first dose in the pain and fever analyses. No study included more
“acetaminophen,” and “paracetamol.” Hand searches of refer- than 1 acetaminophen treatment arm, but 4 studies used 2 ibu-
ence lists of located studies, as well as relevant review articles, profen treatment arms at different dosages.9,13,20,22 To preserve
Web sites, textbooks, and 4 key medical journals, did not independence of effect sizes,23 we included only the ibuprofen
yield any additional reports. No relevant data sets were treatment arm at the higher dosage, which was less than or equal
obtained from approaches to pharmaceutical companies mar- to the corresponding acetaminophen dosage.
keting the drugs, or from requests placed on the international
Pediatric Pain listserv. DATA EXTRACTION AND OUTCOME DEFINITIONS
INCLUSION AND EXCLUSION CRITERIA The independent coders (D.A.P. and T.P.) were blinded to iden-
tifying information about the author, institutional affiliation,
We included studies with participants younger than 18 years financial support, source, and year of publication until the meta-
receiving either drug for treatment of fever or moderate to se- analyses were completed. Outcome variables were indepen-
vere pain, randomly allocated to treatment arms in a blinded dently coded with a median agreement across coded variables
design. Otherwise relevant studies were excluded if any prior of 100% (median, = 0.99; minimum, = 0.75).24 Disagree-
or concurrent medication was a potential confound (eg, lido- ments were resolved by discussion.
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24 1 1.00 (0.02 to 45.13) 1.00 (0.02 to 45.13) 0.37 (−0.71 to 1.46)¶ 1.06 (−0.11 to 2.23)¶ 1.20 (0.00 to 2.39)¶
12 1 1.00 (0.02 to 49.28) 1.0 (0.02 to 49.28) 0.00 (−0.40 to .40)¶ 0.99 (0.57 to 1.42)¶ 1.21 (0.78 to 1.65)¶
342 1 4.13 (0.47 to 36.61) 0.97 (0.14 to 6.81) 0.01 (−0.19 to 0.22) −0.03 (−0.24 to 0.17) 0.04 (−0.17 to 0.24)
8 1 1.03 (0.37 to 2.86) 7.97 0.97 (0.40 to 1.53) 0.86 (0.30 to 1.42) 0.57 (0.03 to 1.12)
(0.43 to 147.82)
72 12 1.78 (0.62 to 5.07) 1.50 (0.26 to 8.73) NA 0.29 (−0.03 to .62) NA
72 3 0.60 (0.30 to 1.20) 0.85 (0.33 to 2.23) NA 0.08 (−0.26 to .42) NA
24 1 0.73 (0.02 to 35.64) 0.73 (0.02 to 35.64) 1.09 (0.54 to 1.64) 1.74 (1.13 to 2.35) 1.42 (0.84 to 1.99)
72 12 0.79 (0.31 to 2.05) 1.06 (0.02 to 51.84) 0.46 (−0.03 to 0.94 0.49 (0.00 to 0.97) 0.31 (−0.17 to 0.79)
6 1 0.19 (0.01 to 3.81) 0.93 (0.02 to 46.31) 0.00 (−0.37 to 0.37) .25 (−0.13 to 0.62) 0.00 (−0.38 to 0.38)
24 4 NA 0.36 (0.02 to 5.46) NA NA 0.16 (−0.58 to 0.90)
NA NA NA NA 0.19 (0.05 to 0.33) 0.31 (0.19 to 0.44) 0.33 (0.19 to 0.47)
NA NA NA NA 0.34 (0.12 to 0.56) 0.81 (0.56 to 1.03) 0.66 (0.44 to 0.87)
48 6 1.69 (0.42 to 6.82) 1.01 (0.02 to 50.41) NA NA NA
48 6 1.71 (0.43 to 6.91) 1.03 (0.02 to 51.11) NA NA NA
5 1 0.89 (0.36 to 2.19) 1.00 (0.02 to 49.84) NA NA NA
24 3 0.42 (0.04 to 4.31) 0.27 (0.01 to 6.27) NA NA NA
NA NA 0.96 (0.68 to 1.36) 1.00 (0.55 to 1.82) NA NA NA
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(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 158, JUNE 2004 WWW.ARCHPEDIATRICS.COM
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