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Antipyretic Effects of Dipyrone Versus
Ibuprofen Versus Acetaminophen in Children:
Results of a Multinational, Randomized,
Modified Double-Blind Study
Anthony Wong, MD1Andres Sibbald, MD2Fernando Ferrero, MD3Mauricio Plager, MD4Maria Elena Santolaya, MD5Anna Maria Escobar, MD6Sandra Campos, MD7Sergio Barragan, MD8Maximiliano De Le6n Gonzalez, MD9Gustavo LF Kesselring, MDlOon behalf of the Fever Pediatric Study Group
Summary: This study compared the antipyretic effectiveness of acetaminophen, ibuprofen, and
dipyrone in young children with fever. The results were based on a modified double-blind,
randomized, multinational trial that evaluated 628 febrile children, aged 6 months to 6 years.
All three drugs lowered temperature in the 555 patients completing the study. Temperature
normalization rates in the ibuprofen and dipyrone groups (78% and 82%, respectively) were
significantly higher than the acetaminophen group (68%, P=0.004). After 4 to 6 hours, mean
temperature in the dipyrone group was significantly lower than the other groups, demonstratinglonger temperature normalization with dipyrone. All three drugs showed comparable tolerability
profiles. Clin Pediatr. 2001;40:313-324
Introducfion'Hospital de Clinicas, University of Sao Paulo, Brazil, 2Hospital Britanico, Argentina, 3Hospital deNinos "Pedro Elizalde," Argentina, 4Hospital de Ninos "Ricardo Gutierrez," Argentina, 5Hospital _ ever is among themost
Luis Calvo Mackenna, Chile, 6Hospital de Clfnicas, University of Sao Paulo, Brazil, 7Hospital Sao common symptomsfor
Paulo, Brazil, 8Hospital Regional "Lic. Adolfo L6pez Mateos," Mexico, 9Hospital Juarez de which medical attentionis
Mexico, Mexico, 10Aventis Pharma, Brazil. sought in pediatric clinics and
Reprint requests and correspondence to: Anthony Wong, MD, Children's Institute, Department emergency rooms.1 While there isof Medicine, University of Sao Paulo, Av. Dr. Eneas Carvalho de Aguiar 647, 05403-900, Sao no consensus on whether fever,Paulo, Brazil. the body's response to infection
or inflammation, needs to be2001 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A. treated, 2 antipyretic therapy is
JUNE 2001CLINICAL PEDIATRICS 313
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Wong, Sibbald, Ferrero, et al.
commonly used to relieve discom-fort and to prevent serious conse-
quences like febrile seizures. Mostparents (58%) administer some
form of antipyretic medicationbefore their child's temperaturereaches 37.8°C, while an addi-tional 29% use medication forfevers between 37.9°C and38.80C.3
The antipyretic drugs usedmost often worldwide are acetyl-salicylic acid, acetaminophen(paracetamol), ibuprofen, anddipyrone. Acetylsalicylic acid is a
very effectiv antipyretic, but itsuse in children has declined dras-tically as a result of its associationwith Reye's syndrome.4'5
Acetaminophen also pro-
duces good antipyretic results inchildren,6,7 but recent reports ofhepatic and renal toxicity at highdoses have prompted caution.8 Aretrospective study of pediatricpatients admitted for aceta-minophen overdose identified39% with severe liver toxic effectsand 8% who underwent livertransplants.9 A more recent studyhas shown that hepatic toxicityoccurs commonly at normaldoses in normal livers in certainclinical situations, even in pedi-atric patients.39
Ibuprofen, a relative late-comer to the pediatric antipyreticarmamentarium, has been usedin febrile children since 1989.However, ibuprofen is prescribedat 2 dosages, depending on theinitial temperature: 5 mg/kg fortemperatures of less than 39.2°C,and 10 mg/kg for temperatureshigher than 39.2°C. Given the in-herent problems with accuracy
and correctness of over-the-counter dosing by caregivers,'0this two-dose regimen can cause
considerable confusion.Finally, as shown in this study,
dipyrone is another very effectiveantipyretic agent. However, an as-
sociation between dipyrone usage
and agranulocytosis has alsoprompted caution,911,12 even
though large epidemiologicalstudies argue this concern may beunwarranted.13-15
Many or all of these com-
pounds are readily available to thepublic and therefore tend to bechosen based on regional or localnorms, rather than according toan appropriate medical rationaleor scientific basis. Moreover, thesedrugs are often administered athome, without medical control or
help. It is therefore importantthat medical practitioners and thepublic are reasonably well ap-
prised of each drug's therapeuticcharacteristics. This knowledgeshould be based on large-scale,controlled, and prospective epi-demiological analyses that assess
the efficacy and tolerability ofeach drug.
The purpose of this multina-tional study was to carry out sucha trial. Specifically, the primarygoal was to compare the an-
tipyretic effectiveness of aceta-minophen, dipyrone, and ibupro-fen among young childrenpresenting with high fever. Secon-darily, the study addressed the tol-erability of these three drugs on
the test population.
Methods
SubjectsSix hundred twenty-eight chil-
dren, aged 6 months to 6 years
(body weight .5.0 kg), able to re-
ceive oral medication, and pre-
senting with tympanic tempera-ture between 38.5°C and 40.5°Cwere recruited from May to De-cember 1998. These patients wereidentified either in inpatient pe-
diatric wards or from outpatientemergency clinics of universityhospitals in Buenos Aires, Ciudad
de Mexico, Santiago, and SioPaulo. Signed, informed, writtenconsent was obtained, and an ex-
planation of the study objectiveswas given to each subject's par-
ents or legal guardian. The EthicsCommittees and Institutional Re-view Boards of the respective in-stitutions approved the protocol.
Study Design/Exclusion CriteriaThis was a multiracial, multina-
tional (Brazil, Argentina/Chile,and Mexico), multicenter (8 cen-
ters), single, oral-dose, prospec-
tive, randomized, modified dou-ble-blind, parallel group study.Since the trial in Chile was coor-
dinated from Argentina, Ar-gentina/Chile was grouped as
one country for the purpose ofthe study. Retrospective analysisof the final data indicated thatthis grouping had no effect on
the ultimate conclusions (datanot shown).
Children were excluded fromthe study for any of the followingreasons: having a history offebrileseizures within 6 months prior tothe study; receiving antibioticsmore than 12 hours before studyonset; receiving any antipyreticdrugs within 4 hours of study on-
set; receiving treatment with any
investigational drug in the prior 4weeks; and having a history of hy-persensitivity or adverse reactionto any of the study drugs. Chil-dren were also excluded if theyhad poor prognosis (tropical dis-eases such as dengue fever, yellowfever, malaria, fever, cramps,
and/or severe dehydration); con-
ditions that might interfere withdrug absorption; histories of con-
nective tissue disease or AIDS;hematological toxic effects withinthe past 3 months; changes inmood or consciousness; or clini-cally relevant cardiovascular, he-patic, neurological, endocrine, or
renal dysfunction.
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Dipyrone vs. Ibuprofen vs. Acetaminophen
During the study, anticonvul-sants, antacids, corticosteroids,or nonsteroidal anti-inflamma-tory drugs were not permitted as
concomitant treatments. Physi-cal methods to decrease bodytemperature were also not per-
mitted. Treatment of the under-lying disease state, including an-
tibiotic therapy when indicated,was instituted according to thetreatment algorithm practicedat the respective participatinginstitutions.
Study MedicationsAfter initial clinical evalua-
tion, patients were randomly as-
signed 1:1:1 to receive one of thethree antipyretic medications in a
single oral dose by syringe. Allthree drugs were commerciallyavailable preparations in syrup
form. The dosage and manner
were administered per manufac-turers' labeling instructions in thepackaging insert, exactly as thecaregiver would do in a domesticsituation. These dosages were
equivalent, in each case, to thesuggested dosages recommendedin the Physician's Desk Reference(PDR).16 The dose for dipyrone(NovalginaTM; Brazil) was 15mg/kg.'7 The dose for aceta-
minophen (TylenolTM; Argen-tina) was adjusted according toeach patient's age, followingpackage insert instructions (inmilliliters per age bracket), andaveraged 12 mg/kg.'8 Ibuprofen(IbupiracTM; Argentina) was givenbased on initial temperature (To),using a dose of 5 mg/kg forTo<39.20C and 10 mg/kg forTo.39.20C. 16 Administrations ofthe study drugs were supervisedby the investigator or the coinves-tigator, who had no knowledge ofwhich drug was being given. Thisconstituted a "modified" double-blind or "observer-blind" ap-
proach, where neither the patient
nor the evaluator knew whichtreatment had been administeredby a third party. No food or liquidwas allowed within the first hourof dosing.
EvaluationsUpon entry into the trial, tem-
perature readings of the right ear
were obtained with a digital oto-
scopic temperature device. (Ther-moscan HM2W/C; Braun, Inc;USA. Prior to the trial, all partici-pating investigators completed a
training course for the Ther-moscan otoscope.) In childrenyounger than 3 years of age, threesuccessive readings were taken,and the highest temperature was
recorded, as recommended bythe manufacturer.19 These valuesconstituted the baseline readings.Subjects were then given a singledose of medication, and tympanictemperature was measured 0.25,0.5, 0.75, 1.0, 1.5, 2, 3, 4, 5, and 6hours later.
In addition to tympanic tem-peratures, supine blood pressures
and pulse rates were recorded.Blood pressures were taken on
the right arm with a TycosTMsphygmomanometer, with appro-
priate cuff width for the partici-pant's age.
Tolerabilities of the medica-tions were evaluated in all subjectsby standard medical observation.Adverse events were assessed dur-ing the 6-hour study period andfor an additional 14 days afterdrug ingestion to monitor any
late adverse events. Patients couldbe withdrawn from the study attheir own request or that of a par-
ent/guardian, in case of ineffi-cacy or any adverse event consid-ered unsafe for that specific use.
A rescue drug (as determined bythe investigator) was also availablein the case of inefficacy or if thepatient's temperature rose duringthe course of the study.
Statistical Methodsand Sample Size
The primary efficacy variablein this study was the number ofpatients (%) with a tympanic tem-perature reduction of at least1.5°C from baseline. Secondary ef-ficacy variables included the timefor patients to achieve a reductionof 1.5°C, the time for patients to
achieve temperature normaliza-tion (tympanic temperature
<37.50C), and the percentage ofpatients who achieved tempera-ture normalization.
The total number of subjects(628) met the stipulated samplesize of 180 patients per treatmentarm, which was calculated basedon the hypotheses that the threetreatment regimens had similar(null hypothesis) or different (al-ternative hypothesis) abilities to
reduce tympanic temperature1.5°C from baseline (primary ef-ficacy variable). This calculationassumed a statistical power of0.90 and an estimated drop-outrate of 0.15.
Statistical evaluations in-cluded a description of the studypopulation, a comparison ofbaseline values of the threegroups, and analyses of the effi-cacy and tolerability of the threeantipyretics. Continuous demo-graphic data and clinical vari-ables were tested for comparabil-ity by analysis of variance(ANOVA). Discrete demographicvariables, summarized by fre-quency tables, were tested forcomparability by chi-square tests.The continuous efficacy variableswere evaluated as changes frombaseline and compared for ho-mogeneity among the groups us-
ing ANOVA, with treatmentgroup and country considered as
fixed elements.Patients who remained in the
trial for at least 2 hours were eligi-ble for efficacy analysis. In others
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needing rescue medication, thelast recorded temperature was
carried forward to the end of thestudy. Tolerability data from ad-
verse events are presented in thetables with absolute and relativefrequencies, and the chi-squaretest was performed to compare
incidence rate within the threegroups.
All tests were two-tailed. Thelevel of significance for all tests
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Dipyrone vs. Ibuprofen vs. Acetaminophen
was P.0.05. Statistical evaluationswere carried out using the SAS(version 6.11) software.20
Results
DemographicsA total of 628 children met the
eligibility criteria, with 209 ran-
domized to receive dipyrone(mean dose, 15.0 +0.3 mg/kg),210 to receive acetaminophen(mean dose, 11.8 +0.3 mg/kg),and 209 to receive ibuprofen(mean doses, 5.0 +0.5 and 9.7 ±1.1mg/kg, respectively). Demo-graphic characteristics were com-
parable in all three groups (Table1). Patient distribution withintreatment groups based on un-
derlying pathology was also com-
parable, with the exception of uri-nary tract infection, which was
present less often in the aceta-
minophen group. Baseline mea-
surements of pulse, systolic anddiastolic blood pressures (datanot shown), and tympanic tem-perature (see Table 1) were alsocomparable among all threegroups.
Withdrawals during thecourse of the trial are shown inTable 2. The total withdrawalrates between groups were not sta-
tistically different. The main rea-
sons for withdrawal were lack ofefficacy (dipyrone 8.6%; aceta-minophen 15.2%; ibuprofen12.4%) and requested with-drawals (dipyrone 8.1%; aceta-minophen 3.8%; ibuprofen3.8%). Patients withdrawn on par-
ents' requests included those whoexperienced adverse events (12%[2/17] with dipyrone; 13% [1/8]with acetaminophen; and 13%[1/8] with ibuprofen), or re-
ceived wrong or unknown doses
(one with dipyrone and two withibuprofen). A majority of patientsrequesting withdrawal showed re-
duced temperatures at or close tonormalization values (65%[11/17] with dipyrone; 63%[5/8] with acetaminophen; and75% [6/8] with ibuprofen). Ofthe 628 patients randomized, 555patients (179 in the dipyrone, 191in the acetaminophen, and 185 inthe ibuprofen groups) completedthe study and were evaluable forefficacy analyses per protocol.
Temperature ReductionsAll three drugs were effective
in reducing tympanic tempera-ture (Tables 3 and 4, Figures 1-3).The percentage of patients whodemonstrated temperature re-
ductions of 21.5°C ranged from77% in the acetaminophengroup, to 86% with dipyrone, and83% with ibuprofen. The time to
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Dipyrone vs. Ibuprofen vs. Acetaminophen
41
0
1
1
0
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reach this reduction was statisti-cally comparable for all threegroups (dipyrone, 103 minutes;acetaminophen, 109 minutes;ibuprofen, 120 minutes; see Table3). However, the number of pa-tients who achieved normaliza-tion (tympanic temperature<37.50C) was significantly greaterin the dipyrone and ibuprofengroups than in the aceta-minophen group (P=0.004, seeTable 3, Figure 1).
When mean changes in tem-perature were monitored overtime, dipyrone produced a rapidtemperature reduction from base-line (observed as early as 1.5hours after drug ingestion) thatwas significantly greater than withibuprofen or acetaminophen(P=0.004, Figure 2). Meanchanges in temperature at the 3-,4-, 5-, and 6-hour assessment timepoints were also significantlygreater with dipyrone and ibupro-fen than with acetaminophen(P=0.004, Figure 2). Furthermore,temperature reductions of at least1.5LC were maintained until theend of the 6-hour observation pe-riod only with dipyrone. Reduc-tions in a similar range were main-tained with acetaminophen andibuprofen for up to 3 hours(Table 4).
Figure 3, which depicts ab-solute temperatures over time,shows that the decreases in tem-perature were very similar duringthe first 2 hours of the study for alltreatment groups. However, at the4-, 5-, and 6-hour assessments,mean temperature in the dipy-rone group was significantly lowerthan that observed with ibupro-fen or acetaminophen (P=0.004).
TolerabilityAdverse events recorded in in-
tent-to-treat patients are shown inTable 5. Most of the adverseevents were gastrointestinal in na-
100 -
80 -
5
N
0z
60 -
40 -
20
a
*
82 *
78
68
Dipyrone Acetaminophen
I I I.. I
Ibuprofen
*P =0.004, vs acetaminophen
Figure 1. Proportion of patients (%) who achieve normalization of tympanic temperature (<37.50C).*P=0.004, vs. acetaminophen.
ture, such as vomiting and diar-rhea. Of the total adverse eventswithin each group, those consid-ered by investigators to be possi-bly drug-related comprised 17%of the dipyrone, 15% of the aceta-minophen, and 27% of theibuprofen groups. There were nostatistically significant differencesamong the three groups with re-spect to incidence of adverseevents. Blood pressure and pulserate tended to decrease uniformlyin all study groups.
A total of nine patients (threein the dipyrone, two in the aceta-minophen, and four in theibuprofen groups) showed tem-peratures <36°C, which could rep-resent hypothermia, for at leastone assessment time point. Onlytwo patients presented tempera-tures <36°C at more than oneconsecutive measurement (one
each in the acetaminophen andibuprofen groups, respectively).The three lowest recorded tem-peratures (35.6°C, 34.4°C, and35.4°C) occurred among theibuprofen users.
Discussion
Appropriate care of the febrilechild includes physical measures,such as sponging, and the judi-cious use of antipyretic medica-tion. Physicians and parents oftenreceive confounding and contro-versial information about the effi-cacy and safety of medications,and consequently, compliancewith dosing instructions varies. Atherapeutic plan for treating fevershould include appropriateknowledge of the absolute andrelative efficacy of a medication,
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Dipyrone vs. Ibuprofen vs. Acetaminophen
0 1 2n nn
41.25 4
-0.50
-0.75
-1.00
-1.50
Hours3 4 5 6
Dipyrone-*-Acetaminophen*Ibuprofen
conclusion was based on an analy-sis of temperature normalizationfrequencies, the time-rates oftemperature reduction, and themaintenance of nonfebrile tem-peratures over time.
Temperature NormalizationFrequencies
Frequencies of temperaturenormalization, defined as the per-centage of febrile children in thetest population whose tempera-ture was reduced to 37.5°C, were78% for ibuprofen and 82% fordipyrone. Both of these frequen-cies were significantly greaterthan the value for acetaminophen(68%, P-0.004). Considering thelarge numbers of patients usingthese medications worldwide,these relative differences in re-sponse could translate into a largeabsolute number of patients.
-2.00 J
FP =O.X4, vs acetaminophentP =0.004, vs ibuprofen
Figure 2. Time-course mean change from baseline in tympanic temperature after antipyreticdrug ingestion. *P=0.004, vs. acetaminophen; tP=0.004, vs. ibuprofen.
as well as the dose/efficacy ratio,magnitude of response, onset andduration of effect, and the signifi-cant adverse reactions and side ef-fects. Studies such as the presentone attempt to address some ofthese issues.
To the best of our knowledge,the number of enrolled patientsin this study (N=628) representsthe largest pool of febrile patientsin which three frequently usedantipyretics have been investi-gated in head-to-head compar-
isons. Patient enrollment in pre-
vious comparative studies ofacetaminophen and ibuprofen
ranged from <50 patients2'-23 to116-224 patients.2428 As reportedby Carley,29 while some compara-
tive studies showed ibuprofen tobe more effective than aceta-minophen,21 25'26'28 others showedcomparable effects between thetwo drugs.23'2427
In this study, all three an-
tipyretic drugs showed a loweringof temperature in the 555 patientswho completed the study and,therefore, had clinically usefulantipyretic effects. However,when the three drugs were com-
pared, dipyrone appeared to bethe most effective agent. This
Time-Rates of TemperatureReduction
When the time-rates of tem-
perature reduction relative tobaseline values were determined,dipyrone reduced temperaturesignificantly more rapidly than ei-ther acetaminophen or ibuprofen(P=0.004, Figure 2). However,when the time-rates of tempera-ture normalization were com-
pared, there were no statisticaldifferences in the absolute tem-perature readings among the 3medication groups in the first 3hours of observation (see Figure3). The interpretation of these re-
sults is necessarily complex, but a
conservative conclusion wouldposit that dipyrone reduces tem-perature more rapidly than aceta-
minophen or ibuprofen.
Maintenance ofNonfebrileTemperatures
Even though it remains ar-
guable whether dipyrone de-creased temperature more
JUNE 2001 CLINICAL321~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
0
m
E0I-
0'(UU.(Ua)
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DipyroneI--Acetaminophen-2-buprofen
*
0 1 2 3 4 5 6
Hours
*P0.004, vs acetaminophen
Figure 3. Time-course change in tympanic temperature after antipyretic drug ingestion. *P=0.004,vs. acetaminophen.
rapidly than acetaminophen or
ibuprofen (see previous section),the data in Figures 2 and 3 unam-biguously demonstrate that tem-perature reductions were main-tained longer by dipyrone. Thus,at the 1.5-, 3-, 4-, 5-, and 6-hr timepoints in Figure 2, as well as the 4-
,5-, and 6-hr time points in Figure3, the dipyrone group presented a
significantly lower mean tempera-ture than both the aceta-minophen and ibuprofen groups.
Dipyrone therefore has thelongest lasting effects for temper-ature normalization.
This prolonged maintenanceof low temperature in the dipy-rone group may present its clear-
est potential clinical advantagewhen compared to ibuprofen(and acetaminophen). As statedearlier, in the absence of concernover febrile seizure, the primaryreason for issuing antipyretics isto improve the patient's subjec-tive feeling about his/her physio-logical state. This may be particu-larly true for the pediatric patient,in whom fever is reportedly asso-
ciated with significant levels ofdiscomfort.30 Among parents/guardians, fever is also considereda significant problem, being thecomplaint that most often bringsa child to the emergency clinic or
pediatric office. A survey among
parents of children who were ob-
served in a clinical trial to preventfebrile seizures revealed that 45%expressed fear of fever and febrileseizures.31 Therefore, agents thatprolong the period of normal ornear-normal temperatures shouldbe an attractive therapeutic op-tion for the treatment of child-hood fever.
Despite its demonstrated effi-cacy, dipyrone is unique amongthe antipyretics analyzed in thisstudy in that it is used extensivelyonly by children in continentalEurope, Asia, and Latin Amer-ica.32-36 Children in the UnitedStates and United Kingdom donot have access to the medicationbecause of a reported linkage be-tween dipyrone use and agranulo-cytosis.37 However, publishedstudies on dipyrone use and thecause of agranulocytosis havetended to analyze spontaneous re-ports or single-outcome studies,which can distort the overallsafety evaluation of drugs.'3
As evidence for this, largerepidemiological studies havereached significantly differentconclusions regarding the safetyof dipyrone. For example, onestudy, conducted by the Interna-tional Agranulocytosis and Aplas-tic Anemia Society (also known asthe Boston Study), examined thestatistical association betweendipyrone use and agranulocytosisin more than 22.2 million peopleliving in eight European citiesand Israel.'4 The excess risk ofagranulocytosis with dipyrone wasestimated to be 1.1/million inone geographic region (Ulm,Berlin, Barcelona), while in an-other geographic region (Israeland Budapest), where overall us-age of dipyrone was higher, theexcess risk was even lower.'4 Thestudy therefore concluded thatabsolute risks of agranulocytosiswith dipyrone use were "verylow."'14 Subsequent analysis of
322 CLINICAL PEDIATRICS JUNE 2001
39.50
39.25
39.00
38.75
38.50
38.25
38.00
S(U
ak.ECD
37.75
37.50
37.25
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Dipyrone vs. Ibuprofen vs. Acetaminophen
data from a third region (Bul-garia) also showed no associationbetween agranulocytosis anddipyrone usage.'5
In another meta-analysis thatcompared epidemiological studiespublished from 1970 to 1995, theestimated excess mortality due to
community-acquired agranulocy-tosis, aplastic anemia, anaphylaxis,and serious upper gastrointestinalcomplications was 185/million foracetylsalicylic acid, 20/million foracetaminophen, and 25/millionfor dipyrone.13 By these criteria,dipyrone presents risks of medicalcomplications commensurate withother antipyretics. In view of thesetypes of findings, it has been sug-
gested that the regulatory restric-tions on dipyrone should be re-
assessed.38This study also examined the
tolerability of the three medica-tions on the test population. Aspredicted from the larger epi-demiological studies, no statisti-cally significant differences in tol-erability were observed.
In conclusion, in this large,multiracial study conducted inthree distinct geographical re-
gions, three widely used an-
tipyretic drugs, namely, dipyrone,acetaminophen, and ibuprofen,appeared safe and effective in re-
ducing temperature. Dipyroneand ibuprofen were significantlymore effective than aceta-minophen in achieving a normal-ization of tympanic temperature<37.50C. Dipyrone produced a
significantly greater temperaturereduction from baseline thanibuprofen and acetaminophenand maintained low temperaturesfor a longer time.
Acknowledgments
We thank Carla B.B. Asseburg,BSc Biometrician, Aventis Pharma
and Tatiana Caniato, Pharmacist,Aventis Pharma for their helpwith the preparation of thismanuscript.
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