PHARMACODYNAMICS AND

DRUG ACTION
Acetaminophen has greater antipyretic
efficacy than aspirin in endotoxemia: A
randomized, double-blind, placebocontrolled trial
Objective: To compare the antipyretic efficacy of aspirin and acetaminophen (INN, paracetamol) in 30 male
volunteers with the use of endotoxin (lipopolysaccharide) to elicit a standardized febrile response.
Methods: A randomized, double-blind, placebo-controlled trial was conducted in parallel groups. Subjects
received an intravenous endotoxin bolus of 4 ng/kg after premedication with either placebo, 1000 mg
aspirin, or 1000 mg acetaminophen by mouth.
Results: Peak body temperatures were 38.5C 0.2C in the placebo group, 37.6C 0.2C in the acetaminophen group (P = .001 versus placebo), and 38.6C 0.2C in the subjects treated with aspirin (P =
.001 versus acetaminophen; P = .570 versus placebo) at 4 hours after lipopolysaccharide infusion. Subjective symptom scores for chills and perception of fever were higher in the placebo group than in the acetaminophen group (chills, 2.5 0.3 versus 1.0 0.2, P = .009 and fever, 2.5 0.2 versus 2.0 0.2, P =
.021). Tumor necrosis factor, interleukin-6, and interleukin-8 levels rose by several orders of magnitude (P < .001 versus baseline in all groups), without significant intergroup differences.
Conclusions: Acetaminophen was the superior antipyretic drug in endotoxemia compared with aspirin.
Treatment with acetaminophen ameliorates subjective symptoms induced by endotoxemia without compromising the humoral response of a subject to endotoxin. This observation has clinical interest and may
also help to improve the lipopolysaccharide model, which can be used to test anti-inflammatory and anticoagulatory drugs. (Clin Pharmacol Ther 1999;66:51-7.)

Thomas Pernerstorfer, MD, Rainer Schmid, PhD, Christian Bieglmayer, PhD,

Hans-Georg Eichler, MD, MSc, Stylianos Kapiotis, MD, and Bernd Jilma, MD
Vienna, Austria
From the Departments of Clinical Pharmacology, TARGET (The
Adhesion Research Group Elaborating Therapeutics), the
Department of Cardiothoracic and Vascular Anesthesia and
Intensive Care, and the Clinical Department of Medical and
Chemical Laboratory Diagnostics, Vienna University Hospital
School of Medicine.
Supported by a grant from the Kamillo-Eisner-Stiftung, Hergiswil,
Switzerland.
Received for publication Jan 20, 1999; accepted March 26, 1999.
Reprint requests: Bernd Jilma, MD, Klinische Pharmakologie, TARGET, The Adhesion Research Group Elaborating Therapeutics,
Vienna University Hospital School of Medicine, Whringer Grtel 18-20, A-1090 Vienna, Austria.
Copyright 1999 by Mosby, Inc.
0009-9236/99/$8.00 + 0 13/1/98796

Lipopolysaccharide (endotoxin), a constituent of the

cell wall of gram-negative bacteria, is considered to be
a major mediator for the pathogenesis of the systemic
reaction to sepsis.1,2 Endotoxemia causes an overexuberant host response by eliciting the release of a wide
array of mediators, including cytokines and prostaglandins.3,4 Accordingly, tumor necrosis factor
(TNF-), interferon-, interleukin-1 (IL-1), interleukin6 (IL-6), and interleukin-8 (IL-8) have been identified
as predominant pyrogens.5 Because cytokines are
unable to cross the blood-brain barrier, prostaglandins
generated within the brain are considered to be second
messengers for these pyrogens.6-8

51

52 Pernerstorfer et al

Although fever is often the first and leading symptom to suggest an infectious disease, the practice of
fever control in sepsis is still controversial.9 A recent
trial found that ibuprofen reduced fever and pulse rate
and lessened lactic acidosis in patients with sepsis,
despite unchanged mortality.10 A clue for this puzzling
discrepancy could be given by seminal experimental
studies that unequivocally showed ibuprofen to enhance
the release of TNF-, IL-6, and IL-8 in human volunteers infused with endotoxin.11,12 Thus it appears that
the potentially beneficial effects of ibuprofen on the
lipopolysaccharide-induced febrile response are outweighed by the enhanced systemic inflammatory reaction. Yet it is ill characterized whether other antipyretic
drugs, such as acetaminophen (INN, paracetamol) and
aspirin (the most commonly used antipyretics), may
have a more favorable anti-inflammatory profile in
endotoxemia. Although several comparisons on the
analgesic and antipyretic activity of ibuprofen and
ketorolac versus acetaminophen have been made,13-15
direct comparisons of the antipyretic activity of aspirin
and acetaminophen in adults are scarce. Furthermore,
direct comparisons of the antipyretic efficacy of aspirin
and acetaminophen have mainly been done in pediatric
patients,16-18 whereas to the best of our knowledge, no
controlled trial has yet compared the antipyretic efficacy in adults.
Infusion of endotoxin is an established model that has
previously been used to test antipyretic drugs.15,19 We
therefore planned to compare the antipyretic efficacy of
aspirin and acetaminophen in volunteers receiving
lipopolysaccharide intravenously, which produces clinical symptoms of a systemic inflammatory response.
METHODS
Study design and study subjects. The study was
approved by the Institutional Ethics Committee of the
Vienna University Medical School, and all participants
gave written informed consent before they enrolled in
the study. Block randomization (n = 3) was used
because one vial of endotoxin was used for every three
subjects in the study. The study was designed as a randomized, double-blind placebo-controlled trial in three
parallel groups (n = 10 per group) in 30 healthy male
subjects (mainly students) with body mass indices that
ranged from the 15th to the 85th percentile (because
different clearance rates for acetaminophen have been
reported in relation to weight and sex20).
Health status was determined by a battery of laboratory and clinical tests, including evaluation of medical
history, physical examination, and hematologic, biochemical, virologic, and drug screening as described

CLINICAL PHARMACOLOGY & THERAPEUTICS

JULY 1999

previously.21,22 Exclusion criteria were hypersensitivity to either aspirin or acetaminophen and regular or
recent (within 3 weeks) intake of any drugs, including
over-the-counter medication.
Study protocol. Volunteers reported to the study ward
at 8 AM in the morning after fasting overnight. Throughout the entire study period they had to stay in bed in the
supine position, and they fasted for 812 hours after endotoxin infusion. A glucose 5% infusion (Leopold Pharma,
Austria) was started at 8:30 AM and continued over an
812-hour period at 3 mL/kg/h to ascertain adequate blood
glucose levels and adequate urinary output.
Vital parameters (electrocardiography, heart rate, and
oxygen saturation continuously; blood pressure at 20minute intervals) were monitored on a Care View System (Hewlett-Packard, Bblingen, Germany), and tympanic temperature was recorded hourly with an electronic thermometer (Thermoscan, San Diego, Calif).
Temperature measurements were performed by a single operator who calculated the mean values of measurements from both ears.23 For safety reasons, subjects in the study had to stay at the research ward
overnight until 24 hours after endotoxin infusion.
After the glucose infusion was started, placebo
(Genericon Pharma, Lannach, Austria), 1000 mg acetaminophen (Paracetamol Genericon Pharma, Lannach,
Austria), or 1000 mg acetylsalicylic acid (ASS Genericon Pharma), which is bioequivalent to aspirin from
Bayer, was administered orally. Aspirin, acetaminophen, and placebo tablets were not identical in
shape; to ensure adherence to the double-blind study
design, the tablets were therefore dissolved by a study
nurse who was otherwise not involved in the conduct
of the trial. At 9 AM the subjects received 4 ng/kg
lipopolysaccharide (National Reference Endotoxin,
Escherichia coli; United States Pharmacopeial Convention Inc, Rockville, Md) as an intravenous infusion over
a 1- to 2-minute period. For each randomization block
one vial of lipopolysaccharide was dissolved in sterile
physiologic saline solution less than 5 days before use
to achieve a final concentration of 20 ng/mL (ie, stock
solution). Aliquots of this stock solution (10 mL each)
were kept frozen at 20C and were thawed only once
to prevent repeated freezing-thawing cycles. After
thawing, lipopolysaccharide was filtrated through a 0.2
m filter (Syringe filters, Nalge, Nunc International,
Rochester, NY).
Sampling and analysis. Venous blood was drawn into
citrated Vacutainer tubes before any drug was administered and thereafter as indicated in the figures from an
indwelling venous line. Blood samples were centrifuged
at 2000g for 15 minutes at 4C and stored at 80C until

CLINICAL PHARMACOLOGY & THERAPEUTICS

VOLUME 66, NUMBER 1

analysis as duplicates was performed. All samples from

individual subjects were run in the same assay.
Plasma levels of salicylic acid were determined by
enzyme fluorescence polarization immune assay (TDx,
Abbott Park, Ill). Because acetaminophen plasma levels in this study were somewhat lower than those in a
previous study from our group, detection of acetaminophen concentrations with fluorescence polarization immune assay was not possible.24 Acetaminophen
levels were therefore determined with an HPLC method
as described previously,25 except that a Merck-Hitachi
D-7000 HPLC system (Merck, Darmstadt, Germany)
with an ultraviolet detector set to a wavelength of 256
nm was used.
Plasma levels of cortisol and cytokines. Assays of
cortisol plasma levels were obtained by Enzymun-Test
Cortisol from Boehringer Mannheim, with a detection
limit of 27.6 nmol/L and an interassay variation of 4.6%.
Levels of TNF-, IL-6, and IL-8 underwent assay by
quantitative sandwich enzyme-linked immunosorbent
assay (R&D Systems, Oxon, England) as described previously.26 Detection limits for TNF-, IL-6, and IL-8
were 0.18 pg/mL, 0.094 pg/mL, and 10 pg/mL, respectively. Intraassay and interasssay coefficients of variation for all assays were less than 11%.
Safety parameters and subjective symptoms. Mean
arterial pressure was measured hourly, and 24-hour creatinine clearance was obtained during the 24 hours
before and after the endotoxin administration to identify impairment of renal function. To assess the tolerability of lipopolysaccharide, all participants were asked
to subjectively rate chills, fever, myalgia, cephalgia,
and nausea on a scale ranging from 0 to 4 (nonexistent
to very severe) immediately after the trial. Furthermore,
all of the subjects were asked whether they would participate in a future trial on human endotoxemia.
Data analysis. Changes in body temperature were
defined a priori as the main outcome variable. Normal
distribution of all parameters was tested with use of the
Kolmogorov-Smirnov test. Because data were not normally distributed, nonparametric tests were applied.
Serial measurements within groups were tested for significance with the Friedman ANOVA and the Wilcoxon
signed-rank test. Differences among groups were analyzed with use of the Kruskal-Wallis ANOVA and the
Mann-Whitney U test for post hoc comparisons. Values are reported as mean values SEM.
RESULTS
Demographic data and baseline values for temperature and hemodynamics were not different among
groups (Table I).

Pernerstorfer et al

53

Plasma levels of aspirin and acetaminophen. Mean

acetaminophen levels peaked at 44 3 mol/L. Salicylate levels averaged 221 25 mol/L and remained at
that level until 3 hours (218 27 mol/L) after aspirin
administration (Fig 1).
Fever. The body temperature started to increase 2
hours after lipopolysaccharide administration (Fig 1).
Fever peaked 4 hours after injection of 4 ng/kg endotoxin irrespective of pretreatment. At 4 hours the body
temperature reached 38.5C 0.1C in the placebo
group, 37.6C 0.2C in the acetaminophen group
(P = .001 versus placebo), and 38.6C 0.2C in subjects treated with aspirin (P = .001 versus acetaminophen). Aspirin delayed the increase in body temperature by only 1 hour (P = .012 versus placebo).
Therefore pretreatment with acetaminophen compared
with aspirin and placebo significantly attenuated the
febrile response after endotoxin challenge (Fig 1).
Hemodynamic response. Increases in heart rate were
more pronounced in the placebo group ( 8 2 versus
0 2 versus 0 1 beats/min for placebo, acetaminophen, and aspirin, P = .02 and P = .003 for comparisons between placebo and either treatment group,
respectively) at 2 hours after endotoxin injection. Maximum increases in heart rate were observed 4 to 5 hours
after endotoxin injection and paralleled the course of
body temperature in all groups ( 30 3 beats/min in
the placebo group, 29 4 beats/min in the aspirin
group, and 21 6 beats/min for the acetaminophen
group (P < .01 versus baseline for all groups, no differences between the groups, Fig 1).
The mean arterial pressure decreased moderately by
10% 1.5% (pooled data from all groups, P > .05 versus baseline), reaching a minimum at 8 hours after
injection of endotoxin.
Cortisol response. As a measure of stress response,
we measured plasma levels of cortisol. Cortisol plasma
levels increased in all groups at 2 and 4 hours after endotoxin administration to approximately 150% and 200%
over baseline, with somewhat smaller increases in the
acetaminophen group (placebo, from 331 130 nmol/L
to 701 132 nmol/L; acetaminophen, from 331 77
nmol/L to 546 226 nmol/L; aspirin, from 373 105
nmol/L to 718 265 nmol/L at baseline and at 4 hours,
respectively; P = .088 acetaminophen versus placebo).
Cytokine responses. As expected, TNF-, IL-6, and
IL-8 levels rose by several orders of magnitude (P <
.001 versus baseline in all groups) (Fig 2). No significant intergroup differences were detected (Fig 2).
Subjective symptoms. Subjective symptom scores for
chills and the perception of fever were higher in the
placebo group than in subjects pretreated with aceta-

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JULY 1999

54 Pernerstorfer et al

Table I. Demographic variables and baseline values for body temperature and hemodynamics
Placebo (n = 10)

Age (y)
Height (cm)
Weight (kg)
Body mass index
Body temperature (C)
Heart rate (beats/min)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)

Acetaminophen (n = 10)

Aspirin (n = 10)

Mean

Range

Mean

Range

Mean

Range

25.7
179
71.7
22.4
36.3
66
119
61

20.1-37.8
165-189
63-87
20.3-24.8
35.5-37.3
56-74
109-131
53-72

26.9
181
79.5
24.2
36.2
66
125
68

20.4-37
174-190
64-98
21.1-27.2
34.7-37.2
46-92
113-134
56-76

29.8
177
77.2
24.7
36.0
69
124
70

21-37.8
168-184
69-90
22.2-27.1
35.2-36.8
59-86
109-139
57-84

P > .05 for comparisons between the groups (Kruskal-Wallis ANOVA).

minophen (chills, 2.5 0.3 versus 1.0 0.2, P = .009;

fever, 2.5 0.2 versus 2.0 0.2, P = .021). Symptom
scores in the subjects pretreated with aspirin were not significantly lower than those in the placebo group. Scores
for myalgia, cephalgia, and nausea were indistinguishable between the groups. When asked for their readiness
to participate in another lipopolysaccharide trial, one third
of all study subjects indicated no objection, whereas
another third would abstain. The remainder were undecided immediately after this trial was complete.
DISCUSSION
To our knowledge, this is the first study to directly
compare the antipyretic efficacy of the two most commonly used over-the-counter drugs for fever in adults.
The principal finding of our study was that acetaminophen exhibited superior antipyretic activity compared with aspirin in experimental endotoxemia (Fig
1). The difference in antipyretic activity between acetaminophen and aspirin was unexpected and in contrast
to the general assumption of equipotence.27-29
In general, a single 1000-mg dose of either drug is
considered to cause sufficient antipyretic activity. Both
drugs are comparable in pharmacokinetic behavior, and
biologically effective plasma levels after oral ingestion
are reached within 30 minutes.24,30,31 Salicylate concentrations in our trial were maintained at levels of
antipyretic activity for approximately 3 hours. However, increasing aspirin doses may disproportionally
enlarge the pool of unbound salicylic acid.32 Because
free drug levels determine the antipyretic activity, this
may indicate that, in this particular model, higher doses
of aspirin than currently used would have been needed.
It is interesting that the generalization of equal
antipyretic efficacy was mostly derived from pediatric
studies.14,33,34 In children an approximate 30% lower
volume of distribution for salicylates35 compared with
adults36 may result in its higher plasma levels.

Furthermore it has been estimated that fever in children is caused by bacteria in approximately 30% of all
cases.33 The heterogenous cause in these patients may
therefore at least partially explain the discrepancy from
our findings. In some of these studies patients were concomitantly treated with antibiotics, which may present
an additional confounding effect.14,37
Finally, both drugs were introduced into clinical routine for adults before controlled trials became the gold
standard of clinical pharmacology of clinical drug evaluation, which may account for the lack of placebocontrolled trials that directly compared the two drugs.38
Cardiovascular response. The differences in temperature were closely mirrored by a blunted increase in
heart rate in the acetaminophen group (Fig 1). There
may be two determinants of heart rate increases during
endotoxemia. The early upstroke in pulse rate could be
the result of the increases in body temperature because
aspirin and acetaminophen suppressed both fever and
heart rate at 2 hours after lipopolysaccharide administration. It is conceivable that vasodilation, as indicated
by the decreased diastolic blood pressure, may be an
additional determinant of heart rate during endotoxemia.
Accordingly, mean arterial pressure in the subjects
in this study declined by less than 10% throughout the
entire study period, suggesting fairly unchanged cardiovascular function. Although this minor decline in
arterial blood pressure occurred equally in all groups,
a blunted increase in heart rate was noted only in the
subjects treated with acetaminophen who also showed
an attenuated febrile response. Because we did not measure cardiac output, we cannot answer whether effective antipyretic therapy could have influenced cardiac
output by changes in stroke volume. Still, we assume
that acetaminophen not only reduced the extent of the
febrile response but also blunted the cardiovascular
response. Our data are in general agreement with a
well-established rule of thumb that for every lC

CLINICAL PHARMACOLOGY & THERAPEUTICS

VOLUME 66, NUMBER 1

Fig 1. Top panel, Plasma levels (mean values SEM) of

acetaminophen (INN, paracetamol; solid squares) and aspirin
(open circles) before and during endotoxemia (4 ng/mL
lipopolysaccharide [LPS]) in human volunteers after oral premedication with either placebo, 1000 mg acetaminophen, or
1000 mg aspirin (n = 10 per group). Middle panel, Tympanic
body temperature before and during endotoxemia (4 ng/mL
lipopolysaccharide) in human volunteers after oral premedication with either placebo (open triangles), 1000 mg acetaminophen (solid squares), or 1000 mg aspirin (open circles).
Bottom panel, heart rate before and during endotoxemia
(4 ng/mL lipopolysaccharide) in human volunteers after oral
premedication with either placebo (open triangles), 1000 mg
acetaminophen (solid squares), or 1000 mg aspirin (open
circles). *P < .05, acetaminophen versus placebo; #P < .05,
aspirin versus placebo.

increase of body temperature, an increase of the heart

rate by 8 beats/min is expected (Liebermeister rule).39
We therefore assume that the increased heart rate in
endotoxemia is at least partly dependent on the degree
of the febrile response. Consequently, it may be
assumed that effective antipyresis not only reduces
heart rate, as observed in our study population, but may

Pernerstorfer et al

55

Fig 2. Top panel, Plasma levels (mean values SEM) of

tumor necrosis factor (TNF-) before and during endotoxemia (4 ng/mL lipopolysaccharide) in human volunteers after
oral premedication with either placebo (open triangles), 1000
mg acetaminophen (solid squares), or 1000 mg aspirin (open
circles). Middle panel, Plasma levels of interleukin-6 (IL-6).
Bottom panel, Plasma levels of interleukin-8 (IL-8).

also blunt the metabolic response, going along with

increased energy demand in this situation. Therefore
the effect of antipyretic therapy in endotoxemia on this
metabolic response should be the subject of additional,
more invasive investigations.
Levels of pyrogenic cytokines. It is interesting that
pretreatment with ibuprofen or indomethacin (INN,
indometacin) heightens lipopolysaccharide-induced
plasma levels of TNF-, IL-6, and IL-8 in human
volunteers.11,12,40 In contrast to ibuprofen or
indomethacin,11,12 a standard dose of 1000 mg aspirin
had no effect on the plasma levels of pyrogenic
cytokines in our study. Along these lines, salicylates
have been shown to inhibit nuclear translocation of
nuclear factor kappa B (NF--B) in lipopolysaccharide-

CLINICAL PHARMACOLOGY & THERAPEUTICS

JULY 1999

56 Pernerstorfer et al

treated monocytes, which resulted in reduced TNF-

release.41,42 It was therefore tempting to speculate that
aspirin could exhibit even more pronounced antiinflammatory activity than ibuprofen because it may
dampen the release of proinflammatory cytokines in
this model of human endotoxemia. Plasma levels of salicylic acid were in the expected range of approximately
220 mol/L at the time of maximal febrile response.
Again, this may indicate that in the lipopolysaccharideinduced febrile response substantially higher doses of
aspirin than those currently used would be needed.
Alternatively, it may be that during endotoxemia different nonsteroidal anti-inflammatory drugs have intrinsic effects on the production of cytokines.
As expected from the weak anti-inflammatory action
of acetaminophen, the increase in plasma levels of circulating cytokines and cortisol was not dampened. Our
findings therefore underscore that acetaminophen
inhibits mediators of fever downstream from established pyrogens such as IL-6, IL-8, and TNF- or stress
hormones such as cortisol. Acetaminophen is considered to exert its antipyretic activity by blocking
prostaglandin E2 production from cyclooxygenases in
the brain.6,7,43 Recent animal studies suggest the presence of constitutively expressed cyclooxygenase-2
(COX-2) in endothelial cells of the brain vasculature,
which releases prostaglandin E2 after lipopolysaccharide administration.8,44,45 We therefore speculate that
the superior antipyretic activity of acetaminophen
might be explained by its approximately 20 times
higher ratio of COX-2/COX-1 activity compared with
aspirin.46 Clinical studies with highly COX-2-selective
nonsteroidal anti-inflammatory drugs should be able
to elucidate whether fever is also mediated by
COX-2dependent prostaglandin E2 production in
humans.47
Finally, our results showing that acetaminophen alleviates lipopolysaccharide-induced fever and subjective
symptoms without compromising the humoral
response could help to improve the lipopolysaccharide
model. Because this model can be used to test a variety of anti-inflammatory or anticoagulatory drugs, pretreatment of healthy volunteers with acetaminophen
may increase the acceptance of this model for clinical
pharmacology studies.
In conclusion, acetaminophen exhibited a more pronounced antipyretic effect than aspirin, which was also
reflected in less severe subjective symptoms. Furthermore, unchanged levels of cytokines, despite effective
acetaminophen treatment, suggest that the alleviation
of fever and chills does not alter the humoral response
of a subject to endotoxemia.

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