REVIEW

Antipyretics: Mechanisms of Action and Clinical

Use in Fever Suppression
David M. Aronoff, MD, Eric G. Neilson, MD
Fever is a complex physiologic response triggered by infectious
or aseptic stimuli. Elevations in body temperature occur when
concentrations of prostaglandin E
2
(PGE
2
) increase within cer-
tain areas of the brain. These elevations alter the ring rate of
neurons that control thermoregulation in the hypothalamus.
Although fever benets the nonspecic immune response to
invading microorganisms, it is also viewed as a source of dis-
comfort and is commonly suppressed with antipyretic medica-
tion. Antipyretics such as aspirin have been widely used since
the late 19th century, but the mechanisms by which they relieve
fever have only been characterized in the last few decades. It is
now clear that most antipyretics work by inhibiting the enzyme
cyclooxygenase and reducing the levels of PGE
2
within the hy-
pothalamus. Recently, other mechanisms of action for antipy-
retic drugs have beensuggested, including their ability to reduce
proinammatory mediators, enhance anti-inammatory sig-
nals at sites of injury, or boost antipyretic messages within the
brain. Although the complex biologic actions of antipyretic
agents are better understood, the indications for their clinical
use are less clear. They may not be indicated for all febrile con-
ditions because some paradoxically contribute to patient dis-
comfort, interfere with accurately assessing patients receiving
antimicrobials, or predispose patients to adverse effects from
other medications. The development of more selective fever-
relieving agents and their prudent use with attention to possible
untoward consequences are important to the future quality of
clinical medicine. Am J Med. 2001;111:304315. 2001 by
Excerpta Medica, Inc.
Humanity has but three great enemies: fever, famine,
and war, and of these by far the greatest, by far the most
terrible, is fever
T
his bon mot from Osler cleverly paints the pall of
apprehension felt by those who attend febrile pa-
tients at the bedside. Practitioners still debate the
role or value of fever in disease, and even iatrogenic pyr-
exia undergoes periodic revival (1). As victor or villain,
perhaps no symptomhas been viewed so dichotomously.
Fever today is generally regarded as a form of patient
discomfort. Among acts of caring, pyrexia is treatable,
and so it often is treated.
Physicians since antiquity have used various physical
means to lower body temperature (2). Applying Peruvian
cinchona bark as an antipyretic dates to the early 1600s
(3), but by the 18th century overharvesting of cinchona
created scarcity (4) and a search for substitutes. In 1763,
Reverend Stone reported to the Royal Society of London
on the antipyretic effects of fever bark from English
willow(4). Althoughhis nding appearednovel, it simply
conrmed what was known to Hippocrates, Galen, and
ancient Egyptians centuries before (5,6). Salicylic acid
was rst prepared in 1838 from the glucoside salicin, the
active component in willow bark (5,7). Another deriva-
tive, acetylsalicylic acid (aspirin) was later synthesized in
1853 and made commercially available as an antipyretic
in 1899 (2,5). Since then, numerous antipyretics have
been introduced into clinical medicine.
The prescription of acetaminophen for fever is more
recent. Although precursors such as acetanilid and phen-
acetine were developed in the second half of the 19th
century, the popular use of acetaminophen as an antipy-
retic and analgesic did not occur until the 1950s (8). The
antipyretics in common use today include acetamino-
phen, aspirin, and other nonsteroidal anti-inammatory
drugs (NSAIDs). The principal actionof antipyretics rests
in their ability to inhibit the enzyme cyclooxygenase
(COX) and interrupt the synthesis of inammatory pros-
taglandins (9). Recent studies on the mechanism of anti-
pyretic action of these drugs, however, reveal effects in-
dependent of COX inhibition as well.
We review here the mechanisms of commonly used
antipyretics, emphasizing their ability to block the febrile
response at multiple sites along a physiologic cascade that
connects peripheral inammation with the central ner-
vous system, and conclude with some thoughts on the
proper use of antipyretics for patients with fever.
From the Divisions of Infectious Diseases and Clinical Pharmacology
and the Departments of Medicine and Cell Biology, Vanderbilt Univer-
sity School of Medicine, Nashville, Tennessee.
Requests for reprints should be addressed to David M. Aronoff, MD,
Division of Clinical Pharmacology, 514 RRB, 23rd Avenue at Pierce,
Nashville, Tennessee 37232-6603.
Supported in part by Grants GM-15431, DK-46282, and GM-07569
from the National Institutes of Health, and the Tinsley Harrison Soci-
ety.
Manuscript submitted March 27, 2001, and accepted in revised form
June 6, 2001.
304 2001 by Excerpta Medica, Inc. 0002-9343/01/$see front matter
All rights reserved. PII S0002-9343(01)00834-8
NORMAL THERMOREGULATION
Normal body temperature is circadian and varies froman
approximate low of 36.4C (97.6F) in the morning to a
high of 36.9C (98.5F) in the late afternoon (10). At the
heart of thermoregulation is an integrated network of
neural connections involving the hypothalamus, limbic
system, lower brainstem, the reticular formation, spinal
cord, and the sympathetic ganglia (11). An area in and
near the rostral hypothalamus is also important in or-
chestrating thermoregulation. This region, the preoptic
area, includes the preoptic nuclei of the anterior hypo-
thalamus (POAH) and the septum.
In simple terms, the POAHmaintains mean body tem-
perature around a set point. This thermoneutral set point
temperature is modulated by the balanced activities of
temperature-sensitive neurons. These neurons integrate
afferent messages regarding core body and peripheral
(skin) temperatures and evoke various behavioral and
physiologic responses controlling heat production or dis-
sipation (11).
Fever describes a regulated rise in body temperature
after an increase in the hypothalamic set point (12). Un-
der the inuence of the hypothalamus, physiologic and
behavioral functions favoring heat production and heat
retention are stimulated until arriving at a newly elevated
set point temperature (12). Typical early behavioral
changes prior to fever include seeking a warmer environ-
ment or adding clothing. Physiologic alterations include
cutaneous vasoconstriction, shivering, and nonshivering
thermogenesis through enhanced release of thyroid hor-
mones, glucocorticoids, and catecholamines (11). Upon
reaching the elevated set point of fever, an increase or
decrease in core temperature will stimulate thermoregu-
latory mechanisms similar to those evoked at normal
body temperature (5). In other words, normal thermo-
regulation modulates at this higher set point.
THE PATHOGENESIS OF FEVER
Many of the mediators underlying pyrexia have been de-
scribed in recent years (Figure 1). The critical endoge-
nous pyrogens involved in producing a highly regulated
inammatory response to tissue injury and infection are
polypeptide cytokines. Pyrogenic cytokines, such as in-
terleukin-1 (IL-1), tumor necrosis factor (TNF), and
interleukin-6 (IL-6), are those that act directly on the
hypothalamus to effect a fever response (13). Exogenous
pyrogens, such as microbial surface components, evoke
pyrexia most commonly through the stimulation of py-
rogenic cytokines. The gram-negative bacterial outer
membrane lipopolysaccharide (endotoxin), however, is
capable of functioning at the level of the hypothalamus,
in much the same way as IL-1 (14).
These signals trigger the release of other mediators,
most notably prostaglandin E
2
(PGE
2
), in the region of
the POAH (12). PGE
2
is believed to be the proximal me-
diator of the febrile response. Preoptic neurons bearing
E-prostanoid receptors alter their intrinsic ring rate in
response to PGE
2
, evoking an elevation in the thermoreg-
ulatory set point. There are four known cellular receptors
for PGE
2
: EP
1
through EP
4
(15). The particular receptor
subtype involved in pyrogenesis is unknown. Although
mice lacking the neuronal PGE
2
receptor subtype EP
3
demonstrate an impaired febrile response to both exoge-
nous (endotoxin) and endogenous pyrogens (15), studies
in rats appear to implicate the EP
4
receptor (16). The
intracellular events triggering pyrexia after PGE
2
-EP re-
ceptor coupling among species are unclear.
Fever is tightly regulated by the immune response. In-
ammatory stimuli triggering the generation of propy-
retic messages provoke the release of endogenous antipy-
retic substances (17). Substances such as arginine vaso-
pressin (AVP), -melanocyte stimulating hormone, and
glucocorticoids act both centrally and peripherally to
limit pyrexia (17). The cytokine interleukin-10 (IL-10)
has numerous anti-inammatory properties, including
fever suppression (18,19). In addition, a class of lipid
compounds known as epoxyeicosanoids generated by
certain cytochrome P-450 enzymes play an important
role in limiting the fever and inammation (20) [re-
viewed in (21)].
Analogous to a biochemical feedback pathway, fever
itself appears capable of countering the release of pyro-
genic cytokines (22,23). For example, febrile tempera-
tures augment early TNF release inendotoxin-challenged
mice, yet limit its prolonged (and perhaps detrimental)
expression after either lipopolysaccharide injection or
bacterial infection (22,23).
THE ROLE OF PROSTAGLANDINE
2
PGE
2
is synthesized from arachidonic acid, which is re-
leased from cell membrane lipid by phospholipase. Ara-
chidonic acid is metabolized by two isoforms of the COX
enzyme, COX-1 and COX-2. COX-1 usually is expressed
constitutively and generates prostanoids important to
housekeeping functions supporting homeostasis (24).
COX-2, on the other hand, is inducible by inammatory
signals such as the pyrogenic cytokines, IL-1, TNF, and
IL-6, and bacterial lipopolysaccharide (24). Genetically
engineered mice that lack either the COX-1 or COX-2
gene demonstrate that the inducible isoform is responsi-
ble for hypothalamic PGE
2
production during a febrile
response (25). As COX-2 is the key provider of PGE
2
during pyrexia, it is not surprising that the selective
COX-2 antagonist, rofecoxib, is an effective antipyretic in
humans (26).
Antipyretics/Aronoff and Neilson
September 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 111 305
Many cells, including synoviocytes, macrophages, en-
dothelial cells, and chondrocytes, have the capacity to
rapidly up-regulate the expression of the COX-2 during
inammation (24). The most likely cell type in the central
nervous system responsible for producing PGE
2
is the
microvascular endothelial cell, which expresses COX-2
exuberantly after stress (25,27,28).
An effective febrifuge might interrupt pyrexogenesis at
any step that connects peripheral inammation with the
central production of PGE
2
. Stated differently, an antipy-
retic might blunt peripheral inammation or depress
central pyrogenic signals, or affect both. Inhibiting cen-
tral production of PGE
2
is a well-known mechanism of
antipyretic agents, but activated leukocytes and endothe-
lial cells in peripheral areas of inammation also repre-
sent potential drug targets (Table 1).
THE CYCLOOXYGENASE HYPOTHESIS
The antipyretic drug aspirin was in wide clinical use for
more than 70 years (9) before Vane (29) demonstrated in
1971 that it exerted its physiologic action by inhibiting
the production of prostaglandins. Further work suggests
a current model of howaspirin and similar NSAIDs act as
antipyretics.
Aspirin interferes with the biosynthesis of cyclic pro-
stanoids derived from arachidonic acid, such as throm-
boxane A
2
and prostaglandins (30). As a nonselective
COX inhibitor, aspirin has been widely studied for its
anti-inammatory, antipyretic, and antithrombotic
traits. The major mechanism of action of aspirin and
other antipyretics involves lowering PGE
2
by directly in-
hibiting COX enzyme activity (31). Worth noting, how-
Figure 1. Fever generation after infection. Microbial tissue invasion sparks an inammatory response and activates local vascular
endothelial cells and leukocytes. The extravasation of white blood cells into inamed areas depends on a multistep interaction with
endothelial cells regulated by a variety of cytokines, chemokines, and adhesion molecules. Activated leukocytes release the pyrogenic
cytokines interleukin-1 (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6). Hematogenous dissemination (depicted
here) allows these endogenous pyrogens to stimulate vascular endothelial cell production of prostaglandin E
2
(PGE
2
) within the
central nervous system. Peripheral inammatory signals may also travel along neural connections (such as the vagus nerve) to trigger
central nervous system PGE
2
production (96). Neurons within the preoptic area of the anterior hypothalamus (POAH) bearing
specic E-prostanoid receptors orchestrate the febrile response after the PGE
2
signal. PGE
2
alters the ring rate of these neurons,
resulting inanelevatedthermoregulatory set point. The febrile set point body temperature is reachedthroughthe regulatedevocation
of behavioral and physiologic changes aimed at enhancing heat production and reducing heat dissipation. Fever is believed to
augment the peripheral and systemic inammatory response to infection in part by modulating the expression of inammatory
cytokines and enhancing leukocyte function.
Antipyretics/Aronoff and Neilson
306 September 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 111
ever, is that sodiumsalicylate, aspirins major metabolite,
exhibits similar antipyretic and anti-inammatory prop-
erties as aspirin but shows only weak inhibition of COX-1
and COX-2 in vitro (32,33).
NSAIDs are also capable of reducing PGE
2
production
by down-regulating the expression of COX enzymes, as
opposed to directly inhibiting their enzymatic action. So-
dium salicylate and aspirin also inhibit COX-2 transcrip-
tion induced by lipopolysaccharide and IL-1 (34). The
clinical effects of sodiumsalicylate are likely due inpart to
its actions on COX gene transcription by disabling the
transcriptional activator nuclear factor-B(NF-B) (34).
NF-B is a heterodimeric protein capable of binding
DNA in the 5-promoter regions of many genes involved
in the inammatory response (35). Once bound, NF-B
facilitates the transcription of genes encoding pyrogenic
cytokines, chemokines, adhesion molecules, and inam-
matory enzymes, including inducible nitric oxide syn-
thase and COX-2 in certain cell types (35,36). NF-B re-
sides in an inactive state in the cytoplasm, complexed to
another protein, IB (37). Upon activation, the IB si-
lencer is sequentially phosphorylated, ubiquinated, and
degraded, releasing NF-Bto translocate into the nucleus
(35).
Salicylates reduce the nuclear translocation of NF-B
through stabilization of cytoplasmic IB (38) by interfer-
ing with its phosphorylation (Figure 2) (39). The ability
of antipyretics to disable transcription varies among
agents and cell type studied. Salicylate and its progenitor
aspirin prevent NF-B translocation in endothelial cells
and leukocytes induced by proinammatory cytokines or
lipopolysaccharide (3842). NSAIDs like ibuprofen also
block the nuclear trafcking of NF-B in certain tumor
cell lines (43) but fail to do so in activated macrophages
(38). Indomethacin, another COXinhibitor, does not ap-
pear to affect NF-B (41,42), and therapeutic doses of
acetaminophen also fail to suppress it (41,44). The reason
for this heterogeneity is unknown.
An NF-B/IB mechanismfor COX-2 expression may
not be the whole story, either, as the COX-2 gene is not
solely dependent on activation by the NF-B cascade
(36). In human microvascular endothelial cells, for ex-
ample, COX-2 activation by IL-1 occurs independently
of NF-B through other transcriptional activators (36).
NONCYCLOOXYGENASE TARGETS FOR
ANTIPYRETICS
Interestingly, clinically useful actions of antipyretics may
also be COXindependent (45), and relevant anti-inam-
matory effects of aspirin, sodium salicylate, and other
NSAIDs are seen only with doses much higher than those
required to suppress COXactivity (46). Thus, a variety of
noncyclooxygenase-dependent functions have been pro-
posed to explain the full effects of salicylates on the pyro-
genic cascade (Table 2). For example, salicylates and
other antipyretics also suppress tissue inammation
through diminished leukocyte-endothelial cell interac-
tions (39), reduced pyrogenic cytokine production (38),
or enhanced expression of anti-inammatory molecules
(45,47). Other mechanisms, such as boosting the activity
of endogenous antipyretic messengers, may further con-
tribute (Figure 3) (48). We consider each of these puta-
tive actions in turn.
EFFECTS ONLEUKOCYTES AND
ENDOTHELIAL CELLS
Fever frequently begins with inammation in peripheral
tissues (Figure 1). Infectious and noninfectious diseases
Table 1. Putative Targets and Mechanisms of Action for Antipyretic Medications
Neutrophils, macrophages, and other immune effector cells:
Reduced production of inammatory mediators (such as cytokines, proteases, and reactive oxygen species)
Enhanced local production of anti-inammatory molecules (such as adenosine, aspirin-triggered lipoxins, interleukin-10)
Endothelial cells at sites of local infection/inammation:
Reduced expression of leukocyte adhesion molecules
Endothelial cells of the central nervous system:
Reduced prostaglandin E
2
production (cyclooxygenase inhibition)
Endogenous antipyretics:
Enhanced production or activity of arginine vasopressin, -melanocyte stimulating hormone, glucocorticoids, and
epoxyeicosanoids
Table 2. Evidence Supporting Cyclooxygenase-independent Effects of Antipyretics
Ability of aspirin to inhibit inammation only at concentrations well above levels required to inhibit cyclooxygenase (COX)
Ability of sodium salicylate, a poor COX inhibitor, to block fever at concentrations similar to those required for aspirin
Recognition of immunomodulatory properties of aspirin and related NSAIDs apart from COX inhibition
NSAIDs nonsteroidal anti-inammatory drugs.
Antipyretics/Aronoff and Neilson
September 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 111 307
stimulate regional inammatory reactions involving ac-
tivated leukocytes and endothelial cells. Leukocyte adhe-
sion to, and migration through, activated vascular endo-
thelium can be inhibited by aspirin and other NSAIDs
(32,39,46,49). Aspirin and sodium salicylate, for exam-
ple, inhibit leukocyte accumulation at sites of tissue in-
jury (50).
Reduced Adhesion Molecule Expression
Ibuprofen, a relatively nonselective COX inhibitor, in-
hibits neutrophil adherence, swelling, aggregation, and
lysosomal enzyme release in high doses (51). Adherence
of peripheral blood monocytes, basophils, and mast cells
to pyrogen-stimulated human endothelial cells is also re-
duced by ibuprofen (IC
50
0.5 mM) (49). This antipyretic
reduces the expression of endothelial cell adhesion mol-
ecules (intercellular adhesion molecule-1 [ICAM-1] and
vascular cell adhesion molecule-1 [VCAM-1]) upon cy-
tokine stimulation, leading to depressed leukocyte at-
tachment (49). Ibuprofen also suppresses leukocyte mi-
gration through cytokine-activated endothelial cell
monolayers (52).
Expression of VCAM-1 or ICAM-1 in endothelial cells
is also inhibited by sodium salicylate and aspirin, with
associated defects in neutrophil adhesion and transmi-
Figure 2. Effects of antipyretics on gene transcription. The predominant mode of action of antipyretic drugs involves reducing
central nervous system concentrations of prostaglandin E
2
by directly inhibiting cyclooxygenase. Another postulated mechanism
involves suppressive effects on inammatory gene expression. Aspirin and sodiumsalicylate reduce the activity of the transcriptional
regulator NF-B, a heterodimeric protein that resides in an inactive state in the cytoplasm, complexed to another protein, IB. When
endothelial cells or leukocytes are appropriately stimulated (by proinammatory cytokines or gram-negative bacterial lipopolysac-
charide depictedhere), the IBsilencer is phosphorylatedby the proteinIBkinase, thenubiquinatedanddegraded, releasing NF-B
to translocate into the nucleus. In many cell types, NF-B promotes the expression of cyclooxygenase, pyrogenic cytokines, and
endothelial/leukocyte adhesion molecules involved in the febrile response. Sodium salicylate and its parent compound, aspirin,
reduce the translocation of NF-B through stabilization of cytoplasmic IB by interfering with its phosphorylation, effectively
preventing active NF-B from entering the cell nucleus (red arrow). This effect is not characteristic of all nonsteroidal anti-
inammatory agents, however, and is not shared by therapeutic doses of acetaminophen. AA arachidonic acid; COX cycloox-
ygenase; IL interleukin; PGH
2
prostaglandin H
2
; TLRtoll-like receptor for lipopolysaccharide; TNF tumor necrosis factor.
Antipyretics/Aronoff and Neilson
308 September 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 111
gration through cytokine-stimulated endothelial mono-
layers (39,53). Additionally, human monocyte expres-
sion of ICAM-1 induced by lipopolysaccharide is inhib-
ited by sodium salicylate (54). L-selectin, an adhesion
molecule that mediates rolling of leukocytes along vascu-
lar endothelium, is rapidly shed from circulating neutro-
phils in response to treatment with aspirin and other
NSAIDs (55).
Although the mechanismunderlying the NSAIDeffect
on leukocyte-endothelial cell adhesion is incomplete, the
reduction in VCAM-1 and ICAM-1 expression is associ-
ated with reduced endothelial transcription, suggesting
an effect on gene regulation (39,49). NF-B can activate
the expression of adhesion molecules (39). As noted
above, inhibition of NF-B may be an important mech-
anism of action for certain NSAIDs and salicylates. Tem-
pering such a conclusion, however, is a human model of
systemic endotoxemia that failed to show an effect of
a single dose of aspirin on circulating endothelial and
leukocyte adhesion molecule concentrations (56). Dose-
response effectiveness in humans is unknown.
Diminished Cytokine Production
Cytokine production by cells of the immune system also
can be inhibited by antipyretics. More than 30 years ago,
it was demonstrated that endogenous pyrogen produc-
tion by leukocytes could be reduced by salicylates (57).
The intracellular events underpinning these results are
now understood.
Macrophage production of the pyrogenic cytokine
TNF is activated by inammatory stimuli such as expo-
sure to lipopolysaccharide. It has recently been observed
that both aspirin and salicylate, at high therapeutic con-
centrations (1 to 3 mM), inhibit the transcription and
Figure 3. Mechanisms of antipyresis. Antipyretics such as acetaminophen, aspirin, and related nonsteroidal anti-inammatory
drugs (NSAIDs) reduce fever by depressing inammatory messages at both peripheral sites of tissue inammation and within central
nervous system thermoregulatory sites. Peripherally, aspirin and other NSAIDs suppress production of pyrogenic cytokines such as
tumor necrosis factor and interleukin-1 and block endothelial cell/leukocyte interactions through effects on adhesion molecule
expression. These agents also promote the creation of anti-inammatory molecules such as adenosine and aspirin-triggered lipoxins.
Centrally, antipyretics lower the thermoregulatory set point primarily by blocking cyclooxygenase production of prostaglandin E
2
(PGE
2
). Additional effects may stemfromprovoking the release of endogenous antipyretic compounds such as arginine vasopressin.
Acetaminophen differs from other antipyretic agents by its inability to reduce peripheral inammation and its lack of effect on
endogenous antipyretics.
Antipyretics/Aronoff and Neilson
September 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 111 309
secretion of TNF by murine macrophages exposed to li-
popolysaccharide (38). Similar data were found in acti-
vated human endothelial cells exposed to sodium salicy-
late (39). Not surprisingly, NF-B mediates enhanced
TNF production. As noted, these agents interrupt NF-B
nuclear translocation through stabilization of cytoplas-
mic IB (38). In agreement with these data, NF-B activ-
ity in endotoxin-stimulated human monocytes is dimin-
ished by ibuprofen, sulindac, aspirin, and sodium salicy-
late (54).
The antipyresis of NSAIDs also involves the activation
of the intracellular protein, heat shock factor-1 (HSF1).
HSF1 is anactivating polypeptide for the heat shock genes
in many cell types that also acts as a repressor of IL-1
gene transcription (54). Millimolar doses of sodium sa-
licylate and sulindac induce HSF1 activity and simulta-
neously reduce transcription of IL-1 in vitro (54).
Whether these effects oncytokine productionhave im-
portant clinical consequences remains unclear. The inu-
ence of antipyretics on circulating levels of pyrogenic cy-
tokines has been studied in human volunteers after lipo-
polysaccharide injection. With respect to TNF and IL-6,
both aspirin and acetaminophen have no effect on circu-
lating levels (58), whereas ibuprofeneither does not affect
or increases cytokinemia in this model (5961). Impor-
tantly, the intravenous injection of endotoxin provokes a
tremendous systemic inammatory response not charac-
teristic of most fever-producing diseases. Clinical studies
of localized inammation are necessary to further evalu-
ate the effects of antipyretics on peripheral cytokine gen-
eration.
Stimulation of Anti-inammatory Mediators
Another hypothesis explaining the impaired leukocyte
adhesionor accumulationseenwith aspirinand salicylate
during inammation involves the anti-inammatory
mediator adenosine. Aspirin and sodium salicylate cause
leukocytes to produce adenosine at sites of inammation,
and the effect can be reversed by endogenous adenosine
deaminase (45,50,53). Adenosine is an autacoid that
some investigators believe mediates the immunosuppres-
sive effects of methotrexate andsulfasalazine (62). Ingen-
eral, salicylates promote the breakdown of intracellular
adenosine triphosphate (ATP) and extracellular release
of adenosine (53). Adenosine acts through four known
receptors and inhibits polymorphonuclear leukocyte ad-
herence, superoxide generation, phagocytosis, and secre-
tion (63). The adenosine-mediated effects of salicylates
may represent an important anti-inammatory mecha-
nism for this class of agents.
Another hypothesis regarding aspirins ability to in-
hibit leukocyte function involves alterations in eico-
sanoid biosynthesis independent of PGE
2
(64). Aspirin
inhibits COX-2 through an irreversible acetylation reac-
tion. In so doing, traditional COX-2 activity is shifted to
produce 15R-hydroxyeicosatetraenoic acid from arachi-
donic acid (64). Human neutrophils are able to use this
compound to make 15-epi-lipoxin A
4
and 15-epi-li-
poxin-B
4
(47,64). These compounds are known as aspi-
rin-triggered lipoxins (ATL) and share physiologic prop-
erties with the endogenous enantiomers lipoxin A
4
and
lipoxin B
4
(47). ATLs display potent anti-inammatory
effects and interrupt neutrophil chemotaxis, transmigra-
tion through endothelial and epithelial cell layers, and
diapedesis from postcapillary venules (47). Recently li-
poxin A
4
analogs were shown to inhibit adhesion of hu-
man neutrophils to endotoxin-activated endothelial cells
(65).
EFFECTS ONENDOGENOUS
ANTIPYRETICS
Enhancing the production of the bodys own antipyretic
mediators would appear to be a useful method for reduc-
ing fever. As noted, hormones such as hypothalamic AVP
(5), -melanocyte stimulating hormone, and glucocorti-
coids are capable of buffering the magnitude of the febrile
response. AVP participates in the antipyretic mecha-
nisms of salicylates and related NSAIDs, but not acet-
aminophen (48,66,67). The antipyretic effect of sodium
salicylate and indomethacin is blocked by administration
of an AVP V
1
-receptor antagonist (48,66). Interestingly,
the degree of fever inhibition by acetaminophen is not
inuenced by V
1
-receptor blockade. In fact, the antipy-
retic response to indomethacin in rats is accompanied by
an increase in hypothalamic AVP, whereas acetamino-
phen does not alter central AVP concentrations (67).
The epoxyeicosanoids are a class of endogenous anti-
pyretic compounds that may facilitate the action of fever-
suppressing medications. These substances are derived
from arachidonic acid not by COX but by cytochrome
P-450 mono-oxygenase enzymes. It has been postulated
that aspirin enhances the effect of epoxyeicosanoids
through induction of cytochrome P-450 isoforms (20).
Acetaminophen
Acetaminophen is an analgesic that deserves special com-
ment because it is an effective febrifuge but a weak anti-
inammatory drug (68). Its effects differ considerably
from salicylates and other NSAIDs. As opposed to
aspirin, acetaminophen is a poor inhibitor of platelet
function. Believed to be an inhibitor of cyclooxygenase,
acetaminophens mechanism of action is still poorly un-
derstood. Although suprapharmacologic doses of acet-
aminophen inhibit NF-B stimulation of inducible nitric
oxide synthase (44), it does not possess the same inhibi-
tory effects on NF-Bmediated gene transcription that
salicylates enjoy (38).
Explanation of the antipyretic and analgesic actions of
acetaminophen has been based on tissue-specic COX
Antipyretics/Aronoff and Neilson
310 September 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 111
inhibition not seen with NSAIDs (31). Acetaminophen
penetrates the blood-brain barrier, achieving cerebrospi-
nal uid levels comparable to those in serum (69), and
may act preferentially within the central nervous system
(31). Central nervous system levels of PGE
2
rise during
fever and fall to normal levels upon administration of the
drug (70). Acetaminophen reduces the production of
prostaglandins in brain preparations more potently than
it does from other organs such as spleen (31,71).
In certain cell lines, acetaminophen weakly inhibits
COX-1 more than COX-2, but it is a poor inhibitor of
either isoenzyme (72,73). The in vitro anti-COX activity
of acetaminophendepends onthe availability of cofactors
such as glutathione and hydroquinone (73). Unlike the
majority of other NSAIDs, acetaminophen requires an
environment low in peroxides in order to inhibit COX
activity (74,75). Neurons may fulll this requirement, but
inamed peripheral tissues are ooded with leukocytes
that generate cellular peroxides (75). Thus, the tissue
specicity of acetaminophen may reect the intracellular
balance or availability of cofactors or inhibitors (73).
THE USE OF ANTIPYRETICS
Although the complex biochemistry of antipyretics is in-
creasingly understood, their indications for use are not.
Despite the pervasive application of antipyretics by phy-
sicians, nurses, pharmacists, and parents, it remains un-
clear whether reducing the core temperature benets fe-
brile patients (2). Animal models of infection demon-
strate that fever plays an important role in host defense
(23,76), and the potential salutary role of pyrexia in dis-
ease has been reviewed elsewhere (76,77).
There are certain groups of patients for whom antipy-
retics are routinely used out of concern that the risks of
fever may outweigh its benet. One such group is chil-
dren. Febrile seizures occur with a frequency of 2%to 5%
in children between 6 and 36 months of age (78). The
majority of children with febrile seizures have tempera-
tures above 39.0C at the time of convulsion (78). Pro-
phylaxis against febrile seizures of childhood has been
supported by many. A recent controlled trial using ibu-
profen to prevent recurrent febrile seizures failed (79),
however, as has acetaminophen (80).
Another group of patients felt to be at risk from the
deleterious effects of fever includes those with underlying
cardiopulmonary disorders (2). The metabolic cost of fe-
ver is substantial, particularly during the chill phase of
thermogenesis (2). Although antipyretics, by reducing
this metabolic burden, could help patients with impor-
tant cardiopulmonary disease, there are no experiments
to support this view (2). In fact, nearly 20 years ago, in-
domethacin given to patients with serious coronary ar-
tery disease decreased coronary blood ow, prompting
the authors to warn that indomethacin should be used
cautiously for patients with severe anginal symptoms
(81). It has also been observed that the repetitive sweating
of patients treated intermittently with antipyretics may
contribute to unwanted reductions in intravascular vol-
ume (82). That has led some to suggest dosing antipyret-
ics on a scheduled basis rather than pro re nata (2,82).
Perhaps the most common rationale for dispensing
antipyretics is providing comfort. However, febrile pa-
tients feel ill not simply because of an elevated tempera-
ture. In fact, an elevated body temperature per se may not
be particularly noxious, as evidenced by the popular use
of recreational saunas and hot tubs. Much of the discom-
fort during sickness arises from the symptoms accompa-
nying the inammatory response. Focal symptoms such
as cough, abdominal pain, and back pain can be discon-
certing, as can generalized symptoms such as anorexia,
arthralgias, headache, nausea, malaise, and myalgias. As a
consequence of additional anti-inammatory and anal-
gesic characteristics, agents such as acetaminophen, aspi-
rin, and other NSAIDs are capable of mollifying many of
these other somatic symptoms.
Fever, of course, is a surrogate marker for disease ac-
tivity in many infectious and inammatory disorders.
Squelching the febrile response removes a clinically im-
portant indicator of therapeutic efcacy. A small pediat-
ric study, for example, demonstrated that appropriate
changes in antibiotic regimens were delayed for children
receiving antipyretics compared with those who were not
(83).
Although some antipyretics depress the host immune
response to infection, evidence is sparse that these medi-
cations adversely affect the outcome of febrile illnesses in
humans. Animal models of infection show that antipy-
retic therapy increases the morbidity and mortality of the
host (77). Humanstudies, althoughmuchless controlled,
suggest the same (8488). The notion that antipyretics
depress the immune response to bacterial infections dates
to the mid-1960s when the activation of latent infection
was reported in patients after the use of NSAIDs (89).
Twenty years later, the development of fulminant necro-
tizing fasciitis and a 36% mortality rate were reported
among previously healthy persons exposed to therapeutic
doses of NSAIDs (84,87). In contrast, 48 hours of intra-
venous ibuprofen in a large trial of patients with sepsis
did not affect the incidence of organ failure or mortality
at 30 days (90). Interestingly, ibuprofen treatment dras-
tically reduced mortality among septic patients who were
hypothermic (91). This seemingly paradoxic increase in
survival (from 10% in the placebo-treated group to 46%
in the ibuprofen-treated group) is not understood but
perhaps related to the suppression of overwhelming in-
ammation by the NSAIDs.
Viral infection may also be affected by antipyresis. A
randomized trial with acetaminophen prolonged the
Antipyretics/Aronoff and Neilson
September 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 111 311
time to crusting of lesions in childhood varicella (85).
Aspirin increases the rate of virus shedding in patients
with rhinovirus-related common colds (88). It is notable
that IL-6 appears to modulate the host response and
symptom development after rhinovirus infection (92).
Rhinovirus stimulation of host IL-6 expression occurs
through an NF-Bmediated pathway (92). If the sup-
pressive effect of aspirin on NF-B activity is found to
occur in humans, this might explain the agents ability to
augment viral shedding. Studies of parasitic disease also
indicate that acetaminophen may lengthen the host re-
sponse to malaria in children (86).
Finally, similar to many other pharmaceuticals, anti-
pyretics also possess both direct and indirect toxicities.
N-acetylimidoquinone, a metabolite of acetaminophen,
has intrinsic hepatotoxic effects, particularly when the
recommended dose of the parent compound is exceeded
or the patient coingests other hepatotoxins such as etha-
nol. Concomitant use of medications, such as rifampin
and phenytointhat induce the cytochrome P-450 enzyme
system, may potentiate toxicity through enhanced me-
tabolism of acetaminophen to N-acetylimidoquinone.
NSAIDs, particularly those with substantial COX-1 in-
hibitory effects, are also potentially damaging to the kid-
neys and gastrointestinal tract (93). Athorough reviewof
the potential adverse effects of these medications is be-
yond the scope of this discussion.
RECOMMENDATIONS FOR THE USE OF
ANTIPYRETICS
If antipyretic effects were truly limited to reducing fever,
their use might be appropriate in few circumstances. For
example, treating fever in patients with underlying car-
diopulmonary disease might be reasonable, as discussed
above, assuming these patients cannot tolerate the dila-
tory effects of pyrexia (2,82). Patients suffering fromnon-
infectious febrile diseases (such as malignancy or autoim-
mune phenomena) might also be given antipyretics in an
effort to reduce their catabolic rates. Unfortunately, data
are not available to assess the efcacy of such practices.
Considering that fever may be animportant windowto
clinically relevant information, one approach to treating
acute febrile illnesses is to use alternative, nonantipyretic
medications for analgesia and symptom relief. Unfortu-
nately, few substitutes are available apart from oral nar-
cotic analgesics such as codeine, hydrocodone, and oxy-
codone, which are controversial. If antipyretics are used
during acute fevers, they should be prescribed ona sched-
uled basis, as opposed to as needed, for reasons noted
above. Of course, this approach requires careful attention
to the potential adverse effects induced by the antipyretic
agents themselves. Examples of scheduled regimens for
common antipyretic medications are listed in Table 3.
Deciding on a particular antipyretic also necessitates
considering toxicities and comorbid conditions. Predict-
ing temperature-lowering response to a given agent is
difcult. Although many head-to-head trials of antipy-
retics have been performed in pediatric groups, few data
exist for adults (58). On balance, pediatric studies dem-
onstrate equal efcacy, on a milligram-for-milligram ba-
sis, between acetaminophen and aspirin in reducing fever
(94). The ability of ibuprofen to decrease fever in chil-
dren, onthe other hand, appears to be 50%to 100%more
potent than that of acetaminophen (95). Adult trials are
conicting, although a recent single-dose study with en-
dotoxin-challenged volunteers suggests that acetamino-
phen is superior to aspirin for endotoxemia (58).
SUMMARY
The antipyretic effects of acetaminophen, aspirin, and
other NSAIDs are complex and repress inammatory sig-
nals at many levels. Although COX enzyme inhibition
plays a central role in the antipyretic actions of these
drugs, other immunomodulatory actions appear to con-
tribute. As our understanding of these medications deep-
ens, indications for their use in treating febrile patients
may also change.
ACKNOWLEDGMENT
We thank Drs. Allen Kaiser, Nancy Brown, and John Oates for
their careful reading of an earlier version of this manuscript.
Table 3. Selected Regimens of Antipyretic Medications for Scheduled Use during Acute Febrile
Episodes
Antipyretic Dose Comments
Acetaminophen 3251000 mg PO q46h Max. daily dose 4 g
Aspirin 3251000 mg PO q46h Max. daily dose 4 g
Ibuprofen 200800 mg PO q68h Max. daily dose 3.2 g
Rofecoxib* 12.525 mg PO q24h A selective cyclooxygenase-2 inhibitor
po orally
* Rofecoxib is not approved by the Food and Drug Administration as an antipyretic, although it has been
demonstrated to reduce fever (26).
Antipyretics/Aronoff and Neilson
312 September 2001 THE AMERICAN JOURNAL OF MEDICINE Volume 111
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