Aronoff and Neilson - 2001 - Antipyretics Mechanisms of Action and Clinical Us

REVIEW

Antipyretics: Mechanisms of Action and ClinicalUse in Fever Suppression

David M. Aronoff, MD, Eric G. Neilson, MD

Fever is a complex physiologic response triggered by infectiousor aseptic stimuli. Elevations in body temperature occur whenconcentrations of prostaglandin E2 (PGE2) increase within cer-tain areas of the brain. These elevations alter the firing rate ofneurons that control thermoregulation in the hypothalamus.Although fever benefits the nonspecific immune response toinvading 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 sincethe late 19th century, but the mechanisms by which they relievefever have only been characterized in the last few decades. It isnow clear that most antipyretics work by inhibiting the enzymecyclooxygenase and reducing the levels of PGE2 within the hy-pothalamus. Recently, other mechanisms of action for antipy-

retic drugs have been suggested, including their ability to reduceproinflammatory mediators, enhance anti-inflammatory sig-nals at sites of injury, or boost antipyretic messages within thebrain. Although the complex biologic actions of antipyreticagents are better understood, the indications for their clinicaluse 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 receivingantimicrobials, or predispose patients to adverse effects fromother medications. The development of more selective fever-relieving agents and their prudent use with attention to possibleuntoward consequences are important to the future quality ofclinical medicine. Am J Med. 2001;111:304 –315. q2001 byExcerpta Medica, Inc.

—Humanity has but three great enemies: fever, famine,and war, and of these by far the greatest, by far the mostterrible, is fever—

This bon mot from Osler cleverly paints the pall ofapprehension 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 symptom has been viewed so dichotomously.Fever today is generally regarded as a form of patientdiscomfort. Among acts of caring, pyrexia is treatable,and so it often is treated.

Physicians since antiquity have used various physicalmeans to lower body temperature (2). Applying Peruviancinchona bark as an antipyretic dates to the early 1600s(3), but by the 18th century overharvesting of cinchonacreated 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 Englishwillow (4). Although his finding appeared novel, it simplyconfirmed what was known to Hippocrates, Galen, andancient Egyptians centuries before (5,6). Salicylic acidwas first prepared in 1838 from the glucoside salicin, theactive component in willow bark (5,7). Another deriva-tive, acetylsalicylic acid (aspirin) was later synthesized in1853 and made commercially available as an antipyreticin 1899 (2,5). Since then, numerous antipyretics havebeen introduced into clinical medicine.

The prescription of acetaminophen for fever is morerecent. Although precursors such as acetanilid and phen-acetine were developed in the second half of the 19thcentury, the popular use of acetaminophen as an antipy-retic and analgesic did not occur until the 1950s (8). Theantipyretics in common use today include acetamino-phen, aspirin, and other nonsteroidal anti-inflammatorydrugs (NSAIDs). The principal action of antipyretics restsin their ability to inhibit the enzyme cyclooxygenase(COX) and interrupt the synthesis of inflammatory 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 usedantipyretics, emphasizing their ability to block the febrileresponse at multiple sites along a physiologic cascade thatconnects peripheral inflammation with the central ner-vous system, and conclude with some thoughts on theproper use of antipyretics for patients with fever.

From the Divisions of Infectious Diseases and Clinical Pharmacologyand 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-07569from the National Institutes of Health, and the Tinsley Harrison Soci-ety.

Manuscript submitted March 27, 2001, and accepted in revised formJune 6, 2001.

304 q2001 by Excerpta Medica, Inc. 0002-9343/01/$–see front matterAll rights reserved. PII S0002-9343(01)00834-8

NORMAL THERMOREGULATION

Normal body temperature is circadian and varies from anapproximate low of 36.48C (97.68F) in the morning to ahigh of 36.98C (98.58F) in the late afternoon (10). At theheart of thermoregulation is an integrated network ofneural connections involving the hypothalamus, limbicsystem, lower brainstem, the reticular formation, spinalcord, and the sympathetic ganglia (11). An area in andnear the rostral hypothalamus is also important in or-chestrating thermoregulation. This region, the “preopticarea,” includes the preoptic nuclei of the anterior hypo-thalamus (POAH) and the septum.

In simple terms, the POAH maintains mean body tem-perature around a set point. This thermoneutral set pointtemperature is modulated by the balanced activities oftemperature-sensitive neurons. These neurons integrateafferent messages regarding core body and peripheral(skin) temperatures and evoke various behavioral andphysiologic responses controlling heat production or dis-sipation (11).

Fever describes a regulated rise in body temperatureafter an increase in the hypothalamic set point (12). Un-der the influence of the hypothalamus, physiologic andbehavioral functions favoring heat production and heatretention are stimulated until arriving at a newly elevatedset point temperature (12). Typical early behavioralchanges prior to fever include seeking a warmer environ-ment or adding clothing. Physiologic alterations includecutaneous vasoconstriction, shivering, and nonshiveringthermogenesis through enhanced release of thyroid hor-mones, glucocorticoids, and catecholamines (11). Uponreaching the elevated set point of fever, an increase ordecrease in core temperature will stimulate thermoregu-latory mechanisms similar to those evoked at normalbody 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 regulatedinflammatory response to tissue injury and infection arepolypeptide cytokines. Pyrogenic cytokines, such as in-terleukin-1b (IL-1b), tumor necrosis factor (TNF), andinterleukin-6 (IL-6), are those that act directly on thehypothalamus to effect a fever response (13). Exogenouspyrogens, such as microbial surface components, evokepyrexia most commonly through the stimulation of py-rogenic cytokines. The gram-negative bacterial outermembrane lipopolysaccharide (endotoxin), however, iscapable of functioning at the level of the hypothalamus,in much the same way as IL-1b (14).

These signals trigger the release of other mediators,most notably prostaglandin E2 (PGE2), in the region ofthe POAH (12). PGE2 is believed to be the proximal me-diator of the febrile response. Preoptic neurons bearingE-prostanoid receptors alter their intrinsic firing rate inresponse to PGE2, evoking an elevation in the thermoreg-ulatory set point. There are four known cellular receptorsfor PGE2: EP1 through EP4 (15). The particular receptorsubtype involved in pyrogenesis is unknown. Althoughmice lacking the neuronal PGE2 receptor subtype EP3

demonstrate an impaired febrile response to both exoge-nous (endotoxin) and endogenous pyrogens (15), studiesin rats appear to implicate the EP4 receptor (16). Theintracellular events triggering pyrexia after PGE2-EP re-ceptor coupling among species are unclear.

Fever is tightly regulated by the immune response. In-flammatory stimuli triggering the generation of propy-retic messages provoke the release of endogenous antipy-retic substances (17). Substances such as arginine vaso-pressin (AVP), a-melanocyte stimulating hormone, andglucocorticoids act both centrally and peripherally tolimit pyrexia (17). The cytokine interleukin-10 (IL-10)has numerous anti-inflammatory properties, includingfever suppression (18,19). In addition, a class of lipidcompounds known as epoxyeicosanoids generated bycertain cytochrome P-450 enzymes play an importantrole in limiting the fever and inflammation (20) [re-viewed in (21)].

Analogous to a biochemical feedback pathway, feveritself appears capable of countering the release of pyro-genic cytokines (22,23). For example, febrile tempera-tures augment early TNF release in endotoxin-challengedmice, yet limit its prolonged (and perhaps detrimental)expression after either lipopolysaccharide injection orbacterial infection (22,23).

THE ROLE OF PROSTAGLANDIN E2

PGE2 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 COXenzyme, COX-1 and COX-2. COX-1 usually is expressedconstitutively and generates prostanoids important tohousekeeping functions supporting homeostasis (24).COX-2, on the other hand, is inducible by inflammatorysignals such as the pyrogenic cytokines, IL-1b, TNF, andIL-6, and bacterial lipopolysaccharide (24). Geneticallyengineered mice that lack either the COX-1 or COX-2gene demonstrate that the inducible isoform is responsi-ble for hypothalamic PGE2 production during a febrileresponse (25). As COX-2 is the key provider of PGE2

during pyrexia, it is not surprising that the selectiveCOX-2 antagonist, rofecoxib, is an effective antipyretic inhumans (26).

Antipyretics/Aronoff and Neilson

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Many cells, including synoviocytes, macrophages, en-dothelial cells, and chondrocytes, have the capacity torapidly up-regulate the expression of the COX-2 duringinflammation (24). The most likely cell type in the centralnervous system responsible for producing PGE2 is themicrovascular endothelial cell, which expresses COX-2exuberantly after stress (25,27,28).

An effective febrifuge might interrupt pyrexogenesis atany step that connects peripheral inflammation with thecentral production of PGE2. Stated differently, an antipy-retic might blunt peripheral inflammation or depresscentral pyrogenic signals, or affect both. Inhibiting cen-tral production of PGE2 is a well-known mechanism ofantipyretic agents, but activated leukocytes and endothe-lial cells in peripheral areas of inflammation also repre-sent potential drug targets (Table 1).

THE CYCLOOXYGENASE HYPOTHESIS

The antipyretic drug aspirin was in wide clinical use formore than 70 years (9) before Vane (29) demonstrated in1971 that it exerted its physiologic action by inhibitingthe production of prostaglandins. Further work suggestsa current model of how aspirin and similar NSAIDs act asantipyretics.

Aspirin interferes with the biosynthesis of cyclic pro-stanoids derived from arachidonic acid, such as throm-boxane A2 and prostaglandins (30). As a nonselectiveCOX inhibitor, aspirin has been widely studied for itsanti-inflammatory, antipyretic, and antithrombotictraits. The major mechanism of action of aspirin andother antipyretics involves lowering PGE2 by directly in-hibiting COX enzyme activity (31). Worth noting, how-

Figure 1. Fever generation after infection. Microbial tissue invasion sparks an inflammatory response and activates local vascularendothelial cells and leukocytes. The extravasation of white blood cells into inflamed areas depends on a multistep interaction withendothelial cells regulated by a variety of cytokines, chemokines, and adhesion molecules. Activated leukocytes release the pyrogeniccytokines interleukin-1b (IL-1b), tumor necrosis factor (TNF), and interleukin-6 (IL-6). Hematogenous dissemination (depictedhere) allows these endogenous pyrogens to stimulate vascular endothelial cell production of prostaglandin E2 (PGE2) within thecentral nervous system. Peripheral inflammatory signals may also travel along neural connections (such as the vagus nerve) to triggercentral nervous system PGE2 production (96). Neurons within the preoptic area of the anterior hypothalamus (POAH) bearingspecific E-prostanoid receptors orchestrate the febrile response after the PGE2 signal. PGE2 alters the firing rate of these neurons,resulting in an elevated thermoregulatory set point. The febrile set point body temperature is reached through the regulated evocationof behavioral and physiologic changes aimed at enhancing heat production and reducing heat dissipation. Fever is believed toaugment the peripheral and systemic inflammatory response to infection in part by modulating the expression of inflammatorycytokines and enhancing leukocyte function.


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ever, is that sodium salicylate, aspirin’s major metabolite,exhibits similar antipyretic and anti-inflammatory prop-erties as aspirin but shows only weak inhibition of COX-1and COX-2 in vitro (32,33).

NSAIDs are also capable of reducing PGE2 productionby down-regulating the expression of COX enzymes, asopposed to directly inhibiting their enzymatic action. So-dium salicylate and aspirin also inhibit COX-2 transcrip-tion induced by lipopolysaccharide and IL-1b (34). Theclinical effects of sodium salicylate are likely due in part toits actions on COX gene transcription by disabling thetranscriptional activator nuclear factor-kB (NF-kB) (34).

NF-kB is a heterodimeric protein capable of bindingDNA in the 59-promoter regions of many genes involvedin the inflammatory response (35). Once bound, NF-kBfacilitates the transcription of genes encoding pyrogeniccytokines, chemokines, adhesion molecules, and inflam-matory enzymes, including inducible nitric oxide syn-thase and COX-2 in certain cell types (35,36). NF-kB re-sides in an inactive state in the cytoplasm, complexed toanother protein, IkB (37). Upon activation, the IkB si-lencer is sequentially phosphorylated, ubiquinated, anddegraded, releasing NF-kB to translocate into the nucleus(35).

Salicylates reduce the nuclear translocation of NF-kBthrough stabilization of cytoplasmic IkB (38) by interfer-ing with its phosphorylation (Figure 2) (39). The abilityof antipyretics to disable transcription varies amongagents and cell type studied. Salicylate and its progenitoraspirin prevent NF-kB translocation in endothelial cellsand leukocytes induced by proinflammatory cytokines orlipopolysaccharide (38 – 42). NSAIDs like ibuprofen alsoblock the nuclear trafficking of NF-kB in certain tumorcell lines (43) but fail to do so in activated macrophages(38). Indomethacin, another COX inhibitor, does not ap-

pear to affect NF-kB (41,42), and therapeutic doses ofacetaminophen also fail to suppress it (41,44). The reasonfor this heterogeneity is unknown.

An NF-kB/IkB mechanism for COX-2 expression maynot be the whole story, either, as the COX-2 gene is notsolely dependent on activation by the NF-kB cascade(36). In human microvascular endothelial cells, for ex-ample, COX-2 activation by IL-1b occurs independentlyof NF-kB through other transcriptional activators (36).

NONCYCLOOXYGENASE TARGETS FORANTIPYRETICS

Interestingly, clinically useful actions of antipyretics mayalso be COX independent (45), and relevant anti-inflam-matory effects of aspirin, sodium salicylate, and otherNSAIDs are seen only with doses much higher than thoserequired to suppress COX activity (46). Thus, a variety ofnoncyclooxygenase-dependent functions have been pro-posed to explain the full effects of salicylates on the pyro-genic cascade (Table 2). For example, salicylates andother antipyretics also suppress tissue inflammationthrough diminished leukocyte-endothelial cell interac-tions (39), reduced pyrogenic cytokine production (38),or enhanced expression of anti-inflammatory molecules(45,47). Other mechanisms, such as boosting the activityof endogenous antipyretic messengers, may further con-tribute (Figure 3) (48). We consider each of these puta-tive actions in turn.

EFFECTS ON LEUKOCYTES ANDENDOTHELIAL CELLS

Fever frequently begins with inflammation in peripheraltissues (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 inflammatory mediators (such as cytokines, proteases, and reactive oxygen species)Enhanced local production of anti-inflammatory molecules (such as adenosine, aspirin-triggered lipoxins, interleukin-10)

Endothelial cells at sites of local infection/inflammation:Reduced expression of leukocyte adhesion molecules

Endothelial cells of the central nervous system:Reduced prostaglandin E2 production (cyclooxygenase inhibition)

Endogenous antipyretics:Enhanced production or activity of arginine vasopressin, a-melanocyte stimulating hormone, glucocorticoids, and

epoxyeicosanoids

Table 2. Evidence Supporting Cyclooxygenase-independent Effects of Antipyretics

Ability of aspirin to inhibit inflammation 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 aspirinRecognition of immunomodulatory properties of aspirin and related NSAIDs apart from COX inhibition

NSAIDs 5 nonsteroidal anti-inflammatory drugs.



stimulate regional inflammatory 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 ExpressionIbuprofen, a relatively nonselective COX inhibitor, in-hibits neutrophil adherence, swelling, aggregation, andlysosomal enzyme release in high doses (51). Adherenceof peripheral blood monocytes, basophils, and mast cells

to pyrogen-stimulated human endothelial cells is also re-duced by ibuprofen (IC50 0.5 mM) (49). This antipyreticreduces the expression of endothelial cell adhesion mol-ecules (intercellular adhesion molecule-1 [ICAM-1] andvascular 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 cellmonolayers (52).

Expression of VCAM-1 or ICAM-1 in endothelial cellsis also inhibited by sodium salicylate and aspirin, withassociated defects in neutrophil adhesion and transmi-

Figure 2. Effects of antipyretics on gene transcription. The predominant mode of action of antipyretic drugs involves reducingcentral nervous system concentrations of prostaglandin E2 by directly inhibiting cyclooxygenase. Another postulated mechanisminvolves suppressive effects on inflammatory gene expression. Aspirin and sodium salicylate reduce the activity of the transcriptionalregulator NF-kB, a heterodimeric protein that resides in an inactive state in the cytoplasm, complexed to another protein, IkB. Whenendothelial cells or leukocytes are appropriately stimulated (by proinflammatory cytokines or gram-negative bacterial lipopolysac-charide depicted here), the IkB silencer is phosphorylated by the protein IkB kinase, then ubiquinated and degraded, releasing NF-kBto translocate into the nucleus. In many cell types, NF-kB promotes the expression of cyclooxygenase, pyrogenic cytokines, andendothelial/leukocyte adhesion molecules involved in the febrile response. Sodium salicylate and its parent compound, aspirin,reduce the translocation of NF-kB through stabilization of cytoplasmic IkB by interfering with its phosphorylation, effectivelypreventing active NF-kB from entering the cell nucleus (red arrow). This effect is not characteristic of all nonsteroidal anti-inflammatory agents, however, and is not shared by therapeutic doses of acetaminophen. AA 5 arachidonic acid; COX 5 cycloox-ygenase; IL 5 interleukin; PGH2 5 prostaglandin H2; TLR 5 toll-like receptor for lipopolysaccharide; TNF 5 tumor necrosis factor.



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 adhesionmolecule that mediates rolling of leukocytes along vascu-lar endothelium, is rapidly shed from circulating neutro-phils in response to treatment with aspirin and otherNSAIDs (55).

Although the mechanism underlying the NSAID effecton leukocyte-endothelial cell adhesion is incomplete, thereduction in VCAM-1 and ICAM-1 expression is associ-ated with reduced endothelial transcription, suggestingan effect on gene regulation (39,49). NF-kB can activatethe expression of adhesion molecules (39). As notedabove, inhibition of NF-kB 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 ofa single dose of aspirin on circulating endothelial andleukocyte adhesion molecule concentrations (56). Dose-response effectiveness in humans is unknown.

Diminished Cytokine ProductionCytokine production by cells of the immune system alsocan 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 arenow understood.

Macrophage production of the pyrogenic cytokineTNF is activated by inflammatory stimuli such as expo-sure to lipopolysaccharide. It has recently been observedthat 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-inflammatorydrugs (NSAIDs) reduce fever by depressing inflammatory messages at both peripheral sites of tissue inflammation and within centralnervous system thermoregulatory sites. Peripherally, aspirin and other NSAIDs suppress production of pyrogenic cytokines such astumor necrosis factor and interleukin-1b and block endothelial cell/leukocyte interactions through effects on adhesion moleculeexpression. These agents also promote the creation of anti-inflammatory molecules such as adenosine and aspirin-triggered lipoxins.Centrally, antipyretics lower the thermoregulatory set point primarily by blocking cyclooxygenase production of prostaglandin E2

(PGE2). Additional effects may stem from provoking the release of endogenous antipyretic compounds such as arginine vasopressin.Acetaminophen differs from other antipyretic agents by its inability to reduce peripheral inflammation and its lack of effect onendogenous antipyretics.



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-kB mediates enhancedTNF production. As noted, these agents interrupt NF-kBnuclear translocation through stabilization of cytoplas-mic IkB (38). In agreement with these data, NF-kB 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 activationof the intracellular protein, heat shock factor-1 (HSF1).HSF1 is an activating polypeptide for the heat shock genesin many cell types that also acts as a repressor of IL-1bgene transcription (54). Millimolar doses of sodium sa-licylate and sulindac induce HSF1 activity and simulta-neously reduce transcription of IL-1b in vitro (54).

Whether these effects on cytokine production have im-portant clinical consequences remains unclear. The influ-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 ibuprofen either does not affector increases cytokinemia in this model (59 – 61). Impor-tantly, the intravenous injection of endotoxin provokes atremendous systemic inflammatory response not charac-teristic of most fever-producing diseases. Clinical studiesof localized inflammation are necessary to further evalu-ate the effects of antipyretics on peripheral cytokine gen-eration.

Stimulation of Anti-inflammatory MediatorsAnother hypothesis explaining the impaired leukocyteadhesion or accumulation seen with aspirin and salicylateduring inflammation involves the anti-inflammatorymediator adenosine. Aspirin and sodium salicylate causeleukocytes to produce adenosine at sites of inflammation,and the effect can be reversed by endogenous adenosinedeaminase (45,50,53). Adenosine is an autacoid thatsome investigators believe mediates the immunosuppres-sive effects of methotrexate and sulfasalazine (62). In gen-eral, salicylates promote the breakdown of intracellularadenosine triphosphate (ATP) and extracellular releaseof adenosine (53). Adenosine acts through four knownreceptors and inhibits polymorphonuclear leukocyte ad-herence, superoxide generation, phagocytosis, and secre-tion (63). The adenosine-mediated effects of salicylatesmay represent an important anti-inflammatory mecha-nism for this class of agents.

Another hypothesis regarding aspirin’s ability to in-hibit leukocyte function involves alterations in eico-sanoid biosynthesis independent of PGE2 (64). Aspirininhibits 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 thiscompound to make 15-epi-lipoxin A4 and 15-epi-li-poxin-B4 (47,64). These compounds are known as aspi-rin-triggered lipoxins (ATL) and share physiologic prop-erties with the endogenous enantiomers lipoxin A4 andlipoxin B4 (47). ATLs display potent anti-inflammatoryeffects and interrupt neutrophil chemotaxis, transmigra-tion through endothelial and epithelial cell layers, anddiapedesis from postcapillary venules (47). Recently li-poxin A4 analogs were shown to inhibit adhesion of hu-man neutrophils to endotoxin-activated endothelial cells(65).

EFFECTS ON ENDOGENOUSANTIPYRETICS

Enhancing the production of the body’s own antipyreticmediators would appear to be a useful method for reduc-ing fever. As noted, hormones such as hypothalamic AVP(5), a-melanocyte stimulating hormone, and glucocorti-coids are capable of buffering the magnitude of the febrileresponse. AVP participates in the antipyretic mecha-nisms of salicylates and related NSAIDs, but not acet-aminophen (48,66,67). The antipyretic effect of sodiumsalicylate and indomethacin is blocked by administrationof an AVP V1-receptor antagonist (48,66). Interestingly,the degree of fever inhibition by acetaminophen is notinfluenced by V1-receptor blockade. In fact, the antipy-retic response to indomethacin in rats is accompanied byan 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 derivedfrom arachidonic acid not by COX but by cytochromeP-450 mono-oxygenase enzymes. It has been postulatedthat aspirin enhances the effect of epoxyeicosanoidsthrough induction of cytochrome P-450 isoforms (20).

AcetaminophenAcetaminophen is an analgesic that deserves special com-ment because it is an effective febrifuge but a weak anti-inflammatory drug (68). Its effects differ considerablyfrom salicylates and other NSAIDs. As opposed toaspirin, acetaminophen is a poor inhibitor of plateletfunction. Believed to be an inhibitor of cyclooxygenase,acetaminophen’s mechanism of action is still poorly un-derstood. Although suprapharmacologic doses of acet-aminophen inhibit NF-kB stimulation of inducible nitricoxide synthase (44), it does not possess the same inhibi-tory effects on NF-kB–mediated gene transcription thatsalicylates enjoy (38).

Explanation of the antipyretic and analgesic actions ofacetaminophen has been based on tissue-specific COX



inhibition not seen with NSAIDs (31). Acetaminophenpenetrates the blood-brain barrier, achieving cerebrospi-nal fluid levels comparable to those in serum (69), andmay act preferentially within the central nervous system(31). Central nervous system levels of PGE2 rise duringfever and fall to normal levels upon administration of thedrug (70). Acetaminophen reduces the production ofprostaglandins in brain preparations more potently thanit does from other organs such as spleen (31,71).

In certain cell lines, acetaminophen weakly inhibitsCOX-1 more than COX-2, but it is a poor inhibitor ofeither isoenzyme (72,73). The in vitro anti-COX activityof acetaminophen depends on the availability of cofactorssuch as glutathione and hydroquinone (73). Unlike themajority of other NSAIDs, acetaminophen requires anenvironment low in peroxides in order to inhibit COXactivity (74,75). Neurons may fulfill this requirement, butinflamed peripheral tissues are flooded with leukocytesthat generate cellular peroxides (75). Thus, the tissuespecificity of acetaminophen may reflect the intracellularbalance 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 benefits 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 offever may outweigh its benefit. 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). Themajority of children with febrile seizures have tempera-tures above 39.08C at the time of convulsion (78). Pro-phylaxis against febrile seizures of childhood has beensupported 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 thedeleterious effects of fever includes those with underlyingcardiopulmonary disorders (2). The metabolic cost of fe-ver is substantial, particularly during the chill phase ofthermogenesis (2). Although antipyretics, by reducingthis metabolic burden, could help patients with impor-tant cardiopulmonary disease, there are no experimentsto support this view (2). In fact, nearly 20 years ago, in-domethacin given to patients with serious coronary ar-tery disease decreased coronary blood flow, prompting

the authors to warn that indomethacin should be usedcautiously for patients with severe anginal symptoms(81). It has also been observed that the repetitive sweatingof patients treated intermittently with antipyretics maycontribute 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 dispensingantipyretics 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 notbe particularly noxious, as evidenced by the popular useof recreational saunas and hot tubs. Much of the discom-fort during sickness arises from the symptoms accompa-nying the inflammatory response. Focal symptoms suchas cough, abdominal pain, and back pain can be discon-certing, as can generalized symptoms such as anorexia,arthralgias, headache, nausea, malaise, and myalgias. As aconsequence of additional anti-inflammatory and anal-gesic characteristics, agents such as acetaminophen, aspi-rin, and other NSAIDs are capable of mollifying many ofthese other somatic symptoms.

Fever, of course, is a surrogate marker for disease ac-tivity in many infectious and inflammatory disorders.Squelching the febrile response removes a clinically im-portant indicator of therapeutic efficacy. A small pediat-ric study, for example, demonstrated that appropriatechanges in antibiotic regimens were delayed for childrenreceiving antipyretics compared with those who were not(83).

Although some antipyretics depress the host immuneresponse to infection, evidence is sparse that these medi-cations adversely affect the outcome of febrile illnesses inhumans. Animal models of infection show that antipy-retic therapy increases the morbidity and mortality of thehost (77). Human studies, although much less controlled,suggest the same (84 – 88). The notion that antipyreticsdepress the immune response to bacterial infections datesto the mid-1960s when the activation of latent infectionwas 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 reportedamong previously healthy persons exposed to therapeuticdoses of NSAIDs (84,87). In contrast, 48 hours of intra-venous ibuprofen in a large trial of patients with sepsisdid not affect the incidence of organ failure or mortalityat 30 days (90). Interestingly, ibuprofen treatment dras-tically reduced mortality among septic patients who werehypothermic (91). This seemingly paradoxic increase insurvival (from 10% in the placebo-treated group to 46%in the ibuprofen-treated group) is not understood butperhaps related to the suppression of overwhelming in-flammation by the NSAIDs.

Viral infection may also be affected by antipyresis. Arandomized trial with acetaminophen prolonged the



time to crusting of lesions in childhood varicella (85).Aspirin increases the rate of virus shedding in patientswith rhinovirus-related common colds (88). It is notablethat IL-6 appears to modulate the host response andsymptom development after rhinovirus infection (92).Rhinovirus stimulation of host IL-6 expression occursthrough an NF-kB–mediated pathway (92). If the sup-pressive effect of aspirin on NF-kB activity is found tooccur in humans, this might explain the agent’s ability toaugment viral shedding. Studies of parasitic disease alsoindicate 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 therecommended dose of the parent compound is exceededor the patient coingests other hepatotoxins such as etha-nol. Concomitant use of medications, such as rifampinand phenytoin that induce the cytochrome P-450 enzymesystem, 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). A thorough review ofthe potential adverse effects of these medications is be-yond the scope of this discussion.

RECOMMENDATIONS FOR THE USE OFANTIPYRETICS

If antipyretic effects were truly limited to reducing fever,their use might be appropriate in few circumstances. Forexample, treating fever in patients with underlying car-diopulmonary disease might be reasonable, as discussedabove, assuming these patients cannot tolerate the dila-tory effects of pyrexia (2,82). Patients suffering from non-infectious febrile diseases (such as malignancy or autoim-mune phenomena) might also be given antipyretics in aneffort to reduce their catabolic rates. Unfortunately, dataare not available to assess the efficacy of such practices.

Considering that fever may be an important window toclinically relevant information, one approach to treatingacute febrile illnesses is to use alternative, nonantipyreticmedications 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 usedduring acute fevers, they should be prescribed on a sched-uled basis, as opposed to “as needed,” for reasons notedabove. Of course, this approach requires careful attentionto the potential adverse effects induced by the antipyreticagents themselves. Examples of scheduled regimens forcommon antipyretic medications are listed in Table 3.

Deciding on a particular antipyretic also necessitatesconsidering toxicities and comorbid conditions. Predict-ing temperature-lowering response to a given agent isdifficult. Although many “head-to-head” trials of antipy-retics have been performed in pediatric groups, few dataexist for adults (58). On balance, pediatric studies dem-onstrate equal efficacy, 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, on the other hand, appears to be 50% to 100% morepotent than that of acetaminophen (95). Adult trials areconflicting, 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, andother NSAIDs are complex and repress inflammatory sig-nals at many levels. Although COX enzyme inhibitionplays a central role in the antipyretic actions of thesedrugs, other immunomodulatory actions appear to con-tribute. As our understanding of these medications deep-ens, indications for their use in treating febrile patientsmay also change.

ACKNOWLEDGMENTWe thank Drs. Allen Kaiser, Nancy Brown, and John Oates fortheir careful reading of an earlier version of this manuscript.

Table 3. Selected Regimens of Antipyretic Medications for Scheduled Use during Acute FebrileEpisodes

Antipyretic Dose Comments

Acetaminophen 325–1000 mg PO q4–6h Max. daily dose 4 gAspirin 325–1000 mg PO q4–6h Max. daily dose 4 gIbuprofen 200–800 mg PO q6–8h Max. daily dose 3.2 gRofecoxib* 12.5–25 mg PO q24h A selective cyclooxygenase-2 inhibitor

po 5 orally* Rofecoxib is not approved by the Food and Drug Administration as an antipyretic, although it has beendemonstrated to reduce fever (26).



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