Antipyretic Therapy Physiologic Rationale, Diagnostic Implications, and Clinical Consequences
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REVIEW ARTICLE Antipyretic Therapy Physiologic Rationale, Diagnostic Implications, and Clinical Consequences Karen I. Plaisance, MD; Philip A. Mackowiak, MD arious treatments have been used to suppress fever since antiquity. Surprisingly, few studies have been performed to ascertain the physiologic consequences of antipyresis and validate the rationale behind such therapy. More importantly, it has not been es- tablished conclusively that the benefits of antipyretic therapy outweigh its risks. The Vpresent review considers these issues in light of currently available data and formulates guidelines for antipyretic therapy based on these data. Arch Intern Med. 2000;160:449-456 Antipyretic agents have been used to lower picion that fever is inherently noxious. This febrile body temperature for well over two suspicion is reflected in the results of sur- millennia.1,2 AncientAssyrian,Egyptian,and veys reporting that approximately 40% of Greek physicians all apparently knew of parents and other caregivers regard tem- and exploited the antipyretic property of ex- peratures encountered during fever as tracts of the bark of the willow (Salix alba).2 harmful,11,12 and that 12% of physicians be- However, it was not until 1763 that the Rev- lieve that fever has the capacity to cause erend Edward Stone gave the first scientific brain damage.8 Perhaps most indicative of description of the clinical benefits of willow the medical profession’s inherent antipa- bark to the Royal Society of London.3 Less thy toward fever is the fact that an esti- than 80 years later, Piria4 succeeded in pre- mated 70% of nurses and 30% of physi- paring salicylic acid from salicin, a glycoside cians routinely use antipyretic drugs to component of willow bark. Salicylic acid suppress fever.8,9 was first synthesized by Gerland5 in 1852, The present review critically evalu- some 8 years before Kolbe and Lautemann,6 ates the physiologic rationale, the diag- who are frequently credited with this ac- nostic implications, and the clinical con- complishment, and just a year before von sequences of antipyretic therapy. The data Gerhardt7 developed acetylsalicylic acid (as- reviewed are also used to formulate rec- pirin) during efforts to find a more palatable ommendations regarding the appropri- form of salicylate. In 1899, the Bayer Com- ate clinical application of such therapy. pany launched the modern era of antipyretic therapy with the introduction of aspirin as DEFINITIONS the world’s first commercially available antipyretic drug.1 During this same period, Fever is “a state of elevated core tempera- acetanilideandphenacetinwerederivedfrom ture, which is often, but not necessarily, part para-aminophenol compounds in coal tar, of the defensive response of multicellular and pyrazolon compounds such as amino- organisms (hosts) to the invasion of live (mi- pyrine were developed.2 croorganisms) or inanimate matter recog- A little less than a century later, the nized as pathogenic or alien by the host.”13 marketplace is replete with drugs capable The febrile response, of which fever is but of suppressing fever. Their widespread ap- 1 component, is a complex physiologic re- plication by primary care physicians,8 emer- action to disease involving a cytokine- gency department nurses,9 pharmacists,10 mediated rise in core temperature, genera- parents, and other caregivers11,12 has been, tion of acute-phase reactants, and activation at least in part, motivated by a general sus- of numerous physiologic, endocrinologic, and immunologic systems.14 The rise in core From the University of Maryland School of Pharmacy (Dr Plaisance), the Medical temperature during fever is to be distin- Care Clinical Center, Veterans Affairs Maryland Health Care System guished from the unregulated rise that oc- (Dr Mackowiak), and the Department of Medicine, University of Maryland School curs during hyperthermia, in which pyro- of Medicine (Dr Mackowiak), Baltimore, Md. genic cytokines are not directly involved and ARCH INTERN MED/ VOL 160, FEB 28, 2000 WWW.ARCHINTERNMED.COM 449 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 never been shown in humans that in- ANTIPYRETIC DRUGS creases in core temperature encoun- tered during fever, which rarely ex- The essential elements of the fever ceed 41°C (105.8°F), are harmful per physiologic pathway are release of py- 17 Exogenous Pyrogen se. Nevertheless, many clinicians rogenic cytokines by inflammatory believe that even the relatively mod- cells in response to some exogenous est increases in core temperature en- pyrogen (eg, infection), induction of countered during fever are delete- cyclooxygenase (COX) 2 activation rious to certain patients and should of the arachidonic acid cascade, and therefore be suppressed. enhanced biosynthesis of prostaglan- Activated Leukocytes Children, primarily between din E2 (PGE2) by hypothalamic vas- ages 3 months and 5 years, are 1 such cular endothelial cells.28 Through its category of patients. In these chil- effect on thermoregulatory neurons Temperature- dren, seizures have occurred during located in the preoptic area of the an- Pyrogenic Cytokines Dependent α γ Feedback on episodes of fever at a frequency of terior hypothalamus, PGE2 acts to IL-6 (IL-1, TNF- , IFN- ) Cytokine from 2% to 5% in the United States raise the hypothalamic thermal set IL-6 Expression and Western Europe18,19 to as high as point (Figure) and thereby induce 14% in other selected countries.20 Al- peripheral and thermogenic mecha- though most children have tempera- nisms to increase core temperature. tures of 39.0°C or lower at the time Theoretically, antipyretic agents of their seizure,21 many tolerate might interrupt the fever response at higher fevers at later dates without any step along this pathway.29 convulsing.22 Unfortunately, antipy- The drugs most commonly used retic therapy has not been shown to today to suppress fever are the sa- Circumventricular Organs protect against recurrences of fe- licylates (eg, sodium salicylate and PGE2 brile seizure in the few controlled tri- acetylsalicylic acid), ibuprofen, and als conducted thus far.23 the other nonsteroidal anti-inflam- It has also been suggested that matory drugs (NSAIDs), and the patients with underlying cardiovas- para-aminophenol derivative acet- 39.5°C (103°F) cular or pulmonary disorders might aminophen. Until the 1970s, little Fever be especially susceptible to the ad- was known about mechanisms re- verse effects of fever because of the sponsible for the antipyretic activity Hypothetical model for the fever response 28 increased metabolic demands im- of any of these compounds. In 1970, (reprinted from Mackowiak with permission). 24 30 IL indicates interleukin; TNF, tumor necrosis posed by the elevated temperature. Milton and Wendlandt demon- factor; IFN, interferon; and PGE2, Such demands, which peak during strated both that prostaglandins of the prostaglandin E2. the chill phase, largely as a result E series cause rapid onset of fever of shivering, include increases in sym- when injected into the cerebral ven- against which standard antipyretics pathetic tone,25 oxygen consump- tricles of cats and rabbits, and that are largely ineffective. Antipyretics tion, respiratory minute volume, and PGE2 is released within the brain dur- block or reverse fever’s cytokine- respiratory quotient.26 Although these ing fever. These observations, in con- mediated rise in core temperature, but have been proffered as prima facie junction with those of Vane31 show- do not affect body temperature in the justification for antipyretic therapy in ing that aspirin and other antipyretic afebrile state. They are to be distin- patients with underlying cardiopul- drugs inhibit synthesis of prostaglan- guished from hypothermia agents monary disorders, the risk-benefit dins, suggest that antipyretic drugs (cryogens), which are capable of low- ratio of such therapy has yet to be reduce fever primarily by inhibiting ering core temperature even in the ab- determined. the formation of PGE2 in the brain. sence of fever. Antipyretic therapy might also However, not all experimental data be justified, at least in theory, if fe- obtained since the early work of RATIONALE ver’s metabolic cost exceeded its Milton and Wendlandt30 and Vane31 physiologic benefit, if the treatment have supported this hypothesis. Two critical assumptions are made provided symptomatic relief with- Injection of PGE2 into appropriate when prescribing antipyretic ther- out adversely affecting the course of brain regions of animals capable of apy. One is that fever is, at least the febrile illness, and/or if the toxi- mounting a febrile response to en- in part, noxious, and the other, that cologic costs (adverse effects) of the dotoxin, for example, does not con- suppressing fever will reduce if not antipyretic regimen were apprecia- sistently cause fever in the ani- eliminate fever’s noxious effects. Nei- bly lower than its beneficial effects. mals.32 Moreover, salicylate infusions ther assumption has been validated Unfortunately, although clinicians into the ventral septal area of ex- experimentally. In fact, there is con- have long argued the validity of each perimental animals blocks the fe- siderable evidence that fever is an of these propositions as justification brile response caused by intraven- important defense mechanism that for antipyretic therapy, few experi- tricular injection of PGE,33 suggesting contributes to the host’s ability to re- mental observations exist to sup- that the mechanisms of action of at sist infection.15,16 Moreover, it has port any of these arguments.27 least some antipyretic drugs might ARCH INTERN MED/ VOL 160, FEB 28, 2000 WWW.ARCHINTERNMED.COM 450 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 involve more than simple inhibition eral COX.35-37 The relatively weak ac- ver are instructive.41,43-51 In the aggre- of PGE synthesis. tivity of acetaminophen against pe- gate, they suggest that orally admin- Acetaminophen, aspirin, and the ripheral COX most likely accounts for istered ibuprofen is a more potent other NSAIDs all seem to block con- its poor anti-inflammatory activity.