USES AND ABUSES OF ANTIPYRETIC THERAPY

By Alan K. Done, M.D. Department of Pediatrics, Stanford University School of Medicine

F undoubtedly the most common ben of points which deserve consideration symptom confronting the physician before one elects to use an antipyretic. who treats children. It is fought as though DuBois’ summarized a lifetime of study it were the patient’s primary disease, and on fever and the regulation of body tem. its mere presence is often accepted as being penature with the statement: “Fever is only sufficient indication for the institution of a symptom and we are not sure that it is antipyretic therapy. It is not surprising, an enemy. Perhaps it is a friend.” The litena- therefore, that therapeutists and pharma- tune concerning the possible role of fever in ceutical concerns have energetically sought body defenses is extensive and inconclusive. new and better drugs for the control of There is little question that artificially in- fever. In the past few years there has ap- duced fever is of some value in the treat- peared on the market a number of new ment of such diseases as neurosyphilis, cer- formulations which are purported to offer tam inflammations of the eye, and arthritis. distinct advantages in terms of antipyretic In animal experiments, elevation of body potency, acceptance by children, and/or temperature has been shown to be of im- reduced toxicity. portance in resistance to certain infections.2 It is axiomatic that virtually any claim Body temperatures of greater than 106#{176}F regarding a drug can be supported by pub- (41.1#{176}C) rarely occur except under highly lished data, if the proper study is selected anomalous circumstances, and this level is and interpretation is sufficiently influenced probably safely below the point at which by conviction. Particularly is this true of temperature itself poses an immediate antipyretic-analgesic drugs, where such fac- threat to the individual.3 Circumstances tons as lability in the case of fever and lack which may lead to higher temperatures in- of objectivity in the case of pain, make elude: exposure to a sudden overwhelming evaluation difficult. The claims and counter- heat load, such as injection of pynogen or claims which have been made concerning placement in a steam cabinet; excessively antipynetic drugs have led to considerable prolonged exposure to a heat load with re- confusion and misunderstanding on the part sultant “exhaustion” of temperature-regulat- of clinicians in general. The purpose of this ing processes; and the loss of temperature presentation is to attempt to provide some regulation seen in association with severe clarification of this problem. brain damage and in moribund patients. It has been postulated that, except under cm- IS ANTIPYRESIS INDICATED? cumstances such as these, an “emergency More critical than the choice of an anti- regulatory mechanism” in fever operates to pyretic is the question of whether or not prevent the elevation of body temperature such therapy is indicated in the individual to levels at which fever per se is life- case, for there is little doubt that these threatening.3 drugs are grossly overused, at times to the It is doubtful whether body temperatures detriment of the patient. Therefore, before in the range of 104#{176}F(40.0#{176}C) are harm- discussing the antipyretics themselves, it ful, even if prolonged for several days.1 In- seems appropriate to review briefly a num- deed, this is the temperature level found in

Presented, in part, before the Annual Meeting of the American Academy of Pediatrics, October 20, 1958. ADDRESS: 2351 Clay Street, San Francisco 15, California. PEDIATRICS, April 1959

774

Downloaded from www.aappublications.org/news by guest on September 23, 2021 AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 775 athletes during hard exercise. Thus, the disaster. Moreover, each time a drug is re- rationale for the administration of antipy- moved from its usual storage place, the retics is open to serious question, except in likelthood that it will be ingested acciden- rare instances of severe hyperthemia and tally by a child is markedly increased. In in patients in whom the increased circula- recent studies on the epidemiology of ac- tory demands imposed by fever may be un- cidental poisonings in childhoods it was desirable; for example, children with myo- found that in the majority of instances of cardial disease. In the child who has a his- accidental ingestion of drugs by children, tory of convulsions, the administration of the material involved had been removed an anticonvulsant during febrile illnesses is from its usual place of storage to be ad- more rational and effective as a prophylac- ministered either to the child who ulti- tic measure against convulsions than the mately ingested it or to another member of routine use of antipyretics, and it permits the family. Of course, there is the addi- preservation of fever as a diagnostic and tional danger that therapeutic overdosage prognostic index. may occur despite (or because of) specific instructions from the physician. DISADVANTAGES OF ANTIPYRETIC DRUGS 5) Antipyresis is not the only therapeutic The potential disadvantages of the use effect of antipyretic drugs and the addi- of antipyretic drugs deserve consideration: tional effects may “mask” or suppress signs 1) The temperature course can be a valu- and symptoms which could be of diagnostic able diagnostic clue and an indicator of the importance. Most antipyretic drugs are an- severity or duration of illness, the adequacy algesics to a greater or lesser degree and of therapeutic response and the occurrence can therefore prevent the occurrence of of complications or relapse. It is rather in- pain. Most antipyretic drugs also have an- congruous that we should be so hesitant tirheumatic properties and will prevent the about administering an analgesic to a pa- development of such overt manifestations tient with unexplained abdominal pain, but as arthritis in the patient with rheumatic so willing to order an antipyretic for the fever, without altering the progression of patient whose only apparent abnormality at carditis. For this reason, their use in the the moment is unexplained fever. After a patient with unexplained fever, in whom diagnosis is established, fever may be the rheumatic fever is a diagnostic possibility, best, or the only, available sign for follow- is contraindicated until such time as this ing the course of illness. For example, sub- diagnosis is definitely confirmed or elimi- sidence of fever is a valuable indicator of nated. effectiveness of antibiotic therapy. 6) Finally, and perhaps most important, 2) There is, of course, the previously antipyretic therapy all too frequently is al- mentioned possibility that fever may actu- lowed to replace or delay efforts to estab- ally be a “friend” rather than an “enemy.” lish a definitive diagnosis and to institute The possibility that body defenses are specific treatment. strengthened in the presence of fever has The foregoing was not intended to imply neither been proved nor refuted. that sick children should not be made com- 3) The fact that severe allergic or idio- fortable. Although there is considerable syncratic reactions are relatively uncommon question whether fever per se is responsi- is little comfort to the patient who has one, ble for malaise, aches and pains, every or to his physician, particularly when mdi- physician has occasionally seen utter misery cations for the use of the drug were ques- give way to relaxation and sleep upon the tionable at best. administration of an antipyretic to a fe- 4) Where there are children, the mere bnile child. On the other hand, children presence of a potentially toxic substance often feel surprisingly well despite high (and this includes all antipyretics) invites fevers, and antipyretic therapy is employed

Downloaded from www.aappublications.org/news by guest on September 23, 2021 776 ANTIPYRETIC THERAPY more for the benefit of the parents or the lowing the environmental temperature to physician than the child. Recent publicity rise. This resulted in a gradual increase in has sensitized parents somewhat to the body temperature to 104#{176}F(40.0#{176}C). Re- dangers of the indiscriminate use of drugs, ducing the environmental temperature by and a word of explanation as to why treat- replacing ice in the enclosure was sufficient ment is being withheld will usually be ac- alone to cause a rapid reduction in fever. cepted and respected. An additional factor which is of impon- tance in determining heat diffusion is the OTHER MEASURES TO LOWER degree of hydration of the patient. Every BODY TEMPERATURE physician has observed children whose In the home care of the febnile child, fevers diminished when adequate hydration much of what is done actually interferes was accomplished. It has been shown that with heat diffusion from the body and tends heat loss through perspiration varies di- to elevate temperature further. Fever oc- recfly with the degree of hydration.5 curs because heat production exceeds heat Simple measures, such as those men- loss; the latter being dependent primarily tioned, will help to prevent the develop- upon conduction, convection and evapora- ment of excessive fever and, furthermore, tion. As the only factor which will diminish will increase the reliability of fever as a heat production is subsidence of the basic diagnostic and prognostic clue. Such steps disease process, any other reduction of body are important even when antipyretic drugs temperature must come about through en- are being used, as these compounds act hancement of heat loss. through the central nervous system to ne- The common practice of bundling the duce febnile temperatures by promoting febnile child in heavy blankets interferes heat 1085.6 with heat loss through evaporation, con- When it is deemed necessary to institute duction and convection. Excessively high additional measures to reduce fever, cau- environmental temperature interferes with tious sponging with tepid water, together heat loss by conduction; this can be cor- with gentle massage to promote cutaneous rected simply by cooling the sickroom suffi- vasodilatation, offer certain advantages over ciently to promote heat loss without pro- the use of antipyretic drugs. The accidental ducing discomfort. Heat diffusion by con- poisoning danger is lessened. The possibil- vection and evaporation can be augmented ity of toxic or idiosyncratic reactions and by increasing the circulation of air about the effects of antipyretic drugs other than the patient. Excessive humidity of the air antipyresis are eliminated. Temperature diminishes heat loss, because evaporation is control can be “titrated” more closely, and dependent upon the moisture content, as the temperature can be allowed to return well as the temperature, of the surrounding to its natural levels at will in order to de- air. The importance of some of these en- termine what course it is following. vironmental factors is illustrated in Figure SELECTION OF AN ANTIPYRETIC DRUG 1. This graph shows the temperature course of an infant with pneumonia and diarrhea; As for antipyretic drugs, the most enen- she had only a mild temperature elevation getic promotion and the greatest obfusca- until the temperature within the enclosure tion concerns various preparations of two in which she was kept (a “Baby Haven”) compounds, salicylamide and N-acetyl-p- was allowed to rise by removal of the ice amino-phenol (acetaminophen), and the container. The enclosure itself interfered comparison of these preparations with with heat loss by convection (which, in turn, acetylsalicylic acid (aspirin). Widely diver- would be expected to interfere to some ex- gent claims have been made regarding com- tent with cooling by evaporation), and heat parative toxicities and antipyretic potencies. loss by conduction was diminished by al- Much of the prevalent confusion has arisen

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Fio. 1. Increase in fever induced by impeding heat diffusion. as the result of poorly controlled clinical ex- reversed: salicylamide was more toxic than periments, attempts to compare animal aspirin in rats, and less toxic in mice and studies from one laboratory to another, and guinea pigs. The greatest difference in the efforts to extrapolate experience from one toxicities of the two compounds found in species of experimental animal to another or TABLE I even to humans. Table I presents data from published re- COMPARATIVE ORAL ToxiclTlxs OF SALICYLAMIDE AND ASPIRIN IN ANIMALS* ports concerning the comparative oral toxic- ities for animals of salicylamide and aspi- (Aspirin Toxicity= 1) rin. Only those studies which made simul- Species taneous comparisons of the two drugs are 1k!e summarized here. Each figure represents Rat Mous6 Guinea Pig the ratio of the LD50 for aspirin and sali- cylamide. A figure of one indicates that the Drebinger7 . 83 1.64 Hart9 1.07 .79 oral toxicities of the two drugs were equal; Bavin’#{176} .8 a figure of greater than one indicates that Carron’1 1.38 salicylamide was more toxic than aspirin, Boxill8 1.46 .80f .6 and a figure of less than one that it was .676* less toxic. Matsumur&2 .65

These data illustrate well the fallacy of * Based on ratio of inferring that a compound will have a par- Aspirin ticular toxicity in one species on the basis LD50: -. of its toxicity in another. In the experiments Salicylamide of Drebinger,T for example, salicylamide (A figure of greater than one indicates that salicylamide was 83% as toxic as aspirin in rats, but was was more toxic than aspirin and a figure Qfle8s than one 64% more toxic than aspirin in the mouse. that it was less toxic.) In the studies of Boxill8 the situation was t Fasted vs. non-fasted animals.

Downloaded from www.aappublications.org/news by guest on September 23, 2021 778 ANTIPYRETIC THERAPY these studies was 64%, and in most instances feature is central nervous system depres- the differences were much less. These data sion, and death may occur as the result of indicate that when salicylamide and aspirin respiratory failure. Hyperpnea does not oc- are compared in the same laboratory under cur, nor do the respiratory alkalosis and identical conditions, there appear to be no metabolic acidosis seen in salicylate intoxi- consistent or striking differences in their cation. There is no specific antidote, and toxicities in experimental animals. treatment is entirely symptomatic. There are fewer data regarding the corn- Claims regarding the comparative anti- parative oral toxicities of acetaminophen pyretic potencies of salicylamide, aceta- and aspirin in animals (Table II). Species minophen and aspirin are conflicting. Fig- differences are at least as striking here as ure 2 presents a comparison, adapted from in the evaluations of salicylamide toxicity. the data of Boxill,8 of the effects of these In the experiments of Boxill, acetaminophen three drugs in rats. The curves depict the was much less toxic than aspirin in rats and differences in temperature from those found guinea pigs, and much more toxic in fasted in untreated, febnile rats and therefore pro- mice, and the toxicities of the two corn- vide an estimate of the degree of tempera- pounds were essentially equal in mice that ture reduction which was achieved at vary- were not fasted. ing intervals of time after the oral adminis- In these and in the salicylamide studies, tration of the test drugs. In these expeni- it is apparent that marked species differ- ments, both salicylamide and acetamino- ences preclude making even an intelligent phen produced a more rapid fall in tern- guess as to the comparative toxicities of penature than did aspirin. However, the aspirin, salicylamide and acetaminophen in temperature did not fall as far in salicyla- human beings. At the present time, there mide-treated animals and returned within 2 are not sufficient data regarding human hours nearly to the levels seen in the fe- cases of intoxication with the latter two bnile controls. Acetaminophen provoked es- compounds to permit direct estimations of sentially the same degree of temperature comparative toxicities. reduction as aspirin, but its effect was Intoxication either with salicylamide or somewhat less prolonged. acetaminophen differs markedly from in- These results agree well with those ob- toxication with aspirin. The most striking tained by other 14 although one investigator found no antipyretic effect of TABLE II salicylamide in rabbits,15 even when twice COMPARATIVE ORAL TOXICITIES OF ACETAMINOPHEN the effective dose of aspirin was given. AND ASPIRIN IN ANIMALS* These data cannot, of course, be trans- (Aspirin Toxicibj= 1) posed directly to human subjects. However, the fact that the curves depicted here paral- Species lel the blood levels obtained with these Reference Rat Mouse Guinea Pig compounds in human suggests that similar curves of antipyretic effect Boxill’ .39 2.05f .41 might be expected. 1.18** In a recent report by Vignec18 on the antipyretic effectiveness of salicylamide in * Based on ratio of febrile infants, it was suggested that this Aspirin compound and aspirin were equally effec- LD50: Acetaminophen tive. However, despite the fact that the dose of salicylamide used was twice as (A figure of greater than one indicates that acetami- large as the dose of aspirin, the degree of nophen was more toxic than aspirin and a figure of less antipyresis which was achieved was no than one that it was less toxic.) t Fast.ed vs. non-fasted animals. greater, and actually may have been less.

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HOURS AFTER DRUG (Each drug given orally in a dose of 125mg/kg.)

FIG. 2. Comparative antipyretic activities of aspirin (A), N-acetyl-p-aminophenol, acetaminophen (N) and salicylamide (S) in rats. Curves depict differences of tern- perature between treated and untreated febrile animals. Adapted from the data of Boxill.8

Colgan and Mintz19 found that the anti- by mixing it with honey or jam) than to pyretic effects of acetaminophen and aspi- invite disaster by storing it about the home nfl were essentially equivalent in febnile disguised as candy or a tasty beverage. This children, though the duration of action of remark applies as well to candied aspirin as acetaminophen was somewhat shorter than to flavored liquid preparations. Aspirin ac- that of aspirin. tually is not so unacceptable to children as The foregoing suggest that aspirin and to warrant its substitution by other prepa- acetaminophen are closely comparable, rations or the addition of flavoring, for while salicylamide is somewhat inferior, in- reasons of acceptability alone. sofar as antipynetic effectiveness is con- At least in the home care of children, cerned. accuracy of dosage is a highly overrated There are, of course, additional factors factor. It is certain that, if the material in which should be considered and which have question were being injected from a syringe been brought forth in claims regarding or instilled directly from a pipette into the these compounds. The fact that salicyla- child’s stomach, a liquid preparation could mide, acetaminophen and a number of ad- be handled with much greaten accuracy. ditional analgesic-antipyretic formulations However, this difference largely disappears are available as palatable liquids purport- when the drug is measured in units of tea- edly makes for greater acceptance and “ac- spoonful or approximate fractions thereof, curacy of dosage.” Acceptability of any and an unknown amount is dispensed down potentially-toxic material is a doubtful the child’s chin. Furthermore, when anti- blessing. The more acceptable the material, pyretic drugs are used properly, the thera- the more likely that it will be ingested in peutic dose is so far removed from the potentially toxic amounts by a child. It toxic dose that a high degree of accuracy seems far safer to make a drug palatable at is not necessary. the time it is administered (for example, Salicylamide and acetaminophen are not

Downloaded from www.aappublications.org/news by guest on September 23, 2021 780 ANTIPYRETIC THERAPY salicylates and are not converted to salicy- analgesic and antipyretic properties of late in the Consequently, these some derivatives of salicylamide. J. Pharm. & Pharmacol., 4:872, 1952. compounds can be used in patients who are 11. Cannon, M., Tabart, J., and Tabart, J.: sensitive to aspirin. Etude des propni#{233}t#{233}sanalgesiques de Aside from the latter point, there appear quelques d#{233}riv#{233}sdesubstitution de la to be no highly cogent reasons for selecting salicylamide. Th#{233}rapie, 7:27, 1952. one of these newer antipyretics over one 12. Matsumura, M. : Pharmacological studies which may have stood the physician in good on salicylamide and its derivatives. I. Experimental investigations of analgesic stead in the past. This statement is meant and antipyretic actions. Folia pharmacol. not to champion the cause of older prepa- japon., 50:60, 1954. rations, but rather to inject what seems to 13. Bor#{233}us, L., and Sandberg, F. : A corn- be an appropriate attitude of reasonable- panison of some pharmacological effects ness into a problem which for many has of acetophenetidin and N-acetyl-p- aminophenol. Acta physiol. scandinav., been perplexing indeed. 28:261, 1953. 14. Buller, R. H., Miya, T. S., and Carr, C. J.: REFERENCES The comparative antipyretic activity of 1. DuBois, E. F. : Fever and the Regulation acetylsalicylic acid and salicylamide in of Body Temperature. Springfield, fever-induced rats. J. Pharm. & Phar- Thomas, 1948. macol., 9:128, 1957. 2. Bennett, I. L., Jr. : The significance of fever 15. Carisson, A., and Magnusson, T. : Failure in infections. Yale J. Biol. & Med., 26: to demonstrate antipyretic and analgesic 491, 1954. properties of salicylarnides. Acta phar- 3. DuBois, E. F. : Why are fever tempera- macol. et toxicol., 11 :248, 1955. tures over 106#{176}F.rare? Am. J. M. Sc., 16. Hidalgo, J., Seeberg, V. P., and Gul Den- 217:361, 1949. zopf, J. : A note on serum levels and ex- 4. Price, R., Newman, W. R. E., and Done, cretion of salicylamide in man. J. Am. A. K. : The epidemiology of accidental Pharm. A. (Scient. Ed.), 44:384, 1955. poisonings in children, in preparation. 17. Weikel, J. H., Jr. : A comparison of human 5. Manchester, R. C., Husted, C., and Mc- serum levels of acetylsalicylic acid, Quarrie, I. : Influence of state of hydra- salicylamide, and N-acetyl-p-amino- tion of body on insensible loss of weight phenol following oral administration. J. in children. J. Nutrition, 4:39, 1931. Am. Pharm. A. (Scient. Ed.), 47:477, 6. Selle, W. A. : Body Temperature: Its 1958. Changes with Environment, Disease, 18. Vignec, A. J., and Gasparik, M. : Anti- and Therapy. Springfield, Thomas, 1952. pyretic effectiveness of salicylamide and 7. Drebinger, J. : Salicylamid. Die Medizi- acetylsalicylic acid in infants. J.A.M.A., nische, 7:795, 1952. 167:1821, 1958. 8. Boxill, G. C., Nash, C. B., and Wheeler, 19. Colgan, M. T., and Mintz, A. A. : The A. G. : Comparative pharmacological and comparative antipyretic effect of N- toxicological evaluation of N-acetyl-p- acetyl-p-aminophenol and acetylsalicylic aminophenol, salicylamide, and acetyl- acid. J. Pediat., 50:552, 1957. salicylic acid. J. Am. Pharm. A. (Scient. 20. Brodie, B. B. : Basic chemistry of N- Ed.), 47:479, 1958. acetyl-p-aminophenol, in Symposium on 9. Hart, E. R. : Toxicity and analgetic potency N-acetyl-p-aminophenol. Ellchart, Ind., of salicylamide and certain of its deniva- Institute for the Study of Analgesic and tives as compared with established Sedative Drugs, 1952, pp. 11-18. analgetic-antipyretic drugs. J. Pharmacol. 21. Mandel, H. G., Rodwell, V. W., and Smith, & Exper. Therap., 89:205, 1947. P. K. : A study of the metabolism of 10. Bavin, E. M., Macrae, F. J., Seymour, C14 salicylamide in the human. j. Phar- D. E., and Waterhouse, P. D. : The macol. & Exper. Therap., 106:433, 1952.

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1959 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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