uses and abuses of antipyretic therapyfever, without altering the progression of carditis. for this...

USES AND ABUSES OF ANTIPYRETIC THERAPY

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

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

F� � undoubtedly the most commonsymptom confronting the physician

who treats children. It is fought as though

it were the patient’s primary disease, and

its mere presence is often accepted as being

sufficient indication for the institution of

antipyretic therapy. It is not surprising,

therefore, that therapeutists and pharma-

ceutical concerns have energetically sought

new and better drugs for the control of

fever. In the past few years there has ap-

peared on the market a number of new

formulations which are purported to offer

distinct advantages in terms of antipyretic

potency, acceptance by children, and/or

reduced toxicity.

It is axiomatic that virtually any claim

regarding a drug can be supported by pub-

lished data, if the proper study is selected

and interpretation is sufficiently influenced

by conviction. Particularly is this true of

antipyretic-analgesic drugs, where such fac-

tons as lability in the case of fever and lack

of objectivity in the case of pain, make

evaluation difficult. The claims and counter-

claims which have been made concerning

antipynetic drugs have led to considerable

confusion and misunderstanding on the part

of clinicians in general. The purpose of this

presentation is to attempt to provide some

clarification of this problem.

IS ANTIPYRESIS INDICATED?

More critical than the choice of an anti-pyretic is the question of whether or not

such therapy is indicated in the individual

case, for there is little doubt that these

drugs are grossly overused, at times to the

detriment of the patient. Therefore, before

discussing the antipyretics themselves, it

seems appropriate to review briefly a num-

ben of points which deserve consideration

before one elects to use an antipyretic.

DuBois’ summarized a lifetime of study

on fever and the regulation of body tem.

penature with the statement: “Fever is only

a symptom and we are not sure that it is

an enemy. Perhaps it is a friend.” The litena-

tune concerning the possible role of fever in

body defenses is extensive and inconclusive.

There is little question that artificially in-

duced fever is of some value in the treat-

ment of such diseases as neurosyphilis, cer-

tam inflammations of the eye, and arthritis.

In animal experiments, elevation of body

temperature has been shown to be of im-

portance in resistance to certain infections.2

Body temperatures of greater than 106#{176}F

(41.1#{176}C) rarely occur except under highly

anomalous circumstances, and this level is

probably safely below the point at which

temperature itself poses an immediate

threat to the individual.3 Circumstances

which may lead to higher temperatures in-

elude: exposure to a sudden overwhelming

heat load, such as injection of pynogen or

placement in a steam cabinet; excessively

prolonged exposure to a heat load with re-

sultant “exhaustion” of temperature-regulat-

ing processes; and the loss of temperature

regulation seen in association with severe

brain damage and in moribund patients. It

has been postulated that, except under cm-

cumstances such as these, an “emergency

regulatory mechanism” in fever operates to

prevent the elevation of body temperature

to levels at which fever per se is life-

threatening.3

It is doubtful whether body temperatures

in the range of 104#{176}F(40.0#{176}C) are harm-

ful, even if prolonged for several days.1 In-

deed, this is the temperature level found in

by guest on March 30, 2021www.aappublications.org/newsDownloaded from

AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 775

athletes during hard exercise. Thus, the

rationale for the administration of antipy-

retics is open to serious question, except in

rare instances of severe hyperthemia and

in patients in whom the increased circula-

tory demands imposed by fever may be un-

desirable; for example, children with myo-

cardial disease. In the child who has a his-

tory of convulsions, the administration of

an anticonvulsant during febrile illnesses is

more rational and effective as a prophylac-

tic measure against convulsions than the

routine use of antipyretics, and it permits

preservation of fever as a diagnostic and

prognostic index.

DISADVANTAGES OF ANTIPYRETIC DRUGS

The potential disadvantages of the use

of antipyretic drugs deserve consideration:

1) The temperature course can be a valu-

able diagnostic clue and an indicator of the

severity or duration of illness, the adequacy

of therapeutic response and the occurrence

of complications or relapse. It is rather in-

congruous that we should be so hesitant

about administering an analgesic to a pa-

tient with unexplained abdominal pain, but

so willing to order an antipyretic for the

patient whose only apparent abnormality at

the moment is unexplained fever. After a

diagnosis is established, fever may be the

best, or the only, available sign for follow-

ing the course of illness. For example, sub-

sidence of fever is a valuable indicator of

effectiveness of antibiotic therapy.

2) There is, of course, the previously

mentioned possibility that fever may actu-

ally be a “friend” rather than an “enemy.”

The possibility that body defenses are

strengthened in the presence of fever has

neither been proved nor refuted.

3) The fact that severe allergic or idio-

syncratic reactions are relatively uncommon

is little comfort to the patient who has one,

or to his physician, particularly when mdi-

cations for the use of the drug were ques-

tionable at best.

4) Where there are children, the mere

presence of a potentially toxic substance

(and this includes all antipyretics) invites

disaster. Moreover, each time a drug is re-

moved from its usual storage place, the

likelthood that it will be ingested acciden-

tally by a child is markedly increased. In

recent studies on the epidemiology of ac-

cidental poisonings in childhoods it was

found that in the majority of instances of

accidental ingestion of drugs by children,

the material involved had been removed

from its usual place of storage to be ad-

ministered either to the child who ulti-

mately ingested it or to another member of

the family. Of course, there is the addi-

tional danger that therapeutic overdosage

may occur despite (or because of) specific

instructions from the physician.

5) Antipyresis is not the only therapeutic

effect of antipyretic drugs and the addi-

tional effects may “mask” or suppress signs

and symptoms which could be of diagnostic

importance. Most antipyretic drugs are an-

algesics to a greater or lesser degree and

can therefore prevent the occurrence of

pain. Most antipyretic drugs also have an-

tirheumatic properties and will prevent the

development of such overt manifestations

as arthritis in the patient with rheumatic

fever, without altering the progression of

carditis. For this reason, their use in the

patient with unexplained fever, in whom

rheumatic fever is a diagnostic possibility,

is contraindicated until such time as this

diagnosis is definitely confirmed or elimi-

nated.

6) Finally, and perhaps most important,

antipyretic therapy all too frequently is al-

lowed to replace or delay efforts to estab-

lish a definitive diagnosis and to institute

specific treatment.

The foregoing was not intended to imply

that sick children should not be made com-

fortable. Although there is considerable

question whether fever per se is responsi-

ble for malaise, aches and pains, every

physician has occasionally seen utter misery

give way to relaxation and sleep upon the

administration of an antipyretic to a fe-

bnile child. On the other hand, children

often feel surprisingly well despite high

fevers, and antipyretic therapy is employed


776 ANTIPYRETIC THERAPY

more for the benefit of the parents or the

physician than the child. Recent publicity

has sensitized parents somewhat to the

dangers of the indiscriminate use of drugs,

and a word of explanation as to why treat-

ment is being withheld will usually be ac-

cepted and respected.

OTHER MEASURES TO LOWER

BODY TEMPERATURE

In the home care of the febnile child,

much of what is done actually interferes

with heat diffusion from the body and tends

to elevate temperature further. Fever oc-

curs because heat production exceeds heat

loss; the latter being dependent primarily

upon conduction, convection and evapora-

tion. As the only factor which will diminish

heat production is subsidence of the basic

disease process, any other reduction of body

temperature must come about through en-

hancement of heat loss.

The common practice of bundling the

febnile child in heavy blankets interferes

with heat loss through evaporation, con-

duction and convection. Excessively high

environmental temperature interferes with

heat loss by conduction; this can be cor-

rected simply by cooling the sickroom suffi-

ciently to promote heat loss without pro-

ducing discomfort. Heat diffusion by con-

vection and evaporation can be augmented

by increasing the circulation of air about

the patient. Excessive humidity of the air

diminishes heat loss, because evaporation is

dependent upon the moisture content, as

well as the temperature, of the surrounding

air. The importance of some of these en-

vironmental factors is illustrated in Figure

1. This graph shows the temperature course

of an infant with pneumonia and diarrhea;

she had only a mild temperature elevation

until the temperature within the enclosure

in which she was kept (a “Baby Haven”)

was allowed to rise by removal of the ice

container. The enclosure itself interfered

with heat loss by convection (which, in turn,

would be expected to interfere to some ex-

tent with cooling by evaporation), and heat

loss by conduction was diminished by al-

lowing the environmental temperature to

rise. This resulted in a gradual increase in

body temperature to 104#{176}F(40.0#{176}C). Re-

ducing the environmental temperature by

replacing ice in the enclosure was sufficient

alone to cause a rapid reduction in fever.

An additional factor which is of impon-

tance in determining heat diffusion is the

degree of hydration of the patient. Every

physician has observed children whose

fevers diminished when adequate hydration

was accomplished. It has been shown that

heat loss through perspiration varies di-

recfly with the degree of hydration.5

Simple measures, such as those men-

tioned, will help to prevent the develop-

ment of excessive fever and, furthermore,

will increase the reliability of fever as a

diagnostic and prognostic clue. Such steps

are important even when antipyretic drugs

are being used, as these compounds act

through the central nervous system to ne-

duce febnile temperatures by promoting

heat 1085.6

When it is deemed necessary to institute

additional measures to reduce fever, cau-

tious sponging with tepid water, together

with gentle massage to promote cutaneous

vasodilatation, offer certain advantages over

the use of antipyretic drugs. The accidental

poisoning danger is lessened. The possibil-

ity of toxic or idiosyncratic reactions and

the effects of antipyretic drugs other than

antipyresis are eliminated. Temperature

control can be “titrated” more closely, and

the temperature can be allowed to return

to its natural levels at will in order to de-

termine what course it is following.

SELECTION OF AN ANTIPYRETIC DRUG

As for antipyretic drugs, the most enen-

getic promotion and the greatest obfusca-

tion concerns various preparations of two

compounds, salicylamide and N-acetyl-p-

amino-phenol (acetaminophen), and the

comparison of these preparations with

acetylsalicylic acid (aspirin). Widely diver-

gent claims have been made regarding com-

parative toxicities and antipyretic potencies.

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-

periments, attempts to compare animal

studies from one laboratory to another, and

efforts to extrapolate experience from one

species of experimental animal to another or

even to humans.

Table I presents data from published re-

ports concerning the comparative oral toxic-

ities for animals of salicylamide and aspi-

rin. Only those studies which made simul-

taneous comparisons of the two drugs are

summarized here. Each figure represents

the ratio of the LD50 for aspirin and sali-

cylamide. A figure of one indicates that the

oral toxicities of the two drugs were equal;

a figure of greater than one indicates that

salicylamide was more toxic than aspirin,

and a figure of less than one that it was

less toxic.

These data illustrate well the fallacy of

inferring that a compound will have a par-

ticular toxicity in one species on the basis

of its toxicity in another. In the experiments

of Drebinger,T for example, salicylamide

was 83% as toxic as aspirin in rats, but was

64% more toxic than aspirin in the mouse.

In the studies of Boxill8 the situation was

reversed: salicylamide was more toxic than

aspirin in rats, and less toxic in mice and

guinea pigs. The greatest difference in the

toxicities of the two compounds found in

TABLE I

COMPARATIVE ORAL ToxiclTlxs OF SALICYLAMIDEAND ASPIRIN IN ANIMALS*

(Aspirin Toxicity= 1)

1k!��e

Species

Rat Mous6 Guinea Pig

Drebinger7 . 83 1.64Hart9 1.07 .79Bavin’#{176} .8�

Carron’1 1.38Boxill8 1.46 .80f

.676*

.6�

Matsumur&2 .65

* Based on ratio of

Aspirin

LD50: -.Salicylamide

(A figure of greater than one indicates that salicylamidewas more toxic than aspirin and a figure Qfle8s than onethat it was less toxic.)

t Fasted vs. � non-fasted animals.



these studies was 64%, and in most instances

the differences were much less. These data

indicate that when salicylamide and aspirin

are compared in the same laboratory under

identical conditions, there appear to be no

consistent or striking differences in their

toxicities in experimental animals.

There are fewer data regarding the corn-

parative oral toxicities of acetaminophen

and aspirin in animals (Table II). Species

differences are at least as striking here as

in the evaluations of salicylamide toxicity.

In the experiments of Boxill, acetaminophen

was much less toxic than aspirin in rats and

guinea pigs, and much more toxic in fasted

mice, and the toxicities of the two corn-

pounds were essentially equal in mice that

were not fasted.

In these and in the salicylamide studies,

it is apparent that marked species differ-

ences preclude making even an intelligent

guess as to the comparative toxicities of

aspirin, salicylamide and acetaminophen in

human beings. At the present time, there

are not sufficient data regarding human

cases of intoxication with the latter two

compounds to permit direct estimations of

comparative toxicities.

Intoxication either with salicylamide or

acetaminophen differs markedly from in-

toxication with aspirin. The most striking

TABLE II

COMPARATIVE ORAL TOXICITIES OF ACETAMINOPHEN

AND ASPIRIN IN ANIMALS*

(Aspirin Toxicibj= 1)

Reference

Species

Rat Mouse Guinea Pig

Boxill’ .39 2.05f

1.18**

.41

* Based on ratio of

Aspirin

LD50:Acetaminophen

(A figure of greater than one indicates that acetami-nophen was more toxic than aspirin and a figure of lessthan one that it was less toxic.)

t Fast.ed vs. � non-fasted animals.

feature is central nervous system depres-

sion, and death may occur as the result of

respiratory failure. Hyperpnea does not oc-

cur, nor do the respiratory alkalosis and

metabolic acidosis seen in salicylate intoxi-

cation. There is no specific antidote, and

treatment is entirely symptomatic.

Claims regarding the comparative anti-

pyretic potencies of salicylamide, aceta-

minophen and aspirin are conflicting. Fig-

ure 2 presents a comparison, adapted from

the data of Boxill,8 of the effects of these

three drugs in rats. The curves depict the

differences in temperature from those found

in untreated, febnile rats and therefore pro-

vide an estimate of the degree of tempera-

ture reduction which was achieved at vary-

ing intervals of time after the oral adminis-

tration of the test drugs. In these expeni-

ments, both salicylamide and acetamino-

phen produced a more rapid fall in tern-

penature than did aspirin. However, the

temperature did not fall as far in salicyla-

mide-treated animals and returned within 2

hours nearly to the levels seen in the fe-

bnile controls. Acetaminophen provoked es-

sentially the same degree of temperature

reduction as aspirin, but its effect was

somewhat less prolonged.

These results agree well with those ob-

tained by other � 14 although one

investigator found no antipyretic effect of

salicylamide in rabbits,15 even when twice

the effective dose of aspirin was given.

These data cannot, of course, be trans-

posed directly to human subjects. However,

the fact that the curves depicted here paral-

lel the blood levels obtained with these

compounds in human � suggests

that similar curves of antipyretic effect

might be expected.

In a recent report by Vignec18 on the

antipyretic effectiveness of salicylamide in

febrile infants, it was suggested that this

compound and aspirin were equally effec-

tive. However, despite the fact that the

dose of salicylamide used was twice as

large as the dose of aspirin, the degree of

antipyresis which was achieved was no

greater, and actually may have been less.


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 dataof Boxill.8

Colgan and Mintz19 found that the anti-

pyretic effects of acetaminophen and aspi-

nfl were essentially equivalent in febnile

children, though the duration of action of

acetaminophen was somewhat shorter than

that of aspirin.

The foregoing suggest that aspirin and

acetaminophen are closely comparable,

while salicylamide is somewhat inferior, in-

sofar as antipynetic effectiveness is con-

cerned.

There are, of course, additional factors

which should be considered and which have

been brought forth in claims regarding

these compounds. The fact that salicyla-

mide, acetaminophen and a number of ad-

ditional analgesic-antipyretic formulations

are available as palatable liquids purport-

edly makes for greater acceptance and “ac-

curacy of dosage.” Acceptability of any

potentially-toxic material is a doubtful

blessing. The more acceptable the material,

the more likely that it will be ingested in

potentially toxic amounts by a child. It

seems far safer to make a drug palatable atthe time it is administered (for example,

by mixing it with honey or jam) than to

invite disaster by storing it about the home

disguised as candy or a tasty beverage. This

remark applies as well to candied aspirin as

to flavored liquid preparations. Aspirin ac-

tually is not so unacceptable to children as

to warrant its substitution by other prepa-

rations or the addition of flavoring, for

reasons of acceptability alone.

At least in the home care of children,

accuracy of dosage is a highly overrated

factor. It is certain that, if the material in

question were being injected from a syringe

or instilled directly from a pipette into the

child’s stomach, a liquid preparation could

be handled with much greaten accuracy.

However, this difference largely disappears

when the drug is measured in units of tea-

spoonful or approximate fractions thereof,

and an unknown amount is dispensed down

the child’s chin. Furthermore, when anti-

pyretic drugs are used properly, the thera-

peutic dose is so far removed from the

toxic dose that a high degree of accuracy

is not necessary.

Salicylamide and acetaminophen are not



salicylates and are not converted to salicy-

late in the � Consequently, these

compounds can be used in patients who are

sensitive to aspirin.

Aside from the latter point, there appear

to be no highly cogent reasons for selecting

one of these newer antipyretics over one

which may have stood the physician in good

stead in the past. This statement is meant

not to champion the cause of older prepa-

rations, but rather to inject what seems to

be an appropriate attitude of reasonable-

ness into a problem which for many has

been perplexing indeed.

REFERENCES

1. DuBois, E. F. : Fever and the Regulationof Body Temperature. Springfield,Thomas, 1948.

2. Bennett, I. L., Jr. : The significance of feverin infections. Yale J. Biol. & Med., 26:491, 1954.

3. DuBois, E. F. : Why are fever tempera-

tures over 106#{176}F.rare? Am. J. M. Sc.,217:361, 1949.

4. Price, R., Newman, W. R. E., and Done,A. K. : The epidemiology of accidentalpoisonings in children, in preparation.

5. Manchester, R. C., Husted, C., and Mc-Quarrie, I. : Influence of state of hydra-tion of body on insensible loss of weightin children. J. Nutrition, 4:39, 1931.

6. Selle, W. A. : Body Temperature: ItsChanges with Environment, Disease,and Therapy. Springfield, Thomas, 1952.

7. Drebinger, J. : Salicylamid. Die Medizi-nische, 7:795, 1952.

8. Boxill, G. C., Nash, C. B., and Wheeler,A. G. : Comparative pharmacological andtoxicological evaluation of N-acetyl-p-aminophenol, salicylamide, and acetyl-salicylic acid. J. Am. Pharm. A. (Scient.Ed.), 47:479, 1958.

9. Hart, E. R. : Toxicity and analgetic potencyof salicylamide and certain of its deniva-tives as compared with establishedanalgetic-antipyretic drugs. J. Pharmacol.& Exper. Therap., 89:205, 1947.

10. Bavin, E. M., Macrae, F. J., Seymour,D. E., and Waterhouse, P. D. : The

analgesic and antipyretic properties of

some derivatives of salicylamide. J.Pharm. & Pharmacol., 4:872, 1952.

11. Cannon, M., Tabart, J., and Tabart, J.:Etude des propni#{233}t#{233}sanalgesiques dequelques d#{233}riv#{233}sde substitution de lasalicylamide. Th#{233}rapie, 7:27, 1952.

12. Matsumura, M. : Pharmacological studies

on salicylamide and its derivatives. I.Experimental investigations of analgesicand antipyretic actions. Folia pharmacol.japon., 50:60, 1954.

13. Bor#{233}us, L., and Sandberg, F. : A corn-panison of some pharmacological effectsof acetophenetidin and N-acetyl-p-aminophenol. Acta physiol. scandinav.,

28:261, 1953.

14. Buller, R. H., Miya, T. S., and Carr, C. J.:The comparative antipyretic activity ofacetylsalicylic acid and salicylamide in

fever-induced rats. J. Pharm. & Phar-macol., 9:128, 1957.

15. Carisson, A., and Magnusson, T. : Failureto demonstrate antipyretic and analgesicproperties of salicylarnides. Acta phar-

macol. et toxicol., 11 :248, 1955.16. Hidalgo, J., Seeberg, V. P., and Gul Den-

zopf, J. : A note on serum levels and ex-cretion of salicylamide in man. J. Am.Pharm. A. (Scient. Ed.), 44:384, 1955.

17. Weikel, J. H., Jr. : A comparison of humanserum levels of acetylsalicylic acid,salicylamide, and N-acetyl-p-amino-phenol following oral administration. J.Am. Pharm. A. (Scient. Ed.), 47:477,1958.

18. Vignec, A. J., and Gasparik, M. : Anti-pyretic effectiveness of salicylamide and

acetylsalicylic acid in infants. J.A.M.A.,

167:1821, 1958.

19. Colgan, M. T., and Mintz, A. A. : Thecomparative antipyretic effect of N-acetyl-p-aminophenol and acetylsalicylicacid. J. Pediat., 50:552, 1957.

20. Brodie, B. B. : Basic chemistry of N-acetyl-p-aminophenol, in Symposium on

N-acetyl-p-aminophenol. Ellchart, Ind.,Institute for the Study of Analgesic andSedative Drugs, 1952, pp. 11-18.

21. Mandel, H. G., Rodwell, V. W., and Smith,P. K. : A study of the metabolism ofC14 salicylamide in the human. j. Phar-macol. & Exper. Therap., 106:433, 1952.


1959;23;774Pediatrics Alan K. Done


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uses and abuses of antipyretic therapyfever, without altering the progression of carditis. for this...

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