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
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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
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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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AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 777
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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.
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778 ANTIPYRETIC THERAPY
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.
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HOURS AFTER DRUG(Each drug given orally in a dose of 125mg/kg.)
AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 779
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
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780 ANTIPYRETIC THERAPY
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.
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