1. health and fitness
2. disease

S219
Toxicities of Drugs Used in the Management of Fever
Karen I. Plaisance
University of Maryland School of Pharmacy, Baltimore
Fever is frequently managed outside the purview of medical professionals, and antipyretic
therapy, on the whole, is generally considered safe. However, each of the drugs used in the
management of fever has significant toxicities. The purpose of this review is to examine the
relative safety of such agents with a focus on the nonsteroidal anti-inflammatory drugs and
acetaminophen. Toxicity to the gastrointestinal, renal, and hepatic systems are considered;
the comparative safety profile of acetaminophen and ibuprofen as antipyretics are highlighted;
and specific recommendations to improve the safe use of these therapies are advanced.
Reprints or correspondence: Dr. Karen Plaisance, University of Maryland
School of Pharmacy, 100 Penn St., Rm. 540, Baltimore, MD 21201 (kplaisan
@rx.umaryland.edu).
Clinical Infectious Diseases 2000; 31(Suppl 5):S219–23
q 2000 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2000/3104S5-0011$03.00
viral infections (influenza and varicella) and the development of
Reye’s syndrome—a disorder characterized by encephalopathy,
fatty degeneration of the liver, and metabolic dysfunction. This
association resulted in public admonitions against use of aspirin
in children, culminating in warning labels mandated in 1986. The
decline in the use of aspirin in children in the United States has
been associated with a parallel decline in the incidence of Reye’s
syndrome. Indeed, from 1994 to 1997, no more than 2 cases of
the syndrome per year have been reported through the National
Reye’s Syndrome Surveillance System [2].
Acetaminophen is generally regarded as the safest antipyretic
drug; it has minimal activity against peripheral COX-1 and has
not been linked to Reye’s syndrome. Nevertheless, liver failure
is a well-recognized consequence of acetaminophen overdose.
Moreover, recent series and case reports have suggested that administration of multiple doses of the drug at just slightly higher
than the recommended maximum dose can also cause liver failure
[3]. In addition, recent evidence suggests that the metabolic pathways involved in the production of metabolites responsible for
acetaminophen’s liver toxicity are also present in the kidney. If
acetaminophen has a role in analgesic-associated nephropathy,
as some have suggested, generation of such toxic metabolites by
the kidney would be the likely mechanism [4].
GI Toxicity
Antipyretic-induced GI toxicity can be divided into 3 categories: mucosal lesions that are visible radiographically or
endoscopically, GI discomfort (such as dyspepsia, nausea, and
heartburn), and severe GI complications, such as perforated
ulcers and GI bleeding. Endoscopic lesions are common and
seen in a majority of people treated with NSAIDs [5]. Such
lesions are usually asymptomatic, healing and reappearing, despite continued NSAID therapy. Although gastric injury is a
general side effect of NSAIDs, there are differences in the incidence of such toxicity among the various over-the-counter
agents. Analysis of data from a single endoscopist suggests that
the mean gastric injury scores are greatest with aspirin (3.07)
and ketoprofen (2.38), lower with naproxen (1.17), and insignificant with ibuprofen (0.46) and acetaminophen (0.25) [6].
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The treatment of fever is often undertaken in the absence of
supervision from medical professionals, in no small part because
multiple antipyretic agents are available without a prescription.
Although aspirin and acetaminophen have been used medically
for a century, and acetaminophen has been available as a nonprescription drug since 1960, the past decade has seen the transition of nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen and ketoprofen from prescription-only to
nonprescription status. This multibillion-dollar industry offers
1300 products containing aspirin, acetaminophen, or NSAIDs,
either alone or in combination with other active drugs [1]. Although episodic use of these agents at appropriate doses for the
treatment of fever or analgesia is relatively safe, this safety profile
may be compromised in certain at-risk populations. In addition,
because many products contain several active drugs, the label
must be inspected carefully to prevent inadvertent overdosing.
Much of the toxicity associated with the NSAIDs and aspirin
arises because of well-known effects on constitutive isoforms of
cyclooxygenase (COX), especially COX-1. However, NSAIDs and
aspirin can also cause non–COX-mediated side effects. When minor side effects lead to the discontinuation of one agent, another
class is frequently empirically substituted [1]. Figure 1 summarizes
both the COX- and non-COX–mediated toxicities of drugs commonly used to treat fever.
Inhibition of COX is responsible for the more serious toxic
effects of these agents, particularly renal and gastrointestinal (GI)
toxicity. Although data pertaining to the incidence, severity, and
risk factors for the occurrence of these COX-mediated adverse
events have been obtained largely in patients receiving prescription, anti-inflammatory doses for long periods of time, there is
concern that these observations also apply to antipyretic
regimens.
In addition to COX-mediated effects, there is a well-known
epidemiologic association between aspirin use in children with
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Plaisance
Potential adverse effects of antipyretic agents. GI, gastrointestinal.
However, these observations must be interpreted with caution,
because, in as many as 50% of patients with serious GI hemorrhages, endoscopy fails to identify an active ulcer. Furthermore, a reduction in the incidence of endoscopic ulcers in clinical trials has not translated into a concomitant decrease in
clinically significant GI events. Therefore, endoscopic evidence
of mucosal damage is not a reliable predictor of NSAIDinduced serious GI complications [5].
On average, 10%–20% of patients experience dyspepsia while
taking NSAIDs, and, within 6 months of beginning therapy
with a NSAID, 5%–15% of patients with rheumatoid arthritis
discontinue the drug because of dyspepsia. However, dyspepsia
correlates poorly with both GI bleeding and endoscopically
identified GI lesions. In a prospective cohort of 1921 patients
with rheumatoid arthritis treated with NSAIDs, those with GI
symptoms were only slightly more likely to have serious GI
complications (2.7%) than were those without antecedent symptoms (2%). The majority (81%) of those developing major GI
complications had no previous GI symptoms [7].
Over-the-counter use of both aspirin and NSAIDs is frequent
among patients admitted for bleeding peptic ulcers. In one series, the overall prevalence of NSAID use among patients with
bleeding peptic ulcers in the week before admission was 56%
[8]. At the time this series was accumulated (1990–1992), ibuprofen was the only NSAID available without a prescription.
The annual relative risks of NSAID-induced GI complications serious enough to require hospitalization in patients with
osteoarthritis and rheumatoid arthritis are 2.51 and 6.77, respectively [5]. The lower relative risk of such toxicity in patients
with osteoarthritis probably reflects a lack of concomitant use
of corticosteroids, as well as use of lower doses of NSAIDs,
than by patients with rheumatoid arthritis. In the United States,
NSAIDs are used chronically by as many as 13 million people
with rheumatoid arthritis and osteoarthritis. At an estimated
cost per NSAID-related hospitalization of $15,000–$20,000,
such toxicity has a probable annual direct cost of 1$2 billion
[5]. Advanced age is the primary risk factor for serious NSAIDinduced GI toxicity. Other risk factors are listed in table 1 [9].
Of these risk factors, one of the most relevant to episodic use
for the treatment of fever is the shorter duration of therapy.
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Figure 1.
CID 2000;31 (Suppl 5)
CID 2000;31 (Suppl 5)
Fever and Drug Toxicity
Table 1. Risk factors for serious gastrointestinal toxicity from nonsteroidal anti-inflammatory drugs (NSAIDs).
Risk factor(s)
Advanced age
High doses of NSAIDs
History of peptic ulcer disease or gastrointestinal bleeding
Concomitant corticosteroid use
Shorter duration of therapy
Concomitant anticoagulant therapy
Renal Toxicity
Four forms of renal toxicity have been associated with
NSAIDs, aspirin, and acetaminophen: fluid and electrolyte disturbances, acute renal failure, acute interstitial nephritis, and
analgesic-associated nephropathy. The first 3 are renal abnormalities most commonly associated with the use of nonselective
COX inhibitors. Analgesic-induced nephropathy has been associated primarily with the habitual consumption of combination analgesic products that contain phenacetin.
The severe renal effects of NSAIDs are most evident in the
setting of reduced intravascular volume, where prostaglandins
are needed to moderate the adverse renal effects of circulating
neurohumoral vasoconstrictors. Under such circumstances, the
loss of vasodilatory prostaglandins can cause an abrupt decline
in the glomerular filtration rate, resulting in oliguric renal failure. When this is due to a NSAID, discontinuing the drug
usually results in the prompt resolution of the acute renal failure
[12]. Risk factors for NSAID-induced acute renal failure include dehydration, New York Heart Association class III and
IV heart failure, and liver failure with ascites [12].
Fluid and electrolyte disturbances are the most common renal side effects of NSAIDs. Most people treated with NSAIDs
retain sodium, although this sodium retention is transient, diminishing over several days. Few people develop frank edema
because of NSAID-induced sodium retention, and prompt natriuresis follows discontinuation of such drugs [12]. However,
NSAID-induced sodium retention can interfere with the activity
of both loop and thiazide diuretics and limit their effectiveness
in the management of cardiovascular disease [1, 12]. Another
major NSAID-induced electrolyte abnormality, hyperkalemia,
rarely occurs in the absence of other factors that affect potassium homeostasis. NSAIDs suppress prostaglandin-mediated
renin release, thereby inducing a state of hyporeninemic hypoaldosteronism [12]. Patients with insulin-dependent diabetes
mellitus, particularly those with impaired renal function, and
patients receiving concomitant therapy with beta blockers or
potassium-sparing diuretics are at risk of acquiring NSAIDinduced hyperkalemia. NSAIDs also cause water retention by
enhancing the action of antidiuretic hormone [12].
Acute interstitial nephritis is a rare side effect of NSAIDs,
generally occurring after 2–18 months of therapy. Although
most cases are reversible, NSAID-induced nephritis may be
severe enough to require dialysis. Reactive, non-COX by-products of arachidonic acid metabolism are the putative mediators
of this adverse reaction [12].
Analgesic-associated nephropathy (AAN) was first recognized
140 years ago as a progressive disorder characterized by renal
papillary necrosis and chronic interstitial nephritis in habitual
overconsumers of phenacetin-containing combination products
[13]. Although AAN has declined in incidence since the banning
of phenacetin in many countries, it has not yet disappeared. This
might be because acetaminophen is a major metabolite of phenacetin, and many products previously containing phenacetin
have had acetaminophen substituted for phenacetin. Although
epidemiologic data incriminating acetaminophen as a cause of
AAN are inconclusive (largely because of confounding by other
analgesics and recall bias) [13], case-control studies have suggested a weak association between habitual use of acetaminophen
and chronic renal insufficiency and end-stage renal disease [14].
Renal papillary necrosis and chronic renal failure have also been
associated with the daily use of prescription and over-the-counter
NSAIDs, although the magnitude of the risk is uncertain [12,
15].
Hepatotoxicity
Acetaminophen is primarily metabolized by glucuronidation
and sulfation, but also, to a lesser extent, via the p450 2E1 pathway to a highly electrophilic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). When primary pathways are saturated,
NAPQI accumulates and binds covalently to cell proteins and
DNA [16]. When such binding is extensive and involves hepatocytes, acute liver toxicity ensues. Under normal circumstances,
NAPQI is detoxified by conjugation to glutathione. If glutathione
stores are depleted (e.g., during chronic ethanol abuse or star-
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Longitudinal endoscopic evaluation of volunteers treated with
aspirin (for <8 weeks) suggests that the gastric mucosa adapts
to the toxic effects of aspirin [10]. Studies have suggested that
GI toxicity occurs most often during the initial month of therapy
[11]. However, a cohort of 1600 patients followed for <15 years
after initiation of NSAID therapy revealed a constant risk of GI
bleeding throughout the study period [5]. Although these data
are conflicting, the duration of NSAID use remains a important
risk factor for GI bleeding. The relative risk of such toxicity with
episodic versus chronic use awaits further study.
In patients with rheumatoid arthritis, the crude death rate due
to NSAID-induced GI toxicity is 0.22% per year, with an annual
relative risk of death of 4.21 [5]. Given that 13 million patients
with arthritides use NSAIDs, if the death rate attributed to
NSAIDs in osteoarthritis is just half that observed in patients
with rheumatoid arthritis, an estimated 16,500 arthritis patients
die of NSAID-induced GI toxicity each year. This estimate would
make NSAID-related mortality the 15th leading cause of death
in the United States [5], even if deaths due to over-the-counter
NSAIDs used for nonarthritic conditions are ignored.
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Comparative Safety of Antipyretic Drugs
From 1991 through 1993, a landmark, randomized, officebased, controlled clinical trial compared the risk of serious, but
uncommon, adverse events due to ibuprofen (at 2 dose levels)
with that due to acetaminophen. Children were excluded if they
were significantly dehydrated or if they had known aspirin sensitivity. The primary outcomes assessed included hospitalization
within 4 weeks of entry to the study for acute GI bleeding,
acute renal failure, anaphylaxis, and Reye’s syndrome. More
than 84,000 children participated in the study, of which the
overall results were published in 1995 [19]. Subsequent analyses
focused on specific areas of interest [20, 21]. The median duration of treatment was 3 days. Approximately 1% of study
subjects in each of the 3 groups was hospitalized, generally for
treatment of an infectious disease. Four children were hospitalized for acute GI bleeding. Interestingly, all had been treated
with ibuprofen [19], and 3 of 4 were aged !2 years [21]. The
risk of hospitalization for acute GI bleeding in those receiving
ibuprofen was 7.2 per 100,000 (17 per 100,000 in children aged
!2 years), which was not significantly different from acetaminophen. There were no episodes of Reye’s syndrome, anaphylaxis,
or acute renal failure in any of the children receiving ibuprofen
[19, 21]. A further analysis of relatively crude measures of renal
function in hospitalized children suggested no greater risk of
renal insufficiency among children treated with ibuprofen than
among those receiving acetaminophen [20]. These studies verify
the safety of both ibuprofen and acetaminophen, given individually in the appropriate doses, for the short-term management of fever.
Alternating acetaminophen with ibuprofen (with doses administered every 2–3 h) is sometimes recommended in cases of
refractory fever. The practice most likely recalls the former use
of the combination of aspirin and acetaminophen in the era
before aspirin was recognized to cause Reye’s syndrome [22].
The time course of antipyretic effects of these agents, however,
does not support such a strategy. Although temperature begins
to decrease within 30 min of ingestion, the maximum druginduced reduction in temperature is generally not achieved until
after 3–4 h [23]. For this reason, and because of the increased
potential for toxicity, such alternating antipyretic regimens are
not recommended [24].
COX-2 Inhibitors
The Food and Drug Administration has recently approved
2 selective inhibitors of COX-2, celecoxib and rofecoxib. Because COX-2 is the primary COX isoform implicated in the
febrile response, the antipyretic effectiveness of COX-2 inhibitors should be similar to the nonselective COX inhibitors. Indeed, analysis of data obtained using rofecoxib suggests that
COX-2 inhibitors have antipyretic activity comparable with
ibuprofen [25]. The major benefit from these agents relates primarily to their COX-1 sparing effect, which has the potential
to reduce drug-related GI and renal toxicity [26]. The results
of a multicenter randomized trial involving 1149 patients [27]
and a combined analysis from 8 randomized clinical trials involving 5435 patients [28] suggest that COX-2 inhibitors do
indeed cause fewer asymptomatic GI lesions than do the nonselective NSAIDs. However, several lines of evidence suggest
that selective COX-2 inhibitors are not devoid of GI and renal
toxicity [29] and that COX-2, like COX-1, is constitutively expressed in tissues such as the GI mucosa, where it has an important role in homeostasis [30]. Nevertheless, the COX-2 inhibitors appear to be cost-effective in certain high-risk patients
receiving chronic high doses of these drugs as an alternative to
nonselective NSAIDs combined with antiulcer prophylaxis [26].
Conclusion
Given the frequency of antipyretic use for the treatment of
fever and the relative paucity of adverse events associated with
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vation), the risk of acetaminophen-induced hepatotoxicity increases markedly [16, 17].
Whereas acute liver failure in the setting of attempted suicide
with acetaminophen is well recognized, only recently has attention focused on the risk of hepatic injury due to acetaminophen administered in doses within or only slightly above the
recommended range (4 g in 24 h). In a recent series of 71 cases
of acetaminophen-induced hepatotoxicity, 30% of the cases
were due to accidental overdoses in patients using the drug for
pain relief [16]. Reasons for excessive dosing included too frequent dosing, simultaneous ingestion of multiple acetaminophen-containing products, and ingestion of cough and cold
remedies not recognized as containing acetaminophen.
Acetaminophen-induced hepatotoxicity has also occurred in
children because of inadvertent administration of multiple
supratherapeutic doses of the drug. Such overdoses occur because of simultaneous administration of several acetaminophen-containing products or of administration of acetaminophen-containing preparations geared to adults; overdoses may
also occur as a result of simple dosage miscalculations. In the
largest pediatric series reported to date [3], half of the children
died (24 deaths), and 3 survived after orthotopic liver transplantation. Although 52% of the children had received adult
formulations of acetaminophen, ∼15% had received doses of
acetaminophen within or only slightly above the approved dosage range (<100 mg/kg/d). Children with comorbidities were
likely be at increased risk of acquiring acetaminophen-induced
hepatotoxicity, both because of drug-mediated perturbations of
the metabolism of acetaminophen (induction of p450) and because of transient glutathione deficiency resulting from their
acute illness [18]. Such data underscore the importance of detailed parental education in the appropriate use of acetaminophen-containing products.
CID 2000;31 (Suppl 5)
CID 2000;31 (Suppl 5)
Fever and Drug Toxicity
Table 2. Recommendations regarding antipyretic selection in specific
populations.
Population, agent
Children
Acetaminophen
Aspirin
Adults (especially those with
hypertension or diabetes)
Acetaminophen
NOTE.
Follow dosing guidelines; avoid multisymptom
products
Avoid in view of Reye’s syndrome
Follow dosing guidelines; avoid multisymptom
products
8.
9.
10.
11.
Avoid in hepatic failure
12.
Avoid and/or reduce dose if malnourished
Avoid habitual use
13.
Avoid if intravascularly depleted
NSAID, nonsteroidal anti-inflammatory drug.
14.
15.
such therapy, treatment of fever with antipyretic agents should
be considered safe. However the following caveats are in order.
First, there are probably some populations at increased risk for
adverse events, even with episodic treatment employing single
agents [15]. Table 2 summarizes recommendations regarding
the selection of agents in specific populations. Second, patients
should receive clear instructions regarding formulation-specific
dosing guidelines and the need to account for antipyretic content of combination multisymptom products. Finally, expectations regarding the response to antipyretic agents should be
addressed. Attempts at achieving euthermia through aggressive
pharmacotherapy should be modulated by the toxicities of the
individual agents. Adherence to these principles should allow
for even safer use of these agents in the management of fever.
16.
17.
18.
19.
20.
21.
22.
23.
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Reduced intravascular volume
Acetaminophen
Dehydration
Acetaminophen
Renal disease
Acetaminophen
Liver disease
NSAID
Cautions
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