Clinical Inquiries

Do antipyretics prolong febrile illness?

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EVIDENCE-BASED ANSWER

Antipyretics appear to have minor and variable effects on the course of febrile illness. Aspirin and acetaminophen do not prolong the course of rhinovirus illness, although they may prolong the period of viral shedding and worsen nasal congestion (strength of recommendation [SOR]: A–, based on small randomized controlled trials).

Acetaminophen did not affect symptoms, overall condition, or time to complete healing in children with varicella, although it increased the time to total scabbing of lesions (SOR: A, based on a small randomized controlled trial). Aspirin and acetaminophen may prolong influenza A illness (SOR: C, based on a poor-quality, retrospective observational study).

Acetaminophen may prolong the course of Shigella sonnei infection (SOR: B–, based on a small retrospective cohort study). It does not affect malaria cure rate, and there are insufficient data to assess clearance of Plasmodium falciparum (SOR: C, based on small randomized controlled trials with heterogeneous results).

Evidence summary

Acetaminophen has a different mechanism of action from other antipyretics. It halts the production of prostaglandin in the brain but not in the periphery, solely lowering fever. Aspirin and other nonsteroidal anti-inflammatory agents inhibit both central and peripheral cyclooxygenase and may cause multiple effects in addition to temperature reduction. Clinical outcome studies of their antipyretic effects are inconclusive.1

A randomized controlled trial involving 60 volunteers given intranasal rhinovirus type 2 monitored the effect of aspirin, acetaminophen, ibuprofen, or placebo on virus shedding, immune response, and clinical status. There was no difference in duration of illness. There was a trend toward longer duration of virus shedding in the aspirin and acetaminophen groups, but serum neutralizing antibody response was suppressed (P<.05 vs placebo). Aspirin and acetaminophen worsened symptoms of turbinate edema and nasal obstruction (P<.05 vs placebo).2

In 2 double-blind trials, 45 adults infected with rhinovirus were given aspirin or placebo for 5 days, beginning on the day after viral exposure (as opposed to the typical use in response to symptoms). Aspirin treatment improved symptoms of conjunctivitis significantly, but did not change the duration of illness. Other symptoms (headache, sneezing, chills, malaise, nasal discharge) were not significantly different. Aspirin increased the amount of viral shedding by 36% in 1 trial and 17% in the other (P<.01), potentially increasing risk of spread.3

In a randomized controlled trial evaluating antipyretic effects on the duration or severity of childhood varicella, 31 children received placebo and 37 received acetaminophen for 4 days. There was no difference in itching, appetite, activity, or overall condition between the 2 groups. Children treated with acetaminophen took 1.1 days longer to total scabbing (P<.05), although the number of days until the appearance of the last new vesicle and the time to total healing were unchanged. The duration of viral shedding was not measured, but it is possible that the delay in healing of lesions would prolong viral shedding as well.4

A retrospective observational study of 54 volunteers demonstrated prolonged illness in subjects infected with influenza A that received antipyretic therapy. Patients who got antipyretics were sick 3.5 days longer than those who did not (8.8 ± 2.3 days vs 5.3 ± 3.0 days; P<.001). Only patients with temperatures >38.9°C on 2 readings 6 hours apart received antipyretics, indicating that the longer course correlated with greater severity of illness as well as with antipyretic use.

In the same study, antipyretics were associated with a trend towards prolonged duration of illness in a group of 21 patients infected with S sonnei (4.6 ± 2.1 days with antipyretics vs 1.9 ± 1.6 days without; P=not significant).5

A Cochrane review examined 3 trials of acetaminophen vs placebo for fever in 128 adults and children with P falciparum malaria. Although fever clearance varied between the trials, the malaria cure rate was similar in all, and the review concluded that data were insufficient to evaluate an effect on parasitemia.6

Recommendations from others

We found no recommendations regarding the use of antipyretics and their effect on the duration of febrile illness.

CLINICAL COMMENTARY

The risk-benefit ratio of antipyretics may not be as favorable as you think
Jon O. Neher, MD
Valley Medical Center Family Medicine Residency

The doctor’s recommendation, “Take two aspirin and call me in the morning,” is an enduring stereotype, not an evidence-based therapy for a fever. This review reevaluates the simplistic notion that antipyretics are uniformly beneficial and safe in febrile illnesses.

Surprisingly, there appear to be some negative impacts from using antipyretics for common disease states without much clear benefit. It can be argued that the studies are small and purported negative consequences modest. Still, enough evidence exists to warrant more research and to cause clinicians to consider that the risk-to-benefit ratio of these medications may not be as favorable as once thought.

Evidence-based answers from the Family Physicians Inquiries Network

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