The Association Between Acetaminophen and Asthma

Should Its Pediatric Use Be Banned?

Antonio Martinez-Gimeno; Luis García-Marcos

Expert Rev Resp Med. 2013;7(2):113-122.

Conclusion

Too liberal use of acetaminophen in children should no longer be recommended. In the general pediatric population there is a good deal of epidemiological evidence suggesting that acetaminophen exposure increases wheezing disorders prevalence, and while awaiting the results of appropriate randomized clinical trials evaluating this intervention, yet to be designed and carried out, it seems reasonable to limit acetaminophen exposure to clinical settings where no alternatives exist, that is, when ibuprofen is not appropriate. In wheezing children, this recommendation is more strongly evidence based: this intervention (avoiding acetaminophen by using ibuprofen) has proved to decrease wheezing morbidity in this population in a large and well-designed clinical trial.

However, acetaminophen banning in the general pediatric population does not seem appropriate yet, because this intervention has not been properly evaluated to date and there are clinical situations in which children and pediatricians are devoid of an appropriate alternative antipyretic and analgesic drug. Moreover, banning or drug withdrawal is a regulatory issue and only regulatory agencies, with their wide access to safety databases, can accomplish this complex task. The time has come for them to do their part.

We cannot avoid the already classic ending: we are in urgent need for well-designed clinical trials evaluating the effect of avoiding acetaminophen exposure in children on wheezing disorders prevalence and morbidity. Pediatric community: please, move on!

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Table 1. Bradford Hill criteria applied to the hypothesis of acetaminophen as wheezing diseases promoter.
Criteria	Evidence
Strength of effect	Increased risk after acetaminophen exposure ≥1.5
Dose response	Present for acetaminophen exposure in utero, childhood and adult life
Consistency/coherence	Consistency among studies, age groups, sex, geography and culture
Exposure before response	Observed in prospective studies of acetaminophen exposure in utero, infancy and adult life Observed in the only prospective double-blind randomized clinical trial in children
Biological plausibility	Increased oxidant-induced airway inflammation Enhanced Th2 response Decreased immune response to rhinovirus infection
Removal of exposure prevents disease	Partially examined in the only double-blind randomized clinical trial on the subject published to date: using ibuprofen instead of acetaminophen in febrile children with concomitant use of anti-asthma drugs reduced the risk for an outpatient visit for asthma in the following month Effect of removal of exposure on prevalence to be determined
Specificity	No increased risk of asthma associated with aspirin or other NSAID
Analogy	Weak, protective effects of antioxidant diet in asthma

Adapted with permission from [17].

Table 2. Overview of arguments in the case against acetaminophen as a promoter of wheezing disorders in children.
Arguments that support a detrimental effect of acetaminophen in asthma	Arguments against a detrimental effect of acetaminophen in asthma
Epidemiologic association between acetaminophen exposure and asthma
Strength of the association Consistency of the association across geography, culture, age and studies Dose dependency of the epidemiologic association Coincidence in time of increase in asthma prevalence and increase in acetaminophen use Ecologic relationship among asthma prevalence and per-capita sales of acetaminophen Uniqueness of this association, more consistent than any other environmental factor	The whole epidemiologic association may be spurious, acetaminophen being an innocent bystander falsely accused due to several bias or confounding factors: Confounding by indication (real culprit, respiratory virus infections producing fever) Confounding by reverse causation (real culprit, asthma itself which induces acetaminophen use) Confounding by preferential use of acetaminophen by children at higher risk of asthma or already asthmatics
Clinical trials
A randomized clinical trial with 1879 children 6 months to 12 years old with asthma exacerbation and fever, showing a lower incidence of outpatient visits for asthma in those randomly assigned to ibuprofen compared with acetaminophen (adjusted relative risk: 0.56 [95% CI: 0.34–0.95] compared with those receiving acetaminophen)	No placebo group included. The lower relative risk for children who received ibuprofen could be due to a protective effect of ibuprofen instead of a detrimental effect of acetaminophen No clinical trials have been performed on the effect of acetaminophen on the prevalence of asthma
Biological plausibility
Acetaminophen depletes glutathione from the airways Acetaminophen reduces immune response to, and prolongs, rhinovirus infection