The Association Between Acetaminophen and Asthma

Should Its Pediatric Use Be Banned?

Antonio Martinez-Gimeno; Luis García-Marcos

Disclosures

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

In This Article

Evidence From Randomized Clinical Trials

Despite the large body of epidemiological evidence supporting acetaminophen as a promoter of wheezing disorders hypothesis, there is only one randomized double-blind clinical trial on this subject (see below[15]). To address the issue of the effect of acetaminophen exposure on wheezing disorders prevalence and severity, several different designs would be necessary to deal with the different questions prompted by epidemiological studies.

The hypothesis that acetaminophen exposure increases wheezing disorders prevalence and its corollary, that avoiding acetaminophen exposure would reduce wheezing disorders prevalence would need a long-term clinical trial recruiting newborns (or even better, pregnant women) to be randomized to one of two groups: an intervention group, avoiding acetaminophen, and a control group with no intervention, with some definition of incidence of wheezing disorder as a primary outcome. Contrary to common claims,[16] a placebo arm would be impractical and unethical, because it would subject participants to a substandard and unacceptable treatment during a very long time. A more stringent double-blind design, with one arm blindly receiving acetaminophen and the other receiving ibuprofen, would be much more difficult to implement and to maintain during the several years necessary to properly assess its relevant primary outcome. The sample size necessary to reach an acceptable power to detect a decrease in prevalence, let us say, from 15 to 10% would be more than 400 participants per arm. This simple description clearly shows the complexity and large budget necessary to develop and implement such a clinical trial that, to date has precluded even its inception. Commercial sponsors do not need to spend their resources in this kind of clinical trial and independent sponsors may find it difficult to obtain the large amount of resources needed to perform such a large and long-term clinical trial. It should be remembered that clinical trials are much more expensive than epidemiological studies because they need to comply with stringent good clinical practice rules for every participant during the whole clinical trial.

To test the hypothesis that acetaminophen exposure increases wheezing disorders severity or morbidity in asthmatic children, and its corollary, that avoiding acetaminophen exposure in asthmatic children would improve asthma control and morbidity, a more attainable clinical trial design would be needed, recruiting asthmatic children (several substudies with different age limits) to be randomized to one of two arms: intervention versus no intervention (open-labeled) or acetaminophen versus ibuprofen (double-blind design). Again, a placebo arm, contrary to common claims, would be impractical and unethical. Primary outcome could be one of the many already used: days free of symptoms, symptoms scores, drug consumption scores, asthma exacerbations or asthma-related quality of life, and the duration necessary to obtain enough statistical power would be in the range of months, not years.

In fact, such a clinical trial already exists.[15] It was performed in the early 1990s but published in the early 2000s, when the hypothesis of the detrimental effect of acetaminophen in asthma had already been launched. Being the only clinical trial ever performed on the subject, it deserves careful reading and a detailed description. From 2 February 1991 to 12 June 1993, 84,192 children between 6 months and 12 years of age with a febrile illness were recruited and randomly assigned to receive suspensions of either acetaminophen (12 mg/kg) or ibuprofen (5 or 10 mg/kg) to test the safety profile of ibuprofen. A subgroup analysis of those children being treated for asthma, defined as those who had received a β-agonist, theophylline (remember, we were in the early 1990) or an inhaled steroid on the day before enrollment, identified an outstanding number of 1879 children, 632 randomized to acetaminophen, 636 to ibuprofen low-dose and 611 to ibuprofen high-dose. Primary outcomes were a report of hospitalization or outpatient visit for asthma in the month after enrollment. The number of hospitalizations was too low to reach significance (eight, four and six in the acetaminophen, low-dose ibuprofen and high-dose ibuprofen groups, respectively), but the number of outpatient visits for asthma was higher in the acetaminophen group compared with both ibuprofen groups (5.0 vs 2.9%). The authors reported this difference computing an adjusted relative risk estimate using the Mantel–Haenszel procedure; adjusting for age, gender and race and considering the acetaminophen group as the reference category: this estimate was 0.56 (0.34–0.95) for ibuprofen. This estimate did not vary when multiple stratifications where performed and did not differ between both ibuprofen doses. It should be taken into account that this clinical trial was originally designed to test the hypothesis that among children with asthma and without a history of aspirin sensitivity, ibuprofen suspension for fever-control increased the risk of acute bronchospasm and other morbidities from asthma. However, they found exactly the contrary. In their paper, the authors did not mention the reason for the 11 years elapsed between the end of the clinical trial and its publication. The possibility exists that their results were so unexpected and so contrary to common beliefs at the time that they only decided to publish them when the whole acetaminophen detrimental effect of wheezing disorders hypothesis begun to arise. Even to date, this large and well-designed clinical trial is not receiving due attention and some authors continue to explain their results as a beneficial effect of ibuprofen instead of a detrimental effect of acetaminophen. As practicing pediatricians, this discussion is absolutely irrelevant: avoiding acetaminophen is absolutely equivalent to using ibuprofen, because no other alternative exists.

Claiming that there is an urgent need for well-powered clinical trials to solve this question has become a classic sentence at the end of every original article and editorial covering the issue since it was first proposed by Shaheen et al. in the very first epidemiological study linking acetaminophen and asthma, in 2000.[6] Despite this constant, repetitive claim, the pediatric research community has been too unreactive or too unbelieving to do so. The authors have already commented on the sole clinical trial on the subject that has been performed to date, and how its original design was not to test the hypothesis that acetaminophen exposure might increase asthma morbidity, but somehow the contrary, that ibuprofen, compared with acetaminophen as a control drug, might increase asthma morbidity.[15] Since then, only two clinical trials on acetaminophen and asthma have been registered on ClinicalTrials.gov.[101] The first one, ClinicalTrials.gov identifier NCT01073748, entitled 'The effect of single dose paracetamol on the lower airways of asthmatic and healthy children' already finished and published, showed that one single dose of acetaminophen neither evokes a bronchoconstriction response nor an increase in airway inflammation in children with asthma.[17] The second one, ClinicalTrials.gov identifier NCT01606319: 'Acetaminophen versus ibuprofen in children with asthma', is a multicenter double-blind randomized clinical trial that will test the primary hypothesis that in preschool children 12–59 months of age with persistent asthma on standardized asthma therapy, the number of asthma exacerbations requiring systemic corticosteroids will be more frequent in children randomized to receive acetaminophen as compared with those randomized to receive ibuprofen on an as-needed basis for fevers and pain.[101] Its results will be available in 2014–2015. No other clinical trial on this pivotal question has been registered. The authors sincerely miss the leadership of pediatric respiratory and allergy societies and other pediatric research networks to address pivotal clinical trials on acetaminophen effect on wheezing disorders prevalence and severity in an orderly and programmed way. Henderson and Shaheen have recently proposed that initial trials should focus on relatively short term outcomes in children with established asthma; the next step should be clinical trials assessing secondary prevention strategies in children at risk for developing asthma and finally, primary prevention trials, which may await the outcomes of the above studies and may even be superseded by them if a robust evidence of a strong causal effect emerges.[18] This is actually a most attractive research program.

Moreover, to overcome the difficulties associated with randomized clinical trials when a placebo arm is not ethically advisable, blinding poses great difficulties and the number of patients needed becomes too large; Moral et al. have recently suggested a more attainable approach by pragmatic trials.[19] These are defined as studies comparing two or more interventions assigned on a random basis but administered in an open-label mode under conditions of routine clinical practice. Despite some important limitations,[18] this design could also provide some useful evidence on the effect of acetaminophen exposure during childhood on the prevalence and morbidity of wheezing disorders.

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