Acetaminophen vs Ibuprofen Does Not Worsen Childhood Asthma

Laurie Barclay, MD

August 17, 2016

As-needed acetaminophen vs ibuprofen was not associated with more asthma exacerbations or worse asthma control among young children with mild persistent asthma, according to a randomized clinical trial published in the August 18 issue of the New England Journal of Medicine.

"Many children younger than 12 years of age receive acetaminophen each week, making it the most commonly used pediatric medication in the United States," write W. J. Sheehan, MD, from the Division of Allergy and Immunology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, and colleagues from the National Institutes of Health/National Heart, Lung, and Blood Institute AsthmaNet. "Observational data from both pediatric and adult cohorts have suggested an association between acetaminophen use and concurrent asthma symptoms and decreased lung function."

Additional controversy and alarm regarding acetaminophen safety in children with asthma surrounded post hoc analysis of a randomized trial on short-term use of acetaminophen vs ibuprofen for febrile illnesses in children. Findings showed markedly higher relative risk for unscheduled visits for asthma after acetaminophen use.

"[S]ome physicians have recommended that until data supporting its safety become available, acetaminophen should be completely avoided in children with asthma," the study authors note.

Because of potential bias and confounding by indication in observational studies and post hoc analyses, however, prospective, methodologically sound randomized trials are needed. The Acetaminophen versus Ibuprofen in Children with Asthma (AVICA) trial therefore aimed to assess whether clinically indicated acetaminophen vs ibuprofen use was associated with greater asthma-related morbidity among children aged 12 to 59 months with mild persistent asthma; it found no such evidence.

"Thus, caregivers of young children who are receiving treatment with asthma-controller medications may be reassured by this result that the use of acetaminophen in usual, as-needed doses will not worsen asthma symptoms in their children and that acetaminophen and ibuprofen can be used similarly in situations for which they are indicated," Augusto A. Litonjua, MD, MPH, from Brigham and Women's Hospital and Harvard Medical School in Boston, notes in an accompanying editorial.

Safety Similar for Acetaminophen, Ibuprofen

Participants (n = 300; mean age, 39.9 ± 13.2 months) in this multicenter, prospective, double-blind, parallel-group trial were randomly assigned to receive either acetaminophen (160 mg/5 mL) or ibuprofen (100 mg/5 mL) grape-flavored suspension when needed to relieve fever or pain during a 48-week period. Because both medications are readily available over the counter, additional open-label use was also recorded.

The groups were well-matched in terms of wheezing episodes in the previous year (mean, 5.9 ± 5.0), urgent care or emergency department visits (3.0 ± 2.4), and hospitalizations for wheezing (0.3 ± 0.5). Both groups received standardized asthma-controller therapies. The number of asthma exacerbations treated with systemic glucocorticoids was the primary outcome.

In both groups, number of study treatment doses was similar (median, 5.5; interquartile range, 1.0 - 15.0), as was the primary outcome. During 46 weeks of follow-up, mean number of asthma exacerbations was 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen (relative rate, 0.94; 95% confidence interval, 0.69 - 1.28; P = .67).

At least one exacerbation occurred in 49% of the acetaminophen group vs 47% of the ibuprofen group, and two or more exacerbations occurred in 21% vs 24%, respectively. There were no significant between-group differences in percentage of asthma-control days (85.8% vs 86.8%), albuterol rescue inhalations per week (2.8 vs. 3.0), or unscheduled asthma visits (0.75 vs 0.76 per participant).

Adverse events and serious adverse events (six with acetaminophen and 12 with ibuprofen) did not differ significantly between groups, and there were no deaths from any cause during the study.

Could Both Medications Worsen Asthma Equally?

"Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen," the study authors write.

To explain why previous evidence suggested a possible association between acetaminophen and asthma-related complications, the authors point to studies supporting confounding by indication. In other words, children with asthma tend to have more symptomatic respiratory tract infections, in which acetaminophen may be prescribed for fever and malaise.

The present study supported a link between greater use of antipyretic analgesics and respiratory illnesses, and thus with asthma exacerbations treated with systemic glucocorticoids. But there was no evidence that acetaminophen had a greater association with these outcomes than ibuprofen.

Limitations of this study include lack of generalizability to other age groups or children with more severe asthma, and inability to determine whether acetaminophen exposure prenatally or during the first year of life is associated with asthma development.

The lack of placebo group (for ethical reasons) precludes assessment of the possibility that both ibuprofen and acetaminophen use may worsen asthma control. However, the editorialist points out that exacerbations per participant in each group were approximately the same as outcome rates in other trials of similarly aged children, suggesting no significant increase in symptoms associated with the use of either analgesic.

"Given the difficulties of designing a trial with a true placebo group, this may be the best answer we can get in this age group," Dr Litonjua writes.

Funded by the National Institutes of Health. The study authors report a variety of financial relationships with pharmaceutical companies, including consulting fees, speaking fees, advisory boards, lecture fees, and honoraria. A complete list of disclosures is available on the journal's website. Dr Litonjua reports personal fees from UpToDate Inc, Springer Humana Press, and AstraZeneca outside the submitted editorial.

N Engl J Med. 2016;375:619-630, 684-685. Article full text, Editorial full text

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