Results of observational studies and posthoc analyses have engendered concern among clinicians about the use of acetaminophen (Tylenol) in children with asthma. Various studies have linked acetaminophen use in children to the development of asthma or to the presence of asthma symptoms.
In the interest of avoiding potential harm, some practitioners have advocated acetaminophen avoidance in children with asthma or a family history of asthma.1 This approach creates a clinical conundrum, as acetaminophen and ibuprofen are the only 2 over-the-counter treatment options for pain relief and fever reduction in young children. Moreover, although acknowledging that an association has been found between acetaminophen use and asthma, the American Academy of Pediatrics points out that a causal link has not been established.2
A fundamental issue underlying the uncertainty regarding acetaminophen use and asthma in children has been the lack of data from randomized, controlled clinical trials.
Prospective evaluation of asthma connection
Results from the Acetaminophen versus Ibuprofen in Children with Asthma (AVICA) trial, recently published in the New England Journal of Medicine,3 shed new light on the association between acetaminophen use and asthma symptoms. The AVICA trial was a 48-week, multicenter, prospective, randomized, double-blind, parallel-group clinical trial funded by the Asthma Network (AsthmaNet) of the National Heart, Lung, and Blood Institute (NHLBI) and conducted at 18 sites in the United States.
The study population consisted of 300 children with mild persistent asthma aged 12 to 59 months who were receiving standardized asthma-control therapies. Mild persistent asthma was defined as the presence of asthma symptoms on more than 2 but less than 7 days per week. Children were assigned to treatment with acetaminophen or ibuprofen to be administered by the parent/caregiver when clinically indicated for the treatment of pain or fever.
The primary outcome measure was the number of asthma exacerbations requiring treatment with oral, intravenous, or intramuscular systemic glucocorticoids. Secondary outcome measures included the percentage of days in which asthma symptoms were controlled (ie, calendar days free from rescue medication use, asthma symptoms, or unscheduled asthma-related healthcare visits), frequency of rescue albuterol use, and the occurrence of unscheduled asthma-related healthcare utilization.
Baseline characteristics were similar in participants assigned to treatment with acetaminophen or ibuprofen. Measures of asthma at the time of randomization indicated a comparable disease burden between the 2 groups, with an average of 85.5% ±18.7% and 85.6% ±16.2%, respectively, asthma-control days; 1.81 ±3.49 and 1.50 ±2.22, respectively, albuterol inhalations per week; and 1.01 ±1.06 and 1.15 ±1.04, respectively, oral glucocorticoid courses in the past 6 months.
Over the course of the study, participants received a median of 5.5 doses of study medication. Medication use did not differ significantly between treatment groups (median of 7.0 and 4.5 doses of acetaminophen and ibuprofen, respectively; P=0.47).
Approximately half of study participants experienced 1 or more asthma exacerbations that required systemic glucocorticoid treatment. The number of asthma exacerbations was not significantly different between children treated with acetaminophen or ibuprofen (mean [95% confidence interval], 0.81 [0.65-1.02] and 0.87 [0.69-1.10] per participant, respectively; P=0.67). Results were similar when the analyses were limited to only participants who completed the study (n=226) or to only those who completed the study and received at least 1 dose of acetaminophen or ibuprofen (n=200). Primary results were further confirmed by sensitivity analyses that were performed to control for missing information attributed to participant attrition.
There was a significant association observed between the number of acetaminophen or ibuprofen doses and the number of asthma exacerbations (P<0.001), although this association did not differ between the acetaminophen and ibuprofen treatment groups.
Secondary outcomes, including the percentage of asthma-control days (85.8% [83.7%-87.8%] and 86.8% [84.6%-88.9%], respectively; P=0.50), use of rescue albuterol (2.8 [2.3-3.3] and 3.0 [2.4-3.6] inhalations per week, respectively; P=0.69), and unscheduled healthcare utilization for asthma (0.75 [0.60 0.95] and 0.76 [0.60-0.97] episodes, respectively; P=0.94), were also comparable between the acetaminophen and ibuprofen treatment groups.
There were no significant differences observed in the adverse event profiles of acetaminophen and ibuprofen in this study.
When queried by Contemporary Pediatrics about the ramifications for clinical practice of the study, corresponding author for the AVICA study publication Wanda Phipatanakul, MD, MS, associate professor of Pediatrics at Boston Children’s Hospital, Massachusetts, responded that the study findings “should help alleviate the concerns for safety that were based on observational data. In young children with asthma, there is no difference in asthma exacerbations between acetaminophen versus ibuprofen for fever or pain.”
The researchers did include the caveat that the applicability of the study results to other age groups or children with more severe asthma is not known. Moreover, this study does not address the potential influence of prenatal acetaminophen exposure or use during the first year of life on asthma prevalence or outcomes. As noted by Phipatanakul, “Blinded, randomized, prospective clinical trials are needed to answer [these] important clinical questions.”
1. McBride JT. The association of acetaminophen and asthma prevalence and severity. Pediatrics. 2011;128(6):1181-1185.
2. Section on Clinical Pharmacology and Therapeutics; Committee on Drugs, Sullivan JE, Farrar HC. Clinical report: Fever and antipyretic use in children. Pediatrics. 2011;127(3):580-587.
3. Sheehan WJ, Mauger DT, Paul IM, et al; NIH/NHLBI AsthmaNet. Acetaminophen versus ibuprofen in young children with mild persistent asthma. N Engl J Med. 2016;375(7):619-630.