By Claudia Morris
Acetaminophen (APAP, Tylenol) is the most commonly dispensed medication in the United States, representing 5% of all treatments, and is generally used to alleviate pain and/or fever. Most agree that treating pain is important, however, treatment to reduce fever is not “medically necessary”. Fever is an evolutionarily conserved natural protective mechanism to fight infection, yet unfounded fever phobia is common among parents and practitioners. This creates an ideal market for antipyretics like acetaminophen, the drug of choice for fever in young children. Originally marketed internationally in the 1950s, its use increased significantly in the 1980s due to concerns of aspirin use and Reye’s syndrome. However nearly 20 years ago, new concerns were raised about the safety of acetaminophen and its potential link to asthma1, including a case-control study that suggested that frequent acetaminophen use in adults was associated with asthma, and among those who already had asthma, with more severe disease2. The mechanism for this association was thought to be the depletion of glutathione in the lung, leading to greater oxidative stress3,4. With asthma prevalence increasing world-wide, this concern leads to more than a decade of observational research on acetaminophen use and asthma in adults, children and pregnant women, with over 2500 publications now in the literature on this topic5-19. A 2009 meta-analysis that considered all clinical and observational studies at the time, ultimately including 425,140 subjects, found a pooled odds ratio for asthma in patients using acetaminophen to be 1.6 [1.46-1.77], increased risk of asthma with prenatal acetaminophen use, and an increased risk of asthma and wheezes in both children and adults exposed to acetaminophen, with a dose-dependent response noted in many studies12. Some experts in the field have begun to take a stand: Dr. Holgate wrote “There is now overwhelming evidence establishing a link between APAP and asthma” 20, while Dr. McBride stated in Pediatrics “In my opinion, the balance between the likely risks and benefits of acetaminophen has shifted for children with a history or family history of asthma. I can understand how those responsible for regulation or policy statements of professional organizations might be more comfortable waiting for incontrovertible evidence. There remains a possibility that confounding variables might explain some or all of the association between APAP and asthma. For this reason, we need further studies. At present, however, I need further studies not to prove that APAP is dangerous but, rather, to prove that it is safe. Until such evidence is forthcoming I will recommend avoidance of APAP by all children with asthma or those at risk for asthma and will work to make patient’s, parents, and primary care providers aware of the possibility that APAP is detrimental to children with asthma”21. Fortunately, some reassurance was recently provided by Sheehan and colleagues, in the Acetaminophen versus Ibuprofen in Children with Asthma (AVICA) trial, a 48-week prospective, blinded, randomized controlled trial that compared the as–needed use of acetaminophen with that of ibuprofen for fever or pain in 300 children 12-59 months of age with mild-persistent asthma receiving treatment with asthma controller therapies. The investigators did not find any significant difference in the primary outcome of asthma exacerbations leading to treatment with systemic glucocorticoids or in any of the secondary outcomes between the two groups, suggesting no greater risk of asthma exacerbation with acetaminophen use compared to ibuprofen22,23. However, the AVICA trial does not address whether acetaminophen use can lead to the development of asthma in otherwise healthy children, nor whether it is associated with worsening of symptoms in children with moderate to severe asthma. Questions and clinical equipoise remain. Several large epidemiologic studies linking acetaminophen use in pregnancy and ADHD 24-26 warrant further investigation. Recent studies identifying an association of ADHD with asthma and allergies 27-30 may foreshadow a potentially unrecognized mechanistic overlap between these conditions. Epidemiologic studies linking maternal use of acetaminophen during pregnancy to increased risk of autism gives further pause 31-34. A small study linking acetaminophen but not ibuprofen use with MMR, and autism, may warrant the discouragement of acetaminophen use during vaccination until more information is available35,36.
According to a 2007 CDC report, acetaminophen is responsible for approximately 56,000 emergency department visits, 26,000 hospitalizations, and over 450 deaths per year. Now, large epidemiologic studies have found an association with acetaminophen use and asthma as well as ADHD and autism. Although a causal relationship cannot be assumed based on the current literature, more studies of safety are needed. In the meantime, just like cold medicines and antibiotic overuse, the risks of acetaminophen need to be reassessed. I personally echo the sentiments of Dr. McBride, and have changed my practice in pediatric emergency medicine. Fever is your friend. It is a physiologic mechanism with benefits. Worried caregivers need reassurance to combat fever phobia and education on appropriate use of antipyretics. Treat misery and discomfort rather than a cut-off temperature. Alternatives to acetaminophen may also be considered, however all medications have risks that need to be weighed against their true benefits.
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