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Consultations & Comments: Acetaminophen and Asthma: Any Connection?

By Ihuoma Eneli, MD

What evidence is there that acetaminophen can cause or exacerbate asthma?

---- MD

The use of analgesics, specifically acetaminophen, has been proposed as one of the mechanisms responsible for an increase in asthma prevalence in the past 30 to 40 years.1 Acetaminophen, approved by the FDA in 1951, is one of the most commonly used analgesics in adults and children. The association between asthma and acetaminophen has been described in case reports, in the setting of oral challenge tests, and in larger clinical studies.2

Possible linking mechanisms. Proposed mechanisms mostly revolve around the acetaminophen-induced glutathione depletion theory. Glutathione (l-g-glutamyl-l-cysteinyl glycine(), found in its largest amount in the respiratory tract lining, is an antioxidant. Primarily, it "mops up" reactive oxygen species (such as superoxide anions, hydroxyl radicals, and peroxyl radicals) that cause inflammation and lung injury.

Overdoses of acetaminophen decrease glutathione levels and can lead to liver toxicity. However, it has been reported that therapeutic doses can produce smaller but significant reductions in glutathione levels in type II pneumocytes and alveolar macrophages.3

Another probable mechanism involves the hepatic P-450 cytochrome pathway (also present in type II pneumocytes), which metabolizes acetaminophen. In the absence of the glutathione conjugation, acetaminophen is converted into N-acetyl-p-benzoquinoneimine, which is toxic to the cell, resulting in death.3 Finally, in the presence of low glutathione levels, defective processing of disulfide bonds can lead to alterations in antigen presentation,4,5 with a possible switch from TH1 to TH2 helper cell pathway in immune response.

Although lower glutathione levels in breath condensate, reduced glutathione peroxidase activity in platelets and whole blood, and genetic polymorphisms of glutathione-S-transferase enzyme systems have all been described in children with asthma, the evidence is not conclusive.6-12 In addition, the resynthesis of glutathione is so rapid that it is unlikely that a window of opportunity for lung damage exists. Other proposed mechanisms involve the lack of suppression of the cyclooxygenase pathway associated with declining aspirin( use.13

What the evidence shows. Results from most of the clinical studies suggest that acetaminophen exacerbates rather than causes asthma.2 Investigators report cough, wheezing, and declines in forced expiratory volume in 1 second and in peak expiratory flow rate in both aspirin-sensitive and aspirin-tolerant persons.2

An ecologic study by Newson and associates,14 using data from the International Study of Asthma and Allergies in Childhood and the European Community Respiratory Health Survey, was the first population-based study to investigate the association. For each per-gram increase in per capita paracetamol( (acetaminophen) sales, the prevalence of wheezing rose 0.52% among 13- to 14-years-olds; wheezing increased by 0.26% among young adults.

In another study, from the United Kingdom, daily and weekly use of acetaminophen was associated with asthma.15 The relationship was much stronger for severe asthma (odds ratio, 8.2; 95% confidence interval [CI], 2.8 to 23). In the United States, a prospective cohort study--the Nurses' Health Study--reported that previous use of acetaminophen was associated with a subsequent physician diagnosis of new-onset asthma (adjusted relative risk, 1.63; 95% CI, 1.11 to 2.39; P = .006 for trend).16 This study suggested that use of acetaminophen might cause asthma, since the analgesic was consumed years before the diagnosis was made.

Researchers in another prospective study in the United Kingdom followed a group of women through pregnancy and asked about acetaminophen use at 18 to 20 and at 32 weeks of gestation.17 In a multivariate analysis controlling for maternal asthma, smoking, and other factors, the risk of wheezing increased 2-fold in children 30 to 42 months old whose mothers frequently used acetaminophen prenatally during weeks 20 to 32. However, similar results were reported for mothers who used aspirin frequently, suggesting an important confounder may not have been considered.

The reported acetaminophen-asthma link may represent physician analgesic-prescribing patterns, such as use of these medications for viral illness, or it may be confounded by prescribing for headaches/migraines. At least 2 studies have found an increased risk of migraine among patients with asthma.2

Finally, Lesko and associates,18 in a randomized clinical trial that examined the safety of ibuprofen( among children with a physician diagnosis of asthma, reported an increased number of office visits and hospitalizations for asthma in children who were given acetaminophen, compared with those who were given ibuprofen.

No hard conclusions yet. Overall, the evidence is intriguing but definitely not conclusive. Misclassification of asthma cases, varying definitions of acetaminophen use, and retrospective data collection can introduce errors into study design. Furthermore, data to support the hypothesized glutathione pathway are still preliminary. Considering the impact of asthma and the frequent use of acetaminophen as an analgesic, further research is warranted. Currently, acetaminophen still appears to be the safest analgesic for patients who have asthma.

----Ihuoma Eneli, MD
Assistant Professor
Michigan State University
Lansing, Mich