Results

Of the 1700 responders in 1997, 1574 (664 cases and 910 controls) had complete information on analgesic use and potential confounding factors and were included in analyses. Table 1 shows the distribution of cases and controls according to risk factors for asthma. Compared with controls, cases were younger, of lower social class, and were more likely to be living in rented accommodation, unemployed, a single parent, and exposed to passive smoking at home. Participants' smoking habits were not related to asthma.

Discussion

We have found a strong positive association between frequent (daily or weekly) use of paracetamol and adult asthma in a population based case-control study. Frequent use of paracetamol was also associated with more severe asthma and, in those without asthma, with rhinitis. To our knowledge these observations have not been reported before. We set out a priori to examine the association between paracetamol and asthma and, in view of the small p values, it seems unlikely that our findings have arisen by chance.

Possible biases need to be considered. Cases and controls were selected from the same clearly defined population of adults registered with 40 general practices. Selection bias seems unlikely as the study was community based and participants were identified before exposure status was measured. Response rates, though not high, were similar in cases and controls. We cannot exclude the possibility that the estimated association between paracetamol and asthma was biased by non-response, but if there was no association in the whole population then paracetamol use would have to be strongly negatively associated with asthma in those individuals who did not take part in the study, which seems unlikely. Our case definition has been used previously in adults of this age,18 is predictive of bronchial hyperresponsiveness,19 and does not depend exclusively on a doctor's diagnosis. We therefore do not think that our findings can be attributed to increased recognition of asthma in frequent users of analgesics who may attend more frequently for health care. Most importantly, we cannot see why selection, response, or diagnostic biases would result in a strong association between asthma and paracetamol, but not aspirin. Similarly, we know of no reason why asthmatic individuals would have overestimated their use of paracetamol. Although we did not collect detailed information about dose of analgesic used, nor about additional use of paracetamol in compound preparations or in cough and cold remedies, such misclassification is likely to be random with respect to asthma and would tend to lead to an underestimation of the strength of the association.

A strong association between paracetamol and asthma remained after controlling for potential confounders. One possible explanation to consider is that conditions requiring analgesics, and paracetamol in particular, are more common in asthmatic than in non-asthmatic individuals. A recent UK survey of adults found that the predominant reason for taking “over the counter” analgesics such as paracetamol was for non-migrainous headache.24 Our findings in the re-survey of frequent analgesic users are in keeping with this. Whilst β₂ agonists can cause headache, this is an uncommon side effect and we found that frequent use of paracetamol for headache was as common in cases who were not on asthma treatment as in those who were. It has been suggested that migraine may be more common in asthmatic individuals, but evidence for a link is contradictory25 and a large population based study of young British adults suggested that the association was not strong.26 We therefore think it is unlikely that the more frequent use of paracetamol in cases is attributable to a higher prevalence of co-morbidity.

An alternative explanation for our findings might be that cases were taking paracetamol to relieve symptoms associated with asthma. However, in the re-survey only 4% of cases, who were still taking frequent paracetamol, said that they took it frequently for asthma. A sensitivity analysis suggested that this percentage does not approach that which would be needed to explain the magnitude of association observed with frequent paracetamol use (data not shown). Furthermore, amongst the 25 cases who reported frequent aspirin use, four said that they took it frequently for asthma, which may reflect the bronchodilator action of aspirin in some individuals.27

Asthmatic individuals may take paracetamol in preference to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) to avoid potential sensitivity reactions and, in the repeat survey of individuals who were still taking frequent paracetamol, 14% more cases than controls said that they avoided aspirin. We did not ask participants about use or avoidance of NSAIDs. However, we believe that aspirin avoidance can explain only part of the association between frequent paracetamol use and asthma. Firstly, aspirin use was not less common in cases as a whole than in controls. Secondly, severe cases, who might be most likely to completely avoid aspirin, were just as likely as controls to report infrequent use of aspirin and were significantly more likely to report weekly use. Thirdly, the strong association between frequent paracetamol use and asthma was not restricted to individuals taking paracetamol but not aspirin, but was also found in those taking both analgesics. Aspirin avoidance is even less likely to explain the association between frequent paracetamol use and rhinitis in individuals who did not have asthma.

The graded nature of the association between paracetamol and asthma is in keeping with a causal relation. We speculate that frequent use of paracetamol could contribute to asthma morbidity in a number of ways. In animal models paracetamol can deplete the lung of GSH.15 ,16 Recent in vitro studies have shown that incubation with paracetamol at non-cytotoxic and clinically relevant concentrations (<1 mM), which may be achieved in human plasma after therapeutic doses (0.5–1 g) of paracetamol, leads to a decrease in cellular GSH concentrations in alveolar macrophages and type 2 pneumocytes from rats28 and in human pulmonary macrophages (Dimova and Nemery, personal communication). Depletion of GSH in airway epithelial lining fluid could increase inflammation through loss of antioxidant defences and upregulation of NF-κB.12 This could cause individuals who would otherwise have subclinical disease to have symptoms, as well as increasing severity of symptoms in those with established asthma. The latter is supported by the inverse association between alveolar GSH levels and bronchial responsiveness in asthmatic adults.10 Also, paracetamol can deplete immune cells of GSH29 which, in antigen presenting cells, leads to preferential Th2 cytokine responses30 and this might further drive the inflammatory process. GSH is also found in nasal lavage fluid31 and hence depletion could also explain the association between frequent paracetamol use and rhinitis. Finally, a few aspirin sensitive asthmatic adults have cross sensitivity to paracetamol following oral challenge with 1g,32 ,33 and this may go unrecognised because the reduction in lung function is smaller and of slower onset than that seen with aspirin.33

Recently, Varner and colleagues proposed that decreasing use of aspirin in favour of paracetamol during the 1980s in the USA may have contributed to the increase in childhood asthma,34 but for entirely different reasons. They suggested that aspirin may protect against asthma through inhibition of prostaglandins and that, as use decreased, so this protection was lost. However, such an explanation would imply that asthma was also common in the more distant past before aspirin was widely introduced, which seems unlikely.

Our findings should be interpreted with caution. A study of this kind cannot establish that the association we have observed is causal. Furthermore, we have shown a clear relation only with daily or weekly paracetamol use. Paracetamol should remain the preferred analgesic and antipyretic because of the potential risks associated with aspirin and NSAIDs—namely, severe sensitivity reactions in those with asthma, gastrointestinal bleeding in adults, and Reye's syndrome in children. However, there may be scope for some individuals who take paracetamol on a daily or weekly basis to reduce their frequency of usage. Furthermore, in a recent survey, 3% of adult analgesic users reported regularly taking more than the recommended dose.24 We believe that there is a need to clarify whether frequent use, and perhaps overuse, of paracetamol contributes to asthma morbidity in the population, particularly in those who have severe disease. Whilst further observational studies in adults and children would be of interest, such clarification can only come from a randomised trial.