The Effect of Regular Paracetamol on Bronchial Responsiveness and Asthma Control in Mild to Moderate Asthma

Over recent decades, the worldwide prevalence of asthma has increased. The reasons for this increase are unknown, which has lead to the search for novel risk factors that may increase susceptibility to atopy and the development of asthma. The growing popularity of paracetamol as a drug to treat pain and fever has occurred contemporaneously with the rising prevalence of asthma, and epidemiological evidence suggests that paracetamol may be a risk factor in the development of asthma and its severity. As a result, there have been numerous calls for randomised controlled trials to be undertaken to investigate the association between paracetamol and asthma, in particular the effect of regular, long-term paracetamol use on asthma severity and control. This thesis presents the results of a randomised, placebo-controlled clinical trial undertaken to determine the effect of regular paracetamol on bronchial responsiveness and asthma control in adult asthma. In a 12-week, randomised, double-blind, placebo-controlled, parallel-group study, 94 adults with mild to moderate asthma received 12 weeks of either 1 g paracetamol twice daily or a placebo medication twice daily. The primary outcome variable was bronchial hyperresponsiveness, measured as the provocation concentration of methacholine causing a 20% reduction in FEV1 (PC20 MCh), at baseline and week 12. Secondary outcome variables included FEV1, FeNO, ACQ score, mean morning peak flow, peak flow variability, blood eosinophil, serum IgE and cytokine (IFN-γ, IL-4, IL-5 and IL-13) levels. 85 participants completed the study. At 12 weeks the mean (SD) logarithm base two PC20 was 1.07 (2.36) in the control group (N=54) and 0.62 (2.09) in the paracetamol group (N=31). Although the mean PC20 was lower in the treatment group, after controlling for baseline PC20, the difference was not statistically significant (paracetamol minus placebo): -0.48 doubling doses (95% CI -1.28 to 0.32), P=0.24. In addition, there were no statistically significant differences in log FeNO (0.09, 95% CI - 0.097 to 0.27), FEV1 (-0.07 L, 95% CI -0.15 to 0.01), ACQ score (-0.04, 95% CI -0.27 to 0.18) or other secondary outcome variables between the paracetamol and placebo groups. The research described in this thesis demonstrates no statistically significant effect of paracetamol on bronchial responsiveness. There were no significant differences observed in any of the pre-specified secondary outcome variables of asthma control or inflammatory and immunological markers, although undetectable baseline cytokine levels in the majority of trial participants precluded meaningful cytokine analysis. The results of the study require cautious interpretation because the study power to detect the large pre-specified effect of a one doubling-dose reduction in PC20 was lower than anticipated. However, the results do not rule out a clinically significant effect of paracetamol on bronchial responsiveness, with the 95% confidence interval containing the pre-specified difference of one doubling dose reduction in PC20. Furthermore, the point estimate of a reduction in PC20 of 0.48 of a doubling-dose could potentially be of major public health significance. As paracetamol is commonly used in all age groups and the global disease burden of asthma is large, the impact of an effect of paracetamol on asthma could be profound. Further adequately powered studies should be performed to determine the effect of paracetamol use on the development of asthma and its severity