Regular use effect of inhaled ipratropium bromide and methacholine responsiveness in well-controlled asthma

Abstract

RATIONALE: Short-acting β2-agonists provide significant bronchoprotection to inhaled methacholine in individuals with asthma. Regular use of β2-agonists results in the development of tolerance to the bronchoprotective effect. A relatively minimal amount is known regarding the development of tolerance following regular use of short-acting muscarinic antagonists. OBJECTIVES The current study was undertaken to assess bronchoprotection after regular use of inhaled ipratropium bromide (“ipratropium”) and after treatment withdrawal. METHODS Twelve adult participants with mild asthma were assigned to treatment in this double-blind randomized placebo-controlled crossover study. Ipratropium, 40 µg thrice daily, and matching placebo were administered for 1 week (22 doses). Methacholine challenges were performed at baseline, 30-min post first and last dose and 24-h after the final dose. A minimum 7-day washout period separated the treatments. MEASUREMENTS AND MAIN RESULTS: Significant bronchoprotection, measured as an increase in methacholine PD20 of 4.3 doubling doses (95% CI 3.62–5.06), occurred following the first dose of ipratropium. Bronchoprotection increased slightly to 4.5 doubling doses (95% CI 3.80–5.27) following regular use. Dose shifts following placebo were significantly lower at 0.23 (95% CI −0.30–0.75) and 0.11 (95%CI −0.63–0.85) after the first and last dose respectively (p < 0.001 vs. ipratropium for both). Changes from baseline methacholine PD20 24-h after treatment withdrawal were not significant between treatments (p = 0.19). CONCLUSIONS Our data provide evidence that regular use of inhaled ipratropium does not result in loss of bronchoprotection or lead to rebound hyperresponsiveness following treatment withdrawal. Muscarinic antagonists appear to have a superior safety profile over β2-agonist use in the treatment of asthma.