The inverse agonist propranolol does not confer steroid-sparing activity in persistent asthma

Background: The murine asthma model shows that switching off airway beta-2 receptors with an inverse agonist may confer anti-inflammatory as well as steroid-sparing activity. We therefore assessed the putative steroid sparing effects of propranolol, an inverse agonist, by comparing propranolol plus low-dose inhaled corticosteroid (ICS) vs. higher dose ICS alone. Methods: Randomised, double blind, placebo-controlled, crossover trial in mild-moderate persistent asthmatics. Run-in (2weeks): HFA-BDP 100μg/day. Randomised treatments (4weeks): propranolol 80mg/day + HFA-BDP 100μg/day; versus placebo + HFA-BDP 400μg/day. Propranolol up-titrated to 80mg/day over initial 2weeks. Tiotropium co-administered until 5 days pre-histamine challenge (primary outcome). Results: 16 patients completed, mean: age 38yr; FEV 1 86·4%; Histamine PC 20 1·39mg/ml; ICS 406μg/day. Histamine PC 20 remained unchanged with propranolol + HFA-BDP100 compared to baseline (HFA-BDP100): 0·17 doubling dilution (dd) difference (95%CI -0·58-0·92). There was a significant improvement with HFA-BDP400 vs. baseline: 1·05dd (95%CI 0·43-1·66), P=0·02; and vs. propranolol + HFA-BDP100: 0·88dd (95%CI 0·45-1·30), P=0·006. Significant improvements occurred with HFA-BDP400 vs propranolol + HFA-BDP100 for FeNO, Eosinophils and ECP, and for AQLQ symptom score. Evening FEV 1 fell with propranolol: 0·22L (95%CI 0·10-0·34L), P=0·012, while ACQ and AQLQ remained unchanged. Conclusion: The inverse agonist propranolol produced no improvements when added to low dose ICS, while further significant improvements in AHR and inflammation were demonstrated with higher dose ICS. Thus propranolol does not confer steroid-sparing activity in persistent asthma.