Onset of relief of dyspnoea with budesonide/formoterol or salbutamol following methacholine-induced severe bronchoconstriction in adults with asthma: a double-blind, placebo-controlled study

Abstract

Background: The long-acting beta2-agonist (LABA) formoterol has an onset of effect comparable to that of salbutamol. Consequently, the combination of formoterol and budesonide in one inhaler, approved for maintenance use, can potentially be used for reliever therapy. This study compared the onset of relief from induced bronchospasm with a single dose of budesonide/formoterol versus standard salbutamol therapy in patients with asthma.

Methods: In this randomised, double-blind, placebo-controlled, cross-over study, 32 patients with asthma underwent a methacholine provocation test leading to a fall in forced expiratory volume in 1 second (FEV1) of > or =30% at enrollment (Visit 1) and three subsequent study visits (Visits 2-4). Immediately after each provocation at Visits 2-4, patients received one of three test treatments: one inhalation of budesonide/formoterol 160/4.5 microg (via Turbuhaler), two inhalations of salbutamol 100 microg (via a pressurised metered-dose inhaler [pMDI]) or placebo. All patients received each of the test treatments in a randomised order, after separate methacholine provocations. The effect of treatment on FEV1 and breathlessness (using the Borg scale) was measured at 1, 3, 5, 10, 15, 20, 25 and 30 minutes after test treatment.

Results: Following methacholine provocation, Borg score increased from a baseline value of below 0.5 to 3.03, 3.31 and 3.50 before treatment with budesonide/formoterol, salbutamol and placebo, respectively. Budesonide/formoterol and salbutamol reversed methacholine-induced dyspnoea (breathlessness) rapidly. At 1 minute after inhalation, statistically significant decreases in Borg score were observed for budesonide/formoterol and salbutamol (p = 0.0233 and p < 0.0001, respectively, versus placebo), with similar rapid increases in FEV1 (both active treatments p < 0.0001 versus placebo). The median time to 50% recovery in Borg score after methacholine provocation was 3 minutes with budesonide/formoterol, 2 minutes with salbutamol and 10 minutes with placebo. All treatments and procedures were well tolerated.

Conclusion: Single doses of budesonide/formoterol and salbutamol both provided rapid relief of dyspnoea and reversal of severe airway obstruction in patients with asthma with experimentally induced bronchoconstriction. The perception of relief, as confirmed by objective lung function assessment, provides evidence that budesonide/formoterol can be used as reliever medication in asthma.

Figure 1

Study design and patient flow.

Figure 2

Mean Borg score for patients with asthma after methacholine challenge (time = 0) and at various timepoints after one inhalation of one of the following as reliever medication: budesonide/formoterol 160/4.5 μg (via Turbuhaler^®), salbutamol 100 μg (via pressurised metered-dose inhaler [pMDI]) or placebo.

Figure 3

Kaplan-Meier plot for time to 50% recovery from methacholine-provoked increases in Borg dyspnoea score in patients with asthma taking one inhalation of one of the following for reliever medication: budesonide/formoterol 160/4.5 μg (via Turbuhaler^®), salbutamol 100 μg (via pressurised metered-dose inhaler [pMDI]) or placebo. Reliever medication was given immediately after methacholine challenge.

Figure 4

Mean FEV₁ for patients with asthma after methacholine challenge (time = 0) and at various timepoints after one inhalation of one of the following as reliever medication: budesonide/formoterol 160/4.5 μg (via Turbuhaler^®), salbutamol 100 μg (via pressurised metered-dose inhaler [pMDI]) or placebo.

Figure 5

Kaplan-Meier plot for time to recovery to 85% of baseline FEV1 values obtained prior to induced bronchospasm in patients with asthma following one inhalation of one of the following as reliever medication: budesonide/formoterol 160/4.5 μg (via Turbuhaler^®), salbutamol 100 μg (via pressurised metered-dose inhaler [pMDI]) or placebo. Reliever medication was given immediately after methacholine challenge.