Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled beta-agonist treatment

There is uncertainty about the development of airway tolerance to beta-agon ists and the phenomenon of rebound bronchoconstriction on beta-agonist with drawal. We have recently completed a study of the regular terbutaline and b udesonide treatment in asthma. We report our observations on the effect of starting and stopping terbutaline treatment on morning and evening peak flo ws. The study was a randomized four-way, double-dummy, cross-over comparison of regular inhaled terbutaline (500-1000 mu g four times daily), budesonide, combined treatment and matching placebo. Each treatment was given for 6 wee ks following a 4 week single-blind placebo washout. Ipratropium was used fo r symptom relief. No other asthma medication was permitted during either th e treatment or wash-out periods. Evaluable data were obtained from 52 subje cts for both placebo and terbutaline treatment. Changes in mean morning and evening peak flows during terbutaline treatment were compared to the basel ine peak flows during the last 2 weeks of the preceding washout. The peak f low changes on slopping terbutaline were also analysed. Mean morning peak flow was not significantly different during terbutaline t reatment when compared to either baseline or placebo treatment. Evening pea k flows were significantly higher during terbutaline treatment [mean increa se 23.11min(-1) (95% CI = 18.8, 27.4)]. Analysis of the peak flow changes o n a day-by-day basis revealed an initial increase in morning peak flows for the first 2 days of treatment of 19.2 and 13.41 min(-1) [increases of 25.0 and 17.31min(-1) in comparison with the corresponding values during placeb o (P < 0.01)] followed by a return to baseline. The increase in evening pea k flows was also greater for the first 2 days of treatment than for the rem ainder of the treatment period (P < 0.01). On ceasing terbutaline treatment there was a fall in mean morning peak flow below the baseline on the follo wing morning of 21.61min(-1) (P < 0.05 compared to placebo). The temporary increase in morning peak flows and greater than expected rise in evening peak flows for the first 2 days of treatment suggest the develo pment of tolerance to the bronchodilator effect of terbutaline. Similarly, the fan in morning peak flows on treatment withdrawal suggests rebound bron choconstriction. These effects are likely to be mediated by downregulation of the beta-receptor during treatment. The clinical significance of these c hanges is uncertain in view of the stability of overall asthma control duri ng terbutaline treatment, but sudden withdrawal of beta-agonist treatment c ould conceivably lead to a deterioration in asthma control.