Randomised placebo controlled trial of beta agonist dose reduction in asthma.

BACKGROUND: Many patients continue to take regular beta agonists, often at high doses, contrary to national and international guidelines. Some studies have suggested that this can worsen asthma control, but whether such patients can reduce their dose of beta agonist and whether they would benefit from this has not been determined. Reduction of beta agonist dose was studied in a placebo controlled parallel group study. METHODS: Following a run in period, 33 subjects with asthma taking regular beta agonists were converted to an equivalent dose of terbutaline via a Turbohaler. Two weeks later terbutaline was continued at the same dose or changed to placebo in two stages a week apart. The change over period was covered by an increased dose of inhaled steroid to attenuate any immediate effects of the change in dose. Subjects then attended weekly for six weeks for measurement of forced expiratory volume in one second (FEV1) and the dose of methacholine that produced a 20% fall in FEV1 (PD20). Peak expiratory flow (PEF) and symptom scores were recorded twice daily throughout the study. Exacerbations, lung function, bronchial responsiveness, bronchodilator response, beta agonist use, and symptoms were compared before and six weeks after reduction in the dose of beta agonist. RESULTS: Twenty five of the 33 subjects completed the study; three patients in each group withdrew due to an asthma exacerbation. The median terbutaline dose fell from 2500 to 500 micrograms/day in the beta agonist reduction group and from 3000 to 2250 micrograms/day in the control group. There were small non-significant changes in FEV1, PEF, symptom scores and PD20 methacholine over the course of the study. The FEV1 response to a beta agonist was greater in those who reduced their beta agonist dose than in the control group although the final FEV1 achieved was the same. CONCLUSIONS: Patients with asthma taking high doses of beta agonists can reduce the amount of beta agonist they use without a significant change in their asthma control. There was no evidence of improved asthma control with beta agonist dose reduction.

The airway effects of stopping regular oral theophylline in patients with asthma.

AIMS: We investigated whether the deterioration in asthma control reported following cessation of theophylline was due to tolerance to theophylline. METHODS: Eighteen subjects with mild stable asthma were given oral theophylline 10 mg kg(-1) day(-1) or placebo for 2 weeks in a double-blind crossover study. FEV1 and PD20 histamine were measured before and 8 h after the first dose of treatment and 8, 32 and 56 h after the final dose. PD20 AMP was measured before treatment and 9 h after the final dose. RESULTS: Six patients did not tolerate theophylline. In the other 12 subjects there were no differences between treatments in daily PEF, symptom scores, rescue bronchodilator use, PD20 histamine or FEV1 up to 8 h post treatment. Following withdrawal of theophylline there were significantly lower values for mean FEV1 (mean difference 0.151, 95% CI 0.03, 026) and PD20 AMP compared to placebo but no difference in other end points. CONCLUSIONS: The small rebound deterioration in lung function following regular treatment with therapeutic doses of oral theophylline is consistent with the development of tolerance.

Effect of regular terbutaline on the airway response to inhaled budesonide.

BACKGROUND: The rebound increase in bronchial reactivity and fall in forced expiratory volume in one second (FEV1) following treatment with beta agonists seen in several studies has occurred regardless of concurrent steroid therapy. Little is known about the effect of adding beta agonists to corticosteroids, but in a recent study regular treatment with terbutaline appeared to reduce some of the beneficial effects of budesonide. The effects of budesonide alone and in combination with regular terbutaline treatment on lung function, symptom scores, and bronchial reactivity were therefore examined. METHODS: Sixteen subjects with mild stable asthma inhaled budesonide 800 micrograms twice daily for two periods of 14 days with terbutaline 1000 micrograms three times daily or placebo in a double blind crossover fashion. FEV1 and the dose of histamine or adenosine monophosphate (AMP) causing a 20% fall in FEV1 (PD20) were measured before and 12 hours after the final dose of treatment, and changes from baseline were compared. Seven day mean values for daily morning and evening peak expiratory flow (PEF) values, symptom scores, and rescue medication were compared before and during treatment. RESULTS: Morning and evening PEF rose more with budesonide plus terbutaline than with budesonide alone, with a mean difference of 19 l/min occurring in the evening (95% confidence interval (CI) 2 to 36). There was no difference in symptom scores during treatment. Following treatment the mean increase in FEV1 was 150 ml higher with budesonide alone (95% CI-10 to 300). There was no difference between treatments in change in histamine and AMP PD20. CONCLUSIONS: Evening PEF was greater when budesonide was combined with regular terbutaline. There was no evidence of a difference in bronchial reactivity following the two treatment regimens. The findings of a previous study were not confirmed as the reduction in FEV1 after budesonide and terbutaline was smaller and not statistically significant. Further work is needed to determine whether this disparity in findings in the two studies is due to a type 2 statistical error in this study or a spurious finding in the previous study.

Effect of cessation of short-term therapy with ipratropium bromide on lung function and airway responsiveness.

Regular exposure to antimuscarinic drugs would be expected to upregulate airway muscarinic receptors and could cause a transient increase in airways obstruction if treatment was stopped or omitted. We have examined peak expiratory flow rate (PEFR) during treatment and forced expiratory flow in one second (FEV1) and airway responsiveness to three constrictor agonists (as the provocative dose of agonist causing a 20% fall in FEV1, (PD20)) following cessation of regular inhaled ipratropium bromide, in 13 subjects with mild stable asthma. Subjects inhaled placebo and ipratropium bromide, 80 microg q.i.d. for 14 days in a cross-over fashion with a 1 week run-in/wash-out period before and after each treatment period. Subjects recorded symptom scores and PEFR throughout the study, and FEV1 and PD20 to histamine, methacholine and metabisulphite were measured before and after cessation of treatment. When compared to baseline, FEV1 was lower after cessation of ipratropium than after placebo, with a significant difference 30 h after the last dose (difference 190 mL; 95% confidence interval (95% CI) 310-70 mL; p<0.02). FEV1 measured 6-10 days later, did not differ significantly. PEFR was significantly lower after cessation of ipratropium than after placebo on Day 15 (19-37 h after the last dose) (mean difference 4.6%; 95% CI 1.6-7.5%; p<0.01) but not on Day 16. There were no significant changes in PD20 histamine, methacholine and metabisulphite, symptom scores or rescue bronchodilator use after cessation of treatment. Thus, transient bronchoconstriction was found around 30 h after cessation of regular therapy with inhaled ipratropium for 2 weeks. The mechanism is unclear, as no evidence of muscarinic receptor upregulation was found. Although the changes were small and unlikely to be important for most patients, the results of this study indicate that the timing of lung function measurements relative to the last dose of ipratropium is important when interpreting the course of lung function in long-term studies.

Interaction between corticosteroids and beta-agonists in asthma.

It is often assumed that there is synergy between corticosteroids and beta-agonists, the two drugs most commonly used to treat asthma. A review of clinical studies of the effect of corticosteroids on the response to a beta-agonist finds no evidence to support this assumption except in subjects taking high doses of beta-agonists and with diminished responsiveness to a beta-agonist. There is some evidence that regular beta-agonist therapy may cause a temporary reduction in the efficacy of corticosteroids in asthma, an effect that is seen when the response to the beta-agonist has worn off. Further studies of this effect are required in view of the very widespread concomitant use of the two drugs.

Systemic effects of salbutamol and salmeterol in patients with asthma.

BACKGROUND: Knowing the extent of the systemic effects of a new beta 2 agonist relative to an established drug is important for the prediction and interpretation of side effects. A recent study in which the effect of cumulative doses of salbutamol was compared with single doses of salmetreol suggested that, weight for weight, salmeterol may be up to 10 times more potent than salbutamol. This current study was designed to investigate further the dose equivalence of salmeterol and salbutamol. METHODS: Twelve patients with mild asthma inhaled cumulative doses of placebo, salmeterol 25, 50, 100, and 200 micrograms, and salbutamol 100, 500, 1000, and 1000 micrograms on separate days at hourly intervals in a randomised double blind crossover study. Changes in forced expiratory volume in one second (FEV1), heart rate, plasma potassium concentration, systolic and diastolic blood pressure were measured. Dose equivalence was determined as the dose ratio of salmeterol to salbutamol for the 50% maximum response to salbutamol. RESULTS: No important changes occurred in any measurements following placebo. Salmeterol and salbutamol caused a near maximum increase in FEV1 following the first dose so the dose equivalence for the airway effects could not be estimated. Heart rate increased and plasma potassium concentration and diastolic blood pressure decreased in a dose dependent manner following salmeterol and salbutamol, with median dose equivalences for salmeterol compared with salbutamol of 17.7, 7.8, and 7.6, respectively. CONCLUSIONS: These results confirm that the systemic activity of salmeterol compared with salbutamol is higher than would be expected from in vitro data, particularly for heart rate. Whether this is because of the relatively high dose of salmeterol used or pharmacokinetic differences between the two drugs is uncertain.