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1 Depts of Medical and Surgical Sciences and 2 Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
CORRESPONDENCE: D.R. Taylor, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. Fax: +6434747641
Keywords: formoterol, long acting beta-agonist, tolerance
Received: March 13, 2000
Accepted August 18, 2000
This work was supported in part, by a GlaxoWellcome Research Fellowship, awarded to S.L. Jones.
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Abstract |
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Ten asthmatic subjects (using inhaled steroids) participated in a randomised, double-blind, placebo-controlled, cross-over study. Formoterol 12 µg b.i.d. or matching placebo was given for 10–14 days with >2 weeks washout. Following each treatment, patients underwent a methacholine challenge to induce a fall in forced expired volume in one second (FEV1) of at least 20%, then salbutamol 100 µg, 100 µg, and 200 µg was inhaled via a spacer at 5 min intervals, with a further 400 µg at 45 min. After a third single-blind formoterol treatment period, hydrocortisone 200 mg was given intravenously prior to salbutamol. Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account ofmethacholine-induced changes in spirometry.
Regular formoterol resulted in a significantly lower FEV1 after salbutamol at each time point compared to placebo (p<0.01). The area under the curves (AUCs) for 15 (AUC0–15) and 45 (AUC0–45) min were 28.8% and 29.5% lower following formoterol treatment (p<0.001). Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration.
It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol. This bronchodilator tolerance is evident in circumstances of acute bronchconstriction.
Current guidelines for the management of chronic asthma propose that long-acting ß-agonists such as salmeterol and formoterol should be added to anti-inflammatory treatment for the control of persistent or breakthrough symptoms 1, 2. This strategy appears to be beneficial not only in controlling symptoms 3–7, but also in reducing the frequency of asthma exacerbations during long-term treatment 8, 9.
Despite these positive outcomes, against a background of concern about the safety of ß-agonists 10 significant attention has been given to the issue of ß-adrenoceptor down-regulation and the advent of drug tolerance. A number of studies using salmeterol and formoterol have been conducted to investigate this issue. These have shown that during treatment with long-acting agents, tolerance to the protective effects of ß-agonists against exercise-induced bronchospasm 11 and nonspecific bronchoconstrictors is easily demonstrated 12 and develops rapidly 13. Concurrent treatment with inhaled corticosteroid does not appear to modify these effects 14–17, although corticosteroids may be used acutely to reverse them 18, 19.
In contrast, evidence for the development of bronchodilator tolerance has been less clear cut. In the majority of studies, no evidence of impaired bronchodilator responsiveness has been found 20–24, although in some investigations a reduction in bronchodilator response has been reported 18, 25, 26. However, a major drawback in the design of these studies is that most have been carried out in patients with stable asthma, in whom a reduction in ß2-adrenoceptor function may be relatively unimportant in maintaining adequate bronchomotor tone. This contrasts with patients with acute asthma.
Recently, using a simple but novel approach, the authors have demonstrated that after six weeks regular treatment with the short-acting ß2-agonist terbutaline, the bronchodilator response to salbutamol is significantly reduced in circumstances of acute bronchoconstriction 27. This is more relevant in determining the clinical importance of tolerance. The present study has extended this approach to assess the development of bronchodilator tolerance during regular treatment with the long-acting ß-agonist formoterol. The study was also designed to confirm whether administering systemic corticosteroid rapidly reverses any observed effect.
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Methods |
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Study design
All patients entered a 2-week run-in phase during which control of asthma was assessed by means of a daily record card in which patients entered morning and evening peak flows and symptom scores. Throughout the study patients were maintained on their usual dose of inhaled steroids. All ß2-agonists were stopped and patients were provided with ipratropium bromide 40 µg·puff–1 (Boehringer, Ingelheim, Germany) for "as required" use. Patients with unstable asthma, or who were unable to obtain adequate relief of breakthrough symptoms using inhaled ipratropium bromide during the run-in, were withdrawn from the study. All other patients then received each of the first two study treatments according to a randomised, double-blind, crossover design. The treatments were formoterol (Foradil, Novartis, Basel, Switzerland) 12 µg twice daily administered as dry powder via an aeroliser for 7–10 days, and matching placebo containing lactose. There was a washout period of at least 2 weeks between each of the first two treatments. Following a further 2 week washout interval, patients proceeded into a third treatment period during which formoterol 12 µg twice daily was administered single-blind (patient) for 7–10 days. This was to permit a subsequent assessment of the effect of intravenous hydrocortisone on the bronchodilator dose-response.
Study visits and measurements
Patients visited the research laboratory at the completion of each of the three treatment periods. Study medications and inhaled ipratropium were withheld for at least 36 and 6 h respectively. On each occasion, and prior to any measurements being obtained, a venous cannula was inserted into a forearm vein, and either normal saline (following each of the first two treatment arms) or hydrocortisone 200 mg (following the third treatment arm, formoterol 12 µg b.i.d.) was given single-blind (patient) intravenously. The administration of steroid 1 h before measuring the dose-response to salbutamol was to mimic what might occur during an acute episode of asthma. Active hydrocortisone was given during the last of the three treatment periods to avoid any steroid-related carry over effect on ß-adrenoceptor function.
Exactly 1 h later, patients underwent a methacholine challenge followed by a bronchodilator response measurement. The methacholine challenge was performed using a modified version of the rapid challenge procedure 28. After measurement of baseline FEV1 according to American Thoracic Society (ATS) criteria 29 using a rolling seal spirometer (Spirotech, Graseby, Georgia, USA), increasing doses (0.044–45 µmol) of methacholine were administered by nebuliser, controlled by a Morgan Nebicheck dosimeter (Morgan, Gillingham, Kent, UK). The procedure was stopped after the FEV1 had fallen by 
20%. The PD20 was calculated by linear interpolation.
Immediately after the PD20 had been reached, an abbreviated dose-response test to inhaled salbutamol (Ventolin, GlaxoWellcome, Greenford, UK) was undertaken. The salbutamol was administered from a metered dose inhaler via a large volume spacer (Volumatic, GlaxoWelcome, Greenford, UK). Doses of 100 µg, 100 µg, and 200 µg were given at 0, 5, and 10 min, respectively. Spirometry was performed immediately prior to each dose, and also at 15, 30 and 45 min.
A further 400 µg of salbutamol was administered at 45 min to maximise bronchodilatation prior to further spirometry and a second methacholine challenge at 60 min, using the same method as previously. The aim of this further challenge was to measure the protective effect of the salbutamol against further methacholine. Once a PD20 had been established for the second methacholine challenge, patients were given inhaled salbutamol ad lib and remained in the research laboratory until their FEV1 had returned to at least 90% of baseline.
Analysis of results
The primary study end-point was area under the curve (AUC) for change in FEV1 following inhaled salbutamol. From a previous investigation 27, the sample size was calculated so that there was 90% power to detect a 30% difference in AUC with a significance of 0.05. Analyses were undertaken to assess treatment-related differences, as well as the effects of intravenous hydrocortisone. Analyses of covariance were performed to take into account any differences in the baseline FEV1, the fall in FEV1 during the methacholine challenge and log PD20 methacholine. Where PD20 was not achieved after the highest dose of methacholine, an arbitrary value of 64 µmol was assigned. The increase in FEV1 after each dose of salbutamol, expressed as a percentage of the fall from baseline during the methacholine challenge, was also analysed. Further comparisons were made for post-salbutamol PD20 values to assess treatment-related differences in the protective effect given by inhaled salbutamol against methacholine-induced bronchoconstriction. When comparing differences in the post-salbutamol PD20s between the first two treatment arms, the pre-salbutamol PD20 was used as a covariate.
Ethical considerations
Asthma control was carefully monitored throughout the study. Each patient had an individualised asthma action plan, a supply of prednisone and an inhaled ß2-agonist for emergency use, and 24 h access to one of the study investigators, in case of an acute exacerbation. The study was approved by the Otago Ethics Committee. Each patient gave written informed consent.
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Results |
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Baseline lung function and bronchial hyper-responsiveness
Baseline FEV1 and mean methacholine PD20 values were not significantly different following each of the three treatment periods. The mean percentage fall in FEV1 did not differ between the treatments (table 1
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. The values were significantly lower with formoterol treatment than placebo at each time point. Dose-response curves following salbutamol, expressed as a percentage of the fall in FEV1 from the pre-methacholine baseline, are shown in figure 2. Prior treatment with formoterol was associated with a significantly smaller increase at each time point. AUC0–15 and AUC0–45 were 28.8% and 29.5% lower following treatment with formoterol than placebo at each time point (p<0.0004 and p<0.0001, respectively). Prior administration of hydrocortisone did not result in any significant difference compared to formoterol alone for either FEV1 at each time point, or AUC0–15 and AUC0–45, although the difference compared to placebo was significant.
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). The protective effect of salbutamol as measured by the increase in methacholine PD20 from baseline and expressed as doubling dose concentrations (d.d.s) was 2.74 d.d.s (95% C.I. 2.19–3.29) following formoterol and 3.97 d.d.s (95% C.I. 3.42–4.52) following placebo (p<0.01). Following formoterol with hydrocortisone the increase in PD20 was 2.62 d.d.s (95% C.I. 2.01–3.23) (p=0.79 for comparison with formoterol alone). |
Discussion |
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The findings provide evidence that the effects of bronchodilator tolerance are more likely to be encountered when patients are experiencing bronchospasm. Most recent studies have failed to demonstrate bronchodilator tolerance with long-acting ß-agonists 20–24. This may be because these investigations have included patients whose asthma is stable and in whom there was no significant bronchoconstriction. For this reason, the validity of these earlier results is questionable. It is difficult to appropriately conduct controlled bronchodilator response studies in patients with unstable asthma. It was in an attempt to address this issue that mild airway obstruction was induced in the patients using a nonspecific bronchoconstrictor. Although the present model does not accurately mimic acute severe asthma, in which other factors besides ß-adrenoceptor down-regulation, induced by continuous ß-agonist therapy, may impair the response to inhaled bronchodilator, it does permit the conclusion that bronchodilator tolerance is more likely to be important in the presence of bronchoconstriction.
The study design included a 36 h period of drug withdrawal prior to testing for bronchodilator tolerance. If anything, this may have resulted in a diminution in the magnitude of the effect that was found, given that the status of ß-adrenoceptors may change rapidly 30. It might also be argued that testing for bronchodilator tolerance without a period of drug withdrawal would have been more clinically relevant. The principal reason for not doing so was to avoid the problem of functional antagonism to methacholine which would have resulted from the continuing action of formoterol. This would have had the potential to make acute bronchoconstriction, upon which demonstrating the development of tolerance was dependent, more difficult to achieve.
At 45 min our patients received a further 400 µg of salbutamol (making a total of 8x100 µg puffs) in order to induce maximal bronchodilatation. Following this, a significantly greater increase in FEV1 was achieved following formoterol treatment when compared to placebo (139 and 58 mL, respectively, p<0.02). This indicates that at that time point, even though baseline FEV1 had been recovered, residual bronchoconstriction was still present following formoterol treatment, despite the fact that the patients had already received 400 µg (4 puffs) of salbutamol. Thus, as might have been anticipated, overcoming the effects of ß-adrenoceptor tolerance required the use of higher doses of salbutamol, although there is evidence that this may not always be successful 31. This suggests that, in circumstances of acute bronchoconstriction, patients taking long-acting ß-agonists may require higher doses of "reliever" short-acting ß-agonist in order to obtain maximum bronchodilatation.
The clinical importance of this is unclear. No studies have been carried out to examine the exact relationship between ß-adrenoceptor tolerance and asthma control during long-term treatment with ß-agonists. Nor is it known whether individual susceptibility to the development of tolerance influences how patients respond to treatment during acute life-threatening episodes. However, the results of other studies offer indirect but reassuring evidence. The frequency of asthma exacerbations is reduced with regular long-acting ß-agonist, not increased 8, 9. Furthermore, in a controlled study, changes in symptoms and peak flow rates during the early phases of an exacerbation do not appear to be different in patients receiving regular formoterol from those who are not 32. In addition, the bronchodilator response to very high doses of nebulised salbutamol, such as would be used to treat acute severe asthma in an emergency department, is no different between patients taking or not taking regular salmeterol 33.
In the present study, prior administration of intravenous hydrocortisone 1 h before inducing bronchoconstriction and giving salbutamol had no significant effect on the magnitude of bronchodilator tolerance. Even when an additional 400 µg of salbutamol was administered at 45 min i.e. 1 h and 45 min after giving hydrocortisone, the corticosteroid had no effect on the magnitude of the increase in FEV1 during the subsequent 15 min. This outcome is in apparent contrast to the report by Tan et al. 18, in which the combined use of both oral prednisone and intravenous hydrocortisone reversed bronchodilator tolerance to formoterol. However, in the present study patients were followed for only 2 h after giving corticosteroid, whereas Tan et al. 18 followed their patients for 8 h. Taken together, these results confirm that although giving corticosteroid is likely to be effective in reversing the effects of ß-adrenoceptor tolerance, it cannot be relied upon to do so in the early phases of an acute episode of asthma.
In conclusion, this study has demonstrated that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after cessation of formoterol. This effect is likely to be more important in circumstances of acute bronchconstriction. Whether or not this effect increases with increasingly severe airway obstruction, or is accentuated when patients take excessive amounts of ß-agonist, requires to be evaluated further.
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: Placebo; 
: Formoterol; 
: Formoterol plus hydrocortisone. : 100 µg salbutamol; : 200 µg salbutamol; : 400 µg salbutamol. **: p<0.01, ***: p<0.001 for formoterol versus placebo comparisons.