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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The development of tolerance to the bronchodilator effects of 
2-agonists used in asthma therapy
has been the subject of debate. We conducted two placebo-controlled crossover studies to assess the
bronchodilator response to a short-acting 2-agonist before and after chronic therapy with salmeterol. Patients in one study were corticosteroid-naive; patients in the other study were using inhaled
corticosteroids. Changes in FEV1 after cumulative doubling doses of inhaled albuterol were assessed
after a 2-wk -agonist washout period, before administering study medication on Day 1, and again
after 28 d of therapy. Ipratropium bromide was provided as rapid-relief treatment for asthma, and
use of any 2-agonist except the study treatment was prohibited. On both assessment days for salmeterol, and during placebo administration periods, significant increases from predose FEV1 values were
observed beginning with the lowest dose of albuterol and continuing throughout the dose-response
assessment (p 
0.001). These increases in FEV1 were maintained for 6 h after the last dose of albuterol (p < 0.05). There were no statistically significant differences in the albuterol dose response
following salmeterol or placebo. These studies indicate that irrespective of concurrent corticosteroid treatment, chronic therapy with salmeterol does not result in tolerance to the bronchodilator effects
of albuterol.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the treatment of patients with asthma, the development of
tolerance to the effects of short- and long-acting 2-adrenoreceptor agonists after their prolonged use has been the subject
of numerous reviews (1). Although tolerance to the extrapulmonary effects of 2-agonists has been demonstrated in a
number of studies (6), the potential for developing tolerance to the bronchodilator effects of these agents, resulting in
a loss of therapeutic efficacy with their prolonged use, is of
greater clinical concern.
Salmeterol is a highly selective, potent, long-acting, inhaled
2-receptor agonist indicated for the long-term maintenance treatment of asthma and prevention of bronchospasm in patients with reversible obstructive airway disease. A major advantage of salmeterol over other inhaled 2-agonists is its
longer duration of action. Salmeterol has been shown to be effective for 12 h after its administration, compared with 4 h to
6 h for the short-acting 2-agonists (10, 11). In addition, the
superior efficacy (as assessed by FEV1, peak expiratory flow
[PEF], and asthma symptom control) of therapeutic doses of
salmeterol over those of the short-acting 2-agonist albuterol
for treatment periods of 12 wk to 12 mo has been demonstrated in numerous studies (12). These well-controlled
studies have shown that the onset of activity, peak effect, and
duration of activity of salmeterol are unchanged after its long-term use. Although there has been no evidence that prolonged
use of salmeterol induces tolerance to its bronchodilator effects, its longer duration of action may raise concern about the
potential development of tolerance to the 2-agonist effects of
short-acting -agonists as a result of -adrenergic-receptor downregulation. Clinically relevant examples of the development of tolerance would be diminution of the onset, peak, or
duration of bronchodilatation with additional 2-agonist therapy.
A recent study suggested that patients who received salmeterol twice daily for 4 wk became tolerant to the bronchodilator effects of albuterol (17). In that study, FEV1 values before treatment with albuterol were notably higher after treatment with salmeterol than after administration of placebo; however, the analysis of the change from baseline did not control for this difference in baseline lung function between the two treatments, making the conclusions of the study questionable.
The two studies presented here were similarly designed to
further characterize the bronchodilator response to a short-acting 2-agonist in patients with asthma who were receiving
salmeterol as maintenance therapy. Because there has been
some debate about whether corticosteroid treatment provides
a protective effect against the development of tolerance to
2-agonists (18, 19), two patient populations were evaluated:
one study enrolled corticosteroid-naive patients, whereas the
other required that patients be maintained on a stable regimen of inhaled corticosteroid treatment for their asthma before and throughout their participation in the study. An initial
2-agonist washout period of 2 wk was included in both studies
to control for the possibility of some patients having developed a degree of tolerance to 2-agonists before study enrollment. Tolerance to the bronchodilator effects of albuterol was
assessed with cumulative doubling doses of albuterol both before and after 28 d of treatment with salmeterol or placebo.
Use of 2-agonists during the placebo period was prohibited in
order to ensure that no tolerance to 2-agonists would develop
as a result of the use of supplemental medications.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Design and Patients
Two randomized, double-blind, placebo-controlled, crossover clinical
trials were conducted at two centers to examine bronchodilator subsensitivity in adult patients with asthma who had been receiving inhaled salmeterol xinafoate (Serevent Inhalation Aerosol; Glaxo Wellcome Inc., Research Triangle Park, NC) at a dose of 42 µg twice daily
for 4 wk. All patients provided written informed consent, and the trials were approved by institutional review boards. The two studies
were identical in design with one exception: one study enrolled corticosteroid-naive patients, whereas the other enrolled patients who had
been treated with daily inhaled corticosteroids (beclomethasone dipropionate 672 µg/d, flunisolide 2,000 µg/d, or triamcinolone acetonide 800 µg/d) for at least 30 d before enrollment and who were
able to continue their inhaled corticosteroid regimen without adjustment for the duration of the study.
Patients at least 18 yr of age were eligible for enrollment in each of
the two studies if they had a diagnosis of asthma, as defined by the
American Thoracic Society (20), that had lasted for at least 12 mo,
had a baseline FEV1 of 50% to 80% of Crapo and colleagues' (21)
predicted normal values after withholding of bronchodilators, and
had at least a 12% increase in FEV1 within 30 min after inhalation of
180 µg albuterol. Eligibility criteria for both studies also specified that
patients had required 2-agonist therapy (on a fixed schedule or on an
as-needed basis with at least one use daily) prior to enrollment. At the
time of enrollment in either study, patients were supplied with supplemental ipratropium bromide (Boehringer Ingelheim Pharmaceuticals,
Inc., Ridgefield, CT) to treat breakthrough asthma symptoms, and
were instructed to discontinue the use of all other bronchodilators for
the duration of the study. Following a 2-agonist washout period of
14 ± 2 d, patients returned for their first day of randomized treatment with salmeterol or administration of placebo. Patients continued dosing with the study medication for 4 wk, entered a washout period of
7 ± 2 d, and then received the alternative treatment for 4 wk in the second crossover period. Concurrent use of any oral or inhaled 2-agonists (other than salmeterol) or of any -adrenergic-receptor antagonists was prohibited throughout the washout and treatment periods.
Eligible patients underwent screening assessments including medical history, physical examination and recording of vital signs, clinical laboratory assessments, pulmonary function testing that included an assessment of FEV1 reversibility (after withholding of short-acting inhaled bronchodilators for at least 8 h, long-acting inhaled bronchodilators for at least 24 h, and any long-acting oral bronchodilators for at least 48 h), a 12-lead electrocardiogram (ECG), and an assessment of adverse events. During the screening visit, patients were instructed in and showed proficiency in the use of the metered dose inhalers (MDIs) and peak flow meters used in the study.
Dose-response assessments for albuterol (Ventolin Inhalation Aerosol, Glaxo Wellcome) were conducted between 6:00 A.M. and 9:00 A.M. before the morning dose of study drug on the first treatment day and after 28 d of therapy during each study period (Study Days 1 and 28). Prior to testing, patients were to withhold ipratropium bromide for at least 8 h, abstain from caffeine consumption for at least 6 h, and avoid exercise or strenuous activity for at least 2 h. At each test session, doubling cumulative doses of inhaled albuterol were administered every 30 min, and pulmonary function tests (FEV1, FVC, and FEF25-75%) were performed in triplicate 25 min after each doubling dose. Doses of albuterol ranged from 180 µg to 1,440 µg (for cumulative doses of 180, 360, 720, 1,440, and 2,880 µg) unless significant signs of adverse events in response to albuterol prohibited further dosing. After the last dose of albuterol, pulmonary function tests were performed every hour for 6 h.
Statistical Analysis
A sample size of at least 20 patients in each population completing both crossover periods was estimated to provide > 80% power to detect a significant difference of 2.5% in the predicted FEV1 at a significance level of 0.05.
Comparisons during treatment were done with t tests, with each patient's data paired with his or her baseline value for pulmonary function data as obtained during albuterol dose-response assessments. Treatment comparisons at baseline were based on mean values, with an analysis of variance (ANOVA) crossover model (22). All other treatment comparisons were based on an ANOVA model of change from predose baseline values, with control for baseline and treatment-period effects. Pretreatment (Study Day 1) measurements of albuterol dose-response with pulmonary function tests were also compared with measurements within each treatment group on study Day 28, using an ANOVA model.
Frequencies of ECG results and adverse events were analyzed with Fisher's exact test (23).
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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A total of 24 corticosteroid-treated patients (16 females and eight males) and 27 corticosteroid-naive patients (13 females and 14 males) participated in the studies. Twenty-one corticosteroid-treated patients and 21 corticosteroid-naive patients completed both crossover periods; a total of nine patients were withdrawn from the studies prematurely. Asthma exacerbations led to premature withdrawal for one corticosteroid-treated and one corticosteroid-naive patient during administration of placebo, and of one corticosteroid-naive patient during salmeterol treatment. Two corticosteroid-naive patients were withdrawn because of adverse events during administration of placebo. Other reasons for withdrawal included withdrawal of consent, use of prohibited medication, and lack of efficacy.
The mean age of the patients in the corticosteroid-treated group was 41 yr (range: 20 to 63 yr) and in the corticosteroid-naive group 32 yr (range: 20 to 56 yr). The majority of patients (> 90%) were white. In the corticosteroid-treated group, the mean prebronchodilation FEV1 at screening was 2.33 L, the % predicted FEV1 was 67.9%, and the percent reversibility was 27.9%. In the corticosteroid-naive group, the mean prebronchodilation FEV1 was 2.68 L, the % predicted FEV1 was 68.7%, and the percent reversibility was 29.0%. For both patient populations, pretreatment values for FEV1 and PEF were similar in the salmeterol and placebo treatment periods (Table 1).
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Albuterol Dose Response
There were no significant differences between the two crossover treatment periods in FEV1, FVC, or FEF25-75% at baseline for either patient population. Prior to either treatment
with salmeterol administration of placebo (at study Day 1),
significant increases in FEV1 in response to inhalation of albuterol were observed in both the corticosteroid-treated and
corticosteroid-naive patients after the first dose of albuterol
(p < 0.001) and continuing throughout dosing (p < 0.001) (Figure 1), and for 6 h after the last dose of albuterol (p 0.003)
(Figure 2). There were no significant differences in either patient population in the albuterol dose response before treatment with salmeterol or administration of placebo.
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During treatment with salmeterol, a significant increase in
prealbuterol FEV1 values from pretreatment on study Day 1 to Day 28 of therapy was noted in both the corticosteroid-treated (p = 0.001) and corticosteroid-naive (p = 0.003) patients (Table 1); no differences were detected during administration of placebo. In the corticosteroid-treated patients, the
change in prealbuterol FEV1 from pretreatment on study Day
1 to Day 28 of therapy was significantly greater after treatment with salmeterol (mean change: 0.21 L) than after placebo (
0.03 L; p = 0.004). Likewise, in the corticosteroid-naive
patients, the change in prealbuterol FEV1 from pretreatment
on study Day 1 to Day 28 of therapy was significantly greater
after treatment with salmeterol (mean change: 0.36 L) than after placebo (0.000 L; p = 0.020).
After 4 wk of treatment with salmeterol or administration
of placebo, albuterol produced significant increases in FEV1
from predose values at all doses in both the corticosteroid-treated and corticosteroid-naive patient populations (p 0.001) (Figure 1). In both patient groups, significant increases
from baseline values were maintained for 6 h after the last
dose of albuterol with both treatment with salmeterol and administration of placebo (p 0.024) (with the exception of
Hour 5 in the salmeterol group of corticosteroid-treated patients (p = 0.055) (Figure 2). There were no significant differences in the albuterol dose-response curves for changes in
FEV1 on study Day 1 versus Day 28 of therapy among recipients of salmeterol or placebo. There were also no significant
differences between the salmeterol and placebo treatments for
either patient population. Results for mean changes in FVC and FEF25-75% in response to albuterol were similar to those for FEV1 (data not shown).
Asthma Exacerbations
One corticosteroid-treated patient was withdrawn from the study because of an exacerbation of asthma during administration of placebo. The investigator reported that respiratory infection was the primary suspected cause of the exacerbation. Two corticosteroid-naive patients were withdrawn from the study because of asthma exacerbations, one during administration of placebo and one during salmeterol treatment. The investigator reported that respiratory infection was the primary suspected cause for the former withdrawal, whereas the latter was of unknown etiology. One additional corticosteroid-naive patient had an asthma exacerbation of unknown cause during administration of placebo, but was not withdrawn from the study.
Heart Rate, Blood Pressure, and 12-Lead ECG
There were no drug-related changes in patients' heart rates or blood pressures during the study. There were also no overall clinically significant differences between treatments in ECG results before treatment or after 28 d of treatment in either the corticosteroid-treated or corticosteroid-naive populations. After the final dose of albuterol on Day 28 of placebo administration, one corticosteroid-naive patient had an asymptomatic, nonspecific ST-T wave ECG abnormality that was considered clinically significant.
Adverse Events
The overall incidence of adverse events did not differ significantly with salmeterol treatment and placebo in either the corticosteroid-treated or corticosteroid-naive populations. The incidence of adverse events in the corticosteroid-treated population was 57% during administration of placebo and was 48% during salmeterol treatment. In the corticosteroid-naive population, the incidences of adverse events were 48% and 42% during placebo and salmeterol treatment, respectively. The most frequently reported adverse event during the treatment periods was headache, 22% which occurred in and 26% of corticosteroid-treated patients during placebo and salmeterol treatment, respectively, and in 28% and 21% of corticosteroid-naive patients during placebo and salmeterol treatment, respectively. Dizziness was noted during administration of placebo and salmeterol treatment in 17% and 4% of corticosteroid-treated patients, respectively, and in 20% and 8% of corticosteroid-naive patients, respectively. There were no serious adverse events in either patient population. Two corticosteroid-naive patients were withdrawn because of adverse events (bronchitis and abnormal ECG, respectively) during administration of placebo.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The optimal assessment of tolerance to the bronchodilator effects of albuterol after treatment with salmeterol requires the inclusion of an adequate washout period for other 2-agonists before beginning salmeterol treatment. This washout period
ensures that tolerance has not already developed in response
to previous treatment with other drugs of this class. The elimination of all 2-agonists during such a study, including elimination of their use as rescue therapy, is also necessary to maintain a true placebo comparator. The inclusion of a cumulative
dose-response curve for assessing the bronchodilator response
to a short-acting -agonist is also essential for thorough assessment of the peak and duration of response following prolonged treatment with salmeterol or administration of placebo.
The studies reported here attempted to adequately control
for several variables that could interfere with the assessment
of bronchodilator tolerance. The design of the studies included a run-in period without 2-agonist use, the use of cumulative doubling doses of albuterol, and the use of a non-2-agonist (ipratropium) as rescue medication. In addition, because of
the data indicating a protective effect of corticosteroids in the
development of tolerance to -agonists (18, 19), we evaluated
bronchodilator tolerance in both corticosteroid-treated and
corticosteroid-naive patients.
The results of our studies indicate that tolerance to the bronchodilator response to albuterol does not develop after 4 wk of treatment with salmeterol at a dose of 42 µg twice daily, irrespective of concurrent corticosteroid treatment. In this study neither the peak nor the duration of the albuterol dose-response as measured with the FEV1 was significantly different at Day 28 of salmeterol treatment from the respective pretreatment baseline values on study Day 1 in either the corticosteroid-treated or corticosteroid-naive patient populations. The comparison of the albuterol response of salmeterol-treated subjects and those given placebo after 28 d of treatment also showed no significant difference. These results were very similar to those in a 6-mo study by Wilding and associates (24) that showed an identical final FEV1 achieved with salmeterol and with placebo in an albuterol dose-response study, indicating that bronchodilator responsiveness is maintained after regular salmeterol treatment. Furthermore, significant increases in FEV1 in response to cumulative doubling doses of albuterol persisted for 6 h after the last cumulative dose of albuterol in both the salmeterol and placebo treatment periods for both patient populations.
Although the prospective albuterol dose-response assessments in our study found no significant differences in the change from baseline with salmeterol or placebo on Day 1 and Day 28, or in the change within treatments from Day 1 to Day 28, we also conducted a more sensitive, post hoc repeated-measures analysis (data not shown) in which we compared the areas under the albuterol dose-response curves for placebo and salmeterol treatment on Day 1 and Day 28. These results also showed no difference in the curves. We therefore conclude that the response after 28 d of salmeterol therapy was not different from that on the pretreatment dose-response curve, and that the albuterol dose-response following salmeterol was not different from that following placebo.
These results are in contrast to those of a similarly designed study by Grove and Lipworth (17), which reported development of tolerance to the bronchodilator effects of albuterol after 4 wk of treatment with salmeterol in corticosteroid-treated patients, as assessed by a shift to the right in the albuterol dose-response curve for changes from baseline in FEV1. However, in their study, the mean baseline FEV1 before the start of the albuterol dose-response assessment was higher after salmeterol treatment than after placebo. Because the amount of change in FEV1 is physiologically limited by the maximal degree of bronchodilation that can occur, the analysis of change in FEV1 from baseline on the same day, as done in Grove and Lipworth's study, may not reflect tolerance after salmeterol treatment, but rather a more limited potential for response in the salmeterol-treatment period. That the peak level of pulmonary function following administration of albuterol did not differ significantly in the placebo and salmeterol treatment periods also suggests this possibility. The present study analyzed the absolute value of FEV1 at each point on the dose-response curve, as well as for 6 h after the last dose of albuterol. No significant differences within treatments between Days 1 and 28 or between salmeterol and placebo were observed at any time, indicating that tolerance did not develop to the bronchodilator effects of albuterol after treatment with salmeterol. The findings in our studies support those in other controlled clinical trials in which the significant bronchodilator effects of salmeterol were maintained throughout 8 wk to 12 mo of treatment (14, 25).
Salmeterol treatment for 4 wk was well-tolerated in our studies. No clinically notable differences were observed in the effects of salmeterol and placebo on heart rate, blood pressure, or 12-lead ECGs. The use of salmeterol is currently recommended in conjunction with inhaled corticosteroids (29), and previous studies have supported the use of salmeterol in conjunction with inhaled corticosteroids as a more effective alternative to increasing the inhaled corticosteroid dose alone (30, 31). The findings of the present studies support the safe and effective use of inhaled corticosteroids in conjunction with salmeterol.
In conclusion, the results of these studies indicate that 4 wk
of treatment with salmeterol does not produce tolerance to the bronchodilator effect of albuterol in patients with asthma, irrespective of concurrent corticosteroid treatment. The results of the present studies are particularly reassuring because
of the frequency with which short-acting 2-agonists such as
albuterol are used in the treatment of acute, or "breakthrough,"
asthma attacks.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Harold S. Nelson, M.D., National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206.
(Received in original form July 24, 1998 and in revised form December 28, 1998).
Acknowledgments: Supported by a grant from Glaxo Wellcome, Inc.
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References |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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 M. Cazzola, G. Di Lorenzo, F. Di Perna, F. Calderaro, R. Testi, and S. Centanni Additive Effects of Salmeterol and Fluticasone or Theophylline in COPD Chest, December 1, 2000; 118(6): 1576 - 1581. [Abstract] [Full Text] [PDF]
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B. J. Lipworth, O. J. Dempsey, and I. Aziz Functional Antagonism With Formoterol and Salmeterol in Asthmatic Patients Expressing the Homozygous Glycine-16 {beta}2-Adrenoceptor Polymorphism Chest, August 1, 2000; 118(2): 321 - 328. [Abstract] [Full Text] [PDF]
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B. J. Lipworth, C. M. Jackson, R. R. Rosenthal, and C. Kalberg Salmeterol and Tolerance Chest, February 1, 2000; 117(2): 609 - 611. [Full Text] [PDF]
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B. J. Lipworth and I. Aziz Bronchodilator Response to Albuterol After Regular Formoterol and Effects of Acute Corticosteroid Administration* Chest, January 1, 2000; 117(1): 156 - 162. [Abstract] [Full Text] [PDF]
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Am. J. Respir. Crit. Care Med., December 1, 1999; 160(6): 2125 - 2126. [Full Text]
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