Tolerance to the Bronchoprotective Effect of Salmeterol 12 Hours After Starting Twice Daily Treatment

Tolerance to the bronchoprotective effect of salmeterol 12 hours after starting twice daily treatment Dawn E Drotar, MD; E Elizabeth Davis, BSc; and Donald W Cockcroft, MD, FRCP(C)

Background: Regular use of salmeterol has been associated with reduced bronchoprotective effect against methacholine as early as 24 hours after initiating treatment. Objective: To determine whether loss of the bronchoprotective effect measured one hour after salmeterol could be demonstrated 12 hours following one previous dose. Methods: Ten subjects with stable, mild asthma were enrolled in a randomized, placebo-controlled, double-blind, crossover study comparing two 2-dose treatment periods: (1) blinded salmeterol 50 ␮g inhaled at bedtime, followed by unblinded salmeterol 50 ␮g inhaled 12 hours later and (2) blinded placebo inhaled at bedtime, followed by unblinded salmeterol 50 ␮g inhaled 12 hours later. The methacholine PC20 was measured one hour after the morning salmeterol; FEV1 was measured just prior to the morning salmeterol dose and at the start of the methacholine inhalation test. Results: The mean log methacholine PC20 recorded one hour after a single dose of salmeterol (1.20 ⫾ 0.17 SE) was significantly higher than the mean log methacholine PC20 recorded after two doses of salmeterol at 12-hour intervals (1.00 ⫾ 0.16 SE; P ⫽ .024). The mean FEV1 12 hours after salmeterol was significantly higher than the mean FEV1 recorded 12 hours after placebo (P ⫽ .0017), however, there was no significant difference between the FEV1 recordings one hour after the two unblinded doses of salmeterol. Conclusions: Tolerance to the bronchoprotective effect of salmeterol against methacholine induced bronchoconstriction occurs extremely quickly as it is evident 12 hours after starting twice daily treatment. Ann Allergy Asthma Immunol 1998;80:31–34.

INTRODUCTION Salmeterol is a long-acting inhaled beta2-agonist which is currently being used for long-term maintenance therapy and prevention of bronchospasm in asthmatic patients. Its long duration of action and prolonged bronchodilator effect has led to the recommendation that it be used on a regular basis, when inhaled steroids are insufficient for asthma control.1–3 Concerns regarding regular beta-agonist use have

Department of Medicine, Royal University Hospital, Saskatoon, SK S7N 0W8 Canada. Received for publication May 30, 1997. Accepted for publication in revised form July 28, 1997.

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prompted investigators to evaluate the effects of salmeterol maintenance therapy on methacholine-induced bronchoconstriction. One study demonstrated that regular use of salmeterol was associated with reduced protective effect against methacholine-induced bronchoconstriction at 4 and 8 weeks.4 More recent data have shown tolerance to the acute bronchoprotective effect by 24 hours of treatment (after the third dose),5 and this was confirmed in the presence of maintenance inhaled corticosteroids.6 The purpose of this study was to determine whether tolerance to the bronchoprotective effect was demonstrable as early as 12 hours, ie, following the second dose of salmeterol.

METHODS Subjects Included in the study were ten volunteers with well controlled, mild asthma who had FEV1 greater than 70% predicted and a methacholine concentration causing a 20% fall in FEV1 (PC20) less than 10 mg/mL.7 Subjects were required to have abstained from betaagonist use and had no respiratory tract infection or allergen exposure for at least 4 weeks prior to starting and for the duration of the study. Avoidance of allergen was achieved by abstaining from animal exposure and conducting the study during the winter (pollenfree) months in a geographic location where house dust mite prevalence is low. Nine of the ten subjects were atopic. Treatment with maintenance inhaled corticosteroids was permitted under the condition that the dose had been stable for at least 4 weeks prior to and throughout the study. Only one of the ten subjects was using inhaled corticosteroids at the time (four others had been on corticosteroids in the past). Treatment with inhaled ipratropium bromide was allowed for use as required, but was withheld for more than 12 hours before testing. No other asthma medications were used. The study was approved by the University of Saskatchewan Ethics Committee and signed, informed consent was given by all subjects. Subject characteristics and baseline lung function are given in Table 1. Methacholine Inhalation Test The methacholine inhalation test was done by the previously described method.7 A Bennett twin jet nebulizer was used with an output of 0.13 mL/ min. The subjects inhaled nebulized

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Table 1. Patient Characteristics FEV1

Subject No.

Age, yr

1 2 3 4 5 6 7 8 9 10

50 31 29 26 37 28 26 23 23 23

Sex M M F F F F M M M M

Ht, cm

Wt, kg

170 172 165 160 168 170 175 180 178 175

L

% Pred

Methacholine PC20 (mg/mL)

2.36 3.03 2.52 2.44 2.99 2.60 4.00 5.80 4.64 3.66

71 74 81 81 98 79 91 123 102 83

0.90 4.8 0.45 2.7 8.9 2.1 8.4 8.2 1.1 5.1

ICS*

63.6 65.9 59.1 56.4 74.1 48.2 62.7 72.7 61.9 72.3

N N N N Y N N N N N

* ICS ⫽ inhaled corticosteroid.

isotonic saline solution through a loose-fitting mask with nose occluded for two minutes of tidal breathing. FEV1 was recorded 30 and 90 seconds after the inhalation and the lower value was taken as baseline for calculations. Methacholine inhalation was done in a similar fashion with the nebulizer loaded with 3 mL of methacholine chloride in doubling concentrations (0.03 to 64.0 mg/mL) every five minutes until the subject had a 20% fall in FEV1. The methacholine PC20 was calculated from log dose versus response curve by an algebraic equation. If the FEV1 fell less than 20% but greater

than 10% after the top concentration (ie, 64 mg/mL) the PC20 was extrapolated (ie, to as high as 128 mg/mL). Study Design At a screening visit, one morning prior to the initial study dose, three baseline FEV1 values were obtained followed by a baseline measurement of methacholine PC20. Subjects were enrolled if they had a methacholine PC20 less than 10 mg/mL and an FEV1 greater than 70% predicted. Ten patients met these criteria. Four additional patients were screened, however, were not eligible

Table 2. Methacholine PC20 Methacholine PC20 (mg/mL) 1 Hr After Salmeterol Subject

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Baseline

First Treatment Placebo (12 hr earlier)

First Treatment Salmeterol (12 hr earlier)

1 2 3 4 5 6 7 8 9 10

0.90 4.8 0.45 2.7 8.9 2.1 8.4 8.2 1.1 5.1

4.7 27 2.1 8.4 116 13 26 67 8.4 21

2.4 24 1.0 8.9 26 6.6 18 34 6.3 32

Mean log10 PC20 SD SE

0.46 0.46 0.14

Geometric mean, mg/mL

2.9

1.20 0.52 0.17 15.8

1.00 0.51 0.16 10.0

because of PC20 measurements greater than 10 mg/mL. A randomized, placebo-controlled, double-blind, crossover study was done comparing two 2-dose treatment periods: (1) blinded salmeterol 2 puffs (50 ␮g) inhaled at bedtime, followed by unblinded salmeterol 2 puffs (50 ␮g) inhaled 12 hours later, and (2) blinded placebo 2 puffs inhaled at bedtime, followed by unblinded salmeterol 2 puffs (50 ␮g) inhaled 12 hours later. The two treatment periods were separated by at least a 7-day washout period. A methacholine PC20 was measured one hour after the inhalation of unblinded salmeterol. Three FEV1 measurements were recorded before the unblinded salmeterol dose and at the start of the methacholine inhalation test. Statistical Analysis Analysis of the results was done using the paired t test method. The primary endpoint was the log10 PC20 following a single dose of salmeterol versus the log10 PC20 following two doses of salmeterol at a 12-hour interval. The secondary endpoint was the FEV1 one hour following the two unblinded (morning) doses of salmeterol. RESULTS All ten volunteers completed the study and there were no adverse events reported. Although we had intended not to enroll subjects in the study within 4 weeks of allergen exposure, two of the ten subjects were allowed to partici-

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pate despite allergen exposure 3 weeks prior to initiating the study. Two of the subjects believed they could identify which inhaler contained active medication because they felt they were able to breath more easily following that inhalation, however, the other eight subjects denied any recognition of this. Lung Function The mean FEV1 recorded 12 hours after salmeterol (3.60 L ⫾ 0.37 SE) was significantly higher than the mean FEV1 recorded 12 hours after placebo (3.39 L ⫾ 0.35 SE; P ⫽ .0017). There was no significant difference between the mean FEV1 recorded one hour after the single dose of salmeterol (3.74 L ⫾ 0.37 SE) and the mean FEV1 recorded one hour after the second of two doses of 12-hour intervals (3.82 L ⫾ 0.41 SE; P ⫽ .44). Methacholine PC20 The mean log10 methacholine PC20 recorded one hour after the single dose of salmeterol (1.20 ⫾ 0.17 SE) was significantly higher than the mean log10 methacholine PC20 recorded one hour after the second of two doses of salmeterol at 12-hour intervals (1.00 ⫾ 0.16 SE; P ⫽ .024). This difference is 0.67 doubling doses. The mean log and geometric mean PC20 values are given in Table 2. DISCUSSION Several studies have demonstrated that regular use of short acting inhaled beta2-agonists leads to a reduction in their bronchoprotective effect on methacholine-induced bronchoconstriction, and this has been shown to occur even at low doses.8 –11 Perhaps more clinically relevant has been the demonstration of increased airway responsiveness to allergen that occurs with regular use of these medications.9 –13 Salmeterol differs structurally from conventional beta2-agonists and consequently provides a prolonged bronchodilator effect of greater than 12 hours.1,3 It has therefore been recommended that salmeterol be used on a regular dosing regimen (every 12 hours) as maintenance therapy for asthma.1–3 This recommen-

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dation has caused concern regarding the possibility of deteriorating asthma control with regular use of salmeterol.4 – 6 Regular use of salmeterol results in tolerance to its bronchoprotective effect on methacholine-induced bronchoconstriction.4 – 6 In a parallel, double-blind study of 24 patients with mild asthma, Cheung et al demonstrated a statistically significant reduction in bronchoprotection (from 10fold to 2-fold) after 4 and 8 weeks of regular salmeterol use compared with the methacholine PC20 on the first treatment day.4 A subsequent study by Bhagat et al compared ten subjects with mild asthma in a double-blind, crossover, placebo-controlled study with two treatment periods: inhaled salmeterol, 50 ␮g twice a day for seven doses, and placebo in a similar fashion. They found that the geometric mean methacholine PC20 after the first dose of salmeterol (6.1 mg/mL) was significantly larger than following the third, fifth, and seventh salmeterol doses (3.4 mg/mL, 2.6 mg/mL, 1.9 mg/ mL, respectively).5 A similar result was found by the same investigators despite the use of inhaled corticosteroids by the eight subjects.6 In the current study, a significant loss in bronchoprotective effect was evident following the second dose of salmeterol (ie, at 12 hours). The geometric mean methacholine PC20 was 15.8 mg/mL following a single dose of salmeterol and decreased to 10.0 mg/mL after a second dose at 12-hour intervals. The clinical significance of this, however, is yet unknown. One study has produced a contradictory result. In this study, the methacholine PC20 was investigated during and after 8 weeks of regular treatment with salmeterol 50 ␮g twice daily in 26 adult asthmatic patients, 19 of whom were receiving maintenance inhaled corticosteroids. Methacholine PC20 was measured 12 hours after the first dose and repeated 12 hours after the last dose of treatment medication at 4 and 8 weeks. No tolerance to the bronchoprotective effect of salmeterol was demonstrated in this 8-week period.14

It has been argued that the negative results in this trial may have been caused because of uncontrolled betaagonist use before and throughout the trial resulting in tolerance occurring before the beginning of the study.15 Despite the fact that methacholine inhalation challenges are routinely used in clinical trials and that the methacholine PC20 correlates with asthma severity,16,17 the clinical relevance of the loss of bronchoprotective effect with regular use of salmeterol has yet to be established. It has been suggested that the results of challenges with indirect stimuli (exercise, cold air, and allergens) have more clinical relevance for asthma.18 One recent study has investigated the effect of a shortterm treatment with salmeterol on protection against early asthmatic response to allergen. The protective effect of a single dose of salmeterol against allergen-induced early asthmatic reaction was completely lost following regular treatment with salmeterol after 1 week.19 Two other studies looking at exercise-induced bronchoconstriction have also demonstrated evidence of tolerance to the bronchoprotective effect of salmeterol. Ramage et al studied 12 patients with exercise-induced bronchoconstriction in a randomized, double-blind crossover study comparing the duration of action of inhaled salmeterol 50 ␮g twice daily for 4 weeks with that of placebo. Salmeterol produced significant protection against exercise-induced bronchoconstriction at 6 and 12 hours after the first dose in comparison to placebo, whereas there was no significant attenuation of exercise-induced bronchoconstriction after 4 weeks of chronic treatment with salmeterol.20 Similarly, a recent study by Simons et al demonstrated that a single dose of 50 ␮g once daily of salmeterol in adolescents receiving regular glucocorticoid inhalations resulted in a diminished bronchoprotective effect against exerciseinduced bronchoconstriction following 28 consecutive days of therapy.21 In this study, tolerance to the bronchoprotective effect of salmeterol is demonstrated after one dose of the

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medication. Given this and the results of other studies it is clear that tolerance to salmeterol does exist and occurs extremely rapidly. Further investigation, however, needs to be done in order to establish the clinical significance of these findings. ACKNOWLEDGMENTS The authors thank Jacquie Bramley for her help in preparing the manuscript.

8.

9.

10.

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Request for reprints should be addressed to: Dr D W Cockcroft, MD Division of Respiratory Medicine Royal University Hospital 103 Hospital Dr Saskatoon, SK Canada S7N 0W8

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