Correspondence
Exercise-Induced Asthma
N Engl J Med 1998; 339:1783-1786December 10, 1998
- Article
To the Editor:
In the study of long-term salmeterol treatment for exercise-induced asthma reported by Nelson et al. (July 16 issue),1 a flaw in the procedure for selecting patients was that not all subjects were receiving concurrent therapy with inhaled corticosteroids, in accordance with asthma-management guidelines. In real life, moreover, patients normally take a β2-adrenergic agonist on an occasional basis before engaging in exercise.
The authors state that they chose to use exercise because it is an example of a clinically relevant bronchoconstrictor stimulus. Since the inhalation of cold air augments the bronchoconstrictor response to exercise,2 the exercise protocol they used is in effect an evaluation of two separate bronchoconstrictor stimuli. Since treatment with β2-adrenergic agonists is not routinely used as prophylaxis against exposure to cold air, the use of dual stimuli added confounding factors to the interpretation of the data.
In their discussion, the authors do not mention the study by Simons et al.3 This study looked at the effect of once-daily treatment with salmeterol on exercise alone in subjects who were concurrently using inhaled corticosteroids and involved an exercise challenge nine hours after the dose was given. Their study, like the study by Nelson et al., showed loss of protection after regular use.
The results at 9 hours in the study by Nelson et al., like those at 6 and 12 hours in the study by Ramage et al.,4 showed that regular treatment with salmeterol provided no significant residual protection, as compared with placebo, after four weeks. These findings suggest that salmeterol should not be administered on a regular basis for exercise-induced asthma. In this respect, the use of albuterol as required before exercise would be more appropriate and cheaper.
The study by Nelson et al. shows that regular treatment with salmeterol leads to bronchoprotective tachyphylaxis. The results are consistent with those of other studies of long-acting β2-adrenergic agonists in which different bronchoconstrictor stimuli have been used.5
5 ReferencesImran Aziz, M.R.C.P.
Brian J. Lipworth, M.D.
Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland1
Nelson JA ,Strauss L ,Skowronski M ,Ciufo R ,Novak R ,McFadden ER Jr . Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med 1998;339:141-146
Full Text | Web of Science | Medline2
Strauss RH ,McFadden ER Jr ,Ingram RH Jr ,Jaeger JJ . Enhancement of exercise-induced asthma by cold air. N Engl J Med 1977;297:743-747
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Simons FE ,Gerstner TV ,Cheang MS . Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment. Pediatrics 1997;99:655-659
CrossRef | Web of Science | Medline4
Ramage L ,Lipworth BJ ,Ingram CG ,Cree IA ,Dhillon DP . Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994;88:363-368
CrossRef | Web of Science | Medline5
Lipworth B ,Tan S ,Devlin M ,Aiken T ,Baker R ,Hendrick D . Effects of treatment with formoterol on bronchoprotection against methacholine. Am J Med 1998;104:431-438
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To the Editor:
Nelson et al. conclude that extended administration of salmeterol “does not result in a loss of protection against clinically relevant precipitants of asthma, but the duration of action of the drug is shortened.” They also state that the dissociation between salmeterol's bronchodilatory effect, which lasts for at least 12 hours, and its bronchoprotective effect, which does not last as long, “suggests an as yet undefined interaction between the stimulus and the drug.” In fact, straightforward explanations of their findings are available. First, there were only 20 subjects in the study, so the power to detect differences between groups was limited. Inspection of Figure 2 and Figure 3 suggests that there was desensitization at both time points after administration of the drug (albeit more so at the later time point), a finding consistent with the results of other studies.1,2
Second, in vitro studies clearly demonstrate that salmeterol, like other β2-adrenergic agonists, causes desensitization as measured physiologically or biochemically, although at a lower rate than that reported with agonists of higher intrinsic efficacy.3,4 Because of receptor reserve, strong functional antagonism is required to reveal a modest degree of desensitization. (Think of this as lifting a heavy weight to demonstrate a subtle weakness.) Thus, the dissociation between the duration of the bronchodilator effect (a setting of relatively weak functional antagonism) and the bronchoprotective effect (a setting of strong functional antagonism) comes as no surprise and has been observed with other β2-adrenergic agonists, as noted by Nelson et al.
In summary, most clinical and in vitro studies (including, arguably, the study by Nelson et al.) indicate that extended use of any β2-adrenergic agonist results in a modest decrease in both the extent and the duration of action that might be revealed only by the use of functional antagonism (e.g., an exercise or methacholine challenge).
4 ReferencesBurton F. Dickey, M.D.
Roberto Adachi, M.D.
Baylor College of Medicine, Houston, TX 770301
Ramage L ,Lipworth BJ ,Ingram CG ,Cree IA ,Dhillon DP . Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994;88:363-368
CrossRef | Web of Science | Medline2
Simons FE ,Gerstner TV ,Cheang MS . Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment. Pediatrics 1997;99:655-659
CrossRef | Web of Science | Medline3
January B ,Seibold A ,Allal C , et al. Salmeterol-induced desensitization, internalization and phosphorylation of the human β2-adrenoceptor. Br J Pharmacol 1998;123:701-711
CrossRef | Web of Science | Medline4
Moore RH ,Khan A ,Dickey BF . Long-acting inhaled β2-agonists in asthma therapy. Chest 1998;113:1095-1108
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To the Editor:
We agree with Leff et al. (July 16 issue)1 that airway hyperresponsiveness to exercise and the response to therapy are important and quantifiable indexes of asthma control. However, several points deserve mention when one is considering the therapeutic effect of montelukast in patients with exercise-induced bronchoconstriction. Although the mean exercise-induced decrease in the forced expiratory volume in one second (FEV1) was smaller in the patients receiving montelukast than in those receiving placebo, the mean maximal decrease in the montelukast group remained more than 20 percent at all scheduled visits during the 12-week treatment period. This constitutes a clinically significant decrease from the value at base line and represents a “positive” mean response to exercise.2 More important, the percentage of montelukast-treated patients who continued to have clinically positive responses remained high throughout the trial, and more than half the patients had positive responses at the end of the study (Figure 1Figure 1
Patients with More Than a 20 Percent Reduction in FEV1 from the Base-Line Value, According to Treatment Assignment.).The subjects in the study by Leff et al. were adults with relatively mild asthma requiring minimal anti-asthma therapy. The results may therefore not be predictive of the response to montelukast in children or in adults with more severe asthma.
In large part because of these observations, approved U.S. product labeling for Singulair (montelukast sodium) does not include an indication for exercise-induced bronchoconstriction. It is specifically stated that Singulair should not be used as monotherapy for exercise-induced bronchoconstriction.3 Although some patients may have a satisfactory response to montelukast, the product labeling recommends that patients continue their usual regimen of inhaled β-adrenergic agonists as prophylaxis against exercise-induced bronchoconstriction unless instructed otherwise by their physicians and that all patients have available as rescue medication a short-acting inhaled β-adrenergic agonist.3
3 ReferencesPeter K. Honig, M.D.
John K. Jenkins, M.D.
Food and Drug Administration, Rockville, MD 208571
Leff JA ,Busse WW ,Pearlman D , et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998;339:147-152
Full Text | Web of Science | Medline2
McFadden ER Jr ,Gilbert IA . Exercise-induced asthma. N Engl J Med 1994;330:1362-1367
Full Text | Web of Science | Medline3
Singulair (montelukast sodium). West Point, Pa.: Merck (package insert).
To the Editor:
Nelson et al. used frigid air and Leff et al. used dry air. Frigid air is a more critical exercise challenge. Nelson et al. present data on the reduction in FEV1. Leff et al. present data on the area under the FEV1 curve. Statistical changes in these analyses are not comparable. Changes in the area under the curve tend to magnify differences. For the comparison of montelukast and placebo, the difference in the degree of change in the FEV1 after the exercise challenge, shown in Figure 2 of the article by Leff et al., was 12 to 14 percent, and the difference in the area under the FEV1 curve was 47.4 percent.
Salmeterol improved FEV1 before exercise, both initially and at four weeks, as shown in Figure 2 of the article by Nelson et al. After exercise in the salmeterol group, the FEV1 fell at week 4 but not to a level significantly below the pre-exercise value in the placebo group. For the study of montelukast, only data on the “global assessment” of patients are presented, although FEV1 was measured during the study. Data on the improvement in FEV1 with montelukast before the challenge are important in order to evaluate the drug's overall effect on FEV1.
It is unclear from these reports which of the medications provides better treatment of exercise-induced asthma. The placement of the articles together suggests their comparability. A comparative trial is needed.
David A. Stempel, M.D.
Virginia Mason Medical Center, Seattle, WA 98101Author/Editor Response
The authors reply:
To the Editor: The statements by Drs. Aziz and Lipworth are confusing. Our subjects, and their medical regimens, were quite typical for our region. Whether their physicians followed guidelines for the management of asthma is irrelevant and had no effect on our findings. Cold air and exercise are not different stimuli. A frigid inspirate merely amplifies the cooling–rewarming sequences leading to obstruction.1-3 We did not mention the study by Simons et al.4 because we could not interpret the results. The placebo effect decreased serially and by the end of the trial was almost 40 percent less than the initial value. The protection offered by salmeterol in the evening, however, remained unchanged. Thus, there was no real loss over time — only an apparent one because of the way the data were compared. Furthermore, since the subjects did not take their drugs consistently, it is exceptionally difficult to assign a meaningful value for a loss of effect, even if real, to desensitization.
We accept the comment by Drs. Dickey and Adachi that the explanation offered for our findings is not optimal. We also acknowledge that the number of subjects in our study was limited, but it exceeded the numbers in the other studies they cite.4,5 We therefore do not understand why their conclusions, based on data from fewer subjects, are “correct” and ours, based on data from more subjects, are “incorrect.” Although there is little doubt that biochemical abnormalities in receptor function follow the prolonged use of β2-adrenergic agonists, the work that Drs. Dickey and Adachi cite in support of their argument was performed in isolated epithelial cells and was unaccompanied by any physiologic assessments of airway function. Unfortunately, as exciting as these studies are, they cannot yet be applied to the treatment of asthma.
Dr. Stempel is correct that the data from the two studies cannot be compared. An appropriately designed protocol that compares the speed of onset, magnitude, and duration of an effect and the presence of desensitization will be required to determine the relative effectiveness of long-acting β2-adrenergic agonists and leukotriene modifiers.
5 ReferencesE.R. McFadden, Jr., M.D.
Louise Strauss, B.S.N.
Jo Ann Nelson, C.R.T.
University Hospitals of Cleveland, Cleveland, OH 44106-50671
Deal EC Jr ,McFadden ER Jr ,Ingram RH Jr ,Strauss RH ,Jaeger JJ . Role of respiratory heat exchange in production of exercise-induced asthma. J Appl Physiol 1979;46:467-475
Web of Science | Medline2
Gilbert IA ,Fouke JM ,McFadden ER Jr . Heat and water flux in the intrathoracic airways and exercise-induced asthma. J Appl Physiol 1987;63:1681-1691
Web of Science | Medline3
McFadden ER Jr ,Pichurko BM ,Bowman HF , et al. Thermal mapping of the airways in humans. J Appl Physiol 1985;58:564-570
CrossRef | Web of Science | Medline4
Simons FE ,Gerstner TV ,Cheang MS . Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment. Pediatrics 1997;99:655-659
CrossRef | Web of Science | Medline5
Ramage L ,Lipworth BJ ,Ingram CG ,Cree IA ,Dhillon DP . Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994;88:363-368
CrossRef | Web of Science | Medline
Author/Editor Response
Drs. Honig and Jenkins accurately present the data from our study and the current labeling information for montelukast. We also agree with their statements concerning the use of short-acting β-adrenergic agonists in patients with exercise-induced bronchoconstriction. However, a few additional comments about our study are required.
It must be stressed that our trial was designed specifically to investigate the effect of montelukast approximately 20 to 24 hours after once-daily administration. Our study clearly shows the protective effect against exercise-induced bronchoconstriction at this critical time in the dosing interval, as well as the maintenance of this effect over a three-month treatment period. Whether there is greater protection against exercise-induced bronchoconstriction early in the dosing interval has not been studied.
In two recently completed, replicative trials,1,2 with exercise performed at the end of the dosing interval, montelukast was compared with the long-acting β-adrenergic agonist salmeterol. In these studies, 67 percent and 64 percent of the patients receiving montelukast had less than a 20 percent decrease in FEV1. The effect of montelukast was maintained over the eight-week treatment period, and unlike salmeterol, it did not cause tachyphylaxis.
A study demonstrating the protective effects of montelukast against exercise-induced bronchoconstriction in children (6 to 14 years old) was recently reported.3 The effect of montelukast on exercise-induced bronchoconstriction in patients with more severe chronic asthma has not been studied.
In response to Dr. Stempel: as we stated in our article, the area under the curve was preselected as the primary end point because it uniquely summarizes the extent of the decrease in FEV1 and the time to recovery, both important end points for exercise-induced bronchoconstriction. The FEV1 data requested by Dr. Stempel are in our article, with values at base line and after 12 weeks provided. There was little difference between the treatment groups, because the patients were selected on the basis of nearly normal pre-exercise FEV1 at base line.
3 ReferencesTheodore F. Reiss, M.D.
Merck Research Laboratories, Rahway, NJ 07065-09141
Turpin JA ,Edelman JM ,DeLucca PT ,Pearlman DS . Chronic administration of montelukast (MK-476) is superior to inhaled salmeterol in the prevention of exercise-induced bronchoconstriction. Am J Respir Crit Care Med 1998;157:A456-A456 abstract.2
Villaran C ,O'Neill S ,Helbling A , et al. Montelukast compared to salmeterol in the treatment of exercise-induced asthma (EIA). Eur Respir J 1998;12:361s-361s abstract.3
Kemp JP ,Dockhorn RJ ,Shapiro GG , et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr 1998;133:424-428
CrossRef | Web of Science | Medline
Author/Editor Response
Honig and Jenkins, of the Food and Drug Administration, see the glass as half empty. I see the glass as half full, as reflected by the comments that Dr. Schotland and I make in the editorial accompanying the reports by Nelson et al. and Leff et al.1 We apparently agree that the therapeutic response to montelukast and other leukotrienes is more variable among persons than is the response to other medications commonly used for asthma. Patients who try montelukast for exercise-induced asthma should continue to use the drug only if there is a significant reduction in the need for a β-adrenergic agonist before or during exercise or a clear improvement in symptom control with continued use of a β-adrenergic agonist.
1 ReferencesJohn Hansen-Flaschen, M.D.
University of Pennsylvania School of Medicine, Philadelphia, PA 19104-42831
Hansen-Flaschen J ,Schotland H . New treatments for exercise-induced asthma. N Engl J Med 1998;339:192-193
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