The Journal of Allergy and Clinical Immunology
Volume 122, Issue 2 , Pages 251-253, August 2008

Long-acting β-agonists and exercise

  • Miles Weinberger, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Miles Weinberger, MD, Pediatric Department, UIHC, 200 Hawkins Dr, Iowa City, IA 52242.

Pediatric Allergy and Pulmonary Division, University of Iowa College of Medicine, Iowa City, Iowa

Received 26 March 2008; received in revised form 14 May 2008; accepted 19 May 2008. published online 26 June 2008.

Article Outline

Key words: Inhaled bronchodilators, exercise-induced dyspnea, asthma, β2 receptor downregulation, tolerance, long-acting β2-agonists

 

Since the first reported use of “adrenal substance” for acute asthma in 1900,1 adrenergic receptor agonists have long been the agents of choice for relieving acute symptoms of asthma. Considerable pharmacologic research has subsequently gone into the development of variations of these receptor agonists, resulting in agents with more specific targeting of the β2-adrenergic receptor and much longer duration of action. Salmeterol and formoterol are the currently available longest-acting β2-agonists, commonly abbreviated as LABAs, although even longer-acting ones have been developed for anticipated marketing.2 The primary established role for a LABA is as additive maintenance therapy to inhaled corticosteroids.3, 4 It is as daily maintenance therapy that LABAs have generated controversy and led to the current “black-box” warning associated with salmeterol and formoterol.5, 6

In addition to providing acute bronchodilatation to relieve acute symptoms of asthma, inhaled β2-adrenergic receptor agonists have been used as highly effective prophylaxis for exercise-induced asthma. Like their shorter-acting predecessors, LABAs also have bronchoprotective effects for exercise-induced bronchospasm. The purpose of this editorial is to examine their role with regard to exercise.

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Exercise and dyspnea 

Exercise-induced asthma has been the most commonly recognized cause of exercise-induced dyspnea in otherwise healthy children and adolescents. Asthma produces dyspnea during exercise because of airway obstruction from bronchospasm, and that airway obstruction can be prevented by the bronchoprotective effect of inhaled β2-adrenergic agonists. When that bronchoprotective effect is not apparent in preventing exercise-induced dyspnea, that might either represent bronchospasm caused by development of tolerance to the bronchoprotective effect of the β2-agonist or a cause of exercise-induced dyspnea other than asthma.7 Because inhaled β2-adrenergic agonists, such as albuterol and terbutaline, have been so effective at preventing exercise-induced dyspnea when it is caused by bronchospasm, there is the expectation that the longer-acting inhaled β2-adrenergic agonists will provide more sustained bronchoprotective effect.

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LABAs and exercise-induced asthma 

Initial doses of both salmeterol and formoterol have similar but more sustained bronchoprotective effects for exercise-induced bronchospasm than shorter-acting bronchodilators, such as albuterol.8 However, an examination of 20 adults given salmeterol twice daily for 4 weeks showed that although a bronchodilator effect was maintained, a decrease in bronchoprotective effect for exercise-induced bronchospasm at 14 and 29 days of administration that was most prominent 9 hours after the dose was demonstrated.9

This loss of bronchoprotective effect has also been reported to occur even with use of inhaled corticosteroids. In a study of sixteen 12- to 16-year-old children receiving an inhaled corticosteroid, Simons et al10 showed an initial protective effect of a 50-μg morning dose of salmeterol against exercise-induced asthma. Although the degree of protective effect in the morning 1 hour after the dose was greater than that at an afternoon exercise study 9 hours after the first morning dose, the protective effect was still significantly greater than that seen during placebo administration. After 28 days, although bronchodilatation persisted, the bronchoprotective effect was reported as having waned based on presenting the data as a maximum percentage decrease in FEV1. However, although the magnitude of decrease in exercise-induced bronchospasm was not significantly different from that with placebo at 9 hours, the actual FEV1 at 9 hours after salmeterol was still better than the 9-hour postexercise value after placebo (Fig 1).

  • View full-size image.
  • Fig 1. 

    Mean percent predicted FEV1 at baseline before and after exercise on days 1 and 28 of 50 μg of salmeterol or placebo administered each morning in sixteen 12- to 16-year-old subjects also receiving twice-daily inhaled corticosteroids. This was a randomized, double-blind crossover study.10

These data suggest the loss of bronchoprotective effect to exercise is, on average, small and likely to be of little importance for most patients. However, Anderson and Brannon,11 in a comprehensive review of β2-agonists and exercise-induced asthma, presented data indicating that, as a class, these agents are associated with considerable interpatient variability in the degree of decrease in duration for bronchoprotective effect and recovery of lung function in response to a β2-agonist. Although the factors underlying this variability have not been defined, there has been both speculation and controversy regarding polymorphisms of the β2-adrenergic receptor and clinical effect of LABAs.12 An editorial regarding studies concluding no relationship of asthma control to polymorphisms suggested there were limitations in the data because patients requiring frequent use of shorter-acting agents were excluded. The concern was expressed that, “…in patients with difficult-to-manage asthma, many of whom take β2 agonists to excess, treatment might itself contribute adversely rather than beneficially to their clinical status.”13

A report of 2 patients presents an extreme example of apparent adverse effects caused by a LABA.14 Two boys, ages 10 and 15 years, were studied as inpatients because of repeated life-threatening episodes of bronchospasm. They both demonstrated complete absence of bronchoprotective effect for exercise-induced bronchospasm caused by a β2-agonist while receiving twice-daily salmeterol. Within a few days after cessation of salmeterol use and substitution of an alternative second agent to the same dose of inhaled corticosteroid, complete blocking of exercise-induced bronchoprovocation with the same β2-agonist could be demonstrated (Table I). The dramatic results in these 2 patients are consistent with Dr Anderson's recommendation: “If a person who takes β2 agonist daily, including a LABA, experiences problems with exercise, then the physician should consider changing the treatment regimen to achieve better control of exercise-induced asthma.”11

Table I. Results of 4 exercise studies in 2 patients, ages 15 and 10 years, receiving inhaled corticosteroids, with and without concurrent administration of salmeterol
Patient no.DayMaintenance medicationMedication taken before exerciseFEV1 before exercise (L)Decrease in FEV1 during exercise (%)Exercise duration and symptoms
1∗1 d after admissionBudesonide (Pulmicort Turbuhaler), 200 μg twice daily, and salmeterol (Serevent MDI), 50 μg twice dailyPirbuterol (Maxair Autohaler), 2 inhalations2.8342Highest heart rate, 157 beats/min; target heart rate not attained because of dyspnea after 4 min
5 d after admissionBudesonide, 200 μg twice daily, and salmeterol, 50 μg twice dailyPirbuterol, 4 inhalations3.2655Highest heart rate, 158 beats/min; target heart rate not attained because of dyspnea after 4 min
9 d after admissionBudesonide, 200 μg twice daily, and SR theophylline, 225 mg twice daily (serum theophylline concentration, 15 μg/mL)Pirbuterol, 4 inhalations3.6019 min, with highest heart rate of 173 beats/min and no dyspnea
18 d after admissionBudesonide, 200 μg twice daily, and SR theophylline, 225 mg twice dailyPirbuterol, 4 inhalations3.56110 min, with highest heart rate of 172 beats/min and no dyspnea
2†Before admission2 inhalations twice daily of fluticasone, 500 μg, in combination with salmeterol, 50 μg (Advair 500/50)Albuterol, 4 inhalations from an MDI1.43713 min, with severe dyspnea and hypoxemia (oxygen saturation, 82%)
Day of admission1 inhalation twice daily of fluticasone 250 μg, in combination with salmeterol, 50 μgAlbuterol, 4 inhalations from an MDI1.88683 min with severe dyspnea and hypoxemia (oxygen saturation, 82%)
2 d after admissionBudesonide, 200 μg twice daily, and SR theophylline, 250 mg twice daily (serum theophylline concentration, 9 μg/mL)Albuterol, 4 inhalations from an MDI1.98519 min, with highest heart rate of 168 beats/min, no hypoxemia, and rapid spontaneous improvement
3 d after admissionBudesonide, 200 μg twice daily, and SR theophylline, 300 mg twice daily (serum theophylline concentration, 16 μg/mL)Albuterol, 4 inhalations from an MDI1.931411 min, with highest heart rate of 172 beats/min, no dyspnea, and no decrease in oxygen saturation

Reproduced with permission from Weinberger M, Abu-Hasan M. Life threatening asthma during treatment with salmeterol. N Engl J Med 2006;335:852-3.14

MDI, Metered-dose inhaler; SR, sustained release.

∗The predicted FEV1 for patient 1 was 3.45 L.

†The predicted FEV1 for Patient 2 was 1.69 L.

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LABAs and exercise in athletes who do not have asthma 

Concern regarding use of β2-agonists among competitive athletes has led to examination of the potential for an ergogenic effect of LABAs on exercise for those with and without asthma. The World Anti-Doping Agency has included β2-agonists in their published Prohibited List with a Therapeutic Use Exemption for formoterol, salbutamol (albuterol), salmeterol, and terbutaline when administered by means of inhalation. The International Olympic Committee requires documented evidence of asthma or exercise-induced bronchoconstriction to allow administration of β2-agonists during the Olympic Games. The importance of bronchodilators for preventing exercise-induced bronchospasm and the high frequency of exercise-induced bronchospasm in competitive athletes led to concern that there could be ergogenic performance-enhancing properties for these medications. Several studies have examined this issue for both LABAs and the shorter-acting β2-agonists. A recent review examined the results of 19 such studies.15 Four of the studies reviewed examined the effects of salmeterol, and 2 used formoterol. Subjects were highly trained athletes in all of the studies. No effects were seen from either the shorter-acting β2-agonists or the LABAs on any ergogenic measurement, including maximal oxygen use, anaerobic threshold, strength performance, blood lactate value, rate of perceived exertion, and psychomotor performance. The conclusion from this and previous reports on the subject was that there was no basis for restricting the use of these agents in competitive athletics because of concern over a doping ergogenic effect.

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Conclusions 

LABAs have been demonstrated to be useful for many patients whose symptoms are not adequately controlled with conventional doses of inhaled corticosteroids alone, and the combination products have provided convenience. Although bronchodilatation is generally maintained, bronchoprotection for exercise-induced bronchospasm will be reduced both for the LABAs and for the traditional shorter-acting β2-agonists used before exercise to prevent exercise-induced bronchospasm in patients receiving maintenance therapy with LABAs. Examination of the variability of the data from various studies suggests the decreased bronchoprotection might be sufficiently small for many patients as to be of minimal clinical importance, but there appears to be considerable individual variability with exceptional patients for whom the consequent loss of bronchoprotective effect for exercise-induced bronchospasm from regular use of the LABAs will be of major clinical importance. Until some predictive marker is found to identify those at risk, clinicians would be wise to add LABAs selectively rather than using combinations as initial therapy so as to identify the occasional patient in whom the induced tolerance results in decreased clinical response to the β2-agonist inhaler that the patient uses for rescue and before exercise.

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References 

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  14. Weinberger M, Abu-Hasan M. Life threatening asthma during treatment with salmeterol. N Engl J Med. 2006;335:852–853
  15. Kindermann W. Do inhaled β2 agonists have an ergogenic potential in non-asthmatic competitive athletes?. Sports Med. 2007;37:95–102

 Disclosure of potential conflict of interest: The author has declared that he has no conflict of interest.

PII: S0091-6749(08)01000-2

doi:10.1016/j.jaci.2008.05.030

The Journal of Allergy and Clinical Immunology
Volume 122, Issue 2 , Pages 251-253, August 2008

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