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December 2, 2013

Role for LABAs before Sports


Is there any role for long-acting beta-agonists given before sport if that is the only intervention that has helped? The patient is a teenager and has no interval asthma, and is not on an inhaled corticosteroid, and trials of short-acting beta-agonists, cromolyn, and anti-leukotriene have failed. The only effective prevention is salmeterol 2 puffs given in the morning of the sports activity, 3 or 4 times a week. We are warned about using LABA alone with inhaled corticosteroids.


Both short- and long-acting beta-2 agonists (SABA and LABA), administered in standard doses immediately before exercise, have been shown to reduce the fall in FEV1 by 70% to 80% in the majority of people with exercise-induced bronchoconstriction (EIB) with or without asthma1.

The mechanism of this protection is mainly related to the beta-2 receptor induced relaxation of bronchial smooth muscle which opposes the contractile effects of the various mediators of bronchoconstriction. Protection from EIB may be also afforded by the beta-2 receptor induced inhibition of mediator release from mast cells.

The choice of the most appropriate beta-2 agonist molecule to be administered should take into consideration sport discipline duration and features (i.e. LABA are often preferred for endurance physical activities).

At present, however, there is no consensus about the efficacy and safety of beta-2 agonists in the pre-treatment of EIB. The role of these molecules in preventing EIB was questioned when patients taking beta-2 agonists daily, reported breakthrough EIB within a dosing period. There are, in fact, several negative findings regarding the efficacy of a daily treatment with beta-2 agonists in controlling the severity of bronchoconstriction and the recovery from EIB.

With special reference to studies addressing the effects of salmeterol, Nelson et al. showed in a cross-over study, performed in 20 adults treated for a month with inhaled salmeterol 42 mcg twice a day, a significant beta-2 agonist protection against EIB for the entire study period. However, the length of time that the drug remained active after a single dose significantly decreased. Furthermore, the number of patients for whom salmeterol did not offer complete protection against EIB (FEV1 % fall < 10%) increased from 2 on study day 1 to 11 on day 29 (P = 0.02)2.

Ramage and coworkers studied 12 adults treated with inhaled salmeterol 50 mcg twice daily for 4 weeks in a cross-over manner. The significant protection provided by the first dose of salmeterol against EIB at 6 and 12 hours, was no more present at the end of the treatment period3.

Fourteen children were included in the 4-week cross-over trial published by Simons. The first dose of salmeterol had an excellent bronchoprotective effect against EIB at 1 and 9 hours. At the end of the study, however, the bronchoprotective effect was significantly greater than that of placebo only at 1 hour4.

In a paper I recently submitted to the American Journal of Respiratory and Critical Care Medicine, a significant loss of bronchoprotection was shown after a 2-week salmeterol treatment period in subjects with EIB independently on the Arg16Gly ADRB2 polymorphism5.

On the other hand, the reported association between the administration of LABA, not in combination with inhaled corticosteroids, and an increased number of severe cardiovascular side-effects and sudden deaths6,7, induced the main international drug agencies (FDA and EMA) to set a "black box" on these drugs, and to recommend their use, for the shortest possible period, only in subjects older than 12 years with moderate-severe asthma and always in association with inhaled corticosteroids.

Despite the warnings, the use of beta-2 agonists as monotherapy is unfortunately quite frequent in the daily clinical practice and has been reported in 25% of athletes applying for their use at the 2010 Olympics8. This therapeutic option has been justified by some authors by the assumption that EIB represents a distinct phenotype of bronchial obstruction with a prevalent neutrophilic inflammation not responsive to ICS.

In view of all above, considering that alternative therapeutic strategies (short-acting beta-agonists, cromolyn, and anti-leukotriene) have failed, I would suggest to continue administering long-acting beta-2 agonists before exercising, but only in association with inhaled corticosteroids (ICS), despite no evidence of interval asthma. The screening of non-invasive inflammatory markers (eNO, exhaled breath condensate, etc.), if not yet performed, might be helpful to reveal a subclinical inflammation and to support a chronic administration of ICS. It would be also advisable to carefully reconsider all potential differential diagnosis (i.e. vocal cord dysfunction, exercise-induced hyperventilation or dyspnea).

For readers who would like to examine in depth this issue, I would at last advise a comprehensive Cochrane systematic review and meta-analysis on the efficacy and safety of beta-2 agonist in the pretreatment of exercise induced bronchoconstriction with- and without asthma, actually in press (Bonini M. et al. 2013)9.


  1. Anderson SD, Caillaud C, Brannan JD. Beta2-agonists and exercise-induced asthma. Clinical Reviews in Allergy & Immunology 2006;31((2-3)):163-80.
  2. Nelson JA, Strauss L, Skowronski M, Ciufo R, Novak R, McFadden ER Jr. Effect of long-term salmeterol treatment on exercise-induced asthma. New England Journal of Medicine 1998;339(3):141-6.
  3. Ramage L, Lipworth BJ, Ingram CG, Cree IA, Dhillon DP. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respiratory Medicine 1994;88(5):363-8.
  4. 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(5):655-9.
  5. Bonini M, Permaul P, Kulkarni T, et al. Loss of salmeterol bronchoprotection against exercise in relation to ADRB2 Arg16Gly polymorphism and FeNO. Am J Resp Crit Care 2013 submitted
  6. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM, SMART Study Group. For the SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15-26.
  7. Salpeter SR, Wall AJ, Buckley NS. Long-acting beta-agonists with and without inhaled corticosteroids and catastrophic asthma events. Am J Med 2010;123(4):322-8.
  8. Fitch KD. An overview of asthma and airway hyper-responsiveness in Olympic athletes. Br J Sports Med 2012;46:413-6
  9. Bonini M, Di Mambro C, Calderon MA, Compalati E, Schünemann H, Durham S, Canonica GW. Beta2-agonists for exercise induced asthma. Cochrane Database of Systematic Reviews Art. No.: CD003564. DOI: 10.1002/14651858.CD003564.pub2.

Matteo Bonini, MD, PhD
Department of Public Health and Infectious Diseases
“Sapienza” University of Rome – Rome, Italy

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