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Beta agonists in asthma: Controversy regarding chronic use

Author
Robert F Lemanske, Jr, MD
Section Editor
Bruce S Bochner, MD
Deputy Editor
Helen Hollingsworth, MD

INTRODUCTION

An inhaled sympathomimetic is the bronchodilator of choice for treatment of an acute asthmatic attack [1,2]. However, it is controversial whether these medications can be used safely for chronic maintenance therapy (monotherapy) or should be reserved for acute symptomatic control. Three arguments have been made against chronic use [3,4]:

Mortality may be increased

Control of asthma may worsen

Equal or superior efficacy can be achieved with inhaled glucocorticoids (corticosteroids)

In the discussion that follows, "short-acting" beta agonists (eg, albuterol) are bronchodilators whose bronchodilator (but not bronchoprotective) effects last four to six hours. Long-acting beta agonists (salmeterol and formoterol) are bronchodilators whose effects last 10 to 12 hours. "Beta agonists" refer to short-acting beta agonists if unspecified.

                          

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Literature review current through: Nov 2016. | This topic last updated: Thu Sep 15 00:00:00 GMT+00:00 2016.
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References
Top
  1. National Asthma Education and Prevention Program: Expert panel report III: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, 2007. (NIH publication no. 08-4051) www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm (Accessed on December 04, 2014).
  2. Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA). Full text available online at: http://www.ginasthma.com (Accessed on January 30, 2015).
  3. Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992; 326:501.
  4. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336:1391.
  5. O'Byrne PM, Kerstjens HA. Inhaled beta 2-agonists in the treatment of asthma. N Engl J Med 1996; 335:886.
  6. Ernst P, Habbick B, Suissa S, et al. Is the association between inhaled beta-agonist use and life-threatening asthma because of confounding by severity? Am Rev Respir Dis 1993; 148:75.
  7. Suissa S, Ernst P, Boivin JF, et al. A cohort analysis of excess mortality in asthma and the use of inhaled beta-agonists. Am J Respir Crit Care Med 1994; 149:604.
  8. Suissa S, Hemmelgarn B, Blais L, Ernst P. Bronchodilators and acute cardiac death. Am J Respir Crit Care Med 1996; 154:1598.
  9. Mullen M, Mullen B, Carey M. The association between beta-agonist use and death from asthma. A meta-analytic integration of case-control studies. JAMA 1993; 270:1842.
  10. Anderson HR, Ayres JG, Sturdy PM, et al. Bronchodilator treatment and deaths from asthma: case-control study. BMJ 2005; 330:117.
  11. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993; 306:1034.
  12. Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129:15.
  13. Walters EH, Gibson PG, Lasserson TJ, Walters JA. Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid. Cochrane Database Syst Rev 2007; :CD001385.
  14. Bateman E, Nelson H, Bousquet J, et al. Meta-analysis: effects of adding salmeterol to inhaled corticosteroids on serious asthma-related events. Ann Intern Med 2008; 149:33.
  15. Jaeschke R, O'Byrne PM, Mejza F, et al. The safety of long-acting beta-agonists among patients with asthma using inhaled corticosteroids: systematic review and metaanalysis. Am J Respir Crit Care Med 2008; 178:1009.
  16. Martinez FD. Safety of long-acting beta-agonists--an urgent need to clear the air. N Engl J Med 2005; 353:2637.
  17. Sears MR, Ottosson A, Radner F, Suissa S. Long-acting beta-agonists: a review of formoterol safety data from asthma clinical trials. Eur Respir J 2009; 33:21.
  18. Wijesinghe M, Weatherall M, Perrin K, et al. Risk of mortality associated with formoterol: a systematic review and meta-analysis. Eur Respir J 2009; 34:803.
  19. Nelson H, Bonuccelli C, Radner F, et al. Safety of formoterol in patients with asthma: combined analysis of data from double-blind, randomized controlled trials. J Allergy Clin Immunol 2010; 125:390.
  20. de Vries F, Setakis E, Zhang B, van Staa TP. Long-acting {beta}2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD. Eur Respir J 2010; 36:494.
  21. Cates CJ, Jaeschke R, Schmidt S, Ferrer M. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2013; :CD006922.
  22. Malone R, LaForce C, Nimmagadda S, et al. The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma. Ann Allergy Asthma Immunol 2005; 95:66.
  23. McMahon AW, Levenson MS, McEvoy BW, et al. Age and risks of FDA-approved long-acting β₂-adrenergic receptor agonists. Pediatrics 2011; 128:e1147.
  24. O'Byrne PM, Adelroth E. Beta2 déjà vu. Chest 2006; 129:3.
  25. Nelson HS. Is there a problem with inhaled long-acting beta-adrenergic agonists? J Allergy Clin Immunol 2006; 117:3.
  26. Ernst P, McIvor A, Ducharme FM, et al. Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids. Ann Intern Med 2006; 145:692.
  27. Cates CJ, Cates MJ. Regular treatment with formoterol for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2012; :CD006923.
  28. Lazarus SC, Boushey HA, Fahy JV, et al. Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001; 285:2583.
  29. Lemanske RF Jr, Sorkness CA, Mauger EA, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001; 285:2594.
  30. Cates CJ, Cates MJ. Regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2008; :CD006363.
  31. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 2006; 144:904.
  32. Drazen JM, O'Byrne PM. Risks of long-acting beta-agonists in achieving asthma control. N Engl J Med 2009; 360:1671.
  33. Sears MR. Safety of long-acting beta-agonists: are new data really required? Chest 2009; 136:604.
  34. Ahmad S, Kew KM, Normansell R. Stopping long-acting beta2-agonists (LABA) for adults with asthma well controlled by LABA and inhaled corticosteroids. Cochrane Database Syst Rev 2015; :CD011306.
  35. Lemanske RF Jr, Busse WW. The US Food and Drug Administration and long-acting beta2-agonists: the importance of striking the right balance between risks and benefits of therapy? J Allergy Clin Immunol 2010; 126:449.
  36. Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network. N Engl J Med 1996; 335:841.
  37. Dennis SM, Sharp SJ, Vickers MR, et al. Regular inhaled salbutamol and asthma control: the TRUST randomised trial. Therapy Working Group of the National Asthma Task Force and the MRC General Practice Research Framework. Lancet 2000; 355:1675.
  38. Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma. Ann Intern Med 2004; 140:802.
  39. Cockcroft DW, McParland CP, Britto SA, et al. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993; 342:833.
  40. Gibson GJ, Greenacre JK, König P, et al. Use of exercise challenge to investigate possible tolerance to beta-adrenoceptor stimulation in asthma. Br J Dis Chest 1978; 72:199.
  41. Bhagat R, Kalra S, Swystun VA, Cockcroft DW. Rapid onset of tolerance to the bronchoprotective effect of salmeterol. Chest 1995; 108:1235.
  42. Cockcroft DW, Swystun VA, Bhagat R. Interaction of inhaled beta 2 agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine. Am J Respir Crit Care Med 1995; 152:1485.
  43. Bhagat R, Swystun VA, Cockcroft DW. Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: dose response. J Allergy Clin Immunol 1996; 97:47.
  44. 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.
  45. McFadden ER Jr. Perspectives in beta 2-agonist therapy: vox clamantis in deserto vel lux in tenebris? J Allergy Clin Immunol 1995; 95:641.
  46. Gauvreau GM, Jordana M, Watson RM, et al. Effect of regular inhaled albuterol on allergen-induced late responses and sputum eosinophils in asthmatic subjects. Am J Respir Crit Care Med 1997; 156:1738.
  47. Penn RB, Panettieri RA Jr, Benovic JL. Mechanisms of acute desensitization of the beta2AR-adenylyl cyclase pathway in human airway smooth muscle. Am J Respir Cell Mol Biol 1998; 19:338.
  48. Sorkness CA. Beta-adrenergic Agonists. In: Middleton's Allergy: Principles and Practice, 7th ed, Adkinson NF, Bochner BS, Busse WW, et al (Eds), Mosby, Philadelphia 2009. p.1485-503.
  49. Taylor DR, Sears MR, Herbison GP, et al. Regular inhaled beta agonist in asthma: effects on exacerbations and lung function. Thorax 1993; 48:134.
  50. Hancox RJ, Sears MR, Taylor DR. Polymorphism of the beta2-adrenoceptor and the response to long-term beta2-agonist therapy in asthma. Eur Respir J 1998; 11:589.
  51. Chapman KR, Kesten S, Szalai JP. Regular vs as-needed inhaled salbutamol in asthma control. Lancet 1994; 343:1379.
  52. Heino M. Regularly inhaled beta-agonists with steroids are not harmful in stable asthma. J Allergy Clin Immunol 1994; 93:80.
  53. Pearlman DS, Chervinsky P, LaForce C, et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med 1992; 327:1420.
  54. Haahtela T, Järvinen M, Kava T, et al. Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991; 325:388.
  55. Apter AJ, Reisine ST, Willard A, et al. The effect of inhaled albuterol in moderate to severe asthma. J Allergy Clin Immunol 1996; 98:295.
  56. Becker AB, Simons FE. Formoterol, a new long-acting selective beta 2-adrenergic receptor agonist: double-blind comparison with salbutamol and placebo in children with asthma. J Allergy Clin Immunol 1989; 84:891.
  57. Simons FE, Soni NR, Watson WT, Becker AB. Bronchodilator and bronchoprotective effects of salmeterol in young patients with asthma. J Allergy Clin Immunol 1992; 90:840.
  58. Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 1995; 346:201.
  59. Aziz I, Hall IP, McFarlane LC, Lipworth BJ. Beta2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. J Allergy Clin Immunol 1998; 101:337.
  60. Haney S, Hancox RJ. Rapid onset of tolerance to beta-agonist bronchodilation. Respir Med 2005; 99:566.
  61. Cheung D, Timmers MC, Zwinderman AH, et al. Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 1992; 327:1198.
  62. O'Connor BJ, Aikman SL, Barnes PJ. Tolerance to the nonbronchodilator effects of inhaled beta 2-agonists in asthma. N Engl J Med 1992; 327:1204.
  63. Tattersfield AE. Effect of beta-agonists and anticholinergic drugs on bronchial reactivity. Am Rev Respir Dis 1987; 136:S64.
  64. Twentyman OP, Higenbottam TW. Controversies in respiratory medicine: regular inhaled beta-agonists--clear clinical benefit or a hazard to health? (1). Beta-agonists can be used safely and beneficially in asthma. Respir Med 1992; 86:471.
  65. Boulet LP, Cartier A, Milot J, et al. Tolerance to the protective effects of salmeterol on methacholine-induced bronchoconstriction: influence of inhaled corticosteroids. Eur Respir J 1998; 11:1091.
  66. Deeks ED. Olodaterol: a review of its use in chronic obstructive pulmonary disease. Drugs 2015; 75:665.
  67. Hanania NA, Feldman G, Zachgo W, et al. The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. Chest 2012; 142:119.
  68. McKeage K. Fluticasone furoate/vilanterol: a review of its use in chronic obstructive pulmonary disease. Drugs 2014; 74:1509.
  69. Kew KM, Dias S, Cates CJ. Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis. Cochrane Database Syst Rev 2014; :CD010844.
  70. Geake JB, Dabscheck EJ, Wood-Baker R, Cates CJ. Indacaterol, a once-daily beta2-agonist, versus twice-daily beta₂-agonists or placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2015; 1:CD010139.
  71. Wechsler ME, Castro M, Lehman E, et al. Impact of race on asthma treatment failures in the asthma clinical research network. Am J Respir Crit Care Med 2011; 184:1247.
  72. Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993; 8:334.
  73. Gardiner PV, Ward C, Booth H, et al. Effect of eight weeks of treatment with salmeterol on bronchoalveolar lavage inflammatory indices in asthmatics. Am J Respir Crit Care Med 1994; 150:1006.
  74. Li X, Ward C, Thien F, et al. An antiinflammatory effect of salmeterol, a long-acting beta(2) agonist, assessed in airway biopsies and bronchoalveolar lavage in asthma. Am J Respir Crit Care Med 1999; 160:1493.
  75. Roberts JA, Bradding P, Britten KM, et al. The long-acting beta2-agonist salmeterol xinafoate: effects on airway inflammation in asthma. Eur Respir J 1999; 14:275.
  76. Nathan RA, Pinnas JL, Schwartz HJ, et al. A six-month, placebo-controlled comparison of the safety and efficacy of salmeterol or beclomethasone for persistent asthma. Ann Allergy Asthma Immunol 1999; 82:521.
  77. Simons FE. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group. N Engl J Med 1997; 337:1659.
  78. O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001; 164:1392.
  79. Sorkness CA, Lemanske RF Jr, Mauger DT, et al. Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. J Allergy Clin Immunol 2007; 119:64.
  80. Greenstone IR, Ni Chroinin MN, Masse V, et al. Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma. Cochrane Database Syst Rev 2005; :CD005533.
  81. Ni Chroinin M, Greenstone IR, Danish A, et al. Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma. Cochrane Database Syst Rev 2005; :CD005535.
  82. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 1994; 344:219.
  83. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153:1481.
  84. van der Molen T, Postma DS, Turner MO, et al. Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators. Thorax 1997; 52:535.
  85. Pauwels RA, Löfdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337:1405.
  86. Wilding P, Clark M, Thompson Coon J, et al. Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study. BMJ 1997; 314:1441.
  87. Langley SJ, Masterson CM, Batty EP, Woodcock A. Bronchodilator response to salbutamol after chronic dosing with salmeterol or placebo. Eur Respir J 1998; 11:1081.
  88. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004; 170:836.
  89. O'Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005; 171:129.
  90. Gibson PG, Powell H, Ducharme F. Long-acting beta2-agonists as an inhaled corticosteroid-sparing agent for chronic asthma in adults and children. Cochrane Database Syst Rev 2005; :CD005076.
  91. Mcivor RA, Pizzichini E, Turner MO, et al. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998; 158:924.
  92. Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010; 362:975.
  93. Chowdhury BA, Dal Pan G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med 2010; 362:1169.
  94. Bateman ED, Jacques L, Goldfrad C, et al. Asthma control can be maintained when fluticasone propionate/salmeterol in a single inhaler is stepped down. J Allergy Clin Immunol 2006; 117:563.
  95. Godard P, Greillier P, Pigearias B, et al. Maintaining asthma control in persistent asthma: comparison of three strategies in a 6-month double-blind randomised study. Respir Med 2008; 102:1124.
  96. Koenig SM, Ostrom N, Pearlman D, et al. Deterioration in asthma control when subjects receiving fluticasone propionate/salmeterol 100/50 mcg Diskus are "stepped-down". J Asthma 2008; 45:681.
  97. Reddel HK, Gibson PG, Peters MJ, et al. Down-titration from high-dose combination therapy in asthma: Removal of long-acting beta(2)-agonist. Respir Med 2010; 104:1110.
  98. Salpeter SR, Wall AJ, Buckley NS. Long-acting beta-agonists with and without inhaled corticosteroids and catastrophic asthma events. Am J Med 2010; 123:322.
  99. Cates CJ, Jaeschke R, Schmidt S, Ferrer M. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2013; :CD006924.
  100. Cates CJ, Wieland LS, Oleszczuk M, Kew KM. Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews. Cochrane Database Syst Rev 2014; :CD010314.
  101. Stempel DA, Raphiou IH, Kral KM, et al. Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone. N Engl J Med 2016; 374:1822.
  102. Wells KE, Peterson EL, Ahmedani BK, et al. The relationship between combination inhaled corticosteroid and long-acting β-agonist use and severe asthma exacerbations in a diverse population. J Allergy Clin Immunol 2012; 129:1274.
  103. Stempel DA, Szefler SJ, Pedersen S, et al. Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma. N Engl J Med 2016; 375:840.
  104. Peters SP, Bleecker ER, Canonica GW, et al. Serious Asthma Events with Budesonide plus Formoterol vs. Budesonide Alone. N Engl J Med 2016; 375:850.