, Volume 15, Issue 3, pp 185–198 | Cite as

What are the Alternatives to Increasing Inhaled Corticosteroids for the Long Term Control of Asthma?

  • Patrick Flood-Page
  • Neil C. Barnes
Therapy in Practice


The Global Initiative for Asthma (GINA) guidelines stated the therapeutic goals for the management of asthma and, through a stepwise approach to treatment, defined the various grades of asthma severity and the therapeutic options available to the clinician at each step. This article considers the options at step 3; the management of a patient with poorly controlled asthma who is already taking low-dose inhaled corticosteroids.

Before considering a change in therapy, the clinician should rule out alternative diagnoses, confirm compliance with treatment, explore potential exacerbants in the patient’s environment and, where possible, remove them. If a change in medication is necessary, the choice of drug will depend on the therapeutic goal that needs to be achieved. If the most important goal is the control of symptoms and optimisation of lung function, most studies support the addition of a long-acting β2-agonist to low dose inhaled corticosteroids. If recurrent severe exacerbations are a major feature of the poor control, increasing the dosage of inhaled corticosteroids may be most effective. The addition of a leukotriene antagonist may be the best choice if exercise-induced symptoms are prominent or in the setting of aspirin-sensitive asthma.

General recommendations supported by the findings of large therapeutic trials do not allow for significant variability in the individual response to a particular drug. Receptor polymorphisms have recently been discovered that may account for variability in the response to β2-agonists and leukotriene receptor antagonists. However, until more is known about the reasons behind this variability, a therapeutic trial may be the most effective way of determining the best drug for an individual patient.

One of the key developments in asthma over the past decade has been the acceptance of the concept of asthma as a chronic inflammatory disorder of the airways. However, the long term significance of this inflammation is not clear and the importance of control of inflammation beyond the suppression of symptoms, reduction of exacerbation frequency and the optimisation of lung function has not been established.


Asthma Budesonide Fluticasone Propionate Salmeterol Montelukast 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    International consensus report on diagnosis and management of asthma. NIH Publication 92. Bthesda (MD): National Heart, Lung and Blood Institute, 1992Google Scholar
  2. 2.
    Spector SL, Kinsman R, Mawhinney H, et al. Compliance of patients with asthma with an experimental aerosolized medication: implications for controlled clinical trials. J Allergy Clin Immunol 1986; 77: 65–70CrossRefPubMedGoogle Scholar
  3. 3.
    Kelloway JS, Wyatt RA, Adlis SA. Comparison of patients’ compliance with prescribed oral and inhaled asthma medications. Arch Intern Med 1994; 154: 1349–52CrossRefPubMedGoogle Scholar
  4. 4.
    Partridge MR. Delivering optimal care to the person with asthma: what are the key components and what do we mean by patient education? Eur Resp J 1995; 8: 298–305CrossRefGoogle Scholar
  5. 5.
    Flood-Page P, Partridge M. Asthma: a changing perspective on management. Curr Anaesth Crit Care 1996; 7: 260–5CrossRefGoogle Scholar
  6. 6.
    Dockery DW, Pope CA. Acute respiratory effects of particulate pollution. Annu Rev Public Health 1994; 15: 107–32CrossRefPubMedGoogle Scholar
  7. 7.
    Harving H, Korsgaard J, Dahl R. Clinical efficacy of reduction in house-dust mite exposure in specially designed, mechanically ventilated “healthy homes”. Allergy 1994; 49: 866–70CrossRefPubMedGoogle Scholar
  8. 8.
    Zeiger RS. Breast feeding and dietary avoidance In: DeWeck A, Sampson H, editors. Intestinal immunology and food allergy. Nestle Nutrition Workshop Series 34. New York: Raven Press, 1995: 203–22Google Scholar
  9. 9.
    Woodcock A, editor. Asthma and the environment: proceedings of a Symposium held on November 7–8, 1996; 1996 Nov 7–8; Wiesbaden. Eur Respir Rev 1998 Apr; 8 (53): 131-182Google Scholar
  10. 10.
    Thorsson L, Edsbacker S, Conradson TB. Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI. Eur Respir J 1994; 7: 1839–44CrossRefPubMedGoogle Scholar
  11. 11.
    Melchor R, Biddiscombe MF, Mak VH, et al. Lung deposition patterns of directly labelled salbutamol in normal subjects and in patients with reversible airflow obstruction. Thorax 1993; 48:506–11CrossRefPubMedGoogle Scholar
  12. 12.
    Selroos O, Pietinalho A, Riska H. Delivery devices for inhaled asthma medication — clinical implications of differences in effectiveness. Clin Immunother 1986; 6: 273–99CrossRefGoogle Scholar
  13. 13.
    Haahtela T, Jarvinen 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: 388–92CrossRefPubMedGoogle Scholar
  14. 14.
    vanEssen-Zandvliet EE, Hughes MD, Waalkens HJ, et al. Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. The Dutch Chronic Non-specific Lung Disease Study Group. Am Rev Respir Dis 1992; 146: 547–54PubMedGoogle Scholar
  15. 15.
    Smith MJ, Hodson ME. High-dose beclomethasone inhaler in the treatment of asthma. Lancet 1983; I: 265–69CrossRefGoogle Scholar
  16. 16.
    Boe J, Rosenhall L, Alton M, et al. Comparison of dose-response effects of inhaled beclomethasone dipropionate and budesonide in the management of asthma. Allergy 1989; 44: 349–55CrossRefPubMedGoogle Scholar
  17. 17.
    Barnes NC, Marone G, Di Maria GU, et al. A comparison of fluticasone propionate, 1mg daily, with beclomethasone dipropionate, 2mg daily, in the treatment of severe asthma. International Study Group. Eur Respir J 1993; 6: 877–85PubMedGoogle Scholar
  18. 18.
    Egan J, Kalra S, Adams J. A randomised double blind study comparing the effects of beclomethasone dipropionate 2000 mcg/day versus fluticasone propionate 1000 mcg/day on bone density over 2 years. Thorax 1999; 50Suppl. 2: A78Google Scholar
  19. 19.
    Hanania NA, Chapman KR, Sturtridge WC, et al. Dose-related decrease in bone density among asthmatic patients treated with inhaled corticosteroids. J Allergy Clin Immunol 1995; 96 (5 Pt 1):571–9CrossRefPubMedGoogle Scholar
  20. 20.
    Hughes JA, Conry BG, Male SM, et al. One year prospective open study of the effect of high inhaled steroids, fluticasone propionate, and budesonide on bone markers and bone mineral density. Thorax 1999; 54: 223–9CrossRefPubMedGoogle Scholar
  21. 21.
    Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids. New developments. Am J Respir Crit Care Med 1998; 157: S1–53PubMedGoogle Scholar
  22. 22.
    Cumming RG, Mitchell P, Leeder SR. Use of inhaled corticosteroids and the risk of cataracts [see comments]. N Engl J Med 1997; 337: 8–14CrossRefPubMedGoogle Scholar
  23. 23.
    Garbe E, LeLorier J, Boivin JF, et al. Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma. JAMA 1997; 277: 722–7CrossRefPubMedGoogle Scholar
  24. 24.
    Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma [see comments]. Lancet 1990; 336: 1391–6CrossRefPubMedGoogle Scholar
  25. 25.
    Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group [published erratum appears in N Engl J Med 1998 Jan 8; 338 (2): 139]. N Engl J Med 1997; 337: 1405–11CrossRefPubMedGoogle Scholar
  26. 26.
    Hummel S, Lehtonen L. Comparison of oral-steroid sparing by high-dose and low-dose inhaled steroid in maintenance treatment of severe asthma [see comments]. Lancet 1992; 340(8834-8835): 1483–7CrossRefPubMedGoogle Scholar
  27. 27.
    Wasserman SI, Gross GN, Schoenwetter WF, et al. A 12-week dose-ranging study of fluticasone propionate powder in the treatment of asthma. J Asthma 1996; 33(4): 265–74CrossRefPubMedGoogle Scholar
  28. 28.
    vanSchayck CP, Dompeling E, van Herwaarden CL, et al. Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomised controlled study [see comments]. BMJ 1991; 303: 1426–31CrossRefPubMedGoogle Scholar
  29. 29.
    Greening AP, Ind PW, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 1994; 344: 219–24CrossRefPubMedGoogle Scholar
  30. 30.
    Woolcock A, Lundback B, Ringdal N, et al. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153: 1481–8PubMedGoogle Scholar
  31. 31.
    Sears MR, Taylor D. The beta2 agonist controversy. Observations, explanations, and relationship to asthma epidemiology. Drug Saf 1994; 2: 259–83CrossRefGoogle Scholar
  32. 32.
    Bhagat R, Kalra S, Swystun VA, et al. Rapid onset of tolerance to the bronchoprotective effect of salmeterol. Chest 1995; 108: 1235–9CrossRefPubMedGoogle Scholar
  33. 33.
    Nelson JA, Strauss L, Skowronski M, et al. Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med 1998; 339: 141–6CrossRefPubMedGoogle Scholar
  34. 34.
    Newnham DM, Grove A, McDevitt DG, et al. Subsensitivity of bronchodilator and systemic beta 2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients. Thorax 1995; 50: 497–504CrossRefPubMedGoogle Scholar
  35. 35.
    Knorr B, Matz J, Bernstein JA, et al. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. Pediatric Montelukast Study Group. JAMA 1998; 279: 1181–6CrossRefPubMedGoogle Scholar
  36. 36.
    Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group. Arch Intern Med 1998; 158: 1213–20CrossRefPubMedGoogle Scholar
  37. 37.
    Fish JE, Kemp JP, Lockey RF, et al. Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. The Zafirlukast Trialists Group. Clin Ther 1997; 19: 675–90CrossRefPubMedGoogle Scholar
  38. 38.
    Tamaoki J, Kondo M, Sakae N, et al. Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid; The Tokyo Joshe-Idai Asthma Research Group. Am J Respir Crit Care Med 1997; 155: A662Google Scholar
  39. 39.
    Israel E, Cohn J, Dube L, et al. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. Arandomized controlled trial. Zileuton Clinical Trial Group. JAMA 1996; 275: 931–6CrossRefPubMedGoogle Scholar
  40. 40.
    O’Shaughnessy KM, Wellings R, Gillies B, et al. Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion [see comments]. Am Rev Respir Dis 1993; 147: 1472–6PubMedGoogle Scholar
  41. 41.
    Nayak AS, Anderson P, Charous BL, et al. Equivalence of adding zafirlukast versus double-dose inhaled corticosteroids in asthmatic patients symoptomatic on low-dose inhaled corticosteroids [abstract]. J Allergy Clin Immunol 1998; 101:1(Pt 2): S233CrossRefGoogle Scholar
  42. 42.
    Leff JA, Israel E, Noonan MJ, et al. Montelukast allows tapering on inhaled corticosteroids in asthmatic patients while maintaining stability. Am J Resp Crit Care Med 1997; 155: A976Google Scholar
  43. 43.
    Busse W, Nelson H, Wolfe J, et al. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. J Allergy Clin Immunol 1999; 103: 1075–80CrossRefPubMedGoogle Scholar
  44. 44.
    Dahlen B, Kumlin M, Margolskee DJ, et al. The leukotrienereceptor antagonist MK-0679 blocks airway obstruction induced by inhaled lysine-aspirin in aspirin-sensitive asthmatics. Eur Respir J 1993; 6: 1018–26PubMedGoogle Scholar
  45. 45.
    Cowburn AS, Sladek K, Soja J, et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 1998; 101: 834–46CrossRefPubMedGoogle Scholar
  46. 46.
    Dahlen B, Nizankowsa E, Szczeklik A, et al. Benefits from adding the 5-Lipoxygenase inhibitor Zileutin to conventional therapy in aspirin sensitive asthmatics. Am J Resp Crit Care Med 1998; 157: 1187–94PubMedGoogle Scholar
  47. 47.
    Turpin JA, Edelman JM, DeLucca PT, et al. Chronic administration of montelukast is superior to inhaled salmeterol in the prevention of exercise induced bronchospasm. Am J Respir Crit Care Med 1998; 157 (Pt 2): A456Google Scholar
  48. 48.
    Zeneca UK Ltd. Accolate UK Data Sheet. Data on file 1998.Google Scholar
  49. 49.
    Merck Sharp and Dohme. Singulair Data Sheet. Data on file 1998Google Scholar
  50. 50.
    Wechsler ME, Finn D, Jordan M, et al. Montelukast and the Churg-Strauss syndrome. Am J Respir Crit Care Med 1999; 159:A641Google Scholar
  51. 51.
    Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticos-teroid withdrawal in patients with asthma receiving zafirlukast. JAMA 1998; 279: 455–57CrossRefPubMedGoogle Scholar
  52. 52.
    Liu MC, Dube LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. J Allergy Clin Immunol 1996; 98: 859–71CrossRefPubMedGoogle Scholar
  53. 53.
    Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996; 334: 1380–8CrossRefPubMedGoogle Scholar
  54. 54.
    Sullivan P, Bekir S, Jaffar Z, et al. Anti-inflammatory effects of low-dose oral theophylline in atopic asthma [published erratum appears in Lancet 1994; 343: 1512]. Lancet 1994; 343: 1006–8CrossRefPubMedGoogle Scholar
  55. 55.
    Evans DJ, Taylor DA, Zetterstrom O, et al. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997; 337: 1412–8CrossRefPubMedGoogle Scholar
  56. 56.
    Crompton GK, Ayres JG, Basran G, et al. Comparison of oral bambuterol and inhaled salmeterol in patients with symptomatic asthma and using inhaled corticosteroids. Am J Respir Crit Care Med 159: 824-8Google Scholar
  57. 57.
    Vignola AM, Chanez P, Campbell AM, et al. Airway inflammation in mild intermittent and in persistent asthma. Am J Respir Crit Care Med 1998; 157: 403–9PubMedGoogle Scholar
  58. 58.
    Phunek P, Roche WR, Turzekora J, et al. Eosinophilic inflammation in the bronchial mucosa of children with bronchial asthma. Eur J Respir Dis 1997; 10: 160SGoogle Scholar
  59. 59.
    Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur J Respir Dis 1987; 70: 171–9PubMedGoogle Scholar
  60. 60.
    Lange P, Parner J, Vestbo J, et al. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998; 339: 1194–1200CrossRefPubMedGoogle Scholar
  61. 61.
    Hoshino M, Nakamura Y, Sim JJ. Expression of growth factors and remodelling of the airway wall in bronchial asthma. Thorax 1998; 53: 21–7CrossRefPubMedGoogle Scholar
  62. 62.
    Chetta A, Foresi A, Del Donno M, et al. Airways remodeling is a distinctive feature of asthma and is related to severity of disease. Chest 1997; 111: 852–7CrossRefPubMedGoogle Scholar
  63. 63.
    Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol 1992; 90: 32–42CrossRefPubMedGoogle Scholar
  64. 64.
    Djukanovic R, Wilson JW, Holgate ST. Effect of an inhaled steroid on airway inflammation and symptoms of asthma. Am Rev Respir Dis 1999; 145: 674–99Google Scholar
  65. 65.
    Calhoun WJ, Lavins BJ, Minkwitz MC, et al. Effect of zafirlukast (Accolate) on cellular mediators of inflammation: bronchoalveolar lavage fluid findings after segmental antigen challenge. Am J Respir Crit Care Med 1998; 157: 1381–9PubMedGoogle Scholar
  66. 66.
    Leff JA, Pizzichini E, Efthimiadis A, et al. Effect of montelukast on airway eosinophilic inflammation in mildly controlled asthma: a randomised placebo control study. Am J Respir Crit Care Med 1997; 155: A977Google Scholar
  67. 67.
    Nakamura Y, Hoshino M, Sim JJ, et al. Effect of the leukotriene receptor antagonist pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma. Thorax 1998; 53: 835–41CrossRefPubMedGoogle Scholar
  68. 68.
    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: 1006–11PubMedGoogle Scholar
  69. 69.
    McIvor RA, Pizzichini E, Turner MO, et al. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 158(3): 924-30Google Scholar
  70. 70.
    Juniper EF, Kline PA, Vanzieleghem MA, et al. Effect of longterm treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990; 42: 832–6Google Scholar
  71. 71.
    Haahtela T, Jarvinen 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: 388–92CrossRefPubMedGoogle Scholar
  72. 72.
    Selroos O, Pietinalho A, Lofroos AB, et al. Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest 1995; 108: 1228–34CrossRefPubMedGoogle Scholar
  73. 73.
    Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994; 88: 373–81CrossRefPubMedGoogle Scholar
  74. 74.
    Olivieri D, Chetta A, Del Donno M, et al. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebo-controlled study. Am J Respir Crit Care Med 155: 1864-71Google Scholar
  75. 75.
    Laitinen A, Altraja A, Kampe M, et al. Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid. Am J Respir Crit Care Med 1997; 156: 951–8PubMedGoogle Scholar
  76. 76.
    Sont JK, Willems LN, Bel EH, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am J Respir Crit Care Med 1999; 159 (4 Pt 1): 1043–5177PubMedGoogle Scholar
  77. 77.
    Jeffery PK, Godfrey RW, Adelroth E, et al. Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma. A quantitative light and electron microscopic study. Am Rev Respir Dis 1992; 145: 890–9PubMedGoogle Scholar
  78. 78.
    Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Montelukast/ Beclomethasone Study Group. Ann Intern Med 1999; 130: 487–95PubMedGoogle Scholar
  79. 79.
    Green SA, Turki J, Innis M, et al. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–9CrossRefPubMedGoogle Scholar
  80. 80.
    Turki J, Pak J, Green SA, et al. Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and non-nocturnal asthma. Evidence that Glyl6 correlates with the nocturnal phenotype. J Clin Invest 1995; 95: 1635–41CrossRefPubMedGoogle Scholar
  81. 81.
    Lipworth BJ, Hall IP, Aziz I, et al. Beta2-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting beta2-agonist therapy. Clin Sci 1999; 96: 253–9CrossRefPubMedGoogle Scholar
  82. 82.
    Hall IP, Wheatley A, Wilding P, et al. Association of Glu 27 beta 2-adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet 1995; 345: 1213–4CrossRefPubMedGoogle Scholar
  83. 83.
    Drazen JM, Yandava CN, Dube L, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genetics 1999; 22(2): 168–70CrossRefPubMedGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  • Patrick Flood-Page
    • 1
  • Neil C. Barnes
    • 1
  1. 1.London Chest HospitalThe Royal Hospitals NHS TrustLondonEngland

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