Clinical Reviews in Allergy & Immunology

, Volume 31, Issue 2–3, pp 279–287 | Cite as

Concluding remarks

Can we explain the associations of β-agonists with asthma mortality? A hypothesis
  • Robert J. Hancox


β-Agonists have clearly demonstrated benefits for the treatment of both acute and chronic asthma. Therefore, it is perhaps surprising that many of the articles in this issue have focused on concerns about their safety. Much of this concern can be traced back to the “β-agonist controversy” —the association of high-dose isoprenaline and fenoterol inhalers with asthma mortality in the 1960s and 1970s. Although a causal link was never proven, lingering doubts about the safety of β-agonists remain. It is unclear whether a similar adverse effect is responsible for recently reported association of long-acting β-agonists with asthma deaths.

No mechanism for the β-agonist controversy was established, but the evidence presented in this collection of articles points to a number of contributing factors. I suggest that a combination of these effects provides a plausible mechanism for the association of frequent β-agonist use asthma mortality.

Rebound bronchoconstriction and bronchial hyperresponsiveness occur on withdrawal of regular β-agonist treatment. Regular use of fenoterol is associated with a reduction in morning peak flow suggesting that the overnight interval between doses is sufficient to allow rebound bronchoconstriction. This has not been observed with terbutaline or salbutamol, although rebound phenomena do occur when these drugs are withdrawn for slightly longer periods.

Regular use of β-agonists also leads to to lerance to their bronchoprotective and bronchodilator effects. Tolerance becomes more apparent with worsening bronchoconstriction. In severe asthma, this could result in a poor response to emergency treatment.

The combination of rebound deterioration of asthma and a poor response to β-agonist treatment resulting from tolerance could explain the increased mortality associated with fenoterol and isoprenaline. Both effects are probably caused by downregulation of β-receptors which occurs with all β-agonists. Long-acing β-agonists cause a similar degree of tolerance to short-acting β-agonists, but avoid the problem of overnight withdrawal. Long-acting β-agonists have also been shown to improve asthma control when taken in combination with inhaled corticosteroids. The clinical significance of tolerance in this context remains to be determined.

Index entries

β-Agonists asthma mortality COPD tolerance tachyphylaxis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bisgaard, H. and Szefler, S. (2006), Long-acting beta2 agonists and paediatric asthma. Lancet. 367, 286–288.PubMedCrossRefGoogle Scholar
  2. 2.
    Taylor, D. R., Sears, M. R., and Cockroft, D. W. (1996), The beta-agonist controversy. Med. Clin. N. America. 80, 719–748.PubMedCrossRefGoogle Scholar
  3. 3.
    Crane, J., Pearce, N., Flatt, A. et al. (1989), Prescribed fenoterol and death from asthma in New Zealand, 1981–83, case-control study. Lancet 1, 917–922.PubMedCrossRefGoogle Scholar
  4. 4.
    Garrett, J., Kolbe, J., Richards, G., Whitlock, T., and Rea, H. (1995), Mojor reduction in asthma morbidity and continued reduction in asthma mortality in New Zealand: what lessions have been learned? Thorax 50, 303–311.PubMedGoogle Scholar
  5. 5.
    Sears, M. R., Taylor, D. R., Print, C. G., et al. (1990), Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 336, 1391–1396.PubMedCrossRefGoogle Scholar
  6. 6.
    McFadden, E. R. Jr. (1995), Perspectives in β2-agonist therapy: Vox clamantis in deserto vel lux in tenebris. J. Allergy Clin. Immunol. 95, 641–651.PubMedCrossRefGoogle Scholar
  7. 7.
    Drazen, J. M., Israel, E., Boushey, H. A. et al. (1996), Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. N. Engl. J. Med. 335, 841–847.PubMedCrossRefGoogle Scholar
  8. 8.
    Taylor, D. R., Town, G. I., Herbison, G. P., et al. (1998), Asthma control during long-term treatment with regular inhaled salbutamol and salmeterol. Thorax 53, 744–752.PubMedGoogle Scholar
  9. 9.
    Hancox, R. J., Cowan, J. O., Flannery, E. M., et al. (1999) A randomised trial of inhaled β2-agonist, inhaled corticosteroid and their combination in the treatment of asthma. Thorax 54, 482–487.PubMedCrossRefGoogle Scholar
  10. 10.
    Wong, C. S., Pavord, I. D., Williams, J., Britton, J. R., and Tattersfield, A. E. (1990), Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma. Lancet 336, 1396–1399.PubMedCrossRefGoogle Scholar
  11. 11.
    Manolitsas, N. D., Trigg, C. J., McAulay, A. E., et al. (1995), Regular albuterol, nedocromil sodium, and bronchial inflammation in asthma. Am. J. Respir. Crit. Care Med. 151, 1925–1930.PubMedGoogle Scholar
  12. 12.
    Gauvreau, G. M., Jordana, M., Watson, R. M., Cockroft, D. W., and O'Byrne, P. M. (1997), Effect of regular inhaled albuterol on allergen-induced late responses and sputum eosinophils in asthmatic subjects. Am. J. Respir. Crit. Care Med. 156, 1738–1745.PubMedGoogle Scholar
  13. 13.
    Aldridge, R. E., Hancox, R. J., Taylor R. et al. (2000), Effects of terbutaline and budesonide on sputum cells and bronchial hyperresponsiveness in asthma. Am. J. Respir. Crit. Care Med. 161, 1459–1464.PubMedGoogle Scholar
  14. 14.
    Crane, J. and Burgess, C. (1998), Differential tolerance to β2 adrenoceptor agonists: an alternative hypothesis to explain the asthma paradox? Clin Asthma Rev. 2, 95–101.Google Scholar
  15. 15.
    Pauwels, R. A., Lofdahl, C. G., Postma, D. S., et al. (1997), Effect of inhaled formoterol and budesonide on exacerbations of asthma. N. Engl. J. Med. 337, 1405–1411.PubMedCrossRefGoogle Scholar
  16. 16.
    Wahedna, I., Wong, C. S., Wisniewski, A. F., Pavord, I. D., and Tattersfield, A. E. (1993), Asthma control during and after cessation of regular beta2-agonist treatment. Am. Rev. Respir. Dis. 148, 707–712.PubMedGoogle Scholar
  17. 17.
    deJong, J. W., van der Mark, T. W., Koîter, G. H., and Postma, D. S. (1996), Rebound airway obstruction and responsiveness after cessation of turbutaline: effects of budesonide. Am. J. Respir. Crit. Care Med. 153, 70–75.Google Scholar
  18. 18.
    Vathenen, A. S., Knox, A. J., Higgins, B. G., Britton, J. R., and Tattersfield, A. E. (1988), Rebound increase in bronchial hyperresponsiveness after treatment with inhaled terbutaline. Lancet 1, 554–558.PubMedCrossRefGoogle Scholar
  19. 19.
    Kraan, J., Koeter, G. H., van der Mark, T. W., Sluiter, H. J., and de Vries, K. (1985), Changes in bronchial hyperreactivity induced by 4 weeks treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J. Allergy Clin. Immunol 76, 628–639.PubMedCrossRefGoogle Scholar
  20. 20.
    Hancox, R. J., Cowan, J. O., Flannery, E. M., Herbison, G. P., McLachlan, C. R., and Taylor, D. R. (2000), Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled β-agonist treatment. Respir. Med. 94, 767–771.PubMedCrossRefGoogle Scholar
  21. 21.
    Plummer, A. L. (1978), The development of drug tolerance to beta2adrenergic agents. Chest 73, 949–956.PubMedCrossRefGoogle Scholar
  22. 22.
    Repsher, L. H., Anderson, J. A., Bush, R. K., et al. (1984), Assessment of tachyphylaxis following prolonged therapy of asthma with inhaled albuterol aerosol. Chest 85, 34–38.PubMedCrossRefGoogle Scholar
  23. 23.
    Cockroft D. W. (1998), Inhaled β2-agonists and the airway responses to allergen. J. Allergy Clin. Immunol. 102, S96-S99.CrossRefGoogle Scholar
  24. 24.
    Cockcroft, D. W., O'Byrne, P. M. Swystun, V. A., and Bhagat, R. (1995), Regular use of inhaled albuterol and the allergen-induced late asthmatic response. J. Allergy Clin. Immunol. 96, 44–49.PubMedCrossRefGoogle Scholar
  25. 25.
    Hancox, R. J., Subbarao, P., Kamada, D., Watson, R. M., Hargreave, F. E., and Inman, M. D. (2002), β2-agonist tolerance and exercise-induced bronchospasm. Am. J. Respir. Crit. Care Med., 165, 1068–1070.PubMedGoogle Scholar
  26. 26.
    Grove, A. and Lipworth, B. J. (1995), Tolerance with β2-adrenoceptor agonists: time for reappraisal. Br. J. Clin. Pharmacol. 39, 109–118.PubMedGoogle Scholar
  27. 27.
    Hancox, R. J., Aldridge, R. E., Cowan, J. O., et al. (1999), Tolerance to beta agonists during acute bronchoconstriction. Eur. Respir. J. 14, 283–287.PubMedCrossRefGoogle Scholar
  28. 28.
    Jones, S. L., Cowan, J. O., Flannery, E. M., Hancox, R. J., Herbison, G. P., and Taylor, D. R. (2001), Reversing acute bronchoconstriction in asthma: the effect of bronchodilator tolerance after treatment with formoterol. Eur. Respir. J. 17, 368–373.PubMedCrossRefGoogle Scholar
  29. 29.
    Wraight, J. M., Hancox, R. J., Herbison, G. P., Cowan, J. O., Flannery, E. M., and Taylor, D. R. (2003), Bronchodilator tolerance: the impact of increasing bronchoconstriction. Eur. Respir. J. 21, 310–315.CrossRefGoogle Scholar
  30. 30.
    van der Woude, H. J., Winter, T. H., and Aglhery R. (2001), Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists. Thorax 56, 529–535.PubMedCrossRefGoogle Scholar
  31. 31.
    Larsson, K., Martinsson, A., and Hjemdahl, P. (1992), Influence of β-adrenergic receptor function during terbutaline treatment on allergen sensitivity and brochodilator response to terbutaline in asthmatic subjects. Chest 101, 953–960.PubMedCrossRefGoogle Scholar
  32. 32.
    Campbell, D. A., Luke, C. G., McLennan, G., et al. (1996), Near-fatal asthma in South Australia: descriptive features and medication use. Aust. N. Z. J. Med. 26, 356–362.PubMedGoogle Scholar
  33. 33.
    Taylor, D. R., Sears, M. R., Herbison, G. P., et al. (1993), Regular inhaled β agonist in asthma: effects on exacerbations and lung function. Thorax 48, 134–138.PubMedCrossRefGoogle Scholar
  34. 34.
    Abramson, M. J., Balley, M. J., Couper, F. J., et al. (2001), Are asthma medications and management related to deaths from asthma? Am. J. Respir. Crit. Care Med. 163, 12–18.PubMedGoogle Scholar
  35. 35.
    Rosenthal, R. R., Busse, W. W., Kemp, J. P., et al. (1999), Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness. Chest 116, 595–602.PubMedCrossRefGoogle Scholar
  36. 36.
    McIvor, R. A., Pizzichini, E., Turner M. O., Hussack, P., Hargreave, F. E., and Sears, M. R. (1998), Potential masking effects of salmeterol on airway inflamation in asthma. Am. J. Respir. Crit. Care Med. 158, 924–930.PubMedGoogle Scholar
  37. 37.
    Salpeter, S. R., Ormiston, T. M., and Salperter, E. E. (2004), Cardiovacular effects of beta-agonists in patients with asthma and COPD: a meta-analysis. Chest 125, 2309–2321.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2006

Authors and Affiliations

  • Robert J. Hancox
    • 1
    • 2
  1. 1.Department of Preventive and Social MedicineDunedin School of MedicineDunedinNew Zealand
  2. 2.Waikato HospitalHamiltonNew Zealand

Personalised recommendations