LACK OF SUBSENSITIVITY TO ALBUTEROL AFTER TREATMENT WITH SALMETEROL IN PATIENTS WITH ASTHMA

To the Editor:

We read with interest the recent article from Nelson and colleagues (1) reporting an apparent lack of subsensitivity to albuterol after treatment for 4 wk with salmeterol in two separate studies. The most relevant study was in patients already taking inhaled corticosteroids with moderate persistent asthma (Step 3) where the guidelines recommend adding salmeterol on top of low to medium dose of inhaled corticosteroid (2). In this group of corticosteroid-treated patients, prealbuterol baseline values for FEV₁ were significantly higher at 12 h after the last dose of salmeterol (Day 28) as compared to pretreatment values (Day 1) or to placebo. This finding is consistent with the prolonged degree of airway ₂-adrenoceptor occupancy exhibited by salmeterol. As a consequence of the higher baseline value after salmeterol, there was relatively little room for bronchodilator improvement in response to cumulative doses of albuterol. Indeed, on Day 28 the mean increase in FEV₁ between 180 µg and 2,880 µg doses of albuterol amounted to approximately 0.2 L. It is therefore not meaningful to draw conclusions regarding the lack of bronchodilator subsensitivity to albuterol in the presence of such a flat dose-response curve. The authors cite a similar study from Wilding and colleagues (3) with the same design flaw, where there was also a flat dose response to albuterol, with a 0.1 L mean improvement between 90 µg and 720 µg doses of albuterol.

We have also previously performed a study in corticosteroid-treated patients with moderate persistent asthma, where there was a rightward shift in the albuterol bronchodilator dose-response curve (200-3,200 µg) after 4 wk treatment with salmeterol compared with placebo, although the absolute peak FEV₁ response to 3,200 µg of albuterol was not significantly attenuated (4). Nelson and coworkers have criticized our study on the basis that there was a limited potential for bronchodilator reversibility after treatment with salmeterol. Inspection of the albuterol dose-response curves from our study reveals a steep dose-response effect with albuterol. The peak bronchodilator response to 3,200 µg of albuterol is of little relevance, as patients would be most unlikely to self-administer 32 repeated puffs for acute relief. It is more pertinent to look at the shift in the dose-response curve at lower doses, where we found that a 2.5-fold higher dose of albuterol (1,557 µg vs. 619 µg) was required after treatment with salmeterol compared to placebo, in order to produce a 0.5 L increase in FEV₁ (4). The occurrence of bronchodilator subsensitivity is supported by the findings of Fuglsang and colleagues (5) in corticosteroid-treated asthmatic children, where the terbutaline dose-response curve was significantly flatter after treatment for 3 wk with salmeterol compared with placebo (18% versus 2% increase in FEV₁). There are also similar findings of bronchodilator subsensitivity with formoterol, another long-acting ₂-agonist (6).

Studies evaluating bronchodilator responsiveness in patients with stable asthma should be interpreted with caution, because the degree of intrinsic ₂-agonist activity will be influenced by the degree of prevailing bronchomotor tone (9). In vivo studies have shown a blunted effect of albuterol on methacholine-contracted bronchi in asthmatic patients taking salmeterol or formoterol (10, 11). Further studies are required to assess whether there is a clinically relevant interaction between long and short-acting ₂-agonists in the setting of increased bronchomotor tone in patients with acute severe asthma. Such studies should also address the acute effects of ₂-agonists in patients who are particularly susceptible to ₂-adrenoceptor down-regulation due to genetic polymorphism (12, 13).

BRIAN J. LIPWORTH

CATHERINE JACKSON

Asthma and Allergy Research Group

Department of Clinical Pharmacology

Ninewells Hospital and Medical School

University of Dundee

Scotland, United Kingdom

	References

1. Nelson, H. S., R. B. Berkowitz, D. A. Tinkelman, A. H. Emmett, K. A. Rickard, and S. W. Yancey. 1999. Lack of subsensitivity to albuterol after treatment with salmeterol in patients with asthma. Am. J. Respir. Crit. Care Med. 159: 1556-1561 [Abstract/Free Full Text].

2. Anonymous National Asthma Education and Prevention Programme. 1997. Expert Panel Report II: Guidelines for the diagnosis and management of asthma. National Institutes of Health, Bethesda, MD. Publication No. 97-4051.

3. Wilding, P., M. Clark, J. T. Coon, J. B. Lewis, L. Rushton, J. Bennett, J. Oborne, S. Copper, and A. E. Tattersfield. 1997. Effective long term treatment with salmeterol on asthma control: a double-blind randomised cross-over study. B.M.J. 314: 1441-1446 [Abstract/Free Full Text].

4. Grove, A., and B. J. Lipworth. 1995. Bronchodilator subsensitivity to inhaled salbutamol after twice daily salmeterol in asthmatic patients. Lancet 346: 201-216 [Medline].

5. Fuglsang, G., J. Vikre-Jorgensen, L. Agertoft, and S. Pedersen. 1998. Effect of salmeterol treatment on nitric oxide level in exhaled air and dose-response to terbutaline in children with mild asthma. Paediatric Pulmon. 25: 314-321 .

6. Newnham, D. M., D. G. McDevitt, and B. J. Lipworth. 1994. Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma. Am. J. Med. 97: 29-37 [Medline].

7. Newnham, D. M., A. Grove, D. G. McDevitt, and B. J. Lipworth. 1995. Subsensitivity of bronchodilator and systemic beta 2-adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients. Thorax 50: 497-504 [Abstract/Free Full Text].

8. Tan, K. S., A. Grove, A. McLean, Y. Gnosspelius, I. P. Hall, and B. J. Lipworth. 1997. Systemic corticosteroid rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients. Am. J. Respir. Crit. Care Med. 156: 28-35 [Abstract/Free Full Text].

9. Molimard, M., E. Naline, Y. Zan, Zhang, V. Le Gross, B. Begaud, and C. Advenier. 1999. Long and short-acting beta2-adrenoceptor agonist: interactions in human contracted bronchi. Eur. Respir. J. 11: 583-588 .

10. Lipworth, B. J., and I. Aziz. 1999. A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic patients receiving regular salmeterol of formoterol. J. Allergy Clin. Immunol. 103: 88-92 [Medline].

11. Aziz, I., and B. J. Lipworth. 1999. In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol. J. Allergy Clin. Immunol. 103: 816-822 [Medline].

12. Tan, K. S., I. P. Hall, J. Dewar, E. Dow, and B. J. Lipworth. 1997. Beta 2-adrenoceptor polymorphism is associated with susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 350: 995-999 [Medline].

13. Martinez, F. D., P. E. Graves, M. Baldini, S. Solomon, and R. Rickson. 1997. Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J. Clin. Invest. 100: 3184-3188 [Medline].

From the Authors:

Drs. Lipworth and Jackson in their comments on our article note that, as would be anticipated, the baseline FEV₁ is higher 12 h following the last dose of salmeterol. They then state that "as a consequence of the higher baseline value after salmeterol, there was relatively little room from bronchodilator improvement in response to cumulative doses of albuterol." However, Figure 1 demonstrates a response to albuterol of 0.50 L or 16% of baseline in the steroid-naive subjects and of 0.40 L or 15% of baseline in the group on regular inhaled corticosteroids. These bronchodilator responses would be considered significant by most experts. Therefore, we must reject the conclusion of Drs. Lipworth and Jackson that "it is not meaningful to draw conclusions regarding the lack of bronchodilator subsensitivity to albuterol in the presence of such a flat dose-response curve."

Drs. Lipworth and Jackson then refer to a previous study by Drs. Lipworth and Grove (2). In that study the authors interpreted their data as indicating a rightward shift in the albuterol bronchodilator dose-response cure after 4 wk treatment with salmeterol compared with placebo. This interpretation is, however, dependent upon ignoring the higher baseline FEV₁ present in the subjects while receiving salmeterol. If, in Figure 1 of that paper, the 0.11 L by which the baseline FEV₁ is higher in the subjects on salmeterol is added to the figure indicating "change in FEV₁", it is clear that the two dose-response curves become superimposible over their entire extent and the so-called shift to the right disappears.

We will leave to the readers to decide which of the two studies cited has a "design flaw."

HAROLD S. NELSON

National Jewish Medical and Research Center

Denver, Colorado

	References

1. Nelson, H. S., R. B. Berkowitz, D. A. Tinkelman, A. H. Emmett, K. A. Rickard, and S. W. Yancey. 1999. Lack of subsensitivity to albuterol after treatment with salmeterol in patients with asthma. Am. J. Respir. Crit. Care Med. 159: 1556-1561 .

2. Grove, A., and B. J. Lipworth. 1995. Bronchodilator subsensitivity to inhaled salbutamol after twice daily salmeterol in asthmatic patients. Lancet 346: 201-216 .