Portal de Periódicos da CAPES

Salmeterol does not cause tolerance during long-term asthma therapy☆☆☆★★★

1996; Elsevier BV; Volume: 98; Issue: 6 Linguagem: Inglês

10.1016/s0091-6749(96)80200-4

1097-6825

T. Arledge, Roger F. Liddle, E. Ståhl, Thomas H. Rossing,

Stress Responses and Cortisol

Controversy regarding tolerance to β 2-agonist asthma therapy has surfaced periodically over the past 20 years, and recently it has again become a focus of attention. Although there is evidence that tolerance develops to the nonpulmonary effects of β 2-agonist,1McFadden Jr, ER Perspectives in β 2-agonist therapy: Vox clamantis in deserto vel lux in tenebris?.J Allergy Clin Immunol. 1995; 95: 641-651Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 2Morgan DJ Paull JD Richmond BH Wilson-Evered E Ziccone SP. Pharmacokinetics of intravenous and oral salbutamol and its sulphate conjugate.Br J Clin Pharmacol. 1986; 22: 587-593Crossref PubMed Scopus (172) Google Scholar there is still uncertainty among many clinicians who treat patients with asthma as to whether any clinically significant tolerance develops to the pulmonary effects of these drugs, particularly to the recently introduced long-acting β 2-agonist salmeterol. This report, which represents results from the largest database of patients receiving salmeterol in clinical studies in the United States, supports the growing body of evidence that patients with asthma do not show any loss of bronchodilator effect after regular exposure to β 2-agonist,3Respsher LH Miller TD Smith S. The lack of tachyphylaxis following prolonged therapy of asthma with inhaled albuterol aerosol.Ann Allergy. 1981; 47: 405-409PubMed Google Scholar, 4Ullman A Hedner J Svedmyr N. Inhaled salmeterol and salbutamol in asthmatic patients. An evaluation of asthma symptoms and the possible development of tachyphylaxis.Am Rev Respir Dis. 1990; 142: 571-575Crossref PubMed Scopus (118) Google Scholar, 5Arvidsson P Larsson S Lofdahl CG Melander B Svedmyr N Wahlander L. Inhaled formoterol during one year in asthma: a comparison with salbutamol.Eur Respir J. 1991; 4: 1168-1173PubMed Google Scholar, 6Cheung D Timmers MC Zwinderman AH Bel HE Dijkman JH Sterk PJ. Long-term effects of a long-acting beta2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma.N Engl J Med. 1992; 327: 1198-1203Crossref PubMed Scopus (396) Google Scholar, 7Pearlman DS Chervinsky P LaForce C Seltzer JM Southern DL Kemp JP et al.A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma.N Engl J Med. 1992; 327: 1420-1425Crossref PubMed Scopus (325) Google Scholar, 8D’Alonzo GE Nathan RA Henochowicz S Morris RJ Ratner P Rennard SI Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma.JAMA. 1994; 271: 1412-1416Crossref PubMed Scopus (162) Google Scholar although some loss of the bronchoprotective effect has been reported in a few exercise-induced bronchospasm and methacholine challenge studies.6Cheung D Timmers MC Zwinderman AH Bel HE Dijkman JH Sterk PJ. Long-term effects of a long-acting beta2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma.N Engl J Med. 1992; 327: 1198-1203Crossref PubMed Scopus (396) Google Scholar, 9Ramage L Ingram C Cree IA Dhillon DP. Chronic dosing with inhaled salmeterol in exercise-induced asthma (EIA).Thorax. 1992; 47 ([abstract]): 255PGoogle Scholar Four randomized, multicenter, double-blind, placebo-controlled, parallel-group studies were conducted in patients with reversible mild-to-moderate asthma (FEV 1 of 50% to 80% of predicted value after medication was withheld); two of the studies (n = 556), identically designed, evaluated salmeterol aerosol from a pressurized metered-dose inhaler (pMDI)7Pearlman DS Chervinsky P LaForce C Seltzer JM Southern DL Kemp JP et al.A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma.N Engl J Med. 1992; 327: 1420-1425Crossref PubMed Scopus (325) Google Scholar, 8D’Alonzo GE Nathan RA Henochowicz S Morris RJ Ratner P Rennard SI Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma.JAMA. 1994; 271: 1412-1416Crossref PubMed Scopus (162) Google Scholar; whereas the other two identically designed studies (n = 451) evaluated salmeterol powder, inhaled from a dry powder device (DPI).10Kemp J Wolfe J Grady J LaForce C Stahl E Liddle R. Inhaled salmeterol powder compared with albuterol aerosol given regularly or as needed for asthma [abstract].Am J Respir Crit Care Med. 1995; 151: A59Crossref Google Scholar All patients provided written informed consent, and the study protocols were approved by institutional review boards at each center. Patients were treated with one of the following for 12 weeks: salmeterol aerosol, 42 μg (actuated dose) twice daily by pMDI or salmeterol powder, 50 μg (blister content) by DPI twice daily through a breath-activated device (DISKHALER, **DISKHALER is a trademark of the Glaxo Wellcome Group of companies. Glaxo Wellcome); albuterol aerosol, 180 μg four times daily (by pMDI); or placebo. All patients could also use albuterol pMDI as needed for acute symptoms, except 8 hours before and on clinic days during pulmonary function testing. Inhaled corticosteroids or cromolyn could also be used, provided that the dosage regimen was held constant throughout the study. Theophylline and oral β-agonists were not permitted during these trials. Patients were seen in the clinic every 2 weeks during the treatment phase. On the first day of treatment and after 4, 8, and 12 weeks of treatment, FEV 1 was measured at least every hour over a 12-hour period after the morning dose of study drug was given. Patients self-measured peak expiratory flow (PEF) every morning before their first dose of study drug and every evening before the last dose of study drug. Patients also recorded daily, on diary cards, the number of times they were awakened by asthma symptoms and the number of puffs of albuterol required each 24 hours. For the purpose of these analyses, data from the two identical salmeterol pMDI studies were combined, as were the data from the two identical salmeterol DPI studies. Area under the curve (AUC) was defined as the area in liter-hours between the 12-hour serial FEV 1 curve and a horizontal line corresponding to the treatment day 1 baseline value. Probability (p) values for comparisons of day 1 and week 12 FEV 1 values were based on analysis of variance F-tests. Within-treatment comparisons of change from the beginning to the end of treatment for morning PEF (predicted value), nighttime awakenings, and albuterol use were based on a Wilcoxon signed-rank test. A p value of 0.05 was considered statistically significant. There were no statistically significant differences between the mean AUC for FEV 1 on the first day of treatment and after 12 weeks of treatment in either the salmeterol pMDI or DPI group, indicating no loss of bronchodilating effect over time (Fig. 1). Although there were statistically significant changes between the day 1 AUC and week 12 AUC in the albuterol and placebo groups (i.e., a decrease in the albuterol group in the DPI studies only and an increase in the placebo group in the pMDI studies only), there was no consistent pattern of tolerance. FIG. 1Mean AUC for FEV 1 (Lhour ± SEM). Only data from patients who completed all four clinic visits and did not receive albuterol within 8 hours of pulmonary function testing were included. BID, Twice daily.View Large Image Figure ViewerDownload (PPT) Morning PEF improved only in the salmeterol group in both the DPI and pMDI studies (mean change: 33 and 25 L/min, respectively, with salmeterol; 0 and –10 L/min, respectively, with albuterol; and 1 and –1 L/min, respectively, with placebo; p < 0.05). Over the 12 weeks of treatment, there was no statistically significant change in the response to therapy within any of the treatment groups. The least variation in morning PEF occurred in patients who received salmeterol (mean changes: 0.4 L/min in both the DPI and pMDI studies compared with 5.9 and 1.0 L/min with albuterol and 2.9 and 8.1 L/min with placebo in the DPI and pMDI studies, respectively). Asthma exacerbations (defined as a worsening of asthma that required treatment in addition to study drug, concomitant antiasthma therapy and rescue albuterol allowed by protocol) occurred least frequently in patients who received salmeterol (50 exacerbations), and exacerbations were evenly distributed throughout the 12 weeks of treatment (Fig. 2). Exacerbations in patients who received albuterol (70 exacerbations) or placebo (60 exacerbations) were similarly distributed. Concurrent inhaled corticosteroid use did not appear to have an impact on the asthma exacerbation rate in the salmeterol and albuterol groups (Table I), because approximately one third (salmeterol 30%, albuterol 36%) of the patients used concurrent inhaled corticosteroids, and approximately one third of the exacerbations occurred in patients using inhaled corticosteroids. In the placebo group, the exacerbation rate (47%) was higher than the concurrent steroid use (35%), perhaps because patients received β 2-agonist therapy only in response to asthma symptoms, rather than prophylactically. FIG. 2Days from begining of treatment to exacerbation, occurring during continuous daily treatment with salmeterol. Excludes exacerbations occurring during clinic visits when supplemental albuterol was withheld as part of the protocol.View Large Image Figure ViewerDownload (PPT)FIG. 2Days from begining of treatment to exacerbation, occurring during continuous daily treatment with salmeterol. Excludes exacerbations occurring during clinic visits when supplemental albuterol was withheld as part of the protocol.View Large Image Figure ViewerDownload (PPT) Table IAsthma exacerbation dataSalmeterol (pMDI and DPI)AlbuterolPlaceboNumber of patients with exacerbations504955Number of patients using concurrent inhaled steroids with exacerbations181726 Open table in a new tab Lastly, analyses of trends within each treatment group showed no evidence of tolerance as measured by changes in nighttime awakenings caused by asthma symptoms or the use of supplemental albuterol over 12 weeks of therapy. These results from a large sample of patients who received either salmeterol pMDI or DPI over a 12-week period clearly demonstrate that there is no tolerance to the bronchodilating properties of salmeterol, confirming the findings of other long-term studies of salmeterol in the maintenance treatment of asthma.11Britton M Earnshaw JS Palmer JBD. A twelve month comparison of salmeterol with salbutamol in asthmatic patients.Eur Respir J. 1992; 5: 1062-1067PubMed Google Scholar, 12Lötvall J Lunde H Ullman A Törnqvist H Svedmyr N Twelve months treatment with inhaled salmeterol in asthmatic patients. Effects on β 2-receptor function and inflammatory cells.Allergy. 1992; 47: 477-483Crossref PubMed Scopus (50) Google Scholar This information, along with data showing that patients receiving salmeterol by pMDI over 12 weeks who had an asthma exacerbation and were then treated with nebulized albuterol were able to achieve significant bronchodilation regardless of how long they had been receiving salmeterol,13Nathan RA Seltzer JM Kemp JP Chervinsky P Alexander WJ Liddle R et al.Safety of salmeterol in the maintenance treatment of asthma.Ann Allergy Asthma Immunol. 1995; 75: 243-248PubMed Google Scholar provides further reassurance to clinicians that there is no loss or diminution of asthma control with salmeterol during long-term use. These analyses evaluated clinically relevant end points appropriate for charting the effectiveness of a maintenance therapy over an extended period. Responses to provocative challenges with nonspecific stimuli were not measured in these studies. However, had a clinically relevant increase in airway responsiveness occurred in these patients, it would have been reflected most likely in the number of asthma exacerbations, the use of rescue medication, and the number of nighttime awakenings.14Makino S. Clinical significance of bronchial sensitivity to acetylcholine and histamine in bronchial asthma.J Allergy. 1966; 38: 127-142Abstract Full Text PDF PubMed Scopus (83) Google Scholar, 15Juniper EF Frith PA Hargreave FE. Airway responsiveness to histamine and methacholine: relationship to minimum treatment to control symptoms of asthma.Thorax. 1981; 36: 575-579Crossref PubMed Scopus (299) Google Scholar In fact, every efficacy variable examined in these studies, including AUC for 12-hour serial FEV 1 (which reflects both magnitude and duration of the bronchodilator response) and PEF, confirmed that maintenance therapy with salmeterol does not produce tolerance to its bronchodilating effects. We thank Rose Mills for writing assistance.