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Rapid onset of tolerance to beta-agonist bronchodilation

  • Sarah Haney
    Affiliations
    Department of Respiratory Medicine, Waikato Hospital, Hamilton, New Zealand
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  • Robert J. Hancox
    Correspondence
    Corresponding author. Dunedin Multidisciplinary Health and Development Research Unit, Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, P.O. Box 913, Dunedin, New Zealand. Tel.: +6434798512; fax: +6434795487.
    Affiliations
    Department of Respiratory Medicine, Waikato Hospital, Hamilton, New Zealand
    Search for articles by this author
Open ArchivePublished:November 30, 2004DOI:https://doi.org/10.1016/j.rmed.2004.10.014

      Summary

      Introduction: Regular use of beta-agonists leads to tolerance to their bronchodilator effects. This is easily demonstrated if dilation is tested following methacholine challenge. It is not known how quickly tolerance develops or how long it lasts after stopping beta-agonist therapy.
      Methods: Ten subjects with stable asthma were studied. Following 2 weeks without beta-agonists, methacholine was inhaled to induce a 20% reduction in FEV1. The response to inhaled salbutamol (100, 100, 200μg at 5-min intervals) was then measured. This procedure was repeated 24h after one dose and 24h after 3, 7 and 14 days of inhaled formoterol 12μg twice daily, and 3 and 5 days after formoterol was discontinued. Unscheduled use of beta-agonists was not permitted.
      Results: Bronchodilator tolerance, assessed by a reduction of the area under the salbutamol dose–response curve, occurred after 1 dose of formoterol (28% reduction, 95% CI 12, 45%), increased up to 1 week and plateaued between 1 and 2 weeks (58% reduction, 95% CI 38, 78%). Three days after stopping formoterol, the response to salbutamol was similar to baseline (12% reduction, 95% CI −9, 33%). The first dose of formoterol provided significant bronchoprotection to methacholine (1.6 doubling doses, P=0.007). This diminished with regular treatment and by 2 weeks the PD20 methacholine was not significantly different to baseline.
      Conclusions: Bronchodilator tolerance occurs after a single dose and reaches a maximum after 1 week of regular formoterol. Sensitivity recovers 3 days after stopping treatment.

      Keywords

      Introduction

      Long-acting beta-agonists are recommended for patients with persistent asthma symptoms despite inhaled corticosteroids.
      British guideline on the management of asthma
      They improve symptoms and lung function and reduce the number of exacerbations and the need for additional bronchodilators.
      • Pauwels R.A.
      • Lofdahl C-G.
      • Postma D.S.
      • et al.
      Effect of inhaled formoterol and budesonide on exacerbations of asthma.
      However, they have not been found to reduce hospital admissions
      • Lanes S.L.
      • Lanza L.L.
      • Wentworth C.E.
      Risk of emergency care, hospitalization, and ICU stays for acute asthma among recipients of salmeterol.
      and there have been indications that they may increase asthma mortality or serious exacerbations, especially in patients not taking inhaled corticosteroids.

      Rickard KA. 2003 Safety alert—Serevent (salmeterol xinafoate). www.fda.gov/medwatch/SAFETY/2003/serevent.htm, Accessed 23/05/03.

      • Mann M.
      • Chowdhury B.
      • Sullivan E.
      • Nicklas R.
      • Anthracite R.
      • Meyer R.J.
      Serious asthma exacerbations in asthmatics treated with high-dose formoterol.
      One mechanism by which long-acting beta-agonists could lead to an adverse event is the development of tolerance to beta-agonists.
      Tolerance is known to occur to the extrapulmonary effects of beta-agonists
      • Lipworth B.J.
      • Struthers A.D.
      • McDevitt D.G.
      Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics.
      and also to their bronchoprotective effects
      • Cheung D.M.
      • Timmers M.C.
      • Zwinderman A.H.
      • Bel E.H.
      • Dijkman J.H.
      • Sterk P.J.
      Long-term effects of a long-acting β2-adrenoceptor agonist, salmeterol, on airway responsiveness in patients with mild asthma.
      • Bhagat R.
      • Kalra S.
      • Swystun V.A.
      • Cockcroft D.W.
      Rapid onset of tolerance to the bronchoprotective effect of salmeterol.
      (the ability to prevent bronchoconstriction). Demonstrating tolerance to bronchodilation has been more difficult. Studies in stable asthmatics have had inconsistent results.
      • Aziz I.
      • Hall I.P.
      • McFarlane L.C.
      • Lipworth B.J.
      β2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma.
      • Lipworth B.J.
      • Aziz I.
      Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration.
      However, studies that have assessed bronchodilation after prior bronchoconstriction with methacholine have consistently shown marked tolerance to bronchodilation.
      • Jones S.L.
      • Cowan J.O.
      • Flannery E.M.
      • Hancox R.J.
      • Herbison G.P.
      • Taylor D.R.
      Reversing acute bronchoconstriction in asthma the effect of bronchodilator tolerance after treatment with formoterol.
      • Hancox R.J.
      • Aldridge R.E.
      • Cowan J.O.
      • et al.
      Tolerance to beta-agonists during acute bronchoconstriction.
      • Van der Woude H.J.
      • Winter T.H.
      • Aalbers R.
      Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists.
      • Wraight J.M.
      • Hancox R.J.
      • Herbison G.P.
      • Cowan J.O.
      • Flannery E.M.
      • Taylor D.R.
      Bronchodilator tolerance the impact of increasing bronchoconstriction.
      A recent meta-analysis also concluded that regular beta-agonist treatment decreased the bronchodilator response to subsequent beta-agonists.
      • Salpeter S.R.
      • Ormiston T.M.
      • Salpeter E.E.
      Meta-analysis respiratory tolerance to regular β2-agonist use in patients with asthma.
      While bronchoprotection tolerance can be shown after a single day of treatment with long-acting beta-agonist,
      • Bhagat R.
      • Kalra S.
      • Swystun V.A.
      • Cockcroft D.W.
      Rapid onset of tolerance to the bronchoprotective effect of salmeterol.
      the time course of the development of tolerance to bronchodilation is unknown.
      • Salpeter S.R.
      • Ormiston T.M.
      • Salpeter E.E.
      Meta-analysis respiratory tolerance to regular β2-agonist use in patients with asthma.
      This study was designed to assess the speed of onset of bronchodilator tolerance using the long-acting beta-agonist formoterol.

      Methods

      Subjects were asthmatics who were not using long-acting beta-agonists. Pregnant and lactating women were excluded, as were those who had used oral corticosteroids in the previous 3 months or had changed asthma treatment in the previous 6 weeks. Subjects with a PD20 methacholine>1.5mg on day 0 were withdrawn.
      There was an initial 2-week washout period during which no beta-agonist was used. Following this, subjects underwent a methacholine challenge and salbutamol response (day 0). Subjects then inhaled formoterol 12μg twice daily (Foradil aeroliser) for the next 2 weeks, except where this was omitted for 24h before each challenge. Methacholine challenges and salbutamol responses were repeated on day 1 (24h after a single dose of formoterol) and on days 3, 7, and 14 of formoterol treatment (after 4, 11 and 24 doses of formoterol, respectively). Challenges were also performed 3 and 5 days after stopping treatment.
      Methacholine challenge was performed using a modified Yan protocol.
      • Yan K.
      • Salome C.
      • Woolcock A.J.
      Rapid method for measurement of bronchial responsiveness.
      Baseline FEV1 was the highest of three consistent measurements. Subjects then inhaled doubling doses of nebulised methacholine from 0.0073 to 3.75mg (0.04–19μmol) via 1 or 2 breaths from a dosimeter to a maximum cumulative dose of 7.5mg. The FEV1 was measured 1min after each dose. Once FEV1 had fallen by ⩾20% from baseline, methacholine challenge was stopped. The PD20 (cumulative dose) was calculated by linear interpolation. Where the FEV1 fell <20% from baseline (1 subject on 2 occasions), an arbitrary value of 15mg was taken as the PD20. Salbutamol 100, 100 and 200μg via metered dose inhaler and Volumatic spacer was given at 0, 5 and 10min after challenge, respectively. FEV1 was measured 5min after each dose of salbutamol. Total measured response time was therefore 15min.
      The main outcome measure was the area under the curve (AUC) for the change in FEV1 after inhaled salbutamol. The change in FEV1 was expressed as a percentage of the fall in FEV1 induced by methacholine. Changes from baseline were assessed by paired Student's t-tests. Previous studies indicate that the baseline FEV1, dose of methacholine used and the fall in FEV1 may be significant covariates of the AUC.
      • Hancox R.J.
      • Aldridge R.E.
      • Cowan J.O.
      • et al.
      Tolerance to beta-agonists during acute bronchoconstriction.
      A further analysis examined the changes in the AUC using these as covariates (repeated measures ANCOVA). Data from previous studies indicated that a sample size of 12 subjects would give 80% power to detect a 30% fall in AUC at α=0.05.
      • Hancox R.J.
      • Aldridge R.E.
      • Cowan J.O.
      • et al.
      Tolerance to beta-agonists during acute bronchoconstriction.
      A secondary outcome measure was the final (15min) FEV1 following salbutamol treatment. Bronchoprotection was assessed by measuring changes in the logPD20 methacholine.

      Results

      Fourteen subjects were recruited of whom three were withdrawn on day 0 because their PD20 was >1.5mg (7.7μmol). One further subject withdrew after day 3 because of an upper respiratory tract infection. Data are therefore available for 10 subjects, 6 female, aged 20–61 years. Five subjects were taking inhaled corticosteroids. One subject did not attend the challenge on day 1. AUC data 3 days after formoterol was stopped are unavailable for technical reasons in another subject.
      The mean baseline FEV1 on day 1, 24h after the first dose of formoterol, increased by 140ml (P=0.006). This remained relatively constant during formoterol treatment, although after 2 weeks the difference from baseline was no longer statistically significant. Three and 5 days after stopping formoterol the FEV1 was not different to day 0 (Table 1).
      Table 1Baseline FEV1, geometric mean PD20 and salbutamol dose–response AUC on each of the study days.
      Day0137143 days post5 days post
      FEV1 (L) (sd)*2.80 (1.19)*2.94 (1.18)*2.92 (1.20)*2.89 (1.21)*2.86 (1.20)*2.76 (1.19)*2.73 (1.12)*
      Change from day 0 (95% confidence interval)0.14* (0.05, 0.22)0.12 (0.05, 0.19)0.10 (−0.01, 0.19)0.07 (−0.04, 0.18)−0.05 (−0.14, 0.04)−0.06 (−0.16, 0.04)
      P for change0.006*0.0050.040.170.250.19
      PD20 methacholine (mg) ** (95% CI for mean)0.11** (0.03, 0.46)0.37** (0.07, 2.14)0.31** (0.05, 1.84)0.24** (0.04, 1.38)0.17** (0.05, 0.60)0.18** (0.04, 0.81)0.16** (0.03, 0.85)
      Change from day 0 (doubling doses) (95% confidence interval)1.57* (0.55, 2.58)1.49* (0.53, 2.45)0.93 (0.09, 1.78)0.44 (−0.11, 1.00)0.33 (−0.57, 1.23)0.29 (−0.38, 0.95)
      P for change0.007*0.007*0.030.110.430.35
      Final FEV1 (L)(sd) **3.10 (1.18)**3.00 (1.19)**2.85 (1.24)**2.56 (1.15)**2.61 (1.11)**2.84 (1.12)**2.88 (1.15)**
      Change from day 0 (95% confidence interval)−0.07* (−0.18, 0.04)−0.20 (−0.36,−0.04)−0.42 (−0.69,−0.16)−0.40 (−0.61,−0.20)−0.24* (−0.40,−0.08)−0.16 (−0.28,−0.05)
      P for change (no covariates)0.18*0.020.0060.0020.008*0.01
      P for change (covariate analysis)0.18*0.220.030.0060.12*0.23
      AUC (%.time) (sd)**244 (152)**166 (151)**126 (48)**77 (62)**92 (112)**211 (169)**219 (150)**
      % change from day 0 (95% confidence interval)−28* (−45, −12)−46 (−85, −7)−61 (−95, −27)−58 (−78,−38)−12* (−33, 9)−11 (−24, 2)
      P for change (no covariates)0.004*0.030.003<0.0010.22*0.10
      P for change (covariate analysis)0.38*0.160.020.0020.07*0.23
      AUC results are expressed as percent recovery of the methacholine-induced fall in FEV1×time. Only subjects with complete data for all study days are included in mean values and standard deviations. All available data are used for calculation of delta values, confidence intervals for change and P values for change. N=10, except *n=9, **n=8.
      The geometric mean PD20 methacholine increased after the first dose of formoterol by 1.6 doubling doses (P=0.007). The bronchoprotection afforded by the formoterol decreased thereafter. After 2 weeks of treatment, the PD20 was not significantly different to day 0 (Table 1).
      The AUC for salbutamol response fell during formoterol treatment (Table 1, Fig. 1). After one dose the AUC had fallen by 28% (95% confidence interval 12, 45%). It continued to decrease up to 1 week (61% (95% CI: 27, 95) lower), and plateaued between 1 and 2 weeks (58% (95% CI: 38, 78) lower). The AUC recovered 3 days after stopping formoterol (12% lower than baseline (95% CI: −9, 33%)).
      Figure thumbnail gr1
      Figure 1Area under the salbutamol dose–response curve on each study day. AUC results are expressed as percent recovery of the methacholine-induced fall in FEV1×time. Error bars represent the standard error of the mean. Only subjects with data for all challenges are included (n=8).
      The change in AUC from baseline was statistically significant for all measurements during formoterol therapy without taking covariates into account (Table 1). In the covariate analysis, the reduction in AUC after the first dose of formoterol was not statistically significant after adjusting for the baseline FEV1, the PD20 and the fall in FEV1 induced by methacholine. After 1 and 2 weeks the decrease in AUC from day 0 was significant, even after adjusting for these covariates (P=0.002 at 2 weeks) (Table 1).
      The final FEV1 after 400μg of salbutamol (15min after the end of the methacholine challenge) showed the same pattern as the AUC, with a substantial reduction at 1 and 2 weeks. The mean post-salbutamol FEV1 was 3.01L on day 0 and 2.60L on day 14 (n=10) (95% confidence interval for difference 0.20–0.61L, P=0.006 on covariate analysis) (Table 1, Fig. 2).
      Figure thumbnail gr2
      Figure 2The mean response to salbutamol after methacholine challenge on days 0, 7 and 14. Subjects with data for all of these challenges are included (n=10).

      Discussion

      This study indicates that bronchodilator tolerance develops rapidly, with a reduced response to salbutamol after a single dose of formoterol. Tolerance appeared to reach a plateau after 1 week of regular therapy. Beta-agonist responsiveness recovered quickly with little tolerance 3 days after stopping therapy.
      The pre-methacholine FEV1 was higher than baseline throughout formoterol treatment, in keeping with the known bronchodilator effects of formoterol. The first dose of formoterol provided significant bronchoprotection against methacholine. This degree of bronchoprotection decreased thereafter as tolerance to bronchoprotection occurred.
      Initially, the reduced response to salbutamol may have been confounded by the bronchoprotective effect of formoterol. This meant that more methacholine was required to produce bronchoconstriction and the higher dose may have reduced the response to salbutamol. Hence the covariate analysis, which adjusts for the PD20, does not show a statistically significant difference in the response to salbutamol after the first dose of formoterol. However, as the study continued and tolerance to bronchoprotection developed, the PD20 approached baseline values but the response to salbutamol continued to decrease. This indicates that a true reduction in the salbutamol response was taking place.
      This was an open-label study without a placebo control. Bronchodilator tolerance has been shown to occur using the methacholine model in several double-blind randomised placebo controlled trials.
      • Jones S.L.
      • Cowan J.O.
      • Flannery E.M.
      • Hancox R.J.
      • Herbison G.P.
      • Taylor D.R.
      Reversing acute bronchoconstriction in asthma the effect of bronchodilator tolerance after treatment with formoterol.
      • Hancox R.J.
      • Aldridge R.E.
      • Cowan J.O.
      • et al.
      Tolerance to beta-agonists during acute bronchoconstriction.
      • Van der Woude H.J.
      • Winter T.H.
      • Aalbers R.
      Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists.
      • Wraight J.M.
      • Hancox R.J.
      • Herbison G.P.
      • Cowan J.O.
      • Flannery E.M.
      • Taylor D.R.
      Bronchodilator tolerance the impact of increasing bronchoconstriction.
      This study was designed to examine the rate of onset of tolerance by comparing the change in response with baseline (day 0). We had no a priori hypothesis about the onset of tolerance and think it is very unlikely that the lack of a placebo control has biased our findings.
      Tolerance to bronchodilation appears to follow a similar time course to tolerance to bronchoprotection. This has been shown to occur after a single dose
      • Drotar D.E.
      • Davis E.E.
      • Cockcroft D.W.
      Tolerance to the bronchoprotective effect of salmeterol 12h after starting twice daily treatment.
      and increase over the first 5 days of long-acting beta-agonist therapy.
      • Bhagat R.
      • Kalra S.
      • Swystun V.A.
      • Cockcroft D.W.
      Rapid onset of tolerance to the bronchoprotective effect of salmeterol.
      Beta-receptor density and activity on human lymphocytes also show a similar pattern, with a decrease over 1 week of beta-agonist treatment, a plateau between 1 and 2 weeks and recovery 1 week after stopping therapy.
      • Van den Berg W.
      • Leferink J.G.
      • Fokkens J.K.
      • Kreukniet J.
      • Maes R.A.A.
      • Bruynzeel P.L.B.
      Clinical implications of drug-induced desensitization of the beta-receptor after continuous oral use of terbutaline.
      Different mechanisms may be responsible for early and later tolerance. It is possible that in parallel with the rapid onset of tolerance (within 24h), there may also be a rapid recovery from tolerance, at least some of which will occur in the first 24h. Cellular studies show that receptor downregulation involves many mechanisms including initial uncoupling of the receptor from its intracellular effector systems, receptor internalisation and reduction in receptor synthesis. The timing of these events in human airway cells is uncertain.
      • Barnes P.J.
      Beta-adrenergic receptors and their regulation.
      It is possible that some of the reduction in salbutamol response in this study was due to residual occupancy of the beta-receptors by formoterol leaving fewer receptors available to bind to salbutamol. The responses were measured 24h after the last dose of formoterol. At this point there is still a small bronchodilator effect and therefore presumably receptor occupancy.
      • Rabe K.F.
      • Jorres R.
      • Nowak D.
      • Behr N.
      • Magnussen H.
      Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness over 24h in bronchial asthma.
      This may partly account for the greater tolerance found in this study than found by Jones et al.
      • Jones S.L.
      • Cowan J.O.
      • Flannery E.M.
      • Hancox R.J.
      • Herbison G.P.
      • Taylor D.R.
      Reversing acute bronchoconstriction in asthma the effect of bronchodilator tolerance after treatment with formoterol.
      who measured the salbutamol response 36h after 2 weeks of formoterol 12μg twice daily (29% reduction in AUC). Although it may have been preferable to measure responses 36h after the last dose of formoterol, we considered this to be too long an interruption in a study designed to look at the onset of tolerance during ‘continuous treatment’.
      Genetic polymorphisms in the beta2-receptor have been shown to influence receptor down-regulation in vitro

      Liggett SB. β2-adrenergic receptor pharmacogenetics. Am J Respir Crit Care Med 2000;S197–S201.

      and in theory these may affect susceptibility to beta-agonist tolerance. The clinical data on this are conflicting,
      • Tan S.
      • Hall I.P.
      • Dewar J.
      • Dow E.
      • Lipworth B.
      Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics.
      • Israel E.
      • Drazen J.M.
      • Liggett S.B.
      • et al.
      The effect of polymorphisms of the β2-adrenergic receptor on the response to regular use of albuterol in asthma.
      and a recent study found no difference in bronchodilator tolerance between subjects homozygous for either the Arg-16 or Gly-16 polymorphisms.
      • Lee D.K.C.
      • Jackson C.M.
      • Bates C.E.
      • Lipworth B.J.
      Cross tolerance to salbutamol occurs independently of β2 adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol.
      No studies have been performed looking at other polymorphisms. Although we observed a large variation in the degree of tolerance experienced by individuals in this study, every subject experienced some decline in salbutamol response. The minimum decrease in AUC was 36% at 2 weeks and the maximum decrease was a complete lack of salbutamol bronchodilation (100% decrease in AUC), which occurred in two subjects.
      Testing bronchodilation after bronchoconstriction may be seen as analogous to drug use by patients, where short acting beta-agonists are taken to relieve symptoms. It is of concern that the results show a mean loss of salbutamol bronchodilation of over 50% after 1 week of treatment. By this time much of the bronchoprotective effect of the long-acting beta-agonist had also been lost. Some subjects had very little response to 400μg of salbutamol. Wraight et al.
      • Wraight J.M.
      • Hancox R.J.
      • Herbison G.P.
      • Cowan J.O.
      • Flannery E.M.
      • Taylor D.R.
      Bronchodilator tolerance the impact of increasing bronchoconstriction.
      showed that tolerance increases with increasing degrees of bronchoconstriction. These patients could be at risk during an acute exacerbation of asthma if bronchoconstriction does not respond to conventional short-acting beta-agonist therapy.
      Given that a reduced response to salbutamol is evident after the first dose of formoterol, it seems impossible to avoid it by altering the dosing strategy. Patients taking long-acting beta-agonists need to be aware that their reliever inhaler may be less effective.

      Acknowledgments

      The authors would like to thank the study participants, Dr. J. McLachlan and the staff of the Waikato Hospital Respiratory Laboratory and Research Unit. The study was funded by the Respiratory Research Fund, Waikato Hospital.

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