The Open Respiratory Medicine Journal




ISSN: 1874-3064 ― Volume 14, 2020

Daily Use of Salmeterol Causes Tolerance to Bronchodilation with Terbutaline in Asthmatic Subjects



Jimmi Elers*, Ulla Strandbygaard, Lars Pedersen, Vibeke Backer
Respiratory and Allergy Research Unit, Bispebjerg Hospital, Copenhagen, Denmark

Abstract

Background:

The purpose was to assess tolerance to terbutaline after daily use of long-acting β2- agonist (LABA) and further to evaluate two designs of reversibility test widely used in research and clinic in order to demonstrate tolerance.

Methods:

Twenty-eight asthmatics were given daily LABA in 12 weeks and were randomized to challenge test and either conventional reversibility test with 2 puffs terbutaline or reversibility test with refracted doses (1 puff) every 5 min, total 4 puffs. FEV1 was measured pre-challenge, post-challenge, during and after reversibility test. All subjects had 3 visits: baseline, after 4 weeks and after 12 weeks of LABA treatment. All subjects were non-smokers, aged 18–45 years and had a positive methacholine challenge.

Results:

The analyses showed a significant fall in reversibility after 4 and 12 weeks of LABA treatment (p=0.001) in the group with the conventional reversibility test. The group with reversibility test using refracted doses also showed a significant fall in reversibility after 4 weeks of LABA treatment (p=0.017) followed by a similar trend after 12 weeks (p=0.054), however, we experienced an interfering number of dropouts at the last visit.

Conclusion:

The bronchodilator response to terbutaline was significantly reduced in asthmatic subjects using daily LABA. The tolerance develops rapidly and is present after 4 weeks of treatment. Our study showed that both the conventional reversibility test and the reversibility test with refracted doses, combined with methacholine challenge is able to demonstrate tolerance to bronchodilator after daily use of LABA.

Keywords: Tolerance, tachyphylaxis, β-2-agonist, bronchodilator, asthma..


Article Information


Identifiers and Pagination:

Year: 2010
Volume: 4
First Page: 48
Last Page: 50
Publisher Id: TORMJ-4-48
DOI: 10.2174/1874306401004010048

Article History:

Received Date: 6/11/2009
Revision Received Date: 30/12/2009
Acceptance Date: 18/3/2010
Electronic publication date: 21/4/2010
Collection year: 2010

© Elers et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Respiratory and Allergy Research Unit, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400 København NV, Denmark; Tel: +45 35313569; Fax: +45 35312179; E-mail: jele0004@bbh.regionh.dk





INTRODUCTION

Long acting β-2-agonists (LABA) are used in management of moderate to severe persistent asthma to gain asthma control. It is used as add-on therapy to inhaled corticosteroids (ICS) [1Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary Eur Respir J 2008; 31: 143-78.], either as a fixed combination (FCICS/LABA) or in two devices, but LABA should never be used as a single drug due to the risk of serious adverse events in case of exacerbation [2Lazarus SC. Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial JAMA 2001; 20: 2583-93.]. Few studies, all with a low number of participants, have shown rapid and short lasting development of tolerance after regular use of LABA, few if any studies have shown long term development of tolerance, whereas other studies have shown significant disease control in those who had LABA added to their basic treatment with ICS [3Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establisning Therapy (FACET) International Study Group N Engl J Med 1997; 337: 1405-1.-6Hancox RJ, Taylor DR. Long-acting beta-agonist tratment in patients with persistent asthma already receiving inhaled corticosteroids Bio Drugs 2001; 15: 11-24.].

The purpose of the present study was to assess development of tolerance to terbutaline after short and long term regular use of salmeterol and to evaluate usefulness of two designs of reversibility tests in order to demonstrate this tolerance. Reduction in lung function was induced by a methacholine challenge test, followed by a conventional reversibility test with short acting β-2-agonist (SABA) inhaling 1 mg terbutaline and measurement of FEV1 before and 15 minutes after inhalation of terbutaline [7The Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma Web site [Internet]. USA: Global Strategy for Asthma Management and Prevention Available from www.ginasthma.org 2008.]. The conventional reversibility test is the most frequently used reversibility test in clinical work. Lastly, another designed reversibility test with SABA given in refracted doses followed by consecutive measurements of FEV1 5 minutes after each dose of SABA, giving a total response time of 20 minutes [8Haney S, Hancox RJ. Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial Respir Res 2005; 6: 107.]. Because, the reversibility test with refracted doses is used in research studies we wanted to assess this design as well.

MATERIAL AND METHODS

Volunteers who responded to an advertisement in a local newspaper were invited to a screening session with assessments of fractional exhaled NO (FeNO), spirometry, methacholine challenge test, and measurement of height/weight and skin prick test. Inclusion criteria were: 1) diagnosis of asthma based on a clinical history and symptoms; 2) age between 18 to 45 years; 3) a positive methacholine challenge test with PD20 ≤ 7.8 micromol. Exclusion criteria were: 1) other medical co-morbidities; 2) respiratory tract infections within 14 days before enrollment; 3) use of oral corticosteroids within the last 3 months and current smoking or history of smoking (more than 10 packyears).

Conventional reversibility test was performed with two puffs Terbutaline (total 1 mg as dry powder) immediately after the methacholine challenge with measurement of FEV1 after 15 minutes [7The Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma Web site [Internet]. USA: Global Strategy for Asthma Management and Prevention Available from www.ginasthma.org 2008.]. Reversibility test with refracted doses was performed with one puff Terbutaline (0.5 mg as dry powder) immediately after the methacholine challenge and one puff after 5, 10 and 15 minutes with measurement of FEV1 at 5, 10, 15 and 20 minutes after the challenge [6Hancox RJ, Taylor DR. Long-acting beta-agonist tratment in patients with persistent asthma already receiving inhaled corticosteroids Bio Drugs 2001; 15: 11-24., 8Haney S, Hancox RJ. Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial Respir Res 2005; 6: 107.].

The present survey was performed as a follow-up study with three visits at week 0 (visit 0), 4 (visit 1) and 12 (visit 2). All visits included interview, measurement of FeNO, lung function, methacholine challenge test, reversibility test and at visit 0 validated questionnaires (ACQ and MiniAQLQ) [9Juniper EF, O Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control Eur Respir J 1999; 14: 902-7.]. Subjects received 50 micrograms salmeterol twice daily. All subjects were instructed to start treatment at visit 0 (week 0) and not to take medicine 12 hours before visit 1 (week 4) and visit 2 (week 12). The study medication was salmeterol/fluticasone proprionate 50+250 microgram/dose (Advair Diskus®).

ANALYSIS

The main outcome was reversibility after methacholine challenge, expressed as the raise in FEV1 after 15 min at the conventional reversibility test and after 20 min at the reversibility test with refracted doses. Mean and standard deviations were calculated for the normally distributed data. Paired data were analyzed by paired T-tests. Values of p<0.05 were considered statistical significant and power was set to 80%. Sample size calculations were based on previous studies by using methacholine [6Hancox RJ, Taylor DR. Long-acting beta-agonist tratment in patients with persistent asthma already receiving inhaled corticosteroids Bio Drugs 2001; 15: 11-24.]. The Ethical Committee of Copenhagen, Denmark approved the study, no. H-C-2007-0132 and written informed consent was obtained from all participants before the first clinical examination.

RESULTS

After the screening session twenty-eight of 54 subjects were enrolled and randomized: 14 to conventional reversibility test and 14 to reversibility test with refracted doses. Seven dropouts were recorded during the study, 3 at four weeks, and 4 at 12 weeks.

Of 28 subjects randomized to the study, 13 subjects were men with 6 and 7 in each group. We found no baseline differences in mean (SD) between participants in the conventional and refracted group in age (32 (8) vs 30 (10) years respectively), FEV1 (3.50 L (0.97) vs 3.22 L (0.63) respectively), and FEV1/FVC (75% (8) vs 79% (10) respectively). None of the subjects in the group with conventional reversibility test used daily ICS, while 7 subjects in the group with reversibility test with refracted doses used daily ICS. At baseline ACQ median was 1.88 and miniAQLQ median 5.48 in conventional reversibility test group and ACQ median was 1.72 and miniAQLQ 5.69 in the group with reversibility test with refracted doses.

FeNO was 41.5 ppb (visit 0), 19.1 ppb (visit 1), and 21.7 ppb (visit 2) in conventional reversibility test group. In the group with reversibility test with refracted doses FeNO was 32.1 (visit 0), 21.2 (visit 1), and 21.3 (visit 2).

There was no significant clinical or statistical difference in pre-challenge mean (SD) FEV1 (L) between the visits within the groups: 3.50 (0.97), 3.67 (1.05), 3.78 (0.93) respectively in conventional reversibility test vs 3.22 (0.63), 3.16 (0.38), 3.19 (0.28) respectively in the reversibility test with refracted doses.

At the three visits the mean (SD) FEV1 (L) after bronchial challenge was 2.63 (0.72), 2.83 (0.80), 2.93 (0.76) respectively in the conventional reversibility test and 2.54 (0.48), 2.49 (0.42), 2.50 (0.36) respectively in reversibility test with refracted doses. This corresponds to a mean reduction in FEV1 during provocation of 0.87 L, 0.84 L, 0.85 L respectively in conventional reversibility test and 0.68 L, 0.67 L, 0.69 L respectively in reversibility with refracted doses, although receiving ICS treatment during a 12 weeks period.

In the group with conventional reversibility test there was a significant reduction in reversibility after methacholine challenge at visit 1 compared to visit 0, i.e. after regular treatment with LABA with the mean difference in FEV1 after reversibility 0.56 L with CI (0.26 – 0.85) (p = 0.001). The mean difference in FEV1 after reversibility at visit 2 compared to visit 0 was 0.61 L with CI (0.37 – 0.84) (p=0.001). If expressed as percentage of reduction in FEV1 after reversibility the mean difference between visit 1 and 0 was 21% with CI (10 – 32) (p=0.001) and between visit 2 and 0 was 24% with CI (12 – 36) (p=0.001).

We observed a significant reduction in reversibility with refracted doses after methacholine challenge at visit 1 compared to visit 0. Mean difference in FEV1 after reversibility was 0.26 L with CI (0.06 – 0.47) (p=0.017). There was no significant difference in reversibility at visit 2 compared to visit 0, however, we experienced an interfering numbers of dropouts at the last visit. Mean difference was 0.28 L with CI (-0.007 – 0.56) (p=0.054). During the study the two groups received identical medication. There is no explanation for the dropouts at the last visit in one group.

DISCUSSION

Our study has shown that regular use of salmeterol results in decreased response to terbutaline after methacholine challenge, i.e. tolerance to bronchodilator. This confirms previous findings by Hancox et al. [8Haney S, Hancox RJ. Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial Respir Res 2005; 6: 107.-10Haney S, Hancox RJ. Rapid onset of tolerance to beta-agonist bronchodilation Respir Med 2005; 99: 566-71.], whom found that eight asthmatics showed development of tolerance after one week of LABA treatment. The present findings show, that giving a combination of ICS and LABA does not protect towards development of decrease in lung function during provocation, and furthermore no protection of FCICS/LABA was found towards development of tolerance during a sufficient period of treatment of 4 and 12 weeks, which confirms previous findings [10Haney S, Hancox RJ. Rapid onset of tolerance to beta-agonist bronchodilation Respir Med 2005; 99: 566-71.].

The new perspective in evaluation of two types of reversibility test shows that the conventional reversibility test is a valid method to detect tolerance to LABA. The conventional reversibility test is widely used in the clinical work, whereas the method mostly used in research is reversibility test with refracted doses of SABA.

In conclusion, we found that asthmatic subjects on fixed combination of ICS and LABA are in risk of developing treatment resistant decrease in lung function.

ACKNOWLEDGEMENTS

We thank all the participants for taking part of this study. The study was supported by research grant from GlaxoSmithKline.

REFERENCES

[1] Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary Eur Respir J 2008; 31: 143-78.
[2] Lazarus SC. Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial JAMA 2001; 20: 2583-93.
[3] Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establisning Therapy (FACET) International Study Group N Engl J Med 1997; 337: 1405-1.
[4] Ni CM, Greenstone I, Danish A, et al. Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma Cochrane Database Syst Rev 2005. CD005535
[5] Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The gaining optimal asthma control study Am J Respir Crit Care Med 2004; 170: 836-44.
[6] Hancox RJ, Taylor DR. Long-acting beta-agonist tratment in patients with persistent asthma already receiving inhaled corticosteroids Bio Drugs 2001; 15: 11-24.
[7] The Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma Web site [Internet]. USA: Global Strategy for Asthma Management and Prevention Available from www.ginasthma.org 2008.
[8] Haney S, Hancox RJ. Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial Respir Res 2005; 6: 107.
[9] Juniper EF, O Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control Eur Respir J 1999; 14: 902-7.
[10] Haney S, Hancox RJ. Rapid onset of tolerance to beta-agonist bronchodilation Respir Med 2005; 99: 566-71.

Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents




Webmaster Contact: info@benthamopen.net
Copyright © 2020 Bentham Open