All beta-2 agonists are prohibited by the World Anti-Doping Agency
(WADA, www.wada-ama.org). However, its use may be permitted in
athletes who are granted a therapeutic use exemption (TUE). [...]info:eu-repo/semantics/publishedVersio

Cardoso, Ana

Gama, Jorge M R

Lourenço, Olga

Marinho, Daniel

Mónico, Beatriz

Neiva, H.P.

English

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Cardoso, Ana Carolina Coelho

UBibliorum repositorio digital da ubi

Allergy. 2021;76:2201–2302.    |  2201wileyonlinelibrary.com/journal/all Received: 24 July 2020  |  Revised: 26 August 2020  |  Accepted: 31 August 2020DOI: 10.1111/all.14588  L E T T E R S  T O  T H E  E D I T O Rβ2-adrenergic agonists do not improve physical performance in healthy individualsTo the Editor,All beta-2 agonists are prohibited by the World Anti-Doping Agency (WADA, www.wada-ama.org). However, its use may be permitted in athletes who are granted a therapeutic use exemption (TUE).As the evidence remains controversial, there has been increasing debate on whether β2-agonists have the potential to improve phys-ical performance.1Therefore, this study aimed to systematically review the avail-able scientific evidence on the effect of β2-agonists on physical per-formance in healthy, nonasthmatic individuals.All randomized controlled studies, written in any language, were considered. A fixed or, when necessary, a random-effects me-ta-analysis was performed for two outcomes (VO2max and endurance time to exhaustion (TTE)), considering the study design, substance, © 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.F I G U R E  1   Forest plot representing the comparison of MD of VO2max between salbutamol, formoterol and placebo. The letters “a” and “b” following the author's name correspond to different studies by the same author published in the same year. The Roman numbering presented after the author's name corresponds to the same study, but different interventions (more than one β2-agonist or more than one dose)2202  |     LETTERS TO THE EDITORadministration and gender of the participants. The mean difference (MD) was used as an effect size measure. Publication bias was assessed using the funnel plot, Duval and Tweedie's trim and fill method, and Eger's regression test (See supporting information for details). The se-lection process of the studies included in the systematic review and meta-analysis is presented in Figure S1 of the supporting information.The fixed-effects meta-analysis studying the effect of β2-ag-onists on VO2max showed no significant effects of salbutamol vs placebo (MD = 0.284; P-value = .45), of formoterol vs. placebo (MD = 0.372; P-value = .71), and neither of overall β2-agonists vs. placebo (MD = 0.295; P-value = .40) (Figure 1). (For summary of meta-analysis, sensitivity analysis and evaluation of publication bias, see supporting information).Two fixed-effects meta-analyses were performed considering the different routes of administration of salbutamol. In the me-ta-analysis considering the effect of inhaled salbutamol on VO2max, no statistically significant effect was shown: MD = 0.323; 95% CI: (−0.47857; 1.123); P-value = .43. Similar results were obtained in the meta-analysis considering the effect of systemic salbutamol on VO2max: MD = 0.053; 95% CI: (−1.898; 2.003); P-value = .95. (For summary of meta-analysis, sensitivity analysis and evaluation of publication bias, see supporting information).To assess the effect of β2-agonists on TTE, three meta-analyses (fixed-effects, random-effects and mixed-effects) were performed, considering different percentages of VO2max: ≥100% VO2max, <100% VO2max and mixed-effects. In the fixed-effects meta-analysis that con-sidered endurance TTE ≥ 100% of VO2max, no statistically significant difference was found between β2-agonists and placebo (MD = −0.054; 95% CI: (−0.163; 0.054); P-value = .32). In the random-effects me-ta-analysis that considered endurance TTE < 100% of VO2max, the MD of endurance TTE between β2-agonists and placebo was not sig-nificantly different from zero (MD = 1.712; 95% CI: (−1.013; 4.437); P-value = .21) (Figure 2). (For summary of meta-analysis, sensitivity analysis and evaluation of publication bias, see supporting information).A fixed-effects meta-analysis was performed using the MD of en-durance TTE as an effect measure. No statistically significant difference was found between inhaled β2-agonists vs. placebo (MD = −0.057; 95% CI: (−0.165; 0.051); P-value = .30). However, the meta-analysis consid-ering the effect of oral β2-agonists on endurance TTE showed a statis-tically significant mean increase (MD = 6.029; 95% CI: (2.653; 9.385); P-value < .001). (For summary of meta-analysis, sensitivity analysis and evaluation of publication bias, see supporting information).Overall, the results reported here were consistent and showed that inhaled β2-agonists do not contribute to the physical perfor-mance improvement of healthy athletes. Previous studies have assessed the effect of β2-agonists vs. placebo in the changes of VO2max, having found that, regardless of the β2-agonist, there were no significant effects on physical performance.2,3 Moreover, inhaled salbutamol did not show a statistically significant effect on VO2max, even when administered at high doses.F I G U R E  2   Forest plot representing the comparison of MD of endurance time to exhaustion (TTE) between β2-agonists and placebo, considering different percentages of VO2max     |  2203LETTERS TO THE EDITORWhen comparing the effect of systemic (oral or IV) salbutamol on VO2max, it appears that this β2-agonist does not have a statistically sig-nificant effect. These results, despite being somewhat inconsistent due to the lack of studies, agree with other studies already performed.4,5Regarding inhaled β2-agonists’ effect on endurance TTE, no signif-icant effect was shown. However, when considering the oral route, the effect was statistically significant for salbutamol, which explains the prohibition of this route of administration for athletes granted a TUE.So far, the only systematic reviews and meta-analysis that as-sessed the effect of β2-agonists on physical performance are those described by Kinderman2 and Pluim.3 Both reviews are dated and considered only a fraction of the studies analysed in the present sys-tematic review, mainly focusing on competitive athletes.This systematic review and meta-analysis included all existing arti-cles which assessed the effect of β2-agonists on physical performance in nonasthmatic athletes and were published until 2018. However, only a few could be included in the meta-analysis, as the others did not present quantitative data. It is important to highlight that it was not possible to evaluate the individual results of the athletes. Additionally, we should be aware that VO2max measures do not represent a direct measure of physical performance. Nevertheless, it is considered a vari-able of physical fitness and training status of each individual.Concluding, the results obtained do not show any effects of this class of drugs on physical performance. Moreover, the exceptions currently allowed by WADA do not include any drug that could con-stitute a competitive advantage. However, further studies should be conducted to assess the effect of β2-agonists on physical perfor-mance in athletes with asthma or exercise-induced bronchospasm.KE Y WORDSdoping, performance, sport, β2-agonistsCONFLIC TS OF INTERE S TThe authors have no conflict of interest to declare.FUNDING INFORMATIONThis work is supported by national funding through the Portuguese Foundation for Science and Technology, IP, under projects UID/04045/2020 and UIDB/ 00709/2020.Ana Cardoso1Beatriz Mónico1Jorge M. R. Gama3Henrique P. Neiva4,5Daniel A. Marinho4,5Olga Lourenço1,21Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal2CICS - UBI Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal3Centre of Mathematics and Applications (CMA-UBI), University of Beira Interior, Covilhã, Portugal4Department of Sport Sciences, University of Beira Interior, Covilhã, Portugal5Research Center in Sports Sciences, Health Sciences and Human Development, CIDESD, Covilhã, PortugalCorrespondenceOlga Lourenço, CICS – UBI Health Sciences Research Centre, Avenida Infante D. Henrique, 6200-506 Covilhã, Portugal.Email: olga@fcsaude.ubi.ptORCIDJorge M. R. Gama  https://orcid.org/0000-0003-3926-580X Henrique P. Neiva  https://orcid.org/0000-0001-9283-312X Daniel A. Marinho  https://orcid.org/0000-0003-2351-3047 Olga Lourenço  https://orcid.org/0000-0002-8401-5976 R E FE R E N C E S 1. Allen H, Backhouse SH, Hull JH, Price OJ. Anti-doping policy, thera-peutic use exemption and medication use in athletes with asthma: a narrative review and critical appraisal of current regulations. Sports Med. 2019;49(5):659-668. 2. Kindermann W, Meyer T. Inhaled beta2 agonists and performance in competitive athletes. Br J Sports Med. 2006;40(Suppl 1):i43-i47. 3. Pluim BM, de Hon O, Staal JB, et al. beta(2)-Agonists and physical performance: a systematic review and meta-analysis of randomized controlled trials. Sports Med. 2011;41(1):39-57. 4. Violante B, Pellegrino R, Vinay C, Selleri R, Ghinamo G. Failure of ami-nophylline and salbutamol to improve respiratory muscle function and exercise tolerance in healthy humans. Respiration. 1989;55(4):227-236. 5. McKENZIE DC, Rhodes EC, Stirling DR, et al. Salbutamol and treadmill performance in non-atopic athletes. Med Sci Sports Exerc. 1983;15(6):520-522.SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.

β2-adrenergic agonists do not improve physical performance in healthy individuals

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β2-adrenergic agonists do not improve physical performance in healthy individuals

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