β-2 Agonists in sport: are the anti-doping rules meeting the needs of asthmatic athletes?
- Correspondence to José Naranjo Orellana, Centro Andaluz de Medicina del Deporte, Glorieta Beatriz Manchón s/n, 41092 Sevilla, Spain;
Contributors Both authors had a substantial contribution to conception, design, analysis and interpretation of data as well as drafting the article and revising it critically. Both authors give final approval of the version to be published.
- Accepted 4 November 2009
- Published Online First 2 December 2009
Objectives (a) To review the methacholine tests performed in our laboratory up until 2008; (b) to compare them with previously reported data in 2006 and (c) to examine if the anti-doping rules are meeting the needs of asthmatic athletes who really need bronchodilator treatment.
Methods Between April 2004 and September 2008, 89 high-level athletes were examined in our laboratory in order to obtain an abbreviated therapeutic use exemption for β-2 agonists. Of these, 50 men (23.31 (7.05) years) and 23 women (20.68 (5.94) years) performed a methacholine inhalation test with increasing concentrations of methacholine (0.025, 0.25, 2.5, 5, 10 and 25 mg/ml) until a fall of 20% in forced expiratory volume in 1 s (FEV1) was achieved.
Results 31 candidates (42.5%) had a provocative concentration causing a 20% fall in FEV1 (PC20) <2 mg/ml; 12 (16.4%) were between 2 and 4 mg/ml; 8 (11%) between 4.1 and 8 mg/ml and 22 candidates (30.1%) had a PC20 >8 mg/ml. Seven of the 73 candidates had an obstructive pattern in the spirometry at rest, demonstrated by a FEV1% <70% but with a FEV1 >70% of the reference value.
Conclusions The anti-doping regulations with respect to β-2 agonists need to be reviewed, and measures should be adopted to include a fall of 70% in FEV1% as an obstruction criterion to indicate a bronchodilation test and to extend the criterion for a positive methacholine test to a PC20 of 8 mg/ml.
β-2 Agonists bronchodilators (salbutamol, salmeterol, formoterol and terbutaline), as well as inhaled corticoids, are prohibited in sports unless the participant follows the procedure known as Therapeutic Use Exemption (TUE).1,–,4
An abbreviated form (ATUE) was accepted until December 2008, but a revised version of International Standard for TUE (approved by the World Anti-Doping Agency (WADA) Executive Committee on 10 May 2008) came into effect on 1 January 2009. In this version, the concept of an ATUE has been abolished.5 With the abbreviated form, the athlete could start (or continue) the treatment while the formal process was in progress (taking into account that this process used to be very long), while with the standard form, treatment can only start after receiving the authorisation notice.
It is the International Olympic Committee Medical Commission who established the criteria for accepting the use of inhaled β-2 agonists late in 2001 for the Salt Lake City Winter Olympic Games. Due to the success of its application,6 these criteria were renewed in January 2004 for the Athens Summer Olympic Games and assumed by WADA. These criteria require an athlete to prove the existence of bronchial hyper-responsiveness and the measures of forced expiratory volume in 1 s (FEV1) at rest, as well as changes in FEV1 in response to either an inhaled bronchodilator or to a bronchial provocation test. These are the essential criteria that must be completed on the TUE form for β-2 agonists.7
Various bronchial provocation tests may be used: (a) eucapnic voluntary hyperpnea, (b) exercise (in the laboratory or in the field), (c) hyperosmolar aerosols (ie, 4.5 g% saline) and (d) methacholine inhalation.
We published a paper in 20068 where 21 methacholine tests performed in our laboratory (from April 2004 to April 2005) were analysed, and we demonstrated that a third of the sports population (33.3%) were considered negative for anti-doping control, but they would be positive in any respiratory service if they were not athletes. The reason was that the provocative concentration causing a 20% fall in FEV1 (PC20) demanded in 2005 for a positive methacholine test in sportspeople was 4 mg/ml for Olympic Games6 or 2 mg/ml in Spain when it was 8 mg/ml for the general population.
Although objective measures of airway function may be useful to prevent the non-indicated use of asthma drugs,9 we should be careful with the existence of differences with clinical criteria for the general population, which could be prejudicial to asthmatic athletes who need treatment with β-2 agonists.
The aim of this study was: (a) to review the methacholine tests performed in the Exercise Physiology Laboratory of the Centro Andaluz de Medicina del Deporte (Seville, Spain) from April 2004 to September 2008; (b) to compare them with the previously reported data in 20068 and (c) to clarify if the anti-doping rules are meeting the needs of asthmatics who really need bronchodilator treatment.
Material and methods
Between April 2004 and September 2008, a total of 89 high-level athletes with a previous diagnosis of asthma were examined in our laboratory in order to obtain an ATUE for β-2 agonists. Between them, 73 (50 men and 23 women) performed a methacholine test to assess the existence of bronchial hyperresponsiveness. The age of men (table 1) was 23.3 (7.1) and the age of women (table 2) was 20.7 (5.9). The sports varied, but the most common were athletics (n=13), swimming (n=17) and rowing (n=14).
All the 89 participants underwent a spirometry at rest, and if FEV1 was <70% of the reference value, a bronchodilation test was performed. This test was considered positive when an improvement of over 12% in FEV1 was found 30 min after the administration of two inhaled doses of salbutamol.
If the spirometry at rest was normal (or the bronchodilation test was negative), a bronchial provocation test was carried out. Eight participants had a positive bronchodilation test, six a positive exercise test and two a positive hyperosmolar aerosol test.
The other 73 participants underwent a methacholine test inhaling progressive doses of methacholine (Provocholine). The inhalation started with saline solution followed by increasing concentrations of methacholine (0.025, 0.25, 2.5, 5, 10 and 25 mg/ml) until a fall of 20% in FEV1 was achieved. These inhalations were performed using an ultrasonic nebulizer Hico-Ultrasonat 806E (Hirtz & Co, Cologne, Germany) according to the regulations and recommendations of the Spanish Society of Respiratory Medicine and Thoracic Surgery (SEPAR).10
All the participants in this study had had a previous diagnosis of asthma made either in a Respiratory Medicine or Allergy Service.
Following the recommendations to provide the optimal circumstances, some medications were stopped prior to the test: short-acting bronchodilators, sodium cromoglycate, nedocromil sodium and ipatropium bromide for 8 h; long-acting bronchodilators, inhaled steroids and antihistamines for 48 h and leukotriene antagonists for 4 days.
All the participants gave written and informed consent, and the study was approved by the ethics committee of the Centro Andaluz de Medicina del Deporte.
As shown in table 3, 31 participants (42.5%) had a PC20 <2 mg/ml; 12 (16.4%) were between 2 and 4 mg/ml; 8 (11%) between 4.1 and 8 mg/ml and 22 participants (30.1%) had a PC20 >8 mg/ml.
Seven of the 73 participants who underwent a methacholine test (four men and three women) had an obstructive pattern in the spirometry at rest, shown as a FEV1% <70% (table 4), but they did not qualify for a bronchodilator test because FEV1 was >70% of the reference value.
The first problem is still the criterion required for the diagnosis of airway obstruction. In clinical practice, the main criterion to assess an airflow obstruction in the spirometry at rest is a reduction in FEV1%11,–,13 in such a way that an index under 70% is an indication for a bronchodilation test by administering a β-2 agonist.
This is now accepted by WADA in the document with medical information to support the decisions of TUEs for asthma.14 However, such a possibility does not exist for athletes in the Spanish anti-doping rules, and it is not clear enough in the IOC Guidelines,15 as the only criterion for a bronchodilation test is a fall in FEV1. The spirometric values for athletes are very often as much as 120% over those for the general population. However, if their FEV1 is assessed in relation to their own forced vital capacity (which is what FEV1% measures), an airway obstruction may become evident.
We observed this situation for a total of seven athletes (table 4), and it was an ethical dilemma for us: to carry out a provocation test (in order to formalise the ATUE) knowing full well that there is an airflow obstruction, or to renounce the use of drugs which represent the basis of treatment under any scheme.16,–,18
This situation was also shown in our previous paper in 2006,8 but now, it is recognised by WADA in the document with medical information to support the decisions of TUEs for asthma14: “Many elite athletes have levels of lung function outside normal predicted values and therefore normal lung function could be a sign of airway obstruction”. For this reason, this document recommends that “a carefully kept peak flow diary should be established to allow the clinician to chart a patient over time”. However, IOC Guidelines for Beijing 200815 prohibited the use of peak flow as a measure of airway obstruction.
The next problem is again in the methacholine test.
Nowadays, criteria are less strict, but in 2005, the PC20 demanded that a positive methacholine test in athletes was 2 mg/ml when it was 8 mg/ml for the general population. According to the recommendations made by the SEPAR,10 it is considered to be positive whenever a fall of 20% occurs in FEV1 with a methacholine concentration <8 mg/ml. The response may be classified as: light (between 2 and 8), moderate (between 0.5 and 2) and serious (under 0.5). Similar criteria are recommended by the American Thoracic Society (ATS).19
When only those tests <2 mg/ml were considered positive for ATUE purposes, a situation of inequality arose in the treatment of athletes who present a positive test with a PC20 between 2 and 8 mg/ml.8 If they were not athletes, they would be classified as having bronchial hyperresponsiveness, and according to the treatment guidelines,14,–,16 they should be treated with β-2 agonists.
Fortunately, these criteria are changing, and nowadays, they are approaching the general population figures (>8 mg/ml in several anti-doping regulations, eg, in Spain). However, the guidelines for the Olympic Games in Beijing 200815 insisted on 4 mg/ml as the PC20 level. With this criterion, we can see in table 3 that 11% of our athletes would not be allowed to be treated with β-2 agonists.
Even more, in accordance with the ATS guidelines for methacholine tests,19 even a PD20 of 16 mg/ml can be positive, depending on the diagnostic pretest probability, because one cannot forget that asthma is a clinical diagnosis. This approach is very interesting because in our experience, athletes do not come to our laboratory looking for a diagnosis; they come with a true diagnosis done by a pulmonary physician or an allergologist, and they are only looking for the test which allows them to take the medication. So, we are starting with a pre-test probability close to 100%, and in this situation, any positive value for the test does confirm the diagnosis!
Another problem arises with the new standard for TUE. The elimination of the abbreviated form will affect the therapeutic use of β-2 agonists because it is at the discretion of the anti-doping organisations either to deliver a TUE prior to the event or to provide a retroactive TUE in case of an adverse analytical finding. The exception are athletes who are part of an international registered testing pool (RTP) who need an approved Standard TUE for asthma prior to using the substance. The problem is that most elite athletes are part of a RTP.
For the rest of the athletes, if the option chosen by the relevant anti-doping organisation or international federation is to provide a retroactive TUE, it may mean a simplification in the procedure. However, the other option (a prior TUE) will complicate the treatment of asthmatic sportspeople even more.
These aspects are, in our opinion, a serious discrimination against the asthmatic athletes as far as treatment is concerned. Currently, it is known that inhaled β-2 agonists have no ergogenic effects at therapeutic doses,20 and this is accepted by the IOC's Consensus Conference21: “Inhaled β2-agonists are not considered to enhance endurance performance, although oral salbutamol does increase strength.”
On the other hand, this Consensus Conference, too, concludes that “the percentage of β2-agonists notified/approved over three Summer Games, 1996 to 2004, for each country closely correlates with the reported prevalence of asthma symptoms in the International Study on Asthma and Allergies in Childhood (ISAAC) study and the European Community Respiratory Health Survey”21.
Even more, the statistics of the Spanish Anti-Doping Control Laboratory since 200222 show that the number of positive findings for β-2 agonists remain relatively constant although the total positives change widely (ranging from 121 to 289).
There is enough evidence to show that: (a) β-2 agonists are the first option for the treatment of asthma23; (b) inhaled β-2 agonists do not enhance endurance performance, and oral salbutamol is distinguishable from inhaled20 23; (c) the percentage of β-2 agonists notified or approved for each country closely correlates with the reported prevalence of asthma21 and (d) the number of positive findings for β-2 agonists seems to remain relatively constant over a period of time.22
In spite of this, the IOC Consensus21 recommends continuation of the strict control of the use of these drugs in sports to protect the health of the athletes, “because of the widespread use and potential for misuse of inhaled β2 agonists by athletes”, although they accept that the treatment of asthma in athletes should follow the guidelines for non-athletes.
The questions are: Why do we continue with different management for asthmatic athletes? Why do we insist on more demanding diagnosis for asthmatic athletes than asthmatics in the general population?
The control of asthmatic athletes is very strict. It requires proving the existence of a bronchial hyper-responsiveness to notify it to the relevant organisation and to wait for the answer before starting the treatment. If we compare this situation to non-athlete asthmatic patients, they do not have to prove bronchial hyper-responsiveness because asthma is a clinical diagnosis, and any complementary test is at the discretion of the physician; they do not have to notify it to anyone and moreover to wait for any authorisation before starting treatment.
In our opinion, the current situation is discriminatory for athletes compared to the rest of asthmatic patients.
The changes in the anti-doping rules are not meeting the needs of asthmatic athletes. So, we have to maintain the same conclusions than in 2006.
In our opinion, it is not justified that the bronchial obstruction criteria are different if the patient is an athlete. We think that these aspects of the anti-doping regulations must be reviewed, and measures should be adopted to include a fall of 70% in FEV1% as an obstruction criterion in order to indicate a bronchodilation test and to extend the criterion for a positive methacholine test to a PC20 of 8 mg/ml.
While this paper was being processed, the WADA has published in its website (http://www.wada-ama.org) the new 2010 list of prohibited substances, and methods with the innovation that β-2 agonists (salbutamol and salmeterol) no longer need a TUE. The therapeutic use of inhaled salbutamol and salmeterol will not be prohibited from 1 January 2010. Only if the urinary concentration of salbutamol is >1000 ng/ml will there be a presumption that the substance was not taken by inhalation. We are very glad about this decision, and we hope that IOC assumes this criterion for Olympic Games.
What is already known on this topic
The use of β-2 agonist bronchodilators is forbidden unless the participant follows the procedure known as Therapeutic Use Exemption (TUE). This procedure requires proving the existence of bronchial hyper-responsiveness at rest or after a provocation test with effort, eucapnic voluntary hyperpnea test, inhalation of hypertonic aerosol or a methacholine test.
What this study adds
Although the non-indicated use of asthma drugs could be forbidden, it is not justified that the bronchial obstruction criteria are different if the patient is an athlete. This study adds new cases to the situation reported in 2004 supporting the need of changes in anti-doping regulations.
Authors thank Dr. R A Centeno, Dr. J D Beas, Dr. J Alonso, Mrs. F Peña, Mrs. E Sánchez and Mr. M de la Osa for their contribution in the indication, supervision and technical execution of the different tests. We are very grateful to Mrs. Joanne Heathcote for checking the English of the manuscript.
Competing interests None.
Ethics approval This study was conducted with the approval of the Ethics Committee of Centro Andaluz de Medicina del Deporte.
Provenance and peer review Not commissioned; not externally peer reviewed.