Introduction of inhaled salbutamol’s existence on the World-Anti-Doping

Introduction

 

Athletes are more susceptible to exercise-induced bronchoconstriction (EIB) than the general population (1). Roughly 8% of all competing Olympic athletes suffer from EIB, making it the most common medical condition among elite athletes.  Indeed, at the 2004 and 2008 Olympic Games, an average of 17% of cyclists and 25% of triathletes were approved by the International Olympic Committee to treat their asthma with inhaled adrenergic B2-agonists (IBAs) (2). Exercise acts as a trigger of EIB, due to the hyperpnoea associated with exercise, causing the narrowing of the airways. Therefore, endurance athletes are more at-risk due to the provocative nature of repeated hyperpnoea in unfriendly, irritant filled environments.

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

There are many pharmaceutical and non-pharmaceutical treatment strategies that exist for EIB. Short-acting B2-agonists and long-acting B2-agonists are used as preventive or acute treatments for EIB (3). Inhaled salbutamol, a short-acting B2-agonist, is the most common therapy used among elite athletes. However, elite athletes must be aware of inhaled salbutamol’s existence on the World-Anti-Doping Agency (WADA) prohibited list. In fact, more changes have been made to the status of inhaled salbutamol on the WADA prohibited list than to any other substance in the last 50 years (3).

IBAs, such as salbutamol, act on adrenergic B2-receptors which are distributed in the lungs, heart and skeletal muscles (2). IBAs relax the smooth muscles surrounding the airways, causing bronchodilation, increased heart rate and increased blood flow in the coronary and skeletal arteries. All these aid on relieving asthma symptoms, such as coughing, wheezing and chest tightness. Therefore, these agents act as powerful bronchodilators by decreasing obstructions in the airways (3); however, they also have the potential to affect physiological factors that can limit athletic performance. Due to this, all IBAs are on the WADA prohibited list, except inhaled salbutamol (Maximum: 1600 µg/day, without exceeding 800 µg in 12 hours), formoterol and salmeterol (3).

Interestingly, asthmatic athletes tend to be more successful at major sporting events compared to non-asthmatic athletes (4,5). In the 2008 Beijing Olympic Games, only 17% of the cyclists were asthmatic, but these athletes won 29% of the individual medals available (2). Several studies have investigated the potential performance-enhancing effects of IBAs in asthmatic and non-asthmatic athletes, but a mechanism to explain the differences in Olympic success between athletes with and without asthma remains unclear (2).

In non-asthmatic athletes, studies have found that IBAs have no effect on VO2max, anaerobic threshold, strength performance, blood lactate, peak power and rate of perceived exertion (RPE) even when supra-therapeutic doses of salbutamol were inhaled (6,7). However, the odd study has seen an improvement in endurance cycling performance when taking supra-therapeutic doses of salbutamol (8), indicating that this route of administration does not exclude the possibility of an ergogenic effect of IBAs.

Therefore, many studies have investigated the effect of IBAs on non-asthmatic, well-trained individuals, but it’s likely that the effects are more pronounced in participants who suffer from asthma given their impaired lung function (2). Hence, in 2013, a study from Koch et al (2) investigated the effect of inhaled salbutamol on lung function and time-trial performance in well-trained athletes with and without EIB.

 

 

 

 

 

 

 

What were the key findings?

 

The study screened seventy-five experienced male cyclists and triathletes between 19 and 40 years of age. The participants performed two simulated 10 km time-trials on a cycle ergometer 60 minutes after the inhalation of either 400 µg of salbutamol or a placebo (2). The performance outcomes measured included, mean power output relative to body weight, heart rate, oxygen consumption, tidal volume, minute ventilation, respiratory rate, dyspnoea and RPE.

Of the 75 athletes screened, only 49 athletes managed to complete the study. Of these 49 athletes, 14 were asthmatic and 35 were not (2). The results showed that thirty minutes after salbutamol-use, the mean forced expiratory volume (FEV1) increased by 4.7% compared to 2.9% after the inhalation of the placebo. The improvement in lung function due to salbutamol was significantly greater in the asthmatic athletes (7.0%) compared to non-asthmatic athletes (2.7%).

However, when focusing on the effect that salbutamol has on time-trial performance, mean power output after salbutamol-use was not significantly different from the mean power output produced in the placebo group. Indeed, the inhalation of salbutamol caused 18 athletes to increase mean power output by more than 1%, however 17 athletes had a decrease in mean power output by more than 1%. Furthermore, no correlation was found between fitness level, assessed VO2max on the screening day and the difference between mean power output between the two time-trials.

Salbutamol didn’t seem to affect fatigue in either of the two time-trials, as neither EVH+ or EVH- perceived a difference in RPE. Likewise, neither EVH+ or EVH- perceived a difference in dyspnoea during the two time-trials. Therefore, salbutamol did not affect time-trial performance in asthmatic athletes or non-asthmatic athletes despite seeing a significant improvement in FEV1. This study therefore, supports previous literature that demonstrated significant improvement in lung function after the inhalation of IBAs in non-asthmatic athletes without any effects on athletic performance (2).

As this study was the first of its kind, the findings on asthmatic athletes are novel. Athletes with asthma had a significantly greater bronchodilatory response to inhaled salbutamol, however, this greater response did not affect power output, exercise ventilation, RPE and dyspnoea during the time-trial.

 

How could the study have been improved?

 

There is limited data to suggest whether exercise performance is affected in athletes with no history of EIB. Performance can improve considerably when focusing on time-trials to exhaustion when asthmatic patients receive inhaled corticosteroids, which is largely due to an improvement in lung function and protection against bronchoconstriction (9). Therefore, it’s assumed that athletes with a positive hyperpnoea challenge will experience an improved endurance performance if they inhale salbutamol prior to exercise. However, this study reports that the inhalation of 400 µg salbutamol prior to a 10-km time-trial performance did not influence cycling performance in athletes with an EVH positive challenge (2). A possible limitation is that the 10-km time-trial was completed in laboratory conditions, which has been shown to be an environment that is not provocative for EIB and perhaps in a more provocative environment this study may have reported a performance detriment in EVH positively challenged athletes (1). Therefore, the study may have been improved by using an environmental chamber to decrease the humidity, due to dry air being more provocative to EIB (20). This would allow for a more provocative environment as the dry air would increase the burden on the lower airways in conditioning the inspired air, possibly increasing the benefit of inhaled salbutamol.

The effects of IBAs on athletic performance have been investigated in male athletes in multiple studies, however, despite sex-based pulmonary anatomical differences causing differing respiratory responses to exercise (3), highly trained female participants have been overlooked. Women on average have smaller lung sizes, lung volumes, maximal expiratory flow rates and decreased diffusion surfaces (3).  Therefore, due to these anatomical differences, female athletes may benefit more from the use of IBAs compared to male athletes; thus, IBAs could lead to greater relative improvements in FEV1 and athletic performance. Consequently, the findings from the current study should not be generalised to female athletes. Future studies should focus on the effects of IBAs on female athletes to see if the findings of this current study can be applied to women.

Whilst there were no differences in the performance parameters between the two time-trials, the study could have been improved by adding a familiarisation time-trial. Adding a familiarisation time-trial would allow for the learning effect, typically sufficient pacing information is gained from the first time-trial to enable participants to adopt an appropriate pacing strategy in the subsequent trials (10,11). Also, feedback such as distances, cadences and gears were visible to the athlete during the 10-km time-trial. It has been seen that different pacing strategies can emerge depending on the sources of information available to the athletes (12). Therefore, the negative results may be due to athletes concentrating on a consistent pacing strategy rather than seeing no effect of inhaled salbutamol. 

The methodology could have been improved by adding a power calculation. Power analysis can be used to calculate the minimum sample size required so that a given effect size can be detected. The power calculation can also calculate what percentage is required to see a significant improvement in performance. Furthermore, the study does not comment on whether a warm-up was present. Including a warm-up comes with benefits and limitations, a warm-up will allow the athletes to cycle at their maximal time-trial performance but also may induce a refractory period during the time-trial and bronchoconstriction may not be evident for this reason.

Another limitation is the relatively low number of EVH+ cyclists compares to EVH- cyclists. However, the ergogenic effect of inhaled salbutamol on 10-km time-trial performance was independent of EVH status. Indeed, both EVH- and EVH+ athletes presented similar performance increases and decreases. Therefore, while adding more EVH+ cyclists would increase the power and reliability of the study, the results would most likely have remained the same

Therefore, whilst the results of Koch et al (2) are novel, the study does come with some limitations. This study would have benefited from experimenting with an environmental chamber to allow for a more provocative environment for EIB and by using female athletes to focus on whether inhaled salbutamol would have a greater effect due to the differences in pulmonary anatomy. Future studies should take these limitations into consideration.

 

Does salbutamol make a difference at all?

 

There is no compelling evidence that salbutamol and other IBAs can increase performance in healthy athletes (1,2,3,6,7,13,14,18,19). However, in spite of this, salbutamol required a “declaration of use in accordance with the International Standard for Therapeutic Use Exemptions” under the 2010 WADA Prohibited List, which has since been relaxed in the 2011 edition to a maximum use of 1600 µg over 24 hours when taking by inhalation. Whilst Koch et al (2) focused on a therapeutic dose of 400 µg, recent studies have since been concentrating on a supra-therapeutic dose up to the maximum threshold of 1600 µg.

Even though there doesn’t seem to be an ergogenic effect for salbutamol at low or moderate doses (1,2), there is potential for the maximally allowed daily dose of 1600 µg of inhaled salbutamol to be ergogenic in elite athletes (3). Dickinson et al (13) investigated the impact of the acute inhalation of 1600 µg on endurance running performance and reported that despite an increase in VE of 10 L/min at every kilometre over a 5-km cycling time-trial, inhalation did not lead to an improvement in running performance. Furthermore, only a limited number of studies have examined the salbutamol elimination in urine of inhaled doses as high as 1600 µg and have reported urine concentrations close to the WADA upper limit of 1000 ng.ml-1 (13). This study demonstrated the possibility of a urinary salbutamol concentration above the threshold of 1000 ng.ml-1. However, whilst the WADA prohibited list threshold is 1000 ng.ml-1, salbutamol should only be reported as an adverse analytical finding (AAF) when detected at a concentration greater than 1200 ng.ml-1 (13). Therefore, on this basis, this study would not warrant any sample to be reported as an AAF.

In a second study by Dickinson et al (14) investigating the ergogenic effect of long-term use of high dosage salbutamol, found that inhaling 1600 ?g daily over 6 weeks does not result in significant improvements in peak oxygen consumption, 3-km running performance or a one-repetition maximum for bench and leg press (14). To what extent these results from Dickinson et al (13,14) can be extrapolated to elite athletes is debatable due to a small sample size (n = 7) (13), low cardiovascular fitness levels (13,14) and a heterogeneous athletic background of the participants (14). In contrast to these findings, are the results from a study combining maximal doses of multiple IBAs in swimmers with and without airway hyperresponsiveness (15). Swim ergometer sprint performance and MVC was significantly improved after the inhalation of 1600 µg salbutamol, 200 µg salmeterol and 36 µg formoterol, regardless of airway hyperresponsiveness. In addition, a study investigating the inhalation of an acute salbutamol dose following a quadriceps fatigue test showed that an intermediate dose (800 ?g) of salbutamol induced a significant improvement in quadricep endurance despite similar amounts of fatigue and had a positive effect regarding the capacity to maintain intermittent isometric contractions (16). Other inhaled B2-agonists, such as terbutaline, have also shown a significant increase in maximal voluntary contraction, which has led to an enhancement in muscle strength and sprint performance (17).

Therefore, while there does not seem to be an ergogenic effect with inhaled doses at low or moderate doses, there is potential for a high, supra-therapeutic dose to have an ergogenic effect on athletic performance. Furthermore, it’s unclear if there is a relationship between the relative IBA dose and ergogenic potential (3). The maximum allowed daily use of IBAs are not normalised by body mass in the WADA guidelines, therefore a lighter athlete may benefit more from a greater IBA dose per kg than a heavier athlete, however, a lighter athlete may also be at a greater risk of breaching the maximum threshold when administering high doses compared to a heavier athlete

While a few studies have showed a possible ergogenic effect when inhaling the maximum amount of salbutamol, other studies, show no ergogenic effect. Koch et al (18) continued from their previous study, but focusing on the impact that a supra-therapeutic dose had on 10-km time-trial performance. Trained male cyclists with and without EIB were analysed and found that the inhalation of 1600 ?g salbutamol improved FEV1 regardless of EVH status but did not improve 10-km time trial performance regardless of relative dose per kilogram of body weight or EVH status (18).  Later that same year, Koch et al (19) focused on how inhaled salbutamol affected female athletes with and without EIB, to allow the present study and their two previous to be applied to women. Much like their study in 2013, participants performed a simulated 10-km cycling time-trial after the inhalation of either 400 ?g or placebo. Despite a significant increase in lung function after the inhalation of salbutamol in female athletes, mean power output maintained over the duration of the time-trial was significantly reduced. This is the first study to report an increase in lung function after IBA use with a decrease in athletic performance (19). This reduction in mean power output represents a potential ergolytic effect of salbutamol on female athletes and could be explained by an overstimulation of the adrenergic B2-agonist system impairing athletic performance (3). Therefore, this suggests that despite sex differences in pulmonary anatomy, the inhalation of 400 ?g salbutamol does not increase cycling time-trial performance in men or women.

However, much like their previous two studies, this study was also performed in laboratory conditions, and therefore still has similar limitations. Due to this, Molphy et al (1) investigated the effect that 400 ?g of inhaled salbutamol on 3-km running time-trial performance in an EIB provocative environment, in line with the notion that dry air is more provocative for EIB (20). Despite significantly increased heart rate and FEV1, the administration of 400 ?g of inhaled salbutamol did not improve 3-km time-trial performance in athletes who do or do not suffer from EIB. While in general higher doses of inhaled salbutamol have shown no improvements in athletic performance, a reason for not seeing an ergogenic effect in this study could be due to the comparatively small doses used. There also remains the possibility that performance improvements may not have been seen because this study solely focused on endurance performance. Recent studies have indicated that inhaled B2-agonists may enhance strength and power performance rather than endurance performance (15,17).

 

Recommendations and conclusions

 

Oral B2-agonists administration in humans has substantial effects on muscle function (21) and exercise performance (22). Doses of inhaled B2-agonists of salbutamol, however, are more than 20 times smaller (100 ?g/puff) than oral (2 mg per pill up to 12-20 mg/day) (16) doses. In general, most studies having tested the effect of inhalation of therapeutic (400 ?g), intermediate (800 ?g) or even supra-therapeutic (1600 ?g) doses of salbutamol on exercise performance revealed no ergogenic effect.

These findings suggest that the current WADA guidelines, which allows athletes to inhale up to 1600 ?g is sufficient to avoid pharmaceutical enhancement during athletic competition. However, a dose of 1600 ?g suggests poor management of asthma and increases the risk of an athlete violating the current maximum threshold (13).

In conclusion, previous studies, such as Koch et al (2), have showed that small therapeutic doses of inhaled salbutamol have no effect on athletic performance, however, the odd study has found that a possible ergogenic effect of inhaled salbutamol at the maximum dose. Therefore, while the current WADA guidelines are sufficient, inhaled salbutamol at the maximum dose should continue to be monitored, especially during strength and power performances.