Exercise-induced asthma is a common entity in high-performance sports. There are a number of nonpharmaceutical methods used in the treatment of this disease, but virtually all athletes require some form of medication in order to compete. The International Olympic Committee (I.O.C.) has sanctioned the use of several antiasthmatic medications for use by athletes with this disorder. The issue of specific inhaled bronchodilators as ergogenic aids in athletes without asthma has been addressed (22,23,24).
Formoterol, as a long-acting β2-agonist, has a role in the management of athletes with asthma and reactive airway disease. In combination with an inhaled corticosteroid, there appears to be a need for a long-acting bronchodilator in this population of elite athletes (17). Before acceptance for use in this population, the question of possible performance-enhancing properties of this medication needs to be investigated.
In regard to formoterol, the issue of performance enhancement has two implications. Banning its use unnecessarily would likely preclude some asthmatics from participation in competitive sport, as the therapeutic efficiency of formoterol has been shown to be equal to or greater than that of salbutamol, fenoterol, and terbutaline (1). Also, if it was found to have a performance-enhancing effect, it would be at risk of becoming an abused medication. Therefore, the purpose of this study was to determine the effect of formoterol, administered in a therapeutic dose before exercise, on the aerobic and anaerobic performances of highly trained athletes.
Subjects reported to the laboratory on five occasions. On the first occasion, anthropometric measures were taken, pulmonary function assessed, and maximal oxygen uptake (V̇O2max) for each subject measured using an incremental cycle ergometer test. The second session involved measurement of diffusion capacity and a methacholine challenge test. In each of the remaining three sessions, a similar protocol was followed (Fig. 1). Each trial consisted of height and body mass evaluation followed by administration of formoterol, salbutamol, or placebo. A Wingate anaerobic cycle test and a maximal aerobic cycle test were then performed. This study was conducted using a double-blind, randomized, three-way crossover design.
Ten highly trained male athletes were recruited. The subjects had a mean age of 26.2 yr (range 20–30), mean height (± SEM) of 180.0 ± 2.8 cm, and mean weight of 73.8 ± 3.0 kg. No subject was on any medication, and none had a history of asthma. Cardiopulmonary physical examination was normal in all subjects, and no subject had a fall > 20% in FEV1 from baseline with a methacholine dose of ≤16 mg·mL−1. All subjects had normal pulmonary function (Table 1). There were no adverse effects of the medication administered as part of the experimental protocol, nor was any subject excluded on the basis of abnormal pulmonary function. Written informed consent was obtained from all subjects before participation. The experiment was approved by the University of British Columbia Committee on Human Experimentation.
An initial session was used to measure height and body mass and to screen the potential subjects for healthy pulmonary function and adequate aerobic capacity (subjects V̇O2max must have been greater than 60 mL·kg−1·min−1 or 5 L·min−1). After height and body mass were recorded, each subject had his pulmonary function measured. This consisted of a flow-volume loop using a Medical Graphics CPX-D Metabolic cart (St. Paul, MN) with 1070 Pulmonary Function Software. Calibration was performed before each session. After familiarization with this procedure, the subject performed three trials in a standing position, and the data from the trial with the highest forced expiratory volume in 1 s (FEV1) was recorded. The trial was considered valid if the value was greater than 90% of the predicted value and was reproducible.
The maximal aerobic power test was conducted on an electronically braked cycle ergometer (Quinton Excalibur, Lode, Groningen, Netherlands) utilizing a 30 W·min−1 incremental protocol. Expired gases were collected and analyzed using Ametek analyzers (Cambridge, UK) every 15 s and ventilation by a flow transducer (Flo-1B, Physio-Dyne Fitness Instrument Technologies, Quogue, NY). Oxygen consumption (V̇O2), minute ventilation (V̇E), production of carbon dioxide (V̇CO2), and respiratory exchange ratio were all measured. Heart rate was measured by telemetry (Polar Vantage XL, Kempele, Finland) and recorded every 15 s. Standard indicators for achieving V̇O2max were used: volitional fatigue, a plateau in V̇O2 with increasing work rate, heart rate ≥ 90% of age predicted maximum, and a respiratory exchange ratio ≥ 1.15. Once three of the preceding criteria were met values for maximal V̇O2max, V̇E and RER were determined by calculating the average of the four greatest consecutive 15-s values.
The second session involved a measurement of diffusion capacity and a methacholine challenge test. Diffusion capacity was used as a descriptive measure and was determined by the single-breath method (25) on a Collins DSII Pulmonary Function Testing System. The subject was required to make a maximal inspiration from residual volume of a gas mixture containing 20.9% O2, 9.7% helium, and 0.3% carbon monoxide (CO), balanced with nitrogen. Subjects were instructed to hold their breath for 10 s and then maximally and rapidly expire. The expired breath was analyzed for CO. Diffusing capacity was then calculated, using the method of Ogilvie et al. (25), by subtracting the expired fraction from the inspired fraction of CO. Two measurements were taken separated by 5 min to ensure elimination of the test gas from the lungs. If both tests were not within 10%, a third test was performed.
A methacholine challenge test was used to screen each potential subject for bronchial reactivity. Only individuals with minimal bronchial reactivity to aerosols (indicated by a negative methacholine challenge test result) were permitted to participate as subjects in this study. After a baseline FEV1 was established with saline, methacholine was inhaled in doubling concentrations (0.125, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 16.0 mg·mL−1) every 5 min (18). Aerosols were administered using a Wright nebulizer attached to a face mask, calibrated to deliver the aerosols at a rate of 7.0 L·min−1. Aerosols were inhaled for periods of 2 min followed by 30- and 90-s FEV1 determinations. The test was continued until one of the following test termination criteria was achieved: 1) a 20% reduction in FEV1 (PC20), 2) a methacholine concentration of 16.0 mg·mL−1, or 3) the onset of respiratory symptoms that prevented the subject from continuing. A negative methacholine challenge test was determined by having a PC20 > 16 mg·mL−1.
Anaerobic and aerobic maximal performance tests were conducted on each of the testing days under the three experimental conditions, formoterol, salbutamol, and placebo. The subjects were requested to not perform any exhaustive exercise 24 h before the laboratory visit. The testing sessions were separated by at least 1 wk.
For each testing session, the subjects took two puffs from two coded dry powder inhalers (Turbuhaler; AstraZeneca, Wilmington, DE), for a total of four puffs of either formoterol (12 μg), salbutamol (400 μg), or placebo (no active medication). The Turbuhalers were individually (randomly) coded, thereby blinding both the subject and the investigator as to their contents. Because the subjects were not accustomed to using the Turbuhaler, detailed instruction was given and a practice Turbuhaler, with no medication, was provided to ensure optimal delivery of the substance and to lessen the learning effect common with the use of inhalers.
Upon arrival, each subject had his height and weight recorded. The subject then took four inhalations from the Turbuhalers as detailed above. After at least 10 min, the subject performed a 30-s Wingate anaerobic power test. It was conducted using a Monarch cycle ergometer linked to an IBM-XT computer loaded with Labtech Notebook data acquisition software. The subjects were permitted a warm-up after the medication was taken. The workload (Kp) was calculated by multiplying the subjects body mass (kg) by 0.075. This value was rounded down to the next lowest 0.5 Kp level. As the subject increased the revolutions, the load was abruptly added and time started. The total work (J) and 5-s average of peak power (W·kg−1) were calculated from the raw data with the software program.
After the Wingate test, the subject was allowed at least 15 min before the maximal aerobic test, which was conducted in an identical manner to the screening V̇O2max test.
The dependent variables of V̇O2max, peak power, maximum heart rate, V̇E, RER, Wingate fatigue index, Wingate total work, and peak power were analyzed with repeated-measures ANOVA. An a priori power calculation, setting α = 0.05 and determining a physiologically significant difference of 5% in the aerobic and anaerobic capacity measurements of a homogenous group of subjects, indicated that 10 subjects would give a statistical power of 0.95 (26).
There were no significant differences between groups in V̇O2max (Fig. 2;Table 2) or Wingate peak power (Fig. 3;Table 2). No differences were observed in maximum ventilation, respiratory exchange ratio, heart rate, or work, between the three drug conditions during the maximal aerobic test (Table 2). There were also no differences in the Wingate anaerobic test variables, total work, or fatigue index (Table 2).
This is the first study to demonstrate that formoterol has no effect on anaerobic or aerobic performance in highly trained male athletes without asthma. It also confirmed the findings that salbutamol imparts no performance enhancing effects on nonasthmatics (8,13,22,23,29,30) (Table 2).
When comparing therapeutic doses, formoterol has a similar maximum bronchodilatory effect, but the duration of the effect is approximately double that of salbutamol (11,33). The efficacy of formoterol in preventing exercise-induced asthma has also been shown to be greater than that of salbutamol when administered 3, 8, and 12 h before exercise (3,10,15,27). The use of formoterol also decreases the reliance on rescue medication (1).
The I.O.C. has classified β2-agonists as anabolic agents as well as stimulants. β2-agonists are not anabolic steroids, but they do have anabolic effects. Experiments in animals with oral clenbuterol have shown augmentation in muscle bulk across numerous species (20,28), but human studies cannot confirm similar muscle mass enlargement in healthy men (9,21).
It is unlikely that the bronchodilatory action of β2-agonists has an ergogenic effect, because in nonasthmatics bronchodilation is not a performance-limiting factor. Two studies have identified a significant effect of a single inhaled dose of salbutamol. However, both have subsequently been questioned as to whether a true effect of the drug was observed. Bedi et al. (2) demonstrated an improvement in sprint time after a 45-min endurance ride at 70% of V̇O2max. In contrast, Meeuwisse et al. (23) found a nonsignificant decrease following the same procedure in a group of highly trained cyclists. According to Meeuwisse et al. (23), the use of a nonhomogenous group and the influence of two outliers accounted for the statistically significant improvement in the Bedi study. The other study to identify a positive result of an acute inhaled dose was conducted by Signorile et al. (31). The authors reported a significant improvement in peak power obtained during a 15-s all-out cycle in recreational athletes. Subsequent studies measuring anaerobic power output in elite endurance athletes (23,24), including the present, have failed to identify any significant effect. Meeuwisse et al. (23) questioned the accuracy of the method employed by Signorile et al. (31) of calculating power by using a single pedal stroke compared with the more conventional 5-s average.
Despite the dosage or the medication involved, acute, inhaled administration of β2-agonists has been shown repeatedly to have no aerobic or anaerobic performance-enhancing effect in a population of elite athletes (8,13,19,22,23,24,29,30). The present study indicates that formoterol could also be included within this group of β2-agonists, although further studies are required to examine the effects of long-term formoterol use on performance.
Oral administration results in higher plasma concentrations than inhalation; therefore, the systemic actions rather than bronchial actions are involved in its ergogenic effect. Oral formoterol, 20–300 μg, produced dose-related increases in heart rate and decreases in blood pressure (12). In a comparison of repeated inhalation with salbutamol 400 μg and fenoterol 400 μg, formoterol 24 μg resulted in inotropic, chronotropic, and electrophysiological effects similar to salbutamol but less than those of fenoterol. All three drugs significantly increased heart rate and decreased blood pressure (5). After a single inhalation, similar cardiovascular responses were only noted at doses exceeding 48 μg (6). The mechanism of this positive inotropic effect has not been fully identified but has been suggested to involve alterations in resting potential, Ca2+ myosin ATPase, and contractile properties (34). Although these studies do suggest mechanisms by which subtle changes in cardiovascular function could affect performance, most research to date has focused on significantly higher than therapeutic doses. As an ergogenic aid, the willingness of an athlete to take large doses is increased with the idea of an enhanced performance. However, gas and liquid chromatography make detection of deliberate administration of large doses of β-sympathomimetic agents relatively simple (4,7).
The possible effect of a therapeutic dose of formoterol enhancing performance via changes to vascular resistance, blood flow, contractility, and other cardiovascular system parameters seems unlikely as exercise would have already resulted in maximal responses of these variables. The only cardiovascular variable measured in the present study, heart rate, showed no difference between the three experimental conditions during all stages of exercise. Previous investigations of the effect of salbutamol on cardiovascular variables during exercise have shown no difference compared with placebo in asthmatics (14,16) and nonasthmatics (22,23,32).
In conclusion, no aerobic or anaerobic performance-enhancing effect was observed when an acute, inhaled, therapeutic dose of formoterol or salbutamol was administered to highly trained male athletes without asthma.
This study was performed with a grant from AstraZeneca.
Address for correspondence: Ian B. Stewart, Allan McGavin Sports Medicine Centre and School of Human Kinetics, University of British Columbia, 3055 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada; E-mail: firstname.lastname@example.org.
1. Bartow, R. A., and R. N. Brogden. Formoterol: an update of its pharmacological properties and therapeutic efficacy in the management of asthma. Drugs 55: 303–322, 1998.
2. Bedi, J. F., H. Gong, and S. M. Horvath. Enhancement of performance with inhaled albuterol. Can. J. Sport Sci. 13: 144–148, 1988.
3. Boner, A. L., E. Spezia, P. Piovesan, E. Chiocca, and G. Maiocchi. Inhaled formoterol in the prevention of exercise-induced bronchoconstriction in asthmatic children. Am. J. Respir. Crit. Care Med. 149: 935–939, 1994.
4. Braat, M. C. P., E. J. G. Portier, and B. T. J. van den Berg. Formoterol detection and pharmacokinetics in human subjects after an oral dose of 168 micrograms. Am. Rev. Respir. Dis. 145: A60, 1992.
5. Bremner, P., K. Woodman, B. C., J. Crane, G. Purdie, N. Pearce, and R. Beasley. A comparison of the cardiovascular and metabolic effects of formoterol, salbutamol and fenoterol. Eur. Respir. J.
6. Burgess, C., M. Ayson, and S. Rajasingham. The cardiovascular and metabolic effects of increasing doses of formoterol in patients with asthma. Eur. Respir. J. 7: 204, 1994.
7. Butler, J. J., B. T. J. van den Berg, and E. J. G. Portier. Determination by HPLC with electrochemical detection of formoterol enantiomers in urine of healthy human subjects after single dose racemate inhalations. Pharmacol. World Sci. 26: D6, 1995.
8. Carlsen, K. H., F. Ingjer, H. Kirkegaard, and B. Thyness. The effect of inhaled salbutamol and salmeterol on lung function and endurance performance in healthy well-trained athletes. Scand. J. Med. Sci. Sports 7: 160–165, 1997.
9. Caruso, J. F., J. F. Signorile, A. C. Perry, et al. The effects of albuterol and isokinetic exercise on the quadriceps muscle group. Med. Sci. Sports. Exerc. 27: 1471–1476, 1995.
10. Daugbjerg, P., K. G. Nielsen, M. Skov, and H. Bisgaard. Duration of action of formoterol and salbutamol dry-powder inhalation in prevention of exercise-induced asthma in children. Acta Paediatr. 85: 684–687, 1996.
11. Dermon, E. Y., and R. A. Pauwels. Time course and duration of bronchodilating effect of inhaled formoterol, a potent and long acting sympathomimetic. Thorax 47: 30–33, 1992.
12. Faulds, D., L. M. Hollingshead, and K. L. Goa. Formoterol: a review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Drugs 42: 115–137, 1991.
13. Fleck, S. J., A. Lucia, W. W. Storms, J. M. Wallach, P. F. Vint, and S. D. Zimmerman. Effects of acute inhalation of albuterol on submaximal and maximal VO2
and blood lactate. Int. J. Sports Med. 14: 239–243, 1993.
14. Freeman, W., G. E. Packe, and R. M. Cayton. Effect of nebulized salbutamol on maximal exercise performance in men with asthma. Thorax 44: 942–947, 1989.
15. Henriksen, J. M., L. Agertoft, and S. Pedersen. Protective effect and duration of action of inhaled formoterol and salbutamol on exercise-induced asthma in children. J. Allergy Clin. Immunol. 89: 1176–1182, 1992.
16. Ienna, T. M., and D. C. McKenzie. The asthmatic athlete: metabolic and ventilatory responses to exercise with and without pre-exercise medication. Int. J. Sports Med. 18: 142–148, 1996.
17. Jack, D. Drug treatment of bronchial asthma 1948–1995: years of change. Int. Pharmacol. J. 10: 50–52, 1996.
18. Juniper, E. F., D. W. Cockroft, and F. E. Hargreave. Histamine and Methacholine Inhalation Tests: Tidal Breathing Method. Lund, Sweden: Canadian Thoracic Society, 1991, pp. 5–47.
19. Larsson, K., D. Gavhed, L. Larsson, I. Holmer, L. Jorfelt, and P. Ohlsen. Influence of a beta2
-agonist on physical performance at low temperature in elite athletes. Med. Sci. Sports. Exerc. 29: 1631–1636, 1997.
20. MacLennan, P. A., and R. H. T. Edwards. Effects of clenbuterol and propranalol on muscle mass. Biochem. J. 264, 1989.
21. Maltin, C. A., M. I. Delday, J. S. Watson, S. D. Heys, I. M. Nevison, and I. K. Ritchie. Clenbuterol, a beta-adrenoceptor agonist, increases relative muscle strength in orthopaedic patients. Clin. Sci. 84: 651–654, 1993.
22. McKenzie, D. C., E. C. Rhodes, D. R. Stirling, et al. Salbutamol and treadmill performance in non-atopic athletes. Med. Sci. Sports. Exerc. 15: 520–522, 1983.
23. Meeuwisse, W. H., D. C. McKenzie, S. R. Hopkins, and J. D. Road. The effect of salbutamol on performance in elite nonasthmatic athletes. Med. Sci. Sports. Exerc. 24: 1161–1166, 1992.
24. Morton, A. R., K. Joyce, S. M. Papalia, N. G. Carroll, and K. D. Fitch. Is salmeterol ergogenic? Clin. J. Sport Med. 6: 220–225, 1996.
25. Ogilvie, C. M., R. M. Forster, W. S. Blakemore, and J. Morton. A standardized breath holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide. J. Clin. Invest. 36: 1–17, 1957.
26. Park, I., and R. W. Schutz. Quick and easy formulae for approximating statistical power in repeated measures ANOVA. Meas. Phys. Ed. Exerc. Sci. 3: 249–270, 1999.
27. Patessio, A., A. Podda, M. Carone, N. Trombetta, and C. F. Donner. Protective effect and duration of action of formoterol aerosol on exercise-induced asthma. Eur. Respir. J. 4: 296–300, 1991.
28. Ricks, C. A., R. H. Dalrymple, P. K. Baker, and D. L. Ingle. Use of a beta-agonist to alter fat and muscle deposition in steers. J. Animal Sci. 59: 1247–1255, 1984.
29. Sandsund, M., M. Sue-Chu, J. Helgerud, R. E. Reinertsen, and L. Bjermer. Effect of cold exposure and Salbutamol treatment on physical performance in elite nonasthmatic cross-country skiers. Eur. J. Appl. Physiol. 77: 297–304, 1998.
30. Sandsund, M., M. Sue-Chu, R. E. Reinertsen, J. Helgerud, B. Holand, and L. Bjermer. Treatment with inhaled beta2
-agonists or oral leukotriene antagonists do not enhance physical performance in nonasthmatic highly trained athletes exposed to −15°C. J. Thermal Biol. 25: 181–185, 2000.
31. Signorile, J. F., T. A. Kaplan, B. Applegate, and A. C. Perry. Effects of acute inhalation of the bronchodilator, albuterol, on power output. Med. Sci. Sports. Exerc. 24: 638–642, 1992.
32. Violante, B., R. Pelligrino, C. Vinay, R. Selleri, and G. Ghinamo. Failure of aminophylline and salbutamol to improve respiratory muscle function and exercise tolerance in healthy humans. Respiration 55: 227–236, 1989.
33. Wallin, A., T. Sandstrom, and L. Rosehall. Time course and duration of bronchodilatation with formoterol dry powder in patients with stable asthma. Thorax 48: 611–614, 1993.
34. Yang, Y. T., and M. A. McElliogott. Multiple actions of beta agonists on skeletal muscle and adipose tissue. Biochem. J. 261: 1–10, 1989.