Study Suggests New Strategy for Long-Term Asthma Treatment – and It’s Not on the Banned List

This is the first of two pieces looking at the use of bronchodilating drugs to treat asthma in athletes – and their changing place on WADA’s prohibited list.

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Asthma is far from uncommon in cross-country skiers: a 1994 study in Norway found that high-level skiers were about three times as likely to self-report as asthma patients compared to the normal population. A 1999 study by researchers in Norway, Sweden, and Nebraska found that even non-asthmatic skiers had a higher level of airway inflammation than your average Joe, and deemed the condition “ski asthma.”

With so many breathing-challenged winter athletes, and a list of banned substances a mile long from the World Anti-Doping Agency (WADA), how are doctors to treat the condition? Standard drugs to treat asthma, such as salbutamol, taken by Norway’s Marit Bjørgen among others, have been on and off the banned list, although as FasterSkier wrote last year, it’s doubtful that the drug is actually performance-enhancing.

But there’s another option on the table: a recent paper in the New England Journal of Medicine suggested using different drugs to treat asthma – specifically, those currently used to treat chronic obstructive pulmonary disease (COPD), a long-term disease suffered primarily by smokers.

Tiotropium, unlike salbutamol, is not a b-2 agonist, a class of drugs prohibited by WADA (salbutamol itself and two other drugs are allowed for the treatment of asthma only, and only in specific doses). Classified as an anticholinergic agent – a class of drugs not currently on the WADA list – tiotropium is marketed under the trade name Spiriva.

(FasterSkier was unable to reach anybody at the U.S. Anti-Doping Agency for comment on tiotropium; understandably, they’re a little busy right now.)

Both salbutamol and tiotropium are bronchodilators, meaning that they work by opening up the airways, allowing lungs to get plenty of oxygen rather than leaving their owners wheezing. Long-acting b-2 agonists (LABA’s) like salbutamol work with the b-2 adrenergic receptors in smooth muscle tissue, and through a complex chemical pathway relax muscles in the lungs. Besides salbutamol, another high-profile LABA is clenbuterol, for which Spanish cyclist Alberto Contador tested positive in 2010.

Anticholeinergics work by blocking some of the effects of acetylcholine, the main neurotransmitter in the lungs. In asthma and COPD patients, there’s more acetylcholine released and more receptors for it in the smooth muscles of the lungs; that means muscle constriction and airway inflammation, with a net result of less oxygen. Tiotropium works with those specific receptors to achieve the same effect as LABA’s: relaxing the muscle and soothing airways.

The research team, led by Dr. Huib Kjerstens of the University of Groningen in the Netherlands, started from the problem that some asthmatics can’t control their symptoms even with a combination of steroids to reduce airway inflammation and long-acting bronchodilators like salbutamol. They tried adding a daily dose of tiotropium to roughly 400 asthmatics’ daily regimen, while 400 other patients got a control inhaler with no medicine.

After finding that the tiotropium group generally had better lung function after 24 weeks, fewer hospitalizations due to asthma, and a longer period of time before asthma worsened, Kjerstens’ team concluded that adding a second long-acting bronchodilator could help patients with severe asthma.

Kjerstens’ work follows an earlier paper in the same journal, which suggested in 2010 that tiotropium could help patients with uncontrolled asthma. That study was based on a 210-patient trial.

In an editorial from the more recent issue of the journal, Dr. Elisabeth Bel of the University of Amsterdam noted that while LABA’s are delivered as large, dry particles from inhalers, tiotropin is a much finer mist; the smaller particles may go deeper into a patient’s lungs and reach some of the smaller airways, thus working better than LABA’s, which is good news for asthma sufferers.

But Bel also warned that tiotropin may disperse into the bloodstream in greater quantities and pose a risk to cardiovascular health. Indeed, a 2011 review in the British Medical Journal showed that COPD patients using Spiriva mist inhalers had a 52 percent higher death rate than patients using a placebo inhaler. That’s a big risk for an asthmatic to take when other bronchodilators, such as salbutamol and other LABA’s, are available.

What does the new study mean for skiers? Like salbutamol, tiotropin would likely only be prescribed to serious asthmatics, and it’s not for an acute attack – it works over the long term. That, along with the drug’s risks, is part of the reason that it hasn’t been prescribed in the past, despite being on the market since 2004; as early as 1996, researchers were suggesting that it provided relief from asthma-like bronchial constriction, yet the drug still has not been used to treat asthma.

It’s likely that even more studies will be done before doctors start prescribing Spiriva to asthma patients on a large scale. Still, the evidence that it is effective in relieving severe asthma might be comforting to patients – it’s always nice to know that there’s another treatment option out there, and one that at no time was considered a illegal peformance enhancer.

The Studies

Bel, E.H., 2012. Tiotropium for Asthma — Promise and Caution. New England Journal of Medicine 367, 1257–1259.

Gosens, R., Zaagsma, J., Meurs, H., Halayko, A., 2006. Muscarinic receptor signaling in the pathophysiology of asthma and COPD. Respiratory Research 7, 73.

Heir, T., Oseid, S., 1994. Self-reported asthma and exercise-induced asthma symptoms in high-level competitive cross-country skiers. Scandinavian Journal of Medicine & Science in Sports 4, 128–133.

Kerstjens, H.A.M., Engel, M., Dahl, R., Paggiaro, P., Beck, E., Vandewalker, M., Sigmund, R., Seibold, W., Moroni-Zentgraf, P., Bateman, E.D., 2012. Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy. New England Journal of Medicine 367, 1198–1207.

Peters, S.P., Kunselman, S.J., Icitovic, N., Moore, W.C., Pascual, R., Ameredes, B.T., Boushey, H.A., Calhoun, W.J., Castro, M., Cherniack, R.M., Craig, T., Denlinger, L., Engle, L.L., DiMango, E.A., Fahy, J.V., Israel, E., Jarjour, N., Kazani, S.D., Kraft, M., Lazarus, S.C., Lemanske, R.F., Lugogo, N., Martin, R.J., Meyers, D.A., Ramsdell, J., Sorkness, C.A., Sutherland, E.R., Szefler, S.J., Wasserman, S.I., Walter, M.J., Wechsler, M.E., Chinchilli, V.M., Bleecker, E.R., 2010. Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma. New England Journal of Medicine 363, 1715–1726.

Singh, S., Loke, Y.K., Enright, P.L., Furberg, C.D., 2011. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. British Medical Journal 342, d3215–d3215.

Sue-Chu, M., Larsson, L., Moen, T., Rennard, S.I., Bjermer, L., 1999. Bronchoscopy and bronchoalveolar lavage findings in cross-country skiers with and without “ski asthma”. European Respiratory Journal 13, 626–632.