Take a Deep Breath

The FDA is currently re-evaluating warnings on long-acting beta-agonist drugs used for asthma. This isn't the first time that the subject has come up. It made the news way back in 2003 and was discussed again in 2005. What's the deal?

Beta-agonist drugs stimulate part of the body's autonomic nervous system, or ANS. The ANS is responsible for managing many body functions, some of which are unconscious and others which are conscious. The ANS is further subdivided into the sympathetic and the parasympathetic systems. Put simply, the sympathetic nervous system is associated with the "fight or flight" response; for example, stimulation results in an increase in heart rate. The parasympathetic nervous system is associated with the "rest and digest" response. Among other things, stimulation results in increased movement of the musculature of the stomach and bowels and salivation.

One of the reactions associated with "fight or flight" is the widening of the bronchial tubes, the cartilaginous passageways through the lungs that carry air. Because the sympathetic nervous system receptors on the bronchi are different from those on the heart or the skeletal muscle, it is possibly to stimulate them selectively. These receptors are called "beta-2" receptors, and an agonist is a drug that stimulates a response; therefore, selective beta-2 agonists stimulate only the bronchi, dilating them and making it easier for patients to breathe without simultaneously increasing the heart rate. In asthma, the bronchi become inflamed and constrict, making breathing considerably more difficult, especially during periods of exercise or physical activity.

The most well-known beta-2 agonist is probably albuterol, staple of asthmatics of all ages. If you were ever on a sports team as a kid or even just played outdoors you probably knew at least one person who used an albuterol inhaler. Albuterol is an excellent drug, and it works quickly but its duration of action is relatively short--about six hours. Six hours may sound like a lot, but most people need to breathe all the time. Patients with asthma who find themselves gasping every time their albuterol starts to wear off may find themselves in serious trouble, and shortness of breath can be very scary.

So pharmaceutical chemists developed drugs that work the same way as albuterol, but that would have a longer duration of action. Serevent is one of them. Advair is much more commonly prescribed; it combines salmeterol, the long-acting beta-2 agonist in Serevent, with an inhaled corticosteroid for further bronchodilation and relief of asthma-related inflammation. Before long-acting beta-2 agonists became available, inhaled corticosteroids were the first option for long-term control of asthma symptoms. Salmeterol even has a neat pharmaceutical mechanism; it is structurally similar to albuterol, but has a long chemical "tail" that embeds itself in cell surfaces, resulting in very slow release of the drug to its site of action.

Logically, it seems like salmeterol should be just like albuterol, only better.

A 28-week placebo-controlled study conducted in 1996 in the U.S. (the SMART study) suggested that patients on long-acting beta-2 agonists actually had more asthma related deaths than those on placebos. However, the increase in deaths was not statistically significant in the Caucasian participants in the study--and they made up 71% of the study's population of 25,858 patients. African Americans made up the second-largest group at 17%, and while the number of deaths in African Americans was statistically significant, only 1% of African Americans enrolled in the study suffered an asthma-related death. This could be attributed to the smaller sample size; the study was not designed to provide strong data about possible differences in drug effect between ethnic groups.

So what's going on? Is salmeterol killing people? Is it an ineffective drug? This "salmeterol paradox" is certainly strange. The whole purpose of long-acting beta-2 agonists was to add another option to improve long-term control of asthma. Researchers at Cornell suggest that using long-acting beta-2 agonists may ultimately worsen underlying inflammation and increase "bronchial hyper-responsiveness." Some other data suggests that use of salmeterol causes roughly five deaths per year.

I, of course, really don't know for sure. What I do know is that the statistics here look kind of funny. The FDA has to be conservative in its rulings; some evidence of risk is good enough for them to put a warning on a drug to cover their backs. But in nearly three-quarters of the sample group the number of deaths due to asthma-related causes was not statistically significant. What other factors might cause an increase in asthma-related deaths?

Well, the patients on salmeterol obviously have worse asthma than those who can manage with nothing more than an albuterol inhaler. The SMART study also mentions that deaths were higher in patients taking salmeterol but not taking an inhaled steroid. Er. This doesn't necessarily strike me as a "blame salmeterol" situation. Again, wouldn't patients requiring a steroid in addition to both long and short-acting beta agonists to get control of their asthma obviously be the worst off? The need for salmeterol and other drugs in its class is an indication in itself that the patient's condition is deteriorating.

I'm not convinced by the SMART study or any of the follow-up research that I've seen that long-acting beta-agonists are the cause of asthma-related deaths. More robust studies are going to be required to weed out other possible underlying causes. The real question, then, is whether anyone is going to bother to do them.