Asthma, Advair, Symbicort, Foradil, and Serevent: More Harm than Good?

Between 7-10% of children and 3-5% of adults suffer from asthma; this serious and disabling condition causes inflammation in the airways so that they contract and fill with mucus. Asthma is now the number one cause of children missing school and things are only getting worse. The asthma-related death rate in children has increased 80% since 1980. Allergists agree that asthma control is best accomplished through lack of contact with the trigger–if it is known and possible to avoid, but if not, treatment is vital. Acute attacks are routinely treated with inhaled short-acting beta-agonists (SABA), such as Albuterol, which work by stimulating a receptor on the surface of the cells. This is kind of like pressing a doorbell on a house. The response is a relaxation of the muscles lining the airways and results in opening of the airways so the patient can breathe. Because of the cell’s quick response to the SABAs, these drugs are known as rescue inhalers.

There are, however, a couple of problems with SABAs. First, they are what the name implies: short-acting. Just like soon after a doorbell rings the household goes back to its original tasks and forgets the interruption, the cell returns to normal function shortly after being stimulated by a SABA. For this reason, use of a rescue inhaler needs to be repeated every four hours or even more often. Another issue is that the cell reacts in very much the same way as a person in a house would if someone kept ringing the doorbell: if receptors are over-stimulated they are either internalized or switched off.

In comparison, the long-acting beta-agonists (LABA), such as Serevent and Foradil, irreversibly attach to beta-2 receptors, forcing the airways to stay open for longer than possible with the SABA. But, soon after release onto the market, it was found that this advantage came with a price: an increase (now known to be trifold) in asthma exacerbations and deaths. Basically, patients quickly became tolerant of the effects of the LABAs because the receptors were inactivated due to the continuous stimulation. Since the LABAs use the same receptors as the rescue inhalers, the airways became impervious to “rescue”—patients died. I remember discussing this problem while I was working at Creighton University Allergic Disease Center during the 1990’s—but prescription of the LABAs continued. The reason has to do with patient compliance.

Another problem with beta-agonists (short or long-acting) is that they do not treat the underlying cause of asthma—inflammation. Because long-standing inflammation can lead to scarring and irreversible lung damage, allergists frequently prescribe glucocorticosteroids (GC), which are anti-inflammatory, for use in asthma. The problem is that, where SABAs give instant relief of symptoms and LABAs work within an hour, GCs can take several days to come to full effect. Therefore, because the patients perceive that the GC inhaler does not “work” and the physician does not take the time to explain or may not know why they are important, the asthmatic patient may be less than cooperative about using GCs.

This is the reasoning behind development of combination inhalers like Advair and Symbicort, which contain both GC and LABA. The prior drug controls inflammation and prevents lung damage and the latter opens the airways, giving the patient reassurance that the medicine is working. The fact that the LABA also trebles the risk of asthma death or intubation was not really made public until a FDA safety announcement released in 2010. It is disturbing that this was sixteen years after the initial problem with Serevent, a LABA, was reported in a letter to the New England Journal of Medicine. In 1996 Glaxo began a study that confirmed Serevent’s safety issues, but the results were not publicly reported until 2003. Meanwhile, Symbicort sales totaled $1.2 billion in 2006 and Advair made $6.9 billion in 2007. It has been estimated that 4,000 out of the 5,000 asthma deaths that occur every year are due to these medications.

I have personal experience of a physician telling me that my daughter should use her SABA every four hours whether she needs it or not. If we had complied, the drug would soon have ceased to help her. I have also been told that my son should use a GC as needed. GC do not work as needed; they must be used regularly because the full effect is not seen for days. There are many patients using Advair or Symbicort when their asthma would respond to GCs and SABAs. This increases their risk of asthma-related death. Perhaps it is time to insist that patients are educated on the medications they use, doctors are fully informed about the drugs they prescribe, and pharmaceutical companies put patient safety above profit margin.