"Clinicians need to be aware of how to identify and manage patients for whom beta-agonist treatment is a problem rather than a solution. They constitute a small but important sub-group of patients with difficult asthma".
As a consequence of recent conversations with hospital staff in Hamilton about our management of a patient with difficult asthma, I thought it would be appropriate to post a blog on this topic. Although beta agonists (such as salbutamol, terbutaline, eformoterol, salbutamol) are essential tools in the management of asthma - either as 'reliever' medications or as part of a 'preventer / maintenance' regime, their role in chronic persistent asthma may not be as simple as we would like to think.
The above quote is from Dr. D.Robin Taylor, at the University of Otago in Dunedin, New Zealand. Dr Taylor was at the coal-face of this issue in New Zealand in the early 1990s, when use of the beta-agonist fenoterol was associated with a spike in asthma related deaths which only ended when that medication was taken off the market. Although the Wikipedia entry on this drug suggests that the surge in deaths was all due to cardiac side effects from patients irresponsibly managing their asthma with massive doses of the medication out of hospital, the issue may not be quite that simple. The 'epidemic' of asthma deaths associated with that medication has helped to generate persistent research into the hypothesis that beta-agonists may paradoxically worsen asthma control in some situations.
I first heard Dr Taylor on this issue as a registrar back in 2002. I was struck by his description of a difficult asthmatic patient who was using bucket-loads of salbutamol as reliever, and who did not improve until - in a carefully managed hospital environment - that beta-agonist was withdrawn. The peak flow record was instructive and convincing.
In a recent issue of the American Journal of Respiratory and Critical Care Medicine (Vol 179, pp976-978) Dr Taylor's summary of evidence and opinion on the question of whether beta-agonists may sometimes be harmful has been published - as a 'clinical commentary'. (The material was initially presented at the 2008 American Thoracic Society conference).
The points I underlined in my copy are as follows:
- the FDA in the USA issued, in 2005, a 'black box' warning about the safety of long acting beta agonists eformoterol and salmeterol. The majority of the relevant committee felt that these medications should only be used in combination with an inhaled corticosteroid (ICS) in treatment of asthma, as the risk of treatment with the beta-agonist alone, without ICS, outweighed the benefit).
- beta-agonists are, if used consistently, pro-inflammatory in human airways (both in-vitro and in-vivo studies). ICS, which are anti-inflammatory, may therefore protect against adverse effects from beta-agonists. To my mind, however, this situation is far from ideal - i.e. that we would need to need to use a medication to treat a medication related side effect.
- although acute use of beta-agonists leads to airway smooth muscle relaxation, in a mouse model chronic beta-agonist stimulation leads to increased airway smooth muscle contractility - and potentially a heightened response to an asthma trigger (i.e. another mechanism - apart from the pro-inflammatory effects - by which the medication may make the disease worse!) "It would appear that acute and chronic B-agonist effects are not the same thing".
So there is evidence that persistent overuse of beta-agonists may cause, within the airways, a process that is difficult/impossible to distinguish from a worsening of the underlying disease process. Now that takes some mulling over!
Two quotes from Dr Taylor's article to summarize:
"...monotherapy with beta-agonists should clearly be avoided, and the use of combination inhalers to some extent guards against the possibility of LABA-related adverse effects. However, the concomitant use of ICS does not mean that adverse effects of beta-agonist are a non-issue: there is likely to be a threshold for adverse effects in relation to total beta-agonist exposure that may be crossed even when patients are taking ...ICS".
"Good asthma management should include appropriate diagnosis and treatment of beta-agonist toxicity......the characteristic features include unstable or intractable asthma with evidence of psychological and/or pharmacological beta-agonist inhaler dependence. The need for frequent "reliever" ... should cause alarm bells to ring, especially if the treatment yields progressively diminishing benefits in a patient with severe asthma (my emphasis)".
Now, I do not want any of my patients to simply stop using their reliever medication. However, we clearly must have a 'zero tolerance' approach to treating asthma with regular beta-agonist alone. Inhaled corticosteroids are essential. If asthma control is difficult then the first priority should be to review the delivery technique for any 'preventer' medication, as even the most competent patients often make a hash of it. But if, in spite of this, more and more salbutamol is required by a patient, with less and less response, then we should ask whether the beta-agonist might be part of the problem - and be ready to do something about that.
Andrew
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