Why is monotherapy with LABAs contraindicated in asthma?

Why is the chronic use of long-acting beta agonists (LABAs) alone without the concomitant use of an inhaled corticosteroid contraindicated in asthma? What about short-acting beta agonists (SABAs), can they be used without taking an inhaled corticosteroid at the same time?

Activation of β₂-adrenoceptor promotes bronchodilation. β₂-adrenoceptor agonists are the most potent bronchodilators in current clinical use. Inhaled short-acting beta agonists (SABAs), for example salbutamol (known as albuterol in the USA) have a bronchodilator effect that lasts for 4 to 6 hours, while long-acting beta agonists (LABAs), for example salmeterol, have a  bronchodilator effect that lasts for 12 to 24 hours (depending upon the drug). SABAs are used to relieve acute bronchoconstriction. Use of a SABA can be a life-saving intervention during an asthma attack. In contrast, LABAs are used chronically to mainain bronchodilation improving airway function and controlling occurance of symptoms.

Chronic use of LABAs causes tolerance due to downregulation of β₂-adrenoceptors. This is associated with an increased risk of mortality in patients with asthma. Therefore the use of LABAs alone is contraindicated. The downregulation of β₂-adrenoceptors by chronic use of LABAs can impair the response to SABAs when they are need for acutre relief of symptoms during an asthma attack.

Inhaled corticosteroids are used to control the inflammatory processes underlying asthma. Corticosteroids also upregulate  β₂-adrenoceptor expression. Combination of inhaled corticosteroids with LABAs reduces the risk of development of tolerance to β₂-adrenoceptor agonists.  Therefore, LABAs are only used concomitantly with corticosteroids.

Whether or not SABAs increase the risk of mortality is controversial. SABAs being shorter acting are less likely to cause downregulation of β₂-adrenoceptors. When used only intermittently for acute relief of symptoms of asthma, there does not appear to be a clear association between SABA usage and increased mortality. Even when SABAs are used chronically, there is less clearcut evidence for increased mortality. Nevertheless, it would usually be the case that the patient with asthma is advised only to use the SABA intermittently when needed for acute reflief of symptoms of asthma rather than chronically.  Use of a SABA only when needed will help to ensure that the  β₂-adrenoceptors are not downregulated and are responsive when the SABA is needed for acute relief of the symptoms of an asthma attack.

Reference:

Lemanske, RF (2018) Beta agonists in asthma: Controversy regarding chronic use. Bochner BS, Hollingsworth, H.  ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on October 5, 2018).