Regular treatment with both long- and short-acting β₂-agonists results in tolerance to their bronchoprotective effects, although the relevance of this phenomenon in terms of long term asthma control remains unclear. However, there appears to be no appreciable difference between the 2 long-acting β₂-agonists, salmeterol and formoterol, in their propensity to induce β₂-adrenoceptor down-regulation and subsensitivity.

The degree of subsensitivity appears to be somewhat greater with indirect stimuli such as exercise and allergen challenge, compared with direct stimuli such as histamine and methacholine. This loss of functional antagonism with long-acting β₂-agonist therapy is partial and is not prevented by concomitant inhaled corticosteroid therapy. However, the protective effects of inhaled corticosteroids on their own appear to be additive to those of long-acting β₂-agonists when both drugs are concomitantly administered in the long term.

The subsensitivity to bronchoprotection may be of clinical relevance in terms of patients who are inadvertently exposed to indirect bronchoconstrictor stimuli such as allergens or exercise, suggesting that long-acting β₂-agonists should not be taken on a regular basis for this particular indication.

There is a greater tendency for bronchodilator subsensitivity to develop with longer-acting, than with shorter-acting β₂-agonists, and this may reflect the longer duration of β₂-adrenoceptor occupancy and consequent downregulation. As with the bronchoprotective effects of long-acting β₂-agonists, the development of bronchodilator subsensitivity is only partial and occurs regardless of whether patients are taking concomitant inhaled corticosteroid therapy. The long-term bronchodilator action of the long-acting β₂-agonist itself is maintained within the twice daily administration interval. However, subsensitivity occurs in relation to a blunted response to repeated doses of short-acting β₂-agonists, as in the setting of an acute asthma attack. There is considerable inter-individual variability in the propensity for downregulation and subsensitivity, which is determined by genetic polymorphism of the β₂-adrenoceptor.

Current international asthma management guidelines suggest that long-acting β₂-agonists should only be used on a regular basis in patients who are inadequately controlled on inhaled corticosteroid therapy, so the addition of long-acting β₂-agonist therapy is an alternative to using higher doses of inhaled corticosteroids. There are, however, concerns that regular long-acting β₂-agonists might result in masking of inadequately treated inflammation in patients receiving suboptimal inhaled corticosteroid therapy.

Physicians should be aware of the airway subsensitivity that develops with long-acting β₂-agonist therapy, and patients should be warned that they may have to use higher than conventional dosages of short-acting β₂-agonists to relieve acute bronchoconstriction in order to overcome this effect. In patients receiving an optimised maintenance dose of inhaled corticosteroid, if long-acting β₂-agonists are to be used on an as required basis, it would seem rational to use formoterol for this purpose, due to its faster onset of action than salmeterol.