The beta 2-agonist controversy. Observations, explanations and relationship to asthma epidemiology

Links between frequent use of inhaled beta 2-agonists and morbidity and mortality from asthma appear probable. Two mortality epidemics followed the marketing of potent inhaled adrenergic agents. Case-control studies in New Zealand linked mortality with prescription of fenoterol, especially in severe asthma. A Saskatchewan case-control study confirmed an association of mortality with fenoterol, and also with frequent use of salbutamol (albuterol). Cardiac effects of beta 2-agonists do not cause mortality, but frequent use of these agents may increase the chronic severity of asthma, hence increasing the number of asthmatic patients at risk of death in an acute attack. Frequent use of beta 2-agonists may reduce lung function, increasing airway responsiveness, and impair control of asthma, despite use of inhaled corticosteroids. Mechanisms for this effect may include tachyphylaxis to nonbronchodilator effects, increased responsiveness to allergen, interaction with corticosteroid receptors, altered mucociliary function, differential effects of enantiomers, and masking of symptoms by beta 2-agonist use. The withdrawal of fenoterol from New Zealand in 1990 was associated with a substantial decline in morbidity and mortality. Overall, the evidence suggests that frequent use of inhaled beta 2-agonists has a deleterious effect on the control of asthma. Epidemics of mortality are explained by an increase in chronic severity of asthma following introduction of more potent beta 2-agonists. While beta 2-agonists remain essential for relief of breakthrough symptoms, long term use, particularly with high doses of potent agents, appears to be detrimental.