Corticosteroids

CORTICOSTEROIDS

If asthmatic symptoms occur frequently or if significant airflow obstruction persists despite bronchodilator therapy, inhaled corti-costeroids should be started. For patients with severe symptoms or severe airflow obstruction (eg, FEV₁< 50% predicted), initial treatment with a combination of inhaled and oral corticosteroid (eg, 30 mg/d of prednisone for 3 weeks) is appropriate. Once clinical improvement is noted, usually after 7–10 days, the oral dose should be discontinued or reduced to the minimum neces-sary to control symptoms.

An issue for inhaled corticosteroid treatment is patient adher-ence. Analysis of prescription renewals shows that corticosteroids are taken regularly by a minority of patients. This may be a func-tion of a general “steroid phobia” fostered by emphasis in the lay press on the hazards of long-term oral corticosteroid therapy and by ignorance of the difference between corticosteroids and ana-bolic steroids, taken to enhance muscle strength by now-infamous athletes. This fear of corticosteroid toxicity makes it hard to per-suade patients whose symptoms have improved after starting treat-ment that they should continue it for protection against attacks. This context accounts for the interest in reports that instructing patients with mild but persistent asthma to take inhaled cortico-steroid therapy only when their symptoms worsen is as effective in maintaining pulmonary function and preventing attacks as is tak-ing the inhaled corticosteroid twice each day (see above).

In patients with more severe asthma whose symptoms are inad-equately controlled by a standard dose of an inhaled corticoster-oid, two options may be considered: to double the dose of inhaled corticosteroid or to combine it with another drug. The addition of theophylline or a leukotriene-receptor antagonist modestly increases asthma control, but the most impressive benefits are noted from addition of a long-acting inhaled β₂-receptor agonist (salmeterol or formoterol). Many studies have shown this combination therapy to be more effective than doubling the dose of the inhaled corticosteroid for reducing symptoms, reducing the “as-needed” use of albuterol, and preventing attacks of asthma. Combinations of an inhaled corticosteroid and a long-acting β agonist in a single inhaler are now commonly prescribed (eg, flu-ticasone and salmeterol [Advair]; budesonide and formoterol [Symbicort]). Offsetting the clear benefits is evidence of a statisti-cally significant increase in the very low risk of fatal asthma attacks from use of a long-acting β agonist, perhaps even when taken in combination with an inhaled corticosteroid. This evidence prompted the FDA to issue a “black box” warning that the use of a long-acting β agonist is associated with a small but statistically significant increase in the risk of death or near-death from an asthma attack, especially in African Americans. The FDA did not withdraw approval of these drugs, for it recognizes that they are clinically effective. The major implications of the “black box” warning for the practitioner are: (1) that patients with mild to moderate asthma should be treated with a low-dose inhaled corti-costeroid alone, and additional therapy considered only if their asthma is not well controlled; and, (2) that if their asthma is not well controlled, the possible increase in risk of a rare event, asthma fatality, should be discussed in presenting the options for treatment—an increase to a higher dose of the inhaled corticosteroid versus addition of a long-acting β agonist.

The FDA’s warning has not so far had much effect on prescrip-tions for combinations of an inhaled corticosteroid with a long-acting β agonist, probably because their combination in a single inhaler offers several advantages. Combination inhalers are convenient; they ensure that the long-acting β agonist will not be taken as monotherapy (known not to protect against attacks); and they produce prompt, sustained improvements in clinical symp-toms and pulmonary function and reduce the frequency of exac-erbations requiring oral corticosteroid treatment. In patients prescribed such combination treatment, it is important to provide explicit instructions that a rapid-acting inhaled β₂ agonist, such as albuterol, should be used as needed for relief of acute symptoms.

An emerging approach to treatment takes advantage of the rapid-ity of onset of the bronchodilator action of the long-acting β agonist formoterol delivered in fixed-dose combination with the inhaled corticosteroid budesonide in Symbicort metered-dose inhalers. Several studies have confirmed that twice-daily and as-needed inhala-tion of this combination is as effective in preventing asthma exacer-bations as a four-times-higher dose of budesonide twice daily with only albuterol for relief of symptoms. Use of this flexible dosing strategy is widespread in Europe, but is not approved in the USA.