Nocturnal Asthma Uncontrolled by Inhaled Corticosteroids: Theophylline or Long-acting β2 Agonists?

Asthma is an inflammatory disease of the airways that is frequently characterised by marked circadian rhythm. Nocturnal and early morning symptoms are quite common among patients with asthma. Increased mortality and decreased quality of life are associated with nocturnal asthma. Although numerous mechanisms contribute to the pathophysiology of nocturnal asthma, increasing evidence suggests the most important mechanisms relate to airway inflammation. According to international guidelines, patients with persistent asthma should receive long term daily anti-inflammatory therapy. A therapeutic trial with anti-inflammatory therapy alone (without a long-acting bronchodilator) should be assessed to determine if this therapy will eliminate nocturnal and early morning symptoms. If environmental control and low to moderate doses of inhaled corticosteroids do not eliminate nocturnal symptoms, the addition of a long-acting bronchodilator is warranted. Long-acting inhaled β2 agonists (e.g. salmeterol, formoterol) are effective in managing nocturnal asthma that is inadequately controlled by anti-inflammatory agents. In addition, sustained release theophylline and controlled release oral β2 agonists are effective. In patients with nocturnal symptoms despite low to high doses of inhaled corticosteroids, the addition of salmeterol has been demonstrated to be superior to doubling the inhaled corticosteroid dose. In trials comparing salmeterol with theophylline, 3 studies revealed salmeterol was superior to theophylline (as measured by e.g. morning peak expiratory flow, percent decrease in awakenings, and need for rescue salbutamol), whereas 2 studies found the therapies of equal efficacy. Studies comparing salmeterol to oral long-acting β2 agonists reveal salmeterol to be superior to terbutaline and equivalent in efficacy to other oral agents. Microarousals unrelated to asthma are consistently increased when theophylline is compared to salmeterol in laboratory sleep studies. In addition to efficacy data, clinicians must weigh benefits and risks in choosing therapy for nocturnal asthma. Long-acting inhaled β2 agonists are generally well tolerated. If theophylline therapy is to be used safely, clinicians must be quite familiar with numerous factors that alter clearance of this drug, and they must be prepared to use appropriate doses and monitor serum concentrations. Comparative studies using validated, disease specific quality of life instruments (e.g. Asthma Quality of Life Questionnaire) have shown long-acting inhaled β2 agonists are preferred to other long-acting bronchodilators. Examination of costs for these therapeutic options reveals that evening only doses of long-acting oral bronchodilators are less expensive than multiple inhaled doses. However, costs of monitoring serum concentrations, risks, quality of life and other outcome measures must also be considered. Long-acting inhaled β2 agonists are the agents of choice for managing nocturnal asthma in patients who are symptomatic despite anti-inflammatory agents and other standard management (e.g. environmental control). These agents offer a high degree of efficacy along with a good margin of safety and improved quality of life.