Hemlock or Healer? The Mercurial Reputation of Theophylline

In this issue of Annals, two articles [1, 2] discuss facets of theophylline administration that recall a hoary clinical dilemma: Is the drug useful enough to justify the danger of serious toxicity and, if so, how should it be used?

In the first article, Huang and coworkers [1] describe a carefully performed double-blind, placebo-controlled study that shows convincingly that during the first 48 hours after hospitalization for asthma, theophylline, when added to albuterol and methylprednisolone, produces more rapid and sustained improvement in airflow rates than the same regimen lacking theophylline.

In the second, Shannon [2] describes theophylline overdose in 249 consecutive patients referred to the Massachusetts Poison Control System with a peak serum theophylline concentration of 167 mol/L (30 mg/L) or greater to identify risk factors for major toxicity. In this select population, major toxicity occurred in 62 patients and caused death in 13. It is important to note that 37% of the patients with toxicity had been inadvertently overmedicated while receiving long-term theophylline therapy and that major toxicity was more common in this group than in those with acute (presumably intentional) overdosage. Although the study shows that peak level is the most important risk factor for major toxicity in acute overdosage, advancing age is the most critical factor in chronic overdosage. The study design does not allow investigation of the reasons for this disparity, but the findings indicate that different patient populations have clinically important variability in response to theophylline administration. In the important subset of older patients who are receiving theophylline for management of chronic asthma, toxicity can be inadvertent and serious. Shannon also cites previous evidence that up to 21% of patients receiving long-term theophylline therapy may have at least some toxic manifestations. In fact, the long-standing controversy over theophylline use has centered not only on the …