Remembering theophylline

My registrar recently asked me why some of my patients with chronic obstructive pulmonary disease (COPD) were on theophylline - the implication being that this is an outmoded drug, and I am an anachronistic practitioner.

Actually, it was put very politely - but the question hung in the air for a moment before I answered.

Theophylline is an old drug - having been used first for the treatment of asthma in the 1950s - which has long been recognised to relax airway smooth muscle. It has retained its place in the treatment of chronic obstructive pulmonary disease over decades. Every consensus statement on the management of COPD includes a place for methylxanthines, which in Australia means either oral theophylline or intraveinous aminophylline. Its use predates the era of 'evidence based medicine' and, as the medication is long out of patent, the resources being put into research of its effects are limited. Nevertheless there is ongoing research into the impact of theophylline in the airways (and the kidneys).

Most of the recent research focuses on the potential role of theophylline to reverse steroid resistance in COPD. A recent review in the Lancet (2009,373;1905-17) by Professor Peter Barnes covers this ground in great detail. A study published in Thorax journal in May (64(5);424-9) randomised a small number of patients (35) to receive either steroids and placebo or steroids and low dose theophylline during an exacerbation. All patients demonstrated evidence of relatively reduced airway inflammation over time - out to 3 months - but there was evidence of a greater reduction in some inflammatory markers (particularly histone deacetylases) in the theophylline group. The study did not evaluate clinically significant parameters.

Incidentally, the European Journal of Clinical Investigation has a forthcoming article (2009 Sep;39(9):793-9) reporting a study in which 217 patients with impaired renal function (GFR 30-60 ml/min) undergoing coronary angiography were randomised to receive either IV saline, IV saline + n-acetyl cysteine or IV saline + NAC + theophylline 200mg twice daily for the day prior and on the day of the angiogram. Contrast induced nephropathy occured in 5, 7 and zero patients in each of the groups respectively.

So, if theophylline protects the kidneys and reduces inflammation in the airways, why are we so slow to use it?

Side effects! Theophylline needs to be kept within a therapeutic range. Caffeine-like side effects occur in many people (nausiea, vomiting, headache, insomnia) at initiation of treatment - and persist in up to 10% . In overdose, side effects can include intractable vomiting, cardiac arrhythmias and seizure. So it's not an entirely safe drug.

Nevertheless, it's a drug with a place - and an old drug that may end up with some real evidence to support our continued use of it after all!

Andrew