It's not only the selective COX-2 inhibitors that may be under scrutiny after Oxford University researchers, writing in the British Medical Journal this week, found that people taking high doses of the common pain drugs ibuprofen and diclofenac also have an increased risk of heart attack and stroke. However, the possibility is only moderate, they say, with three in every 1,000 experiencing an event.

The researchers' meta-analysis of 138 published and unpublished randomised trials showed that allocation to a COX-2 was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year versus 0.9%/year), particularly heart attack. And the rate of vascular events for patients taking high-dose traditional NSAIDs (800mg ibuprofen and 75mg diclofenac) was similar at 1%/year versus 0.9%/year, leading the authors to conclude that both selective COX-2s and traditional NSAIDs come with a moderately increased in heart attack and stroke. However, high-dose naproxen (500mg twice daily) was not associated with cardiovascular risk - in fact it has a protective effect on the heart.

COX-2s were developed as an alternative to the traditional non-steroidal anti-inflammatory drugs, which exert their action via both the COX-1 and COX-2 receptors, which had been linked to gastrointestinal side effects such as ulcers and gastric bleeding. The market leaders - Merck & Co's Vioxx (rofecoxib) and Pfizer's Celebrex (celecoxib) - reaped billions of dollars for their companies, but the latter was withdrawn in September 2004 after a study showed a doubling in the risk of heart attack and stroke in patients given the drug for 18 months-plus. The news shook the whole field, sending sales of Celebrex into a downward spiral and pushing many patients back onto the older NSAIDs, ibuprofen, diclofenac and naproxen.