Safety and efficacy of paracetamol and NSAIDs in osteoarthritis: which drug to recommend?
Clinical use of non-steroidal anti-inflammatory drugs (NSAIDs) carries cardiovascular risk, which acquires implications for public health against the backdrop of rising chronic disease rates in lowand middleincome countries (LMICs). New evidence from an international study conducted by Patricia McGettigan and David Henry and published this week in PLOS Medicine  sheds light on how emerging evidence about NSAID risk is poorly translated into practice and sales in countries around the world, raising questions about the use and promotion of potentially harmful drugs. NSAIDs are extensively prescribed for pain management in patients with osteoarthritis and several other painful conditions. The large number of drugs in this group is broadly divided into nonselective cyclooxygenase (COX) inhibitors and selective COX inhibitors. This classification is based on the selective inhibition of COX-2 enzyme, which is primarily responsible for the generation of inflammatory mediators. The emergence of selective COX-2 inhibitors in the 1990s was widely welcomed by physicians, as these drugs were expected to reduce the adverse gastrointestinal effects associated with inhibition of COX-1. However, the enthusiasm evaporated when it was discovered that rofecoxib (Vioxx), an early and aggressively marketed molecule of this drug class, increased the risk of serious cardiovascular events [2,3]. Subsequently, several systematic reviews and meta-analyses showed that other NSAIDs too were associated with adverse cardiovascular events [4–6]. The adverse cardiovascular profile of NSAIDs includes risk of atherothrombotic events like myocardial infarction (MI) and stroke, which can be fatal. The increased cardiovascular risk has been observed both in people with a prior high risk of cardiovascular disease and in previously healthy individuals , and this risk appears to be dose dependent . What is intriguing, however, is that the increase in cardiovascular risk has been variable with the different molecules. Apart from rofecoxib, diclofenac is the agent most associated with an increased risk of cardiovascular events: a 40%–60% higher relative risk of serious cardiovascular events, compared to non-use of NSAIDs, has been reported [4–6,9]. This is a rate equivalent to or possibly higher than that of rofecoxib, now withdrawn from the market. In contrast, another traditional NSAID, naproxen, has been found to be relatively benign, with a cardiovascular risk that was observed to be neutral or much lower than that of diclofenac [4–6,9]. The reason for this variability in cardiovascular risk among the non-selective NSAIDs is not completely understood, but mechanistic research suggests it could be related to the extent of COX-2 inhibition by drugs that do not block COX-1 completely . The higher the level of COX-2 inhibition and the lower the level of COX-1 inhibition, the greater appears to be the risk of thrombotic cardiovascular events like fatal or non-fatal MI and stroke. This probably explains the low cardiovascular risk of naproxen, which completely blocks COX-1 and thus has anti-platelet effects that reduce cardiovascular events. When COX-1 inhibition is incomplete (,95%), enough thromboxane A2 (TxA2) is generated for platelet activation . The inhibition of COX-2 reduces the generation of vaso-protective prostacyclin (PGI2), a prostaglandin that guards against thrombogenesis, atherogenesis, and high blood pressure . The inhibition of COX-2, coupled with an incomplete inhibition of COX-1, provides a potent thrombogenic stimulus by altering the PGI2-TxA2 balance. While both diclofenac and naproxen are non-selective, the differences in the COX-1 and COX-2 inhibition each drug achieves may explain the variability in their cardiovascular risk profiles.