Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins. The reduction in prostaglandin levels provides the analgesic and anti-inflammatory properties of NSAIDs, but it is also responsible for side effects, since prostaglandins have a role in protecting the gastric mucosa and maintaining renal blood flow.
COX exists in at least two structurally different forms. COX-1, the constitutive form, produces prostaglandins that mediate gastric cytoprotection, renal perfusion and platelet aggregation. COX-2, the inducible form, is activated by inflammatory stimuli and produces prostaglandins that mediate an inflammatory response.
Differences in the selectivity of NSAIDs to block the two enzymes may explain why, at equipotent doses, some NSAIDs are more likely to cause side effects than others.
Selective COX-2 inhibitors such as celecoxib, etodolac, etoricoxib and meloxicam may have less potential to cause gastric and renal side effects than other, non-selective NSAIDs. Like all NSAIDs, the selective COX-2 inhibitors are contraindicated in patients at risk of GI perforations, ulcers and bleeds, but they should be considered in preference to non-selective or standard NSAIDs in patients at high risk of developing serious GI problems, such as those aged 65 and over, those needing prolonged use of standard NSAIDs at maximum recommended doses, those taking other medicines which can cause GI problems, and those with a history of GI problems or with serious co-morbidity.
There is concern about the use of NSAIDS, particularly selective COX-2 inhibitors, in patients with cardiovascular disease or patients with significant risk factors for cardiovascular events. By decreasing prostacyclin production without reducing thromboxane synthesis (in contrast to aspirin), COX-2 inhibitors may adversely affect the balance between antithrombotic and prothrombotic actions. NSAIDs, in general, may be associated with a small increase in the risk of arterial thrombotic events, such as a heart attack or stroke when used in high doses for long-term treatment. In particular, high doses of diclofenac (150mg daily) and ibuprofen (2.4g daily) are thought to be associated with an increased thrombotic risk. Naproxen (1g daily) may be associated with a lower thrombotic risk. Selective COX-2 inhibitors, diclofenac and ibuprofen doses ≥2.4g daily are contraindicated in patients with established ischaemic heart disease, cerebrovascular disease or those with moderate or severe heart failure (all NSAIDs are contraindicated in severe heart failure). Caution needs to be exercised in those with hypertension.
For all patients, the balance of gastrointestinal and cardiovascular risk should be considered before prescribing a COX-2 inhibitor, particularly for patients with risk factors for heart disease and those taking low dose aspirin. In all cases, the lowest effective dose of NSAIDs should be used for the shortest possible time. Selective COX-2 inhibitors are not a substitute for aspirin for cardiovascular or cerebrovascular prophylaxis as they do not inhibit platelet aggregation. Antiplatelet therapies should not be discontinued and, if indicated, should be considered in patients at risk of thrombotic events.
All patients on long-term NSAID therapy, particularly the elderly or those with renal, cardiovascular or GI disorders, should be monitored regularly for changes in gastric and renal function.