Diclofenac's COX-2 Selectivity Profile
Diclofenac is not a selective COX-2 inhibitor but rather a nonselective NSAID with preferential COX-2 inhibitory activity. 1
Mechanism of Action and COX Selectivity
Diclofenac inhibits both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, but demonstrates relatively greater COX-2 selectivity compared to many traditional NSAIDs:
- Diclofenac is classified as an acetic acid derivative NSAID that inhibits prostaglandin synthesis by blocking both COX isoforms 2
- While not a selective COX-2 inhibitor like celecoxib or rofecoxib, diclofenac shows preferential COX-2 inhibition 3
- It lies on the "more COX-2-selective end of the spectrum of COX inhibition" 1
- Studies have demonstrated that diclofenac has COX-2 selectivity similar to celecoxib 4
Cardiovascular Risk Implications
The degree of COX-2 selectivity correlates with cardiovascular risk profiles:
- Diclofenac's preferential COX-2 inhibition contributes to its increased cardiovascular risk compared to less COX-2 selective NSAIDs 1
- The American Heart Association notes that diclofenac has been associated with an increased risk of thrombotic events 5
- In a large registry study, diclofenac was associated with a hazard ratio of 2.40 (95% CI 2.09-2.80) for mortality in patients with prior myocardial infarction 1
- The FDA requires a black box warning on diclofenac's label regarding cardiovascular thrombotic risk 1
Clinical Significance
The COX-2 selectivity profile of diclofenac has important clinical implications:
- Despite not being marketed as a "coxib," diclofenac's COX-2 selectivity is comparable to celecoxib 4
- This selectivity profile explains why diclofenac and etoricoxib showed similar cardiovascular risk profiles in comparative trials 1
- The American College of Cardiology/American Heart Association guidelines recommend against using NSAIDs with increasing degrees of COX-2 selectivity in patients with STEMI 1
- For patients requiring pain relief who have cardiovascular risk factors, a stepped-care approach is recommended, starting with acetaminophen, small doses of narcotics, or non-acetylated salicylates before considering NSAIDs 1
Practical Considerations
When considering diclofenac use:
- Be aware that diclofenac's COX-2 selectivity contributes to its cardiovascular risk profile, which is higher than some other NSAIDs like naproxen 1, 4
- For patients with cardiovascular disease, diclofenac should not be among the first choices for pain relief 1
- Use the lowest effective dose for the shortest possible duration to minimize risks 1
- Consider the patient's individual cardiovascular risk profile when selecting an NSAID 5
In summary, while diclofenac is not classified as a selective COX-2 inhibitor in the same category as celecoxib or rofecoxib, it demonstrates preferential COX-2 inhibition that contributes to its unique efficacy and safety profile.