Ever since the voluntary withdrawal of rofecoxib (Vioxx) from the market, debate has raged regarding the risks of COX-2 drugs. Another casualty of the COX-2 "wars" was valdecoxib (Bextra), for an unrelated reason (rashes).

The debate has been fueled, in part, by hysteria, rather than data. What do we know about COX-2 drugs right now? For one, we know that they cause many fewer severe side effects in the gastrointestinal tract than traditional non-steroidal anti-inflammatory drugs (NSAIDS).

Also, investigations regarding specific damage to the small bowel show that COX-2 drugs cause less damage in this location than NSAIDS combined with proton-pump inhibitors (drugs like Nexium, Protonix, Prilosec, etc.) As a result, it is recommended that in patients requiring an anti-inflammatory drug, that COX-2 preparations are preferred for patients with gastrointestinal risk factors such as a prior history of ulcers or who are taking medicines such as anticoagulants (Coumadin) or corticosteroids.

Two other advantages of COX-2 drugs are that they cause much less bleeding than standard NSAIDS because they do not affect platelet function and that they can be used in patients who have aspirin-induced asthma.

An increase in cardiovascular events in patients taking COX-2 drugs was first noted during studies assessing the effect of COX-2 drugs in patients with adenomas of the colon.

Other studies then showed that regular tradtitional NSAIDS such as diclofenac (Voltaren) result in a similar cardiovascular risk. Further research has shown that all NSAIDS have this increase in cardiovascular risk that is indistinguishable from that associated with COX-2 drugs. This indicates that there is, at present, no distinction as far as cardiovascular risk associated with COX-2 drugs versus standard NSAIDS.

Another interesting twist is that standard non-NSAID analgesics such as acetaminophen (Tylenol) also inhibit COX-2 in vivo and should be evaluated for cardiovascular risk.

A recent analysis of the Nurses' Health Studies showed that volunteers taking acetaminophen at daily doses of more than 500 mg had a significantly higher risk of developing hypertension in comparison with a group not taking acetaminophen. The relative risk of hypertension associated with acetaminophen was surprisingly similar to that of NSAIDS. Confirming this finding, a large, prospective study showed that use of more than 15 tablets of acetaminophen per week leads to about the same risk as NSAIDS for cardiovascular events.

Current practice is to advise that patients take the lowest dose of COX2 inhibitor for as brief as time as possible. Exactly what the "safest" dose is and what the "safest length of time" is, still are unclear.

Additional studies are being performed that hopefully will identify and characterize laboratory markers that could be utilized to identify patients at cardiovascular risk before a decision is taken concerning the use of NSAIDS and COX2 inhibitors, in particular.

What's the take home message here? The first is that both traditional NSAIDS as well as COX-2 inhibitors carry the same risk for cardiovascular risks. In patients with gastrointestinal risk factors who require anti-inflammatory drugs, COX-2 preparations may be preferred over a combination of traditional NSAIDS and proton pump inhibitors. Data regarding this recommendation are still not set in concrete.

Analgesics such as acetaminophen may not be as safe as once supposed.

The "safest" dosing regimen for COX-2 drug administration remains to be defined. Further research is required to develop safer and more effective medicines.