Introduction

Two years ago the introduction of the first cyclooxegenase-2 inhibitors was heralded as a new era in anti-inflammatory treatment (see below our previous article "Are COX-2 inhibitors worth it?"). The theoretical advantage of COX-2 inhibitors over nonsteroidal anti-inflammatory drugs (NSAIDs) -- a lack of COX-1 inhibition, meaning absent gastrointestinal and platelet side effects -- appeared to be borne out in early clinical studies. Since then, the different effects of the two drug classes have become clearer in some respects, and more obscure in others.

Effectiveness

The enzyme COX-2 is up-regulated (i.e. production is increased) during inflammation. It's expressed in neutrophils, macrophages, endothelial cells and fibroblasts. Its expression is increased in the synovial tissues in inflammatory forms of arthritis, whereas COX-1 is not. It's clear, therefore, that the beneficial effects of both COX-2 and NSAIDs in arthritis are due to their inhibitory effects on COX-2. Inhibition of COX-1, a parallel effect of NSAIDs, does not counter the effects of inflammation.

The effectiveness of the two available COX-2 inhibitors, celecoxib (Celebrex®) and rofecoxib (Vioxx®), has been shown in comparative clinical trials to be equal to that of NSAIDs. To date, there is no reason to believe that COX-2 inhibitors offer any superiority over NSAIDs with regard to efficacy.

Gastrointestinal toxicity

Adverse gastrointestinal effects of NSAIDs are generally attributed to their COX-1 inhibitory action. Theoretically, therefore, COX-2 inhibitors should be devoid of any gastrointestinal toxicity, based on their high selectivity. It should be recognized, however, that there are no 'pure' COX-2 inhibitors (as yet); in other words, the most potent COX-2 inhibitor available, rofecoxib, has a >50-times greater inhibitory effect on COX-2 than on COX-1, but nevertheless it has a measurable inhibitory effect on COX-1. The laboratory tests that ranked COX inhibitors based on in vitro inhibition found that rofecoxib was in the >50-times 'COX-2 selective' group, celecoxib was in the 5 to 50-times selective group (along with meloxicam, nabumetone and etodolac), while the typical NSAIDs were in the <5-times selective group.¹

How about actual clinical results? Two large studies have found that arthritis patients not taking low-dose aspirin (325 mg/day or less) who were given one or other of these COX-2 inhibitors had significantly fewer symptomatic and complicated gastrointestinal ulcers than patients given nonselective NSAIDs.²,³ However, in one of the trials a significant reduction was not demonstrated in patients who were taking low-dose aspirin. Low-dose aspirin is itself a risk factor for these side effects, thanks to its COX-1 inhibitory effect, but it's likely to be used in a number of candidate patients for anti-inflammatory drugs. Obviously, further studies are needed to determine whether COX-2 selective inhibitors are safer than nonselective NSAIDs when used in patients receiving low-dose aspirin.

Clinical studies with the 'relatively-selective' COX-2 inhibitors (meloxicam, nabumetone and etodolac) give equivocal results -- most show superiority of these drugs to nonselective NSAIDS with regard to gastrointestinal effects, while a few show the reverse.

Renal toxicity

NSAIDs may cause deleterious effects on kidney function, especially with respect to solute homeostasis and maintenance of renal perfusion and glomerular filtration. It has been shown that COX-2 is expressed in renal tissues, and may be involved in prostaglandin-dependent homeostasis in the kidneys. Inhibitors of COX-2 might, therefore, be expected to produce effects on renal function similar to nonselective NSAIDs that inhibit both COX-1 and COX-2.

Clinical studies show that both rofecoxib and celecoxib produce qualitative changes in urinary prostaglandin excretion, glomerular filtration rate, and sodium retention similar to those caused by nonselective NSAIDs.

Effects on thrombosis

The COX enzymes have opposing roles in the thrombotic process. Prostacyclin, which inhibits platelet function and causes vasodilatation, is synthesized by the action of COX-2. On the other hand, the production of thromboxane A2, a promoter of platelet aggregation and vasoconstriction, is regulated by COX-1. Nonselective NSAIDs inhibit COX-1 and COX-2, exerting a balanced effect on these systems; however, COX-2 selective inhibitors may be expected to tip this balance in a 'pro-thrombosis' direction.

In August 2001, a meta-analysis of published clinical studies was reported that suggested an increased cardiovascular risk associated with the use of COX-2 inhibitors.⁴ The relative risk of developing a thrombotic cardiovascular event (e.g. myocardial infarction, unstable angina, sudden cardiac death, ischemic stroke, transient ischemic attack) was 2.38 in the rofecoxib vs. naproxen study. There was no significant difference in cardiovascular events in the celecoxib vs. NSAID study. It seems possible that the risk -- if any - is associated with the degree of COX-2 selectivity. However, the findings emphasize the need for the concomitant use of low-dose aspirin in patients at risk for such events, especially myocardial infarction.

Effects on Blood Pressure

In a 6-week study involving hypertensive patients with osteoarthritis, both rofecoxib and celecoxib were found to increase systolic and diastolic blood pressure to a slight degree, and cause edema in some patients -- rofecoxib more than celecoxib.⁵

COX-2 and colon cancer

There is experimental evidence that COX-2 expression can contribute to tumorigenesis, especially colorectal cancer and polyposis. In animal models, COX-2 inhibitors attenuate the formation of colon adenomas in mice.

Celcoxib given twice daily for 6 months reduced the mean number of colorectal polyps in patients with familial adenomatous polyposis. This appears to be a fruitful area for further studies.

Conclusions

The available information on COX-2 selective inhibitors shows that these drugs probably have clear-cut advantages with regard to gastrointestinal side effects. However, the design of the major clinical trials are not well-suited to proving this -- in nearly all of them, comparisons were made between fixed doses of the drugs, without use of the 'optimal' individual doses, i.e. the minimal effective dose. Further studies are needed to determine the actual risk of gastrointestinal side effects at minimally effective doses, and whether concomitant use of low-dose aspirin is feasible without loss of efficacy and tolerability.

The potential for cardiovascular toxicity requires further exploration in clinical studies -- again with the addition of low-dose aspirin. And the recent benefits shown by the 2-year administration of NSAIDs in reducing the risk of Alzheimer disease (see below "NSAIDs and Alzheimer Disease -- What to Advise?") need to be clarified with regard to the use of COX-2 selective inhibitors.

Today, we only stand on the threshold of the development of COX-2 inhibitors as useful therapeutic entities. In addition to further studies with the available selective and 'relatively selective' COX-2 inhibitors, the introduction of new drugs in this class will help clarify the distinct clinical relevance of each COX enzyme.