RxNews: Are New Painkillers Really Safe?

Healthfacts, Feb, 1999

A highly touted new class of arthritis drugs has the potential to cause serious cardiovascular problems. Known as COX-2 inhibitors, these new drugs have been the subject of glowing reports in the scientific and popular press. No one is claiming that the new drugs are more effective, just that they are less likely to cause the severe gastrointestinal reactions associated with other, older nonsteroidal anti-inflammatory drugs (NSAIDs), which include aspirin, ibuprofen, naproxen.

In the course of their biochemical analysis, Garret A. FitzGerald, M.D., chairman of the department of pharmacology, University of Pennsylvania Medical Center, and colleagues, discovered that the first FDA-approved COX-2 inhibitor, Celebrex (generic name: celecoxib), suppresses prostacyclin (Proceedings of the National Academy of Science, 1/5/99). Prostacyclin, a naturally occurring hormone-like substance produced in the walls of blood vessels, inhibits the aggregation of platelets (clotting). If suppressed, blood clots may be more likely to occur and cause a heart attack or stroke. The finding raises special concerns about the drugs safety in older adults who are both more likely to need relief from arthritis pain and to have heart problems. Dr. FitzGerald cautioned RxNews that his study of the drugs activity in the body only raises a flag and that much more experience would be needed to see if Celebrex actually increases the incidence of adverse cardiovascular events.

While aspirin, ibuprofen, naproxen and all of the older NSAIDs also suppress prostacyclin, they have an additional action which paralyzes the blood platelets, thus limiting the potential for clots to occur. This is why low-dose aspirin is currently recommended as a preventive for heart attack and stroke.

When Celebrex was approved by the FDA at the end of 1998, the drugs maker was denied permission to include in the product labeling any claims that the drug caused significantly fewer gastrointestinal problems than other NSAIDs. Last month, Murray Lumpkin, the FDAs deputy director for drug evaluation, told the Wall Street Journal that Celebrex may hold the promise of being safer, but that question has not been fully answered yet.

Adding to the uncertainty is evidence from England that another type of COX-2 inhibitor, meloxicam, may not have a substantially lower risk of gut problems than older NSAIDs. The British Medicines Control Agency and the Committee on Safety of Medicines have received 1,339 reports of adverse reactions subsequent to its approval. (Current Problems in Pharmacovigilance, 8/98) Included were 99 reports of gastric perforation, ulcers or bleeding which in five cases were fatal.

There is no convincing evidence that the risk of the severest adverse gastrointestinal events, namely peptic ulceration, perforation and bleeding, is lower with meloxicam than with other NSAIDs when given in equi-effective doses . . . , according to Drug and Therapeutics Bulletin (8/98), a British publication for physicians that accepts no drug advertising.

Adverse effects of new drugs often become apparent only after approval and much larger numbers of people have been exposed over longer periods of time. The lack of convincing evidence of Celebrexs superior gastrointestinal safety and the possibility of its cardiovascular risks suggests a need for post-marketing safety studies. But the FDA lacks the necessary resources and relies on manufacturers who often do not follow through with the necessary studies. In addition, the agency is likely to face tremendous pressure to approve additional Celebrex-type drugs (brand names: Vioxx and Relafen) whose makers want a piece of the projected $5 billion market.

The COX-2 inhibitors are considerably more expensive (approximately $2.50 per pill) than older NSAIDs, many of which are available over-the-counter. For the time being, at least, RxNews suggests that consumers may want to wait for more convincing evidence of their safety before using these so-called super aspirins.