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The Pain Medicines: Another Chapter is Written
But will it allow us to answer questions about their cardiovascular risks?

Michael Weber, M.D.
Medical Progress Today
January 27, 2006

It is now well over a year since Merck & Co. took their pain medication Vioxx (rofecoxib) off the market after an ongoing long-term clinical trial raised concerns that it might increase the risk of heart attacks and other cardiovascular events. Vioxx was a widely used drug of a class called COX-2 (cyclo-oxygenase-2) inhibitors.

The popularity of these modern pain-relieving drugs was based on the fact that since they did not disrupt COX-1 mechanisms, which are responsible for protecting the lining of the stomach and other sensitive parts of the intestine, they would able to reduce serious problems like peptic ulcers and gastrointestinal bleeding that can be caused by older non-selective pain medications.

After Vioxx, another of the COX-2 drugs, Bextra, was also taken off the market, though not primarily because of cardiovascular issues. At this time, only one drug of this type – Celebrex (celecoxib) – remains on the market.

Now, Celebrex is in the news, though for a potentially positive reason. Its manufacturer, Pfizer, has recently announced that they plan to fund a major clinical trial – probably costing upwards of a hundred million dollars – to test once and for all how Celebrex compares with older pain drugs – in particular, ibuprofen (Advil) and naproxen (Aleve) – in terms of cardiovascular safety.

Is such a study really necessary? It would be convenient and cost-effective if safety and efficacy questions could be answered by mechanistic research carried out in the laboratory or among relatively small groups of human subjects. In fact, there are some theoretical reasons to believe that drugs with differing effects on the COX systems might have opposing effects on causing or preventing the blood clots that can precipitate heart attacks and strokes. Unfortunately, as yet it has not been possible to reliably link these actions to clinical outcomes with the pain medicines, and so right now there is not a good alternative to classical clinical observations.

All this aside, it could be argued that we do not really need further information about these safety issues. After all, the potential cardiovascular problems with Vioxx were already in evidence some years ago, stimulating a great deal of research into safety issues not only with that drug but also with drugs like Celebrex as well. By and large, there appears to be a difference between Vioxx and Celebrex. When used in higher doses, particularly over longer time periods, a number of studies have shown that Vioxx might increase the risk of cardiovascular events when compared with traditional pain medications. This problem has not generally been seen with Celebrex. In 2002 the Food and Drug Administration (FDA) asked Merck to put warnings about possible cardiovascular risks in the official label of their drug.

But soon afterwards the whole situation got more complicated. Somewhat troubling, some retrospective studies based on patient treatment data showed that most of these agents – even the older drugs that had become staples of pain treatment for many years – appeared to have some cardiovascular risk when compared with taking no medicines at all.

In addition, two ongoing trials with Celebrex were abruptly stopped due to safety concerns, again attracting public attention. In one study, where Celebrex was being compared with placebo in patients at risk of bowel tumors, high doses of the drug appeared to increase the risk of heart disease. In contrast, in a second study conducted in patients with Alzheimer’s disease, there was no evidence of increased risk with Celebrex. Rather, the traditional pain drug naproxen, which was being used as a comparison in the study, was found to be more likely than placebo to cause serious events. The FDA, not surprisingly, decided to take a conservative tack and require that all of these drugs, old and new, when used in full prescription strength, be labeled to indicate the possibility of cardiovascular risk.

In view of all this somewhat confusing information, it seems that Pfizer’s plan to do a definitive prospective trial in patients with arthritis makes a great deal of sense. One limitation, though, is that it is designed to compare Celebrex with traditional pain drugs, but not with placebo. This decision is understandable since it would be improper to ask people in true need of pain relief to take placebo over an extended period of time. Even so, we will still not get definitive information about whether, or to what extent, Celebrex really raises the risk of cardiovascular events. On the positive side, since this is a prospective, randomized trial we can have confidence that whatever results are obtained will be credible.

A key attribute of this planned multi-year trial is that the 20,000 patients who will participate will be selected because they already have risk factors for cardiovascular disease. This will make them typical of many older people who are dependent on long term use of pain medicines. As well, along with their pain medicines, many people in the study who have already suffered a cardiovascular event will be taking low-dose aspirin to help protect them from further heart disease.

Of course, for those people who simply have painful conditions but do not have heart risk factors, the results of this trial may not be completely relevant. Other questions come up as well. For instance, much use of pain medicines is for relatively short term treatment, days or weeks. This new study will probably not help determine whether such people are at any increased risk.

Another critical question has to do with dose. This planned trail will utilize full prescription doses of Celebrex and the other drugs, but this may not be relevant to the way that the older medicines – ibuprofen and naproxen – are often used. After all, every convenience store and supermarket busily sells brands like Advil or Aleve with recommended doses about half those to be used in the new clinical trial. Are there any cardiovascular risks associated with this very widespread use of pain drugs? This is not a trivial concern, for in the trial mentioned previously in which combined cardiovascular events were greater with naproxen than with placebo, patients received the recommended over-the-counter dose rather than the even higher prescription dose. Lack of definitive data regarding these products is troubling, particularly in an era when as a cost saving measure many insurance plans tell physicians to encourage their patients to buy these over-the-counter products rather than filling prescriptions.

In some ways this planned trial is as much about political correctness as scientific correctness. Though Pfizer will fund this work, it will be done under the banner of the Cleveland Clinic. The study data will be housed at the Clinic and will be shared with the National Institutes of Health. Moreover, the physicians charged with management of the trial will have no direct connection with Pfizer or with other companies that make any of the drugs being studied.

Though this type of independence and openness may seem attractive, it should not be interpreted in any way as questioning the integrity and effectiveness of the traditional processes that continue to be employed in the clinical development of pharmaceutical agents. And regardless of what might have motivated this new trial, we should not overlook the currently available information about drugs like Celebrex, Advil and Aleve that can already allow patients and doctors to make reasonably informed decisions about their use.

Dr. Michael Weber is a Professor of Medicine at the State University of New York Downstate College of Medicine. He serves as a consultant to the Center for Drug Evaluation and Research at the FDA and is a former member of the Agency's Cardiovascular and Renal Drugs Advisory Board. His major research interests are in preventive cardiology and he has served a President of the American Society of Hypertension. He is a mamber of the editorial boards of several journals in the area of cardiovascular medicine.

Note: The writer provides consulting services to pharmaceutical companies, including those whose products are mentioned in this article.

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