Vanderbilt Research Shows High Doses Of Popular Pain Reliever Prescribed Despite Heart Risk

Yet a “substantial number” of patients continue to be prescribed high doses of the drug, according to researchers at Vanderbilt University Medical Center.

The researchers counted the number of prescriptions for non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, naproxen, Celebrex and Vioxx, given to participants over age 49 in Tennessee’s Medicaid program, called TennCare.

Of 40,000 participants who had prescriptions for any NSAID as of July 1, 2001, nearly 10,000 were taking Vioxx, and more than 1,000 of them were “high-dose” Vioxx users, with 30-day supplies of 50-milligram pills. Half that amount — 25 milligrams a day — is the recommended dose for long-term use.

The 50-milligram dose has not been shown to be more effective than lower doses of the drug in relieving chronic pain, and it has been linked to an increased risk of heart attacks. “Such use should be discouraged,” the researchers concluded in the June issue of the journal Pharmacoepidemiology and Drug Safety.

Vioxx (the brand name for rofecoxib) and Celebrex (celecoxib) are selective COX-2 inhibitors. They relieve inflammation by blocking the cyclooxygenase-2 enzyme, but they don’t inhibit the related COX-1 enzyme, which protects the stomach lining. Therefore they don’t irritate the stomach as much as NSAIDs that block both enzymes.

“They cause fewer ulcers,” explained the study’s lead author, Marie R. Griffin, M.D., MPH, professor of Preventive Medicine and Medicine. “That’s a good thing in many ways, although there’s a lot of people using them who are pretty low risk for GI (gastrointestinal) events.”

COX-2 inhibitors also cost $80 to $100 per month, compared to about $10 to $15 for a month’s supply of generic naproxen.

“We think that the rationale is that if 25 milligrams works well, then 50 milligrams is going to work better,” Griffin said. “But when you look at the scant data that’s out there for chronic pain, there’s been no study that shows that 50 is better than 25.

“This is really common with a lot of drugs, that there’s a ceiling on the effective dose … But unfortunately, there’s usually not a ceiling on the side effects.”

Griffin and her colleagues, who include Wayne A. Ray, Ph.D., professor of Preventive Medicine, and C. Michael Stein, M.D., professor of Medicine, have been sounding the alarm about high-dose Vioxx use since 2002.

In a study of TennCare participants published in the journal Lancet that year, the researchers reported patients on high doses of Vioxx had nearly twice the rate of serious heart problems, including heart attacks and heart-related deaths, compared to patients not on the drug.

Other groups have reported similar findings among high-dose Vioxx users: an increased risk of heart attack and congestive heart failure, a rise in blood pressure and a greater incidence of edema, or swelling, in the arms and legs, which can put extra strain on the heart. Griffin said that high doses of Vioxx might be particularly hard on the kidney, resulting in fluid retention, edema and a rise in blood pressure.

Some doctors won’t prescribe Vioxx for patients at risk for developing high blood pressure, because the drug could make that condition more difficult to control, Griffin said. However, many other doctors apparently underestimate the drug’s ability to cause edema, hypertension and heart failure, she added.

Of the TennCare patients in the Vanderbilt study who were receiving over 25 milligrams of Vioxx a day, 15 percent had been treated for congestive heart failure during the previous 12 months, and 22 percent had been treated for other forms of heart disease, the researchers reported.

“Educating all clinicians about this is a very difficult task. There are so many drugs out there,” Griffin said. “I personally think that the best thing would be to get rid of the 50-milligram dose, or sell it only in packages of five.

“You hate to make people jump through hoops to get things but … it should be harder to prescribe drugs that would potentially do harm.”

Others who contributed to the Vanderbilt study were Patrick G. Arbogast, Ph.D., assistant professor of Preventive Medicine; James R. Daugherty, M.S., computer systems analyst in the department; and David J. Graham, M.D., of the U.S. Food and Drug Administration.

Griffin consults for Merck Research Laboratories, part of Merck & Co., Inc., which makes Vioxx, but none of the funding for this study was provided by Merck or any other pharmaceutical company.

The study was supported in part by a grant from the U.S. Centers for Education and Research on Therapeutics.