Less than 24 hours after federal authorities announced that yet another painkiller was possibly linked to heart attacks, an arthritis sufferer e-mailed her Baltimore doctor yesterday a question that echoed across the country:
"So what now?"
The patient had shifted from Vioxx to Bextra to Celebrex and finally to naproxen - each time abandoning a drug that worked when news of possible cardiovascular risks emerged.
Now, with the surprise announcement that naproxen had come under scrutiny, Dr. Marc C. Hochberg had no choice but to admit his limitations.
"This is an area which is in flux, and I really can't give a Grade-A, excellent opinion to my patients because I haven't seen the data," said the chief of rheumatology at the University of Maryland Medical Center.
Like many other doctors swamped with queries from confused patients, Hochberg recommended trying to get by with a low dose of naproxen - but told her not to abandon the drug altogether. The plain truth, he said, is that patients with severe arthritis need relief.
Naproxen is sold over the counter as Aleve, as well as under proprietary labels. In prescription strength, it is sold as Naprosyn, Anaprox and Naprelan.
Monday's announcement by the National Institutes of Health that the 30-year-old drug might increase a person's risk of heart attack or stroke came at a uniquely confusing time for doctors and patients.
Over the past 11 weeks, a spate of studies have called into question the safety of four popular pain-relieving drugs that millions of people depend on to go about their daily lives.
Dr. Elias Zerhouni, director of the NIH, said the agency had stopped giving naproxen and Celebrex to volunteers in a three-year trial designed to determine whether either drug prevented Alzheimer's disease.
Early data from that trial indicated that people on naproxen were 50 percent more likely to suffer a heart attack or stroke than those on Celebrex or a placebo. Officials at NIH and the Food and Drug Administration recommended that naproxen-takers follow manufacturers' recommendations - no more than two 220-milligram tablets - and not take the drug for more than 10 days without consulting their physicians.
Four in a row
The announcement followed news in recent months that three anti-inflammatories - Vioxx, Bextra and Celebrex - might raise heart attack risks.
The news about naproxen was particularly surprising because it is in a different class than the other three, known as COX-2 inhibitors. Naproxen is an older medicine that works differently.
Yesterday, as many doctors were advising patients to stay on naproxen for now, some experts said the NIH might have spread unnecessary alarm.
"Everybody's running around gun-shy now," said Dr. Alastair Wood, professor of medicine and pharmacology at Vanderbilt University Medical School in Nashville, Tenn.
Like many colleagues, Wood noted that data from the canceled trial contradicted several previous studies, which found that naproxen actually has mild heart-protective properties.
While researchers debated the wisdom of the NIH's decision, doctors and their patients were grappling with the everyday realities of pain.
Nothing without risk
At the Johns Hopkins Hospital, Dr. Joan Bathon said she could not tell patients with crippling arthritis that there was no drug for them.
"If you have a disease like rheumatoid arthritis, where 50 joints are swollen and hot and painful, and you can't get out of bed in the morning, and it takes three hours to loosen up and button your shirt or diaper your baby, it is devastating," she said. "I told patients they have to be on something, and no medications are without some risk."
Before yesterday, Bathon had been advising patients to switch from the COX-2 inhibitors like Vioxx and Celebrex to old standbys like naproxen.
Because naproxen and similar drugs can cause stomach problems, doctors generally advise patients to take them with anti-ulcer drugs such as Prilosec and Nexium.
Bathon noted that no other study has implicated naproxen in cardiovascular disease. Now, she said, there is a desperate need for clarity on what the data from the Alzheimer's study show. She wonders, for example, whether certain patients in the study were particularly vulnerable to heart problems for reasons that are not now apparent.
"And we can't lose sight of the fact that aspirin in combination [with naproxen] may provide some cardio protection," Bathon said. Millions of people today take low-dose aspirin to reduce their risk of heart attack.
Dr. John Breitner, the geriatric psychiatrist at the University of Washington who ran the trial, said yesterday that the evidence against naproxen wasn't strong enough to justify stopping the trial. As recently as last week, a safety committee had looked at all three arms of the trial, in which patients were randomly assigned to take naproxen, Celebrex or a placebo.
"Their recommendation was to continue the trial unaltered," Breitner said.
But when Pfizer announced Friday that it would stop advertising Celebrex, investigators realized volunteers in the Alzheimer's trial would probably stop taking the drug on their own. And if researchers were to stop dispensing Celebrex, it made sense to stop naproxen as well. After all, it was naproxen - not Celebrex - that appeared to have the higher risk in their trial.
"The problem came when outside circumstances effectively forced us to stop naproxen," he said. "It's not something we would have chosen to do based on what we saw."
It is important for consumers to know, said Breitner, that the threshold for stopping a prevention trial - such as the ones involving Celebrex and naproxen - is much lower than it is in a trial aimed at controlling a serious disease.
In the Alzheimer's trial, for instance, healthy volunteers 70 and older had nothing to gain other than helping scientists prevent a crippling disease. Any success was surely years off.
Subjecting them to even a small risk might not be ethical under standard medical protocols. The same risk, however, might be acceptable to patients desperate for relief from a painful or potentially deadly disease.
Earlier studies have generally found that naproxen can reduce heart attack risk by 10 percent to 14 percent, according to Dr. Eric Topol, chairman of cardiovascular medicine at the Cleveland Clinic.
An early critic of Vioxx, Topol did not prescribe that drug to his patients even before it was withdrawn. When Pfizer announced the worrisome Celebrex findings last week, he recommended that patients avoid the drug if possible. By contrast, he said he will still tell those taking naproxen to continue using the medicine - despite the NIH announcement.
"Until we see more evidence, I would discount this trial," he said.
Topol noted that even if the increased risk for naproxen were confirmed by further research, the hazard would still be relatively small compared with Vioxx and Celebrex.
Naproxen - and similar drugs such as ibuprofen - work differently from COX-2 inhibitors such as Vioxx and Celebrex.
The latter two block an enzyme called cyclooxygenase-2 (COX-2). COX-2 triggers pain and inflammation, but it also seems to somehow protect the heart. So COX-2 inhibitors might simultaneously reduce pain and raise the risk of heart problems.
Naproxen inhibits COX-2, but it also blocks another enzyme called COX-1, which can harm the cardiovascular system. By reducing COX-1, naproxen might have a beneficial effect on the cardiovascular system, said Dr. Garrett Fitzgerald, a University of Pennsylvania cardiologist and pharmacologist who has studied COX inhibitors and heart disease.
The downside is that naproxen and similar drugs - called nonsteroidal anti-inflammatories - can cause gastrointestinal bleeding.
But the relationship between naproxen and heart disease is far from clear. Some researchers said that because naproxen and similar anti-inflammatories such as ibuprofen block COX-2, they too might raise the risk of heart attack.
'Some brief respite'
Mark Zinda, of Strewsbury, Pa., said the reality for rheumatoid arthritis sufferers like him is that all drugs have side effects. Some cause kidney or liver problems if taken for a long period of time. Others can cause ulcers.
"The medications provide some brief respite of relief, but there have always been concerns of side effects," said Zinda, 50, who is now on Celebrex but has also taken naproxen and Vioxx.
If additional data show that Celebrex is dangerous, he might have to consider starting something else. But that, too, will likely bring its own problems, he said:
"I'm going to do whatever I can to keep myself going."