THE unfolding US drug scandal, and the run of bad news about the risks of taking some popular pain-killers, expanded this week when the US Food and Drug Administration (FDA) announced that naproxen, a painkiller sold over the counter in the US as Naprosyn or Aleve, and available 'behind the counter' in Bermuda, might increase a consumer's risk of having a heart attack or stroke.

Pharmaceutical and medical sources in Bermuda continued to express confidence in the FDA and other regulatory regimes, and in the ability of the medical profession to respond appropriately to any negative news about prescription drugs.

In the US, acrimony over the performance of the FDA boiled over into the political arena with Republican Senator Charles Grassley and Democratic Senator Edward Kennedy excoriating the FDA's lack of commitment to drug safety and the White House being forced to come to its defence.

The Mid-Ocean News reported last week on mounting alarm over the dangers associated with 'cox-2 inhibitor' drugs in the wake of the withdrawal of Vioxx and concerns associated with other drugs in the 'cox-2' class.

We reported that an editorial to run in the February 2005 edition of Annals of Internal Medicine had recommended that doctors discontinue prescribing any of the cox-2 inhibitors (including Arcoxia, Celebrex, Mobic, and Bextra, all still being prescribed today in Bermuda) "as a first-line agent" in patients with a high risk of heart attack, and instead prescribe non-aspirin, non-steroidal anti-inflammatory drugs known as NSAIDs, and only prescribe celecoxib (Celebrex) for patients with a high risk of stomach problems or internal bleeding.

But also last Friday, Pfizer, the manufacturer of Celebrex, announced that it had found an increased risk of heart attack in patients taking Celebrex, and the beleaguered FDA, under fire for an alleged dangerously close relationship with the drug industry, said on the same day it was considering regulatory measures that would include severe label warnings or even require the withdrawal of Celebrex in the US.

On Sunday, Pfizer announced that it would suspend all consumer advertising, but would neither withdraw the drug nor suspend marketing Celebrex to doctors.

The news on Tuesday about naproxen further complicates the lives of doctors, pharmacists and patients because it is the precisely the type of NSAID recommended by Dr. Axel Finckh and Dr. Mark Aronson, authors of the AIM editorial, to replace the apparently riskier 'cox-2 inhibitors', and the news about naproxen and Celebrex has broken long before their editorial's formal publication date.

This avalanche of disturbing news has caught the stoic defenders of the role of the FDA off guard. Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs, was a bureaucratic adversary of FDA "whistle-blower" Dr. David Graham, the scientist who spoke out about the dangers of cox-2 inhibitors and other drugs in the face of intense personal and professional pressure.

He was essentially responsible for the withdrawal of Vioxx and for the spotlight currently being shone on the FDA and "Big Pharma", the global drug industry which has come under increasing political and media pressure for allegedly putting profit before drug safety.

"This is a very confusing situation," conceded Dr. Kweder at a hastily convened telephonic news conference on Tuesday. "Naproxen has been on the market since 1976, and this is the first evidence we've seen that suggests there is a risk."

However, she and other officials acknowledged that no one seems to have studied the long-term safety of naproxen or any of the other popular pain-killers known as NSAIDs. It is a large class of drugs that includes such widely used medications as ibuprofen (such as Motrin or Advil), naproxen (such as Naprosyn and Aleve), and the already withdrawn or tarnished 'cox-2 inhibitors' such as rofecoxib (Vioxx), celecoxib (Celebrex) and valdecoxib (Bextra).

Researchers uncovered the potential problem with naproxen last Friday during a quick review of data from a large, ongoing three-year-old National Institutes of Health (NIH) study. As part of that study, which aimed to see if anti-inflammatory drugs could help delay the onset of Alzheimer's disease, 2,500 elderly people had been receiving regular doses of naproxen or Celebrex.

Ironically, the review was ordered because of recent concern about Celebrex, but officials were surprised to discover that participants taking naproxen were 50 per cent more likely to suffer a heart attack or stroke than those taking a placebo. In this review, and contrary to other recent evidence to the contrary, those taking Celebrex saw no apparent increase in any life-threatening events.

With many participants already expressing concern about other negative reports on Celebrex, the new evidence about potential problems with naproxen led NIH officials and study leaders to suspend both parts of the Alzheimer's study as a "precautionary measure".

"It may be a problem for all non-steroidal anti-inflammatory drugs, because we've never had the opportunity to examine this question," said John Breitner of the University of Washington, the leader of the study.

Pfizer announced last Friday that the National Cancer Institute, which was conducting one of two long-term cancer prevention trials for Pfizer, suspended the use of Celebrex after discovering that patients taking 400mg to 800 mg of the drug daily, at least four times the regular dose, had 2.5 times greater risk of experiencing major heart problems than those who were not. A separate cancer study found no increased risk for patients taking 400mg a day.

Tracey Marra, president of the Bermuda Pharmaceutical Association, was surprised by the news about naproxen, remained confident that the FDA would continue to operate as a dependable drug regulator, but accepted that the situation with some individual drugs was uncertain.

"With Celebrex, as of two days ago, (Pfizer) wasn't removing it from the market," said Ms Marra, "and that seems a reasonable position given that one study showed some risk with very high doses, and another did not.

"And there is quite a considerable proportion of people who are at some risk of bleeding, or whose stomachs would not otherwise respond well to taking aspirin or Voltarin, enough so that a 'cox-2' got added to the medications available at the hospital."

Ms Marra accepted that the pharmaceutical association had a responsibility to warn local physicians about any problem with drugs being prescribed locally.

"It should be that way," advised Ms Marra. "The pharmacists are the drug experts, and it's our job to inform the physicians. It's not done in an entirely official way, and everyone is expected to keep up with things.

"I haven't lost faith in the FDA, and it's not surprising that they form relationships with the drug companies. I think that drugs coming out of the US will continue to be as safe, or safer, than drugs from other countries, and that if anything untoward is going on, we are more likely to hear about it sooner.

"I just feel that these drugs offer so much benefit to people and, yes, there are going to be risks for any drugs out there, and some have serious 'black-box' warnings, but it's always a question for the doctor and the patient, and the pharmacist, of weighing the benefits and the risks.

"I don't think drugs should be taken off the market just because of an identified risk, even a heart risk, if it offers enough benefit otherwise.

"I am surprised to hear the news about naproxen, but we don't have that 'over-the-counter' here. All of the Advils and ibuprofens are kept behind the counter, and so anyone coming in for those medications has to see the pharmacist."

Dr. Brenda Davidson (pictured) , acting Chief Medical Officer in the absence of Dr. John Cann, agreed with Ms Marra that consumers had to weigh the benefits and risks of all drugs, and that it was up to individual doctors to stay abreast of news about drugs and current best practice.

"I think they should be aware of the controversy," said Dr. Davidson, "but this whole issue underlines the principle that doctors shouldn't be prescribing, and patients shouldn't be taking, medications that perhaps aren't absolutely necessary.

"There's a temptation to treat every complaint, but not all complaints need to be treated, and doctors and patients should be aware of the benefits and risks of taking medication, or of not doing so. I think that the knee-jerk reaction is to treat every complaint, and that situation is not helped by the volume of advertising directly to consumers, particularly on US television, where every twinge seems to need a pill. Patients and doctors should be able to make an informed choice."

This week, the Bush administration took issue with critics of the FDA over whether the agency is doing an adequate job overseeing drug safety, or whether it needs major reform. During an appearance last Sunday on ABC's This Week, White House Chief of Staff Andrew Card said the FDA was doing a "spectacular job" and should "continue to do the job they do".

Asked whether he supported Senator Grassley's call last week for an investigation of the FDA similar in scale to the 9/11 Commission, Card said, "I don't know that we need a commission" and "I've got great confidence in the FDA". He said the news coming out about previously unaddressed drug safety risks was "a testament to the FDA in how they do their job".

Later, Senator Edward Kennedy responded that the FDA's "record of protecting us from harmful prescription drugs is a catastrophic failure. Early action on bipartisan FDA reforms is possible in Congress, and I hope that the White House and congressional leadership will not stand in the way."

Mr. Card, a senior figure in a White House administration that boasts of not reading newspapers or watching television news, seemed unaware that the FDA had gone to extraordinary lengths to try to stop negative testimony about Vioxx and other drugs being given to Senator Grassley's committee by Dr. David Graham, who also appeared on This Week.

"The FDA wasn't concerned about Vioxx, and wouldn't have removed it from the market if Merck hadn't, yet over 100,000 patients had heart attacks because of Vioxx," Dr. Graham said. "The fact that the FDA now says that it's concerned about Celebrex to me is a very serious signal. I wouldn't prescribe it to my mother-in-law."