27 December 2005

Vioxx litigation

By JOHN CURRAN Associated Press Writer
December 26,2005 | ATLANTIC CITY, N.J. -- For someone mired in judicial purgatory, Superior Court Judge Carol Higbee is remarkably upbeat. She doesn't want pity -- many judges work as hard, she says. She doesn't want publicity -- it makes her uncomfortable, and she grants interview requests grudgingly. She just wants justice -- and she's ready to dispense it, one Vioxx case at a time, even if it takes a lifetime.

And at the current rate, it could, assuming the cases are not settled or withdrawn.

Higbee, 55, is the New Jersey judge assigned to thousands of cases brought in state court against Merck & Co. over its now-withdrawn painkiller Vioxx. The lawsuits -- all 4,333 of them -- blame the Whitehouse Station-based pharmaceutical company for heart attacks and strokes suffered by users.

Merck has acknowledged links between Vioxx and heart attacks and strokes in clinical studies, but only after 18 months' use.

If they all go to trial and take as long as a recent, seven-week case, Higbee would need 583 years to hear them all.

"I don't foresee that that's the way things will happen," she said in a recent interview with The Associated Press. "I'm going to be a judge for X many more years and during those years, I'll be trying cases. Maybe they're Vioxx cases, maybe they're others."

The way things are going, they'll be Vioxx cases. With 9,200 cases filed nationwide and former users still streaming into courthouses with new claims, the litigation shows no signs of slowing.

Merck & Co. has said it plans to fight the lawsuits, one by one. In New Jersey, the responsibility for trying them all falls to Higbee, a soft-spoken former medical malpractice attorney known for cutting through the cant without playing favorites.

Higbee says patience isn't one of her strong points. But she has shown plenty of it so far, refereeing battling lawyers in the recent trial -- which ended Nov. 3 with a Merck victory -- and meeting with lawyers for Merck and the plaintiffs to schedule the trials to come.

On Feb. 27, it's back to the courtroom for the next Vioxx trial. As in the first, Higbee will spend her days on the bench and her nights at home reviewing trial transcripts in preparation for the next day's session. And when she isn't dealing with a Vioxx issue, she'll be tending to the 375 non-Vioxx cases on her docket.

"Vioxx is important. Every other piece of litigation I have is important. Even though it's more high-profile, it's not more important than any other case," Higbee said.

A native of Mishawaka, Ind., Higbee attended Temple University and its law school before spending 17 years in private practice, working as a plaintiffs attorney on behalf of victims of slip-and-falls, bad drugs and negligent doctors. In 1993, she was appointed to the bench by then-New Jersey Gov. James Florio, a position that now pays $141,000 annually.

When it became clear that Vioxx litigation was going to tax New Jersey courts, the state Administrative Office of the Courts looked to Higbee.

"Judge Higbee was an obvious choice," spokeswoman Winnie Comfort said. "She's experienced and she can manage the incredible workload that comes with some of these mass tort cases."

When she's off the bench, Higbee spends her time at home tending to her rose bushes and tomatoes, reading mystery novels and -- with her husband, a high school English teacher and part-time actor -- raising their 5-year-old granddaughter.

For now, though, her eyes are squarely on the mountain of work ahead of her.

Will the Vioxx workload ever ease up?

"It depends on the participants," she said. "They can choose what they want to do. And what they want to do today may be different from what they want to do later. Litigation, it's just like the rest of life. You never know what's around the corner."
© 2005 The Associated Press. Link

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Tylenol tragedies

I've railed about acetaminophen here before. It really is ugly: People who just need more pain-relief; attempted suicides (often first-attempts involving people who aren't really trying to kill themselves); and recreational drug users who don't know that its the acetaminophen that's more dangerous (to them) than the hydrocodone or oxycotin.

December 26,2005 | WASHINGTON -- Think popping extra pain pills can't hurt? Think again: Accidental poisonings from the nation's most popular pain reliever seem to be rising, making acetaminophen the leading cause of acute liver failure.

Use it correctly and acetaminophen, best known by the Tylenol brand, lives up to its reputation as one of the safest painkillers. It's taken by some 100 million people a year, and liver damage occurs in only a small fraction of users.

But it's damage that can kill or require a liver transplant, damage that frustrated liver specialists insist should be avoidable.

The problem comes when people don't follow dosing instructions -- or unwittingly take too much, not realizing acetaminophen is in hundreds of products, from the over-the-counter remedies Theraflu and Excedrin to the prescription narcotics Vicodin and Percocet.

"The argument that it's the safest sort of has overruled the idea that people cannot take any amount they feel like," says Dr. William Lee of the University of Texas Southwestern Medical Center, who laments that acetaminophen is popped like M&Ms.

Acetaminophen bottles currently recommend that adults take no more than 4,000 milligrams a day, or eight extra-strength pills.

Just a doubling of the maximum daily dose can be enough to kill, warns Dr. Anne Larson of the University of Washington Medical Center.

Yet, "if two is good, 10 is better in some patients' minds," she says with a sigh.

The Food and Drug Administration has long wrestled with the liver risk, warning two years ago that more than 56,000 emergency-room visits a year are due to acetaminophen overdoses and that 100 people die annually from unintentionally taking too much.

A study published this month by Larson and Lee has agency officials weighing whether to revisit the issue.

Over six years, researchers tracked 662 consecutive patients in acute liver failure who were treated at 22 transplant centers. (Acute liver failure is the most severe type, developing over days, unlike chronic liver failure that can simmer for years because of alcohol abuse or viral hepatitis.)

Almost half were acetaminophen-related. More remarkable was the steady increase: Acetaminophen was to blame for 28 percent of the liver poisonings in 1998, but caused 51 percent of cases in 2003.

That makes acetaminophen the most common cause of acute liver failure, the researchers report in the journal Hepatology.

While most patients pulled through with intensive care, 74 died and 23 others received a transplant.

Some 44 percent of the cases were suicide attempts.

But more, 48 percent, were unintentional overdoses, which "isn't hard to do," Larson says.

Say you take Tylenol Cold & Flu Severe for the flu's aches and stuffiness -- 1,000 mg of acetaminophen, every six hours. A headache still nags so between doses you pop some Excedrin -- 500 mg more of acetaminophen. Switch to Nyquil Cold/Flu at bedtime, another 1,000 mg.

Maybe you already use arthritis-strength acetaminophen for sore joints -- average dose 1,300 mg.

Depending on how often they're taken, the total acetaminophen can add up fast.

That's the nonprescription realm. Surprisingly, 63 percent of unintentional overdoses involved narcotics like Vicodin and Percocet that contain from 325 mg to 750 mg of acetaminophen inside each pill.

Some were chronic pain sufferers taking more and more narcotics as their bodies adjusted to the powerful painkillers, not knowing they were getting ever-higher acetaminophen at the same time. Or they added over-the-counter products for other complaints.

Just this month, Larson treated an 18-year-old whose liver crashed after using Vicodin for three or four days for car-crash injuries. "She was just taking too much because her pain was bothering her."

Led by Tylenol manufacturer McNeil Consumer & Specialty Pharmaceuticals, most over-the-counter products now voluntarily list acetaminophen on front labels.

McNeil also runs ads about the risk, saying "if you're not going to read the label, then don't buy our products," says spokeswoman Kathy Fallon.

But how strongly labels warn varies by product. A rule to standardize warnings, urged by FDA's scientific advisers in 2002, still is working its way through the agency.

While FDA runs a consumer education campaign about the liver risk, nonprescription drugs chief Dr. Charles Ganley says the new study suggests the agency may need to further target narcotic-acetaminophen combinations.

Lee wants to copy Britain, which saw a 30 percent drop in severe liver poisonings after restricting how much acetaminophen could be bought at once.

That's unlikely. Meanwhile, the advice is simple: Read drug labels and add up all your acetaminophen, avoiding more 4,000 mg a day. For extra safety, Lee advises no more than 2,000 to 3,000 mg for more vulnerable people, who regularly use alcohol or have hepatitis.Link

It's not that I think acetaminophen should be discouraged or even removed from OTC. But I do think we need some more effective education campaigns.
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08 December 2005

Starting off, and update

For you new readers of PFP, let me entice you with my two favorite (apparent) facts about pain:
Pain hurts less when it is inflicted by a woman, researchers have found.
Students were asked to put their fingers in a clamp which was tightened until the pain was unbearable. Researchers from the University of Westminster found that people allowed women to turn the clamp much further than men.

Dr David Williams, who led the research said the study suggested people do not expect women to inflict as much pain. He said: "This effect is likely to be a result of what participants subconsciously expect, based on socially acquired gender stereotypes - people feel that they are less likely to experience intense pain from a stimulus given by a woman rather than a man.

"This effect is less likely to be down to males trying to appear macho in front of a female - a conscious and deliberate act - as the result applied to both genders." He said the fact there were no differences in how men and women responded to the test suggested women do not actually handle pain better.

Dr Williams said people's sensitivity to pain was also shown to depend on their surroundings. In the study, people appeared to suffer more if there was a poster on the wall which might trigger negative feelings, such as a chart of wounds or a poster calling for blood donors.

Dr Williams, who carried out the research for his PhD, said: "People subconsciously evaluate their environment. "This evaluation can result in identical stimuli being perceived as more or less painful for the same participant or, in some cases, an innocuous stimulus being perceived as painful or a relatively intense stimulus perceived as innocuous."

He said the finding could have implications for how patients are given potentially painful treatments. "Individuals can be 'primed' for pain by qualities of their environment and, as a result, may suffer unnecessarily during acutely painful clinical procedures. "Awareness of these principles may be useful in developing methods of reducing suffering in those situations." Link

I originally posted about this here,
and for the past year I've been waiting for the study to show up in a peer-reviewed journal, and for some corroboration. It's time to go to the source. More soon.

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07 December 2005

Another pain blog

Here's a very, very, very good blog on pain:
Hope posting this doesn't drive me out of business.

Biofeedback and pain modulation

From Wired:
Pain can be mysterious, untreatable and debilitating, and its causes can be unknown. But if you could see the pain -- or, at least, your brain's reaction to it -- you might be able to master it.

A study from researchers at Stanford University and MRI technology company Omneuron suggests that's possible, and the results could lead to better therapies for those suffering from crippling chronic pain.

The researchers asked people in pain to try to control a pain-regulating region of the brain by watching activity in that area from inside a real-time functional magnetic resonance imaging, or fMRI, machine. Initial results showed subjects could reduce their pain, some quite dramatically.

It's the first evidence that humans can take control of a specific region of the brain, and thereby decrease pain, said Stanford professor Sean Mackey, who co-wrote the paper, which was published last week in Proceedings of the National Academy of Sciences.

"(Similar to) going to a gym and working muscle using weights, here we're using the real-time fMRI technology to exercise a certain brain region," he said.

Study co-leader and Omneuron CEO Christopher deCharms said for many people with chronic pain, available treatments like medication or surgery simply don't work. But this exercise, which researchers have termed "neuroimaging therapy," could one day help some of the millions of Americans who suffer from untreatable chronic pain.

In the study, eight healthy subjects who'd been subjected to a painful stimulus and eight chronic pain patients underwent a series of fMRIs. The images tracked activity in the brain's rostral anterior cingulate cortex -- an area deCharms said is related to pain. Subjects watched this area on a monitor in real time during the procedure. Prompted by researchers' suggestions of trying to lessen their own pain by ignoring it or imagining it as benign, they set out in a mental game of hot-and-cold to lessen their discomfort.

Twenty-eight healthy subjects and four pain patients were also put into control groups that tried to control pain by viewing other patients' brain data or using other mental strategies, but no fMRIs. These tactics didn't show a significant reduction in pain, deCharms said.

The pain patients reported that the fMRI helped them decrease their overall pain 64 percent. Healthy subjects said they saw a 23 percent increase in their ability to control the strength of their pain, and a 38 percent increase in their ability to master its unpleasantness.

"I think most people found it very exciting to be able to watch the activity in their own brain, moment by moment, as it took place," deCharms said.

Vera A. Gonzales, a pain psychologist in League City, Texas, said she thinks the study lends scientific data to what scientists already knew empirically -- that people can decrease their own pain by focusing on certain thoughts.

It probably also helped that subjects could watch their brain activity unfold on a screen, she said. For years, some therapy methods have allowed patients to monitor and try to control their biofeedback by concentrating on things like skin temperature and heart rate.

Mackey and deCharms cautioned it will be some time before such therapy could be available for commercial use. They're investigating the process of getting Food and Drug Administration approval, and right now they're focusing on a study to investigate the effects of long-term neuroimaging therapy, deCharms said. One day, patients may even be able to think away other problems like depression, anxiety and dyslexia.

"We don't yet have a good answer to what happens if you keep practicing and practicing," he said.

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06 December 2005

Another resource

Just found this website on pain geared toward patients:
Haven't looked into who underwrites it so caveat lector.


Merk deleted data on Vioxx

[ed: I'm going to post new stuff below the welcome post for a bit. Thus some articles will magically appear in posts before they were written.]
From Forbes.com:
Merck's Deleted Data
Robert Langreth and Matthew Herper, 12.08.05, 8:10 PM ET
A top editor of The New England Journal of Medicine says that he was stunned to find out that data linking Vioxx to cardiovascular risk was deleted from a major study his journal published five years ago--and that it appears that Merck researchers may have deleted that data.

"I was somewhere between surprised and stunned," Dr. Gregory Curfman, executive editor of The Journal, says. "They allowed us to publish an article that was just incomplete and inaccurate in some respects and was misleading and may have contributed to the detriment to the public health."
Merck recalled Vioxx after its own study linked long-term use of the drug to an increased risk of heart attacks and strokes. Now, the question is if that alarm should have been sounded much earlier.

Just days after Merck recalled Vioxx from the market, editors at The Journal discovered....early versions of the manuscript [that] contained a blank table entitled "CV events"--which is standard jargon for cardiovascular events. Time stamps in the software indicated that the table was deleted two days before the manuscript was submitted to The New England Journal on May 18, 2000. "When you hover the cursor over the editing changes, the identity of the editor pops up, and it just says 'Merck,'" Curfman says.
The editors weren't sure what to make of the finding, so they kept quiet. It wasn't clear that the information that had been in the table would have changed the conclusions of the study...."We talked internally. Should some action be taken? We did not feel we had sufficient evidence to act on it," Curfman says.
an internal Merck document dated July 5, 2000--after the VIGOR manuscript was submitted to the journal, but well before the study went to press....it indicated that two Merck authors on the VIGOR study knew of three additional heart attacks among Vioxx patients in the study, which had not been disclosed to The New England Journal of Medicine. The heart attacks occurred in the final five weeks of the trial and in patients at low risk for heart problems.
Curfman says the editors had assumed that the VIGOR manuscript only included limited data on heart attacks because that was all that was available at the time. "It turns out that they had quite a bit more already worked up," he says. He raced back to the office and spent the next few weeks analyzing all the VIGOR drafts, raw data and correspondence.
Curfman says he called lead author Claire Bombardier of the University of Toronto, on Monday, indicating that the statement [noting the potential trouble] would be published. She told him that she would begin working on a correction.....Bombardier said that the VIGOR paper appropriately disclosed the data and that the authors were working on finalizing a response to the editorial.
Hints that Vioxx might cause heart attacks had existed for years, as basic research pointed to a mechanism by which the drug might cause more clots. When VIGOR was published in The New England Journal of Medicine, there were already questions among scientists about the potential of Vioxx and related drugs
In a statement, Merck disputed The New England Journal analysis. "The VIGOR publication, which was peer-reviewed, fairly and accurately described the results of the study as of the prespecified cutoff for analysis. The additional events referred to in the editorial were events that were reported after the prespecified cutoff date and, therefore, these were not included in the primary analysis reported in the article.

"Nevertheless, the additional events were disclosed to the FDA in 2000, presented publicly to the FDA's Advisory Committee in February 2001 and included in numerous press releases subsequently issued by Merck. We also note that these additional events did not materially change any of the conclusions in the article."

Curfman responded, "We're not buying into that."

Here's a bit of hearsay: when these stories came out last year, a close friend and former Pfizer statistician told PFP that her department had been warning management for quite awhile that their studies on Celebrex and heart trouble were using the wrong endpoints and potentially distorting the conclusions.
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