Statin's...Recipe for disaster

Dr. Graveline has an interesting background that makes him particularly suited to speak on the topic of statin drugs. He's a medical doctor with 23 years of experience whose health was seriously damaged by a statin drug. His personal questions brought him out of retirement to investigate statins, which he's been doing for the past 10 years.

As a former astronaut, he would get annual physicals at the Johnson Space Center in Houston. In 1999 his cholesterol hit 280 and he was given a prescription for Lipitor.

"When they suggested Lipitor (10 mg), I went along with it because I had no reason to be particularly worried about statin drugs," he says. "I had used it a year or so before my retirement, but I wasn't a big user."

However, it quickly became apparent that something was seriously wrong.

"It was six weeks later when I experienced my first episode of what was later diagnosed as transient global amnesia," Dr. Graveline says.

"This is an unusual form of amnesia wherein you immediately, without the slightest warning, are unable to formulate new memory and you can no longer communicate. Not because you cannot talk, but you can't remember the last syllable that was spoken to you. So nothing you say is relevant anymore. In addition, you have a retrograde loss of memory, sometimes decades into the past."

He "woke up" about six hours later in the office of a neurologist, who gave him the diagnosis: transient global amnesia. He quit taking the Lipitor despite the reassurances from his doctors that the drug was not of concern, and that it was just a coincidence.

He had no relapses during the remainder of the year, but his cholesterol was still around 280 at his next physical. He was again urged to take Lipitor, and he relented.

"I admit I was concerned, but I had talked to maybe 30 doctors and a few pharmacologists during the interval," Dr. Graveline says. "They all said "statins don't do that." So I allowed myself to go back on statins but this time I took just 5 mg.

…[E]ight weeks later, I had my second, and my worst episode. In this one, I was a 13-year-old high school student for 12 hours... This is what convinced me, when I finally woke up, that something was wrong with the statin drugs. And yet, the doctors were, for years after that, still saying that this was just a remarkable coincidence.

This took me out of retirement and I've been actively involved in researching statin drugs ever since."

Statin Drugs: Not Nearly as Safe as You're Told

Dr. Graveline has since published a book about his discoveries called Lipitor: Thief of Memory.

"In trying to reach an explanation, I called Joe Graedon and asked him if he had ever heard of any unusual reactions associated with statins," Dr. Graveline says of his initial investigations.

He was directed to the statin effects study by Beatrice Golomb in San Diego, California, and his story was also published in a syndicated newspaper column. Within weeks, the web site he had created received reports of 22 cases of transient global amnesia, along with hundreds of cases of cognitive damage. At present, over 2,000 cases of transient global amnesia associated with the use of statins have been reported to FDA's MedWatch.

But cognitive problems are not the only harmful aspect of these drugs. Other serious adverse reactions include:

• Personality changes / mood disorders
• Muscle problems, polyneuropathy (nerve damage in the hands and feet), and rhabdomyolysis (a serious degenerative muscle tissue condition)
• Sexual dysfunction
• Immune suppression
• Pancreas or liver dysfunction, including a potential increase in liver enzymes
• Cataracts

According to Dr. Graveline, a form of Lou Gehrig's disease or ALS may also be a side effect, although the US FDA is resistant to accept the link found by their Swedish counterpart, and has so far refused to issue a warning.

"The World Health Organization (WHO) reported on this in July 2007 when Ralph Edwards, who directs the Vigibase in Sweden (the equivalent of the US MedWatch), reported ALS-like conditions in statin users worldwide," Dr. Graveline says.

He has since forwarded hundreds of cases to MedWatch, but the FDA still has not been moved to act, and doctors are therefore unaware of the connection between this deadly disease and statin use.

"[W]e have anecdotal evidence that if you stop the statin drug early enough, some of these cases regress. That's why we thought it was important that FDA issue a warning, but they haven't," Dr. Graveline says.

Today, all of these adverse effects, including the cognitive problems Dr. Graveline warned about 10 years ago, are supported by published research. MedWatch has received about 80,000 reports of adverse events related to statin drugs, and remember, only an estimated one to 10 percent of side effects are ever reported, so the true scope of statins' adverse effects are still greatly underestimated.

For a more in-depth explanation of how statins damage your mitochondria and DNA, resulting in a variety of health problems, please listen to the interview in its entirety or read through the transcript as he discusses far more than I can include here.

How Statins Harm Your Brain Function

As is often the case with pharmaceutical drugs, the side effects end up teaching us new things about how the human body works. When statins first hit the market, conventional medicine was unaware of the importance of cholesterol for proper brain function. Now, researchers believe that statins' adverse effects on cognition are due to cholesterol insufficiency.

Research also began to emerge in 2001 showing the importance of cholesterol in the formation of memories.

"Then we have… dolichols," Dr. Graveline says. "[W]hen a statin is used, it blocks the mevalonate pathway to get at cholesterol inhibition. It works very beautifully. But in so doing, it blocks CoQ10, dolichols, as well as other major biochemicals…

[D]olichol is one that most doctors have never even heard of before, but it just so happens that dolichols are almost as important as CoQ10 and cholesterol in cell processing."

In fact, dolichols are vital to a number of cellular processes, including:

• Glycoprotein synthesis
• Cell identification
• Cell communication
• Immunodefense
• Neurohormone formation

Dr. Graveline goes on to explain that dolichols influence all the hormones involved with your mental condition, including your emotions and moods. And if you do not have sufficient dolichol, your entire process of neurohormone production will be altered—with potentially devastating results.

"[T]here are thousands of reports of aggressiveness and hostility, increased sensitivity, paranoia, depression and homicidal ideation," Dr. Graveline says.

There are also numerous reports of suicide.

"This whole range of what I call personality- or emotion and behavioral responses have to do with the dolichol deficiency brought on by the mevalonate blockade," Dr. Graveline explains.

"It's not just something that occurs in an occasional person… You know we're all the same and yet we're all different… You give one medicine to 10 people and if you're really lucky, in six of them it will do what it's supposed to do. That's the way it is with this. I expect there are some people that won't get any effects of dolichol suppression because they have alternative pathways. The same thing probably holds for CoQ10."

That said, it's important to realize that your brain also requires cholesterol in order for memory formation to function normally. In essence, statins suppress a number of vital elements for proper brain functioning, including cholesterol, antioxidants and co-factors like CoQ10, and dolichol.

At the same time, statins also create mitochondrial DNA and cellular damage, including in your brain.

Your brain uses glial cells as factories for producing its own cholesterol on demand. Unfortunately, glial cells are affected by statins in the same way as your liver cells, or any other cell in our body. So if you take a statin, you're also harming your glial cells and when they cease to function normally, that on-demand cholesterol capability also ceases and your brain can no longer function properly.

The Importance of CoQ10 or, if You're Over 40, Ubiquinol

It's now clear that if you take statin drugs without taking CoQ10, your health is at serious risk as statin drugs deplete your body of this essential co-enzyme. As your body gets more and more depleted of CoQ10, you may suffer from fatigue, muscle weakness and soreness, and eventually heart failure. Coenzyme Q10 is also very important in the process of neutralizing free radicals.

So when your CoQ10 is depleted, you enter a vicious cycle of increased free radicals, loss of cellular energy, and damaged mitochondrial DNA.

Unfortunately, the majority of people who take statins are unaware of their need for CoQ10, and physicians rarely advise their patients to take this supplement along with their statin—at least in the United States. It's also important to supplement right from the start. According to Dr. Graveline, once the mitochondrial damage and mutations are formed they cannot be reversed—no matter how much CoQ10 you take.

So early intervention is key. (Dr. Graveline goes into further detail of how CoQ10 offers protection against mitochondrial DNA damage in this interview, so for more information, please listen to it in its entirety.)If you decide to take a CoQ10 supplement and are over the age of 40, it's important to choose the reduced version, called ubiquinol.

Ubiquinol is a FAR more effective form—I personally take 1-3 a day as it has far-ranging health benefits. Dr. Graveline concurs with this recommendation.

As for dosage, Dr. Graveline makes the following recommendation:

• If you have symptoms of statin damage such as muscle pain, take anywhere from 200 to 500 mg
• If you just want to use it preventively, 200 mg or less should be sufficient

There's also evidence that CoQ10/ubiquinol is beneficial for Parkinson's disease and Alzheimer's disease, and even cancer, and that large doses may be justified in those cases as well.

In addition, CoQ10 is believed to play an important role in preventing premature aging in general by preventing telomere shortening, which can slow or potentially even reverse the aging process. This is just one of the additional benefits of CoQ10, and one of the reasons why I take ubiquinol daily even though I've never been on a statin drug.

There are no reported side effects of CoQ10 supplementation, and neither I nor Dr. Graveline have ever heard of anyone overdosing on it. The only drawback is cost.

However, if you're taking ubiquinol, here's some cost-saving information for you.

Certified reduced ubiquinol is only manufactured by one company in the entire world, a Japanese company called Kaneca. They own the patent. So, as long as it's certified ubiquinol, you can buy the cheapest brand you can find, because they're all the same.

Other Valuable Antioxidants for Optimal Health—Especially if You're Taking a Statin

CoQ10, or preferably the reduced version, ubiquinol, is at the top of the list of important supplements when you're taking a statin drug. But there are also other antioxidants and nutrients that can be helpful. For example, selenium is also seriously inhibited by statin drugs, and selenium, along with magnesium, are commonly involved as co-factors in a variety of biological functions.

Other important nutrients include:

• Vitamin C
• Vitamin D
• Vitamin E—An emerging form of vitamin E called tocotrienol is 50 times more powerful than tocopherol, which has been used for the past 60 years. It also helps produce cholesterol and has other biochemical advantages
• Alpha-lipoic acid
• L-carnitine—which helps metabolize fats properly. Since about 70 percent of your muscles' energy comes from fats, it's important to have the ability to metabolize them. INSERT LINE BREAK According to Dr. Graveline: "If you take L-carnitine and find that you suddenly feel much better, then you've just proven you need it for the rest of your life because you're one of those people who have a dysfunction in this capability; you don't have the means to properly burn fats at our muscle level… naturally you would then get weak when exercising. So it's useful for making a diagnosis. If nothing happens after three months of a good dose, then I would say you can forget about L-carnitine."

The Sad Truth: Even Your Doctor has Been Mislead About Cholesterol

That said, aside from taking CoQ10 if you're on a statin, your diet really should be your primary source of nutrients. (For vitamin D, you'd ideally get it from sun exposure.) Supplements are just that; supplemental to an otherwise healthy diet.

"I think that when you have a statin associated muscle or nerve or even brain dysfunction, this is where you've got to go because that's where the trouble is," Dr. Graveline agrees.

"[I]f it's cholesterol inhibition, you just eat more eggs… I can't believe I went 17 years and never ate an egg. I can't believe how gullible I was. I was this young medical doctor; I marched to that band of the cholesterol-causation people… I did everything I was supposed to do, and it was all wrong. I can't believe that I was led astray, maybe for 25 years of my practice! It's so bad to have to look back and realize you've been treating cardiovascular disease erroneously because you were doing what you were asked to do.The sad truth is that cholesterol, our supposed enemy for 35 years, has nothing to do with cardiovascular disease. it is the most important biochemical in your body.

… We all listened to what amounts to brainwashing. The brainwashing that we got from 1955 on, to just recently… They have liberalized the diet stuff recently though, so people are back to eating eggs and drinking whole milk and eating butter. I went around recommending margarine for so long, and margarine is what's causing disease—butter is what's helping to cure it. It's incredible!"

This is true for the majority of our conventional medical professionals. They simply do not know better… which is all the more reason to arm yourself with the information you need to take control of your own health. Shunning statin drugs and addressing your lifestyle is theway to go if you have high cholesterol. For more information, please see my statin index page which includes a plethora of free guidance and clear advice.

More Information

Dr. Graveline covers a lot of information in this interview, so I highly recommend you listen to the entire interview, or read through the transcript. You can also find more information on his web site: www.SpaceDoc.net .

Dr. Graveline's site serves both as a tool for reporting statin complications, and a database of adverse effects, which are then forwarded to the appropriate agencies.

China Didn’t Check Drug Supplier, Files Show

By WALT BOGDANICH and JAKE HOOKER

A Chinese factory that supplies much of the active ingredient for a brand of a blood thinner that has been linked to four deaths in the United States is not certified by China’s drug regulators to make pharmaceutical products, according to records and interviews.

Because the plant, Changzhou SPL, has no drug certification, China’s drug agency did not inspect it. The United States Food and Drug Administration said this week that it had not inspected the plant either — a violation of its own policy — before allowing the company to become a major supplier of the blood thinner, heparin, to Baxter International in the United States.

Baxter announced Monday that it was suspending sales of its multidose vials of heparin after 4 patients died and 350 suffered complications. Why the heparin caused these problems — and whether the active ingredient in the drug, derived from pig intestines, was responsible — has not been determined.

The plant in Changzhou, west of Shanghai, appears to fall into the type of regulatory void that American and Chinese health officials are trying to close — in which chemical companies export pharmaceutical ingredients without a Chinese drug license.

China provides a growing proportion of the active pharmaceutical ingredients used in drugs sold in the United States. And Chinese drug regulators have said that all producers of those ingredients are required to obtain certification by the State Food and Drug Administration. However, some of the active ingredients that China exports are made by chemical companies, which do not fall under the Chinese drug agency’s jurisdiction.

In December, American and Chinese regulators signed an agreement under which China promised to begin registering at least some of the thousands of chemical companies that sell drug ingredients. Some of these companies are the source of counterfeit or diluted drugs, including those used to treat malaria.

Discussions that led to the accord began after an unlicensed chemical plant in China made a tainted drug ingredient that poisoned more than 170 people in Panama, killing at least 115.

The heparin plant in China has not been accused of providing a harmful product. The American majority owner of that plant, Scientific Protein Laboratories, also owns a plant in Wisconsin that produces the active ingredient in heparin for Baxter.

In response to questions, Scientific Protein issued a statement confirming that its Chinese plant had no license from the Chinese agency, but said that its raw ingredients come from a licensed supplier.

The statement added that an “independent private U.S. validation company” had found the plant to be in compliance with good manufacturing practices. And a spokeswoman for Baxter, which buys heparin’s active ingredient from Scientific Protein, said it had inspected the China plant less than six months ago.

A spokesman for China’s State Food and Drug Administration, Shen Chen, said Friday that “as far as we know, it is not a drug manufacturer — it is a producer of chemical ingredients.”

Eric S. Langer, managing partner of BioPlan Associates, which prepares and publishes reports on the biopharmaceutical and biotechnology industry, said he found it hard to believe that a company exporting the heparin ingredient would not be licensed by Chinese drug regulators.

“Being able to produce a pharmaceutical or a biologic in the U.S. or anywhere without having regulatory oversight really doesn’t happen,” Mr. Langer said, adding, “I find it surprising from a regulatory perspective, and I find it surprising from a business perspective.”

Karen Riley, a spokeswoman for the United States Food and Drug Administration, said inspectors from that agency would be visiting the Changzhou plant soon. Ms. Riley said she could not be more specific. Earlier in the week she described her agency’s failure to inspect the plant as a “glitch.”

Congress has criticized the oversight by the Food and Drug Administration of bulk pharmaceutical ingredients made by foreign manufacturers and sold in the United States. A growing number of those ingredients now come from China. Of the 700 approved Chinese drug plants, the United States agency has inspected only 10 to 20 each year.

Baxter makes roughly half of the United States supply of heparin, which is used widely for surgical and dialysis patients. Problems with Baxter’s heparin were first noticed late last year when four children undergoing dialysis in Missouri had severe allergic reactions minutes after being injected with the drug.

The F.D.A. then allowed Baxter to deliver heparin that it was in the midst of shipping, for fear that a total recall would lead to a shortage of the drug, but cautioned doctors to use as little of it as possible and to administer it very slowly.

The agency also suggested that doctors give steroids or antihistamines with the Baxter heparin to help prevent allergic reactions.

Erin Gardiner, a spokeswoman for Baxter, defended Scientific Protein, saying it had been making the heparin ingredient for more than 30 years. “They have been a good supplier,” she said.

Although the cause of the adverse reactions has yet to be determined, she said tests performed by her company had detected unspecified differences between some lots of the ingredient. She did not say whether the lots had come from China or from the Wisconsin plant, which Scientific Protein also owns.

Those differences had not turned up in routine testing that the company does on active ingredients, Ms. Gardiner said, but she said Baxter had used “advanced testing techniques” to find the differences. She added that it was unclear whether the finding was significant.

Two Congressional committees have asked the Food and Drug Administration for more information about inspections of plants making the active ingredient of heparin.

Andrew W. Lehren contributed reporting.

Antidepressant Studies Unpublished

January 17, 2008

By BENEDICT CAREY

The makers of antidepressants like Prozac and Paxil never published the results of about a third of the drug trials that they conducted to win government approval, misleading doctors and consumers about the drugs’ true effectiveness, a new analysis has found.

In published trials, about 60 percent of people taking the drugs report significant relief from depression, compared with roughly 40 percent of those on placebo pills. But when the less positive, unpublished trials are included, the advantage shrinks: the drugs outperform placebos, but by a modest margin, concludes the new report, which appears Thursday in The New England Journal of Medicine.

Previous research had found a similar bias toward reporting positive results for a variety of medications; and many researchers have questioned the reported effectiveness of antidepressants. But the new analysis, reviewing data from 74 trials involving 12 drugs, is the most thorough to date. And it documents a large difference: while 94 percent of the positive studies found their way into print, just 14 percent of those with disappointing or uncertain results did.

The finding is likely to inflame a continuing debate about how drug trial data is reported. In 2004, after revelations that negative findings from antidepressant trials had not been published, a group of leading journals agreed to stop publishing clinical trials that were not registered in a public database. Trade groups representing the world’s largest drug makers announced that members’ companies would begin to release more data from trials more quickly, on their own database, clinicalstudyresults.org.

And last year, Congress passed legislation that expanded the type of trials and the depth of information that must be submitted to clinicaltrials.gov, a public database operated by the National Library of Medicine. The Food and Drug Administration’s Web site provides limited access to recent reviews of drug trials, but critics say it is very hard to navigate.

“This is a very important study for two reasons,” said Dr. Jeffrey M. Drazen, editor in chief of The New England Journal. “One is that when you prescribe drugs, you want to make sure you’re working with best data possible; you wouldn’t buy a stock if you only knew a third of the truth about it.”

Second, Dr. Drazen continued, “we need to show respect for the people who enter a trial.”

“They take some risk to be in the trial, and then the drug company hides the data?” he asked. “That kind of thing gets us pretty passionate about this issue.”

Alan Goldhammer, deputy vice president for regulatory affairs at the Pharmaceutical Research and Manufacturers of America, said the new study neglected to mention that industry and government had already taken steps to make clinical trial information more transparent. “This is all based on data from before 2004, and since then we’ve put to rest the myth that companies have anything to hide,” he said.

In the study, a team of researchers identified all antidepressant trials submitted to the Food and Drug Administration to win approval from 1987 to 2004. The studies involved 12,564 adult patients testing drugs like Prozac from Eli Lilly, Zoloft from Pfizer and Effexor from Wyeth.

The researchers obtained unpublished data on the more recently approved drugs from the F.D.A.’s Web site. For older drugs, they tracked down hard copies of unpublished studies through colleagues, or using the Freedom of Information Act. They checked all of these studies against databases of published research, and also wrote to the companies that conducted the studies to ask if specific trials had been published.

They found that 37 of 38 trials that the F.D.A. viewed as having positive results were published in journals. The agency viewed as failed or unconvincing 36 other trials, of which 14 made it into journals.

But 11 of those 14 journal articles “conveyed a positive outcome” that was not justified by the underlying F.D.A. review, said the new study’s lead author, Dr. Erick H. Turner, a psychiatrist and former F.D.A. reviewer who now works at Oregon Health and Sciences University and the Portland Veterans Affairs Medical Center. His co-authors included researchers at Kent State University and the University of California, Riverside.

Dr. Turner said the selective reporting of favorable studies sets up patients for disappointment. “The bottom line for people considering an antidepressant, I think, is that they should be more circumspect about taking it,” he said, “and not be so shocked if it doesn’t work the first time and think something’s wrong with them.”

For doctors, he said, “They end up asking, ‘How come these drugs seem to work so well in all these studies, and I’m not getting that response?’ ”

Dr. Thomas P. Laughren, director of the division of psychiatry products at the F.D.A., said the agency had long been aware that favorable studies of drugs were more likely to be published.

“It’s a problem we’ve been struggling with for years,” he said in an interview. “I have no problem with full access to all trial data; the question for us is how do you fit it all on a package insert,” the information that accompanies many drugs.

Dr. Donald F. Klein, an emeritus professor of psychiatry at Columbia, said drug makers were not the only ones who can be reluctant to publish unconvincing results. Journals, and study authors, too, may drop studies that are underwhelming.

“If it’s your private data, and you don’t like how it came out, well, we shouldn’t be surprised that some doctors don’t submit those studies,” he said.

OxyContin Maker, 3 Execs Fined $634.5M

Purdue Pharma, 3 Executives Ordered to Pay $634.5M Fine for Misleading Public About OxyContin ABINGDON, Va. (AP) -- Purdue Pharma L.P., the maker of OxyContin, and three of its executives were ordered Friday to pay a $634.5 million fine for misleading the public about the painkiller's risk of addiction.

U.S. District Judge James Jones levied the fine on Purdue, its top lawyer and former president and former chief medical officer after a hearing that lasted about three-and-a-half hours. The hearing included statements by numerous people who said their lives were changed forever by addiction to OxyContin, a trade name for a long-acting form of the painkiller oxycodone.

Designed to be swallowed whole and digested over 12 hours, the pills can produce a heroin-like high if crushed and then swallowed, snorted or injected.

From 1996 to 2001, the number of oxycodone-related deaths nationwide increased fivefold while the annual number of OxyContin prescriptions increased nearly 20-fold, according to a report by the U.S. Drug Enforcement Administration. In 2002, the DEA said the drug caused 146 deaths and contributed to another 318.

Purdue, its top lawyer and former president and former chief medical officer pleaded guilty in May to claiming to doctors that OxyContin was less addictive and less subject to abuse than other pain medications. The sentencing Friday ends the national case.

Michael Friedman, who retired in June as Purdue's president, general counsel Howard Udell and former chief medical officer Paul Goldenheim each pleaded guilty to a misdemeanor count of misbranding the drug. Of the total fine, $34.5 million was levied on those three.

Jones placed the company on probation for five years and each of the executives on probation for three years. He also ordered the three to perform 400 hours of community service related to prevention of prescription drug abuse.

Former New York City Mayor Rudolph Giuliani played a central role in negotiating on behalf of Purdue with federal prosecutors, but Jones said "I completely reject" suggestions that political influence resulted in a lesser punishment for Purdue.

Many of the nearly 20 speakers called for jail terms for Friedman, Udell and Goldenheim, saying the fines were a small price for the devastation to lives from OxyContin addiction.

"Money can't buy all the lives that are lost," said Robert Palmisano, 23, who said he was addicted to OxyContin for four years but has been off the drug for 17 months.

Attorneys for the three executives said giving them criminal convictions was punishment enough, and noted they were charged because of their job titles, not because they themselves promoted OxyContin as a drug with little addiction potential.

"They are not here today because of any acts of misconduct on their part," defense attorney Howard Shapiro said. "They are good men."

The speakers, many of whose children died after trying the drug only once, disagreed.

"I feel you are legal drug users, nothing more than a large corporate drug cartel," Lee Nuss of Palm Coast, Fla., said as she addressed the Purdue Pharma contingent.

Nuss held up a stone urn slightly larger than a pill bottle that she said contained her 18-year-old son's ashes.

Attorneys for both sides acknowledged the pain of those who had lost loved ones, but urged Jones to accept the plea agreement.

"By pleading guilty they acknowledged that doing nothing was not good enough," Assistant U.S. Attorney Randy Ramseyer said. "We cannot bring those people back. It's not something this case can do."

Dillie Walker and his wife Joyce of Bay City, Mich., testified on behalf of Purdue that OxyContin has enabled them to function again despite chronic pain.

"I don't get high from it. It goes straight to my pain," Dillie Walker said.

But Kenny Keith of Roanoke said it took very little time for him to get addicted after he was prescribed OxyContin.

"The withdrawals were worse than the pain I was having," he said.

Jones said he would have preferred to have the plea agreements call for spending money on education of those at risk of drug abuse and treatment of those who are addicted to OxyContin. But Jones said he would not reject the agreement.

"Many young people mistakenly believe today that prescription drugs are safer than other drugs," Jones said.

The fines are to be distributed to state and federal law enforcement agencies, the federal government, federal and state Medicaid programs, a Virginia prescription monitoring program and individuals who had sued the company. About $5 million will go toward a six-year company program to monitor compliance with the agreement.

Survivors of the victims want the Food and Drug Administration to reclassify OxyContin for use only for severe pain. The drug currently can be prescribed for moderate pain.

Purdue, based in Stamford, Conn., has said it accepted responsibility for its employees' actions and has put in place training and monitoring programs to ensure overpromotion of OxyContin doesn't happen again. But officials objected to any ties between the plea agreement and abuse of the drug.

The coal-mining region of southwest Virginia where the sentencing took place has had a number of oxycodone-related deaths -- 119 from 2003 through 2005, according to the state medical examiner's office.