Category Archives: Opiates

The Drug War’s Effect On Bodies And Minds

The Drug War’s Effect On Bodies And Minds. – DISINFORMATION.COM

The Drug War’s Effect On Bodies And Minds

Posted by JacobSloan onMarch 7, 2012

brokenglassfaceVia Brooklyn Rail, Jason Flores-Williams, a defense lawyer whose father spent sixteen years in prison on drug charges, on the influence of the War on Drugs on how we think:

There are two kinds of power and the drug war’s got them both in spades. The first is we’ll-kick-your-ass power. If you don’t go along with our vision of things, then we’re going to throw you in jail and try to ruin you. It’s the kind of power we think of when we think of China, except that when it comes to the prison-industrial complex we’re actually more repressive than they are.

The second power is foundational to all other forms of power: the power to make people doubt and dislike themselves. All we have to do is look in the mirror to know that the drug war has been an absurdity. Have you ever used drugs? Are you a felon who deserves to go to state prison for it? Are you an enemy of the state? That time last year that you and your husband dropped the kids off for the night at your brother’s house, then smoked weed to have sex in the privacy of your own bedroom—you do realize that makes you a bad person, yes? A good parent would right now call the cops. You should testify against each other. In fact, you and your husband should proceed immediately to the police station and turn yourselves in. And that time last May when your best friend from college came into town and you went out together to that bar that you’ve always wanted to check out and did some blow in the bathroom. Have you reported yourself to the D.E.A.? You unpatriotic scumbag. Or the shrooms you took that Fourth of July at your friend’s pool party—have you cooperated with state and federal authorities, given over the names and addresses of everyone who was there that night? We need you to name names. You must name names. Are you, or have you ever been, a member of the Communist Party?

We let ourselves be criminalized. Forced into the shadows. Made to feel like bad people for relaxing on a Friday night after working 75-hour weeks for the last month and a half. You shouldn’t have been over at your friend’s smoking a joint, talking about what the government needs to do—you should have been back home alone watching TV. We need you isolated. Under control. You don’t know what’s best for you. We know what’s best for you. We are better than you. And everyone on our side, all the people we’ve bought off and put on the payroll, are better than you, too. You just don’t get it: We control the idea of America.

American citizens are being beaten down and oppressed every day because every soul incarcerated means cash money to law enforcement. And more important, the war is a constant reminder that the U.S. government can jail your body and try to own your soul.

I don’t want to sully an article of this calber, but speaking generally America isn’t even remotely in this war.  In fact it has been some time since anyone that isn’t an overbearing sociopath has thought 2 times on the issue to the negative of the current failed (since the 70’s) policy/ policies that we call the rule of law… with a wink, nod, and payment made to South American and Central Asian violent gangs who we probably started or support the fight they do against someone we don’t support for a reason that no one that isn’t on the UNODCP or DEA, INTERPOL, BATFE, or inteligence community INC payment plan could give a half of a shit and 3 drops of piss about.

That’s why Americans sit in jail in the HIGHEST NUMBERS [per capita] in the WORLD (China’s not even close) and you may say: “well those countries just shoot people rather than jail them… guess what ass, we do too.  DEA kicks in the wrong door… bam, your amendment rights are getting on his boot, and what was your floor… before your untimley departure from spaceship earth. Sorry to get all graphic,but this is all too real and it’s time to STOP THE MADNESS! Please do SOMETHING!.

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FDA Panel Urges Ban on Vicodin, Percocet

“Also recommends dosing limits for OTC painkillers that contain acetaminophen, like Tylenol or Excedrin, because of link to liver damage.”

“TUESDAY, June 30 (HealthDay News) — The popular prescription painkillers Vicodin and Percocet, which combine acetaminophen with an opiate narcotic, should be banned, and the maximum dose of over-the-counter painkillers with acetaminophen, like Tylenol or Excedrin, should be lowered, a U.S. Food and Drug Administration advisory panel urged Tuesday.

The panel’s recommendations followed the release of an FDA report last month that found severe liver damage, and even death, can result from a lack of consumer awareness that acetaminophen — which is easier on the stomach than such painkillers as aspirin and ibuprofen — can cause such injury.

The dangers from use or abuse of Vicodin and Percocet may be even more concerning, one key panelist said.

"It seems to me that problems with opiate combinations are clearly more prevalent," Dr. Lewis S. Nelson, chairman of the FDA’s Drug Safety and Risk Management Advisory Committee, said during a Tuesday press conference held after the two-day meeting.

Explaining the panel’s 20-17 vote to ban prescription acetaminophen/opiate drugs, Nelson said, "There are many deaths that relate to problems with prescription opiate combination acetaminophen products, whereas the number of deaths clearly related to the over-the-counter products are much more limited."

But the FDA advisers also took aim at over-the-counter (OTC) acetaminophen products. The agency’s report found that many people may consume more than the recommended dose of these pain relievers in the mistaken belief that taking more will prove more effective against pain without posing health risks. Consumers may also not know that acetaminophen is present in many over-the-counter products, including remedies for colds, headaches and fevers, making it possible to exceed the recommended acetaminophen dose, the report said.

Based on that, the FDA advisory panel voted 21-16 to lower the maximum daily dose of nonprescription acetaminophen, which is currently 4 grams — equal to eight pills of a drug such as Extra Strength Tylenol. The panel was not asked to recommend another maximum daily dose.

The panel also voted 24-13 to limit the maximum single dose of acetaminophen to 650 milligrams. The current single dose of Extra Strength Tylenol, for instance, is 1,000 milligrams.

The panel also voted 26-11 to make the 1,000-milligram dose of acetaminophen available only by prescription.

The advisers voted against other safety restrictions for other over-the-counter drugs such as NyQuil or Theraflu, which contain acetaminophen and other ingredients that treat cough and runny nose. Patients often mix the cold medications with pure acetaminophen drugs, like Tylenol, leaving them vulnerable to dangerously high levels of acetaminophen.

The FDA is not obligated to follow the recommendations of its advisory panels, but it typically does so.

Dr. Sandra L. Kweder, deputy director of the FDA’s Office of New Drugs at the Center for Drug Evaluation and Research, gave a strong hint of what the agency might do with the advisory panel’s recommendations.

"I think the top recommendation of this committee was that the agency needs to do something to address and decrease the usual dose of acetaminophen, both for over-the-counter products and also prescription combination products," Kweder said during the press conference.

She added, "There was a clear message that there is a high likelihood of overdose from prescription narcotic/acetaminophen combination products. If we don’t eliminate these combination products, we should certainly at least lower the usual acetaminophen dose patients receive in those prescription combination products."

At the very least the agency should require new warning labels on these prescription combinations that alert patients to the potential of liver damage if they take too much acetaminophen, she said.

Speaking for the OTC drug industry, Lynda A. Suydam, of the Consumer Healthcare Products Association (CHPA), said her group was "pleased the committee did not recommend eliminating these important nonprescription products."

However, in a statement, she added that CHPA was "disappointed in [the panel’s] divided vote to lower the maximum daily dose and the single dose of 1000 mg acetaminophen. There was a notable lack of data referenced by the committee to support these recommendations and overwhelmingly strong data affirming the efficacy and safety of acetaminophen in its current dosage forms."

Another expert took a different view. Dr. John H. Klippel, chief executive officer of the Arthritis Foundation, said Tuesday’s votes were very important to "people with arthritis because acetaminophen is a very commonly used medication to control pain."

"Lowering the maximum dose, providing that kind of guidance to patients, if it increases safety, would be something the arthritis community would support," he said. "Every person who takes this drug sees it as valuable, but they want clear guidance so they won’t be harmed by the drug."

Dr. Lewis W. Teperman, director of transplant surgery and vice chairman of surgery at New York University School of Medicine, said he also supported the panel’s decision to recommend lowering doses of acetaminophen.

"It’s not that the doses can get you in trouble, but the very young and the very old can get into trouble easily," he said. Also if you are sick, there is the danger of taking cold remedies that contain acetaminophen plus taking pure acetaminophen drugs as well, he noted.

But Klippel added that the vote to make the 1,000-milligram dose of acetaminophen available by prescription only would overburden the health-care system. "Given the massive number of people who rely on this drug for pain control, making the maximum dose requiring a prescription, I think, is going to place undo burden on the health-care system," he said.

Teperman disagreed.

"The 1,000 milligram pill should never be at the patient’s discretion. It should only be prescribed by a physician," Teperman said. "If you took an entire bottle of Tylenol Extra Strength, three days later you would be in a coma and needing a liver transplant."

For more on acetaminophen, visit the U.S. National Library of Medicine.

SOURCES: June 30, 2009, press conference with Sandra L. Kweder, M.D., deputy director, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, and Lewis S. Nelson, M.D., chairman, FDA Drug Safety and Risk Management Advisory Committee, and associate professor, department of emergency medicine, NYU Langone Medical Center; John H. Klippel, M.D., CEO, Arthritis Foundation; Lewis W. Teperman, M.D., director of transplant surgery, vice chairman of surgery, New York University School of Medicine, New York City; June 30, 2009, news release, Consumer Healthcare Products Association; May 28, 2009, news release, U.S. Food and Drug Administration”

 

I wonder what this will do to the millions of people who are in pain consistently.  Conversely what about those in acute pain? The extremely numerous Rx’s written daily for hydrocodone/APAP will not be available… then maybe they should be put over the counter.  Civilized people should be treated as though they have a brain and not looked at in a biblical or moral controlled light which hurts so many due to the prohibition and lack of health care providing adequate pain relief.  I will try and stay on this story… interesting.

THE MEDICAL – Mis-MANAGEMENT OF PAIN

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Quotations:

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All types of pain in all parts of the world are inadequately treated…” C. S. Hill, MD. JAMA 1995: 274: P. 1881-1882

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“We all must die. But if I can save someone from days of torture, that is what I feel is my great and ever new privilege. Pain is a more terrible lord of mankind than even death itself.” Albert Schweitzer, humanitarian, physician, theologian and composer.

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The United States is the only advanced industrial society in the world where a patient’s ability to pay determines access to health care.” D. E. Joranson, MSSW, Pain Research Group, University of Wisconsin Medical School

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Overview:

Many terminally ill patients experience severe pain. Some forms of cancer are notorious causes of pain in dying patients. A statement from a NIH Consensus Development Conference suggested that:

  • …there is no ‘magic bullet’ or universally accepted treatment for the relief of pain and suffering.
  • Contemporary science and clinical practice cannot assure the full relief of all pain.”
  • The data indicate that there remains a proportion of patients whose pain presents difficult, and so far unsolved, problems for successful management.
  • Concerns are focused on reported undermedication of individuals with acute pain and chronic pain associated with malignant diseases as well as reported overmedication of people with chronic pain not associated with malignant disease.

There are barriers to pain relief. They include:

  • Some types of pain in some individuals cannot be adequately controlled with current technology and medications that are now available.
  • Some patients and their physicians are concerned about the possible side effects of pain medication, including addiction.
  • Inadequate training of medical professionals.
  • Pain management is not universally available, particularly to the over 40 million Americans who lack health insurance, and as many as 80 million who are under-insured.

Dr. Robin Bernhoft comments:

Experience consistently shows that patients often want to die because of undertreated pain. Yet with good medical care their pain is almost always manageable, and they almost always regain their desire to live. Pain relief typically can be achieved without impairing mental ability…” 8

Referring to doctors who “simply don’t know how to treat depression and pain.” Dr Bernhoft states:

According to many studies, between 50 and 70 percent of U.S. doctors fit that description.8

Dr Bernhoft, and many others, believe that if terminally ill people were given access to adequate pain management, then requests for physician assisted suicide would be greatly reduced.

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Scope of the problem:
  • Pain management appears to be in a state of chaos in North America
  • Medical writer John Horgan cited an article in the Journal of the American Medical Association for 1995-NOV which described the results of a study called “Study to Understand Prognoses and Preferences for Outcomes and risks of treatments (SUPPORT).” The study involved over 9,000 patients in five hospitals. They reported “substantial shortcomings in care for seriously ill hospitalized adults.” Horgan commented: “More often than not, patients died in pain, their desires concerning treatment neglected, after spending 10 days or more in an intensive care unit.1 A Massachusetts legislature subcommittee report on pain management mentioned that the SUPPORT study “found that half of patients who died in the hospital experienced moderate or severe pain at least half the time during their last three days of life.
  • The American Pain Society (APS) issued a news release in 1999-FEB concerning individuals with chronic pain. They found that over 40% “with moderate to severe chronic pain have yet to find adequate relief, saying their pain is out of control…” The study found that “only 22% had been referred to a specialized pain treatment program or clinic.”  APS president, Dr. Russell Portenoy, said “This survey suggests that there are millions of people living with severe uncontrolled pain. This is a great tragedy. Although not everyone can be helped, it is very likely that most of these patients could benefit if provided with state-of-the-art therapies and improved access to pain specialists when needed.” (This study may not be indicative of the problems of the terminally ill; patients with cancer were not included in the study.) 2
  • A 1997 study of cancer patients receiving oral medication for their pain showed that two concerns prevented them from accepting pain medication:
  • inadequate information about how to manage pain, and
  • exaggerated concern about addiction and side effects. 3
  • A 1997 article reported that too many cancer patients continue to experience unrelieved pain. Roadblocks to treatment include:
  • lack of knowledge of modern pain medications among doctors and nurses, and
  • government regulations concerning some important pain medications in many jurisdictions. 4
  • Another 1997 article found  that only 35% of members of ethnic minorities received pain medication at recommended dosage strengths. This was compared to 50% of Caucasian patients. 5
  • A survey of 48 families of deceased cancer patients in a comprehensive cancer center revealed that 10 families (21%) considered pain treatment to be incomplete or inefficient. 6
  • Patient’s rating of pain is often different from caregivers’ impression. Using a pain scale of 0 to 10 (0 = no pain; 10 being the most severe pain) only 64% of caregivers at one hospital matched their patients’ scores within 2 points. 7

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Physician ignorance:

Everyone is aware of the extremely addictive properties of drugs such as morphine and heroin. But what is less known is that these drugs’ addictive properties are primarily seen among healthy people who are not in pain. They become addicted when they use these drugs illegally for the feeling of euphoria that they generate. If a person who is in severe pain properly uses these narcotics for the relief of pain, they do not feel euphoria; they do not become addicted; they simply have relief from intense pain. A wide range of people are in need of such medication; they include from individuals who are suffering from advanced cancer, untreatable back pain, and limb amputations.

Unfortunately, most physicians are not trained in the use of opioid therapy for the relief of intense chronic pain. Even worse, the members of some state medical boards are also unaware of the need for this use of narcotics. When they review physicians in their jurisdiction who specialize in the relief of pain, all they see is “oversubscription” of controlled substances. They have put pressure on physicians to prescribe lower quantities of these narcotics, thus causing their patients to live in continuous pain. Some boards have pulled the medical licenses of physicians specializing in this field. Each time this happens, the pain management of dozens of patients is terminated. Without narcotics, at least some probably commit suicide; with narcotics, they can lead productive lives.

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Sponsored link:

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The money trail:

David E. Joranson, of the Pain Research Group, at the University of Wisconsin Medical School wrote in 1994: “Access to professional services, prescription drugs, and medical equipment is critical to obtaining effective pain management and to restoring quality of life. The US is one of the few countries in the world where access to these products and services is based on the ability of a person to pay for them, either through personal resources or third-party private or government health insurance.” 11 He estimated about 34 million Americans under the age of 65 have no health insurance. By 2002, this had grown to over 45 million; it continues to increase at about 1 million a year. On top of that group are others — perhaps as many as 80 million. These are individuals who have limited insurance, and cannot afford to pay the extra costs associated with their illness. Racial minorities comprise a disproportionately large share of these groups. 12 According to the American Cancer Society, low income Americans suffer greater pain from cancer than average. 13

Many people over the age of 65 have less ability to pay for prescription drugs because they are on fixed and low incomes. Yet these are the individuals who are most likely to need pain medication due to age-related degenerative diseases like arthritis and terminal illnesses like cancer. 14

Some pharmaceutical manufacturers have limited programs to make their medication available to indigent patients. The American Cancer Society is one referral source for these programs for cancer patients.

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The Pain Relief Promotion Act

In 1999-OCT, the federal Pain Relief Promotion Act (PRPA) was passed by the House, by a vote of 271 to 156. If the bill had been passed by the Senate and signed into law by the president, it would have prevented the use of federally regulated drugs in cases of physician-assisted suicide. It would have prohibited the U.S. Attorney General from making exceptions. Its effect would have been to overrule the Oregon Death-With-Dignity Law which allows physicians to assist terminally ill people to commit suicide. The constitutionality of such a Federal law is highly doubtful. The U.S. Supreme Court decision of 1997 implied that states can pass laws which permit physician assisted suicide, and that individuals have a right to take advantage of these laws if they wish. The Federal Government can hardly prevent such access.

If the law had been passed, it would have have a profound effect on the management of pain:

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On the positive side, some patients who are currently unmedicated or severely undermedicated may have their pain relieved, to a degree. The law would allow doctors to prescribe narcotics for the relief of pain, even if the drugs have the side effect of shortening a patient’s life. Passage of the law would legalize this very common method of pain control; it is currently on shaky legal ground in some jurisdictions. Some physicians currently leave their patients in agony out of fear of prosecution. They could theoretically be charged with murder in some states if they shorten the patient’s life by even a small amount. If the bill becomes law, doctors would be able to prescribe some level of medication, and reduce their patient’s agony, without endangering the doctor’s safety.

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On the negative side, many physicians would fear giving adequate levels of narcotics to manage properly their patients’ pain. If the physician misjudged the dose and give the patient too much medication, they could cause that patient’s quick death. The physician may be charged under the act, and end up with a 20 year jail sentence. Each physician who prescribes a narcotic for pain relief will have an army of DEA investigators looking over their shoulders, evaluating each dose and trying to assess the doctor’s intent. The tendency will be for many doctors to err on the side of their own safety and prescribe inadequate medication to control the pain. This way, they will make certain that the patient’s death will not be accelerated sufficiently to attract the attention of the DEA. Compassion in Dying ®  comments: “…study after study reveals that doctors usually under-treat pain. They often use mild, ineffective drugs when morphine or another opiate would be appropriate. The reason often given is fear of scrutiny or discipline from state and federal authorities.15 This law would greatly aggravate this situation.

It is ironic that a bill called the “Pain Relief Promotion Act” will result in leaving countless patients in severe, continuous pain, if it becomes law. In addition, the main purpose of the bill is to prevent Oregon citizens who are dying in pain from taking advantage of their state’s assisted suicide law.

The bill became stalled in the Senate, and died.

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References used:

The following information sources were used to prepare and update the above essay. The hyperlinks are not necessarily still active today.

  1. Journal of the American Medical Association (JAMA), 1995-NOV. Cited in John Horgan, “Right to Die,” Scientific American, 1996-MAY.
  2. American Pain Society, “New survey of people with chronic pain reveals out-of-control symptoms, impaired daily lives,” 1999-FEB-17. Available at: http://www.ampainsoc.org/whatsnew/release030499.htm
  3. A. Riddell, article, Oncology Nurse Forum, 1997; 24: Pages 1775 to 1784.
  4. K. Redmond, article, Support Care in Cancer, 1997; 5: Pages 451 to 456.
  5. C.S. Cleeland et al., article, Ann. Intern. Med., 1997; 127: Pages 813 to 816.
  6. Y. Merrouche, et al., “Quality of final care for terminal cancer patients in a comprehensive cancer centre [sic] from the point of view of patients’ families,” Support Care in Cancer, 1996; 4: Pages 163 to 168.
  7. E. au, et al., “Regular use of a verbal pain scale improves the understanding of oncology inpatient pain intensity,” Journal of Clinical Oncology, 1994, 12: 2751 to 2755.
  8. Robin Bernhoft, MD, “How we can win the compassion debate,” Focus on the Family, Citizen Magazine, 1996-JUN-24.
  9. The integrated approach to the management of pain,” National Institutes of Health: Consensus Development Conference Statement, 1986-MAY 19-21. Available at
  10. Report of the special subcommittee on the management of acute and terminal pain: Joint committee on health care,” 1997-JAN-8. at: http://www.magnet.state.ma.us/dph/dcp/pnrep2.htm
  11. David Joranson, “Are Health-Care Reimbursement Policies a Barrier to Acute and Cancer Pain Management?Journal of Pain & Symptom Management, 1994, 9(4): Pages 244 to 253. Available at: http://www.medsch.wisc.edu/painpolicy/publicat/94jpsma.htm
  12. M. Earnest, “Access to health care in the United States: barriers for neurologic patients, challenges for neurologic physicians,” Neurology 1990; 40: Pages 1815 to 1819
  13. Cancer and the poor: a report to the nation.” American Cancer Society, 1989.
  14. M.E. Gluck, “A Medicare prescription drug benefit,” National Academy of Social Insurance, at: http://www.nasi.org/Medicare/Briefs/medbr1.htm
  15. Advocating for better pain management,” Compassion in Dying ® at: http://www.compassionindying.org/pain/pain.html

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Support and advocacy groups

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An Internet support group exists for pain sufferers and their relatives. You can join PAIN-L by sending an Email to listserv@sjuvm.stjohns.edu with a message: subscribe pain-l [your name]

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MedSupport Pain Forum offers 24 hour online pain support. See: http://www.medsupport.org/pforum/pain2.html

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Compassion in Dying ® is an Oregon-based agency that is concerned about the under-treatment of pain in terminally ill people. They offer a no-cost review of patients’ pain management from a clinical and legal perspective. They are “challenging the states with unreasonable legal barriers to good pain management.” See: http://www.compassionindying.org/

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Tianeptine: Opiate, Speed, Anti-Depressant?

Source: Journal of Psychiatric Practice
Date: Volume 10(5) September 2004 pp 323-330

Tianeptine : A Facilitator of the Reuptake of Serotonin and Norepinephrine as an Antidepressant?

PRESKORN, SHELDON H. MD

SHELDON H. PRESKORN, MD, is Professor and Chairman, Department of Psychiatry, University of Kansas School of Medicine-Wichita, and Medical Director, Clinical Research Institute, Wichita, Kansas. He has more than 25 years of drug development research experience at all levels (i.e., preclinical through Phase IV) and has been a principal investigator on over 150 clinical trials including every antidepressant marketed in the United States over the last 15 years. Dr. Preskorn maintains a website at http://www.preskorn.com where readers can access previous columns and other publications.

This column is the third in this series examining the pharmacology of a number of antidepressants marketed in other countries but not in the United States: reboxetine, milnacipran, and tianeptine. The previous two columns reviewed reboxetine, a norepinephrine (NE) selective reuptake inhibitor (NSRI),1 and milnacipran, a dual norepinephrine and serotonin (SE) reuptake pump inhibitor (DNSRI).2 Duloxetine, which has just been approved for marketing in the United States, will be reviewed in the last column in this series.

Like milnacipran, tianeptine and amineptine (a related molecule) are marketed in France and a few other countries around the world but there is little knowledge of these drugs in the United States and many other English-speaking countries around the world.3 Tianeptine stands out in this series because its apparent mechanism of action contradicts accepted theories concerning the mechanisms of action of antidepressants. In contrast to most, if not all, other putative antidepressants, tianeptine facilitates rather than retards the re-uptake of the biogenic amine neurotransmitters, SE and NE.4,5 The question, of course, is whether tianeptine is an antidepressant. This column reviews the available data so that readers can form their own opinion on that issue as well as on the question of why tianeptine is not available in the United States.

Like the other columns in this series, this one follows a standard format, first presenting a review of the drug’s chemistry, preclinical pharmacology, and metabolism and then giving an overview of its human pharmacology including safety, tolerability, and efficacy. As with the previous columns, an extensive review of the drug’s pre-clinical pharmacology is presented for two reasons. First, this serves to illustrate the amount of preclinical research that is done to evaluate the pharmacology of an investigational antidepressant as part of its development, thus providing an example of the preclinical stage of drug development described in an earlier series of columns on drug development in psychiatry and the human genome project.6 Second, these preclinical studies illustrate the effects that drugs can have on brain function and hence their potential to interact pharmaco-dynamically to alter brain function and thus influence behavior. These considerations are relevant to the issue of drug-drug interactions, another recurrent theme discussed in a number of columns.7

As with other columns in this four-part series, it is worthwhile to review information on tianeptine for several reasons. First, even though it may never be marketed in the United States, it is marketed in other countries. Hence, U.S. clinicians may encounter patients who have been started on this medication elsewhere. In fact, one of my colleagues recently asked me if I knew anything about tianeptine, because she had a patient who had been started on this medication when living in Russia and the person had now moved to Kansas. Second, this column, like the previous ones on reboxetine and milnacipran, will help answer the frequently asked question: Why are some drugs marketed in other countries but not in the United States?

CHEMISTRY

Tianeptine is a 3-chlorodibenzothiazepine nucleus with an aminoheptanoic side chain.8 It can also be chemically described as a substituted dibenzothiazepine nucleus with a long lateral chain.9 There are highly specific structural requirements for molecules in the tianeptine series to be active, including the requirement for an aminocarboxylic chain with an optimal length of six methylene links, a tricyclic nucleus with an electron donor heteroatom in position 5, and an aromatic substitution with a moderate electron-acceptor atom in position 3. These highly specific requirements for the tianeptine series are in marked contrast with the lack of specific requirements for the classical tricyclic antidepressants.8 Tianeptine is chiral with (+) and (-) enantiomers.10 The drug is marketed as a racemic mixture. Both of the enantiomers are active but the (-) enantiomer is more active than the (+) enantiomer.

CENTRAL NERVOUS SYSTEM PHARMACOLOGY

A substantial amount of research, particularly preclinical, has been done with tianeptine. Tianeptine does not bind to α- or β-adrenergic, dopamine, SE, GABA, glutamate, benzodiazepine, muscarinic, or histamine receptors, nor does it affect calcium channels or the neuronal transport protein for NE or dopamine.11,12 Chronic administration of tianeptine also does not alter the density or the affinity of α2, β1, SE-1, SE-2, or GABA receptors or imipramine or benzodiazepine binding sites.11

Tianeptine in vivo, after both acute and repeated treatment, enhances SE uptake in the cortex and hippocampus but not in the mesencephalon and has no direct effect on NE or DA uptake.13 These findings were confirmed in a study in which tianeptine increased but sertraline decreased the concentration of 5-HIAA, the major metabolite of SE formed by oxidation mediated by monoamine oxidase (MAO)-A, particularly in the hippocampus and hypothalamus.14,15

Short-term treatment with tianeptine also increases NE levels in the preoptic area, the parietal sensory cortex, and dorsal raphe and decreases NE turnover in the parietal sensory cortex, dorsal raphe, and parietal motor cortex, indicating that tianeptine can also alter the central NE system, perhaps indirectly through its action on the SE system.16 In addition, short-term tianeptine treatment increased extracellular DA concentration in the nucleus accumbens and, at higher doses, in the frontal cortex but not in the striatum, and the effect on DA was not diminished by marked depletion of SE by intracerebroventricular administration of 5,7-dihydroxytryptamine, suggesting this effect is not dependent on a central SE mechanism.17,18

Microiontophoretic application of tianeptine onto dorsal hippocampus CA3 pyramidal neurons increased their firing frequency. This effect was unchanged by the coadministration of 5,7-dihydroxytryptamine, indicating that the SE transporter is not involved in this effect of tianeptine.19,20 Acute treatment with tianeptine also reduced acetylcholine release from the dorsal hippocampi by 40% and from the frontal cortices by 30%.21 In contrast to the increase in firing of CA3 pyramidal neurons, this effect on acetylcholine release does appear to be mediated by effects on central SE mechanisms, as witnessed by the fact that it is abolished by chemical lesion of the median raphe nucleus and by coadministration of metergoline, a SE receptor blocker.

Sustained treatment with tianeptine did not modify the firing of SE neurons in the dorsal raphe or their responsiveness to intravenous injections of lysergic acid diethylamide (LSD) or 8-OH-DPAT, which are agonists at the somatodendritic SE autoreceptor.22 The firing of hippocampal CA3 pyramidal neurons in response to microiontophoretic application of SE also remained unchanged. However, chronic administration (14 days) of tianeptine did reduce the expression of the SE transporter mRNA and the number of SE transporter binding sites.23,24 This finding is more in line with the effects of antidepressants that are classic SE uptake pump inhibitors and suggests a difference between the acute effects of tianeptine and the chronic adaptive changes, which may be more relevant to its antidepressant properties in man. Sustained treatment with tianeptine also decreases corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH) levels, abolishing the stress-induced reduction of hypothalamic CRF concentration and markedly reducing the stress-induced increase in plasma ACTH and corticosterone levels.25,26

In addition to studies of the effect of tianeptine alone, a number of preclinical drug-drug interaction studies have looked at tianeptine in combination with other drugs. In rats, both tianeptine and citalopram reduced in a concentration-dependent manner the inhibitory effect of a 5HT1B receptor agonist on stimulation-induced release of acetylcholine in the hippocampus.27 5HT1B presynaptic heteroreceptors are located on cholinergic terminals in this and other brain structures. Conversely, tianeptine did not antagonize the inhibitory effect of the muscarinic receptor agonist carbachol on K(+)-evoked release, indicating that the effect is most likely not mediated by a direct effect on the cholinergic system.

While tianeptine shares with the classical antidepressants the ability to reduce the expression of the SE transporter mRNA and the number of SE transporter binding sites, it does not modify the efficacy of SE synaptic transmission in the rat hippocampus even after sustained treatment. Nevertheless, tianeptine, like a number of other classical antidepressants, is active in several animal models of depression. It antagonizes stress-induced spatial memory impairment in the rat,28 isolation-induced aggression in mice and behavioral despair in rats,5 hyperactivity in the olfactory bulbectomized rat,29 and rat pup ultrasonic vocalizations, which may be even a better model for anxiety disorders.30

Tianeptine has a number of effects on stress responses. Specifically, it reverses stress-induced deficits in exploratory activity31 and attenuates the behavioral signs of sickness behavior in rats induced by the cytokine inducer lipopolysaccharide (LPS) and the prototypical proinflammatory cytokine, interleukin (IL)-1β.32 Tianeptine shares with several tricyclic antidepressants and fluoxetine the ability to inhibit corticosterone-induced gene transcription.33 Tianeptine prevents atrophy of apical dendrites in the CA3 region of the hippocampus caused by chronic daily restraint stress or by daily administration of corticosterone.34-36

This latter effect does not generalize to all antidepressants: tianeptine produced this effect in several studies, while desipramine, fluoxetine, and fluvoxamine did not.37,38 This neuroprotective effect was not mediated through neurotropic factors such as brain-derived neurotropic factor (BDNF), neurotrophin-3 (NT-3), or basic fibroblast growth factor (bFGF), nor through effects on neuronal developmental factors, GAP-43 or MAP2.34 This finding may be relevant to the ability of tianeptine to improve working and reference memories in rodents.39,40 Tianeptine has been postulated to have a beneficial effect on memory by counteracting the SE-induced inhibition of medial septal neurons.39 These findings suggest a potential role for tianeptine in the treatment of cognitive impairment in the elderly, particularly in those with dementing illness.

Taken together, the extensive preclinical pharmacology described above suggests that tianeptine is a unique and pharmacologically interesting CNS medication with a number of potential uses and implications beyond being an antidepressant. Unfortunately, as discussed later, tianeptine has not been studied as rigorously in phase I-III studies as one would like in order to fully understand and exploit its human pharmacology.

PRECLINICAL METABOLISM

Tianeptine is converted by hamster, mouse, and rat CYP enzymes into a reactive metabolite. 41 That finding has been extended to human liver microsomes and involves glucocorticoid inducible CYP enzymes, possibly CYP 3A but not CYP 2D6 or CYP 1A2.42 Based on further studies in animals, high doses of tianeptine (360 times the human therapeutic dose) produced covalent binding to liver, lung, and kidney proteins, depleted hepatic glutathione by 60%, and increased SGPT levels fivefold.43 The significance of this finding to humans, including its possible predictive value for the potential for idiosyncratic and immunoallergic reactions, has not been determined.

Tianeptine inhibits both β-oxidation and tricarboxylic acid cycle in the mouse. At higher doses (600 times the human oral dose), tianeptine in the mouse inhibits the oxidation of medium- and short-chain fatty acids and causes microvesicular steatosis in the liver.44 Again, the implications of these findings for humans are uncertain; however, severe and prolonged impairment of mitochondrial β-oxidation can cause microvesicular steatosis and may in severe cases cause liver failure, coma, and death.45 As discussed in the section on adverse effects below, there have been cases of hepatotoxicity with microvesicular steatosis reported in patients treated with tianeptine.

HUMAN METABOLISM

Tianeptine does not undergo first pass metabolism during absorption from the gastrointestinal (GI) tract, and has high bioavailability and a low volume distribution.46 There is a modest food effect with increased time to the maximum peak (by 0.5 hour) and lower peak concentrations by 25%; however, the magnitude of these effects are of doubtful clinical significance.47 Tianeptine is highly bound to plasma protein (approximately 95%), particularly to human serum albumin, and has saturable binding to α1-acid glycoprotein.48 High non-esterified fatty acids (NEFA), which are seen in patients with chronic renal failure, increased the unbound fraction of tianeptine threefold.48

Tianeptine is rapidly eliminated from the body and is primarily cleared via the kidneys.4,49 It has a short half-life of 2.5 hours.46 The major metabolites are analogs of tianeptine with a C5 and C3 lateral chain and a N-demethylated derivative.46

Given the importance of the kidneys in the clearance of tianeptine, a number of studies have been done in volunteers with various degrees of impaired renal function. There was a 1-hour prolongation of the half-life in elderly subjects and in patients with renal failure.46,48 However, the terminal half-life of the C5 metabolite was almost tripled in patients with chronic renal failure (i.e., creatinine clearance less than 19 ml/min).48 Based on preclinical evidence that the C5 metabolite is pharmacologically active, the dose of tianeptine should be reduced in such patients. In addition, tianeptine and its C5 metabolite show low dialyzability so that hemodialysis is unlikely to be an effective method to speed the elimination of tianeptine after an overdose.48

Given that cirrhosis secondary to alcoholism is a significant health concern in France as well as in the rest of the world, a number of studies have been done examining the interactions between tianeptine and alcohol and between tianeptine and various hepatic conditions.50,52 Acute alcohol administration decreased the absorption rate of tianeptine and lowered its plasma levels by approximately 30% but did not affect the pharmacokinetics of the C5 metabolite.52 The pharmacokinetics of tianeptine in individuals with significant alcohol-induced hepatitis did not differ from what is seen in normal controls to any degree that is likely to be clinically relevant.

The pharmacokinetics of tianeptine are similar in elderly (72-81 years old) versus young volunteers, but the C5 metabolite levels were higher, suggesting the need for a possible dose reduction.53 Women have a modestly lower (31%) volume of distribution compared to males, but the magnitude of this effect is of dubious clinical significance.54

SAFETY AND ADVERSE EFFECTS

While the acute putative antidepressant mechanism of action of tianeptine differs radically from other antidepressants, its side-effect profile is similar to that of other newer antidepressants, particularly in terms of having low abuse potential and a low risk of adverse effects on the cardiovascular system, the cholinergic systems, sleep/arousal, cognition, psychomotor functioning, and weight.4,55

Adverse Effects

The most common adverse effects include nausea, constipation, abdominal pain, headache, dizziness, and altered dreaming.4 The following adverse effects were more common with amitriptyline than tianeptine: dry mouth (38% vs. 20%), constipation (19% vs. 15%), dizziness/syncope (23% vs. 13%), drowsiness (17% vs. 10%), and postural hypotension (8% vs. 3%). However, insomnia and nightmares were more common with tianeptine than amitriptyline (20% vs. 7%).56 Another report based on 1,458 outpatients on 37.5 mg/day of tianeptine who were followed for 3 months by 392 general practitioners in an open-label study found that fewer than 5% of patients stopped prematurely due to adverse effects and that none of the adverse effects was clinically severe and/or serious. No cardiovascular, hematological, hepatic, or other biochemical abnormalities were found nor was there any evidence of abuse, dependence, or withdrawal symptoms.57

Hepatotoxicity has been reported but is rare. In one such patient, there were hypersensitivity manifestations suggestive of an immunoallergic mechanism and histological evidence of microvesicular steatosis. Discontinuation of tianeptine was followed by complete recovery.58 This case was possibly due to oxidation of tianeptine to reactive metabolites and the inhibition of mitochrondial β-oxidation of fatty acids.

The cardiovascular effects of tianeptine have been assessed in specific placebo-controlled trials in healthy volunteers59 and by analysis of heart rate, blood pressure, and ECG data in five trials involving 3,300 depressed patients.60 Based on these studies, tianeptine does not affect heart rate, blood pressure, ventricular function (i.e., cardiac output), or intracardiac conduction; these studies included elderly patients, patients with alcoholism, and patients with pre-existing cardiac abnormalities. There were few instances of orthostatic hypotension.

In a placebo-controlled and mianserin-controlled crossover study in healthy volunteers, tianeptine, in contrast to mianserin, did not affect several measures of alertness, vigilance, and ability to react in clinically important situations such as driving, as measured by brake-reaction time, choice reaction time, critical flicker fusion, or self-assessed ratings of sedation.61

Overdose

There are limited published data on the tianpetine overdose risk. In a long-term maintenance study, seven patients attempted suicide by tianeptine overdose and all had uneventful recoveries.62 In addition to this report, there was a case study of a patient who abused tianeptine for stimulant effect taking 150 tablets daily (i.e., 50 times the recommended dose) for an unspecified period of time.63 No severe toxicity, including hepatotoxicity, was observed. This patient initially experienced nausea, vomiting, abdominal pain, anorexia with weight loss, and constipation but these adverse effects progressively disappeared despite continued and even escalating drug use. When tianeptine was abruptly discontinued in this patient, she experienced a mild withdrawal syndrome consisting of mylagia and cold sensation.

Drug-Drug Interactions

In a study testing the effects of antipsychotics, benzodiazepines, and a number of other drugs on tianeptine’s plasma protein binding, only salicylic acid at high plasma concentrations was found to be able to displace tianeptine from its binding sites and thus possibly potentiate its effects.51 Only limited drug-drug interaction studies have been published with tianeptine. One reported no interaction either way between tianeptine and oxazepam,64 as would be expected since oxazepam does not require oxidative drug metabolism for its elimination.

Tianeptine significantly reduced the wet dog shakes induced by 5-hyroxytrytophan, which would reduce the likelihood of the serotonin syndrome in the event that tianeptine is inadvertently used with other drugs capable of causing the serotonin syndrome.65

CLINICAL USE/THERAPEUTIC INDICATIONS

Efficacy for Acute Treatment

Like reboxetine1 and milnacipran2 and consistent with its primarily European development, most of the published trials of tianeptine have been active rather than placebo-controlled and results were not published in full with rigorous peer review, compromising the ability to critically assess efficacy.

A summary report of three multicenter, randomized, double-blind, placebo-controlled trials involving a total of 556 patients has been published.66 One of these studies was conducted in Brazil and has been published separately.67 In this Brazilian study involving 126 depressed outpatients meeting DSM-III-R criteria for major depression or bipolar disorder (depressed phase), tianeptine, 25-50 mg/day, produced a 58% response rate compared with 41% for placebo and statistically significantly superior (p < 0.01) reduction in the final Montgomery-Asberg Depression Rating Scale (MADRS) scores. In a second study in 186 patients with major depression or bipolar disorder (depressed phase), there was a statistically significantly greater reduction (p < 0.05) in the final MADRS scores both in patients treated with tianpetine (37.5 mg/day) and with imipramine (150 mg/day) compared with those who received placebo. The response rates were 56% for tianeptine, 48% for imipramine, and 32% for placebo.66 In the largest study involving 244 patients with major depression, tianeptine at doses of 37.5 and 75 mg/day did not produce superior response compared with placebo; however, the placebo response rate was more than 65%.66 The other published studies in major depression have been active- rather than placebo-controlled.

In an overview briefly summarizing 5 double-blind, active but not placebo-controlled studies, tianeptine was found comparable in efficacy and better tolerated than reference antidepressants, mainly amitriptyline, in patients with either DSM-III major depression, single or recurrent (without melancholia and psychotic features) or dysthymic disorder with or without an additional diagnosis of alcohol abuse or dependence.68 One of these was a 6-week, multicenter trial conducted in Italy involving 300 inpatients or outpatients with DSM-III major depression. There was no difference in efficacy but tianeptine produced fewer adverse effects.69 There was also a study that compared tianeptine and fluoxetine in 387 patients with major depression, recurrent depressive disorder, or bipolar affective disorder based on ICD-10 criteria. There was no difference on any efficacy parameter and the response rate was 58% and 56% for tianeptine and fluoxetine, respectively.68

There have also been some trials of tianeptine in patient populations not typically studied in U.S. registration trials. A placebo-controlled trial reported greater improvement with tianeptine in patients with psychasthenia.70 A maprotiline-controlled trial in 83 menopausal or premenopausal women with anxiodepressive disorder reported statistically superior (p < 0.01) response and better tolerability in the patients treated with tianeptine.71 In a 4-8 week, random assignment, double-blind study involving 129 chronic patients with alcoholism and comorbid major depression or dysthymia, tianeptine (37.5 mg/day) produced comparable efficacy but was better tolerated in comparison to amitriptyline (75 mg/day).72 In a 6-week, double-blind, random assignment study in 265 outpatients with DSM-III dysthymic disorder with manifest anxiety, tianeptine (37.5 mg/day) produced comparable efficacy to amitriptyline (75 mg/day), with treatment response rates of 78% versus 83%, respectively.73

There have also been some studies in elderly patients. In a 12-week, double-blind, random assignment study in 237 elderly patients (> 65 years of age) with DSM-III-R major depression, fluoxetine (20 mg/day) produced a higher remission rate (MADRS ≤ 10) compared with tianeptine (37.5 mg/day) (p < 0.01).74 There have been two other open-label trials in elderly patients, with one trial published twice.75-77 In these studies, tianeptine was well tolerated.

In addition to acute efficacy trials, there have also been relapse prevention studies. While most were open label, a double-blind, placebo-controlled study has been reported.78 In this study, 286 patients meeting DSM-III-R criteria for recurrent major depression (i.e., at least one previous episode in the last 5 years) were initially treated open label with tianeptine, 37.5 mg/day, for 6-weeks; the 185 responders were then randomly assigned in a double-blind fashion to either continue tianeptine or be switched to placebo and followed for 18 months. By 18 months, the relapse rate in the placebo-treated patients was 36% versus 16% in the patients treated with tianeptine. In addition to this study, there have been open-label studies of several patients maintained on tianeptine for more than 1 year with maintenance of response in over 80% and no late emergent unexpected adverse effects.62,79 Finally, there was an interesting, albeit open-label, study of 130 patients treated with tianeptine for both major depression and comorbid alcoholism.80 Only one patient dropped out because of late-emergent adverse effects and 5% because of relapse of their alcoholism.

Dosing Recommendations

Doses of tianeptine used in most of the clinical trials have been between 25 and 50 mg/day, with 37.5 mg/day appearing to be the most efficacious for most patients.

Onset of Action

There have been no published studies demonstrating a faster onset of action for tianeptine than other antidepressants currently marketed in the United States.

CONCLUSION

Like the previous columns on reboxetine1 and milnacipran,2 this review illustrates the substantial effort that can go into developing a drug, which nevertheless fails to gain approval for marketing in the United States. Such an effort costs money and takes time off the patent life. The portfolio of studies with tianeptine reviewed here, if performed today in the United States, would cost hundreds of millions of dollars-illustrating the risky nature of drug development.

This review also illustrates the specific stages through which a drug goes in clinical development. Each stage is designed to yield information to make Go, No Go decisions about whether the drug is likely to have sufficient efficacy relative to any safety or tolerability concerns to gain market approval. Based on its preclinical studies, tianeptine does reach the brain and does have novel effects on both central NE and SE uptake pumps (i.e., facilitating rather than inhibiting these uptake pumps).

Given this novel pharmacology, it would be particularly helpful if reliable surrogate markers for antidepressant response in man existed to provide more cost-effective and time-effective guidance for antidepressant drug development. Unfortunately, such surrogate markers do not currently exist or at least are not widely accepted. As has generally been the case, the pharmacodynamic translational studies with tiapneptine in humans have been limited to assessing the side effects of the drug, its effects on the cardiovascular system, and most importantly its potential antidepressant effects.

While its apparent novel acute mechanism of action has raised questions about the simplest version of the biogenic amine theory of antidepressant efficacy, the clinical trials with tianeptine have not been sufficient to lead to approval as an antidepressant in most countries, including the United States, which generates by far the largest revenue for antidepressants anywhere in the world. Hence, failure to win approval for U.S. marketing significantly limits return on investment for an antidepressant.

In the case of tianeptine, its patent life may have run out before the company could develop the resources to more actively purse the development of the drug in the United States. In this regard, tianpetine, like reboxetine and a number of other antidepressants, is chiral, raising the possibility that one of its enantiomers could be the object of a development program. If confidence in tianeptine’s apparent novel mechanism of action were sufficiently high, its structure could also provide a platform for the development of structural analogs with sufficient patent life to warrant more extensive development efforts. Time will tell whether any of these possibilities will come to pass with this interesting molecule.

Readers interested in further discussion of drug development in psychiatry, particularly with regard to antidepressants, are referred to earlier series of columns. 6,7

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OxyCon Game: Anatomy of a Media-made Drug Scare

Reprinted from the AlterNet story by Sandeep Kaushik

oxycontin

In early January, Time Magazine became the first major media outlet in America to report on the growing abuse of a synthetic opioid prescription painkiller named OxyContin. According to the story, the drug was "so popular and addictive" that it was generating "a blizzard of a crime wave" in several "pockets of the nation." While the article admitted that it "has been hailed as a miracle" by legitimate users, it added that OxyContin pills were nicknamed "killers" in some areas due to the rapidly escalating toll of overdose deaths allegedly associated with its illicit use.

These two themes, that OxyContin is an ultra-powerful narcotic coveted by junkies for its uniquely intense high, and that it is responsible for scores if not hundreds of fatalities — the specific numbers would vary widely — were to be repeated ad nauseam in a spate of succeeding media accounts. Indeed, readers didn’t know it at the time, but the Time piece was only the opening salvo in a sustained journalistic campaign — conducted over the angry protests of pain specialists and their patients — which has, in a space of a few short months, irredeemably stained the public image of a medication previously acknowledged as a major breakthrough in the treatment of debilitating, chronic pain.

In fact, in the last four months, reporting on OxyContin abuse has become a national media craze, with often sensational, fear-mongering stories appearing in hundreds of publications from Newsweek to small town newspapers in rural Midwestern hinterlands.

"Pain Pills Blamed for Rash of Deaths" the Associated Press proclaimed. "The ‘poor man’s heroin,’" U.S. News described the drug. "Prescription Painkiller Gains Status as Thrill Pill," claimed the Indianapolis Star, while the Cincinnati Enquirer called it the "’Heroin of the Midwest;’ Traffickers’ and Abusers’ First Choice." But none could match the Port St. Lucie News, which called it the "New Crack" and touted its "Heroin-Like High" in the same headline.

Taken together, all of these stories (and countless others) have misleadingly and preemptively proclaimed a major epidemic of OxyContin abuse. Yet experts say no evidence exists that increases in the abuse of the drug are outpacing increases in prescriptions for the drug. In fact, several incidents seem to suggest that the media’s sensational coverage — which advertises to the addicted the existence of the new drug and explains how to get it and use it — may be contributing to the increase in OxyContin abuse.

Meanwhile, doctors and legitimate users have become needlessly afraid of utilizing an important advance in the treatment of pain.

The Dukes of Hazard

OxyContin was an instant hit with doctors when first introduced in December 1995. Hailed by pain management specialists as a wonder drug, the oxycodone-based formulation was considered a major advance in the medical profession’s expanding effort to battle the debilitating effects of chronic pain. As the good news spread sales of the drug mushroomed, rising from $40 million in 1996 to more than $1 billion last year, outstripping even Viagra.

And the drug was a godsend for a bevy of patients who were not finding relief for their pain from other medications. "Without OxyContin I wouldn’t be able to get out of bed in the morning, much less hold down a fill-time job," says Tracey Jordan of Houston, Texas, who suffers from three degenerative disks in her back. Prior to going on it in August 2000 she took a host of other medications, but they "were just too harsh, and didn’t really take care of my pain," she said.

Media accounts of OxyContin’s effectiveness were also glowing, though relatively few in number. For instance, in a September 1996 article Oxy was said to be enjoying "a groundswell of international support" at the annual meeting of the International Association of the Study of Pain (IASP), as members touted it as "an excellent opioid for moderate to severe pain."

But about 18 months ago — roughly three-and-a-half months after OxyContin’s auspicious debut — some cases involving the illegal use of the drug surfaced in rural Maine. Soon after, the drug’s popularity began to rise in rural Appalachia, especially parts of western Virginia, eastern Kentucky, West Virginia and southern Ohio (in and around Cincinnati). If claims of epidemic levels of abuse are true anywhere, it’s here, says Ashland, KY pain specialist, Dr. Shelley Freimark. "In this area right now it is a severe problem," she states.

This can largely be chalked up to the fact that the usual street drugs are simply not as readily available in these rural outposts, says Dr. Phil Fisher, head of the Appalachian Pain Foundation (APF), a group formed last year by pain doctors devoted to educating the medical community and public about the uses and benefits of OxyContin: "This is an isolated area where it’s hard for people to get real street drugs. By and large, OxyContin is not a street drug in most places."

Also, demographic and economic conditions in Appalachia have contributed to an established, long-term problem with prescription drug abuse in the region. In general, the population is older, Fisher says, and many suffer from chronic illnesses and debilitating diseases born of years working in the mines, increasing both the number of addicts and the availability of such drugs.

Still, outside of the region this development initially went largely ignored by the press. The media lacked a "hook," some spectacular news event around which to build their coverage of OxyContin. But that all changed on February 6 with "Operation Oxyfest 2001:" more than 100 Kentucky cops fanned out in "the largest drug raids in state history." Sweeping a five county area, they netted 207 dealers and users.

Within days, the OxyContin "epidemic" was national news, turning small town cops into minor celebrities. For example, Detective Roger Hall of the Harlan County Kentucky Sheriff’s Department had the distinction of being quoted in two separate AP articles printed in scores of papers, despite the fact his claim that abusers "will kick a bag of cocaine aside to get to the Oxy" failed to make the absolutely fundamental distinction between nervous system depressants like OxyContin and stimulants like cocaine — addicts of one are usually not addicted to the other.

Naturally, politicians weren’t shy about chasing the free publicity either. With the heightened press interest, they convened a series of press conferences and public meetings in order to maximize press coverage of their efforts, such as on March 1 when Virginia Attorney General Mark Earley convened a major "summit" on the Oxy epidemic which included high ranking officials from five states. Not to be outdone by his neighbors, Kentucky governor Paul Patton, who had already proclaimed a "near epidemic" in his own state, announced the creation of the state-wide OxyContin task force, comprised of officials from 15 separate agencies.

Coverage built until April 9, the day Newsweek‘s cover screamed "Painkillers." Inside, the popular newsmagazine’s writers penned two articles, one on the rising tide of prescription drug abuse in general and the other, titled "How One Town Got Hooked," on events in Hazard, KY, the town said to be at the center of the epidemic.

With the raids’ success, and the massive press coverage they engendered, the existence of an Oxy epidemic became an integral part of the cultural zeitgeist, one which the press rapidly nationalized. After the wave of Kentucky stories by the big boys, the major urban newspapers in the East and Midwest assigned reporters to look for indications of a rising tide of abuse in their own localities. Unsurprisingly, they found what they were looking for.

Dying for a Fix

Many of the media’s "thrill pill" stories have been centered on widely disseminated and divergent claims that OxyContin has been responsible for a shocking number of overdose deaths. Just how many is an open question. The numbers vary from paper to paper, and are at best unverifiable, at worst wildly inflated. Some of the published figures appear only once, in a single article, and leave no clue as to their origins. Others are widely used; most papers across the country claim that the drug has been responsible for more than 120 deaths, 59 since February 2000 in eastern Kentucky alone.

Repeated across the country, that latter figure originated in early February with public statements from Joseph Famularo, the U.S. Attorney for the Eastern District of Kentucky, who used it to justify the eight month investigation leading to Operation Oxyfest. In Virginia, the second hardest hit state, Attorney General Mark Earley struck next, claiming 32 deaths in southwestern Virginia since 1997, a figure that was later increased to 39 by Assistant Medical Examiner William Massello.

The press responded to these announcements with a flurry of stories. But none of the accounts, which repeatedly asserted these contentions of a fast-rising death toll in bold, large-type headlines and gut-punching story leads, bothered to ask how solid the numbers were and what they meant. If they had, they might have been a little more circumspect in their reporting.

"That figure was given to us by local law enforcement," says Wanda Roberts, U.S. Attorney Famularo’s spokeswoman, about the 59 alleged Kentucky deaths. That it was generated by the same police officials who used it to justify Operation Oxyfest does not appear to trouble Ms. Roberts, though when asked she declines to confirm the figure as accurate.

The search for the truth leads to David W. Jones, executive director of the Kentucky State Medical Examiner’s Office. "As far as deaths go, I’ve heard different numbers in different places at different times; I have no idea where these people are getting their facts and figures," he said. While he stresses that not every drug-related death is necessarily reported to his office, according to his data there were 27 oxycodone-related deaths in the entire state in 2000.

Of course at first glance 27 deaths over 12 months in a single state — even in Kentucky, a state at ground zero in the spread of OxyContin abuse — appears to support the implication that there has been an explosion in the number of Oxycontin drug abusers. But when Jones parses the numbers further, the situation appears far less grave.

Two of the 27 victims, he explains, were found to have traces of both oxycodone and alcohol in their bodies, with death caused by their interaction. What’s more, 23 others evinced traces of a head-spinning multiplicity of other drugs in their systems, including highly potent prescription painkillers such as Dilaudid as well as powerful illegal drugs like heroin. In the final analysis, Jones reveals, only two of the 27 fatalities can be shown to have been due to the effects of oxycodone alone — not just two in eastern Kentucky, two in the entire state.

As for Virginia, medical examiner Massello became notably tightlipped when asked for further details about his cases, though he did admit that a "significant number" of victims had multiple drugs in their bodies.

Other jurisdictions report similar findings. In Blair County, PA, which encompasses the city of Altoona, the county coroner has collected data which shows that of the 7 oxycodone-related deaths in her jurisdiction in the last five-plus years, six involved the presence of multiple drugs, often including heroin, and one was a suicide.

Moreover, there are additional facts that most accounts don’t bother to mention: oxycodone is the opioid agent in around 40 separate brand-name prescription medications besides OxyContin; and OxyContin only accounts for about 25 percent of the oxycodone consumed annually. While Oxycontin is the strongest oxycodone formulation available, there is absolutely no way of telling, Jones explains, whether an oxycodone-related fatality was due to OxyContin.

For that matter, not everyone who dies from an oxycodone overdose does so accidentally. For the long-suffering, often terminal patients who comprise the vanguard of legitimate OxyContin users, suicide by opiate overdose often seems like a painless way to escape a life of terrific suffering. Yet such suicide cases are often lumped in with accidental overdoses, making the already inflated Oxy death numbers appear even greater.

Even when the deaths can be reliably confirmed, for the most part they do not point to a vast increase in the overall number of prescription drug abusers. Rather, the evidence of multiple-drug usage implies that a substantial portion of OxyContin abusers are long-standing drug addicts who have either switched to Oxy from other prescription or illegal drugs, or alternatively, take OxyContin occasionally as a substitute for other more preferable drugs which may be in short supply in areas such as rural Kentucky.

"Most of these people have been abusing prescription drugs for awhile, and have just switched over to OxyContin," says Kentucky state representative Jack Coleman, a legislative expert on prescription drug abuse and a member of the recently state-formed OxyContin task force. "The problem is not particularly the abuse of OxyContin," he adds, "it’s with prescription drug abuse in general."

His view is echoed by Dr. Karla Berkholz, board member of the American Academy of Family Physicians, who says that "6 to 7 percent of the American population uses illicit substances, and that number has held pretty steady over time."

Consistent with Dr. Berkholz’s analysis is the number of oxycodone-related emergency room (ER) visits — a more reliable figure than oxycodone-related overdoses. There was a 72 percent increase in the number of oxycodone-derived ER incidents, from 3,060 in the first half of 1999 to 5,261 in the equivalent period in 2000, according to the federal government’s Drug Abuse Warning Network (DAWN). But that’s still tiny compared to other drugs; for example, there were 18 cocaine-related ER visits for each involving oxycodone.

And legitimate use of OxyContin rose by a similar amount, argues Dr. Fisher. Vicodin poses a much more serious prescription drug problem, since illegal usage of it as a percentage of total sales is rising much faster than with oxycodone: "Compared to it, Oxy only accounts for 10 percent of the cases but gets 90 percent of the attention," Dr. Fisher said.

Old Wine, New Bottles

So if the OxyContin abuse phenomenon isn’t nearly as bad as it’s made out to be, why has it received so much media attention?

Much of the problem stems from the advent of the openly declared War on Drugs in the early 1980s, when the media signed on as a full partner in the government’s effort to demonize drug use and stigmatize users. "The media presented the drug problem as a war of the holy people against the depraved people, and we haven’t gone far past that moralizing tone unfortunately" says nationally recognized media critic Norman Solomon.

But the war on drugs only worsened the media’s sensational coverage of the abuse of drugs like OxyContin. OxyContin is new, and the media are constantly in search of something different, unusual or unknown with which to titillate its audience. "The media are thrill-seekers looking for the next big ratings turn-on," Solomon said.

At the beginning of the last decade the media grew fixated with "ice," a smokable form of speed, which a slew of print articles and television reports touted as "the crack of the 90s." But ice never attained the exalted heights media prognosticators prematurely predicted – it was apparently too expensive and difficult to manufacture.

And Dr. June Dahl, professor of pharmacology at the University of Wisconsin Medical School and president of the American Alliance of Cancer Pain Initiatives, likens the current spate of "ultimately exaggerated" Oxy stories to the 1930s era film Reefer Madness, with its laughably over-the-top rendering of the evils of marijuana use.

Racism and the media’s thrill seeking tendency probably best explain why OxyContin receives more media attention than heroin for example. Though contradicted by statistics compiled by the federal government, the public perception persists that heroin and crack are ghetto drugs abused by poor people of color. Could it be we don’t see 15 heroin stories for every Oxy one because prescription drug abuse is known to be primarily a white, middle-class phenomenon?

Whites accounted for about 60 percent of the heroin-related ER visits, according to DAWN. But a whopping 87 percent of oyxcodone-related ER patients were white, more than for any other significantly abused drug.

Epidemic in a Teapot

Unfortunately, the media’s wrongheaded anti-OxyContin zeal is more than just a cultural oddity. It is dangerous.

While levels of Oxy abuse do appear to be rising in some urban areas, particularly in the East and Midwest, that growth seems to follow rather than precede the heavy attention devoted to the phenomenon by major metropolitan dailies, leading to the strong suspicion that the overblown reports are largely responsible for the rise.

"I never heard of the stuff until about a month ago when one of my customers asked me about it," one Cleveland heroin dealer said in mid-April. "He showed me an article in the paper that talked about how everyone wanted to get hold of this shit, so I did a little checking and found some available."

In Cleveland, the local daily, the Plain Dealer, had taken its first stab at the OxyContin story on Feb. 10. The story, "Abuse of prescription painkiller spreading: Overdoses are believed to have killed dozens," opened by recounting a pharmacy holdup in the area. And within two months not only had a drug dealer found an OxyContin supply, but two copycat holdups had occurred.

The first pharmacy was robbed on Feb. 16, six days after the publication of the story. As in the story, a masked man wielding a firearm demanded the store’s entire supply of OxyContin and escaped with more than 1,100 OxyContin pills of various doses. On Sunday, April 22 a second pharmacy in the Cleveland suburbs was robbed; again, the robber zeroed in on the Oxy.

The Real Victims

All of the media hype, complete with gripping headlines and fear-generating content, is provoking anger and derision from growing numbers of medical professionals who specialize in chronic pain management. For years, this area of medical treatment was largely ignored or underemphasized by most physicians, says Dr. Dahl. "Historically, there have been a lot of inaccurate preconceptions and over-sensitivity about opioid analgesics and other narcotics, which has kept them from being used as much as they should."

Now, the flurry of accounts surrounding Oxy has not only stalled progress in this area, but has sent the treatment of chronic pain reeling backwards into ignorance and fear.

As the media flurry has heightened, the Drug Enforcement Agency (DEA) has begun to take action against Purdue, the makers of OxyContin, and the doctors who prescribe OxyContin. In early May, in a first for the agency — it had never before fixed its sights on a single prescription drug — it began to pressure Purdue into discontinuing all marketing of OxyContin to general practitioners, who comprise the vast majority of doctors.

So far Purdue has resisted the DEA effort, much to the relief of pain experts. "It’s a ridiculous idea," snorts Dr. Barry Cole of the American Academy of Pain Management. "There are only 7,000 pain doctors in the entire country, not nearly enough to treat everyone who needs this medication." However, Purdue has temporarily halted shipments of the largest 160mg size pills, introduced two years ago for the treatment of terminal cancer patients.

In addition, the DEA has publicly announced that it is launching a crackdown on "over-prescribing" physicians. One doctor in southern Virginia recently reported that 30 minutes after a visit from a Purdue sales representative, local DEA agents descended on his office to question him about what the rep had told him and whether he intended to prescribe the drug to any of his patients.

In light of such developments, more and more doctors are becoming leery of prescribing OxyContin though thousands of patients desperately need the medication, as even the Washington Post admitted in a May 2 story. One doctor in St. Charles, Virginia has even begun a petition drive to pressure Purdue into withdrawing the drug from the market.

"As a pain specialist, my job is to take care of the worst of the worst cases," Dr. Fisher says, "but now I’m seeing run-of-the-mill patients whose doctors are afraid that they’ll be prosecuted for prescribing OxyContin, or that they’re somehow being duped and the drugs they prescribe will end up on the street."

In addition, the negative media attention is not only making it more difficult for legitimate patients to get the medicine they need, it is making them afraid of taking it when it is prescribed to them. "I’m treating two little old preacher’s wives," Fisher relates. "Both are afraid of getting addicted, and one is sure someone’s going to break into her home to get her supply of the drug."

Bi-Centennial of Morphine Brings New Info (along with a brief history)

As Morphine Turns 200, Drug That Blocks
Its Side Effects Reveals New Secrets

On May 21, 2005, the world of medicine will celebrate the 200th anniversary of the crystallization of morphine in Einbeck, Germany. Since 1805, morphine and its derivatives have become the most widely used treatment for severe pain. Now more than 230 tons of morphine is used each year for medical purposes including pain relief for patients with chronic pain or advanced medical illness and post-operative analgesia.

Although many new pain relievers have been synthesized since the crystallization of morphine from opium almost 200 years ago, "morphine remains the standard against which all new medications for postoperative pain relief are compared," notes Jonathan Moss, M.D., Ph.D., professor of anesthesia and critical care at the University of Chicago.

Despite 200 years of increasingly frequent use however, even the medical uses of morphine still present problems, such as severe nausea, itching, and constipation.

Moss has been invited to speak at the Einbeck morphine-commemorative conference in May on the relationship between morphine and a drug known as methylnaltrexone — a peripheral opiate antagonist developed at the University of Chicago — which can prevent many of these troubling side effects.

Moss’s lecture, "Morphine’s secrets revealed," will focus on how methylnaltrexone enables scientists to distinguish between the central analgesic effects of morphine and its peripheral side effects.

Discovery of morphine

Morphine was discovered by Freidrich Wilhelm Adam Serturner (1783-1841), an obscure, uneducated, 21-year-old pharmacist’s assistant with little equipment but loads of curiosity.

Serturner wondered about the medicinal properties of opium, which was widely used by 18th-century physicians. In a series of experiments, performed in his spare time and published in 1806, he managed to isolate an organic alkaloid compound from the resinous gum secreted by Papaver somniferum — the opium poppy.

Serturner found that opium with the alkaloid removed had no effect on animals, but the alkaloid itself had ten times the power of processed opium. He named that substance morphine, after Morpheus, the Greek god of dreams, for its tendency to cause sleep. He spent several years experimenting with morphine, often on himself, learning its therapeutic effects as well as its considerable dangers. Although his work was initially ignored, he recognized its significance. "I flatter myself," he wrote in 1816, that "my observations have explained to a considerable extent the constitution of opium, and that I have enriched chemistry with a new acid (meconic) and with a new alkaline base (morphium), a remarkable substance."

As he predicted, chemists and physicians soon grew interested in his discoveries. Serturner’s crystallization of morphine was the first isolation of a natural plant alkaloid. It sparked the study of alkaloid chemistry and hastened the emergence of the modern pharmaceutical industry.

Other researchers soon began to isolate similar alkaloids from organic substances, such as strychnine in 1817, caffeine in 1820 and nicotine in 1828. In 1831, Serturner won a lucrative prize for the discovery.

In 1818, French physician Francois Magendie published a paper that described how morphine brought pain relief and much-needed sleep to an ailing young girl. This stimulated widespread medical interest. By the mid-1820s morphine was widely available in Western Europe in standardized doses from several sources, including the Darmstadt chemical company started by Heinrich Emanuel Merck.

By the 1850s the first reliable syringes were developed and injected morphine became a standard method of reducing pain during and after surgery. Since then, various delivery systems for morphine have been developed, including epidural injection and pumps that allow patient-controlled analgesia.

Although morphine was originally touted as a cure for many maladies, even for opium addiction, by the 1870s physicians had become increasingly aware of its own addictive properties. Ironically, C.R. Alder Wright, a chemist at a London hospital who was searching for a non-addictive alternative to morphine, came up with a more potent narcotic, diacetylmorphine, in 1874.

Heinrich Dreser, a chemist at Bayer Laboratories developed and tested Wright’s new semi-synthetic drug on animals, humans, and most notably himself. Finding that it was a powerful painkiller and appeared effective for a variety of respiratory ailments, Bayer began producing and marketing this drug as an analgesic and a "sedative for coughs" in 1898. Because of its "heroic" ability to relieve pain, they called it heroin.

The medical profession initially welcomed the new drug but soon recognized it’s addictive potential. In 1913, Bayer halted production, edited the drug out of their official company history and focused instead on marketing their second blockbuster drug, aspirin.

Discovery of Methylnaltrexone

Yearly, more than 500,000 patients with advanced cancer depend on powerful opioid-based pain relievers such as morphine, or its derivatives OxyContin or Percocet, for pain relief. One side effect of all narcotic pain relievers is severe constipation, which can be so distressing that many patients discontinue their pain medication.

To solve this problem, the late Leon Goldberg, a University of Chicago pharmacologist, developed methylnaltrexone (MNTX). In order to help a friend with morphine-induced constipation, Goldberg modified naltrexone, an established drug that blocks the effects of morphine, so that it could no longer cross the protective barrier that surrounds the brain. Consequently, it did not interfere with morphine’s effect on pain, which is centered in the brain, but it did block morphine’s effects on gut motility, which are mediated by receptors in the gastrointestinal tract.

Goldberg’s university colleagues continued to develop the compound, testing it in animals and performing the initial human safety trials and clinical studies in volunteers and patients.

The University of Chicago licensed the MNTX technology to UR Labs, Inc. and in 2001, Progenics Pharmaceuticals of Tarrytown, NY, sub-licensed the worldwide exclusive rights to develop MNTX from UR Labs. One phase 3 trial of MNTX for treatment of opioid-induced constipation in patients with advanced medical illness has been completed and results from a second trial were reported May 17 at the American Society of Clinical Oncology annual meeting. Progenix has a target date of New Drug Application submission in late 2005.

Meanwhile, Moss and his University colleagues have identified multiple uses of MNTX, beyond the original discovery by Goldberg. Some of these additional uses of MNTX include treatment of post-operative bowel dysfunction (a serious impairment of the gastrointestinal tract following surgery), opioid-induced itching, urinary retention, and possibly HIV.

Opiates appear to increase the ability of HIV to infect certain immune system cells. In 2003, Moss reported that very small amounts of methylnaltrexone blocked these increases. "If our studies are borne out in future clinical trials, methylnaltrexone may improve the care of patients who take opioids for pain caused by AIDS," he said.

"Two hundred years after Serturner’s work, we continue to learn a great deal about morphine," Moss said. "The ability to facilitate pain relief while minimizing side effects is both conceptually important and very relevant to patient care."