The Search for the Killer Painkiller

The Search for the Killer Painkiller
Posted by CN Staff on February 14, 2005 at 17:40:22 PT
By Andrew Pollack
Source: New York Times 
Despite all the advances of modern medicine, the main drugs used to fight pain today are essentially the same as those used in ancient times. Hippocrates wrote about the pain-soothing effects of willow bark and leaves as early as 400 B.C. Opium was cultivated long before that. Aspirin and morphine, based on the active ingredients in these traditional remedies, were isolated in the 1800's and helped form the foundation of the modern pharmaceutical industry.
But scientists are now trying to find new ways of fighting pain. The effort has been given new impetus by the recent withdrawal of Vioxx and the questions surrounding the safety of similar pills like Celebrex and Bextra. Those concerns come on top of the problems of abuse of narcotic painkillers like OxyContin. "There's a huge void, and no one is filling it," said Remi Barbier, chief executive of Pain Therapeutics, a company in South San Francisco, Calif. But Dr. Barbier's company and dozens of others are trying. And some new treatments may come from things in nature that soothe or sting, like marijuana, hot chili peppers, nicotine and deadly toxins of snails and fish. While the withdrawal of Vioxx leaves more room for newcomers, it also makes their challenge harder. Not only have opioids and aspirin been hard to beat, but the Food and Drug Administration is now expected to demand more evidence that drugs are safe before approving them. But what scientists have going for them now is a more detailed, though still not complete, understanding of the molecular mechanisms by which pain is perceived. The goal is to create drugs that block specific parts of the mechanism while avoiding the side effects that have plagued opioids and anti-inflammatory drugs like aspirin. Tens of millions of Americans suffer from chronic pain, according to various surveys, and millions more suffer acute pain from an illness or injury each year. Specialists say pain has received inadequate attention and treatment. "Pain has historically been viewed as a symptom of other things that are more important," said Dr. Russell Portenoy, chairman of pain management and palliative care at Beth Israel Medical Center in New York. But now, he said, there is a growing realization that "chronic pain is itself an illness, and it's a complex illness." Normal pain - from touching a hot stove, for example - is a beneficial warning system. After an injury nerves can become extra sensitive to pain. A warm shower can be painful on a sunburned back. That, too, is protective, said Dr. Clifford J. Woolf, a professor of anesthesia research at Harvard and Massachusetts General Hospital. The sensitivity forces a person to protect an injured area so it can heal. But in some cases this nerve hypersensitivity continues well after the stimulus is gone, like an alarm frozen in the "on" position. The pain takes on a life of its own. "Persistent pain is not just long-term acute pain," said Dr. Allan I. Basbaum, a professor of anatomy at the University of California, San Francisco and editor of the journal Pain. "The nervous system has changed." Doctors classify pain into various categories, but there are two main types of persistent pain. One, sometimes called nociceptive pain, results from damage to tissues, as from arthritis or a burn. The other, called neuropathic pain, results from damage to the nerves themselves and is often set off by diseases like diabetes or shingles. Opioids, like morphine or OxyContin, are used for more severe tissue-type pain. But the drugs have side effects, including constipation and a slowdown in breathing. Users can become tolerant, meaning that they need increasingly higher doses, or they become addicted to the drugs. Aspirin and similar drugs like naproxen (sold under names like Aleve and Naprosyn) and ibuprofen (Advil and Motrin) are called nonsteroidal anti-inflammatory drugs or Nsaid's and are used for less serious pain. They block certain chemicals that contribute to inflammation, but they can also cause stomach ulcers and bleeding. Vioxx, Celebrex and Bextra are newer types of Nsaid's called cox-2 inhibitors, which were intended to cause fewer gastrointestinal problems. But Vioxx was found to raise the risk of heart attacks and stroke, and there is concern the other cox-2 inhibitors may do so as well. Nsaids don't work for neuropathic pain, specialists say, and there is disagreement on how effective opioids are. Doctors often use epilepsy drugs like Pfizer's Neurontin, which calm overexcited nerves that can cause seizures. Certain antidepressants are also used, most recently Eli Lilly's Cymbalta, which is also approved as a treatment for diabetic neuropathic pain. Some efforts to develop better pain relievers focus on variations of the existing treatments. For example, DOV Pharmaceutical, based in Hackensack, N.J., is in the final stages of testing a drug, bicifadine, for lower back pain. Like some antidepressants, it helps prolong the action of two brain chemicals, serotonin and norepinephrine. Pain Therapeutics is in the final stages of testing a combination of an opioid with a small amount of a drug that counteracts the opioid's effect. The theory is that this will stop the buildup of tolerance, allowing opioids to be used more effectively. NicOx, a French company, is testing a drug that breaks down in the body into naproxen and a chemical that releases nitric oxide. Nitric oxide plays many roles in the body, including dilating blood vessels and spurring mucus formation in the gastrointestinal tract. Some early trials suggest, though not definitively, that the drug may have lower gastrointestinal and cardiovascular risks than other Nsaid's. But experts say there is also a need for totally new categories of pain relievers, ones that work in entirely different ways. One such drug, called Prialt, was approved by the F.D.A. in December. It is a synthetic version of a toxin that a South Pacific marine snail uses to paralyze its prey. The drug impedes the transmission of pain signals through the nerves by blocking channels through which calcium ions flow into nerve cells. "This is really the first new analgesic in two decades," said Lars Ekman, head of research and development at Elan, the Irish company that developed the drug. He said the drug was nonaddictive and 1,000 times as potent as morphine. Potent, yes, but also problematic. To minimize side effects as diverse as heart rhythm disturbances and hallucinations, the drug must be injected directly into the fluid surrounding the spinal cord with a catheter and implanted pump. That will limit its use, as will the F.D.A. approval, which is only for severe pain that is not responsive to other analgesics. Neuromed Technologies of Vancouver, British Columbia, says it has a calcium channel blocker that is safe enough to be taken orally. But the drug is only in the first stage of clinical trials, so there is no real proof yet that it is safe and effective. Another approach is to block sodium channels. This is how local anesthetics like those given by dentists work. Wex Pharmaceuticals of Vancouver is testing tiny amounts of a toxin from the fugu, or puffer fish, a dangerous delicacy in Japan. Chili peppers are less deadly, but their main ingredient, capsaicin, can cause intense pain when put in the mouth or rubbed on skin. Exposure desensitizes and temporarily damages the pain sensors. Some over-the-counter pain ointments contain capsaicin. NeurogesX of San Carlos, Calif., is developing a patch containing highly concentrated capsaicin to be put on the skin for an hour in a doctor's office. A local anesthetic would be used to blunt the pain of the treatment itself. But after the patch is removed, pain in that area is diminished for weeks, the company's studies have shown. AlgoRx of Secaucus, N.J., is developing a capsaicin formulation that can be injected into joints or spread on surfaces exposed during surgery. A different approach would be to block the sensors on nerve cells activated by capsaicin, called the TRPV1 or VR-1. That would theoretically provide pain relief without the initial pain. The drug giant Merck and tiny Neurogen of Branford, Conn., are working together on drugs to block this receptor, as are other companies like Amgen and GlaxoSmithKline. Derivatives of marijuana are also being looked at. "Certainly with marijuana there's thousands of years of human experience that in addition to the psychoactive effects there are also medicinal effects," said Dr. James E. Shipley, senior vice president for clinical development and medical affairs at Indevus Pharmaceuticals in Lexington, Mass. "The problem heretofore is that you can't have one without the other." Indevus is testing a drug based on a chemical, tetrahydrocannabinol-11-oic acid, that THC, the main ingredient in marijuana, turns into in the body. In healthy volunteers, Dr. Shipley said, the drug caused no psychoactive effects. But there has been only one small trial showing that the drug provided better pain relief than a placebo. GW Pharmaceuticals, a British company, is further ahead. It says it is close to getting approval from Canada to sell a mouth spray derived from marijuana as a treatment for neuropathic pain in patients with multiple sclerosis. Nicotine, the poisonous substance in tobacco, also has soothing effects. Companies like Abbott Laboratories and Targacept, which was once part of cigarette maker R. J. Reynolds, are in early testing of drugs designed to bind to some of the same receptors in the body as nicotine but not be addictive. Rinat Neuroscience of Palo Alto, Calif., and Genentech are working together on an antibody that blocks nerve growth factor, a protein made by the body that stimulates the growth of nerve cells. Genentech initially tested the growth factor to see if it would reverse nerve damage from diabetes. But patients getting the drug experienced severe pain. It turns out that nerve growth factor has a second role: it is released after an injury and helps activate the pain pathway. So the companies figure that blocking it will stop pain. Experts like Dr. Basbaum and Dr. Woolf, who consult for various pharmaceutical companies, say that controlling pain may require a combination of drugs hitting different mechanisms, just as cancer is treated with combinations. Ultimately, they say, the goal will be to tailor drug therapy to each patient based on the mechanisms underlying that person's pain. New drugs are not expected to reach the market for a few years, and many may fail or have unacceptable side effects. Still, the void left by Vioxx has buoyed companies like NicOx, which two years ago faced a bleak future when a big drug company it was working with decided not to pursue its drug. "You're standing on a rock surrounded by water," said Vaughn Kailian, a director of NicOx, "and just when you think you're going to vanish under the waves, the water recedes and you're standing on a mountain." Source: New York Times (NY)Author:  Andrew PollackPublished: February 15, 2005Copyright: 2005 The New York Times Company Contact: letters Website: Related Articles & Web Sites:GW Pharmaceuticals Marijuana Information Links Marijuana Gets Backing Prescribing The Miracle Weed Painkiller Hope for Cancer Patients 
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Comment #5 posted by FoM on February 15, 2005 at 08:08:30 PT
Really good comment. Euphoria to me is a term of a sense of well being. That is good for people's health. 
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Comment #4 posted by Sam Adams on February 15, 2005 at 06:48:23 PT
FDA/Vioxx update
The latest on the FDA treatment of the NSAID problem, including a story of a girl who was blinded by taking "Children's Motrin"..... reading this stuff makes me seethe with anger, our society is so messed our kids toxic pills like it's candy, then jailing medical marijuana makes me want to move into the mountains & start a commune
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Comment #3 posted by breeze on February 15, 2005 at 00:25:24 PT
Pain control begins with...euphoria
 Notice the thing that is wrong with the following statement-"In healthy volunteers, Dr. Shipley said, the drug caused no psychoactive effects. But there has been only one small trial showing that the drug provided better pain relief than a placebo."IN HEALTHY volunteers- first thing in the sentence. I have known a number of people who have had a disease that is privately referred to as living death- they exist, but that is about it. They cannot function as a normal person would, all that they can do is languish on in extreme pain.
One had AIDS, another had shingles inside of the stomach, throat and mouth, another had a bone density degenerative disease- the spine was literally disolving- but it HURT as it did so, another had leukemia, and a few others had cancer. A couple of these people had access to morphine, Oxycottin- and they STILL insisted that marijuana was more of a pain reliever than these two very dangerous drugs.But as I stated earlier- the citizens, in particularly the elderly, will have to be the ones to change the need for pain control for simple wasting disease.While this article was uniquely informative, it also seems that the author has a forebearing against the side effect of using marijuana in its two most common states of injestion- it creates a euphoria.Euphoria is a condition of nature, it's purpose it to cause the body to relax, to slow down and to sleep- so that the body can spend its energy making repairs instead of spending energy, running the fat burning processes- such as walking, running, talking, sitting, or moving about. It is harder for the body to regenerate if it is spending its resources using energy elsewhere. Even sitting up takes energy- so euphoria suppresses that desire. Its NATURE in action.I am sure that there is a significant need for a pain reliever that will deaden pain, and allow people to move about, coherent and alert- but even here, there are consequences. Very dangerous territory indeed. I have seen video of a man being shot SIX times, and he was still on a rampage- he felt absolutely no pain- and yes, he was high, on cocaine. But my point is, he felt nothing. People go on rampages when they AREN'T high on some dangerous/lethal drug. Imagine taking away the pain receptors of someone who is deranged and/or violent- not disillusioned or intoxicated, just simply being irrational and ignorant. Could this person be controlled?Now,this does not mean that the majority of users of this type of therapy for pain management would abuse such a drug to that extent, but there would be a use for it somehow recreationally. Take this pill, and you will feel nothing at all- give it to a friend and chop off one of his fingers when he isn't looking- as a prank. And with tommorow's technology- it could happen, because of the ease of reattaching limbs. The scene in my mind is comical- but it not a laughing matter, its only to demonstrate the dangers of technology- even when they are beneficial. I do not doubt someone would do it, there are a lot of people who would do such a thing just for the sheer alleviation of boredom.Still, these type drugs won't be available for years- considering the possible side effects. But yet, a plant that has been used for thousands of years to treat pain is still greatly ignored for its value in light of it being illegal, because of outdated laws and attitudes.In referring back to what I stated about euphoria, the herb is also a treatment for depression and panic attacks, as well as a host of other diseases and afflictions of the mind. It is a wonderful stress reliever. Though I have read before that marijuana has caused episodes of schizophrenia- I attribute this mostly to the person, not to the use of the plant. If scientists were more upfront and truthful in their publications considering cannabis, they would proclaim it as a "wonder drug"- if it indeed can even be called a DRUG- its really a plant, a flower, an herb- drugs are manufactured in labs, not grown wild or deliberately. A drug is anything that has gone through a process assisted by the hand and intellect of mankind- marijuana is just simply natures cure for several symptoms of disease.But I suppose science is a career just as any other, you can't get a grant if you don't/can't say what some higher authourity demands you present as "truth" even when it is a blatant falsehood, a lie in bold face lettering.I find it odd that society is so hypocritical about euphoria, when every weekend millions of people spend their free time getting drunk on alcohol. If someone is dying and in pain, then let them at least die pain free, and in a blissful, happy state of mind. Its the way I would want anyone I love to leave this world, and especially for myself. I certainly don't want to be drunk as it is different than being calmed by the effects of cannabis, and just being pain free would probably be even more stressful for me- I would be dying, but nothing to relax me, calm me, or sedate me. It would be both an emotional and mental stress I could do without in my time of dying. If I were given the choice of dying in pain, or given a drug that ceased the pain but no euphoria, I would likely chose pain- because in such states of trauma, the brain allows flow of chemicals that induces euphoria, though be it mild- the body knows best. Those chemicals may not alieve the pain, but they relax the functions of the body that are involved in the process- to basically prepare the soul of the person for what is happening, the transition. If I offended anyone who is an atheist for using the word "soul," then so be it. I believe that Einstein said it best when he stated that nothing ever truly dies, all energy merely transforms or morphs into a different state of being. Death is nothing to fear, its quite simply, nature. And mankind has always had a fear of nature, even though nature is what provides us with everything we have ever needed to survive and prosper. Even when nature provides people with the very thing they desire or need in an era of pain reduction hysteria, they still fear the very thing that could help them the most- cannabis. 
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Comment #2 posted by FoM on February 14, 2005 at 18:12:22 PT
CA Patients File Lawsuit on 215 Against CHP 
ASA: CA Patients File Lawsuit on 215 Against CHP   
Monday, February 14, 2004 MEDIA CONTACT: Hilary McQuie (510) 333-8554 
Press Conference Tuesday, February 15:
Medical Marijuana Group Lawsuit Against CHP, Governor
Patients Say CHP Defied State Law in Traffic Stops
OAKLAND – A medical marijuana rights group, Americans for Safe Access, is filing a group lawsuit on behalf of seven legal medical marijuana patients and caregivers against the California Highway Patrol (CHP) and Governor Schwarzenegger for the CHP policy of confiscating marijuana despite valid documentation of their legal patient status. All the plaintiffs are qualified medical marijuana patients who possessed very small amounts of marijuana, which they were legally entitled to possess and transport under California law. All were stopped by the CHP for alleged traffic offenses, and had their medicine confiscated by the police as an added punishment. "A number of patients were told by CHP officers that they don't recognize Proposition 215," said Kris Hermes, ASA's legal director. "CHP officers are sworn to uphold the laws of this state, not subvert them." The suit argues that the CHP’s policy of disregarding the Compassionate Use Act not only violates California law, but both the federal and state constitutions. It has been more than eight years since the passage of the Compassionate Use Act (CUA) in 1996, where California voters approved the use of marijuana for medical purposes. Since then, the California legislature has enacted law (SB 420) clarifying the CUA and explicitly allowing for transportation of marijuana by qualified patients and caregivers. Local law enforcement in California has exhibited ongoing resistance to enforcing state law, despite the enactment of both the CUA and SB 420. A report issued last August by Americans for Safe Access stated that while this inappropriate conduct by law enforcement occurs in the vast majority of California’s 58 counties, the worst offender is the California Highway Patrol. The medical marijuana group is suing the CHP to change their official policy stating that, “[e]ven if a Section 11362.5 H&S claim is alleged, all marijuana shall be confiscated and booked as evidence.” The only state-required documentation of legal patient status is a copy of a current doctor's recommendation, which the CHP refuses to accept as anything but an 'alleged' claim.  One of the plaintiffs, Mary Jane Winters, a registered nurse who uses marijuana to treat chronic pain stemming from three herniated discs in her spine, was pulled over by the CHP on Thanksgiving Day, 2004 while on her way to deliver flowers to a homeless shelter. The officer seized her two ounces of marijuana, despite being presented with a physician’s recommendation to use marijuana medicinally. "Confiscation from legal patients is a civil rights violation," said Winters. "They had no reason to believe that I was not in compliance with California law." WHEN:      Tuesday, February 15, 2004, 10 amWHERE:     Alameda County Administration Building plaza, 1221 Oak St., Oakland WHO:       Medical marijuana patient plaintiffs and legal staff of Americans for Safe AccessWHAT:      Press conference to announce filing of patient lawsuit against CHP          To see the complaint, go to To read the CHP policy on medical marijuana, go to: national coalition of 12,000 patients, doctors and advocates, Americans for Safe Access is the largest organization working solely on medical marijuana. For more information, see
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Comment #1 posted by FoM on February 14, 2005 at 17:42:28 PT
I Know What To Do
Let sick people use this ancient medicinal plant, Cannabis. That would be a good beginning to helping solve pain.
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