"What will limit the use of Prialt, and other potential drugs derived from tree frogs and other creatures with natural venoms, is that it cannot be taken in pill form. It has to be delivered directly into the fluid that surrounds the spinal cord, which carries it to the brain without affecting other organs. Because it is so potent, tiny amounts of the drug could be dangerous to the heart and possibly other organs.

"This drug is for patients in chronic and severe pain who are not getting substantial and meaningful relief with oral opiates, or are having unacceptable side effects with them," said Robert Meyer, director of the FDA's Office of Drug Evaluation II. "At this point we don't see this class of drug expanding to general use."
 

For more information on this cone snail, Google "Cone snail"

Synthetic Snail Venom Is Considered a Last Resort

By Marc Kaufman
Washington Post Staff Writer
Wednesday, December 29, 2004; Page A03

A synthetic form of a sea-snail venom was approved yesterday by the Food and Drug Administration as a novel approach to treating severe, chronic pain.

The drug, called Prialt, was approved for hard-to-treat pain associated with cancer, AIDS and neuropathies. Based on a compound found in the poison of the South Pacific cone snail, it controls pain in a new way -- by blocking the calcium channels in nerve cells that transmit pain signals -- and may have broad implications for the future of pain management.

Because it is as much as 1,000 times more powerful than morphine, it is considered a last resort for long-suffering patients, rather than a first-line pain medication. But the manufacturer, Elan Corp. of Ireland, hopes that will change.

Researchers believe the snail venom, and products like it, can become an alternative to opioid drugs such as OxyContin and morphine. Ultimately, it may also provide an alternative for severely affected patients dependent on medications such as Celebrex, Aleve and now-withdrawn Vioxx -- which have come under fire because of indications that they may cause heart problems.

"This drug is very exciting because it's a very potent analgesic but isn't a narcotic," said Richard L. Rauck of Wake Forest University medical center and the Carolinas Pain Institute. Rauck, an investigator for one of the Elan-funded clinical trials that led to yesterday's FDA approval, said he found the drug to be "effective in almost all types of chronic pain it's been studied in."

What will limit the use of Prialt, and other potential drugs derived from tree frogs and other creatures with natural venoms, is that it cannot be taken in pill form. It has to be delivered directly into the fluid that surrounds the spinal cord, which carries it to the brain without affecting other organs. Because it is so potent, tiny amounts of the drug could be dangerous to the heart and possibly other organs.

"This drug is for patients in chronic and severe pain who are not getting substantial and meaningful relief with oral opiates, or are having unacceptable side effects with them," said Robert Meyer, director of the FDA's Office of Drug Evaluation II. "At this point we don't see this class of drug expanding to general use."

Nonetheless, Elan's president for global research and development, Lars Ekman, said as many as 100,000 people in the United States might be helped by the drug.

He said about 50,000 patients have implanted or external devices that pump morphine directly into the spinal column, and many of them may want to try Prialt because opioids can gradually lose their effectiveness. In addition, he said, many patients in severe pain who take pain pills may want to try the spinal cord route if the drug involved is not an opioid.

"There are thousands of people out there who have pain like a bad toothache all day and night, week after week," Ekman said. "Many of these people have tried morphine and it either didn't work or made them unable to function."

Elan, a relatively small company, has won FDA approval for two novel drugs in two months. In November, the FDA approved its multiple sclerosis drug Tysabri.

Prialt is a synthetic form of the venom that the Conus magus cone snail, which lives in tropical saltwater shallows, uses to stun passing prey.

Efforts to turn the substance into a pill faltered because of its potency, but researchers found that small drips of the drug into the spinal cord fluid went safely to the brain.

In 2000, the FDA required an additional clinical trial to better determine the best dosages, and Ekman said patients will initially receive smaller amounts as a result.

Chris McNeil, a California small-business man who has taken the drug for almost a year as part of a clinical trial, said it has changed his life. He said sharp, unexplained pain in his legs -- and the fog that enveloped him when he took opioid painkillers -- had kept him virtually homebound for six years.

"Once I started taking the new drug, I could walk again and laugh again and start having a life," said McNeil, 48. "I lift heavy boxes in my shop and even play a little soft tennis."

Prialt, which is expected to reach the market next month, will come with a "black box" warning regarding its risks, which include hallucinations and even psychosis in vulnerable people. McNeil said he experienced hallucinations in the first two weeks he was taking the drug, but they stopped.

Despite the limitations of Prialt, Mary Pat Aardrup, executive director of the National Pain Foundation, a nonprofit education group, called yesterday a "red-letter day" for pain patients. "To have another pain drug in an entirely new class is very exciting and very hopeful."

 

From The Times
July 10, 2006
 

Source The deadly sea snail venom that will take away your pain

For millions of chronic pain sufferers, big relief could come from a small sea snail. **This ScienCentral News video has more. ** 

Please use your back button to return to CHN after visiting the numerous hyperlinks on this page

It strikes without warning, harpooning its prey and injecting a toxic cocktail that paralyzes its victim. Despite its small size—only a few inches in length—predatory cone snails wield a venom weapon deadly enough to kill a human. Together, the chemicals in a cone snail's venom do serious damage, but each one on its own can actually do some good.

Roughly 50 million people in the United States suffer from pain lasting more than three to six months. "There's been a big venom movement in the chronic pain field," says Michel Dubois, director of NYU Medical Center's Pain Program. "That's some kind of reflection on the fact that our patients are quite desperate for treatment." According to the National Institute of Neurological Disorders and Stroke, chronic pain is usually caused by nerve signals misfiring in the central nervous system that continuously send pain messages to the brain.

Many chronic patients have tried a host of treatments, ranging from physical therapy to electrostimulation to heavy-duty drugs like morphine. "Morphine is the gold stallion for any analgesics," says Dubois. "It is very effective on pain and any new drug will likely be tested against morphine." The problem with morphine—in addition to side effects like constipation and nausea, for example—is its addictive nature. People build up a tolerance to the drug and need more and more of it to kill any pain. Venom-based medications can have their own side effects like dizziness, but patients don't build up a tolerance to the drug.

"Prialt is as effective the first day as the thirtieth day," says Toto Olivera, who pioneered research on cone snail venom some 20 years ago. A 19-year-old undergraduate first isolated the chemical, called ziconotide, on which this drug is based, back in the early 1980s. "We were just trying to figure out why cone snails were able to use their venom to paralyze their prey and why certain snail killed people. So it was really a basic science investigation and we never dreamt when we started that it would lead to a therapeutic application."

"We feel pain because pain fibers carry an electrical signal to the spinal cord, and then that signal is transmitted across a gap, a synapse, to a nerve cell that then sends a signal to the brain," explains Olivera. "In order to communicate across that gap, the key thing is the electrical signal has to be converted into a chemical signal. What is important is that calcium enters the end of the pain fiber to allow the chemical signal to be released."

Administered in the right dose, ziconotide blocks the calcium gateways, so the chemical pain signal never crosses the synapse. "It blocks the transmission of the chemical across the gap, the synapse," continues Olivera. "As a result, you don't perceive any pain because your brain isn't receiving the signal."

Prialt was tested in human clinical trials over the past few years. One volunteer, Brian Braun, started using the drug in 1999, after suffering 10 years of excruciating pain that left him in a wheelchair. "I couldn't walk," says Braun. "The pain just got overwhelming." Braun's chronic pain resulted as a delayed complication to back surgery he had in 1974. "The pain began about 1989," he says. "They treated me with heavy steroids, all types of drugs, and that didn't do any good. Then I had an implanted stimulator for three years, then they started me on morphine for a good many years, but morphine just wasn't doing it." On Prialt, Braun slowly regained mobility, and no longer needs his wheelchair. He says he cooks and cleans and even cuts the grass.

Not everyone has enjoyed Braun's success with ziconotide, but his doctor, Michel Dubois, is happy to see such a good response. "If this drug has changed his life," says Dubois, "this is a major step forward in the modalities available to our patients. This drug is not for everyone, but it is definitely useful for a few selected patients who are desperately in need of help."

Meanwhile, Toto Olivera will continue to sift through the more than 50,000 individual chemicals found in the venom of the 500 different species of cone snails. His recent review of cone snail venoms was published in the January 2004 issue of Physiological Reviews, and the study was funded by the National Institute of General Medical Sciences and the Biofuture Prize for the German Ministry of Education and Research.

~~Journal Neurology  Back Pain Brain  

Brain Pain (07.22.04) - The pain of severe burns may be the most excruciating pain a person can experience. But the August issue of Scientific American describes how the ultimate in pain may be eased by the ultimate in high-tech distractions. (After visiting Brain Pain  and other hyperlinks in this article, please use your back button to return to CHN )

Brain Mechanisms of Pain 

Pain.com  

That pain in your back could be more than uncomfortable. As this ScienCentral News video reports, for the first time researchers have found evidence that it could be shrinking your brain.

Achy Breaky Back

Here's what Mary Jo O'Kelley avoids thanks to a warehouse accident that left her with chronic back pain: bending, squatting, exercising and lifting anything of almost any kind. But that might not be all the damage her injury caused. For the first time, researchers have found evidence that chronic back pain may be at least partially responsible for shrinking the brain.

Neuroscientist Vania Apkarian of Northwestern University used magnetic resonance imaging (MRI) scans to collect 26 brain images from people who reported suffering back pain that lasted for a year or more and 26 images from pain-free subjects matched for age and sex. After looking at average brain size across each group, he compared the pain subjects with subjects free of pain and found significant differences in brain density in gray matter­the tissue in the brain that houses neurons, or nerve cells, that communicate with each other to help us process information. With age, we naturally lose some gray matter but Apkarian notes a difference when pain comes into play.

"The amount of gray matter decrease per year that we see for normal aging is about 2.5 ccs in volume; that's about a teaspoon," he explains. "The chronic back pain condition has an additional half a teaspoon, about 1.5 cc of additional of gray matter brain atrophy on top of the normal aging effect."

Loss of gray matter that results from chronic pain­he's found it's generally in the pre-frontal cortex and the thalamus­can bring cognition problems, as Apkarian explains: "Neurons are probably not functioning as well as they should be functioning, all of which will decrease that ability of that area of the brain to process the kinds of things that are involved in processing in everyday behavior."

With the American Chiropractic Association reporting 50 percent of all working Americans with back symptoms each year, a third over age 18 reporting a back problem in the past five years severe enough to require professional help and as many as 80 percent of Americans expected to experience back pain during their lives at a cost of $50 billion yearly, neutralizing that pain in our backs could change millions of lives.


Pain specialist Carmen Green of the University of Michigan treats O'Kelley and suspects Apkarian's research might prove something she says she's long believed: "It really supports the fact that pain is not a symptom, it is a disease because now you have MRI evidence that pain is in the brain."

O'Kelley tells Green with some bitterness that getting a diagnosis was difficult and not until she went to "doctor after doctor after doctor" did someone finally find that she had bulging discs and hip problems probably caused by her accident. But even with diagnosis she can no longer do the work she once enjoyed.

Green's own research on pain investigates how it might manifest differently based on age and race. She reported in the journal Pain Medicine that of the 5,834 African-American and Caucasian adult pain patients who filled out questionnaires about their symptoms, those over age 50 reported being better able to cope with pain than younger people. She says she'd like to see Apkarian's next study include minority pain patients to gauge whether there are brain density differences in pain patients based on race. "That is important in the context of the fact [that studies] are showing that African-Americans have more disability, have increased problems," she says. "And then you talk about access to pain care, inadequate treatment."

Whatever fresh evidence Apkarian's study ultimately provides could change the way chronic back pain is treated. Woefully lacking are most drug therapies used to treat such pain, he says, adding that chronic back pain sufferers have an additional burden in that they don't generally respond to painkillers and even when they do, they can't stay on the strongest, opiate-based pain relievers because of their addictive properties. Instead, Apkarian believes he'll be able to use his research findings to develop "drugs that will… either reverse or control this shrinkage and inhibit the emotional component of the pain perception itself."

Should that day come, Mary Jo O'Kelley may finally be able to live with her achy back without it compromising her lifestyle.

This research appeared in the November 23, 2004 issue of the Journal of Neuroscience and was funded by the National Institutes of Health.

Source http://www.sciencentral.com/articles/view.php3?language=english&type=&article_id=218392338

**CHN invites the reader to visit the source of these articles to view photographs, which are not included on this page.**

Back to the top