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Quest for Super Painkiller that Won't Addict

Snail venom may key a breakthrough.

By Jeffrey Helm 27 Jun 2006 | TheTyee.ca

Jeffrey Helm, a former neuroscientist, writes about science issues for The Tyee.

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High risk: narcotics addicts with chronic pain.

In the coastal waters of the South Pacific lives a deadly snail. Its harpoon-like tooth, when sunk into a fish, delivers venom that shuts down nerves, paralyzes muscles, and kills. The venom, which contains chemicals 10 times more powerful than morphine, is leading scientists to develop a new category of painkillers that won't hook patients on their prescriptions.

One of the most promising drugs in the new pain game, NMED-160, was developed at a bio-tech company in Vancouver that recently made a multi-million dollar deal with Merck for the further development of the drug. Although NMED-160 has not yet made it through all the required testing, the prognosis so far looks good. In fact, the arrival of drugs like NMED-160 would profoundly improve the treatment of chronic pain since there would be no addiction risk.

Right now, the best way to deal with pain is with narcotics. Narcotics are drugs derived from the opium poppy and are referred to in scientific circles as opioids. Morphine, codeine, heroin, methadone and oxycotin are all narcotics and they are all very good at blocking pain -- far better, for example, than anti-inflammatories like Aspirin and Tylenol. But all narcotics are also addictive.

Which caused scientists to take a very close look at certain species of predatory marine snails within the genus Conus. The venom of these snails contains chemicals that block cellular communication in the body. The venom not only does a very effective job of killing fish, it has been known to inflict death on humans, as well. The lungs shut down and people die of asphyxiation within hours.

But they do so painlessly, scientists noted, which prompted a search for the painkilling component of the snail toxin.

From three different species of snail, chemicals were isolated that blocked the flow of calcium. That bodes well for alleviation of suffering, because calcium does more than just make strong bones; it is also plays a major role in telling the brain to feel pain.

Blocking channels

Chronic pain (as opposed to the sharp shock of immediate, acute pain) is communicated through specific sensory neurons and in order for those neurons to send a signal they need calcium. By allowing a rapid flow of calcium into the cell, the electrical charge of the neuron changes and neurotransmitters are released which signal the next neuron in the signalling chain to fire. The calcium channels in these sensory neurons that communicate chronic pain are called N-type calcium channels. If you can block those channels, you can prevent pain signals from reaching the brain.

That's what narcotics do, indirectly shutting down N-type calcium channels. But they also increase pleasure chemicals in the brain like dopamine and serotonin in addition to painkilling effects.

The more narcotics a person takes, the more the body becomes physically dependent upon and tolerant of their effects. That process, plus the painkilling pleasure of narcotics, can lead to addiction getting hardwired into the brain.

What makes scientists excited about the potential of the N-type channel blocker from the snail is that it shuts down pain neurons without creating pleasure or other triggers for addiction common to narcotics.

'All systems go'

When the painkilling effects of the snail toxin were unravelled, labs and drug companies around the world raced to make a drug. Initial efforts resulted in Prialt, which was modelled off the snail chemical. But the drug only works when injected into the spinal chord, which is not a very easy thing to do, especially in the treatment of chronic pain when frequent doses are often needed.

So Dr. Terry Snutch took a different approach and started from scratch. Through Neuromed, the bio-tech company he co-founded in 1998, he designed molecules to block the N-type calcium channel. "[I] synthesized several hundreds of derivatives, and then tested each derivative one by one against whether or not they would block the N-type calcium channel that I had cloned, and NMED-160 came out of that screening program,"

NMED-160 is a small molecule that specifically targets N-type calcium channels and can be taken orally. It is also big news in the pharmaceutical industry, which has been having a hard time finding new drugs to develop and market. A partnership with Merck allows Neuromed to expand its research program. The deal grants $25 million and $202 million more when FDA approval is given and NMED-160 goes to market, but that is still another seven years down the road; NMED-160 still has a lot of testing to go through.

Right now the drug is in clinical trials and not much information is available about its performance. But the primary research shows that NMED-160 "works as well as morphine in animals for chronic neuropathic pain," says Snutch. Whether that effectiveness will carry over when the drug is tested in humans remains to be seen. NMED-160 is two years into a process that takes up to seven years and so far there are "no indications that it's not going to work, so it's all systems go," says Snutch.

New era for pain management?

Researchers investigating the possible use of N-type calcium blockers are pointing to some mouse research to stress the feasibility and safety of using the calcium blocker strategy in treating chronic pain. Mice that were genetically altered to not have N-type calcium channels anywhere showed no serious side effects. The development and lifespan of these mice were normal, and no physical or behavioural abnormalities were found apart from increased pain resistance and decreased anxiety.

Prialt, the first generation of N-type calcium blockers, did affect some calcium channels in neurons that regulated blood pressure, which resulted in low blood pressure in some patients. But that was the only notable side effect of that drug, and thus far NMED-160 has not caused the same problem. So the future looks good for drugs like NMED-160, but the final verdict won't be out until all the tests are done and the data is analyzed.

By targeting chronic pain without addiction, painkillers like NMED-160 used as a substitute for morphine and other narcotics would radically change how chronic pain is treated. Researchers also expect this potential new class of painkillers would avoid other complications associated with narcotics, in including respiratory depression and the need to administer more and more of the drug to create the same effect.

Even if such drugs pass clinical trials, however, a lot will depend on how affordable the drugs are, and how much access family doctors will have to them.

Addicts in pain

Dr. Paul Farnan is a specialist in addiction medicine who will speak at an upcoming Vancouver conference on workplace health. He says that the people on the front lines battling chronic pain and addiction are family doctors. In an interview with The Tyee, he stressed that medical narcotics are very useful in the treatment of chronic pain if prescribed properly.

"The risk of somebody without any pre-existing risk factors becoming addicted to opiates in the true sense of addiction is minimal," says Farnan. As a result, new drugs might not be necessary for everyone with chronic pain because medical narcotics have been well studied and their limits and potential are known.

Farnan thinks that if a drug like NMED-160 works like it's suppose to, it could be an import new treatment option that would "particularly be suitable for people who had a previous history of confirmed addiction that they had treated in the past."

For many people living with chronic pain, medical narcotics are the only things strong enough to allow them to carry on. When that person is also addicted to narcotics or has a previous history of addiction, medical narcotic treatment of their pain can cause a relapse into addictive behaviour.

Farnan believes it is still possible to use medical narcotics to successfully treat people with chronic pain who struggle with addiction. "It involves good history-taking, good discussion with the patient of the pros and cons, good follow-up and after-care."

The level of attention and care that is needed for proper treatment of people with chronic pain and addiction is very high, and our health system is not providing the level of care that is needed, Farnan says. "People with the disease of addiction do not get enough care and enough money injected into the system for proper treatment."

The development of N-type calcium channel blockers, if made affordable, could help meet the challenges of treating people with addiction and chronic pain. And researchers, who got started down this path thanks to a venomous shelled denizen of the South Pacific, are hoping their progress towards that day continues much faster than a snail's pace.

Jeffrey Helm, a former neuroscientist, is writing about science and addiction issues for The Tyee this summer.

Related Tyee stories: Jessica Werb wrote about addiction to the prescribed drug Paxil; Mexican Pavel Gonzalez explained why foreigners find B.C. a perfect place to kick smoking; and public opinion expert Angus Reid surveyed views on drugs and the law in North, Central and South America.  [Tyee]

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