Myrl Jeffcoat myrlj@jps.net

8 mars, 2005 20:27

Researchers seek new ideas for an old malady

Scientists try to develop new painkillers in an effort

to stop the problem of constant pain.

Posted March 8, 2005

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 COX-2 pills such as Celebrex and Bextra. Those concerns come on top of the problems of abuse of narcotic painkillers.  "There's a huge void, and no one is filling it," says Remi Barbier, chief executive of Pain Therapeutics, a company in South San Francisco, Calif.

But Barbier's company and dozens of others are trying. And some new treatments may come from things in nature that soothe or sting, such as 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 such as 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," says Dr. Russell Portenoy, chairman of pain management and palliative care at Beth Israel Medical Center in New York. But now, he says, there is a growing realization that "chronic pain is itself an illness, and it's a complex illness."

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 such as diabetes or shingles.

Opioids, such as morphine, 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 such as 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.  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.

Blocking the pain

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 FDA 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," says Lars Ekman, head of research and development at Elan, the Irish company that developed the drug. He says the drug is nonaddictive and 1,000 times as potent as morphine. 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.

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.

Marijuana's benefit

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," says 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 says, 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 such as 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.