The Search for the Killer Painkiller

By ANDREW POLLACK

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."

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