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Biomedicine

Stopping Pain

Insights into the neuroscience behind pain are spawning a new generation of drugs designed to short-circuit the body’s pain signals without side effects.

On April 29, 1997, the supermarket tabloid the National Examiner ran this headline on its cover: “Miracle Pain Cure: Deadly Snail Venom.” The garbled story within contained a kernel of truth. Doctors in fact were injecting a drug derived from the venom of a marine snail into patients suffering from the worst kinds of pain imaginable.

One of the researchers responsible for this unlikely drug, neuroscientist George Miljanich, sits beneath a framed copy of the tabloid cover, which shares wall space above his South San Francisco, CA, desk with more staid covers from the journals Molecular and Cellular Neuroscience and the Journal of Neurocytology, among others. Miljanich works for Dublin, Ireland-based Elan Pharmaceuticals, and his snail-derived drug is called ziconotide.

For the last 50 million years, predatory snails in the Pacific Ocean have been stabbing passing fish and killing them with their venom. In tiny amounts, though, one component of the venom actually blocks the pain in desperately sick and injured people-at least among the nearly 2,000 who have tried it to date. “Ziconotide is about a thousand times more potent than morphine,” Miljanich says. “Upwards of a third of these patients experience significant improvement in their quality of life.”

Ziconotide is not yet approved by the U.S. Food and Drug Administration, and because it can cause severe side effects, its future remains uncertain. But its ultimate fate in the marketplace is, in a way, beside the point. Because of its effectiveness in halting pain, ziconotide has spawned a new generation of drugs deliberately designed to block the electrical impulses that generate pain signals, without affecting other systems in the human body.

These efforts represent an entirely new way to treat pain, one with such commercial promise that at least a dozen companies-from small biotech companies to pharmaceutical powerhouses such as GlaxoSmithKline and Merck-are investing billions of dollars in an effort to improve on nature by creating synthetic molecules more potent and safer than ziconotide. Human trials of some of the drugs could begin within the year. “The idea here would be a drug that only takes out the pain,” says neuroscientist Allan Basbaum of the University of California, San Francisco. “And that’s on the horizon.”

The need is pressing. According to the American Pain Foundation, more than 50 million Americans suffer persistent pain. Morphine, first chemically isolated from the poppy plant 200 years ago, remains the drug of choice for severe pain. Despite its many side effects, including drowsiness, interference with breathing, constipation, and the potential for addiction, “no one has bettered it,” says University of Michigan pharmacologist John Traynor.

Many “new” painkillers are in fact anything but, and they have problems similar to morphine’s. OxyContin, for instance, is actually a morphine derivative that has been in use since 1917. The difficulty with all of these older drugs is that they act throughout the nervous system, not just on pain-sensing nerves-hence their side effects.

A few more-selective new drugs do exist, including the cox-2 inhibitors used to treat arthritis pain (Merck’s Vioxx or Pfizer’s Celebrex, for example), but for really severe pain, they might as well be sugar pills. People with postsurgical pain, intense cancer pain, traumatic injuries, and severe chronic back pain must often still resort to morphine and its narcotic cousins for relief. And sometimes, even morphine is not enough.

Seven years ago, Vicki Wiltshire was rear-ended while driving to a physical-therapy appointment; the collision aggravated a back injury she had suffered earlier and sent her into a spiral of pain and despair. Four surgeries later, the former realtor has screws and rods in her spine, three fused discs, and masses of scar tissue. She cannot bend or twist without excruciating pain.

Suicide, at times, has crossed Wiltshire’s mind. “We don’t have guns in the house,” she says. “You cannot live in that kind of pain day in and day out.” Such chronic pain is not a dull throbbing. “Your body is screaming constantly,” says Elaine Casanova, a former secretary who wrecked her back in a small-plane crash. “Think about having a toothache for 10 years.”

Both Wiltshire and Casanova have taken morphine and other narcotics for long periods. Narcotics dampen but do not douse the pain, and Casanova became addicted, adding another layer of misery to her life. Both women are now on ziconotide, which they say has provided a kind of breathing space in their suffocating world of pain.

It is just those kinds of anecdotes, backed by growing insights into the neuroscience behind pain, that are finally offering realistic hope for new drugs that attack pain without producing debilitating side effects.

Beyond Morphine

The new pain drugs target ion channels, porelike molecules on the surfaces of cells that open and close like tiny, gated tunnels. Ion channels are present in all cells, perhaps because the earliest living organisms evolved in salt water, with its high concentrations of sodium and chloride ions. Indeed, ion channels that control cells’ intake of sodium and calcium regulate everything from the secretion of hormones to the beating of the heart.

In nerve cells, when ions pour in through the opened channels, they generate an electrical spike. In pain-sensing nerve fibers, this spike causes pain. Acute pain has benefits: it alerts the body to injury and can prevent additional damage. But most chronic pain serves no purpose. So if one shuts the gate, the theory goes, chronic pain disappears. Now, with the identification of dozens of ion channels, new knowledge of their biology, and a rapidly growing arsenal of chemical compounds to block them, the theory appears to be on the verge of leading to new drugs.

The key is several recently discovered ion channels that seem to be found exclusively on the specialized nerve fibers that sense pain. “If you can develop drugs to target them,” Basbaum says. He doesn’t need to finish his thought. Analgesia without side effects: the ultimate answer for pain.

Drugmakers have embraced the idea, and one of their most promising targets is the capsaicin receptor. Capsaicin, the chemical that makes chili peppers hot, can cause intense pain, as anyone who’s accidentally touched an eye after handling hot peppers knows. (Paradoxically, capsaicin applied over several hours can actually relieve pain-for reasons that are hotly debated-and capsaicin creams are sold over the counter to treat conditions like arthritis.)

In 1997, University of California, San Francisco, neurobiologist David Julius isolated the capsaicin receptor. It turned out to be an ion channel that opens not only when capsaicin binds to it but also in response to heat and acidity. When the channel opens, calcium ions flow in, causing the nerve to fire and sending a pain impulse toward the spinal cord and brain. Since the capsaicin receptor is only found on pain fibers (and, possibly, in the brain), and because it has the remarkable ability to detect different types of painful stimuli, blocking it could work beautifully for pain relief.

The capsaicin receptor has drawn the interest of Novartis, Pfizer, GlaxoSmithKline, Merck-“Every major drug company, as far as I can tell,” says Julius. “Probably the biggest market is osteoarthritis,” says Jim Krause, senior vice president of biology for Neurogen, a Branford, CT, biotech company working on capsaicin receptor blockers. Cancer pain is another possibility, since bone metastases result in acid conditions that might trigger the receptor or similar ion channels.

And neuropathic pain-that is, pain caused by nerve injury-is yet another tantalizing target. Diabetes, cancer, AIDS, kidney disease, chronic infections, and even some prescription drugs cause neuropathic pain, which is often untreatable. Though it appears that no company is currently testing a drug based on a capsaicin receptor blocker in humans, Neurogen may be the closest and hopes to start testing its compound in humans within a year.

Changing Channels

Blocking the capsaicin receptor prevents pain neurons from firing in the first place, but ion channels that help transmit pain signals could also prove good drug targets. Once a pain receptor like the capsaicin receptor is activated, the initial electrical spike causes sodium ion channels to open in sequence down the length of the nerve, conveying the electrical impulse all the way to the nerve’s end. But this sequential opening happens throughout the nervous system, not just in nerves that signal pain. Local anesthetics, in fact, block sodium ion channels, but do so indiscriminately, thus eliminating all nerve activity. Given orally or injected into the bloodstream, local anesthetics would cause paralysis and death.

A dozen sodium ion channels have been identified. But a second sea creature clued researchers into a sodium ion channel found only on pain-sensing nerves. Like the marine snail, the deadly Puffer fish, or blowfish, uses a toxin to kill its prey; this toxin works by blocking sodium channels-with the exception of the channel unique to pain fibers. In 1996 John Wood of University College London and John Hunter at Roche Bioscience simultaneously isolated that channel by relying on its unique resistance to the blowfish toxin.

Target just this sodium channel, researchers assume, and you take out only pain, leaving other nerves free to fire away, happily transmitting impulses all the way to the brain. “It looks like you will get good analgesia in the absence of side effects,” says Phil Birch, chief scientific officer of Ionix Pharmaceuticals in Cambridge, England. Ionix, cofounded by Wood, has found several drug candidates that block the sodium channel and hopes to try one in humans by 2005. “Because the target is expressed only in pain-sensing nerves, [we] can develop a selective blocker,” Birch says. “We think it’ll have a fantastic profile.”

Merck, GlaxoSmithKline, and Elan are also targeting this ion channel. “It’s localized perfectly for where you want to block the pain signals,” says Elan’s Miljanich. Compounds that inhibit it could treat acute and inflammatory pain, such as that caused by arthritis. But even more alluring is neuropathic pain. Nerves damaged by disease seem to have more of these channels, exacerbating the uncontrolled nerve firing of neuropathic pain-pain disconnected from any external injury. Even the best available drug only helps about 30 percent of patients with neuropathic pain. Selective sodium channel blockers could be the first effective drugs deliberately designed to treat their condition.

No one is yet sure they’ll work. “In theory, it’s a wonderful idea,” says Wendye Robbins, a Stanford University pain specialist. “In practice [it’s] more complicated.” Other sodium channels look virtually identical, so it’s hard to target just one. For example, a similar sodium ion channel regulates electrical impulses in the heart, and shutting down sodium channels in the brain would cause stupor. Ionix says its molecules do not block these channels, but the ultimate test will be in humans.

Killing the Messenger

Other basic questions about the effectiveness of blocking specific ion channels remain unanswered. For one thing, no one is certain that blocking one type of ion channel will be enough; other kinds of channels-there are dozens-might open and cause a spike anyway. “The real question is, will one drug do it?” says Basbaum. He thinks that ion channel blockers may work well for specific kinds of pain, but that no single drug will work for everything. “Is there a magic bullet?” he asks. “The answer is, it may very well be that [drug] cocktails are the way to go.”

Still, ziconotide holds out the tantalizing possibility that a single drug might be enough. Nerve impulses traverse the body through a vast system of neurons laid out end to end, not quite touching. The gaps between neurons are called synapses, and certain calcium ion channels are essential to conveying impulses across the gaps. While capsaicin and sodium channel blockers prevent pain-sensing neurons from firing, ziconotide keeps the impulse from crossing the synapse by blocking these calcium channels. So it doesn’t matter if the other channels are stuck wide open, causing the first nerve in a pathway to fire violently and endlessly. If the impulse can’t cross the synapse, no pain is felt. The first neuron “is firing as fast as it can, but it’s not telling the next neuron that anything’s going on,” explains Bruce Morimoto, director of drug development for NeuroMed, a Vancouver, British Columbia, biotech company.

Ziconotide is too toxic and too hard to deliver ever to be widely used; its side effects include confusion, memory loss, dizziness, and tremors. It fogs the brain the same way it stops pain, by preventing neurons from communicating. But NeuroMed and Ionix are developing next-generation versions of ziconotide. These drugs can be taken as pills and-their developers hope-will avoid ziconotide’s worst side effects. The key is to target only nerves that are sending pain impulses. “Under pain conditions, those neurons are firing at a very rapid rate compared to normal’ neurons,” explains Morimoto. “If our compounds are blocking the channel with this very rapid, high-frequency stimulation, [then] we are more likely to hit only the channels involved in pain transmission, and not other ones in the body.”

Scientists at NeuroMed identified such compounds by applying tiny electrical shocks to nerve cells. They used minuscule glass electrodes clamped onto single neurons to measure the current generated by the opening of individual ion channels as the neurons fired. The company’s compounds were tested, one by one, for their effects on these individual channels. Only those compounds that closed the channels while the nerve fired vigorously became drug candidates.

NeuroMed hopes its lead drug candidate will enter human trials later this year. Ionix anticipates starting tests of its drug candidate by the end of 2004. Only then will we begin to know if ziconotide’s spectacular but erratic analgesia can be bettered.

A Bell in Your Brain

There is one more cautionary footnote to the tale of the new pain drugs. All the approaches, and the billions of dollars the drug industry has invested in them, teeter on an untested assumption: that blocking nerve impulses in the body’s periphery, before the signals reach the spinal cord, is the best way to block pain. This seems self-evident but in fact may be wrong.

In the 17th century, Descartes postulated that injury generates pain by sending a message via nerves to the brain, as if pulling at the end of a rope to ring a bell. You bash your shin, the rope rings the bell in your brain, and you feel pain. It follows that cutting the rope-blocking the peripheral nerves-should prevent the pain from ever reaching the brain.

But it’s not that simple. It’s now clear that the sensation of pain doesn’t match up consistently with stimulation of pain-sensing nerves. The same injury can produce intense pain in some people and nothing in others, depending on the person’s immediate circumstances, past experiences, and state of mind. Soldiers, for instance, may not realize they have been shot until a battle is over. On the other hand, many amputees suffer “phantom limb” pain, in which, say, a missing hand and fingers are felt in every detail.

“There is no such thing as a painful sensation; there are only sensations that get interpreted as pain,” says Tito Serafini, a neuroscientist at the South San Francisco biotech company Renovis. The brain’s role is central. “Looking at the periphery, simply because we can do it, is going off in the wrong direction,” argues John Loeser, a neurosurgeon at the University of Washington. “The processing of information in the brain is probably far more important than what happens in the periphery.”

In fact, neuroscientists now know that pain messages do not flow unchecked from the body to the brain. Instead, “gates” in the spinal cord alter the level and intensity of nerve impulses. And impulses descending from the brain can open and close these pain gates.

“Pain is in the brain,” Basbaum concedes. Unfortunately, he says, we have no idea how to find a drug that will attack pain via the brain, still the most mysterious organ. “We know the brain is an essential part of the pain experience,” he says, “but we just don’t know anything about circuitry or the chemistry.”

Until neuroscientists begin to figure out how the brain controls pain, blocking ion channels could prove the best way to find highly potent painkillers with few side effects. These drugs may not be the last word in analgesia, but if human tests confirm the drugmakers’ theories, they will finally make morphine and its cousins obsolete. That’s good news for Vicki Wiltshire, Elaine Casanova, and the millions like them who suffer from devastating pain.

Target: Ion Channels
Company Target Status
Elan Pharmaceuticals (Dublin, Ireland) Select calcium channels In human trials
GlaxoSmithKline (Brentford, England) Capsaicin receptors Preclinical development
Select sodium channels In human trials
Ionix Pharmaceuticals (Cambridge, England) Select calcium channels Human trials scheduled for 2004
Select sodium channels Human trials scheduled for 2005
Merck (Whitehouse Station, NJ) Capsaicin receptors and select sodium channels Basic research
Neurogen (Branford, CT) Capsaicin receptors Human trials scheduled for 2004
NeuroMed (Vancouver, British Columbia) Select calcium channels Human trials scheduled for 2003
Novartis (Basel, Switzerland) Capsaicin receptors Preclinical development
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