by William Wells
Opiates such as morphine are often not enough. A sea snail and a tree frog may come to the rescue of those with intractable pain.
It was a challenging ski run but not unreasonable. Besides, there was a nice little jump at the end to look forward to. Unfortunately I never made it as far as the jump.
"At least you looked gnarly when you bit it," said my friend Aaron.
"It isnt over until somebody loses an eye," was the cryptic comment from my friend Nicole, observing the arrival of the ski patrol as she sat in the chair lift above.
As the friendly ski-patrol man loaded me onto the stretcher, he asked where I lived. "San Francisco," I said. So far, so good. "And where do you live in San Francisco," he asked, trying to keep me alert. "The Mission district," I said. The ski-patrol man glanced at Aaron, who shook his head ruefully. One day I would live in the Mission, but not just yet. On went the oxygen mask.
A shoulder is one of the bodys ball-and-socket joints. When my left shoulder met the ice, at speed, the ball broke, and half of it went for a vacation somewhere on the way to my neck. Surgeons pinned the ball back together again, and soon I was healing nicely.
But three months later I started to get a heavy feeling in my forearm after exercise. Pretty soon the feeling was there all the time. I felt like a small truck had taken up permanent residence on my arm.
Scar tissue may have clamped around a nerve or two, or perhaps my muscles were re-establishing themselves in a slightly different way, with the new arrangement pressing down on nerves.
Either way, the damage was in or near the shoulder, but it was surfacing in my arm. Its hard to remember now what that felt like, and how it monopolized my thoughts. I do know that I was willing to do anything to make it go away. Over the next three years there was acupuncture, physical therapy, hypnotherapy, pills, injected drugs, more pills, outpatient procedures, inpatient procedures, and surgery.
Being a child of the antibiotics age and a budding scientist, my slow recovery and trial-and-error treatment came as a big shock. I realized that the nervous system, the bodys wiring diagram, doesnt always get things right. Its not very good at fixing itself, and when it tries it often makes the wrong attachments, so things get even worse.
And doctors are not so flash at making up its deficiencies. I went to one of the best pain clinics in the United States, where most patients had conditions far more serious than mine. My neurologist was stunned when I finally reacted to one of his drugs, an old standby called Tegretol that was originally developed to treat epilepsy. "We arent used to people getting better around here," he said.
Pain clinics are big on teaching coping skills, because pain patients have to cope with the shortcomings of pain drugs. I was lucky. By the time I had reached the maximum dosage of one of the weaker opiates, a combination of time, surgery and Tegretol had taken away my need for any opiates at all. After a few days of withdrawal my brain emerged from the opiate-induced fog.
For many the solution is not so easy. My roommate for one of my hospital stays had just had a facial nerve cut, in an attempt to finally silence it. But still he was groaning almost constantly.
The obvious treatment is morphine, the king of the opiates. Unfortunately morphine depresses breathing, causes constipation, and makes the brain sluggish. It is notoriously ineffective against the kind of pain that I had, called neuropathic pain, which is the result of nerve rather than tissue injury. And with chronic use the body develops tolerance, requiring ever greater doses to get the same effect.
"People get a certain response and thats it. After that youre just chasing that same amount of pain relief," says Michael Rowbotham, director of the Pain Clinic Research Center at the University of California, San Francisco (UCSF), and associate director of the UCSF/Mount Zion Pain Management Clinic.
"Theres no type of pain for which we dont need new agents," he says. "When you put it all together the question is where to start."
Replacements for morphine are finally being developed. Neither of the leading candidates discussed in this article are available commercially: Ziconotide may be available by the end of 1999, but ABT-594 is still in early-stage trials. Even if ABT-594 passes these trials, it will not be available for several years. But both candidates, developed from chemicals made by sea snails and tree frogs, respectively, hold the promise of stronger and broader action than morphine, with no tolerance.
The hunting strategy of fish-eating cone snails starts with deception: the cone snails bury themselves, leaving only a proboscis waving above the reef floor. To a passing fish the proboscis looks like a worm -- its next meal. But once the fish comes close enough, the cone snail launches a miniature harpoon from the proboscis and uses it to inject a cocktail of poisons. The cone snail then emerges from the reef floor and devours its paralyzed prey.
As a recent hire at the University of the Philippines, Baldomero Olivera decided to work out how the cone snails killed fish (and, for the species Conus geographus, humans) so quickly and efficiently. "We thought the venoms would be relatively simple," he says. "We just thought we would categorize a couple of toxins."
What came out, after a painstaking process of milking the cone snails, was a complex mixture of chemicals. But Olivera began to suspect that the complexity was a red herring. Many of the chemicals had no effect when they were injected into mice. "There were a lot of peaks, but a lot of them were inactive," says Olivera. "We werent sure what to make of these inactive peaks."
Olivera moved to the University of Utah in Salt Lake City and resumed his work on how DNA is copied. His snail toxins, or conotoxins, were interesting but didnt seem to be the sort of work to build a career on.
Oliveras graduate student Craig Clark had other ideas. Clark realized that many of the conotoxins were probably designed to hit the nervous system of the fish. But in mice and humans, much of the nervous system is shielded from drugs and toxins by a system of impermeable blood vessels called the blood-brain barrier.
To circumvent this system, Clark injected conotoxins directly into mouse brains. Previously inactive, the individual toxins now caused the mice to either jump, sleep, scratch, drag their hind legs, swing their heads or shake.
The toxins caused so many behaviors because they were hitting so many different targets in the mouse nervous system. In the fish, their combined effect is formidable. Some toxins open channels on the outside of the fishs nerve cells, switching the whole nervous system on at once and causing the fish equivalent of an epileptic fit. Other toxins block nerve to muscle communication; still others shut off all communication between nerves.
Cone snails use this chemical overkill so that death comes as quickly as possible. Any struggle would attract other predators, and the meandering cone snail is not about to run after a fish that is wounded but still mobile.
A need for speedy action also explains the size of the conotoxins. As with many toxins, such as those from spiders and scorpions, the conotoxins are strings of amino acids called peptides. But the conotoxin peptides have between ten and thirty amino acids, whereas many other toxins have over one hundred amino acids each. Their small size means that conotoxins diffuse rapidly into the fish.
And this diffusion is not slowed by attachment of the conotoxins to irrelevant protein molecules, because the conotoxins attach themselves very specifically to one protein in the nervous system.
For the pharmaceutical industry this story was starting to sound more and more attractive. Small molecules are easy to make, and specific molecules should work as potent drugs with few side-effects.
The first company to push a conotoxin through drug trials is Neurex Corporation (Menlo Park, Calif.). Their drug, called SNX-111 or ziconotide, is an omega-conotoxin that blocks the entry of calcium ions into nerve cells. This prevents the nerve cells from releasing packets of nerve messengers to communicate with their neighbors.
Olivera had initially focused on fish-eating rather than worm-eating snails because he hoped that toxins designed to hit certain vertebrates (fish) would also work on mice and humans.
But ziconotide doesnt kill humans precisely because it doesnt fit this pattern. In fish, ziconotide causes paralysis by blocking nerve to muscle communication, but mammals have evolved calcium channels at the nerve-muscle junction that are insensitive to ziconotide. As George Miljanich, senior director of biochemistry at Neurex, says, "lucky for pain sufferers, and for Neurex."
The one place that ziconotide binds in the human spinal cord is the part that is used for sending pain signals. Clinical trials of ziconotide for pain were completed in 1998, and Neurex expects to file a new drug application soon.
The drug is delivered directly to the spinal cord using a pump developed by Medtronic, Inc. (Minneapolis, Minnesota). The pump is the size of a hockey puck, and is implanted in the chest and refilled by syringe. A pump is more cumbersome than a pill but, Miljanich says, "hundreds of thousands of patients suffer chronic, otherwise intractable pain, and tens of thousands already have intra-spinal morphine."
Ziconotide causes mental fogginess in some patients, but there is none of the constipation or respiratory suppression seen with morphine, and it is effective against neuropathic pain. Most importantly, there is no tolerance. "We never saw any signs of tolerance in animals or in patients," says Miljanich. "The dose we give in the first week is equally effective a year later."
Tolerance is well understood but difficult to combat. Morphine, for example, turns on a pain-killing process in nerve cells. The body then tries to restore the status-quo, by removing the nerve protein that morphine attaches itself to. Without this on-switch, there is nothing for morphine to latch onto and so no pain killing.
Ziconotide works by turning off the pain signals directly. To combat ziconotide, the body would have to make more and more of the protein that ziconotide turns off, in the hope that it would overwhelm the drug. But, Miljanich says, "theres a limit to that. Theres only so many calcium channels that a cell can jam into a membrane."
John Daly had a problem. True, he had harvested an intriguing chemical from the skin of an Ecuadorian tree frog Epipedobates tricolor, and true, the chemical, called epibatidine, was at least 200 times more potent than morphine as a pain killer in animals. But Daly, a researcher at the National Institute of Diabetes and Digestive and Kidney Diseases, wanted to make epibatidine in quantity, and to do that he needed to know the chemicals shape -- its structure. To determine the structure on his mid-1970s machines, he needed more of the chemical.
Unfortunately the frog was now on the endangered species list, so more collecting was out. As for laboratory-grown frogs, they didnt seem to make the chemical, probably because a bug that supplied the crucial chemical precursor was lacking from their diet. Daly sat on his precious but insufficient supply of epibatidine, waiting for technology to catch up with him.
In the 1980s, help came in the form of more sensitive nuclear magnetic resonance (NMR) machines, which Daly used to determine the structure of epibatidine. Several groups then made synthetic epibatidine.
But there were more problems. Epibatidine was potent against pain, but it was also potent in some unwanted directions -- it caused high blood pressure, paralysis, and seizures. Daly found that it acted by hitting a particular kind of protein on a nerve cell called the nicotinic acetylcholine receptor (nAChR). The nAChR is the receiver in the nerve-cell relay race: it detects the presence of the chemical messenger acetylcholine, which is released by one nerve cell, and relays that message to the next nerve cell. Acetylcholine, epibatidine, and the nicotine found in cigarettes can all turn on the nAChR.
Acetylcholine has many jobs, all over the body, and epibatidine was interfering with too many of them. Enter a research group from Abbott Laboratories (Abbott Park, Ill.), led by Stephen Arneric. This group found that epibatidine attached itself to several forms of the nAChR, including one in the brain, and another at the nerve-muscle junction, where nerves tell muscles to contract. With some clever combinatorial chemistry, the Abbott chemists made 500 variants of epibatidine and tested them in animals. The winner, ABT-594, was just as potent as epibatidine in attaching to the brain nAChR, but 4000-fold less potent as epibatidine at the muscle nAChR.
"This would be the first relatively non-serendipitous effort in pain drugs," says Howard Fields, a pain researcher at the University of California, San Francisco. "The original compound was from the frog, but then there was nice combinatorial chemistry to match it to the one receptor. It looks good."
ABT-594 is a small chemical that should, unlike ziconotide, work as a pill. And in rats it works against acute, chronic, and neuropathic pain, with little or no effect on digestion and breathing. Questions about tolerance and dependence remain. "We dont know yet if, when we have analgesia from a nicotine-like drug, were stuck with the dependence process, or if the two processes are separable," says Edgar Iwamoto (University of Kentucky, Lexington). "For opiates the two are intimately tied."
Rats cut off from a supply of ABT-594 do not suffer from morphine-like withdrawal as measured by eating habits. But nicotine and morphine addiction are not the same thing. Morphine addiction involves a reduction in the number of morphine receptors, but changing numbers of nAChRs do not seem to explain nicotine addiction. Iwamoto says that nicotine addiction is hard to study, because individual responses are so variable.
Recent hopeful news comes from researchers at Novo Nordisk (Denmark), who report that mice do not self-administer epibatidine, as they do with cocaine or nicotine. But real proof will come only from human trials. Results from phase I safety trials are in but not public; phase II dosing studies will start soon.
Although ABT-594 is more specific than epibatidine, Abbott will continue to watch closely for side-effects. "One of the things that probably makes any nicotinic drug difficult is that nicotine causes the release of many [nerve messengers]," says Iwamoto. "This drug is not doing one thing."
ABT-594 may be acting at several levels of the nervous system, illustrating the complexity of pain signaling. Far from being a simple relay from cut finger to brain, pain circuits are modified by local processing in the spinal cord, and by signals that descend from the brain to the spinal cord. In the latter case, says Iwamoto, "the brain can shut off the pain signal so the organism can combat the source of the pain or run away from it." Other factors such as emotional state can also modify pain sensation, and still other nerve systems relay the effects of pain (changes in heart rate, blood pressure, digestion and breathing) to the rest of the body.
All those systems use a multitude of chemical messengers. One by one, most major classes of nerve messengers have been implicated in pain, and drug companies have responded with programs to make drugs that block the messengers. A key to the complexity remains elusive. "We may lack the knowledge of whats essential," says Iwamoto. "Weve found a bunch of [nerve messengers], but we dont know if just one is crucial."
That picture should become clearer as some of the drug candidates, including ABT-594, move from the laboratory to the clinic. With any luck, at least some of the approaches should work out for patients. In the meantime the researchers are busy. "Theres a lot on the horizon," says UCSFs Rowbotham. "Its a great time to be doing pain research."