COLUMN ONE : When Pain Systems Go Awry : There are no reliable cures yet for people who suffer from rare, often inexplicable forms of physical agony, but researchers are offering hope.


Dr. James Campbell, a 43-year-old neurosurgeon at Johns Hopkins Medical School, treats pain, but not simply the throbbing sensations following surgery or the crippling spasms of injured backs. Campbell specializes in treating much rarer, more intense forms of physical agony.

Some of his patients can't put their hands under a faucet. Even a gentle stream of water feels like a torrent of bullets. Others dread the thought of walking outdoors. The touch of clothing or a gentle puff of wind is a torch against their skin. Still others don't dare attend church. The rumble of a pipe organ's bass notes produces sensations that they cannot find words to describe.

Sometimes dismissed as hysterics or lunatics, such patients are actually suffering from real physical manifestations of the body's pain system gone awry. There are as yet no reliable cures for hyperalgesia (excessive sensibility to painful stimuli) or allodynia (sensitivity to stimuli that are not normally painful). But there is hope for patients who suffer from these symptoms and a collection of disorders associated with them, including causalgia (intense burning sensations associated with nerve damage) and reflex sympathetic dystrophy (persistent and severe pain caused by bone and soft tissue damage).

Using animal models and in some cases conducting experiments on human subjects, researchers and clinicians in laboratories and hospitals throughout the United States, Europe and Asia have pieced together explanations for these and other mysteries of the human nervous system.

But they still have a lot to learn. Pain researchers have yet to understand all of the changes that occur within individual cells as the nervous system receives, processes, and interprets neurological information related to pain. And researchers are only beginning to appreciate the physiological and psychological damage that can occur from unabated pain.

"Pain is not always a simple warning signal that some part of the body has been damaged or diseased," Campbell said. "Sometimes pain is an indication that the body's pain system itself has become damaged or diseased. Increasingly, we have come to realize that pain is not a simple sensation, as might be assumed, but a fantastically complex set of neurological, biochemical, physiological and emotional reactions."

Lower back pain--one of the most common and debilitating forms of agony known to modern man--is one example of the complexity. In 70% to 80% of the cases, there is no known cause. Although the initial pain may occur because of an injury, doctors believe it is unlikely that pain persists because of ongoing damage to discs or muscles. "The more likely explanation is that the body's pain system has been turned on and does not know how to turn itself off," said Dr. Patrick D. Wall, a British anatomist and one of the world's leading theoreticians and researchers on pain.

Similarly, there is no apparent explanation for the sharp and burning sensations in the arms and hands of pianists, computer keyboard operators and other victims of repetitive stress injuries. Whatever the initial cause of such injuries, Wall said, the body's pain system seems to have gone on "overdrive and stayed there."

Over the last three decades, scientists have learned much about how the pain system is supposed to work. They have discovered specific sense organs within the nervous system that receive and transmit information about pain. They have traced the flow of information from the peripheral nervous system, where noxious stimuli are first recorded in skin, muscles and internal organs, to the central nervous system--the spinal cord and brain.

Although what happens in the brain remains largely a mystery, scientists have pried loose some remarkable secrets. Researchers have found that the central nervous system contains receptors specifically designed to receive morphine-like painkillers. They also have found that the body produces its own natural morphine-like substances to fight pain.

What they have not learned is how to bring those mechanisms under control at will.

"Perhaps we never will," said John Liebeskind, who runs a pain research laboratory at UCLA. "The more we learn about how complicated the human pain system is, the more many people become convinced that it may be impossible to rid mankind of the scourge of pain."

The body's pain system is so complex that scientists don't entirely understand how common painkillers work.

Acetylsalicylic acid or aspirin, for instance, was discovered in the bark of a willow tree more than 200 years ago. Today, Americans consume more than 16,000 tons of aspirin tablets annually--about 80 million pills. Yet "the mechanisms by which this venerable drug relieves minor pain is only about 80% understood," said Dr. Gerald Weissman, professor of medicine at New York University.

"We know that, unlike morphine and other opiates which work on the brain and spinal cord in the central nervous system, aspirin and aspirin-like substances act in the peripheral nervous system," Weissman said. "We know that aspirin works in part by blocking the release of prostaglandins," a group of ubiquitous hormones that are released when tissues are injured, and play a role in allergies, heart disease, strokes and a variety of body functions, including inflammation.

But scientists did not even know that much until Dr. John R. Vane of the Royal College of Surgeons in London undertook extensive studies of prostaglandins in the 1960s and 1970s. He won a Nobel Prize for his work in 1982.

Similarly, it was not until 1973 that Candace Pert, then a graduate student at Johns Hopkins, and her adviser, Dr. Solomon H. Snyder, recognized the existence of opiate-like receptors, places in the brain where opiate drugs attach to nerve cells and block incoming pain signals.

Thanks to a subsequent discovery by two Scottish neuroscientists, Hans Kosterlitz and John Hughes, researchers know the receptors are there for a reason: to receive an opiate-like substance, known as enkephalin, which the brain manufactures in the course of fighting pain, changing moods and a host of other physiological functions.

For years, scientists assumed that those two discoveries would eventually lead to the development of new, more powerful painkillers and maybe even a treatment to counteract addiction to opiate drugs. That has yet to happen.

Indeed, much of the work in pain has been slow and mind-boggling.

As with most areas of basic research, studying pain involves the use of laboratory animals, which means adherence to strict and often cumbersome government regulations. It also means operating on tight budgets, since money is scarce for any kind of basic research, especially pain.

"Medical science has never put a high priority on pain research," said Dr. John J. Bonica, a retired anesthesiologist at the University of Washington who was one of the first physicians to focus full time on pain.

In 1974, Bonica founded the International Assn. for the Study of Pain and in 1987 was instrumental in establishing an unrestricted pain research grants program at the Bristol-Myers Squibb Co. The program has supported the work of numerous scientists and research physicians who consider themselves full-time pain doctors.

The most recent award, a $50,000 grant, however, went to a researcher who never considered himself a pain expert.

Working in a neurophysiology laboratory at the University of North Carolina in the mid-1960s, Dr. Edward R. Perl discovered specialized organs within the body that sense pain. Until then, many researchers had assumed pain nerves were no different than other nerves that transmit sensation. Perl, however, found the specific nerves, called nociceptors, that receive pain messages in the peripheral nervous system and send them to the spinal cord.

While Perl was conducting his research in Chapel Hill, Wall, the British anatomist, was working in his laboratory at University College London. Wall found the structures in the spinal cord that sent pain messages from the spinal cord to the brain.

As exciting as those twin discoveries were, what "truly has been astounding," Wall said, was to discover how changeable those structures are. "It is not a cleverly wired computer. It is a biological system that is undergoing changes all the time."

When pain sensors are repeatedly stimulated, as often occurs when a body part is traumatized or diseased, they appear to undergo fundamental physiological and biochemical changes, which can make them hypersensitive to later stimulation.

That explains, Wall said, why a serious injury to the body can hurt for hours or days afterward. Usually the transmission of pain signals is relatively short-lived. But sometimes the system goes awry and pain continues indefinitely. Or it is referred to some other part of the body.

That explained to Campbell why some patients experience bizarre pain syndromes. A twisted ankle, a surgical incision, or some simple injury in one part of the body resulted in awful pain in another part.

In its mildest form, this phenomenon happens to people all the time. The discomfort of sunburn, for example, is a common form of hyperalgesia. The skin's pain receptors are over-sensitized over a wide area and become excessively responsive even to something as benign as a gentle touch or a change in temperature. Recent research has suggested that there may be changes in the central nervous system as well.

Just what causes the system to go into overdrive is unclear, although Campbell thinks one factor may be a malfunctioning sympathetic nervous system--the system that normally regulates involuntary bodily functions such as blood pressure, heart rate and sweating.

The sympathetic nervous system appears to play a critical role in activating certain pain fibers. By injecting drugs that temporarily block the action of the system, Campbell has been able to alleviate many of his patients' strange pain states for months at a time. He is now experimenting with ointments he hopes will have the same effect.

Similar approaches are being used to understand and combat pain originating in the central nervous system. One of the most chilling and baffling central pain problems is "phantom" pain, a syndrome in which one in five patients continues to feel unpleasant, sometimes unbearable sensations in a limb or organ after it has been amputated or surgically removed.

Scientists theorize that, under general anesthesia, patients do not consciously feel the extraordinary pain impulses of the amputation, but such impulses still are created and carried to the spinal cord and brain. Sometimes these signals lay down an indelible echo that does not go away even after the limb has been severed.

"The main objective of research in this area is to discover how to prevent the spinal cord from recording the injury, so that it won't relay a pain message later," said Allan I. Basbaum, a pain expert at the UC San Francisco School of Medicine.

One simple way to avoid the echo, researchers have found, is to give nerve blocks or local anesthetics along with general anesthesia. This seems to block production of certain chemicals that may be responsible for initiating the pain memories.

Doctors also are experimenting with using numbing local anesthetics before and during surgery, rather than waiting until afterward. The usual practice in modern surgery is to give a general anesthetic, which puts patients to sleep, but does nothing to control pain. Only after the patient has awakened do doctors and nurses begin administering pain medications.

But with "preemptive analgesia," the nerve cells in the spinal cord never receive the barrage of pain signals. Although only in the experimental stage now, there is evidence that this simple approach may greatly reduce postoperative suffering.

One reason scientists are so eager to stop pain signals before they reach the brain is that they understand so little of what happens inside the brain.

Dr. Kenneth L. Casey, professor of neurology and physiology at the University of Michigan, has been trying to use a PET Scan, a state-of-the-art imaging technique, to try to paint a picture of pain inside the human brain.

In Liebeskind's UCLA lab, seven young researchers are following up on a discovery made nearly 20 years ago when Liebeskind was a young assistant professor. He and another group of graduate students verified the existence of a natural pain inhibition system within the brain.

The researchers found the "brain can control its own pain input. In other words, we helped to show how stress and fear can either reduce or increase the sensation of pain," Liebeskind said.

Now he and his current crop of students are studying pain from a variety of perspectives. They are trying to understand the neurochemistry of non-opiate pain inhibition systems, which may one day help scientists understand why some painkillers are addictive and others are not.

They also are studying the genetics of pain. To do so, they are working with separate strains of mice that have been bred either for extremely low or extremely high tolerance to pain. While they have yet to confirm or publish their findings, Liebeskind and his team believe that a single gene may be associated with pain tolerance. If true, that could have profound practical implications as scientists become more adept at using genetic engineering to treat medical disorders.

Finally, the researchers are investigating the impact that pain has on the immune system. In carefully controlled laboratory studies, they have demonstrated that pain suppresses the body's ability to fight infection and enhances the growth of malignant tumors in laboratory animals. These findings could change the way cancer in humans is treated.

Because of these and other studies, pain experts are increasingly urging doctors to be much more liberal in their use of morphine and other powerful painkillers.

"I predict we will see a dramatic push to use more opiate drugs in the next few years simply because they are the most important and powerful drugs we have at our disposal," Campbell said. "But they are by no means perfect drugs. They have horrible side effects."

The drugs can cause nausea and constipation. Often, they leave patients irritable and groggy.

With some pain conditions, "they are the worst possible drugs to use . . . and yet they are the only drugs many doctors know how to use," said Dr. Steven Graff-Radford, a professor and researcher at UCLA's School of Dentistry.

Although probably the most common form of pain, headache is one of the most difficult syndromes to treat. In its most severe forms, it does not respond well to traditional painkillers. Recent clinical studies have shown that narcotics and over-the-counter pain remedies actually cause rebound headaches if used more than once or twice a week.

Like many pain experts, Graff-Radford is using medications to block chemicals in the body that are associated with pain. But he also urges his patients to make use of a variety of psychological techniques. In certain circumstances, pain can be controlled, if not eliminated, with hypnosis, biofeedback, behavioral modification and psychotherapy.

"We are thankfully getting away from the notion that pain is caused solely by psychological factors, yet we are also becoming increasingly convinced that pain has a strong psychological component," said C. Richard Chapmam, a psychologist at the University of Washington.

"That is likely to be the newest area of research in the future, for it is the area we know least about and may in the end be one of the most important."

"For every question we answer," Campbell said, "we raise a whole set of new questions for which there are as yet no answers. Yet what we have learned over the last 20 or 30 years had been absolutely astounding.

"To me, figuring out how to control pain is clearly one of the most important tasks facing modern medicine. Most physicians concentrate their efforts on extending the lives of people. But at the same time the quality of those lives is a fundamental issue. A major factor affecting the quality of life is pain."

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