Research into Neuropathic Pain Yields Potential Therapies

PHILADELPHIA--An expanding understanding of chronic neuropathic pain has led scientists to promising new treatments. One drug is already approved, as an antiseizure medication, and others may be in use within 3 years, Gary J. Bennett, PhD, said at a special panel held at the American Association for the Advancement of Science (AAAS) meeting.

"Ten years ago, we had theories but no data about what was causing this pain, and we couldn’t treat it," said Dr. Bennett, director of pain research, Allegheny University of the Health Sciences, Philadelphia. "Now we’ve begun to understand the causes, and we’re finding drugs to treat it." Panelist Joyce A. DeLeo, PhD, said that "we may be on the verge of a whole new pharmacopoeia for both preventing and treating this type of pain." Dr. DeLeo is assistant professor of anesthesiology and pharmacology, Dart-mouth Medical School.

An estimated 3.7 million Americans suffer from neuropathic pain, "and most importantly, these pain conditions either do not respond or respond very poorly to our typical pain-controlling drugs," Dr. Bennett said. Some 2.1 million people with lower back pain and 600,000 diabetics suffer neuropathic pain, as do 200,000 cancer and 15,000 AIDS patients.

"We have a great deal of neuropathic pain in cancer patients, especially late-stage cancer," he said. "Nerves get stretched and compressed by tumor masses, damaged by surgical interventions, burned by radiation therapy, and poisoned by chemotherapy."

Animal Model for Neuropathic Pain

An animal model for human neuro-pathic pain developed by Dr. Bennett and his colleagues, and widely used by university and pharmaceutical company research labs, enables screening for drugs that might combat the problem. In his panel presentation, Dr. Bennett focused on three classes of drugs that have shown promise for treating neuropathic pain.

• Several new-generation epilepsy drugs. The most thoroughly tested of these is gabapentin (Neurontin, Parke-Davis), which won FDA approval as an antisei-zure agent in 1993. Recently published preliminary human trials confirm "that the efficacy seen in animals is, indeed, present in people," Dr. Bennett said. "It is not a miracle solution, but at least some people get significant pain relief for the first time with gabapentin."
• Drugs that block the N-methyl-D-aspartate (NMDA) receptor. They also have shown effectiveness in rats and in humans in preliminary tests against neuropathic pain.
• Conopeptides. These are drugs derived from the venom of a poisonous cone snail that inhabits the Indo-Pacific Ocean. "They are a fascinating group of chemicals," Dr. Bennett said. One ingredient isolated and synthesized from the venom’s "complex cocktail of active ingredients" is designated SNX-111 and is being developed by Neurex. It has proved effective in rats and in easing neuropathic pain during preliminary human tests.

The action of these three classes of drugs apparently is unrelated to normal pain sensation and its control. "They don’t seem to work on normal pain. They only seem to work on abnormal neuro-pathic pain," Dr. Bennett said. "We all have great hope that within the next year or two or three, we will be able to come out with really effective pain control medicines for these people who have suffered so terribly long."

Researchers in recent years have discovered that neuropathic pain results from a number of complex events and interactions. Some of these occur in the peripheral nervous system and some in the central nervous system. Frank Porreca, PhD, professor of pharmacology and anesthesiology, the University of Arizona Health Sciences Center, said that "after the central nervous system reorganizes or changes in response to an injury, treating individuals is a challenge because of a difference in the underlying structure and function of the neural elements."

His group’s investigation of some changes that occur in the spinal cord following peripheral nerve injury has provided, among other things, an explanation for why NMDA-receptor blockers may relieve neuro-pathic pain.

Dynorphin, for example, is a normal spinal cord peptide whose expression sharply increases after injury to peripheral nerves. "This expression appears to occur in very localized areas of the spinal cord, over a certain range of spinal cord segments, and seems to be important in conferring some changes in sensitivity to incoming stimuli," Dr. Porreca said.

The team’s evaluation suggests that elevated levels of the peptide contribute to the painful consequences of peripheral nerve damage. It has found that one form of the peptide, dynorphin A, interacts with a binding site on the NMDA receptor and that this seems to promote changes in the spinal cord associated with the pain. "If, in fact, we can target the binding site, we might be able to develop drugs to block it and thus counteract some of the changes that occur in the spinal cord after injury," Dr. Porreca said.

Cholecystokinin, another normal peptide overexpressed in the spinal cord after peripheral nerve injury, seems to confer resistance to treatment by traditional opiate pain medications, he added.

This has led to efforts to synthesize novel molecules to block the increased expression of cholecystokinin, which would then allow traditional therapies to be effective in the treatment of these abnormal pain states.

Role of Cytokines

Work by Dr. DeLeo and her colleagues at Dartmouth into the causes of neuropathic pain has challenged the tenet that the immune and nervous systems operate independently, and this has pointed to other potential new drugs.

The Dartmouth researchers have discovered, using a rat model they developed, that three products first identified as immune system components--interleukin-1, interleukin-6, and tumor necrosis factor (TNF)-alpha--are expressed by CNS cells following nerve injury that results in neuropathic pain. These three cytokines all take part in the inflammatory process.

"We have evidence that hypersensitivity to temperature and touch peaks when the number of immune cells within the damaged nerve and in the periphery is highest," Dr. DeLeo said.

This finding suggests that products of these immune cells, namely cytokines, are involved in producing pain that is located in the periphery. "What we are suggesting is that the immune system and the nervous system are really overlapping in the same products. So they are actually communicating with each other," Dr. DeLeo commented.

The Dartmouth group is focusing on the role of cytokines in neuropathic pain and on which nervous system cells produce the molecules in response to nerve injury. "Our evidence suggests that astrocytes, together with neurons, are playing a key role in the production and maintenance of pain," Dr. DeLeo said.

These findings have suggested that agents that block IL-1, IL-6, and TNF-alpha could prove effective in treating neuropathic pain.

"Research in the neurosciences actually demonstrates an essential role for cytokines in the development and survival of the nervous system," Dr. DeLeo said. "However, proinflammatory cyto-kines, like the ones we are studying, have been shown to have both beneficial and destructive potential. In order to tailor effective treatments, we need to know more about these cytokines and the balance of these powerful immune processes."