NEW YORK--New information about pain pathogenesis is paving the way for future analgesics, Kathryn J. Elliott, MD, said at a conference on chemical dependency and pain management, sponsored by Memorial Sloan-Kettering Cancer Center.
"We know from neuroscience research that the nervous system is really much more dynamic than we were taught in medical school. Changes are going on throughout the entire peripheral and central nervous system all the time," said Dr. Elliott, assistant attending physician, Pain and Palliative Care Service, Memorial Sloan-Kettering.
Blocking N Type Calcium Channels
Pain arises from the activation of nociceptors or peripheral sensory receptors. For this to occur, she explained, there must be primary afferent communication to the first synapse at the spinal dorsal horn. The first synapse releases excitatory amino acids, especially glutamate and substance P, which leads to marked excitation in the nociceptive pathway.
The release of these neurotransmitters is regulated through a type of calcium channel called a neuronal or N type channel, she said. Thus, pain could be controlled by agents that block the release of excitatory neurotransmitters at the first synapse.
Biotechnology companies have cloned highly toxic peptides produced by marine cone snails to catch their prey. Certain varieties of these peptides block the N type sensory calcium channel active in nociceptive pathways.
"These peptides are experimental at the moment, but they are very analgesic when applied to the spinal cord in experimental models," Dr. Elliott commented.
[One such peptide, SNX-111, developed by Neurex Corporation, is in clinical testing for analgesia, and the company expects the trials to have sufficient enrollment during 1997 to provide the foundation for an NDA filing.]
After the neurotransmitters are released at the spinal cord dorsal horn, excitatory amino acid receptors must also be activated for pain to occur, Dr. Elliott said. The NMDA (N-methyl-D-aspartate) receptor, in particular, is the excitatory amino acid receptor that is thought to underlie many changes seen with chronic pain.
Researchers are currently studying a class of drugs known as NMDA receptor antagonists, and two agents with these properties are clinically available--the antitussive dextromethorphan(Drug information on dextromethorphan) and the anesthetic ketamine(Drug information on ketamine) (Ketalar).
"We've done a lot of preclinical laboratory work showing that NMDA receptor antagonists are not only quite analgesic but that they also attenuate and reverse opiate tolerance," Dr. Elliott said. "We think that patients who are having a poor opiate therapeutic index--a poor balance between analgesia and side effects--may actually benefit from the addition of an NMDA receptor antagonist as a clinical analgesic adjuvant."
In experimental models, the coadmin-istration of ketamine and morphine blocked the development of opiate analgesic tolerance; other experimental evidence suggests that methadone(Drug information on methadone) may be an NMDA receptor antagonist.
The concept of homeostasis may also provide a fresh approach to understanding pain transmission, Dr. Elliott said. "The body is a very homeostatic series of systems. Excitation can occur, either from overexcitation--too much excitatory amino acid release and, therefore, too much activation of the NMDA receptor system--or from a relative imbalance caused by a loss of inhibition.
"We know that in the spinal cord and throughout the brain, excitatory neurons are surrounded by inhibitory neurons, which also determine how much nociception is occurring in the system. These new analgesics may work by enhancing the inhibitory surround."
She said that there is some experimental evidence that certain agents used as adjuvant analgesics have this effect, including the muscle relaxant baclofen, the anticonvulsants carbamazepine(Drug information on carbamazepine) and gabapentin (Neurontin), and the tricyclic antidepressant amitriptyline(Drug information on amitriptyline).
Dr. Elliott described some of her experiments in animal models with gaba-pentin. "It is thought to work through the GABA-ergic system," she said. GABA (gamma-amino-butyric acid) is the major rapid inhibitory neurotransmitter in the brain.
Gabapentin has been shown to be a safe anticonvulsant in well-controlled studies; however, despite extensive laboratory research, the actual site of action of this drug is unclear, she said.
There is evidence that it is probably GABA-ergic and increases GABA release, but it does not appear to directly bind to known GABA receptors. There is also evidence that it works through an amino acid transporter.
"It's a really potent analgesic, at least anecdotally," Dr. Elliott said, "and when we study it in the laboratory, in our model of inflammatory pain--the phase II formalin test--you get a nice dose response analgesic effect with absolutely no behavioral side effects with spinal administration of the agent."
She explained that the phase II formalin response is the behavioral response that is predominantly sensitive to NMDA receptors antagonists and is thought to be a model of central sensitization. "We're hypothesizing that gabapentin(Drug information on gabapentin) is increasing the GABA-ergic tone in the inhibitory surround," she said.