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
"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 and the anesthetic 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 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
"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 and gabapentin (Neurontin),
and the tricyclic antidepressant 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 is increasing the GABA-ergic tone in the inhibitory surround,"