New Analgesics Emerge From Pain Pathogenesis Research

NEW YORK--New information about pain pathogenesis is paving the wayfor future analgesics, Kathryn J. Elliott, MD, said at a conference onchemical dependency and pain management, sponsored by Memorial Sloan-KetteringCancer Center.

"We know from neuroscience research that the nervous system isreally much more dynamic than we were taught in medical school. Changesare going on throughout the entire peripheral and central nervous systemall the time," said Dr. Elliott, assistant attending physician, Painand Palliative Care Service, Memorial Sloan-Kettering.

Blocking N Type Calcium Channels

Pain arises from the activation of nociceptors or peripheral sensoryreceptors. For this to occur, she explained, there must be primary afferentcommunication to the first synapse at the spinal dorsal horn. The firstsynapse releases excitatory amino acids, especially glutamate and substanceP, which leads to marked excitation in the nociceptive pathway.

The release of these neurotransmitters is regulated through a type ofcalcium channel called a neuronal or N type channel, she said. Thus, paincould be controlled by agents that block the release of excitatory neurotransmittersat the first synapse.

Biotechnology companies have cloned highly toxic peptides produced bymarine cone snails to catch their prey. Certain varieties of these peptidesblock the N type sensory calcium channel active in nociceptive pathways.

"These peptides are experimental at the moment, but they are veryanalgesic when applied to the spinal cord in experimental models,"Dr. Elliott commented.

[One such peptide, SNX-111, developed by Neurex Corporation, is in clinicaltesting for analgesia, and the company expects the trials to have sufficientenrollment during 1997 to provide the foundation for an NDA filing.]

NMDA Antagonists

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 manychanges seen with chronic pain.

Researchers are currently studying a class of drugs known as NMDA receptorantagonists, and two agents with these properties are clinically available--theantitussive dextromethorphan and the anesthetic ketamine (Ketalar).

"We've done a lot of preclinical laboratory work showing that NMDAreceptor antagonists are not only quite analgesic but that they also attenuateand reverse opiate tolerance," Dr. Elliott said. "We think thatpatients who are having a poor opiate therapeutic index--a poor balancebetween analgesia and side effects--may actually benefit from the additionof an NMDA receptor antagonist as a clinical analgesic adjuvant."

In experimental models, the coadmin-istration of ketamine and morphineblocked the development of opiate analgesic tolerance; other experimentalevidence suggests that methadone may be an NMDA receptor antagonist.

The concept of homeostasis may also provide a fresh approach to understandingpain transmission, Dr. Elliott said. "The body is a very homeostaticseries of systems. Excitation can occur, either from overexcitation--toomuch excitatory amino acid release and, therefore, too much activationof the NMDA receptor system--or from a relative imbalance caused by a lossof inhibition.

"We know that in the spinal cord and throughout the brain, excitatoryneurons are surrounded by inhibitory neurons, which also determine howmuch nociception is occurring in the system. These new analgesics may workby enhancing the inhibitory surround."

She said that there is some experimental evidence that certain agentsused as adjuvant analgesics have this effect, including the muscle relaxantbaclofen, the anticonvulsants carbamazepine and gabapentin (Neurontin),and the tricyclic antidepressant amitriptyline.

Dr. Elliott described some of her experiments in animal models withgaba-pentin. "It is thought to work through the GABA-ergic system,"she said. GABA (gamma-amino-butyric acid) is the major rapid inhibitoryneurotransmitter in the brain.

Gabapentin has been shown to be a safe anticonvulsant in well-controlledstudies; however, despite extensive laboratory research, the actual siteof action of this drug is unclear, she said.

There is evidence that it is probably GABA-ergic and increases GABArelease, 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 modelof inflammatory pain--the phase II formalin test--you get a nice dose responseanalgesic effect with absolutely no behavioral side effects with spinaladministration of the agent."

She explained that the phase II formalin response is the behavioralresponse that is predominantly sensitive to NMDA receptors antagonistsand is thought to be a model of central sensitization. "We're hypothesizingthat gabapentin is increasing the GABA-ergic tone in the inhibitory surround,"she said.