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Conrad Notes IndexspacerPain Management and Chemical Dependency Index

Conrad Notes
a timely medical meeting newsletter
NEW ANALGESICS ON THE HORIZON
K. J. Elliott, MD, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, points to M-methyl-d-aspartate (NMDA) receptor antagonists, calcium channel blockers and nitric oxide synthetase inhibitors as promising new analgesics. Do we need additional analgesics? Improved understanding of sensory nerve transmission, incomplete pain relief, and intolerable side effects or potential habituation to opioids give reason for current research. Promising agents include dextromethorphan, ketamine, baclofen, and gabapentin.
Sensory receptor activation Laboratory research shows that the first synapse at the spinodorsal horn releases excitatory aminoacids such as glutamine and substance P. A neuronal-type calcium channel blocker controls their release. Pain results from glutamine binding to NMDA receptors which in turn trigger calcium influx, and activation of nitric acid synthetase.
NMDA receptor antagonists Dextromethorphan (DM), ketamine (K), and methadone (M) block NMDA receptors. DM, a widely used cough preparation, produces analgesia and is well tolerated at 30- and 60-mg doses. K, a veterinary anesthetic, produces analgesia at low doses; norketamine, a metabolite of K, is also analgetic. Both isomers of M block NMDA receptors but only the d-isomer binds to opioids, according to rodent studies.
Inhibitory neuron enhancers Baclofen (B) and gabapentin (G) probably produce analgesia by increasing the concentration of gamma amino butyric acid (GABA), the major rapid inhibitory transmitter. Rodent studies with G, a safe and clinically useful anticonvulsant, show attenuation or abolition of inflammatory pain and potentiation of morphine. The clinical analgesic starting dose for G, according to Elliott, is 100-300 mg and up to 1800 mg/day for maintenance.
Nitric oxide synthetase (NOS) inhibitors NOS inhibitors interfere with second messenger systems involved in sensory transmission. After NMDA activation, calcium enters the neuron, NOS catalyzes the formation of nitric oxide, and excitatory amino acid release results in pain. Disrupting this pathway offers another opportunity to produce analgesia.

Eugene A. Conrad

Presented at the Conference on Pain Management and Chemical Dependency on 22 Nov 1996
CONRAD NOTES © All Rights Reserved December 1996
Eugene A. Conrad, PhD, MPH / ISSN 1078 / posted on 1-Feb-1997

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