A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain.
BACKGROUND
Nerve injury results in increases in spinal glutamate, which opens the NMDA ionophore channel, causing an influx of calcium. A glycine-binding site must be occupied for the channel to open. GV196771 is a selective antagonist of the glycine-binding site of the NMDA ionophore.


OBJECTIVE
To determine the efficacy of GV196771 in subjects with chronic neuropathic pain in a proof-of-concept study.


METHODS
With informed consent, 63 subjects (31 placebo, 32 GV196771) with neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, or peripheral nerve injury), a visual analogue score averaging > or =30 mm during the screening period, and a well-defined primary area of mechanical allodynia were recruited for the study. A multicenter, randomized, double-blind, placebo-controlled, parallel-group study design was utilized. Subjects came to the research center for a total of five visits over a 21-day period, which consisted of a 14-day treatment period followed by a 7-day washout period. Spontaneous and evoked pain scores, mechanical sensory testing, quantitative sensory testing, Short Form McGill Pain Questionnaire, patient global satisfaction, and safety assessments were made during the study.


RESULTS
There was no significant effect of GV196771 on spontaneous or evoked pain, quantitative sensory testing, or patient global satisfaction. There was a significant effect of GV196771 on the area of dynamic and static allodynia on days 7 and 14. The overall incidence of adverse events during treatment was similar for GV196771 (56%) and placebo (71%). The incidence of drug-related adverse events during treatment was higher for placebo (42%) than GV196771 (28%).


CONCLUSIONS
Although the glycine antagonists show anti-hyperalgesic action in animal models of neuropathic pain, GV196771 does not appear to be an effective treatment in subjects with chronic neuropathic pain. This may be due to insufficient penetration of GV196771 to central sites of action, differences between the human and animal glycine receptors, or differences between neuropathic pain in animal models and humans.
Wallace
M S
MS
University of California-San Diego School of Medicine, La Jolla 92093, USA. mswallace@ucsd.edu
Rowbotham
M C
MC
Katz
N P
NP
Dworkin
R H
RH
Dotson
R M
RM
Galer
B S
BS
Rauck
R L
RL
Backonja
M M
MM
Quessy
S N
SN
Meisner
P D
PD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D005260:Female; D005998:Glycine / Q000037:antagonists & inhibitors*; D018684:Glycine Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006358:Hot Temperature; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D017060:Patient Satisfaction; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000188:drug therapy*; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D012684:Sensory Thresholds / Q000187:drug effects; D016896:Treatment Outcome
C119836:GV 196771A; D018684:Glycine Agents; D007211:Indoles; D011758:Pyrroles; D005998:Glycine