CHF3381, a N-methyl-D-aspartate receptor antagonist and monoamine oxidase-A inhibitor, attenuates secondary hyperalgesia in a human pain model.
CHF3381 is a new low-affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor. The analgesic activity of CHF3381 was investigated in the heat-capsaicin human pain model and compared with those of gabapentin. Twenty-seven young, healthy male volunteers received a single oral dose of CHF3381 (500 mg), gabapentin (1,200 mg), or placebo in a randomized, double-blind, crossover study design. Measurements were done before and 135 to 145 minutes after treatment administration and included area of secondary hyperalgesia around the sensitized skin of the forearm (45 degrees C for 5 minutes followed by topical capsaicin for 30 minutes), area of secondary hyperalgesia after thermal sensitization of the thigh (45 degrees C for 3 minutes), heat pain detection thresholds (degrees C), and pain on a visual analogue scale after long thermal stimulation (45 degrees C for 1 minute). Compared with placebo, both gabapentin and CHF3381 significantly reduced the area of secondary hyperalgesia on the dominant forearm. Median (and interquartile range) percent values over baseline were 86% after placebo (69% to 100%), 56% (41% to 76%) after gabapentin (P < .001), and 67% (49% to 88%) after CHF3381 (P < .009). Both drugs also significantly decreased the area of secondary hyperalgesia on the dominant thigh. The other pain variables were not significantly affected. Adverse events, mainly fatigue and dizziness, were mild to moderate.


CONCLUSIONS
This article presents the antihyperalgesic effect of CHF3381, a new NMDA receptor antagonist and reversible MAO-A inhibitor, in a human pain model and might guide the proper selection of CHF3381 doses to be used in Phase 2 studies in patients with neuropathic pain.
Mathiesen
Ole
O
Department of Anesthesiology, Copenhagen University Hospital, Glostrup, Denmark. olem@glostruphosp.kbhamt.dk
Imbimbo
Bruno P
BP
Hilsted
Karen Lisa
KL
Fabbri
Laura
L
Dahl
Jorgen B
JB
D000328:Adult; D000588:Amines / Q000627:therapeutic use; D000700:Analgesics / Q000627:therapeutic use; D002211:Capsaicin; D018592:Cross-Over Studies; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000077206:Gabapentin; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D007189:Indans / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use
D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D008995:Monoamine Oxidase; D002211:Capsaicin; D005998:Glycine; C431890:indantadol