Metabotropic glutamate receptor 5 (mGlu5) has been shown to modulate nociception in animals, but no mGlu5 antagonists have been developed commercially as
analgesics. The mGlu5 antagonist
fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-
imidazole-2-yl)
urea] was originally evaluated for development as a nonbenzodiazepine
anxiolytic.
Fenobam is
analgesic in numerous mouse
pain models, acting exclusively through mGlu5 blockade. Furthermore,
fenobam showed no signs of
analgesic tolerance with up to 2 weeks of daily dosing in mice.
Analgesic effects of
fenobam in humans have not been reported. The purpose of this investigation was to evaluate
fenobam pharmacokinetics and
analgesic effects in humans. We first evaluated single-dose oral
fenobam disposition in a parallel-group dose-escalation study in healthy volunteers. A second investigation tested the
analgesic effects of
fenobam in an established experimental human
pain model of cutaneous sensitization using
capsaicin cream and heat, in a double-blind placebo-controlled study. The primary outcome measure was the area of
hyperalgesia and
allodynia around the area applied with heat/
capsaicin. Secondary outcome measures included nociception, measured as
pain rating on a visual analog scale, heat
pain detection threshold, and effects on cognition and mood.
Fenobam plasma exposures showed considerable interindividual variability and were not linear with dose.
Fenobam reduced sensitization vs placebo at a single timepoint (peak plasma concentration); we found no other difference between
fenobam and placebo. Our results suggest highly variable
fenobam disposition and minimal
analgesic effects at the dose tested. We suggest that future studies testing
analgesic effects of mGlu5 blockade are warranted, but such studies should use molecules with improved pharmacokinetic profiles.