Abstract
Rates of opioid misuse, abuse, and addiction-related aberrant behaviors have been steadily rising in the past 20 years. The development of effective alternative pharmacologic therapies to treat acute and chronic pain would significantly reduce the need for opioid analgesic use. While metabotropic glutamate receptor 5 (mGlu5) has been shown to modulate nociception in animals, so far 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 non-benzodiazepine anxiolytic. Multiple studies have demonstrated that fenobam is analgesic in a variety of mouse models of inflammatory, neuropathic, and visceral pain, and acts exclusively via mGlu5 blockade. Furthermore, fenobam shows no signs of analgesic tolerance with up to two weeks of daily dosing. Here, we report a translational study of the analgesic effects of fenobam in human. We first established the pharmacokinetic properties of orally administered fenobam, and used this information to conduct a test of the analgesic effects of fenobam in an established experimental human pain model of cutaneous sensitization. While fenobam reduced sensitization in healthy volunteers at a single measurement time (at peak plasma fenobam concentration), we did not observe a statistically significant sustained analgesic (anti-hyperalgesic) effect of fenobam compared to placebo. We suggest that future studies testing possible analgesic effects of mGlu5 blockade should employ molecules with improved pharmacokinetic profiles. Prospective randomized clinical trials are needed to clarify the role of mGlu5 modulation in the development and maintenance of acute and chronic pain conditions in human.
Footnotes
Source of Financial Support This work was supported by the National Institutes of Health - National Institute of Neurological Disorders and Stroke (NS48602 to R.W.G.) and by a Barnes Jewish Hospital Foundation and Washington University Institute of Clinical and Translational Sciences Grant (ID# CTSA310 to R.W.G and L.F.C.).