High-concentration L-menthol exhibits counter-irritancy to neurogenic inflammation, thermal and mechanical hyperalgesia caused by trans-cinnamaldehyde

The TRPM8-agonist L-menthol has been used traditionally for its topical counter-irritant properties. While the use of topical L-menthol for pain is casuistically established, evidence regarding its efficacy is negligible. This study aimed to characterize the effect of L-menthol as a counter-irritant on cutaneous pain and hyperalgesia provoked by topical application of the TRPA1-agonist trans-cinnamaldehyde (CA). In a randomized, double-blinded study CA was applied to a 3x3cm area of the volar forearm evoking neurogenic inflammation, pain, mechanical and thermal hyperalgesia in 14 healthy volunteers. In one of two sessions, 1) 10% CA alone, 2) 40% L-menthol + 10% CA applied simultaneously were administered for 20min throughout which the subjects rated the pain intensity on a VAS0-10. Extensive quantitative sensory testing was conducted and superficial blood flow (neurogenic inflammation) was recorded. Administration of CA evoked spontaneous pain, neurogenic inflammation, thermal hyperalgesia, and primary and secondary mechanical hyperalgesia. Co-administration of topical L-menthol reduced spontaneous pain intensity (P<0.01), neurogenic inflammation (P<0.01), primary mechanical hyperalgesia (P<0.05), secondary mechanical hyperalgesia (P<0.05), and heat hyperalgesia (P<0.05), but not cold hyperalgesia. L-menthol exhibited inhibitory effects on simultaneously established pain, hypersensitivity, and neurogenic inflammation in a human TRPA1-induced pain model. Potent TRPM8-agonists could be useful as topical anti-hyperalgesics. The study and the trial protocol is registered and approved by the local research ethics committee under the jurisdiction of the Danish Medicines Agency no.: N-20130005. The protocol also is registered at Clinicaltrials.gov under the no.: NCT02653703.

PERSPECTIVE: Drugs interacting with TRP-channels are of great therapeutic potential. In the present study we established cutaneous pain and hyperalgesia using the TRPA1-agonist trans-cinnamaldehyde. Subsequently, we showed that the frequently used topical counter-irritant and TRPM8-agonist; L-menthol, decreased evoked pain, hyperalgesia and inflammation, indicating both direct and indirect anti-nociceptive mechanisms.