The role and mechanism of action of menthol in topical analgesic products

Abstract

Each of the major types of analgesic drugs (eg opioids, NSAIDs, paracetamol and pentanoids) has mechanism-associated adverse effect or abuse potential limitations. Thus, there is interest in discovering new agents that produce pain relief by alternative mechanistic pathways. Natural substances have been a rich source of compounds that possess analgesic properties 1 and have spawned a variety of clinically useful synthetic analgesic drugs. Menthol has been used as a topical pain reliever since ancient times. 2 Perhaps because of that, it is tempting to dismiss either its efficacy or its mechanism of action as trivial. However, recent advances in the (patho)physiology of pain have uncovered new pathways-one of which is responsible for the analgesic action of menthol. It is thus timely and important to review the basic science, clinical efficacy data and safety profile related to the pain-relieving attributes of menthol. SummaryWhat is known and objective: Menthol has been used as a non-opioid pain reliever since ancient times. A modern understanding of its molecular mechanism of action could form the basis for generating targets for discovery of novel non-opioid analgesic drugs. Methods:The PubMed database was queried using search words related to menthol, pain and analgesia. The results were limited to relevant preclinical studies and clinical trials and reviews published in English during the past 5 years, which yielded 31 reports. The bibliographies of these articles were sources of additional supporting articles. Results:Menthol is a selective activator of transient receptor potential melastatin-8 (TRPM8) channels and is also a vasoactive compound. As a topical agent, it acts as a counter-irritant by imparting a cooling effect and by initially stimulating nociceptors and then desensitizing them. Topically applied menthol may also activate central analgesic pathways. At high concentrations, menthol may generate cold allodynia.What is new and conclusions: Recent elucidation of TRPM8 channels has provided a molecular basis for understanding the molecular action of menthol and its ability to produce both a cooling sensation and reduction in pain associated with a wide variety of pain(ful) conditions. The more modern mechanistic understanding of menthol and its pharmacologic mechanism of action may lead to an expanded role for this substance in the search for replacements for opioid analgesics, particularly those that can be applied topically. K E Y W O R D Sanalgesic, calcium channel, menthol, non-opioid analgesic, topical analgesic, TRPM8

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“…Menthol, also known as mint camphor, is a compound isolated from the plant genus Mentha that is responsible for the cooling sensation associated with mint extracts (171). Menthol binds the transient receptor potential melatstatin-8 (TRPM8) on peripheral nerve fibers, which detect environmental cold (172).…”

Intestinal Anti-Inflammatory Activity of Terpenes in Experimental Models (2010–2020): A Review

“…Menthol ((1R,2S,5R)-2-isopropyl-5-methylcyclohexanol) ( Figure 7) is a cyclic monoterpene found as the major constituent in the essential oils of Mentha canadensis L. (mint) and M. x piperita L. (peppermint) [80]. It has pharmacological activities known as an analgesic [81], an effect on bladder hyperactivity and cystitis [82] and as an antioxidant [83]. In the study by Ghasemi-Pirbaluti et al (2017), the 3% acetic acid induction model was used in rats.…”

Citronellol, a monoterpene alcohol with promising pharmacological activities - A systematic review

“…In addition, medicinal products containing terpenes in their formulation are already available in the market, such as menthol used in the treatment of pain, again showing the importance of these products (Pergolizzi et al, 2018).…”