Menthol is the chief constituent of oil of Peppermint and other members of the mint family. The oil was first isolated in Europe during the late 17th century in Germany. Since then it has been used as a fresh, medicinal fragrance and flavoring and has many applications in products.
Menthol – A Profile
Menthol is generally considered to be a cooling ingredient in throat and chest remedies. For many years it has been considered a counter-irritant. That is a compound which creates local inflammation in order to relieve inflammation in underlying tissues. This mechanism is more commonly associated with the Gate Control theory of Melzak and Wall, where larger-diameter nerve fibers inhibit pain signals from smaller fibers.
The use of menthol in TPR20 is a significant active ingredient in this topical pain relief formulation. The latest studies shows Menthol relieves pain and reduces inflammation. Menthol’s pain relief action is both direct and indirect through its being an anti-inflammatory agent.
Menthol acts as an agonist (activator) on Kappa (κ) opioid receptors. These receptor sites are found in peripheral pain nerves. They also occur in the dorsal root ganglia in the spinal vertebrae where sensory information is relayed to the central nervous system , the spinal cord itself, and are widely distributed in the brain where they are connected with moods associated with chronic pain. It appears that κ opioid receptors modulate incoming pain information. The decrease in excitability of pain neurons triggers by activation of these opioid receptors is similar to the Mu (μ) opioid receptors acted on by morphine without any of the risks of dependency. κ opioid agonists can also produce analgesic effects through action at the levels of the periaqueductal gray and rostral ventromedial medulla (brain areas involved in pain modulation). Opioid agonists can be effective for treating inflammatory pain and pain after injuries. They are also specific for pain associated with nerve injury.
Drug research shows that κ opioid agonists produce unpleasant moods when active in the brain. However this is not the case with Menthol which induces pleasant moods and alertness. Peripherally restricted κ opioids effectively relieve or prevent hyperalgesia (increased sensitivity to pain) , pain, and potentially even allodynia (pain from a stimulus that does not normally lead to pain, such as the sensation of cold).
Research has shown that κ opioid receptor activation inhibits nerve synapse transmission and the induction of long term potentiation in the amygdala, a part of the limbic system of the brain, which has a central role in the processing and memory of emotional reactions. These findings may be associated with the effects of kappa opioid agonists in chronic pain and pain memory formation.
Menthol produces a cooling effect on contact. This has led to its use in a variety of products to relieve the heat from inflammation. preparations to relieve itching, sunburn and sore throat. Menthol does not actually change temperature. Rather it acts on specific cold (thermoceptive) and Menthol sensing receptors in sensory neurones; the TRPM8 (Transient Receptor potential cation channel, subfamily M member 8).
TRPM8 is an ion channel whose function is to allow sodium and calcium entry into the cell triggering an action potential or nerve discharge. The reaction to Menthol appears to be dose dependant with low doses decreasing sensitivity to pain and high doses inducing a feeling of cold and increased sensitivity.
Clinicians have noted that many patients with chronic pain also have temperature sensitivities. Research shows there is, in fact, a link between chronic pain and temperature (“thermal”) sensation, specifically because these two perceptions share similar paths to the brain in the spinal cord. Therefore, when local pain becomes chronic (lasting more than one month), the pain becomes “centralized” in the central nervous system, meaning the perceptions we have of pain are controlled more by the brain than by the actual site of the pain itself.
The TRPM8 receptors activated by Menthol are a key link between temperature sensation and pain in the nervous system. Research has shown that menthol provides similar effects to ice, such as increased pain threshold and increased cutaneous circulation.
Menthol is classified as a calcium channel blocker. Calcium channel blockers are a class of compounds with effects on many excitable cells of the body, such as the muscle of the heart, smooth muscles of the vessels or neuron cells. Calcium channel blockers work by blocking voltage-sensitive calcium channels. This prevents calcium levels from increasing as much in the cells when stimulated, leading to less contraction. Blocking calcium channels can significantly alter pain behaviour, in particular neuropathic pain.
Menthol also induces vasodilation through the calcium channel relaxation of smooth muscle. This vasodilation produces local vasodilation, which reduces skin barrier function and increases the absorption of other active ingredients. Rapid absorption is a feature of TPR20.
Sodium channel blockage by Menthol may also contributes to skeletal muscle relaxation. Muscle tension is a feature of many rheumatic as well as traumatic injury conditions with associated pain.
Studies show Menthol’s direct anti-inflammatory action to be due to specific inflammatory mediators. In order to evaluate the potential role of Menthol an anti-inflammatory drug, in vitro-investigations were performed using monocytes from healthy volunteers. The inflammatory action of Arachadonic acid metabolites was evaluated via leukotriene, LTB4 and prostaglandin PGE2 as indicators for both the lipoxygenase and the cyclooxygenase pathways. Both showed significant decrease in the presence of Menthol. The action of Menthol on the cytokine IL-1 was also measured and found to decrease. The action of Menthol on these key cellular mediators of inflammatory disorders has therefore been confirmed.
The incorporation of rapid acting Menthol in TPR20 is a significant contribution to the formulation’s pain relief and anti-inflammatory action in application for both chronic and acute conditions.
Bautista DM, et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448 (7150): 204–208.
Black D. Trevethick M. The kappa opioid receptor is associated with the perception of visceral pain. Gut 1998;43:312-313 doi:10.1136/gut.43.3.312.
Braina, et al. The Role of Menthol in Skin Penetration from Topical Formulations of Ibuprofen 5% in vivo, Skin Pharmacol Physiol, 2006;19:17-21.
DrugLib.com Active ingredient: Menthol – Basic Profile / Key Facts.
Haeseler G. et al, Propofol Blocks Human Skeletal Muscle Sodium Channels in a Voltage-Dependent Manner. Anaesthesia & Analgesia. May 2001 vol. 92 no. 5 1192-1198.
Haeseler G, et al. Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol. Eur J Anaesthesiol. 2002 Aug;19(8):571-9.
Huge V et al. Activation of kappa opioid receptors decreases synaptic transmission and inhibits long-term potentiation in the basolateral amygdala of the mouse. Eur J Pain. 2009 Feb;13(2):124-9. Epub 2008 Apr 24.
Juergens U R et al, The anti-inflammatory activity of L-menthol compared to mint oil in human monocytes in vitro: a novel perspective for its therapeutic use in inflammatory diseases. European Journal of Medical Research 1998;3(12):539-45.
National Institute of Neurological Disorders and Stroke. www.nids.nih.gov/disorders/chonic_pain/detail_chronic_pain.htm.
Proudfoot CJ, et al. Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Current biology : CB 16 (16): 1591–605. 2006.
Vanderah TW. Delta And Kappa Opioid Receptors As Suitable Drug Targets For Pain. Clin J Pain. 2010 Jan;26 Suppl 10:S10-15.
Wasner G, et al. Topical menthol–a human model for cold pain by activation and sensitization of C nociceptors. Brain : a journal of neurology 127 (Pt 5): 1159–71. 2004.
Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia Curae; Proin ipsum odio, luctus in vehicula tempor, bibendum at nisl. Proin in facilisis mauris, vitae iaculis felis. Etiam auctor quis tellus quis laoreet. Fusce pretium ex at posuere viverra.
Related article title
Proin in facilisis mauris, vitae iaculis felis. Etiam auctor quis tellus quis laoreet. Fusce pretium ex at posuere viverra. Cum sociis natoque penatibus et magnis dis parturient montes, nascetur ridiculus mus. Aenean in est nec justo lobortis vestibulum eget vel mauris.
Related article title
Duis vel diam tortor. Curabitur iaculis porttitor ante, at dictum nibh volutpat sit amet. Nullam eu quam ac lacus posuere lacinia. Ut interdum dolor et quam dictum, at rhoncus magna commodo. Aliquam tempus ex tristique mi ullamcorper tristique. Praesent vitae vehicula mi. Praesent tempus leo elit, non condimentum mauris vulputate non.