OTC Transdermal Analgesic Patches in Pain Management

Donna M. Lisi, PharmD, BCPS, BCPP, BCGP, BCACP

Disclosures

US Pharmacist. 2019;44(3):15-21. 

In This Article

Menthol

Menthol, which is a natural product from the peppermint plant, Mentha piperita, is a cyclic terpene alcohol.[41] Menthol is metabolized via CYP 2A6.[41] As opposed to MS, menthol has a cooling effect on the skin. However, this is temperature dependent with skin temperatures above 37°C producing feelings of warmth.[23] It is often used in combination with MS to produce a counterirritant effect.[31]

Menthol increases cutaneous blood flow. According to the gate control theory, menthol is thought to work by activating TRPM8 channels, which belong to a family of nonselective cation channels that open in response to cool temperatures (8-28°C). Activation of TRPM8 channels on sensory neurons of the trigeminal and dorsal root ganglia and on C (unmyelinated axons) and Aδ (thinly myelinated axons) nociceptors reduce pain transmission.[23,42] Menthol acts as on TRPM8, TRP3, and TRPA1 channels. TRPV3 and TRPA1 are activated or inhibited by menthol.[23] TRPM8 receptors are expressed in neural and vascular cells. At warmer temperatures, menthol sensitizes TRPV3, and at cooler temperatures it activates TRPM8.[23]

"Pharmacists need to be familiar with both the efficacy data and adverse effects associated with topical OTC analgesics in order to help ensure their safe use, especially since these medications are often used as first-line pain therapy."

Menthol also acts as a vasodilator by dose-dependently (up to a concentration of 4%) increasing blood flow in the microvasculature.[42] At concentrations below 1%, menthol acts as an anesthetic; however, at concentrations greater than 1.25%, it functions as a counterirritant.[14] This vasodilatory effect of menthol is attributed to nitric oxide, endothelium-derived hyperpolarizing factors, and sensory nerves.[42] Additionally, menthol activates GABAA and blocks voltage-gate sodium and calcium channels in the dorsal horn and preferentially binds to inactivated channels, producing a central analgesic effect.[43]

Although concentrations of menthol peak in the skin within 30 minutes, vasoactive effects are seen within 15 minutes. The effects disappear after 45 minutes with the drug cleared from the skin by 60 minutes.[42] Menthol acts as a penetration enhancer for other compounds.[23,41,44]

There is a paucity of studies evaluating menthol patches. Icy Hot patches, which contain 5% menthol, were compared with ThermaCare HeatWraps with respect to effects on skin and deep-tissue temperature in healthy volunteers. The heat wraps increased skin temperature by 25.8% and underlying muscle tissue temperature by 7.7%, whereas the menthol patches decreased skin temperature by 5.4% and muscle temperature by 3.8%. Further, whereas ThermaCare Heat-Wraps caused a 109.7% and 148.5% increase in skin blood flow and in muscle blood flow, respectively, Icy Hot patches caused a reduction in both skin and muscle blood flow (16.7% and 7%, respectively). However, since this was not an efficacy study, the clinical implications of these findings for patients with pain are unclear.[22] Nonpatch dermal exposure to menthol has shown that menthol may attenuate cold allodynia (i.e., pain induced by normally innocuous cool stimuli) in patients with peripheral and central neuropathic pain.[45]

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