How topical analgesics provide immediate relief via mechanisms of action

Topical analgesics with menthol and capsaicin have been used since ancient times to relieve pain, and are effective for a wide range of sports injuries, osteoarthritis, and neuropathic pain

Given the increasing concern about the opioid crisis, the leading edge research in analgesics is focused on topicals. Topical analgesics are not only less invasive than oral analgesics for certain pain conditions, so have a greatly reduced risk of addiction, but are more effective at targeting localized pain.

With this shift toward the use of topical analgesics at the site of pain, understanding both their mechanisms of action and the importance of penetration depth becomes more important.

Types of topicals

Topical analgesics come in a variety of formulations, including creams, foams, gels, lotions, patches, sprays, or ointments. Although different types of analgesics have different properties, the general concept is to relieve pain directly at the affected site.

Menthol and capsaicin, which are two of the most common active ingredients in topical analgesics, have been used since ancient times to relieve pain. While they work along different routes, both have been shown very effective for treating both acute and chronic pain. Two separate reviews, which examined the results from other studies, found that topical analgesics containing either menthol or capsaicin were effective for a wide range of uses, including sports injuries, osteoarthritis, or neuropathic pain.^1,2

Mechanisms of action

Menthol: Menthol is the active volatile oil extract from the mint (genus Mentha) plant. It acts on the transient receptor potential melastatin‐8 (TRPM8) ion-channel receptor by producing a cooling sensation on the skin at the affected site.² Furthermore, menthol works as a local vasodilator to increase its analgesic effectiveness.

TRPM8 is the primary thermoreceptor for cellular and behavioral response to a variety of temperatures, ranging from pleasant to painful. TRPM8 is rather unique in that it is sensitive enough to provide mild to moderate cooling, but not extreme cold, which may produce a burning sensation.² Because of this, TRPM8 is often referred to as the menthol regulator.

Capsaicin: Capsaicin is the active ingredient in chili peppers that produces the sensation of heat.^3,4 As part of a topical analgesic, capsaicin reduces pain and hypersensitivity by desensitizing the affected area by repeated application.

This unique mechanism of action works by stimulating the transient receptor potential vanilloid-1 (TRPV1), which initially produces a burning pain sensation, followed by a warming sensation to help relieve pain. Depending upon the individual patient, it may take several applications for the affected area to become desensitized to the capsaicin.

Topical analgesic penetration

Topical analgesics are localized, meaning that they are formulated to reduce pain at the skin’s surface. In comparison, transdermal analgesics, such as opioid patches are meant to deliver the analgesic through the skin to the peripheral nervous system.

However, both menthol and capsaicin topical analgesics do penetrate just below the surface of the skin to maximize their effectiveness. Recent research has shown that a 3% menthol solution can increase the penetration effectiveness for topical analgesics containing ibuprofen.⁵ There is also ongoing research into the use of topical patches containing an analgesic with 8% capsaicin.⁴ The patches may provide greater pain relief for a longer period of time than creams with a lower percentage of capsaicin.

The main benefit of topical analgesics that use either menthol or capsaicin is that they will provide immediate, effective pain relief directly at the affected site. Additionally, there is less risk of side effects that often come from systemic analgesics. All of this is good news, both for you and your patients.

References

1. Derry S, Wiffen PJ, Kalso EA, et al. Topical analgesics for acute and chronic pain in adults – an overview of Cochrane Reviews. Cochrane Database of Systematic Reviews. 2017;5(5):CD008609.
2. Pergolizzi JV Jr, Taylor R Jr, LeQuang JA, et al. The role and mechanism of action of menthol in topical analgesic products. Journal of Clinical Pharmacy and Therapeutics. 2018;43(3):313-319.
3. Wang XR, Gao SQ, Niu XQ, et al. Capsaicin-loaded nanolipoidal carriers for topical application: design, characterization, and in vitro/in vivo evaluation. International Journal of Nanomedicine. 2017;12:3881-3898.
4. Peppin JF, Pappagallo M. Capsaicinoids in the treatment of neuropathic pain: A review. Therapeutic Advances in Neurologic Disorders. 2014;7(1):22-32.
5. Brain KR, Green DM, Dykes PJ, Marks R, Bola TS. The role of menthol in skin penetration from topical formulations of ibuprofen 5% in vivo. Skin Pharmacology & Physiology. 2006;19(1):17-21.