Understanding TRP Receptors and Musculoskeletal Pain

There are few things as important to your success as a clinician, as being able to effectively communicate to your patients why you’ve chosen a specific product, exercise, or therapy; how we think it works; and what they should expect.

Their buy-in and belief is key to your ability to achieve a desired outcome.

Below is some great info on Topical Analgesics and Mechanism of Action from one of the most thorough and well-respected researchers you’ll find anywhere . . . Dr Phil Page.

Hopefully this article will give you a better understanding of how topical analgesics alter musculoskeletal pain patterns and why they’re an important tool in the quest to address pain.

The Clinical Effectiveness of Biofreeze®

Topical Analgesic on Musculoskeletal Pain: A Systematic Review

Phil Page, PT, Ph.D, ATC and Lacy Alexander Ph.D.

Journal of Performance Health Research Volume 1, Issue 1. Pages 1–10 DOI: 10.25036/jphr.2017.1.1.page

Background: Healthcare providers sometimes recommend topical analgesics instead of oral medication for temporary relief of musculoskeletal pain. Research suggests the mechanism of action of Biofreeze® is based on cryotherapy effect.

Purpose: The purpose of this systematic review was to describe the mechanism of action and determine the clinical efficacy of Biofreeze topical analgesic on musculoskeletal pain.

Study Design: This study uses a systematic review study design.

Methods: Electronic databases were searched for keywords such as “biofreeze” or “topical menthol”. Articles or abstracts on musculoskeletal pain outcomes were included. In total, 279 articles were screened and data were extracted from 9 studies meeting the inclusion criteria.

Results: Both statistical and clinically significant pain reduction were identified in studies of pain in the neck, back, and hand, whereas results were mixed for muscle soreness.

Patients with knee pain had statistically significant reductions in pain that did not meet a clinically significant threshold. This review was limited by a lack of well-controlled clinical trials in large patient populations.

Conclusion: Biofreeze has been shown to provide clinically significant reductions in pain in several musculoskeletal populations.

Keywords: Biofreeze; topical analgesic; menthol; pain relief


The mechanism behind Biofreeze pain reduction is considered to be through the cryotherapy method. The word cryotherapy is derived from the Greek words, krýo (cold) and therapeía (to cure). For the purpose of this review, cryotherapy will be defined as the use of localized cold therapy for treatment of musculoskeletal pain. Other forms of cryotherapy beyond the scope of this review include whole-body cold treatments and localized freezing of the skin for dermatological procedures.

Cryotherapy through the use of ice, cooling sprays, or topical analgesics, is often used for treating musculoskeletal injuries and pain. In general, there are 3 mechanisms for localized cooling of the body, which are as follows: physical cooling, evaporative cooling, and chemically mediated cooling. Each mechanism involves a reduction in skin temperature and/or stimulation of cold-sensitive receptors because of cold source applied to the skin.

Thermal receptors are sensory neurons located in the skin on subcutaneous nerves and blood vessels.

Specific receptors for cold sensation, known as transient receptor proteins (TRP) are activated in response to a cold stimulus. These TRP receptors then send a “cold” signal to the thalamus via the spinothalamic tract where a cold sensation is perceived.

This cold sensation induces a sympathetic response to maintain tissue temperature and protect tissues from excessive cold. Different subtypes of TRP receptors respond to different temperature ranges. In particular, the “TRP Melastatin 8” (TRPM8) is sensitive to cold temperatures that are experienced during application of ice or menthol to the skin. TRP-M8 responds to temperatures ranging between 30°C and 8°C. In addition to temperature, the TRP-M8 channel is also sensitive to menthol, which is an ingredient in Biofreeze.

The following are the local effects of cryotherapy: decreased nerve conduction velocity; decreased sensation; decreased pain threshold; decreased skin temperature, arteriolar vasoconstriction; superficial vasodilation; and decreased tissue metabolism. When prolonged or subjected to very low temperatures, these effects can lead to side effects, such as such as pain, numbness, nerve damage, and frostbite, that are associated with direct ice application.

Menthol activates TRP-M8 receptors, creating a sense of cold from sensory neurons in the skin. The cryotherapy mechanism of Biofreeze is accomplished by stimulating these specific cold receptors in the skin. The localized cooling by Biofreeze also occurs through the evaporation of alcohol and menthol. Alcohol has a lower heat of evaporation and therefore transiently decreases skin temperature, thereby stimulating the cold receptors.

Arterial vasoconstriction is a sympathetic adrenergically mediated response to cryotherapy, reducing blood flow to the cooled area. Superficial cooling with ice application to the knee can reduce arterial blood flow by 38% in less than 5 minutes. Olive et al. found similar reductions in brachial artery blood flow when comparing the effect of the application of Biofreeze and an ice pack over the forearm. Both modalities significantly reduced blood flow by 35% within the first 60 seconds of application.

In several other published studies, Topp et al. have shown that arterial blood flow significantly decreases within 20 minutes after the application of Biofreeze in the upper and lower extremities. Furthermore, the decrease in blood flow with Biofreeze is quantitatively equivalent to the decrease in blood flow with ice application (Table 1), thereby supporting the cryotherapy mechanism of Biofreeze. Figure 1 compares the average change in blood flow of ice and Biofreeze.

Topp et al. have also compared the side effects of Biofreeze and ice. Biofreeze application does not alter measurement of muscle strength 20–30 minutes after application compared with ice. Patients also noted less discomfort with Biofreeze application compared with ice. Bishop et al. reported that patients with neck pain preferred Biofreeze to ice, 2:1.

Ice packs are applied directly to painful areas to reduce pain. Although traditional ice packs have potential side effects of pain, numbness, burns, frostbite, and reduced performance, Biofreeze provides the benefits of cryotherapy without the side effects of ice application.

Both ice and over-the-counter topical analgesics are considered to reduce pain by depressing cutaneous sensory receptors through the gate control theory proposed by Melzac and Wall in 1965. The gate control theory suggests that pain signals from the periphery (carried through small “c-fibers”) are overridden by sensations carried by larger (Adelta) nerve fibers. Therefore, cryotherapy creates a cooling sensation that is perceived over a pain sensation. The TRP-M8 cold receptors discussed earlier have also been recently suggested to play a role in pain management.

Although not well understood, temperature sensation and pain are related as they travel along similar nervous system pathways. Free nerve endings sense both temperature and pain; both pain and temperature travel up the spinal cord through the spinothalamic tract and end in the thalamus. In addition, the extremes of temperature (both hot and cold) produce pain sensations known as allodynia. Interestingly, patients with chronic pain often have hypersensitivity to temperature as well.

For more info or to read the full article please visit https://www.performancehealthresearch.com/article/1641

For more info on this paper, products mentioned in this article or for info on current product specials, please contact your personal MeyerPT Account Manager.

If you don’t know who your Account Manager is, please call 866.528.2144 to find out.

Recommended Products from PT Aligned