Topical analgesics (TAs) are effective. In fact, the American Geriatric Society recommends the use of topical agents for localized neuropathic and non-neuropathic pain as a front-line measure. The benefit of TAs is their high compliance, ease of use, direct application to the painful site, and limited systemic cross-reactions. The real challenge is choosing the appropriate topical for each patient given the myriad choices available.
Whether it is a cream, lotion, spray, or patch, TAs are considered to have either a transdermal or a topical delivery system. Transdermal delivery systems are designed to raise the therapeutic agent up to a level in the blood consistent with oral administration (i.e., a hormone patch); whereas topicals raise the therapeutic agent to levels consistent with systemic administration at the target site with minimal increase in blood levels.
The challenge for all TAs is to penetrate the dense, hydrophobic outer layer of the skin (stratum corneum) to reach the pain-sensing keratinocytes that compose 90 percent of the cells in the epidermis. Their analgesic properties are mediated by the activation of endothelin-1 receptor B and cannabinoid 2 receptors. In addition, CBD receptors are also found in free nerve endings, sebaceous glands and sweat glands within the skin – underscoring the popularity of CBD topicals for pain control.
Clinical Tip: Local enhanced transdermal serums (LETS) are another class of TA. These penetrate through the epidermis to reach the underlying receptors and release the active ingredient over time, with no systemic absorption, only affecting the local tissues.
Common Topical Agents
Counterirritant substances (i.e., camphor, menthol, capsicum) are effective by stimulating and desensitizing nociceptive sensory nerves and via activation of the transient receptor potential (TRP) channels. In the skin, the TRPA (ankyrin), TRPM (melastatin) and TRPV (vanilloid) channels are involved in the development and maintenance of chronic pain via chemical, thermal and mechanical stimuli.
For neuropathic pain, capsaicin is the best referenced. It is used for peripheral neuropathy, diabetic polyneuropathy, chronic neck pain, HIV-peripheral neuropathy, and post-traumatic and postoperative chronic pain. Capsaicin activates TRPV1 to create a burning sensation; however, it can be pungent, which affects tolerance.
Menthol, another counterirritant, creates a cooling sensation via local vasodilation. It stimulates free nerve endings and the TRPVM8 channel for pain control. Menthol levels peak in the skin after 30 minutes, its vasoactive effects last 15-45 minutes, and the cooling sensation of menthol persists for about an hour. However, taken internally (as peppermint, for example), it acts as a vasoconstrictor.
NSAIDs (i.e., diclofenac, ibuprofen, ketoprofen, piroxicam, indomethacin) are widely used, commercially available TAs with diverse formulations. Their mechanism of action is likely related to anti-inflammatory inhibition through prostaglandin synthesis; however, the extent of the anti-inflammatory effect is not proportional to pain relief.
Lidocaine is an analgesic found in TAs as well as in patches. A maximum of three patches per day is allowed on intact skin, with an on-off interval of 12 hours. Although easy to use and with low systemic side effects, it is poorly absorbed – only 3-5 percent.
Clinical Tip: The mechanism of delivery is essential in selection of a TA. If the active ingredient is unable to pass through the stratum corneum and enter into the epidermis, the TA is a waste of money.
Dimethyl sulfoxide (DMSO) is a powerful antioxidant. It can be useful in reducing inflammation, free-radical production and reactive oxygen species-induced cell damage. At a 50 percent concentration in a cream base, DSMO appears to be beneficial for chronic regional pain syndrome. DMSO has a high degree of penetration through the skin and will enter into the bloodstream.
Clinical Tip: DMSO will carry with it any chemicals found on the skin or in the formulation if compounded with other agents. Be attentive to systemic effects and cross-contamination when using DMSO.
Which TA Is Best for Your Patient?
To isolate the optimal TA for a given patient, assess the effectiveness of one agent at a time. If it works, then adjust dosing and concentration. If it is not effective, choose another single TA and repeat. Higher concentrations of a TA are not necessarily more effective. If the agent does not work alone, increasing the dose is most likely a waste of money; or as with capsaicin, may lead to adverse effects.
For example, I start with a local transdermal CBD in the office before and after treatment; one with no counterirritants, which tells me in a few visits if CBD topically is the best option. If needed, the next TA I test is a 10 percent menthol-only agent. My third choice is capsaicin and fourth is a homeopathic gel. Finally, if I want to stack TAs, I always start with the local transdermal CBD and then put the counterirritant on top to ensure there are no cross-reactions that would reduce penetration of the CBD through the stratum corneum.
Topical analgesics are an excellent choice to add to your therapeutic toolbox. For a maximum effect, use them thoughtfully, with a targeted approach, just like you do with your adjustments.
Resources
- Anand P, Bery T. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Brit J Anaesthes, 2011;107(4):490-502.
- Choi E, et al.Topical agents: a thoughtful choice for multimodal analgesia. Korean J Anesthesiol, 2020;73(5):384-393.
- Craighead DH. Mechanisms and time course of menthol-induced cutaneous vasodilation. Microvasc Res,2017 March;110:43-47.
- Fernández-Carvajal A, et al. New strategies to develop novel pain therapies: addressing thermoreceptors from different points of view. Pharmaceuticals, 2012;5:16-48.
- Peppin JF, et al. Skin matters: a review of topical treatments for chronic pain. Part two: treatments and applications. Pain Ther, 2015;4:33-50.
- Sheena Derry S et al, Topical NSAIDs for acute musculoskeletal pain in adults. Cochrane Database Syst Rev, 2015 Jun 11;2015(6):CD007402.
- Silva H. Current knowledge on the vascular effects of menthol. Front Physiol, 2020 Apr 7;11:29.
- Stander S, et al. Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci, 2005 Jun;38(3):177-88.
