Working mechanism of Topical Analgesia
Towards a rationale of topical analgesic creams.
The skin as cybernetic system in neuropathic pain
Love is more than contact between two epidermis (“L’amour: le contact de deux épidermes”), and the skin is more than a cover. The skin is a sophisticated feedback system, consisting of many different tissues influencing each other. In chronic pain there exists a peripheral sensitization component as well as a central one. Everyone focusses on the central one. We wanted to focus on the peripheral one.
For the time being we always tried to reduce chronic neuropathic pain by administering analgesics via the oral route, as tablets and capsules, in order to down regulate central sensitization. This approach however leads to high plasma levels of the administered analgesics and often unacceptable side-effects leading to compliance problems. In 2013 Baron and Dickenson published a seminal paper on the importance of peripheral modulation in chronic pain states characterized by central sensitization. They pointed out that both in the pathogenesis of chronic and neuropathic pain, as well as in the treatment, peripheral input is a neglected factor and presented neurophysiological evidence to illustrate that central sensitization read-outs are reduced after topical treatment with lidocaine. It is clear that this hypothesis opens a whole new chapter of the treatment of neuropathic pain.
Years ago we started with a new project, to administer locally on skin compounding creams consisting of classical analgesics, such as amitriptyline, baclofen and ketamine. We discovered a neutral cream base, where we could also combine these analgesics. The newest analgesic cream is based on phenytoin. This molecule has multiple mechanisms of action.
Multiple mechanisms of action of phenytoin
Firstly, phenytoin as a topical analgesic can reduce burning pain in a number of neuropathic pain states, via blocking sodium channels present in nerve endings, epidermal cells and other skin structures.
Secondly, phenytoin blocks also calcium channels and related targets.
Thirdly, phenytoin downregulates the inflammation cascade and enhanced cytokine production in the skin.
Finally, due to its neuroprotective properties phenytoin cream might be of use not only to dampen pain, but also to support nerve regeneration of small fibres.
Together with the international pain expert Dr Arun Bhaskar from the Pain management Centre, Charing Cross Hospital Imperial Healthcare NHS Trust, London, United Kingdom, and the Dutch professor Nicolette Notermans, Head neuromuscular diseases University of Utrecht in the Netherlands we explored the mechanism of action of topical applied phenytoin. [1,2]
1. Keppel Hesselink JM, Kopsky DJ, AK Bhaskar. Skin matters! The role of keratinocytes in nociception: a rational argument for the development of topical analgesics. J Pain Res. 2017; 10:1-8.
2. Keppel Hesselink JM, Notermans NC. Topical phenytoin formulations for pain in small fiber neuropathy, a pathogenetic approach. Gen Int Med Clin Innov. 2018; 3(1): 2-4.