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Phenytoin cream normalizes neural overactivity in skin in neurogenic inflammation

Phenytoin cream is a newly developed cream by the Institute of Neuropathic Pain and protected by 2 patents, filed on December 6th, 2016. The cream contains 5 or 10% phenytoin and here we picture one of the mechanisms of action, via the keratinocyte.

It is increasingly recognized that in a number of polyneuropathic pain states there are signs of neurogenic inflammation. Pain is induced by a maligne cascade triggered by nerve cells in the epidermis, the keratinocytes and immune competent cells. [1]

“It has been suggested that the skin as a whole may act as a polymodal nociceptor which undergoes functional changes in painful conditions.” [2]

In neurogenic inflammation, the population of keratinocytes in the skin are characterized by upregulated sodium channels. [3] Phenytoin cream can inhibit sodium channels, not only in nerves, but also on keratinocytes:

Keratinocytes in normal skin: a balanced state without peripheral upregulation


In neurogenic inflammation, sodium channnels are upregulated on keratinocytes:

In neuropathic pain also the keratinocytes are participating in the peripheral winding-up


After application of phenytoin cream, pain is decreased, due to amongst others, normalization of the output of the keratinocytes, as the sodium channels are blocked [4], leading to clinical relevant pain reduction:


Phenytoin cream restores the balance and blocks overactive keratinocytes

Keratinocytes have been identified as key players in the peripheral upregulation of pain. By topical treatment using sodium channel blockers, such as phenytoin, pain can be reduced. In our hands pain reduction in neuropathic pain states characterized by neurogenic inflammatory factors (SFN, diabetic neuropathy, CIAP, herpes zoster, chemo-induced PNP [5] [6]), pain can be reduced within 20-30 minutes.

Phenytoin cream has been developed in 2 concentrations: 5 % and 10%. Phenytoin is an 80-years old molecule, but again and again with new applications in medicine. We have as first research group world wide identified phenytoin cream as a potent analgesic cream.

January 2017, Jan M. Keppel Hesselink, MD, PhD


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[2] Wilder-Smith EP1, Ong WY, Guo Y, Chow AW. | Epidermal transient receptor potential vanilloid 1 in idiopathic small nerve fibre disease, diabetic neuropathy and healthy human subjects. | Histopathology. | 2007 Nov;51(5):674-80.

[3] Zhao P1, Barr TP, Hou Q, Dib-Hajj SD, Black JA, Albrecht PJ, Petersen K, Eisenberg E, Wymer JP, Rice FL, Waxman SG. | Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain. | Pain. | 2008 Sep 30;139(1):90-105. doi: 10.1016/j.pain.2008.03.016. Epub 2008 Apr 28.

[4] Sakaue A1, Honda M, Tanabe M, Ono H. | Antinociceptive effects of sodium channel-blocking agents on acute pain in mice. | J Pharmacol Sci. | 2004 Jun;95(2):181-8.

[5] Han SB1, Kim H, Cho SH, Lee JD, Chung JH, Kim HS. | Transient Receptor Potential Vanilloid-1 in Epidermal Keratinocytes May Contribute to Acute Pain in Herpes Zoster. | Acta Derm Venereol. | 2016 Mar;96(3):319-22. doi: 10.2340/00015555-2247.

[6] Baumbauer KM1, DeBerry JJ1, Adelman PC1, Miller RH1, Hachisuka J1, Lee KH1, Ross SE1, Koerber HR1, Davis BM1, Albers KM1. | Keratinocytes can modulate and directly initiate nociceptive responses. | Elife. | 2015 Sep 2;4. doi: 10.7554/eLife.09674.