Phenytoin cream normalizes neural over activity

Phenytoin cream normalizes neural over activity on the skin. It is increasingly recognized that in a number of poly neuropathic pain states there are signs of neurogenic inflammation. Pain is induced by a malign 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]

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.

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:

INP Phenytoin cream activity

In neurogenic inflammation, sodium channels are upregulated on keratinocytes:

INP-Phenytoin-cream2 Phenytoin cream activity

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:


Succesful topical treatment

Keratinocytes have been identified as key players in the peripheral up regulation 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 worldwide identified phenytoin cream as a potent analgesic cream.

January 2017, Jan M. Keppel Hesselink, MD, PhD
‘Phenytoin cream normalizes neural over activity’

Watch here our video’s about Phenytoni cream.

How did we discover Phenytoin Cream?

Green light for NGF antibodies
Paclitaxel and long-lasting sensory neuropathy
Neuropathic pain research in Germany


[1] Radtke C1, Vogt PM, Devor M, Kocsis JD. | Keratinocytes acting on injured afferents induce extreme neuronal hyperexcitability and chronic pain. | Pain. | 2010 Jan;148(1):94-102. doi: 10.1016/j.pain.2009.10.014. Epub 2009 Nov 22.

[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.

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