Phenytoin: a remarkable multipurpose drug

Our interest in repositioning of old analgesic and co-analgesic drugs such as ketamine and phenytoin as topical analgesics originated around 2010 when looking for solutions to treat neuropathic pain.[1]

In our Institute for Neuropathic Pain we have developed a series of topical creams since that period, containing analgesics and co-analgesics, such as amitriptyline, ketamine, baclofen, clonidine, for the treatment of a variety of neuropathic pain syndromes, such as pain in diabetic neuropathy, chemotherapy induced neuropathy, chronic idiopathic axonal neuropathy, CRPS and small fibre neuropathy.[2,3]

We discovered that certain topical formulations support the analgesic efficacy of said analgesics, and unraveled its mechanism of action.[4]

Since 2014 we also found that the old anti-epileptic compound phenytoin has a good analgesic effect in patients, among which patients suffering from small fibre neuropathy.[5-7]

Phenytoin is already known in the clinic for 80 years! We have analyzed its remarkable story in two articles recently published in the Journal of Neurology.[8-9] Phenytoin has been described in literature as a remarkable multipurpose drug, and the Wall street icon Jack Dreyfus was one of the early champions of phenytoin’s repositioning.[10]

We also found that phenytoin indeed is remarkable, as it can augment the analgesic effects of other (co-)analgesics.[11] This was an augmentation of efficacy, time to onset of efficacy and duration. Drug combination therapy is also currently a hot topic within the field of repositioning.[12]

Thus, we concluded that the clinical problem of insufficient therapeutic effects of current analgesics in neuropathic pain in a cohort of patients can be solved by applying topically analgesics in selected formulation, together with phenytoin, and by phenytoin itself.

Phenytoin is indeed a remarkable molecule, and since our discovery that the compound can be used in topical formulations, we have communicated the repositioning potential of phenytoin in literature.[13]


  1. Kopsky DJ, Keppel Hesselink JM. A new combination cream for the treatment of severe neuropathic pain. J Pain Symptom Manage. 2010 Feb;39(2):e9-e10. (PDF)
  2. Kopsky DJ, Keppel Hesselink JM, Bhaskar A, Hariton G, Romanenko V, Casale R. Analgesic effects of topical ketamine. Minerva Anestesiol. 2015;81(4):440-449.
  3. Kopsky DJ, Keppel Hesselink JM. High doses of topical amitriptyline in neuropathic pain: two cases and literature review. Pain Pract. 2012 Feb;12(2):148-53. (PDF preview)
  4. Keppel Hesselink JM, Kopsky DJ, AK Bhaskar. Skin matters! The role of keratinocytes in nociception: a rational argument for the development of topical analgesicsJ Pain Res. 2017; 10:1-8. (PDF).
  5. Kopsky DJ, Keppel Hesselink JM. Topical phenytoin for the treatment of neuropathic pain. J Pain Res. 2017; 10:469-473. (PDF)
  6. Keppel Hesselink JM, Kopsky DJ. Burning pain in small fibre neuropathy treated with topical phenytoin: rationale and case presentations. J Clin Anesth Pain Med. 2017; 1(1): 6. (PDF)
  7. Keppel Hesselink JM, Kopsky DJ. Topical phenytoin in neuralgic pain, peripheral modulation of central sensitization: two case reports. J Pain Relief  2017; 6(2): 284. (PDF)
  8. Keppel Hesselink JM, Kopsky DJ. Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action. Journal of Neurology. 2017:1-5.
  9. Keppel Hesselink JM. Phenytoin: a step by step insight into its multiple mechanisms of action-80 years of mechanistic studies in neuropharmacology. Journal of Neurology. 2017: Mar 27.
  10. Jack Dreyfus and The Story of a Remarkable Medicine.
  11. Kopsky DJ, Keppel Hesselink JM. Phenytoin in topical formulations augments pain reduction of other topically applied analgesics in the treatment of trigeminal neuralgia. J. Clin Anesth.  2017; 38: 154-155.
  12. Sun W, Sanderson PE, Zheng W. Drug combination therapy increases successful drug repositioning. Drug Discov Today. 2016 Jul;21(7):1189-95.
  13. Keppel Hesselink JM. Amantadine and phenytoin: patent protected cases of drug repositioning Clin Invest. 2017; 7(1):11-16.
  14. Keppel Hesselink JM, Kopsky DJ. Topical phenytoin cream reduces burning pain due to small fiber neuropathy in sarcoidosisJ Anesth Pain Med. 2017; 2(1): 1-3. (PDF)