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]

References

  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 analgesics. J 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. www.remarkablemedicine.com
  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 sarcoidosis. J Anesth Pain Med. 2017; 2(1): 1-3. (PDF)