Publications

Topical Innovations is founded in 2016, and its Intellectual Property Platform consists of 2 patents relating to topical phenytoin for the treatment of chronic pain. These patents have been designed, based on insights in the development of topical analgesics gathered during more than a decade. From 2010 onwards a steady stream of papers have been published on the pain reducing effects and other benefits of topical analgesics.

The representatives of Topical Innovations have published several keystone publications in peer reviewed and PubMed indexed Journals. They designed a number of these publications together with Key Opinion Leaders in the field, in order to build a robust fundament for acceptance of this new technology. This strategy has led to a global visibility of the project in the world. For instance, we presented key aspects of our findings recently at meetings of the IASP and EFIC.

References

• • Kopsky DJ, Keppel Hesselink JM, Russell AL, Vrancken AFJE. No Detectable Phenytoin Plasma Levels After Topical Phenytoin Cream Application in Chronic Pain: Inferences for Mechanisms of Action.  J Pain Res. 2022;15:377-383.
  • Crul TC, Stolwijk-Swüste JM, Kopsky DJ, Visser-Meily JMA, Post MWM. Neuropathic pain in spinal cord injury: topical analgesics as a possible treatment. Spinal Cord Ser Cases. 2020;6(1):73.
  • Kopsky DJ, Vrancken AFJE, Keppel Hesselink JM, van Eijk RPA, Notermans NC. Usefulness of a double-blind placebo-controlled response test to demonstrate rapid onset analgesia with phenytoin 10% cream in polyneuropathy. J Pain Res. 2020;13:877-882. (PDF)
  • Russel, AL, Kopsky DJ, Keppel Hesselink JM. Phenytoin cream for the treatment of sciatic pain: clinical effects and theoretical considerations: case report. J Pain Palliat Care Pharmacother. 2020 March 2: 1-7. (PDF)
  • Keppel Hesselink JM. Topical analgesic formulations: following the transdermal treatment paradigm only? J Clin Med Res. 2019;1(3):1-5. (PDF)
  • Kopsky DJ, Bhaskar AK, Zonneveldt HJ, Keppel Hesselink JM. Topical loperamide for the treatment of localized neuropathic pain: a case report and literature review. J. Pain Res. 2019; 12: 1189-1192. (PDF)
  • Keppel Hesselink JM. Fibromyalgia as a localized non-length dependent small fiber neuropathy, responding to topical phenytoin. Med J Clin Trials Case Stud 2019, 3(2): 0002. (PDF)
  • Russell AL, Keppel Hesselink JM. Topical phenytoin in a case of severe fibromyalgia: ex juvantibus proof for fibromyalgia as a localized non-length dependent small fiber neuropathy. J Archives of Medical Case Reports and Case Study. 2019. (PDF)
  • Keppel Hesselink JM, Kopsky DJ, Bhaskar AK. Ethical justification of single-blind and doubleblind placebo-controlled response tests in neuropathic pain and N-of-1 treatment paradigm in clinical settings. J. Pain Res. 2019; 12: 345–352. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Neuropathic pain due to chronic idiopathic axonal neuropathy: fast pain reduction after topical phenytoin cream application. Open J Pain Med. 2018; 2(1): 007-008. (PDF)
  • Kopsky DJ, Keppel Hesselink JM. Opioid Receptors in the Skin. Austin J Anesthesia and Analgesia. 2018; 6(2): 1074. (PDF)
  • Keppel Hesselink JM. Treatment of painful diabetic neuropathy in sub- Saharan countries: Bottlenecks and opportunity for the repositioning of phenytoin as a topical treatment. Ann Pharmacol Pharm. 2018; 3(4): 1154. (PDF)
  • Kopsky DJ, Keppel Hesselink JM. Identification of responders for pain treatments: did we find the holy grail? Neurological Disorders & Epilepsy Journal. 2018; 1(2):117. (PDF)
  • Kopsky DJ, Keppel Hesselink JM. Single-blind placebo-controlled response test with phenytoin 10% cream in neuropathic pain patients. Pharmaceuticals 2018; 11: 122. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. On the importance of precision medicine for neuropathic pain. Pharm Pharmacol Int J. 2018;6(6):432-433. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. [Topical compounded analgesics for neuropathic pain] Topicale magistrale analgetica voor neuropathische pijn. Nederlandstalig Tijdschrift Pijnbestrijding. 2018; 37(73): 6-9. (PDF)
  • Keppel Hesselink JM. Pain in chemotherapy-induced peripheral neuropathy: NGF and the logic of topical phenytoin cream. J Case Rep Clin Images. 2018; 2: 1008. (PDF)
  • Bartollino S, Chiosi F, di Staso S,Uva M, Pascotto A,Rinaldi M, Keppel Hesselink JM, Costagliola C. The retinoprotective role of phenytoin. Drug Des Devel Ther. 2018;12: 3343-3356. (PDF)
  • Keppel Hesselink JM. Chronobiology of neuropathic pain and the use of topical phenytoin in painful diabetic neuropathy. J Diabetol 2018; 2(2): 3-5. (PDF)
  • Keppel Hesselink JM. Phenytoin cream in painful diabetic neuropathy: an evolving chapter. J Diabetol 2018; 2(2): 6-8. (PDF)
  • Keppel Hesselink JM. A case of wasp-induced pain treated with topical phenytoin cream. J Clin Cases Rep  2018; 1(3): 106-108. (PDF)
  • Keppel Hesselink JM. The quest for better analgesics for the treatment of peripheral neuropathic pain: navigating the sodium channels. Trends Gen Pract. 2018; 1(2): 2-3. (PDF)
  • Kopsky DJ, Keppel Hesselink JM. A single-blind n-of-1 study evaluating 4 different doses of phenytoin in a topical analgesic cream for the treatment of peripheral neuropathic pain. J Pain Manage Ther. 2018;2(1):17-20. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Repositioning problems of clonidine as topical formulation in neuropathic pain. EC Pharmacology and Toxicology 2018; 6(8): 756-762. (PDF).
  • Keppel Hesselink JM, Kopsky DJ. Fast onset of relief after topical phenytoin in neuropathic pain after chemotherapy. Trends Cancer Res Chemother. 2018;1(1):1-3. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Topical analgesics in localized neuropathic pain: transdermal delivery or intradermal? Anaesthesia, Critical Care and Pain Management. 2018; 1(2): 86-89. (PDF)
  • Keppel Hesselink JM. Posttranslational sodium ion channel modifications and the use of topical phenytoin in Painful Diabetic Neuropathy (PDN). Int J Diabetes Metab Disord 2018; 3(1)1-3. (PDF)
  • 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. (PDF)
  • Kopsky DJ, Keppel Hesselink JM. Phenytoin Cream for the Treatment of Neuropathic Pain: Case Series. Pharmaceuticals (Basel). 2018;11(2): E53. (PDF)
  • Keppel Hesselink JM. How to Define Neuroprotection: The Case of Phenytoin. Open Access J Neurol Neurosurg. 2018; 7(4): 555719. (PDF)
  • Keppel Hesselink JM. Topical NaV1.7 channel blocker failed in postherpetic Neuralgia (PHN): lessons to learn. Gen Med Open. 2018; 2(2): 1-2. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. The individualized N-of-1 trial: dose-response in a single-blind cross-over response test of phenytoin 10% and 30% cream in neuropathic pain. EC Anaesthesia 2018; 4(6):1-6. (PDF)
  • Keppel Hesselink JM, Mulder JK, Kopsky DJ. Rationale for the repositioning of phenytoin as a topical analgesic for peripheral neuropathic pain and a personalized and investigator-driven development plan. Ann Pharmacol Pharm. 2018; 3(2): 1144. (PDF)
  • Keppel Hesselink JM. Single-blind placebo-controlled response on phenytoin 10% in painful diabetic neuropathy. Gen Med Open. 2018; 2(1): 2-3. (PDF)
  • Kopsky DJ, Keppel Hesselink JM. Phenytoin in topical formulations augments pain reduction of other analgesics in the treatment of neuropathic pain. Int J Anesthetic Anesthesiol 2018; 5: 061. (PDF)
  • Keppel Hesselink JM. Topical phenytoin in painful diabetic neuropathy: rationale to select a non-selective sodium channel blocker. Clinical research in Neurology. 2018; 1(1): 1-5.
  • Keppel Hesselink JM. Phenytoin cream in painful diabetic neuropathy: support for development of new indications for generic drugs needed. Austin Neurology 2018; 3(1): 1011.
  • Keppel Hesselink JM, Kopsky DJ. The value of placebos to individualize pain therapy via a new single-blind test paradigm identifying responders on topical analgesic interventions. J Pain Relief  2018; 7: 313. (PDF)
  • Keppel Hesselink JM. Phenytoin: repurposing an old molecule and patent strategies for neuropathic pain. J Clin Trials Pat 2018;3(1): 3. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Small fiber burning pain in diabetic neuropathy in the elderly, treated with phenytoin cream. BAOJ Anesthesia 2018; 2(1): 003. (PDF)
  • Keppel Hesselink JM. A rationale for using gabapentinoids in topical analgesic formulations? Anaesthesia, Critical Care and Pain Management 2018; 1(3): 59-62. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. The use of topical compounded analgesic creams in neuropathic pain by the primary care physician. J Gen Pract (Los Angel) 2017; 5:345. (PDF)
  • Keppel Hesselink JM. Analgesic onset of action or onset of relief in neuropathic pain. Anaesthesia, Critical Care and Pain Management 2017; 1(2): 48-50. (PDF)
  • Keppel Hesselink JM. Topical amitriptyline: can it reduce localized neuropathic pain? J Clin Trials Regul Aff. 2017; 1(1): 1-4. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Topical compounded analgesic treatment in neuropathic pain: 8 years of experience. J Pain Manage Med. 2017;3(2): 128. (PDF)
  • Keppel Hesselink JM. Moving targets in sodium channel blocker development: the case of raxatrigine: from a central NaV1.3 blocker via a peripheral NaV1.7 blocker to a less selective sodium channel blocker. J. Med. Therap. 2017; 1(1): 1-3. (PDF)
  • Keppel Hesselink JM. Rethinking peripheral sensitization, peripheral neuropathic pain and the putative value of topical analgesics. J of Pharmacol & Clin Res. 2017; 4(2): 555631. (PDF)
  • Keppel Hesselink JM. Repurposing phenytoin as an anti-aggression drug: clinical evidence. Neurol Disord Therap 2017; 1(4)1-5. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Topical phenytoin cream in small fiber neuropathic pain: fast onset of perceptible pain relief. Int J Pain Relief. 2017;1(1): 015-019. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Topical analgesia: transdermal or ‘intradermal’ mechanisms of action? Sci J Neurol Neurosurg. 2017;3(3): 066-069. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Phenytoin cream reduces pain and improves sleep in patients suffering from neuropathic pain. Austin J Anesthesia and Analgesia. 2017; 5(2): 1061. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Pain in chemotherapy induced peripheral neuropathy treated with topical phenytoin cream. CP Cancer Sci. 2017 1(2): 008. (PDF)
  • Keppel Hesselink JM, Schatman ME. Phenytoin and carbamazepine in trigeminal neuralgia: marketing-based versus evidence-based treatment. J. Pain Res. 2017; 10: 1663-1666. (PDF)
  • Keppel Hesselink JM. Phenytoin repositioned in wound healing: clinical experience spanning 60 years. Drug Discov Today. 2017 Oct 6.
  • Chiosi F, Keppel Hesselink JM, Rinaldi M, Di Staso S, Bartollino S, Costagliola C. Phenytoin: its potential as neuroprotective and retinoprotective drug. Br J Clin Pharmacol. 2017 Oct 12.
  • Keppel Hesselink JM. Phenytoin: a step by step insight into its multiple mechanisms of action-80 years of mechanistic studies in neuropharmacology. J Neurol. 2017; 264(9), 2043-2047.
  • Keppel Hesselink JM, Kopsky DJ. Phenytoin: neuroprotection or neurotoxicity? Neurol Sci. 2017 Jun;38(6):1137-1141.
  • 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)
  • Keppel Hesselink JM. Amantadine and phenytoin: patent protected cases of drug repositioning Clin Invest. 2017; 7(1):11-16.
  • Keppel Hesselink JM, Kopsky DJ, Stahl SM. Bottlenecks in the development of topical analgesics: molecule, formulation, dose finding, and phase III design. J Pain Res. 2017; 10: 635-641. (PDF)
  • 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)
  • 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.
  • 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)
  • Kopsky DJ, Keppel Hesselink JM. Topical phenytoin for the treatment of neuropathic pain. J Pain Res. 2017; 10:469-473. (PDF)
  • 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.
  • 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).
  • Keppel Hesselink JM.  Thinking out of the pillbox: the relevance to topiceuticals in the treatment of neuropathic pain. J Pain Relief 2016; 6(5): (PDF).
  • Keppel Hesselink JM, Kopsky DJ, Sajben NL. New topical treatment of vulvodynia based on the pathogenetic role of cross-talk between nociceptors, immunocompetent cells and epithelial cells. J Pain Res. 2016; 9: 757-762. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Topical analgesic creams and nociception in diabetic neuropathy: towards a rationale fundament. Clin Case Rep Rev. 2016; 2(7): 500-502. (PDF)
  • Keppel Hesselink JM. Topical analgesics: critical issues related to formulation and concentration. J Pain Relief 2016; 5(6):245. (PDF)
  • Kopsky DJ. Topical analgesia is a viable option. J Pain Relief 2016; 5(3):245. (PDF)
  • Kopsky DJ. Extending the therapeutic scope for the treatment of neuropathic pain with topical analgesics. J Pain Relief. 2016; 5(3): 251-252. (PDF)
  • Kopsky DJ, Keppel Hesselink JM, Bhaskar AK, Hariton G, Romanenko V, Casale R. Analgesic effects of topical ketamine. Minerva Anestesiol. 2015;81(4):440-449. (PDF)
  • Kopsky DJ, Keppel Hesselink JM, Casale R. Walking with Neuropathic Pain: Paradoxical Shift from Burden to Support? Case Rep Med. 2015;2015:764950. (PDF)
  • Keppel Hesselink JM, Kopsky DJ, Sajben NL. Vulvodynia and proctodynia treated with topical baclofen 5 % and palmitoylethanolamide. Arch Gynecol Obstet. 2014 Aug;290(2):389-93.
  • Keppel Hesselink JM, Kopsky DJ. Treatment of chronic regional pain syndrome type 1 with palmitoylethanolamide and topical ketamine cream: modulation of nonneuronal cells. J Pain Res. 2013 Mar 21;6:239-45. (PDF)
  • Kopsky DJ, Keppel Hesselink JM. Neuropathic pain as a result of acromegaly, treated with topical baclofen cream. J. Pain Symptom Manage 2013 Oct;46(4):e4-5. (PDF)
  • Kopsky DJ, Liebregts R, Keppel Hesselink JM. Central neuropathic pain in a patient with multiple sclerosis treated successfully with topical amitriptyline.Case Rep Med. 2012;2012:471835. (PDF)
  • Kopsky DJ, Amelink GJ, Keppel Hesselink JM. Intractable neuropathic pain in spinal intramedullary cavernoma treated successfully with a novel combination cream. Pain Med. 2012 May;13(5):729-30. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Intractable neuropathic pain due to ulnar nerve entrapment treated with cannabis and ketamine 10%. J Clin Anesth. 2012 Feb;24(1):78-9.
  • Kopsky DJ, Keppel Hesselink JM. Multimodal Stepped Care Approach Involving Topical Analgesics for Severe Intractable Neuropathic Pain in CRPS Type 1: A Case Report. Case Rep Med. 2011;2011:319750. (PDF)
  • 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)
  • Liebregts R, Kopsky DJ, Keppel Hesselink JM. Topical amitriptyline in post-traumatic neuropathic pain. J Pain Symptom Manage. 2011 Apr;41(4):e6-7. (PDF)
  • Keppel Hesselink JM, Kopsky DJ. Letter to the editor. Curr Ther Res Clin Exp. 2010 Dec;71(6):416-7. (PDF)
  • 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)