Single-Blind Placebo-Controlled Response Test with Phenytoin 10% Cream in Neuropathic Pain Patients

David J Kopsky, Jan M Keppel Hesselink, David J Kopsky, Jan M Keppel Hesselink

Abstract

Background: Phenytoin cream applied topically has been explored in neuropathic pain conditions. In several case series, phenytoin 5% and 10% cream could reduce pain in a clinically relevant way with a fast onset of action within 30 min, and with positive effects on sleep.

Objective: To evaluate a single-blind placebo-controlled response test (SIBRET) for use in clinical practice.

Materials and methods: Patients with localized neuropathic pain, having an equal pain intensity in at least 2 areas (e.g., both feet), and a pain intensity of at least 4 on the 11-point numerical rating scale (NRS), were selected to perform the SIBRET. In one area, placebo cream consisting of the base cream was applied, and on the other area, phenytoin 10% cream was applied with separate hands to avoid contamination. Responders were defined as patients who experienced within 30 min at least 2-points difference as scored on the NRS, between the phenytoin 10% and the placebo cream applied areas, in favor of the former. Responders were subsequently prescribed phenytoin 10% cream.

Results: Of the 21 patients, 15 patients (71.45%) were classified as responders. The mean pain reduction after 30 min as measured with the NRS in the phenytoin 10% cream area was 3.3 (SD: 1.3) and in the placebo cream area 1.2 (SD: 1.1). The difference of the mean percentage pain reduction between phenytoin 10% cream and placebo cream was 33.2% (SD: 17.6, p < 0.001). Using a 50% reduction on the NRS as a full response criterion, we could identify 57.1% of responders on phenytoin 10% cream and only 9.5% responders on placebo cream.

Conclusions: The SIBRET helps patients and clinicians to quickly identify the appropriate treatment and can thus be seen as an important contributor to the domain of personalized medicine in pain. These results can also be regarded as a proof of principle for the analgesic activity of 10% phenytoin cream.

Keywords: analgesia; neuropathic pain; phenytoin; response test; single-blind; topical.

Conflict of interest statement

The authors are holders of two patents: (1) topical phenytoin for use in the treatment of peripheral neuropathic pain and (2) topical pharmaceutical composition containing phenytoin and a (co-)analgesic for the treatment of chronic pain. The authors report no other conflicts of interest in this work.

References

    1. Ney J.P., Devine E.B., Watanabe J.H., Sullivan S.D. Comparative efficacy of oral pharmaceuticals for the treatment of chronic peripheral neuropathic pain: Meta-analysis and indirect treatment comparisons. Pain Med. 2013;14:706–719. doi: 10.1111/pme.12091.
    1. Knezevic N.N., Tverdohleb T., Nikibin F., Knezevic I., Candido K.D. Management of chronic neuropathic pain with single and compounded topical analgesics. Pain Manag. 2017;10 doi: 10.2217/pmt-2017-0020.
    1. Kopsky D.J., Keppel Hesselink J.M. Topical phenytoin for the treatment of neuropathic pain. J. Pain Res. 2017;10:469–473. doi: 10.2147/JPR.S129749.
    1. Keppel Hesselink J.M., Kopsky D.J. Topical phenytoin cream reduces burning pain due to small fiber neuropathy in sarcoidosis. J. Anesthesiol. Pain Med. 2017;2:1–3.
    1. Keppel Hesselink J.M., Kopsky D.J. Pain in chemotherapy induced peripheral neuropathy treated with topical phenytoin cream. [(accessed on 30 July 2018)]; Available online: .
    1. Keppel Hesselink J.M., Kopsky D.J. Burning pain in small fibre neuropathy treated with topical phenytoin: Rationale and case presentations. J. Clin. Anesth. Pain Med. 2017;1:1–6.
    1. Keppel Hesselink J.M., Kopsky D.J. Phenytoin cream reduces pain and improves sleep in patients suffering from neuropathic pain. Austin J. Anesth. Analg. 2017;5:1061.
    1. Keppel Hesselink J.M., Kopsky D.J. Topical phenytoin cream in small fiber neuropathic pain: Fast onset of perceptible pain relief. Int. J. Pain Relief. 2017;1:15–19.
    1. Keppel Hesselink J.M., Kopsky D.J. Topical analgesia: Transdermal or ‘intradermal’ mechanisms of action? Sci. J. Neurol. Neurosurg. 2017;3:66–69.
    1. Keppel Hesselink J.M., Kopsky D.J. Topical phenytoin in neuralgic pain, peripheral modulation of central sensitization: Two case reports. J. Pain Relief. 2017;6:284. doi: 10.4172/2167-0846.1000284.
    1. Keppel Hesselink J.M., Kopsky D.J., Bhaskar A.K. Skin matters! The role of keratinocytes in nociception: A rational argument for the development of topical analgesics. J. Pain Res. 2016;10:1–8. doi: 10.2147/JPR.S122765.
    1. Kopsky D.J., Keppel Hesselink J.M. Phenytoin cream for the treatment of neuropathic pain: Case series. Pharmaceuticals. 2018;11 doi: 10.3390/ph11020053.
    1. Edwards R.R., Dworkin R.H., Turk D.C., Angst M.S., Dionne R., Freeman R., Hansson P., Haroutounian S., Arendt-Nielsen L., Attal N., et al. Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations. Pain. 2016;157:1851–1871. doi: 10.1097/j.pain.0000000000000602.
    1. Farrar J.T., Pritchett Y.L., Robinson M., Prakash A., Chappell A. The clinical importance of changes in the 0 to 10 numeric rating scale for worst, least, and average pain intensity: Analyses of data from clinical trials of duloxetine in pain disorders. J. Pain. 2010;11:109–118. doi: 10.1016/j.jpain.2009.06.007.
    1. U.S. Department of Health and Human Services, Food and Drug Administration Guidance for Industry Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. [(accessed on 30 July 2018)]; Available online: .
    1. Ondra T., Dmitrienko A., Friede T., Graf A., Miller F., Stallard N., Posch M. Methods for identification and confirmation of targeted subgroups in clinical trials: A systematic review. J. Biopharm. Stat. 2016;26:99–119. doi: 10.1080/10543406.2015.1092034.
    1. Bostick N.A., Sade R., Levine M.A., Stewart D.M., Jr. Placebo use in clinical practice: Report of the american medical association council on ethical and judicial affairs. J. Clin. Ethics. 2008;19:58–61.
    1. Lichtenberg P., Heresco-Levy U., Nitzan U. The ethics of the placebo in clinical practice. J. Med. Ethics. 2004;30:551–554. doi: 10.1136/jme.2002.002832.
    1. Peterson G.M., McLean S., Aldous S., Von Witt R.J., Millingen K.S. Plasma protein binding of phenytoin in 100 epileptic patients. Br. J. Clin. Pharmacol. 1982;14:298–300. doi: 10.1111/j.1365-2125.1982.tb01981.x.
    1. Derry S., Conaghan P., Da Silva J.A., Wiffen P.J., Moore R.A. Topical nsaids for chronic musculoskeletal pain in adults. Cochrane Database Syst. Rev. 2016;22 doi: 10.1002/14651858.CD007400.pub3.
    1. Kopsky D.J., Hesselink J.M. High doses of topical amitriptyline in neuropathic pain: Two cases and literature review. Pain Pract. 2012;12:148–153. doi: 10.1111/j.1533-2500.2011.00477.x.
    1. Kopsky D.J., Liebregts R., Keppel Hesselink J.M. Central neuropathic pain in a patient with multiple sclerosis treated successfully with topical amitriptyline. Case Rep. Med. 2012;2012:471835. doi: 10.1155/2012/471835.
    1. Liebregts R., Kopsky D.J., Hesselink J.M. Topical amitriptyline in post-traumatic neuropathic pain. J. Pain Symptom Manag. 2011;41:e6–e7. doi: 10.1016/j.jpainsymman.2011.01.003.
    1. Aurilio C., Pota V., Pace M.C., Passavanti M.B., Barbarisi M. Ionic channels and neuropathic pain: Physiopathology and applications. J. Cell. Physiol. 2008;215:8–14. doi: 10.1002/jcp.21280.
    1. Cummins T.R., Waxman S.G. Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J. Neurosci. 1997;17:3503–3514. doi: 10.1523/JNEUROSCI.17-10-03503.1997.
    1. Liu M., Wood J.N. The roles of sodium channels in nociception: Implications for mechanisms of neuropathic pain. Pain Med. 2011;12:1526–4637. doi: 10.1111/j.1526-4637.2011.01158.x.
    1. Keppel Hesselink J.M. Phenytoin: A step by step insight into its multiple mechanisms of action-80 years of mechanistic studies in neuropharmacology. J. Neurol. 2017;264:2043–2047. doi: 10.1007/s00415-017-8465-4.
    1. Lipkind G.M., Fozzard H.A. Molecular model of anticonvulsant drug binding to the voltage-gated sodium channel inner pore. Mol. Pharmacol. 2010;78:631–638. doi: 10.1124/mol.110.064683.

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