No Detectable Phenytoin Plasma Levels After Topical Phenytoin Cream Application in Chronic Pain: Inferences for Mechanisms of Action

David J Kopsky, Jan M Keppel Hesselink, Alan L Russell, Alexander F J E Vrancken, David J Kopsky, Jan M Keppel Hesselink, Alan L Russell, Alexander F J E Vrancken

Abstract

Purpose: Topical phenytoin can act as an analgesic in chronic pain, but it is unclear if topical phenytoin gives rise to systemic side effects. Therefore, the aim of this study is: 1) to evaluate safety in chronic pain patients who used topical phenytoin up to 30% applied daily on intact skin and mucous membrane, through determining phenytoin plasma levels; and 2) to elaborate on the analgesic mechanism of action.

Patients and methods: In this retrospective study, we collected demographic and clinical data from 33 chronic pain patients who used 10% to 30% phenytoin cream, and in whom blood samples were drawn for phenytoin concentration measurement between January 2017 until September 2020. The instruction was to withdraw blood 1 to 4 hours after the last topical phenytoin application. The primary outcome was the detectability of plasma phenytoin after daily use of topical phenytoin.

Results: Blood withdrawal was carried out after on average 14 treatment days with topical phenytoin and on average 2.5 hours after topical phenytoin application. The median daily applied amount of phenytoin cream was 1.2 grams, resulting in a median daily amount of 120 mg phenytoin on the skin. Phenytoin levels were below the limit of detection in all patients and no side effects were reported.

Conclusion: Plasma phenytoin levels were below the limit of detection after topical use of phenytoin cream formulations up to 30% on intact skin and mucous membrane for the treatment of chronic pain, without side effects emerging. This finding suggests that the mechanism of analgesic action resides in the skin.

Keywords: neuropathy; pain; phenytoin cream; plasma concentration; skin.

Conflict of interest statement

DJK and JMKH are holders of two patent applications: Topical phenytoin for use in the treatment of peripheral neuropathic pain (WO2018106107); and Topical pharmaceutical composition containing phenytoin and a (co-)analgesic for the treatment of chronic pain (WO2018106108). AFJEV reports grants from Prinses Beatrix Spierfonds and Dr C.J. Vaillantfonds for EPHENE-study (randomized trial on effectiveness of phenytoin cream vs placebo cream for neuropathic pain in idiopathic polyneuropathy). DJK and JMKH are involved in the EPHENE-study. The authors report no other conflicts of interest in this work.

© 2022 Kopsky et al.

Figures

Figure 1
Figure 1
Topical phenytoin characteristics before blood withdrawal.

References

    1. Keppel Hesselink JM, Kopsky DJ. Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action. J Neurol. 2017;264(8):1617–1621. doi:10.1007/s00415-017-8391-5
    1. Bhatia A, Prakash S. Topical phenytoin for wound healing. Dermatol Online J. 2004;10(1):5. doi:10.5070/D30Z3612W1
    1. Shaw J, Hughes CM, Lagan KM, Stevenson MR, Irwin CR, Bell PM. The effect of topical phenytoin on healing in diabetic foot ulcers: a randomized controlled trial. Diabet Med. 2011;28(10):1154–1157. doi:10.1111/j.1464-5491.2011.03309.x
    1. Anstead GM, Hart LM, Sunahara JF, Liter ME. Phenytoin in wound healing. Ann Pharmacother. 1996;30(7–8):768–775. doi:10.1177/106002809603000712
    1. Lockman LA, Hunninghake DB, Krivit W, Desnick RJ. Relief of pain of Fabry’s disease by diphenylhydantoin. Neurology. 1973;23(8):871–875. doi:10.1212/WNL.23.8.871
    1. Saudek CD, Werns S, Reidenberg MM. Phenytoin in the treatment of diabetic symmetrical polyneuropathy. Clin Pharmacol Ther. 1977;22(2):196–199. doi:10.1002/cpt1977222196
    1. Chadda VS, Mathur MS. Double blind study of the effects of diphenylhydantoin sodium on diabetic neuropathy. J Assoc Physicians India. 1978;26(5):403–406.
    1. Webb J, Kamali F. Analgesic effects of lamotrigine and phenytoin on cold-induced pain: a crossover placebo-controlled study in healthy volunteers. Pain. 1998;76(3):357–363. doi:10.1016/S0304-3959(98)00068-2
    1. Kopsky DJ, Keppel Hesselink JM. Phenytoin cream for the treatment of neuropathic pain: case series. Pharmaceuticals. 2018;11(2):53. doi:10.3390/ph11020053
    1. Russell AL, Kopsky DJ, Hesselink JMK. Phenytoin cream for the treatment of sciatic pain: clinical effects and theoretical considerations: case report. J Pain Palliat Care Pharmacother. 2020;34(2):99–105. doi:10.1080/15360288.2020.1733169
    1. Keppel Hesselink JM, Kopsky DJ, Bhaskar AK. 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. Your research: is it subject to the WMO or not? Central Committee on Research Involving Human Subjects. Available from: . Accessed November 2, 2021.
    1. Regulation (EU) No 536/2014 of the European Parliament and of the council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Available from: . Accessed November 2, 2021.
    1. Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council. Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans; December, 2018.
    1. Peterson GM, McLean S, Aldous S, Von Witt RJ, Millingen KS. Plasma protein binding of phenytoin in 100 epileptic patients. Br J Clin Pharmacol. 1982;14(2):298–300. doi:10.1111/j.1365-2125.1982.tb01981.x
    1. Farage M, Maibach H. Lifetime changes in the vulva and vagina. Arch Gynecol Obstet. 2006;273(4):195–202. doi:10.1007/s00404-005-0079-x
    1. Anderson DJ, Marathe J, Pudney J. The structure of the human vaginal stratum corneum and its role in immune defense. Am J Reprod Immunol. 2014;71(6):618–623. doi:10.1111/aji.12230
    1. Widanapathirana L, Tale S, Reineke TM. Dissolution and solubility enhancement of the highly lipophilic drug phenytoin via interaction with Poly(N-isopropylacrylamide-co-vinylpyrrolidone) excipients. Mol Pharm. 2015;12(7):2537–2543. doi:10.1021/acs.molpharmaceut.5b00202
    1. Nielsen JB, Benfeldt E, Holmgaard R. Penetration through the Skin Barrier. Curr Probl Dermatol. 2016;49:103–111.
    1. Kopsky DJ, Keppel Hesselink JM. Single-Blind Placebo-Controlled Response test with phenytoin 10% cream in neuropathic pain patients. Pharmaceuticals. 2018;11(4):122. doi:10.3390/ph11040122
    1. Kopsky DJ, Vrancken AFJE, 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. doi:10.2147/JPR.S243434
    1. Bergouignan M, d’Aulnay N. Effect of diphenyl-hydantoinate salt on essential trigeminal neuralgia. Rev Otoneuroopthal (Paris). 1951;23:427–431.
    1. Iannone A, Baker AB, Morrell F. Dilantin in the treatment of trigeminal neuralgia. Neurology. 1958;8(2):126–128. doi:10.1212/WNL.8.2.126
    1. Lamberts AE. Tic doulourex. J Mich State Med Soc. 1959;58(1Part 1):95–96.
    1. Ellenberg M. Treatment of diabetic neuropathy with diphenylhydantoin. N Y State J Med. 1968;68(20):2653–2655.
    1. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy. Drugs. 2000;60(5):1029–1052. doi:10.2165/00003495-200060050-00005
    1. Baumbauer KM, DeBerry JJ, Adelman PC, et al. Keratinocytes can modulate and directly initiate nociceptive responses. eLife. 2015;4:e09674. doi:10.7554/eLife.09674
    1. Pang Z, Sakamoto T, Tiwari V, et al. Selective keratinocyte stimulation is sufficient to evoke nociception in mice. Pain. 2015;156(4):656–665. doi:10.1097/j.pain.0000000000000092
    1. Ibrahim MM, Porreca F, Lai J, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A. 2005;102(8):3093–3098. doi:10.1073/pnas.0409888102
    1. Bennett DL, Clark AJ, Huang J, Waxman SG, Dib-Hajj SD. The role of voltage-gated sodium channels in pain signaling. Physiol Rev. 2019;99(2):1079–1151. doi:10.1152/physrev.00052.2017
    1. Zhao P, Barr TP, Hou Q, et al. Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain. Pain. 2008;139(1):90–105. doi:10.1016/j.pain.2008.03.016
    1. Sluka KA, Clauw DJ. Neurobiology of fibromyalgia and chronic widespread pain. Neuroscience. 2016;338:114–129. doi:10.1016/j.neuroscience.2016.06.006
    1. Grayston R, Czanner G, Elhadd K, et al. A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: implications for a new paradigm in fibromyalgia etiopathogenesis. Semin Arthritis Rheum. 2019;48(5):933–940.
    1. Kelley MA, Hackshaw KV. Intraepidermal nerve fiber density as measured by skin punch biopsy as a marker for small fiber neuropathy: application in patients with fibromyalgia. Diagnostics (Basel, Switzerland). 2021;11(3):536.
    1. Niddam DM, Chan RC, Lee SH, Yeh TC, Hsieh JC. Central representation of hyperalgesia from myofascial trigger point. NeuroImage. 2008;39(3):1299–1306. doi:10.1016/j.neuroimage.2007.09.051
    1. Affaitati G, Fabrizio A, Savini A, et al. A randomized, controlled study comparing a lidocaine patch, a placebo patch, and anesthetic injection for treatment of trigger points in patients with myofascial pain syndrome: evaluation of pain and somatic pain thresholds. Clin Ther. 2009;31(4):705–720. doi:10.1016/j.clinthera.2009.04.006
    1. Baron R, Hans G, Dickenson AH. Peripheral input and its importance for central sensitization. Ann Neurol. 2013;74(5):630–636. doi:10.1002/ana.24017

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