Objective: Epicutaneous application of capsaicin causes a long-lasting analgesic effect by binding to the membrane transient receptor potential vanilloid 1 (TRPV1) on mechanoheat-sensitive C and Aδ fibres, changing axonal integrity and inhibiting neurogenic inflammatory processes. To date, no information is available regarding the cutaneous drug delivery of capsaicin following patch application. Methods: Using a Franz diffusion cell, the cutaneous concentration-time profiles 30, 60 and 90 min after application of a patch containing 8% capsaicin (640 µg/cm2) on ex vivo thin (mamma) and thick (plantar) human skin were investigated at 32°C, and additionally at 42°C for thin skin and 10°C for thick skin. An HPLC-MS method was used for the analytic detection of capsaicin. Results: The results show that already after a 30-min application of the 8% capsaicin patch, an equilibrium reservoir can be found in the stratum corneum in both thick and thin skin. Under physiological temperature conditions, a sufficient bioavailability of capsaicin in the cutaneous target compartments can be found. Raising the temperature to 42°C has no relevant impact on the concentration-time profile, while reducing the temperature to 10°C leads to a significantly lower bioavailability. Conclusion: After 30 min of application, a sufficient cutaneous bioavailability of capsaicin is reached in thick as well as thin skin. Whether shorter application times may suffice to achieve therapeutic effectiveness requires further investigation. © 2014 S. Karger AG, Basel

Virus RM, Gebhart GF: Pharmacologic actions of capsaicin: apparent involvement of substance P and serotonin. Life Sci 1979;25:1273-1283.
Toh CC, Lee TS, Kiang AK: The pharmacological actions of capsaicin and analogues. Br J Pharmacol Chemother 1955;10:175-182.
Reyes-Escogido Mde L, Gonzalez-Mondragon EG, Vazquez-Tzompantzi E: Chemical and pharmacological aspects of capsaicin. Molecules 2011;16:1253-1270.
Gunthorpe MJ, Benham CD, Randall A, et al: The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci 2002;23:183-191.
Hagenacker T, Splettstoesser F, Greffrath W, et al: Capsaicin differentially modulates voltage-activated calcium channel currents in dorsal root ganglion neurones of rats. Brain Res 2005;1062:74-85.
Facer P, Casula MA, Smith GD, et al: Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy. BMC Neurol 2007;7:11.
Gopinath P, Wan E, Holdcroft A, et al: Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain. BMC Womens Health 2005;5:2.
Serra J, Campero M, Bostock H, et al: Two types of C nociceptors in human skin and their behavior in areas of capsaicin-induced secondary hyperalgesia. J Neurophysiol 2004;91:2770-2781.
Forst T, Pohlmann T, Kunt T, et al: The influence of local capsaicin treatment on small nerve fibre function and neurovascular control in symptomatic diabetic neuropathy. Acta Diabetol 2002;39:1-6.
Inoue K, Koizumi S, Fuziwara S, et al: Functional vanilloid receptors in cultured normal human epidermal keratinocytes. Biochem Biophys Res Commun 2002;291:124-129.
Stander S, Moormann C, Schumacher M, et al: Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp Dermatol 2004;13:129-139.
Rau KK, Jiang N, Johnson RD, et al: Heat sensitization in skin and muscle nociceptors expressing distinct combinations of TRPV1 and TRPV2 protein. J Neurophysiol 2007;97:2651-2662.
Russell LC, Burchiel KJ: Neurophysiological effects of capsaicin. Brain Res 1984;320:165-176.
McCusker MT, Chung KF, Roberts NM, et al: Effect of topical capsaicin on the cutaneous responses to inflammatory mediators and to antigen in man. J Allergy Clin Immunol 1989;83:1118-1124.
Stephens DP, Charkoudian N, Benevento JM, et al: The influence of topical capsaicin on the local thermal control of skin blood flow in humans. Am J Physiol Regul Integr Comp Physiol 2001;281:R894-R901.
Benham CD, Gunthorpe MJ, Davis JB: TRPV channels as temperature sensors. Cell Calcium 2003;33:479-487.
Magerl W, Fuchs PN, Meyer RA, et al: Roles of capsaicin-insensitive nociceptors in cutaneous pain and secondary hyperalgesia. Brain 2001;124:1754-1764.
Polydefkis M, Hauer P, Sheth S, et al: The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain 2004;127:1606-1615.
Anand P, Bley K: Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth 2011;107:490-502.
Reilly CA, Ehlhardt WJ, Jackson DA, et al: Metabolism of capsaicin by cytochrome P450 produces novel dehydrogenated metabolites and decreases cytotoxicity to lung and liver cells. Chem Res Toxicol 2003;16:336-349.
Fujiuchi A, Toga T: Pharmacological effect of capsaicin on rat avoidance behaviours elicited by sine-wave electrical stimulation of different frequencies by Neurometer. J Pharm Pharmacol 2008;60:467-471.
Richeux F, Cascante M, Ennamany R, et al: Cytotoxicity and genotoxicity of capsaicin in human neuroblastoma cells SHSY-5Y. Arch Toxicol 1999;73:403-409.
Chanda S, Bashir M, Babbar S, et al: In vitro hepatic and skin metabolism of capsaicin. Drug Metab Dispos 2008;36:670-675.
Gooding SM, Canter PH, Coelho HF, et al: Systematic review of topical capsaicin in the treatment of pruritus. Int J Dermatol 2010;49:858-865.
Lambert DG: Capsaicin receptor antagonists: a promising new addition to the pain clinic. Br J Anaesth 2009;102:153-155.
Van der Schueren BJ, Rogiers A, Vanmolkot FH, et al: Calcitonin gene-related peptide8-37 antagonizes capsaicin-induced vasodilation in the skin: evaluation of a human in vivo pharmacodynamic model. J Pharmacol Exp Ther 2008;325:248-255.
Schmelz M, Schmid R, Handwerker HO, et al: Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain 2000;123:560-571.
Del Bianco E, Geppetti P, Zippi P, et al: The effects of repeated dermal application of capsaicin to the human skin on pain and vasodilatation induced by intradermal injection of acid and hypertonic solutions. Br J Clin Pharmacol 1996;41:1-6.
Wallengren J, Chen D: Local skin lesions in the rat after subcutaneous deposition of capsaicin. Skin Pharmacol Physiol 2002;15:154-165.
Fitzgerald M: Capsaicin and sensory neurones: a review. Pain 1983;15:109-130.
Chaiyasit K, Khovidhunkit W, Wittayalertpanya S: Pharmacokinetic and the effect of capsaicin in Capsicum frutescens on decreasing plasma glucose level. J Med Assoc Thai 2009;92:108-113.
Brand LM, Skare KL, Loomans ME, et al: Anti-inflammatory pharmacology and mechanism of the orally active capsaicin analogs, NE-19550 and NE-28345. Agents Actions 1990;31:329-340.
Weisshaar E, Ziethen B, Gollnick H: Lack of efficacy of topical capsaicin in serotonin-induced itch. Skin Pharmacol Physiol 2000;13:1-8.
Zhai H, Simion FA, Abrutyn E, Koehler AM, Maibach HI: Screening topical antipruritics: a histamine-induced itch human model. Skin Pharmacol Physiol 2002;15:213-217.
Davies JW, Hainsworth AH, Guerin CJ, et al: Pharmacology of capsaicin-, anandamide-, and N-arachidonoyl-dopamine-evoked cell death in a homogeneous transient receptor potential vanilloid subtype 1 receptor population. Br J Anaesth 2010;104:596-602.
Babbar S, Marier JF, Mouksassi MS, et al: Pharmacokinetic analysis of capsaicin after topical administration of a high-concentration capsaicin patch to patients with peripheral neuropathic pain. Ther Drug Monit 2009;31:502-510.
Qutenza 179 mg cutaneous patch: summary of product characteristics. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000909/WC500040453.pdf (accessed April 4, 2013).
Backonja M, Wallace MS, Blonsky ER, et al: NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol 2008;7:1106-1112.
Simpson DM, Gazda S, Brown S, et al: Long-term safety of NGX-4010, a high-concentration capsaicin patch, in patients with peripheral neuropathic pain. J Pain Symptom Manage 2010;39:1053-1064.
Irving GA, Backonja MM, Dunteman E, et al: A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. Pain Med 2011;12:99-109.
Clifford DB, Simpson DM, Brown S, et al: A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. J Acquir Immune Defic Syndr 2012;59:126-133.
Webster LR, Tark M, Rauck R, et al: Effect of duration of postherpetic neuralgia on efficacy analyses in a multicenter, randomized, controlled study of NGX-4010, an 8% capsaicin patch evaluated for the treatment of postherpetic neuralgia. BMC Neurol 2010;10:92.
Kennedy WR, Vanhove GF, Lu SP, et al: A randomized, controlled, open-label study of the long-term effects of NGX-4010, a high-concentration capsaicin patch, on epidermal nerve fiber density and sensory function in healthy volunteers. J Pain 2010;11:579-587.
Martini C, Yassen A, Olofsen E, et al: Pharmacodynamic analysis of the analgesic effect of capsaicin 8% patch (Qutenza) in diabetic neuropathic pain patients: detection of distinct response groups. J Pain Res 2012;5:51-59.
Jones VM, Moore KA, Peterson DM: Capsaicin 8% topical patch (Qutenza): a review of the evidence. J Pain Palliat Care Pharmacother 2011;25:32-41.
Simpson DM, Estanislao L, Brown SJ, et al: An open-label pilot study of high-concentration capsaicin patch in painful HIV neuropathy. J Pain Symptom Manage 2008;35:299-306.
Hautkappe M, Roizen MF, Toledano A, et al: Review of the effectiveness of capsaicin for painful cutaneous disorders and neural dysfunction. Clin J Pain 1998;14:97-106.
Rains C, Bryson HM: Topical capsaicin: a review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging 1995;7:317-328.
Tandan R, Lewis GA, Krusinski PB, et al: Topical capsaicin in painful diabetic neuropathy. Controlled study with long-term follow-up. Diabetes Care 1992;15:8-14.
Peppin JF, Majors K, Webster LR, et al: Tolerability of NGX-4010, a capsaicin 8% patch for peripheral neuropathic pain. J Pain Res 2011;4:385-392.
Treede RD, Wagner T, Kern KU, et al: Mechanism- and experience-based strategies to optimize treatment response to the capsaicin 8% cutaneous patch in patients with localized neuropathic pain. Curr Med Res Opin 2013;29:527-538.
Knolle E, Zadrazil M, Kovacs GG et al: Comparison of cooling and EMLA to reduce the burning pain during capsaicin 8% patch application: a randomized, double-blind, placebo-controlled study. Pain 2013;154:2729-2736.
OECD: OECD guideline for the testing of chemicals, section 4. Test No. 428. Skin absorption: in vitro method. 2004. http://www.oecd-ilibrary.org/docserver/download/9742701e.pdf?expires=1365075065&id=id&accname=guest&checksum=17EA2B94BD8400DC17F04BCCE29BCF64 (accessed April 4, 2013).
OECD: OECD guideline for the testing of chemicals, section 4. Test No. 427. Skin absorption: in vivo method. 2004. http://www.oecd-ilibrary.org/docserver/download/9742701e.pdf?expires=1365075386&id=id&accname=guest&checksum=59CF7806275A34C7AD402EC58E753FCF (accessed April 4, 2013).
OECD: Guidance document for the conduct of skin absorption studies. 2004. http://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/jm/mono(2004)2 (accessed April 4, 2013).
Garces-Claver A, Gil-Ortega R, Alvarez-Fernandez A, et al: Inheritance of capsaicin and dihydrocapsaicin, determined by HPLC-ESI/MS, in an intraspecific cross of Capsicum annuum L. J Agric Food Chem 2007;55:6951-6957.
Henderson DE, Slickman AM, Henderson SK: Quantitative HPLC determination of the antioxidant activity of capsaicin on the formation of lipid hydroperoxides of linoleic acid: a comparative study against BHT and melatonin. J Agric Food Chem 1999;47:2563-2570.
Wolf R, Huschka C, Raith K, et al: Rapid quantification of capsaicin and dihydrocapsaicin in human skin extracts after dermal administration using HPLC-ESI-MS. J Liq Chromatogr Relat Technol 1999;22:531-539.
Roberts K, Shenoy R, Anand P: A novel human volunteer pain model using contact heat evoked potentials (CHEP) following topical skin application of transient receptor potential agonists capsaicin, menthol and cinnamaldehyde. J Clin Neurosci 2011;18:926-932.
de Tommaso M, Sardaro M, Pecoraro C, et al: Effects of the remote C fibres stimulation induced by capsaicin on the blink reflex in chronic migraine. Cephalalgia 2007;27:881-890.
Shirakawa H, Yamaoka T, Sanpei K, et al: TRPV1 stimulation triggers apoptotic cell death of rat cortical neurons. Biochem Biophys Res Commun 2008;377:1211-1215.
Ko F, Diaz M, Smith P, et al: Toxic effects of capsaicin on keratinocytes and fibroblasts. J Burn Care Rehabil 1998;19:409-413.
Hermann RC, Taylor RS, Ellis CN, et al: Topical ciclosporin for psoriasis: in vitro skin penetration and clinical study. Skin Pharmacol 1988;1:246-249.
Zesch A, Schaefer H, Hoffmann W: Barrier and reservoir function of individual areas of the horny layers of human skin for locally administered drugs (in German). Arch Dermatol Forsch 1973;246:103-107.
Webster LR, Malan TP, Tuchman MM, et al: A multicenter, randomized, double-blind, controlled dose finding study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. J Pain 2010;11:972-982.
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