Advertisement
Original Reports| Volume 22, ISSUE 7, P778-788, July 2021

Effect of Topical Analgesia on Desensitization Following 8% Topical Capsaicin Application

  • Janne D. Christensen
    Affiliations
    Laboratory for Experimental Cutaneous Pain and Itch Research, SMI, Center for Neuroplasticity and Pain, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Denmark
    Search for articles by this author
  • Silvia Lo Vecchio
    Correspondence
    Address reprint requests to Silvia Lo Vecchio, PhD, MSc, Center for Neuroplasticity and Pain, Faculty of Medicine, Aalborg University, Fredrik Bajers Vej 7D, D3-217, 9220 Aalborg East, Denmark.
    Affiliations
    Laboratory for Experimental Cutaneous Pain and Itch Research, SMI, Center for Neuroplasticity and Pain, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Denmark
    Search for articles by this author
  • Hjalte H. Andersen
    Affiliations
    Laboratory for Experimental Cutaneous Pain and Itch Research, SMI, Center for Neuroplasticity and Pain, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Denmark
    Search for articles by this author
  • Jesper Elberling
    Affiliations
    The Allergy Clinic, Department of Dermato-Allergology, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark
    Search for articles by this author
  • Lars Arendt-Nielsen
    Affiliations
    Laboratory for Experimental Cutaneous Pain and Itch Research, SMI, Center for Neuroplasticity and Pain, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Denmark
    Search for articles by this author
Published:January 29, 2021DOI:https://doi.org/10.1016/j.jpain.2021.01.005

      Highlights

      • EMLA caused significant reductions in capsaicin-induced pain compared with placebo.
      • EMLA enhanced capsaicin-induced superficial blood perfusion.
      • Capsaicin reduced the neurogenic flare induced by histamine compared with EMLA.
      • Topical analgesic pretreatment does not interfere with capsaicin desensitization.

      Abstract

      To prevent pain associated with 8% capsaicin application, pretreatment with local anesthetics, such as EMLA (eutectic mixture of lidocaine 2.5% and prilocaine 2.5%), is considered an option. However, there is contradicting evidence regarding the effects of local analgesia on capsaicin-induced desensitization. In session 1, 2 skin areas in each forearm of 24 healthy volunteers were randomized to 2-hour pretreatment with EMLA/placebo cream. After pretreatment, 8% capsaicin patches were applied for 3 hours in 1 placebo and 1 EMLA pretreated area, obtaining the following four areas: Capsaicin + EMLA, Capsaicin + Placebo, EMLA alone, and Placebo. Pain intensity scores were assessed during the 3-hour application of capsaicin. Warmth detection, heat pain sensitivity, and microvascular reactivity were measured after the removal of capsaicin. After 24 hours, in session 2, all tests were repeated followed by histamine application in each area to examine itch intensity and neurogenic flare.
      Overall, EMLA caused significant reductions in capsaicin-induced pain compared with placebo (P= .007) and enhanced the capsaicin-induced increase in superficial blood perfusion immediately after the 3-hour capsaicin application (P< .01). Regardless of pretreatment, capsaicin induced heat hyperalgesia immediately after the application (P< .001). Twenty-four hours post application, heat pain sensitivity was normalized. However, WDT increased significantly (P< .001). Capsaicin tended to reduce the itch intensity and significantly reduced the neurogenic flare (P< .05) induced by histamine compared with EMLA alone. The findings suggest that pretreatment with topical analgesic cream reduces application site pain without interfering with the 8% topical capsaicin-induced desensitization.

      Perspective

      Pretreatment with local anesthetic EMLA cream might be considered a good therapeutic option to reduce the pain associated with 8% capsaicin application currently used for treatment of neuropathic pain syndromes. This study also suggests the existence of a synergistic effect of capsaicin and EMLA on the process of neurogenic inflammation.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • 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
        • Andersen HH
        • Marker JB
        • Hoeck EA
        • Elberling J
        • Arendt-Nielsen L
        Antipruritic effect of pretreatment with topical capsaicin 8% on histamine- and cowhage-evoked itch in healthy volunteers: A randomized, vehicle-controlled, proof-of-concept trial.
        Br J Dermatol. 2017; 177: 107-116
        • Basbaum AI
        • Bautista DM
        • Scherrer G
        • Julius D
        Cellular and molecular mechanisms of pain.
        Cell. 2009; 139: 267-284
        • Bjerring P
        • Andersen PH
        Arendt-Nielsen L: Vascular response of human skin after analgesia with EMLA cream.
        Br J Anaesth. 1989; 63: 655-660
        • Bjerring P
        • Arendt-Nielsen L
        Depth and duration of skin analgesia to needle insertion after topical application of EMLA cream.
        Br J Anaesth. 1990; 64: 173-177
        • Carpenter SE
        • Lynn B
        Vascular and sensory responses of human skin to mild injury after topical treatment with capsaicin.
        Br J Pharmac. 1981; 73: 755-758
        • Caterina MJ
        • Schumacher MA
        • Tominaga M
        • Rosen TA
        • Levine JD
        • Julius D
        The capsaicin receptor: A heat-activated ion channel in the pain pathway.
        Nature. 1997; 389: 816
        • Chuquilin M
        • Alghalith Y
        • Fernandez KH
        Neurocutaneuous disease: Cutaneuous neuroanatomy and mechanisms of itch and pain.
        J Am Acad Dermatol. 2016; 74: 197-212
        • Dworkin RH
        • O'Connor AB
        • Backonja M
        • Farrar JT
        • Finnerup NB
        • Jensen TS
        • Kalso EA
        • Loeser JD
        • Miaskowski C
        • Nurmikko TJ
        • Portenoy RK
        • Rice ASC
        • Stacey BR
        • Treede R-D
        • Turk DC
        • Wallace MS
        Pharmacologic management of neuropathic pain: Evidence-based recommendations.
        Pain. 2007; 132: 237-251
      1. European Medicin Agency (EMA): Qutenza, INN-capsaicin summary of product characteristics. 2009.

        • Ferland CE
        • Villemure C
        • Michon P-E
        • Gandhi W
        • Ma M-L
        • Chouchou F
        • Parent AJ
        • Bushnell MC
        • Lavigne G
        • Rainville P
        Multicenter assessment of quantitative sensory testing (QST) for the detection of neuropathic-like pain responses using the topical capsaicin model.
        Can J Pain Taylor & Francis. 2018; 2: 266-279
        • Foreman JC
        • Jordan CC
        • Oehme P
        • Renner H
        Structure-activity relationships for some substance P-related peptides that cause wheal and flare reactions in human skin.
        J Physiol. 1983; 335: 449-465
        • Fuchs PN
        • Pappagallo M
        • Meyer RA
        Topical EMLA pre-treatment fails to decrease the pain induced by 1% topical capsaicin.
        Pain. 1999; 80: 637-642
        • Glatte P
        • Buchmann SJ
        • Hijazi MM
        • Illigens BM-W
        • Siepmann T
        Architecture of the cutaneous autonomic nervous system.
        Front Neurol Front. 2019; 10: 970
        • Gooding SMD
        • Canter PH
        • Coelho HF
        • Boddy K
        • Ernst E
        Systematic review of topical capsaicin in the treatment of pruritus.
        Int J Dermatol. 2010; 49: 858-865
        • Henrich F
        • Magerl W
        • Klein T
        • Greffrath W
        • Treede R-D
        Capsaicin-sensitive C-and A-fibre nociceptors control long-term potentiation-like pain amplification in humans.
        Brain Oxford. 2015; 138: 2505-2520
        • Hirota K
        • Smart D
        • Lambert DG
        The effects of local and intravenous anesthetics on recombinant rat VR1 vanilloid receptors.
        Anesth Analg. 2003; 96: 1656-1660
        • Jensen TS
        • Høye K
        • Fricová J
        • Vanelderen P
        • Ernault E
        • Siciliano T
        • Marques S
        Tolerability of the capsaicin 8% patch following pretreatment with lidocaine or tramadol in patients with peripheral neuropathic pain: A multicentre, randomized, assessor-blinded study.
        Eur J Pain. 2014; 18: 1240-1247
        • Julius D
        • Basbaum AI
        Molecular mechanisms of nociception.
        Nature. 2001; 413: 203-210
        • Kennedy WR
        • Vanhove GF
        • Lu S
        • Tobias J
        • Bley KR
        • Walk D
        • Wendelschafer-Crabb G
        • Simone DA
        • Selim MM
        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 Elsevier. 2010; 11: 579-587
        • Kidd BL
        • Urban LA
        Mechanisms of inflammatory pain.
        Br J Anaesth Elsevier. 2001; 87: 3-11
        • Knolle E
        • Zadrazil M
        • Kovacs GG
        • Medwed S
        • Scharbert G
        • Schemper M
        Comparison of cooling and EMLA to reduce the burning pain during capsaicin 8% patch application: A randomized, double-blind, placebo-controlled study.
        Pain Elsevier. 2013; 154: 2729-2736
        • Komai H
        • Mcdowell TS
        Differential effects of bupivacaine and tetracaine on capsaicin-induced currents in dorsal root ganglion neurons.
        Neurosci Lett. 2005; 380: 21-25
        • Lam VY
        • Wallace M
        • Schulteis G
        Effects of lidocaine patch on intradermal capsaicin-induced pain: A double-blind, controlled trial.
        J Pain. 2011; 12: 323-330
        • LaMotte RH
        • Dong X
        • Ringkamp M
        Sensory neurons and circuits mediating itch.
        Nat Rev Neurosci. 2014; 15: 19-31
        • Leffler A
        • Fischer MJ
        • Rehner D
        • Kienel S
        • Kistner K
        • Sauer SK
        • Gavva NR
        • Reeh PW
        • Nau C
        The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons.
        J Clin Invest. 2008; 118: 763-776
        • Lumpkin EA
        • Caterina MJ
        Mechanisms of sensory transduction in the skin.
        Nature. 2007; 445: 858
        • Magerl W
        • Fuchs PN
        • Meyer RA
        • Treede R-D
        Roles of capsaicin-insensitive nociceptors in cutaneous pain and secondary hyperalgesia.
        Brain. 2001; 124: 1754-1764
        • McCormack PL
        Capsaicin dermal patch: in non-diabetic peripheral neuropathic pain.
        Drugs. 2010; 70: 1831-1842
        • Mou J
        • Paillard F
        • Turnbull B
        • Trudeau J
        • Stoker M
        • Katz NP
        Efficacy of Qutenza® (capsaicin) 8% patch for neuropathic pain: a meta-analysis of the Qutenza.
        Clinical Trials Database Pain. 2013; 154: 1632-1639
        • Nau C
        • Wang GK
        Interactions of local anesthetics with voltage-gated Na + channels.
        J Membr Biol. 2004; 2011: 1-8
        • Nolano M
        • Simone DA
        • Wendelschafer-Crabb G
        • Johnson T
        • Hazen E
        • Kennedy WR
        Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation.
        Pain. 1999; 81: 135-145
        • O'Neill J
        • Brock C
        • Olesen AE
        • Andresen T
        • Nilsson M
        • Dickenson AH
        Unravelling the mystery of capsaicin: A tool to understand and treat pain.
        Pharmacol Rev ASPET;. 2012; 64: 939-971
        • Olsen R V
        • Andersen HH
        • Møller HG
        • Eskelund PW
        Arendt-Nielsen L: Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans-cinnamaldehyde in healthy volunteers.
        Eur J Pain. 2014; 18: 1333-1342
        • Papoiu ADP
        • Yosipovitch G
        Topical capsaicin. The fire of a ‘hot'medicine is reignited.
        Expert Opin Pharmacother. 2010; 11: 1359-1371
        • Peier AM
        • Reeve AJ
        • Andersson DA
        • Moqrich A
        • Earley TJ
        • Hergarden AC
        • Story GM
        • Colley S
        • Hogenesch JB
        • McIntyre P
        • Bevan S
        • Patapoutian A
        A heat-sensitive TRP channel expressed in keratinocytes.
        Science (80-) Am Assoce Advance Sci. 2002; 296: 2046-2049
        • Rivera-Acevedo RE
        • Pless SA
        • Ahern CA
        • Schwarz SKW
        The quaternary lidocaine derivative, QX-314, exerts biphasic effects on transient receptor potential vanilloid subtype 1 channels in vitro.
        Anesthesiology. 2011; 114: 1425-1434
        • Roberson DP
        • Gudes S
        • Sprague JM
        • Patoski HAW
        • Robson VK
        • Blasl F
        • Duan B
        • Oh SB
        • Bean BP
        • Ma Q
        Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons.
        Nat Neurosci. 2013; 16: 910
        • Rolke R
        • Baron R
        • Maier C
        • Tölle TR
        • Treede R-D
        • Beyer A
        • Binder A
        • Birbaumer N
        • Birklein F
        • Bötefür IC
        • Braune S
        • Flor H
        • Huge V
        • Klug R
        • Landwehrmeyer GB
        • Magerl W
        • Maihöfner C
        • Rolko C
        • Schaub C
        • Scherens A
        • Sprenger T
        • Valet M
        • Wasserka B
        Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values.
        Pain. 2006; 123: 231-243
        • Russell FA
        • King R
        • Smillie S-J
        • Kodji X
        • Brain SD
        Calcitonin gene-related peptide: Physiology and pathophysiology.
        Physiol Rev Am Physiol Soc. 2014; 94: 1099-1142
        • Schepers RJ
        • Ringkamp M
        Thermoreceptors and thermosensitive afferents.
        Neurosci Biobehav Rev. 2010; 34: 177-184
        • Schmelz M
        • Schmidt R
        • Weidner C
        • Hilliges M
        • Torebjork HE
        • Handwerker HO
        Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens.
        J Neurophysiol Am Physiol Soc Bethesda, MD. 2003; 89: 2441-2448
        • Simone DA
        • Ochoa J
        Early and late effects of prolonged topical capsaicin on cutaneous sensibility and neurogenic vasodilatation in humans.
        Pain. 1991; 47: 285-294
        • Simpson DM
        • Brown S
        • Tobias J
        Group N-4010 CS: Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy.
        Neurol AAN Enterprises. 2008; 70: 2305-2313
        • Smith GD
        • Gunthorpe MJ
        • Kelsell RE
        • Hayes PD
        • Reilly P
        • Facer P
        • Wright JE
        • Jerman JC
        • Walhin J-P
        • Ooi L
        TRPV3 is a temperature-sensitive vanilloid receptor-like protein.
        Nature. 2002; 418: 186-190
        • Tominaga M
        • Caterina MJ
        • Malmberg AB
        • Rosen TA
        • Gilbert H
        • Skinner K
        • Raumann BE
        • Basbaum AI
        • Julius D
        The cloned capsaicin receptor integrates multiple pain-producing stimuli.
        Neuron. 1998; 21: 531-543
        • Tóth-Kása I
        • Jancsó G
        • Bognar A
        • Husz S
        • Obal Jr F
        Capsaicin prevents histamine-induced itching.
        Int J Clin Pharmacol Res. 1986; 6: 163
        • Touska F
        • Marsakova L
        • Teisinger J
        • Vlachova V
        A “cute” desensitization of TRPV1.
        Curr Pharm Biotechnol Bentham Sci Publ. 2011; 12: 122-129
        • Treede RD
        • Meyer RA
        • Raja SN
        • Campbell JN
        Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin.
        J Physiol. 1995; 483: 747-758
        • Usoskin D
        • Furlan A
        • Islam S
        • Abdo H
        • Lönnerberg P
        • Lou D
        • Hjerling-Leffler J
        • Haeggström J
        • Kharchenko O
        • Kharchenko P V
        Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
        Nat Neurosci Nat Publ Grp. 2015; 18: 145-153
        • Lo Vecchio S
        • Andersen HH
        • Arendt-Nielsen L
        The time course of brief and prolonged topical 8% capsaicin-induced desensitization in healthy volunteers evaluated by quantitative sensory testing and vasomotor imaging.
        Exp Brain Res. 2018; 236: 2231-2244
        • Wahlgren C-F
        • Quiding H
        Depth of cutaneous analgesia after application of a eutectic mixture of the local anesthetics lidocaine and prilocaine (EMLA cream).
        J Am Acad Dermatol Elsevier. 2000; 42: 584-588
        • Webster LR
        • Malan TP
        • Tuchman MM
        • Mollen MD
        • Tobias JK
        • Vanhove GF
        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
        • Webster LR
        • Nunez M
        • Tark MD
        • Dunteman ED
        • Lu B
        • Tobias JK
        • Vanhove GF
        Tolerability of NGX-4010, a capsaicin 8% dermal patch, following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with post-herpetic neuralgia.
        BMC Anesthesiol BioMed Central. 2011; 11: 25
        • Wehrfritz A
        • Namer B
        • Ihmsen H
        • Mueller C
        • Filitz J
        • Koppert W
        • Leffler A
        Differential effects on sensory functions and measures of epidermal nerve fiber density after application of a lidocaine patch (5%) on healthy human skin.
        Eur J Pain. 2011; 15: 907-912
        • Wei H
        • Chen Y
        • Xu L
        • Zheng J
        Percutaneous penetration kinetics of lidocaine and prilocaine in two local anesthetic formulations assessed by in vivo microdialysis in pigs.
        Biol Pharm Bull. 2007; 30: 830-834
        • Wooten M
        • Weng H-J
        • Hartke T V
        • Borzan J
        • Klein AH
        • Turnquist B
        • Dong X
        • Meyer RA
        • Ringkamp M
        Three functionally distinct classes of C-fibre nociceptors in primates.
        Nat Commun. 2014; 5: 4122
        • Xu H
        • Ramsey IS
        • Kotecha SA
        • Moran MM
        • Chong JA
        • Lawson D
        • Ge P
        • Lilly J
        • Silos-Santiago I
        • Xie Y
        • DiStefano P
        • Curtis R
        • Clapham D
        TRPV3 is a calcium-permeable temperature-sensitive cation channel.
        Nature. 2002; 418: 181
        • Yosipovitch
        • Maibach Howard I.
        • Mic G
        • Maibach HI
        • Rowbotham MC
        Effect of EMLA pre-treatment on capsaicin-induced burning and hyperalgesia.
        Acta Derm Venereol. 1999; 79: 118-121