Original Report| Volume 16, ISSUE 7, P595-605, July 2015

Effectiveness of High-Frequency Electrical Stimulation Following Sensitization With Capsaicin

  • Catherine R. Jutzeler
    Address reprint requests to Catherine R. Jutzeler, MSc, Spinal Cord Injury Center, University Hospital Balgrist, Forchstrasse 340, 8008 Zurich, Switzerland.
    Spinal Cord Injury Center, University Hospital Balgrist, University of Zurich, Zurich, Switzerland
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  • Armin Curt
    Spinal Cord Injury Center, University Hospital Balgrist, University of Zurich, Zurich, Switzerland
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  • John L.K. Kramer
    Spinal Cord Injury Center, University Hospital Balgrist, University of Zurich, Zurich, Switzerland

    School of Kinesiology, International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada
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      • Lack of transcutaneous electrical nerve stimulation (TENS) induced thermal analgesia in the absence of capsaicin-evoked sensitization.
      • Capsaicin unmasks the analgesic effect of conventional TENS on thermal sensitivity.
      • TENS analgesia is possibly caused by interactions with sensitized small-diameter fibers.
      • Extrasegmental TENS had no effect on thermal sensitivity indicating spinal effect.


      Although nonnoxious, high-frequency electrical stimulation applied segmentally (ie, conventional transcutaneous electrical nerve stimulation [TENS]) has been proposed to modulate pain, the mechanisms underlying analgesia remain poorly understood. To further elucidate how TENS modulates pain, we examined evoked responses to noxious thermal stimuli after the induction of sensitization using capsaicin in healthy volunteers. We hypothesized that sensitization caused by capsaicin application would unmask TENS analgesia, which could not be detected in the absence of sensitization. Forty-nine healthy subjects took part in a series of experiments. The experiments comprised the application of topical capsaicin (.075%) on the left hand in the C6 dermatome, varying the location of TENS (segmental, left C6 dermatome, vs extrasegmental, right shoulder), and assessing rating of perception (numeric rating scale: 0–10) and evoked potentials to noxious contact heat stimuli. The extrasegmental site was included as a control condition because previous studies indicate no analgesic effect to remote conventional TENS. Conventional TENS had no significant effect on rating or sensory evoked potentials in subjects untreated with capsaicin. However, segmental TENS applied in conjunction with capsaicin significantly reduced sensation to noxious thermal stimuli following a 60-minute period of sensitization.


      The study indicates that sensitization with capsaicin unmasks the analgesic effect of conventional TENS on perception of noxious contact heat stimuli. Our findings indicate that TENS may be interacting segmentally to modulate distinct aspects of sensitization, which in turn results in analgesia to thermal stimulation.

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        • Albu S.
        • Gomez-Soriano J.
        • Bravo-Esteban E.
        • Palazon R.
        • Kumru H.
        • Avila-Martin G.
        • Galan-Arriero I.
        • Taylor J.
        Modulation of thermal somatosensory thresholds within local and remote spinal dermatomes following cervical repetitive magnetic stimulation.
        Neurosci Lett. 2013; 555: 237-242
        • Babbar S.
        • Marier J.F.
        • Mouksassi M.S.
        • Beliveau M.
        • Vanhove G.F.
        • Chanda S.
        • Bley K.
        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
        • Baumann T.K.
        • Simone D.A.
        • Shain C.N.
        • LaMotte R.H.
        Neurogenic hyperalgesia: The search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia.
        J Neurophysiol. 1991; 66: 212-227
        • Beydoun A.
        • Dyke D.B.
        • Morrow T.J.
        • Casey K.L.
        Topical capsaicin selectively attenuates heat pain and A delta fiber-mediated laser-evoked potentials.
        Pain. 1996; 65: 189-196
        • Bromm B.
        • Chen A.C.
        Brain electrical source analysis of laser evoked potentials in response to painful trigeminal nerve stimulation.
        Electroencephalogr Clin Neurophysiol. 1995; 95: 14-26
        • Casanova-Molla J.
        • Grau-Junyent J.M.
        • Morales M.
        • Valls-Sole J.
        On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies.
        Pain. 2011; 152: 410-418
        • Chao C.C.
        • Hsieh S.C.
        • Tseng M.T.
        • Chang Y.C.
        • Hsieh S.T.
        Patterns of contact heat evoked potentials (CHEP) in neuropathy with skin denervation: Correlation of CHEP amplitude with intraepidermal nerve fiber density.
        Clin Neurophysiol. 2008; 119: 653-661
        • Cheing G.L.
        • Hui-Chan C.W.
        Analgesic effects of transcutaneous electrical nerve stimulation and interferential currents on heat pain in healthy subjects.
        J Rehabil Med. 2003; 35: 15-19
        • Chen L.
        • Tang J.
        • White P.F.
        • Sloninsky A.
        • Wender R.H.
        • Naruse R.
        • Kariger R.
        The effect of location of transcutaneous electrical nerve stimulation on postoperative opioid analgesic requirement: Acupoint versus nonacupoint stimulation.
        Anesth Analg. 1998; 87: 1129-1134
        • Chesterton L.S.
        • Barlas P.
        • Foster N.E.
        • Lundeberg T.
        • Wright C.C.
        • Baxter G.D.
        Sensory stimulation (TENS): Effects of parameter manipulation on mechanical pain thresholds in healthy human subjects.
        Pain. 2002; 99: 253-262
        • Chesterton L.S.
        • Foster N.E.
        • Wright C.C.
        • Baxter G.D.
        • Barlas P.
        Effects of TENS frequency, intensity and stimulation site parameter manipulation on pressure pain thresholds in healthy human subjects.
        Pain. 2003; 106: 73-80
        • Danziger N.
        • Rozenberg S.
        • Bourgeois P.
        • Charpentier G.
        • Willer J.C.
        Depressive effects of segmental and heterotopic application of transcutaneous electrical nerve stimulation and piezo-electric current on lower limb nociceptive flexion reflex in human subjects.
        Arch Phys Med Rehabil. 1998; 79: 191-200
        • Davis J.B.
        • Gray J.
        • Gunthorpe M.J.
        • Hatcher J.P.
        • Davey P.T.
        • Overend P.
        • Harries M.H.
        • Latcham J.
        • Clapham C.
        • Atkinson K.
        • Hughes S.A.
        • Rance K.
        • Grau E.
        • Harper A.J.
        • Pugh P.L.
        • Rogers D.C.
        • Bingham S.
        • Randall A.
        • Sheardown S.A.
        Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia.
        Nature. 2000; 405: 183-187
        • de Tommaso M.
        • Fiore P.
        • Camporeale A.
        • Guido M.
        • Libro G.
        • Losito L.
        • Megna M.
        • Puca F.
        • Megna G.
        High and low frequency transcutaneous electrical nerve stimulation inhibits nociceptive responses induced by CO2 laser stimulation in humans.
        Neurosci Lett. 2003; 342: 17-20
        • DeSantana J.M.
        • Da Silva L.F.
        • De Resende M.A.
        • Sluka K.A.
        Transcutaneous electrical nerve stimulation at both high and low frequencies activates ventrolateral periaqueductal grey to decrease mechanical hyperalgesia in arthritic rats.
        Neuroscience. 2009; 163: 1233-1241
        • Ellrich J.
        • Lamp S.
        Peripheral nerve stimulation inhibits nociceptive processing: An electrophysiological study in healthy volunteers.
        Neuromodulation. 2005; 8: 225-232
        • Fang J.Y.
        • Wu P.C.
        • Huang Y.B.
        In vivo percutaneous absorption of capsaicin, nonivamide and sodium nonivamide acetate from ointment bases: Pharmacokinetics analysis in rabbits.
        Int J Pharm. 1995; 128: 169-177
        • Faul F.
        • Erdfelder E.
        • Buchner A.
        • Lang A.G.
        Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses.
        Behav Res Methods. 2009; 41: 1149-1160
        • Faul F.
        • Erdfelder E.
        • Lang A.G.
        • Buchner A.
        G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
        Behav Res Methods. 2007; 39: 175-191
        • Fitzgerald M.
        Alterations in the ipsi- and contralateral afferent inputs of dorsal horn cells produced by capsaicin treatment of one sciatic nerve in the rat.
        Brain Res. 1982; 248: 97-107
        • Greffrath W.
        • Baumgartner U.
        • Treede R.D.
        Peripheral and central components of habituation of heat pain perception and evoked potentials in humans.
        Pain. 2007; 132: 301-311
        • Holzer P.
        Capsaicin as a tool for studying sensory neuron functions.
        Adv Exp Med Biol. 1991; 298: 3-16
        • Jin Y.H.
        • Nishioka H.
        • Wakabayashi K.
        • Fujita T.
        • Yonehara N.
        Effect of morphine on the release of excitatory amino acids in the rat hind instep: Pain is modulated by the interaction between the peripheral opioid and glutamate systems.
        Neuroscience. 2006; 138: 1329-1339
        • Kakigi R.
        • Inui K.
        • Tran D.T.
        • Qiu Y.
        • Wang X.
        • Watanabe S.
        • Hoshiyama M.
        Human brain processing and central mechanisms of pain as observed by electro- and magneto-encephalography.
        J Chin Med Assoc. 2004; 67: 377-386
        • Kakigi R.
        • Watanabe S.
        Pain relief by various kinds of interference stimulation applied to the peripheral skin in humans: Pain-related brain potentials following CO2 laser stimulation.
        J Peripher Nerv Syst. 1996; 1: 189-198
        • Kim H.Y.
        • Wang J.
        • Lee I.
        • Kim H.K.
        • Chung K.
        • Chung J.M.
        Electroacupuncture suppresses capsaicin-induced secondary hyperalgesia through an endogenous spinal opioid mechanism.
        Pain. 2009; 145: 332-340
        • Krabbenbos I.P.
        • Brandsma D.
        • van Swol C.F.
        • Boezeman E.H.
        • Tromp S.C.
        • Nijhuis H.J.
        • van Dongen E.P.
        Inhibition of cortical laser-evoked potentials by transcutaneous electrical nerve stimulation.
        Neuromodulation. 2009; 12: 141-145
        • Kramer J.K.
        • Taylor P.
        • Steeves J.D.
        • Curt A.
        Dermatomal somatosensory evoked potentials and electrical perception thresholds during recovery from cervical spinal cord injury.
        Neurorehabil Neural Repair. 2010; 24: 309-317
        • Kramer J.L.
        • Moss A.J.
        • Taylor P.
        • Curt A.
        Assessment of posterior spinal cord function with electrical perception threshold in spinal cord injury.
        J Neurotrauma. 2008; 25: 1019-1026
        • Kramer J.L.
        • Taylor P.
        • Haefeli J.
        • Blum J.
        • Zariffa J.
        • Curt A.
        • Steeves J.
        Test-retest reliability of contact heat-evoked potentials from cervical dermatomes.
        J Clin Neurophysiol. 2012; 29: 70-75
        • LaMotte R.H.
        • Lundberg L.E.
        • Torebjork H.E.
        Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin.
        J Physiol. 1992; 448: 749-764
        • Lazarou L.
        • Kitsios A.
        • Lazarou I.
        • Sikaras E.
        • Trampas A.
        Effects of intensity of transcutaneous electrical nerve stimulation (TENS) on pressure pain threshold and blood pressure in healthy humans: A randomized, double-blind, placebo-controlled trial.
        Clin J Pain. 2009; 25: 773-780
        • Leonard G.
        • Goffaux P.
        • Marchand S.
        Deciphering the role of endogenous opioids in high-frequency TENS using low and high doses of naloxone.
        Pain. 2010; 151: 215-219
        • Lu Y.
        • Pirec V.
        • Yeomans D.C.
        Differential antinociceptive effects of spinal opioids on foot withdrawal responses evoked by C fibre or A delta nociceptor activation.
        Br J Pharmacol. 1997; 121: 1210-1216
        • Lu Y.
        • Sweitzer S.M.
        • Laurito C.E.
        • Yeomans D.C.
        Differential opioid inhibition of C- and A delta-fiber mediated thermonociception after stimulation of the nucleus raphe magnus.
        Anesth Analg. 2004; 98 (table of contents): 414-419
        • Madsen C.S.
        • Johnsen B.
        • Fuglsang-Frederiksen A.
        • Jensen T.S.
        • Finnerup N.B.
        Increased contact heat pain and shortened latencies of contact heat evoked potentials following capsaicin-induced heat hyperalgesia.
        Clin Neurophysiol. 2012; 123: 1429-1436
        • Marchand S.
        • Charest J.
        • Li J.
        • Chenard J.R.
        • Lavignolle B.
        • Laurencelle L.
        Is TENS purely a placebo effect? A controlled study on chronic low back pain.
        Pain. 1993; 54: 99-106
        • Melzack R.
        • Wall P.D.
        Pain mechanisms: A new theory.
        Science. 1965; 150: 971-979
        • Palmer S.T.
        • Martin D.J.
        • Steedman W.M.
        • Ravey J.
        Effects of electric stimulation on C and A delta fiber-mediated thermal perception thresholds.
        Arch Phys Med Rehabil. 2004; 85: 119-128
        • Petersen K.L.
        • Rowbotham M.C.
        A new human experimental pain model: The heat/capsaicin sensitization model.
        Neuroreport. 1999; 10: 1511-1516
        • Ristic D.
        • Spangenberg P.
        • Ellrich J.
        Analgesic and antinociceptive effects of peripheral nerve neurostimulation in an advanced human experimental model.
        Eur J Pain. 2008; 12: 480-490
        • 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
        • Shealy C.N.
        • Mortimer J.T.
        • Hagfors N.R.
        Dorsal column electroanalgesia.
        J Neurosurg. 1970; 32: 560-564
        • Shenoy R.
        • Roberts K.
        • Papadaki A.
        • McRobbie D.
        • Timmers M.
        • Meert T.
        • Anand P.
        Functional MRI brain imaging studies using the contact heat evoked potential stimulator (CHEPS) in a human volunteer topical capsaicin pain model.
        J Pain Res. 2011; 4: 365-371
        • Simone D.A.
        • Baumann T.K.
        • LaMotte R.H.
        Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin.
        Pain. 1989; 38: 99-107
        • Simone D.A.
        • Ochoa J.
        Early and late effects of prolonged topical capsaicin on cutaneous sensibility and neurogenic vasodilatation in humans.
        Pain. 1991; 47: 285-294
        • Srbely J.Z.
        • Dickey J.P.
        • Bent L.R.
        • Lee D.
        • Lowerison M.
        Capsaicin-induced central sensitization evokes segmental increases in trigger point sensitivity in humans.
        J Pain. 2010; 11: 636-643
        • Treede R.D.
        • Kief S.
        • Holzer T.
        • Bromm B.
        Late somatosensory evoked cerebral potentials in response to cutaneous heat stimuli.
        Electroencephalogr Clin Neurophysiol. 1988; 70: 429-441
        • Treede R.D.
        • Meyer R.A.
        • Raja S.N.
        • Campbell J.N.
        Peripheral and central mechanisms of cutaneous hyperalgesia.
        Prog Neurobiol. 1992; 38: 397-421
        • Ulrich A.
        • Haefeli J.
        • Blum J.
        • Min K.
        • Curt A.
        Improved diagnosis of spinal cord disorders with contact heat evoked potentials.
        Neurology. 2013; 80: 1393-1399
        • Vassal F.
        • Creac'h C.
        • Convers P.
        • Laurent B.
        • Garcia-Larrea L.
        • Peyron R.
        Modulation of laser-evoked potentials and pain perception by transcutaneous electrical nerve stimulation (TENS): A placebo-controlled study in healthy volunteers.
        Clin Neurophysiol. 2013; 124: 1861-1867
        • Wall P.D.
        The gate control theory of pain mechanisms. A re-examination and re-statement.
        Brain. 1978; 101: 1-18
        • Warsame Afrah A.
        • Gustafsson H.
        • Olgart L.
        • Brodin E.
        • Stiller C.O.
        • Taylor B.K.
        Capsaicin-evoked substance P release in rat dorsal horn increases after peripheral inflammation: A microdialysis study.
        Neurosci Lett. 2004; 368: 226-230
        • Wasner G.
        • Naleschinski D.
        • Baron R.
        A role for peripheral afferents in the pathophysiology and treatment of at-level neuropathic pain in spinal cord injury? A case report.
        Pain. 2007; 131: 219-225
        • Winter J.
        • Bevan S.
        • Campbell E.A.
        Capsaicin and pain mechanisms.
        Br J Anaesth. 1995; 75: 157-168
        • Woolf C.J.
        • Mitchell D.
        • Barrett G.D.
        Antinociceptive effect of peripheral segmental electrical stimulation in the rat.
        Pain. 1980; 8: 237-252
        • Wydenkeller S.
        • Wirz R.
        • Halder P.
        Spinothalamic tract conduction velocity estimated using contact heat evoked potentials: What needs to be considered.
        Clin Neurophysiol. 2008; 119: 812-821
        • Yarnitsky D.
        Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): Its relevance for acute and chronic pain states.
        Curr Opin Anaesthesiol. 2010; 23: 611-615
        • Ziegler E.A.
        • Magerl W.
        • Meyer R.A.
        • Treede R.D.
        Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input.
        Brain. 1999; 122: 2245-2257