Prolonged Antipruritic Effect of Botulinum Toxin Type A on Cowhage-induced Itch: A Randomized, Single-blind, Placebo-controlled Trial

Authors

  • Leigh A. Nattkemper Department of Dermatology, Miami Itch Center, University of Miami Miller School of Medicine, Miami, FL, USA
  • Ashley Vander Does Department of Dermatology, Miami Itch Center, University of Miami Miller School of Medicine, Miami, FL, USA
  • Carolyn M. Stull Department of Dermatology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
  • Michael J. Lavery Department of Dermatology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
  • Rodrigo Valdes-Rodriguez Department of Dermatology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
  • Marlene McGregory Department of Dermatology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
  • Yiong Huak Chan Biostatistics Unit, National University of Singapore Lon Lin School of Medicine, Singapore, Singapore
  • Gil Yosipovitch Department of Dermatology, Miami Itch Center, University of Miami Miller School of Medicine, Miami, FL, USA

DOI:

https://doi.org/10.2340/actadv.v103.6581

Keywords:

antipruritic, itch, cowhage, botulinum toxin

Abstract

Botulinum toxin type A (Botox®) is thought to have antipruritic effects through inhibition of pruritic factors, including acetylcholine, substance P, and glutamate. The aim of this randomized, single-blind, placebo-controlled trial was to test the effect of botulinum toxin type A on cowhage, a non-histaminergic model for chronic itch. Botulinum toxin type A was injected into the arm of 35 healthy subjects, with a saline control injected into the contralateral arm. Thermal sensory parameters (warmth and heat thresholds and heat pain intensity) and itch intensity after cowhage application were examined on test areas. Botulinum toxin type A reduced itch intensity, overall perceived itch (area under the curve (AUC); percentage change from baseline), and peak itch intensity compared with the control at 1 week, 1 month, and 3 months. Botulinum toxin type A had no effect on thermal thresholds or heat pain intensity. In conclusion, botulinum toxin type A reduced cowhage itch for at least 3 months, which suggests that botulinum toxin type A is a potential long-lasting treatment for localized, non-histaminergic itch.

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References

Yosipovitch G, Bernhard JD. Clinical practice. Chronic pruritus. N Engl J Med 2013; 368: 1625-1634.

https://doi.org/10.1056/NEJMcp1208814 DOI: https://doi.org/10.1056/NEJMcp1208814

Swartling C, Naver H, Lindberg M, Anveden I. Treatment of dyshidrotic hand dermatitis with intra-dermal botulinum toxin. J Am Acad Dermatol 2002; 47: 667-671.

https://doi.org/10.1067/mjd.2002.124605 DOI: https://doi.org/10.1067/mjd.2002.124605

Heckmann M, Heyer G, Brunner B, Plewig G. Botulinum toxin type A injection in the treatment of lichen simplex: an open pilot study. J Am Acad Dermatol 2002; 46: 617-619.

https://doi.org/10.1067/mjd.2002.120455 DOI: https://doi.org/10.1067/mjd.2002.120455

Zanchi M, Favot F, Bizzarini M, Piai M, Donini M, Sedona P. Botulinum toxin type-A for the treat-ment of inverse psoriasis. J Eur Acad Dermatol Venereol 2008; 22: 431-436.

https://doi.org/10.1111/j.1468-3083.2007.02457.x DOI: https://doi.org/10.1111/j.1468-3083.2007.02457.x

Wollina U, Karamfilov T. Adjuvant botulinum toxin A in dyshidrotic hand eczema: a controlled prospective pilot study with left-right comparison. J Eur Acad Dermatol Venereol 2002; 16: 40-42.

https://doi.org/10.1046/j.1468-3083.2002.00361.x DOI: https://doi.org/10.1046/j.1468-3083.2002.00361.x

Gharib K, Mostafa A, Elsayed A. Evaluation of botulinum toxin type A injection in the treatment of localized chronic pruritus. J Clin Aesthet Dermatol 2020; 13: 12-17.

Khattab FM. Evaluation of botulinum toxin A as an optional treatment for atopic dermatitis. J Clin Aesthet Dermatol 2020; 13: 32-35.

Weinfeld PK. Successful treatment of notalgia paresthetica with botulinum toxin type A. Arch Dermatol 2007; 143: 980-982.

https://doi.org/10.1001/archderm.143.8.980 DOI: https://doi.org/10.1001/archderm.143.8.980

Datta S, Mahal S, Bhagavan SM, Govindarajan R. Use of botulinum toxin type A in a patient with refractory itch from notalgia paresthetica. J Clin Neuromuscul Dis 2020; 21: 243-244.

https://doi.org/10.1097/CND.0000000000000276 DOI: https://doi.org/10.1097/CND.0000000000000276

Gazerani P, Pedersen NS, Drewes AM, Arendt-Nielsen L. Botulinum toxin type A reduces hista-mine-induced itch and vasomotor responses in human skin. Br J Dermatol 2009; 161: 737-745.

https://doi.org/10.1111/j.1365-2133.2009.09305.x DOI: https://doi.org/10.1111/j.1365-2133.2009.09305.x

Boozalis E, Sheu M, Selph J, Kwatra SG. Botulinum toxin type A for the treatment of localized recalcitrant chronic pruritus. J Am Acad Dermatol 2018; 78: 192-194.

https://doi.org/10.1016/j.jaad.2017.08.001 DOI: https://doi.org/10.1016/j.jaad.2017.08.001

Gazerani P. Antipruritic effects of botulinum neurotoxins. Toxins (Basel) 2018; 10: 143.

https://doi.org/10.3390/toxins10040143 DOI: https://doi.org/10.3390/toxins10040143

Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum toxin. J Am Acad Dermatol 2000; 43: 249-259.

https://doi.org/10.1067/mjd.2000.105567 DOI: https://doi.org/10.1067/mjd.2000.105567

Heyer GR, Hornstein OP. Recent studies of cutaneous nociception in atopic and non-atopic subjects. J Dermatol 1999; 26: 77-86.

https://doi.org/10.1111/j.1346-8138.1999.tb03516.x DOI: https://doi.org/10.1111/j.1346-8138.1999.tb03516.x

Wessler I, Reinheimer T, Kilbinger H, Bittinger F, Kirkpatrick CJ, Saloga J, Knop J. Increased acetylcholine levels in skin biopsies of patients with atopic dermatitis. Life Sci 2003; 72: 2169-2172.

https://doi.org/10.1016/S0024-3205(03)00079-1 DOI: https://doi.org/10.1016/S0024-3205(03)00079-1

Heyer G, Vogelgsang M, Hornstein OP. Acetylcholine is an inducer of itching in patients with atopic eczema. J Dermatol 1997; 24: 621-625.

https://doi.org/10.1111/j.1346-8138.1997.tb02305.x DOI: https://doi.org/10.1111/j.1346-8138.1997.tb02305.x

Kim DW, Lee SK, Ahnn J. Botulinum toxin as a pain killer: players and actions in antinociception. Toxins (Basel) 2015; 7: 2435-2453.

https://doi.org/10.3390/toxins7072435 DOI: https://doi.org/10.3390/toxins7072435

Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon 2000; 38: 245-258.

https://doi.org/10.1016/S0041-0101(99)00153-1 DOI: https://doi.org/10.1016/S0041-0101(99)00153-1

Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trige-minal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache 2004; 44: 35-43.

https://doi.org/10.1111/j.1526-4610.2004.04007.x DOI: https://doi.org/10.1111/j.1526-4610.2004.04007.x

Ishikawa H, Mitsui Y, Yoshitomi T, Mashimo K, Aoki S, Mukuno K, Shimizu K. Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino and pigmented rabbit iris sphincter and dilator muscles. Jpn J Ophthalmol 2000; 44: 106-109.

https://doi.org/10.1016/S0021-5155(99)00197-5 DOI: https://doi.org/10.1016/S0021-5155(99)00197-5

Apostolidis A, Popat R, Yiangou Y, Cockayne D, Ford AP, Davis JB, et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol 2005; 174: 977-983.

https://doi.org/10.1097/01.ju.0000169481.42259.54 DOI: https://doi.org/10.1097/01.ju.0000169481.42259.54

Cao LF, Si M, Huang Y, Chen LH, Peng XY, Qin YQ, et al. Long-term anti-itch effect of botulinum neurotoxin A is associated with downregulation of TRPV1 and TRPA1 in the dorsal root ganglia in mice. Neuroreport 2017; 28: 518-526.

https://doi.org/10.1097/WNR.0000000000000779 DOI: https://doi.org/10.1097/WNR.0000000000000779

Huang SH, Wu KW, Lo JJ, Wu SH. Synergic effect of botulinum toxin type A and triamcinolone alleviates scar pruritus by modulating epidermal hyperinnervation: a preliminary report. Aesthet Surg J 2021; 41: NP1721-NP1731.

https://doi.org/10.1093/asj/sjab105 DOI: https://doi.org/10.1093/asj/sjab105

Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer G, Skov PS, et al. Proteinase-activated re-ceptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 2003; 23: 6176-6180.

https://doi.org/10.1523/JNEUROSCI.23-15-06176.2003 DOI: https://doi.org/10.1523/JNEUROSCI.23-15-06176.2003

Papoiu AD, Tey HL, Coghill RC, Wang H, Yosipovitch G. Cowhage-induced itch as an experi-mental model for pruritus. A comparative study with histamine-induced itch. PLoS One 2011; 6: e17786.

https://doi.org/10.1371/journal.pone.0017786 DOI: https://doi.org/10.1371/journal.pone.0017786

Papoiu AD, Chaudhry H, Hayes EC, Chan YH, Herbst KD. TriCalm® hydrogel is significantly superior to 2% diphenhydramine and 1% hydrocortisone in reducing the peak intensity, duration, and overall magnitude of cowhage-induced itch. Clin Cosmet Investig Dermatol 2015; 8: 223-229.

https://doi.org/10.2147/CCID.S78809 DOI: https://doi.org/10.2147/CCID.S78809

Papoiu AD, Kraft RA, Coghill RC, Yosipovitch G. Butorphanol suppression of histamine itch is mediated by nucleus accumbens and septal nuclei: a pharmacological fMRI study. J Invest Der-matol 2015; 135: 560-568.

https://doi.org/10.1038/jid.2014.398 DOI: https://doi.org/10.1038/jid.2014.398

Nattkemper LA, Zhi K, Romero KE, Shah SM, Ju T, Fourzali K, et al. Antipruritic effect of topical acetaminophen gel in histaminergic and non-histaminergic itch provocation: a double-blind, ve-hicle-controlled pilot study. Acta Derm Venereol 2022; 102: adv00640.

https://doi.org/10.2340/00015555-3910 DOI: https://doi.org/10.2340/00015555-3910

Abadía Molina F, Burrows NP, Jones RR, Terenghi G, Polak JM. Increased sensory neuropepti-des in nodular prurigo: a quantitative immunohistochemical analysis. Br J Dermatol 1992; 127: 344-351.

https://doi.org/10.1111/j.1365-2133.1992.tb00452.x DOI: https://doi.org/10.1111/j.1365-2133.1992.tb00452.x

Jarvikallio A, Harvima IT, Naukkarinen A. Mast cells, nerves and neuropeptides in atopic derma-titis and nummular eczema. Arch Dermatol Res 2003; 295: 2-7.

https://doi.org/10.1007/s00403-002-0378-z DOI: https://doi.org/10.1007/s00403-002-0378-z

Salomon J, Baran E. The role of selected neuropeptides in pathogenesis of atopic dermatitis. J Eur Acad Dermatol Venereol 2008; 22: 223-228.

Azimi E, Reddy VB, Pereira PJS, Talbot S, Woolf CJ, Lerner EA. Substance P activates Mas-related G protein-coupled receptors to induce itch. J Allergy Clin Immunol 2017; 140: 447-453.e3.

https://doi.org/10.1016/j.jaci.2016.12.980 DOI: https://doi.org/10.1016/j.jaci.2016.12.980

Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong X, Bautista DM. TRPA1 is requi-red for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neu-rosci 2011; 14: 595-602.

https://doi.org/10.1038/nn.2789 DOI: https://doi.org/10.1038/nn.2789

Wilson SR, Nelson AM, Batia L, Morita T, Estandian D, Owens DM, et al. The ion channel TRPA1 is required for chronic itch. J Neurosci 2013; 33: 9283-9294.

https://doi.org/10.1523/JNEUROSCI.5318-12.2013 DOI: https://doi.org/10.1523/JNEUROSCI.5318-12.2013

Ramachandran R, Marino MJ, Paul S, Wang Z, Mascarenhas NL, Pellett S, et al. A study and review of effects of botulinum toxins on mast cell dependent and independent pruritus. Toxins (Basel) 2018; 10: 134.

https://doi.org/10.3390/toxins10040134 DOI: https://doi.org/10.3390/toxins10040134

Matak I, Tékus V, Bölcskei K, Lacković Z, Helyes Z. Involvement of substance P in the antinoci-ceptive effect of botulinum toxin type A: Evidence from knockout mice. Neuroscience 2017; 358: 137-145.

https://doi.org/10.1016/j.neuroscience.2017.06.040 DOI: https://doi.org/10.1016/j.neuroscience.2017.06.040

Oh HM, Chung ME. Botulinum toxin for neuropathic pain: a review of the literature. Toxins (Basel) 2015; 7: 3127-3154.

https://doi.org/10.3390/toxins7083127 DOI: https://doi.org/10.3390/toxins7083127

Additional Files

Published

2023-08-16

How to Cite

Nattkemper, L. A., Vander Does, A., Stull, C. M., Lavery, M. J., Valdes-Rodriguez, R., McGregory, M., … Yosipovitch, G. (2023). Prolonged Antipruritic Effect of Botulinum Toxin Type A on Cowhage-induced Itch: A Randomized, Single-blind, Placebo-controlled Trial. Acta Dermato-Venereologica, 103, adv6581. https://doi.org/10.2340/actadv.v103.6581