The Non–neuronal and Nonmuscular Effects of Botulinum Toxin

An Opportunity for a Deadly Molecule to Treat Disease in the Skin and Beyond

S.A. Grando; C.B. Zachary

Disclosures

The British Journal of Dermatology. 2018;178(5):1011-1019. 

In This Article

Clinical Applications of Botulinum Neurotoxins

Botulinum Neurotoxin Products

The BoNT types A and B have been used therapeutically in various medical conditions for muscle relaxation, and more recently for their analgesic and cosmetic effects. The conditions approved for treatment with BoNT are cervical dystonia, blepharospasm, severe primary axillary hyperhidrosis, chronic migraine and strabismus. The global market for BoNT products, driven by their cosmetic applications, is rapidly growing with estimated annual sales in excess of 5–6 billion U.S. dollars.[26] In the global market, BoNT/A is sold as: Botox (onabotulinumtoxinA) by Allergan (Irvine, CA, U.S.A.); Dysport (abobotulinumtoxinA) by Ipsen Ltd (Slough, U.K.) and Galderma Laboratories (Fort Worth, TX, U.S.A.); Puretox by Mentor Corporation (Santa Barbara, CA, U.S.A.); Evosyal by Alphaeon (Irvine, CA, U.S.A.); Linurase by Prollenium (Aurora, Canada); and Xeomin (incobotulinumtoxinA) by Merz Pharmaceuticals (Frankfurt, Germany). BoNT/B is sold as Myobloc (rimabotulinumtoxinB) by Solstice Neurosciences (Malvern, PA, U.S.A.). In addition, there are several BoNT/A products marketed as: Siax (Neuronox) by Medy–Tox (Seoul, South Korea); Botulax by Hugel, and Nabota (DWP–450) by Daewoong (Seoul, South Korea); Lantox (Prosigne) by the Lanzhou Institute of Biological Products (Lanzhou, China); and Relatox by Mikrogen (Moscow, Russia). Several products, such as ANT–1207 (Anterios/Allergan), CosmeTox (Transdermal Corporation, Birmingham, MI, U.S.A.) and RT001 (Revance, Newark, CA, U.S.A.), have been developed for topical delivery of BoNT.[27,28] Each commercially available product has its toxin complexed with a varied quantity of unique proteins, and its activity has been determined using the assay specific to each manufacturer. These differences complicate an adequate comparison of clinical responses to similar products.[29]

Nontraditional Applications of Botulinum Neurotoxins in Various Nondermatological Conditions

BoNT/A has been used to treat certain neurological, musculoskeletal, ophthalmological, upper aerodigestive, gastrointestinal, urological and gynaecological disorders, including the following conditions: torticollis, dystonic tics/Tourette syndrome, spasticity related to stroke, essential tremor, Bell palsy, deformities related to cerebral palsy, cervical dystonia, upper and lower limb spasticity, chronic migraine, neuropathic pain (trigeminal and diabetic neuralgia), postherpetic neuralgia, head and neck cancer survivors with neck contractures following radiosurgical therapy, occupational cramping (i.e. writer's cramp), Parkinson disease, myofascial pain syndrome, ischaemic digits, movement disorders associated with injury, multiple sclerosis, focal dystonias affecting the limbs, face, jaw and vocal cords, and other vocal cord dysfunction, strabismus, hemifacial spasm, blepharospasm, corneal astigmatism, tear–film conditions, nystagmus, oscillopsia, benign eyelid fasciculation, chronic anal fissures, diffuse oesophageal spasm, oesophageal achalasia not amenable to surgery, anorectal outlet obstruction, rectal spasms, refractory gastroparesis, laryngeal dystonia, oromandibular dystonia, bruxism, cricopharyngeal spasm, stuttering, hot flashes, obesity (by increasing the gastric emptying time), overactive bladder, neurogenic detrusor overactivity with spinal cord injury and multiple sclerosis, benign prostatic hyperplasia, bladder pain syndrome, provoked vestibulodynia, pelvic floor spasm, vaginismus, urinary incontinence owing to detrusor sphincter dyssynergia, benign prostatic hyperplasia, gastric cancer and allergic rhinitis (reviewed in Giordano et al.,[2] Wollina[30] and https://en.wikipedia.org/wiki/Botulinum_toxin). Of particular interest is the use of BoNT to treat patients with major depressive disorder (MDD). Recent studies consistently showed significant reduction in depressive symptoms with BoNT/A injected into the glabellar muscles, indicating that this may be a safe and sustainable intervention in the treatment of MDD.[31–33]

Nontraditional Applications of Botulinum Neurotoxins in Dermatological Conditions (Table 1)

In cosmetic dermatology, BoNTs have been traditionally used for facial muscle relaxation and to improve cutaneous elasticity, pliability and viscoelastic properties, in addition to the organization and orientation of collagen fibres of facial skin.[34] Aside from cosmetic indications, i.e. when treatment is intended to restore or improve a person's appearance, BoNTs have been used for various noncosmetic dermatological indications. Recent studies have demonstrated that BoNT/A affects not only skin texture but also sebum production leading to local skin dryness at the injection site,[35,36] which is in keeping with the experimental finding of reduced amounts of sebaceous cells and hair follicles in skin grafts of Wistar rats injected with BoNT/A.[37] Two female patients and one male patient with severe cystic acne were reported to have achieved a complete resolution of acne following intracutaneous injections of 2·5 U aliquots of botulinum toxin A spaced approximately 1·5 cm apart from one another.[38] Although the number of patients tested was small, all had recalcitrant acne that had not responded to conventional treatment. More recently, a double–blind, placebo–controlled, split–face study with 20 volunteers demonstrated that botulinum toxin effectively reduced sebum production and pore size in the oily skin group, but had no effect in the dry–to–normal skin group.[39] Interestingly, intramuscular injection of BoNT/A significantly reduced sebum production at the injection site but increased the sebum production of the surrounding skin at a radius of 2·5 cm.[40]

BoNT/A is used in different dermatological conditions associated with hyperhidrosis, including pompholyx, dyshidrosis, chromhidrosis and bromhidrosis, hidradenitis suppurativa and Frey syndrome, in addition to skin diseases worsened by hyperhidrosis, such as Hailey–Hailey disease, Darier disease, inverse psoriasis, aquagenic palmoplantar keratoderma, pachyonychia congenita (reviewed in Wollina, Messikh et al. and Campanati et al.).[30,41,42] BoNT/A showed efficacy in various eccrine gland abnormalities, such as multiple eccrine hydrocystomas,[43] eccrine angiomatous hamartoma,[44] eccrine sweat gland naevi and congenital eccrine naevus,[45,46] and as a vasodilator in treating Raynaud phenomenon.[47] BoNT/A improved the quality of life and alleviated pain in patients with painful cutaneous leiomyomas.[48] It was proposed that other painful cutaneous conditions with and without neurological involvements, such as anal fissures, leg ulcers, lichen simplex, postherpetic neuralgia and notalgia paraesthetica, might benefit from BoNT therapy.[41] BoNT/A has also shown therapeutic activity in patients with linear IgA bullous dermatosis,[49] lichen simplex,[50] alopecia areata,[51] androgenetic alopecia,[52] facial erythema and flushing (reviewed in Campanati et al.)[42] and various forms of itch in human skin (Table 1).[53–55]

A search of the ClinicalTrials.gov website, (a registry/results database of publicly and privately supported clinical trials conducted around the world), revealed the following studies concerning botulinum toxin in the following dermatological conditions: alopecia areata (NCT00999869, NCT00408798); recalcitrant alopecia totalis and alopecia universalis (NCT00997815); postexcisional scarring (NCT02623829); forehead scars following Mohs micrographic surgery and reconstruction for skin cancer (NCT01459666); itching from hypertrophic scars (NCT02168634); psoriasis (NCT00816517, NCT02577185); scleroderma–associated Raynaud syndrome (NCT02165111); localized vitiligo (NCT01051687); cutaneous leiomyomas (NCT00971620); herpes labialis (NCT01225341); acne (NCT00765375, NCT01293552); epidermolysis bullosa simplex and pachyonychia congenita (NCT00936533); Hailey–Hailey disease and Darier disease (NCT02782702); and for the itch–relieving effect of BoNT/A in healthy subjects (NCT02639052). On the other hand, several undesirable effects from BoNT/A injections have been reported, including vasculitis with panniculitis,[56] thrombosis of subcutaneous anterior chest veins (Mondor disease),[57] and cutaneous granulomatous reaction, possibly associated with cutaneous sarcoidosis.[58]

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