Botulinum Toxin Type A Reduces Histamine-induced Itch and Vasomotor Responses in Human Skin
Botulinum Toxin Type A Reduces Histamine-induced Itch and Vasomotor Responses in Human Skin
Background Clinical evidence has revealed the antipruritic effect of botulinum toxin type A (BoNT/A). BoNT/A is believed to be effective against itch as it inhibits the release of acetylcholine as well as some other substances that may be involved in itch.
Objectives To investigate the effect of subcutaneous administration of BoNT/A on experimentally histamine-induced itch in human skin.
Methods In this double-blind, placebo-controlled study, 14 healthy men (mean ± SD age 26·3 ± 2·6 years) received BoNT/A (Botox®; Allergan, Irvine, CA, U.S.A.; 5 U) and isotonic saline on the volar surface of either forearm. Histamine prick tests were performed four times at the treatment sites (before treatment, and days 1, 3 and 7 after treatment). The itch intensity (as rated on a 0–10 visual analogue scale), itch area, neurogenic inflammation (visible flare area), blood flow (laser Doppler) and cutaneous temperature (thermographic images) were measured over the course of the trials.
Results BoNT/A reduced the histamine-induced itch intensity (F1,39 = 30·2, P < 0·001) and itch area (F1,39 = 8·8, P = 0·011) compared with saline at all time points after treatment. The duration of itch was also shorter for BoNT/A-treated areas (F1,39 = 19·4, P < 0·001), with a peak effect at day 7. The flare area was smaller in the BoNT/A-treated arm compared with the saline-treated arm at all time points after treatment (F1,39 = 15·4, P = 0·002). Findings from blood flow (F1,26 = 177·3, P < 0·001) and temperature measurements (F1,26 = 27·6, P < 0·001) clearly showed the suppressive effect of BoNT/A on vasomotor reactions, with the maximal effect on days 3 and 7.
Conclusions BoNT/A reduced the itch intensity, blood flow and neurogenic inflammation in response to the histamine prick test in human skin. The findings could be applicable in the treatment of some pruritic conditions that can be difficult to treat with conventional treatments.
Itch (pruritus), an unpleasant sensation which evokes the desire to scratch, is a dominant symptom of many skin diseases (e.g. atopic dermatitis). It also occurs in some systemic disorders such as renal and liver failure. Chronic itch conditions are common and have a significant impact on patients' quality of life and healthcare costs. Such conditions are difficult to manage, and available treatments are only partly effective, with unwanted side-effects.
Many endogenous substances are considered to be mediators of itch, e.g. amines such as histamine, proteases, opioids, lipid peroxidation metabolites such as prostaglandins or leukotrienes, neuropeptides such as substance P, cytokines, and growth factors such as nerve growth factor. These agents may directly stimulate/sensitize the itch either by mediating sensory nerve endings (a subset of specialized C-fibres in human skin) or by acting on mast cells.
Experimentally, the itch sensation can be evoked chemically, electrically and psychologically. Substances such as histamine are known to induce chemical pruritus. Histamine has been used in experimental models of pruritus in humans and in animals. As histamine is unable to penetrate the intact skin barrier, it is applied by intracutaneous injection, iontophoresis or the skin prick test. The latter method delivers histamine to the dermoepidermal junction of the skin, and induces a pure and reproducible itch sensation. It has recently been shown that histamine-induced excitation of sensory neurones and activation of proteinase-activated receptors such as PAR-2 involves the activation/sensitization of transient receptor potential vanilloid (TRPV) 1.
In the light of new insights into the neurophysiology of pruritus, novel treatments are being identified. For instance, botulinum toxin type A (BoNT/A), which is a clostridial neurotoxin, has been used to treat a variety of disorders, including dermatological conditions such as hyperhidrosis. Several studies have shown that BoNT/A has an antipruritic effect. For instance, subcutaneous BoNT/A improved hand eczema and dermatitis with related itch scores, lichen simplex characterized by intense localized pruritus, and also rhinitis accompanied by itching. Successful treatments of notalgia paraesthetica, inverse psoriasis and acne have also been reported. The rationale for the use of BoNT/A against itch is the discovery that acetylcholine mediates itch in atopic dermatitis, and the fact that BoNT/A inhibits the release of acetylcholine from presynaptic vesicles. BoNT/A also inhibits the release of some other substances such as substance P and glutamate, which may be involved in pruritus.
The aim of the present study was to investigate the antipruritic effect of BoNT/A in a human itch model, addressing whether subcutaneous administration of BoNT/A reduces histamine-induced itch and neurogenic inflammation assessed by itch ratings, visible flare, laser Doppler and thermography. Findings from the present study shed light on the efficacy, safety and underlying mechanisms of BoNT/A, which are relevant for the development of treatments for pruritic conditions.
Abstract and Introduction
Abstract
Background Clinical evidence has revealed the antipruritic effect of botulinum toxin type A (BoNT/A). BoNT/A is believed to be effective against itch as it inhibits the release of acetylcholine as well as some other substances that may be involved in itch.
Objectives To investigate the effect of subcutaneous administration of BoNT/A on experimentally histamine-induced itch in human skin.
Methods In this double-blind, placebo-controlled study, 14 healthy men (mean ± SD age 26·3 ± 2·6 years) received BoNT/A (Botox®; Allergan, Irvine, CA, U.S.A.; 5 U) and isotonic saline on the volar surface of either forearm. Histamine prick tests were performed four times at the treatment sites (before treatment, and days 1, 3 and 7 after treatment). The itch intensity (as rated on a 0–10 visual analogue scale), itch area, neurogenic inflammation (visible flare area), blood flow (laser Doppler) and cutaneous temperature (thermographic images) were measured over the course of the trials.
Results BoNT/A reduced the histamine-induced itch intensity (F1,39 = 30·2, P < 0·001) and itch area (F1,39 = 8·8, P = 0·011) compared with saline at all time points after treatment. The duration of itch was also shorter for BoNT/A-treated areas (F1,39 = 19·4, P < 0·001), with a peak effect at day 7. The flare area was smaller in the BoNT/A-treated arm compared with the saline-treated arm at all time points after treatment (F1,39 = 15·4, P = 0·002). Findings from blood flow (F1,26 = 177·3, P < 0·001) and temperature measurements (F1,26 = 27·6, P < 0·001) clearly showed the suppressive effect of BoNT/A on vasomotor reactions, with the maximal effect on days 3 and 7.
Conclusions BoNT/A reduced the itch intensity, blood flow and neurogenic inflammation in response to the histamine prick test in human skin. The findings could be applicable in the treatment of some pruritic conditions that can be difficult to treat with conventional treatments.
Introduction
Itch (pruritus), an unpleasant sensation which evokes the desire to scratch, is a dominant symptom of many skin diseases (e.g. atopic dermatitis). It also occurs in some systemic disorders such as renal and liver failure. Chronic itch conditions are common and have a significant impact on patients' quality of life and healthcare costs. Such conditions are difficult to manage, and available treatments are only partly effective, with unwanted side-effects.
Many endogenous substances are considered to be mediators of itch, e.g. amines such as histamine, proteases, opioids, lipid peroxidation metabolites such as prostaglandins or leukotrienes, neuropeptides such as substance P, cytokines, and growth factors such as nerve growth factor. These agents may directly stimulate/sensitize the itch either by mediating sensory nerve endings (a subset of specialized C-fibres in human skin) or by acting on mast cells.
Experimentally, the itch sensation can be evoked chemically, electrically and psychologically. Substances such as histamine are known to induce chemical pruritus. Histamine has been used in experimental models of pruritus in humans and in animals. As histamine is unable to penetrate the intact skin barrier, it is applied by intracutaneous injection, iontophoresis or the skin prick test. The latter method delivers histamine to the dermoepidermal junction of the skin, and induces a pure and reproducible itch sensation. It has recently been shown that histamine-induced excitation of sensory neurones and activation of proteinase-activated receptors such as PAR-2 involves the activation/sensitization of transient receptor potential vanilloid (TRPV) 1.
In the light of new insights into the neurophysiology of pruritus, novel treatments are being identified. For instance, botulinum toxin type A (BoNT/A), which is a clostridial neurotoxin, has been used to treat a variety of disorders, including dermatological conditions such as hyperhidrosis. Several studies have shown that BoNT/A has an antipruritic effect. For instance, subcutaneous BoNT/A improved hand eczema and dermatitis with related itch scores, lichen simplex characterized by intense localized pruritus, and also rhinitis accompanied by itching. Successful treatments of notalgia paraesthetica, inverse psoriasis and acne have also been reported. The rationale for the use of BoNT/A against itch is the discovery that acetylcholine mediates itch in atopic dermatitis, and the fact that BoNT/A inhibits the release of acetylcholine from presynaptic vesicles. BoNT/A also inhibits the release of some other substances such as substance P and glutamate, which may be involved in pruritus.
The aim of the present study was to investigate the antipruritic effect of BoNT/A in a human itch model, addressing whether subcutaneous administration of BoNT/A reduces histamine-induced itch and neurogenic inflammation assessed by itch ratings, visible flare, laser Doppler and thermography. Findings from the present study shed light on the efficacy, safety and underlying mechanisms of BoNT/A, which are relevant for the development of treatments for pruritic conditions.
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