Contagious itch in humans: a study of visual 'transmission' of itch in atopic dermatitis and healthy subjects

Background Anecdotal evidence suggests that ‘contagious’ itch occurs in daily life when we see other people itch and scratch. This phenomenon has not previously been studied systematically, and factors which can amplify itch perception were unknown. Objectives We investigated whether exposure to visual cues of itch can induce or intensify itch in healthy subjects and patients with atopic dermatitis (AD). Methods Participants received histamine or a saline control delivered to the forearm and were asked to watch short video clips of people scratching. Spontaneous scratching induced by visual cues was monitored and analysed. Results Patients with AD reported a higher itch intensity and scratched more frequently while watching itch videos, even in the presence of mock itch stimuli. Conclusions Human susceptibility to develop itch when exposed to visual cues is confirmed; it appears to be amplified in patients with AD. These findings suggest that interpersonal social cues can dramatically alter the subjective sensory experience of itch.     

Itch and brain

Itch is an unpleasant somatic sensation that evokes the urge to scratch. Chronic itch is a severe problem that diminishes quality of life. There are many patients suffering from chronic itch across the world. The brain is the final terminal to receive itch‐related signals from the body and plays an important role in perceiving the itch sensation. Thus, to understand the cerebral mechanism of itch perception and how this mechanism differs between healthy subjects and chronic itch patients is important for advancing our understanding on the pathophysiology of chronic itch. Itch is suppressed by scratching or applying painful stimuli. The pleasurable sensation evoked by scratching an itch increases the urge to scratch. Viewing others in itch or imagining the itch sensation may evoke real itch sensations and the scratching response. To understand the mechanisms responsible for these phenomena may provide useful information for the development of treatment of itch and advance our understanding of the cerebral mechanism of itch and scratch. Several functional brain imaging studies have addressed these issues and reported interesting findings. In this review article, the authors discussed the findings of previous studies and how they have advanced our understanding of the central mechanisms of itch, scratch and chronic itch.     

Repetitive scratching and noxious heat do not inhibit histamine-induced itch in atopic dermatitis

BACKGROUND: Repetitive scratching is the most common behavioural response to itch in atopic dermatitis (AD). Patients with chronic itch often report that very hot showers inhibit itch. We recently reported that scratching and noxious heat stimuli inhibit histamine-induced itch in healthy subjects. However, no psychophysical studies have been performed in AD to assess the effects of repetitive heat pain stimuli and scratching on histamine-induced itch. OBJECTIVES: To examine the effects of repetitive noxious heat and scratching on itch intensity in patients with AD using quantitative sensory testing devices. METHODS: Itch was induced with histamine iontophoresis in 16 patients with AD in both lesional and nonlesional skin as well as in 10 healthy subjects. Repetitive noxious heat and scratching were applied 3 cm distal to the area of histamine iontophoresis. Subjects rated their perceived intensity of histamine-induced itch with a computerized visual analogue scale. RESULTS: Our results demonstrate that repetitive noxious heat and scratching do not inhibit itch intensity in lesional and nonlesional AD skin but do so in healthy skin. Of note, both these stimuli increase itch intensity in lesional AD skin. CONCLUSIONS: Our results strongly suggest that scratching and noxious thermal stimuli have a different effect upon histamine-induced itch perception in patients with AD when compared with healthy controls. This difference may be associated with both peripheral and central sensitization of nerve fibres in AD.     

Addiction and the itch‐scratch cycle. What do they have in common?

Itch is a multidimensional experience involving various brain regions associated with sensory perception and emotion, as well as an urge to scratch employing the motor system. Scratch temporarily relieves itch sensation in healthy subjects. However, in patients with chronic itch, rather than inhibit, scratch may aggravate itch. Patients with chronic itch, such as those with atopic dermatitis, experience severe itch and a strong desire to scratch. This urge to scratch is the driving force underlying the formation of the itch‐scratch‐cycle, an addictive and vicious cycle in chronic itch patients. This vicious itch‐scratch behaviour and various types of addiction (henceforth, including recreational drug use) were shown to share common sensory mechanisms. Abnormalities have been observed in central neural circuits, including the reward, motivation/drive, control and learning/memory circuits, as well as other brain systems. Reward systems, including the ventral tegmental area (VTA), nucleus accumbens (NAc) and striatum, are important for brain processing of both addiction and itch. In addition to reward, addicted individuals can experience severe disruptions in motor control, cognitive awareness, executive function, learning/memory and even emotional functions. Findings showing that addiction and itch share a common neurobiological foundation could have important mechanistic and therapeutic implications. Here we propose that similar neuroadaptations exist in addiction and chronic itch patients.     

The positive effects of habit reversal treatment of scratching in children with atopic dermatitis: a randomized controlled study

Itching is a main symptom signs of eczema, including the type called atopic dermatitis which is common in children. People often scratch their skin in response to the itching but this only gives temporary relief, and scratching may cause skin damage and infections. Studies of adult patients have shown that reducing scratching can lead to less inflammation and improved healing of the skin, so ways of reducing scratching can be of benefit to eczema patients. Scientists have discovered that the early relief of the itch by scratching serves to reinforce the behaviour, which becomes habitual or compulsive. After a while, scratching behaviour becomes involuntary and automatic. This means that a significant amount of scratching has become a habit, and not necessarily directly in response to itching. One way of reducing this type of habitual scratching in adults is called habit reversal treatment, and this study looked at whether habit reversal, adapted for parents and their children, in combination with a potent steroid cream (which is a normal treatment for eczema), would offer a better outcome in the treatment of scratching and eczema in children compared to the steroid alone. The primary outcome, meaning how they measured the treatment success, was a scoring system called SCORAD that looks at the eczema's severity, the secondary outcome was CDLQI score, which is a questionnaire looking at quality of life (with lower scores indicating less negative impact on quality of life). The treatment of scratching with the HR method in combination with a potent steroid was found to significantly improve both SCORAD and CDLQI after 3 and 11 weeks.     

Histamine release by scratching inflamed skin

Scratching is an exacerbating factor of skin diseases. Plasma histamine level was assessed before and after scratching with a scratch device. Inflamed skin of patients with atopic dermatitis released slight but significant amounts of histamine by scratching, but healthy skin was not affected by scratching.     

The development of an objective method for measuring scratch in children with atopic dermatitis suitable for clinical use

Itch is a major symptom of skin disease and remains poorly studied. We have used limb-worn digital accelerometers, and infrared video of patients as a gold standard, on children with atopic dermatitis and control subjects in their own homes at night. Video analysis shows that nocturnal scratching and restlessness are more complex than we first thought, with many movements that potentially damage the skin not conforming to stereotypical scratch movements. Children with atopic dermatitis spent a mean of 46 minutes less time motionless or sleeping at night than control subjects (468 +/- 3 [SEM] vs 422 +/- 37 [SEM], P<.001). Children with atopic dermatitis showed 2 to 3 times as much scratching or restlessness activity as control subjects, with little overlap between groups (P<.01). Scratching and restlessness were highly correlated with each other (0.94, P<.01). Accelerometer scores were highly correlated with video results (rho>0.02, P<.01, for scratching, restlessness, and sleeping time). Individual limb scores were highly correlated with each other (rho approximately 0.87-0.98), suggesting that little information would be lost if only 1 limb was measured. There was little relation between parental assessment of scratch and objective measured scratch. Accelerometers provide a useful and practical way of assessing scratching at night in the patient's own home and could be used as an objective measure of disease activity both in clinical trials and in everyday clinical practice.     

The pleasurability of scratching an itch: a psychophysical and topographical assessment

Background Scratching an itch is perceived as being pleasurable. However, an analysis of topographical variations in itch intensity, the effectiveness of scratching to provide itch relief and the associated pleasurability has not been performed at different body sites. Objectives To examine the role of scratching pleasurability in providing itch relief by investigating whether itch intensity is perceived differently at three different sites and to assess a potential correlation between the pleasurability and itch attenuation induced by scratching. Methods Itch was induced on the forearm, ankle and back using cowhage spicules in 18 healthy subjects. These sites were subsequently scratched by an investigator with a cytology brush immediately following itch induction. The intensity of itch with and without scratching at these sites and the pleasurability of scratching were recorded by taking visual analogue scale ratings at 30‐s intervals. Results Mean itch intensity and scratching pleasurability ratings at the ankle and back were significantly higher than on the forearm. For the forearm and ankle, the greater the itch while scratching, the higher was the pleasurability. A higher baseline itch was linked to a higher itch reduction secondary to scratching in all tested areas. Pleasurability paralleled the curve of itch reduction for the back and forearm; however, scratching pleasurability at the ankle remained elevated and only slightly decreased while itch was diminishing. Conclusions There are topographical differences in itch intensity, the effectiveness of scratching in relieving itch and the associated pleasurability. Experimental itch induced by cowhage was more intensely perceived at the ankle, while scratching attenuated itch most effectively on the back.     

Why we scratch: Function and dysfunction

Itch is a common sensation that drives an intense urge to scratch. Itch and scratching have persisted in humans and many other species, suggesting that they play an important role in survival. This commentary discusses the function of itch as a danger signal, why itch feels unpleasant and why we feel relief and pleasure when we scratch an itch. In addition, we explore the ways that this system becomes dysfunctional in conditions of chronic itch and important implications for treatment.     

Effects of tacrolimus ointment on facial eruption, itch, and scratching in patients with atopic dermatitis

The action of tacrolimus ointment on pruritus in atopic dermatitis is still unclear. In this open study we investigated both the relationship between the severity of eruptions and the degree of itch and scratching in patients with atopic dermatitis and the effects of topical tacrolimus on these symptoms. Seventy adults with moderate to severe atopic dermatitis with facial eruptions that were recalcitrant to topical steroids applied a 0.1% tacrolimus ointment twice per day after discontinuation of topical steroid. The eruption scores and an assessment of the itch and scratching were recorded for 12 weeks. Oral antihistamine was prescribed at least one month before the study and continued unchanged during the study in each patient. The percentage reduction in the score of itch and scratching after two weeks (n=59) was significantly higher than in the score of eruption. Although there was no significant relationship between the severity of the eruptions and the degree of itch and scratching during steroid application, a relationship became significant after four weeks (n=59) of tacrolimus use by a one-factor ANOVA analysis. This suggests that tacrolimus ointment is effective for the itch and scratching in cases where degrees might be discrepant from the severity of eruptions in patients with recalcitrant facial eruptions of AD.     

Electrode design for skin electroporation with minimal nerve stimulation

Itch is one of the major symptoms of various skin diseases. Although specific neuronal pathways for itch were identified both peripherally and centrally, they still fail to explain itchy skin observed in patients with chronic pruritus. In this study, sensitivity to itchy and painful stimuli in patients with atopic dermatitis was investigated. Histamine-prick evoked enormous itch in their lesional skin, while less itch in their non-lesional skin than healthy subjects. Flare reaction was not significantly different between their non-lesional and lesional skin, rather smaller than healthy subjects. Mechanical (pin-pricks), electrical, heat and chemical (injection of pH3 solution) stimuli evoked intense itch in their lesional skin and partly also in their non-lesional skin, while only pain in healthy subjects. Itch was also, but not intensely, evoked in healthy subjects by injection of pH3 solution after sufficient histamine stimuli. These results confirm the presence of itchy skin with hyperkinesis (excessive itch by itchy stimuli) and allokinesis (itch by non-itchy stimuli) in patients with atopic dermatitis, which is so intense that painful stimuli cannot suppress but evoke itch, and suggest that neuronal sensitization is involved in their itch not only peripherally but also centrally.     

Cowhage can induce itch in the atopic dog

Itch is a cardinal symptom of atopic dermatitis in humans and dogs. Until now, experimental induction of itch in dogs has proven difficult. The objectives of this study were to determine whether protease‐rich spicules, protein extracts and the protease mucunain of the tropical legume cowhage provoked itch and inflammation when rubbed onto canine skin. Native spicules variably induced itch manifestations in about half of the dogs, while challenges with protease‐deactivated spicules remained negative. The epicutaneous application of cowhage extract and mucunain after microneedle roller usage also induced pruritus and inflammation. Importantly, there was an interindividual inconsistency in pruritus and inflammation induction and also marked differences in pruritus intensity after challenge. In conclusion, cowhage spicules, protein‐rich extracts and mucunain can all induce pruritus and inflammation in dogs as in other species, but the inconsistency of provocation is currently a limitation of this challenge type for future studies of pruritus in dogs.     

The characteristics of nocturnal scratching in adults with atopic dermatitis

Patients with atopic dermatitis (AD) are known to suffer from nocturnal itch, and the resultant scratching may worsen the skin lesions. We observed nocturnal scratching for 112 nights in 35 adult patients with AD, using an infrared video camera system. To quantify the amount of scratching, we counted scratching bouts lasting more than 5 s and calculated the duration of all the scratching bouts (total scratching time, TST). The percentage of TST in the total recording time (TST%) was used as an index of nocturnal scratching. Mean +/- SD TST% was 14.3 +/- 13.9 for patients with severe AD, 6.2 +/- 3.7 for those with moderate AD and 0.7 +/- 0.4 for those with mild AD. The higher TST% in the severely affected group was attributed mainly to a longer duration rather than a higher frequency of bouts. Patients scratched more in the first third of the night than in the later two-thirds. Both the group of patients whose disease distribution pattern was generalized and those who showed a head-neck-shoulder type distribution scratched their heads, faces and necks for longer than other parts of the body. Repeated measurement performed on individual subjects resulted in a similar TST% when there was little change in skin lesions. TST% reduced by 15 +/- 21% when the patients showed marked improvement. The measurement of nocturnal scratching helps to evaluate the severity of itch in AD. In addition, the infrared video successfully detected the location and nature of nocturnal scratching in AD.     

Atopic dermatitis and pox-virus superinfections (author's transl)

Subjects afflicted with atopic dermatitis are particularly predisposed to such viral superinfections as verruca, herpes (eczema herpeticum) and vaccinia (eczema vaccinatum). Knowledge of superinfection by the molluscum contagiosum virus is more recent and the authors describe one case. The orf virus (responsible for ovine ecthyma contagiosum), however, has never been described as responsible for the profuse superinfection of an atopic eczema. The authors observed one case of this in a child, atypical as result of his age (16 months), the cervical localization and the aspect, which was a telangiectasic granuloma type of the initial element, and finally of the satellization observed one week later. This child suffered from a generalized atopic eczema. Propagation of the orf lesions could have been favored by scratching, local corticoid treatment and by the deficit in cellular immunity observed in patient with atopic dermatitis. Indeed, viral superinfections, which are unusual by their profusion or their chronic nature, are often observed in immunodepressed subjects.     

Inhibition of scratching behaviour caused by contact dermatitis in histidine decarboxylase gene knockout mice

A neuronal system dedicated to itch consists of primary afferent and spinothalamic projection neurons. Histamine is thought to be one of the main mediators for the transmission of itch sensation. However, there are little available information on the role of histamine in scratching behaviour and sensory transmission of atopic dermatitis and chronic eczema. In the present study, the role of histamine in scratching behaviour and neural conduction of sensation in the chronic eczema model was investigated by using l-histidine decarboxylase (HDC) gene knockout mice lacking histamine. The chronic contact dermatitis was induced with daily application of diphenylcyclopropenone (DCP) on a hind paw of HDC (+/+) and HDC (-/-) mice for 2 months. The observation of scratching behaviour and the hot-plate test were performed in both mice. Histological studies were performed in the skin and spinal cord tissues. Histological examination revealed that both HDC (+/+) and HDC (-/-) mice displayed the similar extent of inflammatory cell infiltration, hyperplastic epidermis and newly spreading of neuronal processes in the skin tissue. Scratching behaviour was exclusively induced in HDC (+/+) mice, whereas it was barely observed in HDC (-/-) mice. The expression of c-Fos was specifically upregulated in HDC (+/+) mice in lamina I of the spinal dorsal horn following repeated DCP application. Scratching behaviour in chronic contact dermatitis in mice was thought mainly mediated with histamine. The afferent pathway of sensation in chronic contact dermatitis model may connect with the central nervous system through lamina I of the spinal dorsal horn.     

Dupilumab treatment improves quality of life in adult patients with moderate‐to‐severe atopic dermatitis: results from a randomized,placebo‐controlled clinical trial

Atopic dermatitis is a skin disease, commonly known as eczema. It affects up to 1 in 10 adults. Atopic dermatitis is usually very itchy, causing people to wake up at night, and feel “low”. This state of general discomfort is known as reduced quality of life. Dupilumab is a new treatment approved in the U.S.A. for adults with moderate‐to‐severe atopic dermatitis. The treatment blocks some of the mechanisms involved in the disease. In a clinical trial conducted in Europe, researchers observed 109 patients with moderate‐to‐severe atopic dermatitis. The patients received dupilumab over 12 weeks. They found that the treatment improved the eczema and its symptoms, such as itch. The researchers also studied how the treatment affected quality of life in 64 out of 109 patients in the study. These patients had answered a set of questions that measures how atopic dermatitis affects their quality of life (Quality of Life Index for atopic dermatitis [QoLIAD]). Thirty‐two patients received dupilumab 300 mg weekly, by injection under the skin, and 32 received placebo. About 6 out of 10 patients treated with dupilumab had better quality of life over the 12 weeks, whereas only about 1 in 10 placebo‐treated patients improved. The researchers also found a relatively strong link between improvements with dupilumab in QoLIAD score and improvements in the eczema and symptoms. Dupilumab was well‐tolerated by the patients. The authors conclude that dupilumab, a new breakthrough treatment for atopic dermatitis, improves eczema and its symptoms, and in turn, the patients’ quality of life.     

Itch and atopic dermatitis: an overview

Itching is the hallmark of atopic dermatitis, and a vicious itch-scratch circle is easily established. Itching and scratching are important factors in the maintenance of symptoms and can have a significant impact on the sufferer's quality of life. The pathophysiology of itch in atopic dermatitis is still not understood. Unlike in urticaria, histamine is not considered to be a major pruritogen in atopic dermatitis. In fact, the peripheral pruritogens and their cellular origin(s) still remain to be identified in this disease. Various treatments are used to relieve the skin inflammation, itching, and scratching in patients with atopic dermatitis, but no specific antipruritic therapy is available. However, several nonspecific therapies can effectively break the vicious itch-scratch circle. The use of topical corticosteroids and emollients and the elimination of individual trigger factors are still first-line measures.     

Topical E6005, a novel phosphodiesterase 4 inhibitor,attenuates spontaneous itch‐related responses in mice with chronic atopy‐like dermatitis

Atopic dermatitis is a chronic inflammatory cutaneous disease with difficult‐to‐treat pruritus. Although phosphodiesterase (PDE) 4 inhibitors have an anti‐inflammatory effect on inflammatory skin diseases, such as atopic dermatitis, their acute antipruritic activities remain unclear. Therefore, in this study, we examined whether E6005, a novel PDE4 inhibitor, has antipruritic activity in dermatitis, using a mouse model of atopic dermatitis (NC/Nga mice). A single topical application of E6005 inhibited spontaneous hind‐paw scratching, an itch‐associated response and spontaneous activity of the cutaneous nerve in mice with chronic dermatitis. The cutaneous concentration of cAMP was significantly decreased in mice with chronic dermatitis, and this decrease was reversed by topical E6005 application. These results suggest that E6005 increases the cutaneous concentration of cAMP to relieve dermatitis‐associated itching. Thus, E6005 may be a useful therapy for pruritic dermatitis such as atopic dermatitis.     

Polidocanol inhibits cowhage ‐ but not histamine‐induced itch in humans

Polidocanol is a local anaesthetic and antipruritic compound that is used in the treatment of itching skin conditions such as eczema. Its mechanisms of action are largely ill defined. This study has compared the antipruritic efficacy of topical polidocanol in histamine‐induced itch and a histamine‐independent, cowhage‐induced model of pruritus. Polidocanol (3%) or vehicle was applied topically under occlusion for 1 h to the forearms of 45 healthy volunteers before itch was provoked by rubbing in 40–45 spicules of cowhage or skin prick testing with 10 mg/ml histamine. Itch was recorded at 1‐min intervals for 30 min on a 100‐mm visual analogue scale. Polidocanol significantly reduced the area under the curve for cowhage‐induced itch by 58% (P < 0.05), but had no significant effect on histamine‐induced itch. This result underlines the importance of histamine‐independent itch models in the development of topical antipruritic agents.