Preclinical and human surrogate models of itch

Pruritus, or simply itch, is a debilitating symptom that significantly decreases the quality of life in a wide range of clinical conditions. While histamine remains the most studied mediator of itch in humans, treatment options for chronic itch, in particular antihistamine‐resistant itch, are limited. Relevant preclinical and human surrogate models of non‐histaminergic itch are needed to accelerate the development of novel antipruritics and diagnostic tools. Advances in basic itch research have facilitated the development of diverse models of itch and associated dysaesthesiae. While experimental itch in humans is induced over a short period of time and usually assessed psychophysically, the study of itch reactions in animals allows for both short‐term and long‐term studies but relies heavily on behavioural assessments. This review provides a background and a presentation of the established models of itch currently applied in animals and humans with emphasis on translatability.     

《伤寒论》身痒从表论治

目的身痒是临床常见症,多见于荨麻疹、银屑病等皮肤疾患,是皮肤科疾患的常见伴随症状之一。通过文献分析及临证体会,证实身痒多见于表证,当从表论治。方法《伤寒论》中对身痒有诸多论述,分析解读后发现其认为身痒多见于表证范畴,临床治疗当从表论治,后世医家也对此多有发挥,临床上用之常常有效。结果临床上对于身痒,判定为属于表证范畴的,采用从表论治的原则,可获得满意疗效。结论身痒可见于六经,但多见于表证,《伤寒论》身痒从表论治。对于诊断为表证的身痒,从表论治可获满意疗效。     

Sensitivity to itch and pain in patients with psoriasis and rheumatoid arthritis

Symptoms of itch and pain in chronic inflammatory conditions of psoriasis (PS) and rheumatoid arthritis (RA) can highly affect patients’ quality of life. Studies in other patient groups indicate that sensitivity to itch and pain is altered in line with the patient's main symptom of either chronic itch or pain, as a result of sensitization processes. This study directly compared whether patients with chronic inflammatory conditions associated with chronic itch or pain display a heightened sensitivity to itch and pain, respectively. Sensitivity to itch and pain was measured by applying stimuli of quantitative sensory testing (QST) in female patients with chronic itch due to PS or chronic pain due to RA. Levels of itch and pain evoked by the QST stimuli as well as the tolerance to the stimuli were determined. Patients with PS reacted to the stimuli with a higher itch response (histamine), while the patients with RA displayed a lowered tolerance to the stimuli (cold pressor test and mechanical stimulation) in comparison with the other patient group. In line with previous studies in other patient groups with chronic itch or pain, further support was found that somatosensory stimuli are processed in line with the patients’ main symptom through generic sensitization processes, also in chronic inflammatory conditions such as PS and RA.     

Generalized and symptom-specific sensitization of chronic itch and pain

Background Physicians are frequently confronted with patients reporting severe itch and pain. Particularly in patients suffering from persistent itch and pain, central and peripheral sensitization processes are assumed to be involved in the long‐term maintenance and aggravation of the symptoms. The present study explores generalized and symptom‐specific sensitization processes in patients suffering from persistent itch and pain. Specifically, it examines whether patients with chronic itch and pain are more sensitive to somatosensory stimuli (generalized sensitization) and simultaneously perceive somatosensory stimuli as a symptom of their main physical complaint, e.g. pain in chronic pain patients (symptom‐specific sensitization). Methods Thresholds for different mechanical and electrical sensory stimuli of Quantitative Sensory Testing were determined in 15 female patients suffering from chronic itch associated with atopic dermatitis, 15 female chronic pain patients diagnosed with fibromyalgia, and 19 female healthy controls. Intensities of itch and pain sensations were rated on a visual analogue scale. Results As expected, the patient groups had significantly lower tolerance thresholds for the somatosensory stimuli applied than the healthy controls, supporting generalized sensitization. Moreover, patients with chronic itch consistently reported more itch, while patients with chronic pain partly reported more pain in response to analogous somatosensory stimuli than the healthy controls and the other patient group, indicating symptom‐specific sensitization. Conclusion The present study provides preliminary support that both generalized and symptom‐specific sensitization processes play a role in the regulation and processing of somatosensory stimulation of patients with chronic itch and pain.     

Clinical characteristics of pruritus in chronic idiopathic urticaria

BACKGROUND: Although pruritus is a predominant symptom of chronic idiopathic urticaria (CIU) its clinical characteristics have not been explored. OBJECTIVES: To characterize the clinical pattern and sensory and affective dimensions of the itch experience, utilizing a comprehensive itch questionnaire. METHODS: A structured questionnaire based on the McGill pain questionnaire was used in 100 patients suffering from CIU randomly recruited from a tertiary referral centre. RESULTS: All 100 patients recruited with CIU completed the questionnaire. In 68 patients pruritus appeared on a daily basis. Most patients experienced their pruritus at night and in the evening (n = 83), and 62 reported difficulty in falling asleep. Pruritus involved all body areas, but mostly the arms (n = 86), back (n = 78) and legs (n = 75). Accompanying symptoms were a sensation of heat in 45 patients and sweating in 15. Most patients (n = 98) were prescribed antihistamines (mainly sedating), of whom 34 experienced long-term relief. The sensation of itch was reported to be stinging (n = 27), tickling (n = 25) and burning (n = 23). Seventy-six patients found their pruritus bothersome, 66 annoying and 14 complained of depression. The itch intensity at its peak was more than double that felt after a mosquito bite. The worst itch scores of those who felt depressed were significantly higher than of those who did not (P = 0.018). There was a positive correlation between the sensory and affective scores during worst itch (P < 0.001). CONCLUSIONS: This study describes the itch experienced in CIU, highlighting sensory and affective dimensions. The itch questionnaire was found to be a valuable tool for evaluating pruritus in CIU and its unique features.     

Costs and cost-effectiveness of the nursing programme 'Coping with itch' for patients with chronic pruritic skin disease

Background  Itch, a major symptom of many skin diseases, has a great impact on quality of life. The nursing programme ‘Coping with itch’ aims at reducing itch and at helping patients to cope with itch. Objectives  To explore costs and cost‐effectiveness of the programme. Methods  A randomized controlled study was carried out with 56 patients. Data were gathered on medical consumption, days off work and the frequency of itching and scratching. Differences between both groups, the cost‐effectiveness ratio and the percentage of patients falling into the four quadrants of the cost‐effectiveness analysis plane were determined. Results  The intervention group experienced a gain of 6 days with little itching [95% confidence interval (CI) –16–28] at 3 months and a gain of 35 days (95% CI –33–96) at 9 months. They paid more visits to the dermatology nurse than the control group. The point estimate of the incremental cost‐effectiveness ratio was €129·91 and €16·60 per day with little itching at 3 months and at 9 months, respectively. At 3 months, 70% of the patients experienced favourable results and 14% of them had lower costs. At 9 months, 87% had favourable results and 31% of them had lower costs. Conclusions  Most of the expenses associated with the ‘Coping with itch’ programme were incurred during the first 3 months, but the benefits in terms of days with little itch appeared to persist and increase beyond 3 months, thus leading to a more favourable incremental cost‐effectiveness ratio.     

Itch in familial lichen amyloidosis: effective treatment with amitriptyline in two cases

Itch is a characteristic feature of lichen amyloidosis and the symptom can be debilitating. Treatments, however, are generally not effective. We report amitriptyline as a novel therapy in treating itch in two patients with familial lichen amyloidosis who did not respond to prior potent topical corticosteroids and antihistamines. Outcomes of treatment were assessed using the itch score on a visual analog scale, itch frequency, and the Dermatology Life Quality Index (DLQI). After taking amitriptyline 10 mg o.n. for 6 weeks, the itch score of one patient was reduced from 8.5 to 2 of 10, whereas the second patient's itch score was reduced from 5 to 1. In the latter, his DLQI concurrently reduced from 14 to 6 of 30. Pathophysiology of itch in lichen amyloidosis may involve both cutaneous and neural components and amitriptyline is known to be useful for neuropathic itch. Low‐dose amitriptyline poses little risk of side effects and may offer an effective and safe alternative for the treatment of itch in familial cutaneous amyloidosis.     

Itch in the community: associations with psychosocial factors among adults

BACKGROUND: Itch is a major symptom in dermatology but is little explored epidemiologically. Objective To describe the prevalence and the severity of itch, and to explore its relation to psychosocial factors. METHODS: The design was cross-sectional and population-based. A total of 40 880 adults in Oslo were invited to answer a questionnaire. RESULTS: Twenty-seven per cent report itch. Individuals reporting itch were younger, the majority were female, were non-Norwegian, had lower income, were more distressed, had experienced more negative life events and had poorer social support. Individuals with poor support who had experienced more negative life events reported more itch than individuals with good support (15. 6% compared to 10. 9%). The strong association with psychosocial factors was confirmed in a logistic regression. CONCLUSION: There is a strong association between itch and psychosocial factors in the general population.     

Life-threatening paraneoplastic cutaneous syndromes

Paraneoplastic syndromes are diseases or symptom complexes associated with malignancy, usually internal. In dermatology, we modify the definition to refer to dermatoses associated with internal malignancy. In this article, we discuss the link between malignancy and such dermatologic disorders as acanthosis nigricans, acrokeratosis paraneoplastica of Bazex, dermatomyositis, erythema gyratum repens, necrolytic migratory erythema (glucagonoma syndrome), and paraneoplastic pemphigus and discuss, where such information is known, the mechanism by which these paraneoplastic diseases occur.     

Non‐corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis

Topical corticosteroid phobia is an important problem in the treatment of atopic dermatitis as it can affect the ability to control disease severity and itch by reducing treatment adherence. Topical corticosteroid phobia often ends up even non‐corticosteroid adherence. As such, non‐corticosteroid adherence, disease severity and itch are likely to be associated with each other, but their relationship has yet to be thoroughly investigated. Thus, the purpose of this study is to investigate it in atopic dermatitis. Using data from 1190 participants in an Internet survey, we identified 255 non‐corticosteroid users and 225 with moderate to severe itch who were defined as non‐corticosteroid adherents. Corticosteroid users with the same itch categories (n = 878) served as controls. We also examined how itch severity affects the perception of itch in atopic dermatitis. Unexpectedly, non‐corticosteroid adherents were less sensitive to the conditions to elicit itch such as perspiring, commuting homeward, drinking alcohol and wearing woolen clothes compared with the control. We also found that patients with severer itch were more sensitive to itch during/after bathing, when lying in bed, commuting homeward, studying/working, drinking alcohol, undressing, getting up in the morning, after a meal, ingesting piquant foods and when they were unoccupied, angry, busy, nervous, sad or enjoying themselves. In conclusion, we found that non‐corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis and discuss possible mechanisms underlying these results. The information obtained in this study may be useful for communication with and education of atopic dermatitis patients and their treatment in outpatient clinics.     

Some historical and epistemological remarks on itch and pruritus

Although very common, itch is very hard to describe. It can be considered as one of the most distressing physical sensations we experience. Going back historically, old Latin and Greek writers cited it in ancient papers. So, etymology is of central importance to investigation in the field of itch, regarding the formation of a word with antique origins and different meanings. Scientists, poets, and painters for centuries tried to describe and represent itch. The study of their work reveals the development of the itch's significance. Today, a clinically relevant distinction defines pruritus and itch as two different sensations. Moreover, some terms like hyperknesis, alloknesis, atmoknesis, protopathic itch, and epicritic itch are described to approaching the complexity of this sensation and are utilized in clinical practice.     

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.     

Transepidermal water loss, serum IgE and beta-endorphin as important and independent biological markers for development of itch intensity in atopic dermatitis

BACKGROUND: Although itch is the predominant symptom of atopic dermatitis (AD), it is poorly characterized and subjective. The objective assessment of itch intensity is important for treatment and follow-up in patients with AD. OBJECTIVES: To determine what objective clinical parameter(s) could be used as biomarker(s) for itch intensity in patients with AD. METHODS: This is a retrospective and cross-sectional study. Seventy-five patients, aged 7 months-49 years with equal sex ratio, were enrolled in 2000 according to criteria proposed by Hanifin and Rajka. Thirty-five age- and sex-matched subjects who visited the dermatological clinic but were otherwise healthy served as controls. Subjective itch intensity was divided into four grades of severity. Disease severity was measured by SCORAD index, which also includes itch intensity as part of the measurement. Transepidermal water loss (TEWL) and skin surface pH were measured by noninvasive methods in clinically normal skin on the forearm. Serum beta-endorphin and vasoactive intestinal peptide (VIP) were determined by radioimmunoassay. Ordinal logistic regression was used to assess the trend of the subjective itch intensity and SCORAD index by serum IgE, beta-endorphin, VIP, TEWL and skin pH. RESULTS: There were significant trends for itch intensity with IgE, beta-endorphin and TEWL. After adjustment for sex, age and other variables, the odds ratio (OR) for itch intensity by log IgE, beta-endorphin and TEWL was 2.103 [95% confidence interval (CI) 1.222-3.618], 1.100 (95% CI 1.005-1.203) and 1.081 (95% CI 1.009-1.158), respectively. The OR for disease severity by log IgE, beta-endorphin and TEWL was 2.250 (95% CI 1.149-4.407), 1.156 (95% CI 1.086-1.231) and 1.071 (95% CI 0.971-1.182), respectively. In contrast, there was no association between serum VIP concentration and itch intensity. CONCLUSIONS: Beta-endorphin and IgE are both useful biomarkers for itch and disease severity in patients with AD, while TEWL is a good biomarker for itch intensity. These biomarkers provide a way to assess the itch intensity in patients with AD.     

Pruritic and antipruritic colors: An exploratory pilot study

Itch is the commonest skin‐related symptom and can be influenced by visual cues as exemplified by the phenomenon of “contagious itch.” Colors are visual cues able to modify somatosensory inputs. We explored the relationship of colors and itch and the impact of color viewing on itch intensity. In this cross‐sectional study, patients suffering from itch with a mean intensity of ≥2 on a Numerical Rating Scale during the last 7 days were evaluated. The study consisted of a questionnaire‐based part using The Manchester Color Wheel and the ItchyQoL, followed by an interventional part. All 72 itch patients were able to match their itchy sensation with a color: In 68 patients (94.4%) this “pruritic” basic color was red. Likewise, all patients were able to define a subjective “antipruritic” color: The leading basic color choice was blue (31/72, 43.0%) followed by green (21/72, 29.1%), yellow (7/72,9.7%) and others. The impairment of the itch‐related quality of life (as measured by the ItchyQoL) correlated with the brightness and saturation of the pruritic and antipruritic colors. Ten patients were visually exposed to their subjective antipruritic and pruritic color during 10 minutes resulting in a significant decrease and increase of itch intensity compared to baseline (5.1 ± 1.52 vs. 2.8 ± 1.47 [0‐10 Numerical Rating Scale, NRS], p=0.0004 and 4.9 ± 1.66 vs. 6.8± 2.09 NRS, p=0.0009). These results indicate that itch can be modified by color viewing and colors matter when treating itch patients. However, further investigations are required to elucidate the therapeutic potential of colors in itch patients.     

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.     

UVB‐ and NGF‐induced cutaneous sensitization in humans selectively augments cowhage‐ and histamine‐induced pain and evokes mechanical hyperknesis

Exaggerated itch responses to pruritic chemical provocations and mechanical stimuli are evident in patients with chronic itch, for example, in atopic dermatitis. Currently used human models of itch do not account for such itch sensitization features, and the mechanisms underlying clinical itch sensitization are unknown. This study utilized two established human models of cutaneous nociceptive sensitization to explore how pre‐established inflammatory hyperalgesia (ultraviolet‐B‐irradiation; “UVB”) and non‐inflammatory neurotrophic pain sensitization (nerve growth factor; “NGF”) alter sensitivity to chemical and mechanically evoked itch. Twenty healthy volunteers participated in the UVB experiment. Six volar forearm areas (2 cm diameter) were UVB irradiated with ≤2 × minimal erythemal dose, and two non‐irradiated areas were used as controls. Sixteen healthy volunteers participated in the NGF experiment and had 2 μg intradermally injected (4 × 50 μL in 2 cm diameter areas) into both volar forearms. Isotonic saline was applied as control. Pain sensitivity measurements (mechanical and heat pain thresholds) were conducted to validate the models. Subsequently, itch was evoked using histamine and cowhage spicules in the sensitized skin areas, and itch/pain was rated using visual analogue scales. Mechanical hyperknesis (increased itch to punctuate stimuli) was probed with von Frey filaments before/after each itch provocation. Both UVB‐ and NGF models induced robust primary mechanical hyperalgesia (P < .01) and hyperknesis (P < .05). Neither of the models augmented itch in response to chemical itch provocations but significant increases specifically for pain ratings were observed for both histamine and cowhage (P < .05). This suggests that these models are of limited value as proxies for itch sensitization to pruritogens observed, e.g., in inflammatory dermatoses.     

Levocetirizine for the treatment of itch in psoriasis patients: An open‐label pilot study in a real‐world setting

Itch is the most bothersome symptom in psoriasis, often leading to impaired quality of life. Treatment of psoriasis‐induced itch is frequently unsatisfactory as the various therapies employed have a delayed onset of effect. Histamine‐1 receptor (H1) antihistamines are not recommended in treatment guidelines as histamine is not considered a key mediator in psoriasis. However, patients using H1 antihistamines frequently report benefits in questionnaire‐based studies. To address these contradictions, we examined the short‐term effects of levocetirizine, a nonsedating H1 antihistamine, on psoriasis‐related itch and itch‐related quality of life. In this pilot study, patients with psoriasis‐related itch received levocetirizine 5–10 mg daily as a concomitant treatment for 5 days. Change of itch intensity as measured by hourly itch ratings and the change of itch‐related quality of life were measured at different time points. A total of 29 of 30 patients (96%) reported a decline in itch within 5 days. Mean itch reduction was 23% after Day 1 (p = .005), 40% after Day 3 (p < .001), and 41% after Day 5 (p < .001). Furthermore, itch‐related quality of life also significantly improved after 5 days (p < .001). Only 2 of 30 patients (6.7%) reported mild sleepiness. Levocetirizine 5–10 mg daily as an add‐on therapy seems to be an effective treatment to improve itch and itch‐related quality of life within only a few days.     

Production of acute and chronic itch with histamine and contact sensitizers in the mouse and guinea pig

Itch is a major symptom of skin disease and is poorly understood, in part due to the lack of adequate small animal models. We show, using iontophoresis of histamine and capsaicin, that it is possible to induce scratching behaviour in both guinea pig and mouse. Use of iontophoresis may obviate the problems of induction of pain as well as itch when injection is used. The behavioural response to capsaicin, however, differs from that seen with histamine, raising the possibility that the use of scratch counts as a method of measuring itch severity needs to be set in the context of other responses. Naloxone partly inhibits scratching in mouse and guinea pig due to histamine. We also show that contact sensitization with 2-4 dinitrochlorobenzene (DNCB) can be used as a simple assay for chronic itch allowing study of scratching over at least a 15-h period. The characteristics of scratching (but not the time course) induced with DNCB are similar to those seen with histamine.     

New therapies for controlling atopic itch

Chronic itch in atopic dermatitis markedly diminishes the quality of life of affected individuals. Sleep disturbance and impaired productivity in work due to chronic itch impose a socioeconomic burden. Conventional therapies for atopic dermatitis are capable of reducing atopic itch. However, the majority of patients are not satisfied with the antipruritic capacity of conventional treatments. In this review, we summarize recent progress in itch signaling in the skin, dorsal root ganglion and spinal cord. New therapies for controlling atopic itch are also discussed.