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Itch: An Integrative Approach
Radomir Reszke and Jacek C. Szepietowski
Department of Dermatology, Venereology, and Allergology, Wroclaw Medical University, Wroclaw, Poland
Introduction
Itch, also called pruritus, is regarded as the most common symptom in dermatology with marked influence on health‐related quality of life (HRQoL), although its relevance in context of systemic disorders, as well as diagnostic and therapeutic dilemmas, results in a significant challenge for different medical specialties. The word “itch” derives from Old English giccan, whereas pruritus derives from the Latin prurire meaning “to itch,” although a burning component was also indicated [1]. Throughout history this bothersome symptom has been described in various contexts, and potential remedies have been sought and documented, e.g. in Papyrus Ebers dating approximately 1550 BCE or Corpus Hippocraticum, compiled since fifth‐century BCE in Greece [2]. In Epidemics, itch was mentioned in the context of the development of burn blisters or the occurrence of “summer fevers” in Perinthian women. Suetonius described various ailments of the Roman Emperor Octavian August, among which multiple lichenous skin lesions were also present, along with severe itch requiring the use of a scratching instrument [3]. According to Avicenna, itch and scabies were supposedly caused by salty water, whereas the beneficial role of southern winds was mentioned [2]. In Dante’s Inferno, falsifiers were suffering from unbearable torment due to burning itch sensation that nothing could relieve [1]. An eighteenth‐century physician and French revolution leader, Jean Paul Marat, suffered most probably from severe eczema and associated itching, the latter being alleviated by long sessions in a bathtub [4]. This is where he met his demise on the 13th of July 1793, as portrayed by Jacques‐Louis David in a famous painting entitled Marat assassiné. In the early nineteenth century Robert Willan described idiopathic pruritus in the elderly resulting in being “uncomfortable for the remainder of life” [5]. Among others, the twentieth and twenty‐first century findings have extensively broadened the pathogenesis of itch and associated disorders, ensuing in increasing clinical success of novel treatment modalities and individualization of the therapy. Recently, based on the holistic approach, an emphasis has also been put on psychological and social aspects of itch as this symptom concomitantly influences the well‐being of the affected individuals and their relatives.
This current work provides a complex and current overview of aspects associated with itch, including its classification, epidemiology, pathogenesis, clinical manifestations, HRQoL issues, diagnostic work‐up, and management.
Definition and Classification
A definition of itch proposed by German physician Samuel Hafenreffer in 1660 is still relevant nowadays, as it is “an unpleasant sensation that provokes the desire to scratch” [2], as mentioned in the European Guideline on the Chronic Pruritus by Weisshaar et al. [6] Itch is categorized as either acute, which lasts less than six weeks, and chronic (CI), lasting more than six weeks, the latter type being more commonly investigated in research papers.
As the pathogenesis of pruritus is of utmost complexity and clinical associations are numerous (these topics are discussed in detail in further paragraphs), it is useful to mention a clinical classification proposed by Ständer et al. [7] in 2007 which is based on two steps. Firstly, a patient suffering from CI is assigned to one of three groups: pruritus on diseased skin (I), pruritus on non‐diseased skin (II), and chronic scratch lesions (III). This step is based on history taking and physical examination. It is important to differentiate primary skin lesions of a specific dermatosis (e.g. papules and plaques covered by scales in psoriasis) from secondary lesions associated with chronic scratching (e.g. excoriations and lichenification). Secondly, based on histological, laboratory, and radiological examinations, six categories of diseases related to CI are mentioned. These include dermatologic diseases (corresponding with group I), whereas systemic, neurologic, and psychogenic diseases can be associated with groups II and III. Additionally, “mixed” category was also mentioned (in a subject with mixed etiology of CI), along with “other” category, which is used when other categories do not fit the case. Apart from dermatoses, in everyday dermatological practice it is important to recognize CI due to systemic disorders, as well as the cases associated with the presence of solid tumors or the use of drugs (Table 13.1).
Table 13.1 Examples of conditions associated with CI.
Source: According to Weisshaar et al. [6], with modification.
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The affection of both central nervous system (CNS) and peripheral nervous system (PNS) may be associated with the development of itch. Prominent examples include brain tumors, spinal cord tumors, systemic sclerosis, notalgia paresthetica, brachioradial pruritus, or postherpetic neuralgia [6, 8]. Psychiatric disorders may also manifest with itch, e.g. in depression, obsessive‐compulsive disorder (OCD), anxiety and somatoform disorders, psychosis, or substance use [9]. In 2007, French Psychodermatology Group (FPDG) proposed the term functional itch disorder (FID), synonymous with psychogenic or somatoform pruritus [10]. In this type of pruritus psychogenic factors are crucial in eliciting the symptom. In order to diagnose this entity all three compulsory and three out of seven optional criteria have to be met. The former include localized or generalized pruritus sine materia without primary skin lesions (I); chronic pruritus of more than six weeks’ duration (II); and absence of a somatic cause of itch (III). Optional criteria include a chronological relationship of pruritus with one or several life events that could have psychological repercussions (i); variations in intensity associated with stress (ii); nocturnal variations (iii); predominance during rest or inaction (iv); associated psychological disorder (v); pruritus that could be improved by psychotropic drugs (vi); and pruritus that could be improved by psychotherapy (vii) [10].
Epidemiology and Clinical Features
Population‐Based Studies
A growing number of studies have recently appeared in the field of epidemiology of CI. In a population study performed on over 18000 Norwegian adults, CI was the most common cutaneous complaint present in 8.4% of subjects, followed by dry and sore skin, scaly skin, pimples, and hand rash (6.2%; 4.4%; 3.5%; and 3.3%, respectively) [11]. Itch was more prevalent among younger adults, both in men (9.6%) and women (11.9%). A recent paper by Miller et al. [12] (n = 20.164) described the prevalence of pruritus as 6.5% among Danish suburban adults. Matterne et al. [13] reported that the lifetime prevalence of CI in the general population (n = 200) of Germany was 22.6%, with the current and 12‐month prevalence estimated at 16.5% and 13.9%, respectively. In contrast, among outpatients from the itch clinic, itch was present in 100%, 79%, and 95%, respectively. Additionally, a later paper on 1190 participants demonstrated that the lifetime CI prevalence may be as high as 25.5% [14]. The investigators also noted that the risk of CI increased by 2% with each additional year of life. Retired subjects were twice as prone to experiencing itch as those currently working. Ständer et al. [15] analyzed the data acquired from 11730 persons working in 144 German companies. Therein it was revealed that the point prevalence of pruritus was 16.8%. Among patients aged 16–30 years itch was present in 12.3%, while elderly individuals (61–70 years old) complained of itch more often (20.3%). Almost 89% of pruritic patients were bothered by this symptom, usually to a small extent. Regarding the Numerical Rating Scale (NRS), the average itch intensity was 5.8 ± 2.1 points, with median 5.0 points. Extremities were mostly affected (55.9%), followed by trunk (24%) and head/neck (22.9%), while only 15.9% of patients complained of generalized involvement.
Several studies on the epidemiology of CI have also focused on specific age groups of patients. As an example, Dalgard et al. [16] investigated itch and stress in 18‐year‐old Norwegian adolescents (n = 2489). The prevalence of current itch was significantly higher for girls (11%) than for boys (6%). It must be noted that epidemiological studies of itch focused solely on pediatric population are currently unavailable. Notably, Weisshaar et al. [17] evaluated itch characteristic and associated HRQoL impact in 823 children and adolescents suffering from AD. The prevalence of CI in children is unknown, although indirect data may be obtained from epidemiological studies on atopic dermatitis [18]or urticaria [19].
In contrast, our group has investigated the prevalence of various skin disorders among patients aged 65 years and over who were hospitalized either in the dermatology ward (n = 102) or in the geriatric ward (n = 96). [20] In total, pruritus was present in 34.8% of subjects and occurred more commonly in patients on the dermatology ward (44.3% vs. 23.9%; p < 0.01). A recent study by Valdes‐Rodriguez et al. [21] investigated CI in 302 elderly Mexicans, among whom 25% suffered from CI. In the latter group, 69% presented xerosis, 28% had itch‐related dermatoses, and 96% had documented comorbidities. These included diabetes mellitus (OR = 2.3, p = 0.003), and chronic venous insufficiency (OR = 4.4, p = 0.002). The mean itch score assessed with the Visual Analogue Scale (VAS) was 6.0 ± 2.1 points and in 88% the sensation occurred on a daily basis. Typically, patients experienced itch on legs (54%), back (45%), scalp (28%), and arms (27%). Patients experienced the greatest amount of itch in the winter (77%) and during the night (65%).
Cutaneous Disorders
CI is a cardinal symptom of numerous skin disorders (Table 13.2), often leading affected individuals to visit their general practitioner (GP) or dermatologist. Australian investigators observed that itch was the cause of visiting GP in 0.6 per 100 cases, representing 600000 cases a year [23]. Kopyciok et al. [24] reported that among 334 patients attending a German dermatology practice over a one‐week period the prevalence of pruritus was 36.2%, while 31.7% complained of CI, 3.6% of acute itch, and 0.9% did not specify the duration. No significant differences were found between each gender, although men with itch were 8.3 years older than women. On average, patients with CI were 11.7 years older than patients with acute itch (p = 0.068). Faye et al. [25] demonstrated that 13.2% of 1761 patients seeking dermatological consultation complained of itch. CI affected 57% of subjects; in 67% it was diffuse. Thirty‐three percent of individuals were able to identify triggering factors; the same percentage complained of nightly exacerbations. Sleep was affected in 63% of patients and daily activities were influenced in 46.6%.
Table 13.2 Dermatoses associated with CI.
Source: According to Szepietowski and Reich [22], modified.
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CI is considered a crucial symptom of atopic dermatitis, as included in the diagnostic criteria proposed by Hanifin and Rajka [26]and UK Working party [27]. It is therefore evident that over the course of the disease 100% of patients experience CI at some point. According to Yosipovitch et al. [28] (n = 100), itch accompanied 87% of respondents on a daily basis, whereas in 8% weekly episodes were described. Forty‐one percent reported itch duration of 12 months or more, with the average duration of 10.7 ± 7.3 years. Almost two out of three individuals reported frequent itch at night, leading to difficulties in falling asleep in 84% and night awakenings in 79%. Concerning the location of itch, lower limbs were affected most commonly (78%), followed flexures, upper limbs, neck and back (72%; 67%; 61%; and 59%, respectively). Comparing the worst itch intensity in AD to that associated with a mosquito bite the former reached significantly higher values according to VAS (9.0 ± 1.2 points vs. 4.8 ± 3.1 points). Concerning the factors precipitating the onset of pruritus respondents mentioned heat (60%), sweating (57%), dust (29%), and stress (22%). Similarly, our group has observed that 83.1% of patients with AD complained of itch at the time of examination (n = 89) [29]. SCORAD (Scoring Atopic Dermatitis) values utilized for assessing the severity of AD significantly correlated with itch intensity.
Itch in chronic urticaria is almost an invariable symptom [30] and in the EAACI (European Academy of Allergy and Clinical Immunology)/GA2LEN (Global Allergy and Asthma European Network)/EDF (European Dermatology Forum)/WAO (World Allergy Organization) Guideline on urticaria, the definition of urticaria (hives) states that they are “associated with itching or sometimes a burning sensation” [31]. Unsurprisingly, a study of 100 patients from Singapore diagnosed with chronic idiopathic urticaria revealed that 97% suffered from pruritus at the time of the examination [32]. Typically, night episodes of itch were reported (46%), followed by evening (37%), morning (25%), and noon (18%). Itch was accompanied by heat sensation in 45%, along with sweating (15%) and pain (9%). The intensity of itch was 1.1 ± 1.9 points according to VAS (at the current moment), while the worst itch intensity and the intensity after a mosquito bite were 7.9 ± 1.9 points and 3.6 ± 2.7 points, respectively. Usually, arms were affected (86% of patients), yet involvement of the back (78%) and legs (75%) was also prevalent. Interestingly, itch in patients with urticaria was relieved by rubbing the skin rather than by scratching; therefore heavily excoriated areas are observed very rarely [30].
Psoriasis, which is another common disease in the general population, presents with pruritus in the majority of patients. The CI prevalence in psoriasis has been analyzed in several papers, ranging from 64% to even 97%, [33, 34] although the number of analyzed patients varied significantly between those two studies (n = 936 vs. n = 87). The former study revealed that females were affected more commonly than males (73.9% vs. 62.8%, respectively; p < 0.001) and psoriasis area and severity index scores (PASI) higher than 10 points were significantly correlated with itch appearance (p = 0.013). Our group reported that the prevalence of CI in 100 patients with psoriasis reached 80% [35]. The PASI scores were significantly higher among pruritic subjects (19.1 ± 12.8 points vs. 11.4 ± 9.4 points, respectively; p < 0.004). Individuals with CI usually reported that itch was limited to psoriatic lesions (81.3%), whereas only 18.7% of affected individuals mentioned healthy skin as well. Concerning the location, lower limbs were affected most often (50%), whereas the involvement of trunk, upper limbs, scalp, and generalized lesions were less prevalent (48.7%, 48.7%, 35%, and 28.7%, respectively). Interestingly, another study on itch in psoriasis reported that the sensation was limited to healthy skin in as high as 43% of subjects [36]. However, psoriasis is not the exclusive papular disorder with marked sensation of itching. Reich et al. [37] compared itch characteristic in patients with psoriasis (n = 76) and lichen planus (LP) (n = 30). In the psoriasis group, 90.8% of subjects complained of itch, whereas in the LP group the prevalence was slightly higher (96.7%), although the difference was not statistically significant (p = 0.53). The mean VAS intensity of itch was VAS: 7.5 ± 2.3 points vs. 5.1 ± 2.5 points, respectively (p < 0.001). In psoriasis, the lesions more often affected lower extremities (70.6% vs. 51.7%, p = 0.08), trunk (66.2% vs. 48.3%, p = 0.1), and scalp (33.8%vs. 3.4%, p < 0.01), while the differences in the prevalence rates of itch on the upper extremities did not differ significantly (52.9% vs. 58.6%, p = 0.61). Interestingly, the appearance of new skin lesions in LP was more commonly associated with the most severe itch (55.2% vs. 14.9%; p < 0.001), while psoriasis patients frequently reported increased intensity during the extension of skin involvement (44.8% vs. 3.4%; p < 0.001). Additionally, after instigating treatment of LP, itch subsided shortly afterwards in 60.0%, whereas its disappearance in psoriasis occurred usually only after resolving cutaneous lesions (p < 0.001). A recent study by Welz‐Kubiak et al. [38] on 78 consecutive patients with LP revealed that the prevalence of itch was 94.9% at some time during the course of the disease and 69.2% at the time of examination. The mean VAS score of maximal itch intensity was 6.9 ± 2.7 points, significantly higher when compared to itch intensity after a mosquito bite (5.1 ± 2.4 points; p < 0.001). Major factors exacerbating itching included sweating in 52.7% of patients, warmth (51.3%), stress (43.2%), and hot water (41.9%), whereas the alleviating factors included cold water (32.9%) and cold air (25.7%).
Itch is commonly experienced in acne vulgaris, as reported by several investigators, although this symptom remains unrecognized in these patients [39–41]. In a study by Lim et al. [39] (n = 120) itch was present in 70% of respondents at some point of their lives. No differences were observed between sociodemographic factors or the clinical type of acne (inflammatory vs. non‐inflammatory) with regards to the presence of itch. The mean VAS score for maximal pruritus intensity was 5.3 ± 2.3 points, similarly to self‐perceived itch intensity after a mosquito bite (5.7 ± 2.9 points according to VAS). Patients were mostly affected at noon (83%), with 70% of those describing itch as lasting for several minutes. Itch was increased by sweat (71%), heat (62%), stress (31%), and fatigue (24%), while 42% of female patients regarded menstruation as a worsening factor. Our group reported lower, yet also significant prevalence of itch (50%) in acne adolescents (n = 108) [40].
The presence of itch may also accompany the development of lesions in autoimmune blistering diseases. Although itch is usually mentioned in the clinical description of these diseases in major textbooks, this issue has not been studied in details for many years. Ghodsi et al. [42] analyzed HRQoL aspects of 61 patients with pemphigus vulgaris, with itch being reported by 47.5% of patients. Recently, Kalinska‐Bienias et al. [43] reported that among 66 patients with autoimmune blistering disorders, itching was present in 60% of individuals. Moreover, Kulczycka‐Siennicka et al. [44] carried‐out a study on 28 patients with BP and 24 patients with Dermatitis herpetiformis (DH). The investigators revealed that according to the four‐item itch questionnaire, patients with BP scored 11.4 points on average (range 5–19 points), whereas DH patients scored 12.4 on average (range 5–19 points). In both entities the majority of patients recognized itch as localized, while generalized forms were encountered rarely (75% vs. 25% in BP; 79.2% vs. 20.8% for DH). Interestingly, in BP 25% of affected patients complained of itch persisting less than 10 minutes, 39.3% reported episodes longer than 10 minutes, and 35.7% experienced constant itch. In DH, however, these percentages were significantly different (16% vs. 30% vs. 54%, respectively).
Concerning the autoimmune connective tissue diseases, the affection of skin is a common and bothersome finding, often resulting in a variety of cutaneous lesions and subjective symptoms such as pain or itch. In a study by Shirani et al. [45], among 26 patients with dermatomyositis (DM) who completed the questionnaires, itch was present in 84.6% of respondents. On average, the 100 mm VAS scores reached 52.5 points concerning current itch; the scores for the worst itch, itch rate on a daily basis and the influence of itch on daily activities were also described (63.0 points; 59.4 points; 42.5 points, respectively). Goreshi et al. [46] evaluated 89 individuals with dermatomyositis and 162 suffering from cutaneous lupus erythematosus (CLE). Median itch score according to VAS was 3.8 points for DM patients and 2.0 for CLE (p < 0.0001). Théréné et al. [47] evaluated 61 patients with systemic sclerosis, among whom 62% reported itch. The mean intensity of itch was 4.4 ± 1.8 points according to VAS, whereas maximum values reached 7.1 ± 1.9 points. Most common locations affected by itch included head (55%), back (53%), dorsal surface of hands (50%), lower limbs (40%), forearms (37%), arms (34%), and shoulders (32%). Among aggravating factors, the authors mentioned fatigue, stress, skin dryness, and specific clothes, while rest, sleep, hot water, and hot ambient temperature provided some alleviation of symptoms.
Systemic Disorders
The vast number of etiopathogenetic aspects associated with the development of itch (reviewed further) warrants its presence in the course of systemic disorders. For example, in a recent paper by Oeda et al. [48] 1631 patients with chronic liver disease were evaluated, with itch being present in 40.3% of affected individuals. In the subgroups of patients, itch was present in 60% of patients with overlap syndrome (primary biliary cirrhosis (PBC) and autoimmune hepatitis), 51.4% of those with PBC, 45.9% among chronic HCV (Hepatitis C virus) infection, 40.6% among non‐alcoholic fatty liver disease, and 40.6% of individuals with active HBV (Hepatitis B virus) infection. The most common location of itch sensation was the back (63.1%), followed by abdomen (29%), calf (25.8%), and the upper arm (22.6%). Among pruritic subjects liver cirrhosis was more prevalent (37.8% vs. 32.7%, p = 0.036), as well as elevated levels of alanine aminotransferase. On the other hand, dyslipidemia was encountered less often (15.0% vs. 19.0%, p = 0.018). Forty‐five percent of patients reported seasonal exacerbation of symptoms, especially in winter. In a previous paper Rishe et al. [49] evaluated 238 patients with PBC, among whom 69% reported itch. Thirty‐five percent of patients described their itch as “bugs crawling” and in 35% it was perceived as “deep itch.” “Something cool” was regarded as an alleviating factor by 64.7%, while heat was the mostly exacerbating factor, as reported by 61.6%. Almost two‐thirds of patients reported that itch was worse at night. Regarding seasonal variation, nearly half of respondents stated that itch worsened in summer.
Chronic kidney disease (CKD) remains a relevant problem in affected patients, with multidimensional impact of health‐related consequences. In later stages of the disease itch is a frequent complaint, especially in end‐stage renal disease (ESRD) patients on hemodialysis (HD). Our group evaluated 130 patients on HD; uremic itch affected 40.8% of subjects, with the additional 36.1% of patients reporting that the symptom had been present during the renal disease period [50]. Similarly, Pisoni et al. [51] reported that the prevalence of uremic itch among 18801 patients undergoing HD reached 42%. Patients had a higher risk of experiencing moderate to extreme pruritus if, for example, they were male, suffered from lung disease, congestive heart failure, neurological disease, or presented specific laboratory values (such as hypercalcemia, hyperphosphatemia, hypoalbuminemia, etc.). Notably, patients with moderate to extreme pruritus had a 17% higher risk of mortality. In a study by Weiss et al. [52] (n = 860), 25.2% of ESRD patients with uremic itch were currently affected by CI, 27.2% reported having CI within the past 12 months, while 35.2% had CI at least once in their lifetime. Over 57% of respondents stated that HD was associated with CI – among them, 40.4% reported the worst intensity after HD and 33.9% during HD, whereas 24.8% denied any relationship. Mean severity of CI was 4.1 ± 1.7 points according to VAS, while the worst severity within the last six weeks was 6.5 ± 2.5 points. Interestingly, localization on the arms and legs was associated with significantly worse severity of mean CI. Another study by our group focused on pediatric patients [53]. Among 72 children with CKD (stages 3–5), itch bothered 20.8% of subjects. The sensation affected 18.4% of patients treated conservatively (without dialysis) and 23.5% patients on dialysis (HD or automated peritoneal dialysis). The mean itch severity was 3.5 points according to VAS and 6.9 points according to the 4‐item Itch Questionnaire.
The term paraneoplastic itch refers to itching in patients with cancer, mostly associated with lymphoproliferative disorders and rarely with solid tumors [54]. According to the current definition it is a sensation of itch as a systemic (not local) reaction to the presence of a tumor or a hematological malignancy which is neither induced by the local presence of cancer cells nor by tumor therapy. The sensation usually disappears with the remission of the tumor but may reoccur with the relapse of an underlying disease. The prominent example is polycythemia vera (PV), in which aquagenic pruritus (AP) is a classic symptom. AP is defined as strong itching, stinging, tingling, or burning sensations after contact with water. [55] However, no lesions on the skin are present in clinical examination. Recently, our group has reported that among 102 PV patients, AP was present in 41.2% [56]. The mean itch intensity according to VAS was 4.8 ± 1.9 points, while maximum itch intensity in patients with AP was 5.2 ± 2.4 points. A significant negative correlation between hemoglobin concentration (HGB), hematocrit level (HCT) and itch severity assessed with the Verbal Rating Scale (VRS) and 4‐item Itch Questionnaire were found (p < 0.05). Concerning the association with VAS score, the trend was also evident, but no significant correlation was met. According to Siegel et al. [55] AP was present 64.8% of subjects with PV. On average, AP occurred 2.9 years before diagnosis of PV. Over 45% of patients stated that warm water caused worse itch intensity than cold water. AP usually manifested less than 10 minutes after contact with water. Typical locations included chest, back, medial side of the arms and ventral side of the legs. On a scale from 1 to 6, the median of AP intensity was 3; 14.6% deemed the strength of AP as “unbearable.”
The 2007 CI classification by International Forum on the Study of Itch (IFSI) lists drug‐induced itch in the second category, which focuses on systemic causes of CI [7]. Due to constantly increasing drug intake in the general population, and the resulting phenomenon of polypharmacy, it is evident that adverse drug reactions will occur more commonly, especially in the elderly. In a classic study by Bigby et al. [57] (n = 15.438) it was reported that the adverse cutaneous drug reaction rate per patient was 2.2%. Among these, 94% comprised generalized morbilliform exanthemas, 5% were associated with urticaria, and generalized itch occurred in 1%. As reviewed by Reich and Szepietowski [58], drug‐induced pruritus may occur after introducing substances from various therapeutic groups, usually after systemic treatment, although topical application may also provoke itch. Prominent examples of drugs causing acute itch without associated skin rash include chloroquine (along with other antimalarials) [59], opioids [60], vancomycin [61], and selective serotonin reuptake inhibitors (SSRIs) [62], while CI may be associated with the use of hydroxyethyl starch (HES) [63, 64] or glimepiride [58].
Pathogenesis
The pathogenesis of itch is a complex issue and is still not fully understood. For decades itch has been regarded as a submodality or subquality of pain, because both sensations share many similarities [65]. Additionally, there is an inverse relation of itch to pain, as the former one is reduced by nociceptive counterstimuli such as scratching [66]. From the physiological point of view itch and the resulting need to scratch might play a role in protecting the integrity of skin from various factors, e.g. parasites, insects, sharp objects, irritants, and allergens [67]. Therefore in a broad sense, itch and scratching might be considered “the cough of the skin” [68]. Several neurophysiological theories of itch were proposed in the past, including intensity theory (transition from itch to pain due to increased discharge frequency of nociceptors), pattern theory (encoding of itch and pain in CNS based on different discharge patterns) and specificity theory (different pathways for pain and itch) [69]. Beginning from the surface of the skin, external stimuli exert their effect on free nerve endings that might also be termed pruriceptors. The stimuli are transmitted via unmyelinated C‐fibers [70] associated with histamine, although the myelinated Aδ‐fibers may also play a role [71]. Subsequently, the impulses reach dorsal roots in the spinal cord. Andrew and Craig [72] investigated the role of lamina I spinothalamic tract neurons as a central neural pathway for itch. Notably, Sun et al. [65] reported that in dorsal root ganglia there is a small subset of neurons producing gastrin‐releasing peptide (GRP), which acts on its specific gastrin‐releasing peptide receptors (GRPRs) located in lamina I. The spinothalamic tract ends in the thalamus, and following the switch to another neuron the impulses reach the brain cortex. In relation to itch, the most relevant regions include somatosensory cortex, cingulate cortex, medial parietal cortex, insular cortex, and motor cortex (Table 13.3) [73]. These regions account for determining itch intensity, location, the urge to scratch, and subjective unpleasantness of itch, while motor cortex is responsible for the preparation and execution of scratching movements. The abovementioned aspects were analyzed in several studies using functional magnetic resonance imaging (fMRI) [74, 75], positron emission tomography (PET) [76, 77], or magnetoencephalography [78]. It seems evident that despite the initial association with the skin, the key role in the development of itch sensation is eventually exerted by the brain. Therefore the statement “it is the brain that itches, not the skin” [67] remains valid.
Table 13.3 Cortical regions and their associated functions in relation to itch.
Source: As reviewed by Mochizuki et al. [73].
| Cortical region | Itch‐related function |
| Somatosensory cortex | Intensity and location of itch |
| Cingulate cortex | Cognition, evaluation, and the urge to scratch |
| Medial parietal cortex | Subjective sensations of itch and pain, memory, and attention. |
| Insular cortex | Unpleasantness of itch |
| Motor cortex | Preparation and execution of scratching |
Numerous mediators of itch have been described (Table 13.4) and the list is constantly growing. In the skin, neurotransmitters are synthesized not only by nerve fibers, but also by Merkel cells, Langerhans cells, keratinocytes, melanocytes, granulocytes, lymphocytes, monocytes, macrophages, and mast cells [102]. As a result, itch is not only a sensation evoked by external stimuli, but also by many inflammatory processes occurring in chronic cutaneous disorders. Concerning the mediators, itch can be divided into histaminergic and non‐histaminergic. Histamine, regarded as a classic mediator of itch, is released from mast cells during inflammation or stimulation by allergens and induces itch by stimulating histamine receptors on unmyelinated C‐fibers [87]. Four types of receptors were described (H1, H2, H3, H4), with H1‐receptor mostly associated with the treatment of various types of itch with H1‐antagonists. After intradermal injection of histamine, wheals, flares, and itch appear, which supports the role of histamine in eliciting urticaria and associated itch [88]. However, in other dermatoses the importance of histamine varies and other mediators are relevant. Acetylcholine was associated with itch in AD [79]. Reddy et al. [103] researched the cowhage (Mucuna pruriens) induced itch and reported that mucaine, a cysteine protease present therein, is a ligand of protease‐activated receptors (PARs), such as PAR‐2 and PAR‐4. The role of the immune system is significant in the pathogenesis of itch, as different types of cells produce and release cytokines, such as interleukin (IL)‐2, IL‐13, IL‐17, or IL‐22. Moreover, from the clinical point of view, opioids are another substance that exert their role in promoting the occurrence of itching, but on the other hand they may also reduce this sensation. Approximately 2%–10%of patients treated systemically with opioids develop itching, with the increased risk following epidural, intraspinal, and especially intrathecal administration of morphine [96]. Opioid receptors are present both in the CNS and the skin [104]. It was shown that the activation μ‐opioid receptors increase itch [105] whereas the alleviation of this symptom occurs after administering μ‐opioid antagonists or κ‐opioid agonists [104]. Apart from the neurogenic inflammation promoting itch in inflammatory dermatoses (e.g. psoriasis) [106], the role of aberrant innervation of the epidermis and dermis [107, 108] as well as an altered parasympathetic response, were postulated as precipitating factors of itch [109], the latter especially in the context of chronic stress.
Table 13.4 Mediators of itch listed alphabetically.
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Supported by everyday clinical practice, itch is closely related to skin dryness, which is also referred to as xerosis. It is a phenomenon of composite pathogenesis and marked frequency, especially in a subset of maintenance HD patients with ESRD [50] or the elderly [20]. As reviewed by Szepietowski et al. [110], several studies demonstrated that xerosis of moderate to severe intensity may be associated with a 50%–100% increase in uremic pruritus, while xerosis severity was supposed to be related to itch severity. This warrants the frequent use of emollients, as they reduce xerosis, decrease itch intensity, and break the vicious itch‐scratch‐itch cycle.
Apart from factors that promote the development of itch, itch‐inhibiting factors were also studied, with promising prospects for future therapeutic approach. Among many, the role of thermal, mechanical, and electrical counterstimuli was postulated, as well as the importance of glycine, gamma‐aminobutyric acid (GABA), dynorphin, glutamate release associated with vesicular glutamate transporter VGLUT2 transporter and Transient Receptor Potential Vanilloid‐1 (TRPV‐1), as well as targeting phosphodiesterase 4 (PDE4), H4 receptors, or Nerve growth factor (NGF) receptors tropomyosin receptor kinase A (TrkA) by selective antagonists [111–116].
Some investigators have pointed out that itch might be considered a contagious phenomenon [117–119]. This may be regarded as a nocebo effect which is associated, in contrast to a placebo effect, with an unfavorable reaction of an individual based solely on a suggestion. The social contagion of itch could be associated with certain areas of the brain, such as anterior insula, premotor cortex, primary somatosensory cortex, and prefrontal cortex [120].
Burden of the Disease
Particularly in cases of CI, patients experience significant deterioration in multiple aspects of everyday life, posing a significant burden for an affected individual to deal with. In general, HRQoL may be defined as a status of well‐being in emotional, physical, social, and functional health‐related dimensions [121]. Regarding the relationship between CI and HRQoL, an abundance of studies have been published, especially for most common dermatological conditions, occasionally including children as well. As an example, in a study by Holm et al. [122] the data were obtained from 250 patients aged four years and older. HRQoL domains were measured using Dermatology Life Quality Index (DLQI) or Children Dermatology Life Quality Index (CDLQI). The mean values in these questionnaires were 9.79 and 7.15 points, respectively. The “itch” variable was among the highest in DLQI/CDLQI, scoring 1.8 ± 0.8 points in adults and 1.6 ± 0.8 points in children. Concerning the severity of itch, no statistically significant difference was noted between adults and children (5.29 points vs. 4.91 points; p = 0.379). Reich et al. [123] investigated 102 patients with plaque psoriasis and itch concerned 89.2% of subjects, with a mean VAS intensity of 4.2 ± 2.4 points. The mean DLQI score was 12.2 ± 7.0 points and the presence of CI significantly decreased HRQoL compared to patients without CI (12.2 ± 7.0 points vs. 6.8 ± 7.1 points, respectively; p = 0.02). Additionally, the intensity of itch correlated with stigmatization (measured by a six‐item Stigmatization Scale) as well as several domains measured by the Feelings of Stigmatization Questionnaire (“Feeling of being flawed,” “Sensitivity to other attitudes,” and “Secretiveness”). In another study, Amatya et al. [36] reported that CI negatively affected mood in 60% of psoriatic individuals, followed by concentration (47%), sleep (35%), sexual desire (21%), and appetite (11%). The influence of nighttime itch on sleep duration and quality in AD individuals has been proven in several papers [124, 125]. The effect on sleep of CI has also been reported in hidradenitis suppurativa [126]. The relationship between CI and HRQoL aspects was also analyzed in patients suffering from other dermatological disorders, the prominent examples being dermatomyositis [127], systemic sclerosis, [128], or cutaneous T cell lymphoma [129]. Decreased quality of life (QoL) was also noted in patients suffering from uremic itch [130, 131]. Suseł et al. [130] observed HRQoL scores assessed by SF‐36 questionnaire among patients with CI as compared to patients without CI (93.0 ± 20.4 vs. 99.6 ± 19.9 points, p = 0.03). General perception of health was worse among pruritic patients (p = 0.0003). Moreover, Beck’s Depression Inventory (BDI) was used in order to determine depression prevalence and severity. DLQI score and intensity of itch assessed with VAS (R = 0.56, p < 0.0001) and four‐item Itch Questionnaire (R = 0.48, p < 0.0001) were positively correlated. Recently, our group has also observed that a significant proportion of patients with ESRD with CI present alexithymia, which is a personality trait characterized by inability to express emotions [132]. When assessed by the Bermond‐Vorst Alexithymia Questionnaire (BVALQ‐40) the patients with CI (n = 42) achieved lower scores in the “fantasizing” domain than those without CI (n = 48) (21.7 points vs. 25.9 points, respectively; p < 0.05).
The other aspect closely associated with CI is stress. This phenomenon has several definitions, e.g. “the nonspecific response of the body to any demand made upon it” [133] or “a relationship with the environment that the person appraises as significant for his or her well‐being and in which the demands tax or exceed available coping resources”.[134]. The relationship between itch and stress is multidimensional and both entities may influence each other in different ways. As reviewed by Grandgeorge and Misery [135], in AD patients stress induces the release of neuropeptides and hormones, which constitute relevant elements of the neuro‐endocrino‐immune‐cutaneous system (NEICS) and hypothalamo‐pituitary‐adrenal axis (HPA axis). For example, mast cells synthesize corticotrophin‐releasing hormone (CRH) and its receptors, cytokines, SP, serotonin, TNF (tumor necrosis factor)‐α, NGF, tryptases, and chymases, which contribute to the development of neurogenic inflammation. Interestingly, in a study by Kim et al. [136] fMRI was utilized to determine crucial areas of brain associated with stress‐induced itch, and it was revealed that hippocampus and subcortical structures are involved. It is evident that stress may induce or exacerbate CI [28, 40, 137, 138], however, the presence of itch results in increased stress level experienced by an affected patient. These observations account for reciprocal perpetuation of stress and itch, as well as associated difficulties in breaking the vicious “itch‐scratch‐itch” cycle. Our group reported that psoriatic patients (n = 79) suffering from heavy or extremely heavy stress were more susceptible to the occurrence of itch (p < 0.05) (evaluated by Social Readjustment Rating Scale and self‐assessment method), while the severity of stress and the intensity of itch were positively correlated (p = 0.015) [138]. In a recent study conducted on 100 patients with plaque psoriasis, 49% of respondents deemed emotional stress as a factor inducing psoriasis, whereas 61% reported exacerbations of the disease caused by stress [139]. Yosipovitch et al. [28] assessed 100 Chinese patients with AD, among which 87% reported daily itch. The onset of itch was associated with stress in 22%, while other factors included heat (60%), sweating (57%), and dust (29%). The severity of itching was augmented by stress in 71% individuals, with other relevant factors being sweat in 96%, dryness (71%), physical effort (73%), activity (55%), specific fabrics (64%), and hot water (48%).
It must be noted that the presence of the disease and associated bothersome symptoms such as itch negatively influences not only the affected patients, but also their families [125, 140], especially in pediatric patients.
Diagnosis
Based on abundant pathogenesis of itch and numerous dermatological and systemic disorders that may lie at the basis of this symptom, the diagnostic measures in CI are profuse. In order to instigate treatment individually for each patient, it is necessary to determine the underlying cause of CI. Although occasionally this proves impossible, at the first step the physician is encouraged to thoroughly take the patient’s history. The location, intensity, and time onset of itch, quality of itch (e.g. burning, stinging, crawling), coexistence with skin lesions, possible causative factors (infections, drugs, food, etc.), exacerbating and alleviating factors, reaction to previous treatment modalities, coexisting comorbidities and pharmacotherapy, known hypersensitivity reactions, family history, occupational and associated exposures, leisure activities, smoking, alcohol consumption, and recreational drug use have to be taken into account. This data may be acquired not only from patients, but also from their families or caregivers, based on their everyday observations, especially in children or the elderly. Medical documents provided by the patients may support the physician with relevant data, although thorough analysis may be time‐consuming and difficult to perform initially. After gathering all the necessary information it is valuable to directly ask the patient if he or she has something else to add concerning their symptoms that was not already addressed. It must be noted that some patients suffer from severe itch which results in marked distress, irritation, and, although rarely, hostility toward the physician. From the clinical experience of the authors, this behavior was noted especially in patients presenting scabies, factitious dermatosis, and delusional infestation. Complete examination of the whole skin, appendages, and mucosa is recommended. A dermatologist may aid oneself with diascopy or dermoscopy. In the case of children it is necessary to obtain the parent’s agreement prior to the examination. Notwithstanding the examination of the skin, it is also important to inspect other organs as well, e.g. via palpation. Otherwise, enlarged liver, spleen, or peripheral lymph nodes may be omitted. These diagnostic clues may direct the physician’s attention toward certain dermatological and/or systemic conditions (Table 13.5).
Table 13.5 Clinical data and possible underlying causes of itch.
| Relevant information from patient’s history and/or characteristic features in clinical examination | Possible diagnosis underlying the sensation of itch |
| Lesions located on hands, around the umbilicus, on mammary glands and genital organs, burrows present in the skin, itch exacerbates at night. Pruritus in family members/caregivers and medical staff | Scabies |
| Lesions in the areas exposed to water (usually several hours following the contact), swimming in fresh water (e.g. lakes) | Swimmer’s itch (cercarial dermatitis) |
| Polymorphic (erythema, papules, vesicles, pustules, urticarial) lesions on buttocks, knees, and elbows, associated intestinal problems, exacerbations after diet rich in gluten and iodium, rapid and dramatic improvement (occasionally next day) after instigating dapsone | Dermatitis herpetiformis |
| Chronic itch (occasionally without lesions such as erythema, papules, vesicles, bullae, crusts, urticarial lesions), usually in an elderly person, polypharmacy, intake of cardiologic drugs (especially diuretics) | Bullous pemphigoid |
| Small urticarial lesions occurring shortly after physical exercise or excessive environmental heat | Cholinergic urticaria |
| Itchy reddish and brownish macules and papules, urticarial lesions appear minutes after scratching the lesions (Darier’s sign) | Maculopapular cutaneous mastocytosis (urticaria pigmentosa) |
| Itch, tingling, paresthesias, pain, usually in asymmetric fashion on the face or trunk, followed by erythema, papules, vesicles, erosions, crusts, scars. Elderly patients and/or associated immunosuppression | Zoster |
| Secondary skin lesions (excoriations, erosions, nodules, fissures). Patient brings specimens for analysis in plastic bags, containers, or matchboxes (specimen sign or matchbox sign), convinced of the causal role of parasites | Delusional infestation |
| Secondary skin lesions in asymmetric distribution (more pronounced contralaterally to dominant hand and within reach), with otherwise healthy underlying skin, associated psychological and/or psychiatric morbidities | Factitious disorder |
| Severe pruritus after contact with hot water. | Polycythemia vera (PV) |
| Itchy lesions in the brachioradial area, exacerbated by sun, ice‐pack sign (alleviation due to local contact with ice), associated cervical spine abnormalities | Brachioradial pruritus |
| Females in the 5th or 6th decade of life, chronic fatigue, initially itch is limited to palms and soles | Primary biliary cirrhosis |
Among additional diagnostic measures, a basic set of laboratory examinations is recommended in CI patients of unknown etiology (Table 13.6).
Table 13.6 First‐step lab screening for possible causes of CI.
Source: According to Weisshaar et al. [6].
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If the aforementioned measures do not support any diagnosis, or the clinical image is unclear, additional examinations can be performed, as reviewed by Weisshaar et al. [6]. These include, among others, phosphate, parathormone, antinuclear antibodies (ANA), serology for viral hepatitis, stool for parasites, chest X‐ray, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), cutaneous biopsy, bone marrow aspiration biopsy, etc. Concerning cutaneous biopsy, the specimen may be subjected to histological examination as well as direct immunofluorescence examination. It is important to refer the patient to specialists other than dermatologists if necessary or doubts should arise.
Treatment
From a clinical point of view, the subject of managing CI can be divided into several groups: general recommendations applicable to most patients, as well as topical therapy, phototherapy, systemic therapy, and miscellaneous modalities. In case of itch associated with systemic disorders it is necessary to treat the underlying disease appropriately according to current standards, while drug‐induced pruritus requires withdrawing of the causative drug. Currently, no universal substance for managing acute and chronic itch is available, reflecting the extremely rich and still not completely understood pathogenesis. Topical therapy, phototherapy, systemic, and miscellaneous therapy modalities are described in Table 13.7.
Table 13.7 Treatment modalities for itch.
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General Recommendations
Xerosis of the skin promotes the development of itch, therefore the prevention of xerosis decreases the prevalence or severity of itch. Patients should avoid dry climate, heat, alcoholic compresses, and ice packs. As reviewed by Weisshaar et al. [6], frequent washing and bathing is also inadvisable, as well as contact with irritant substances, aeroallergens (dust and dust mites), hot and spicy foods, and large amount of drinks and alcohol. Excessive excitement, strain, and negative stress also exacerbate CI. Several bath‐related recommendations include using mild non‐alkaline soaps, moisturizing syndets (synthetic detergents), and bathing oils; the bath should be performed in lukewarm water with a duration of no more than 20 minutes. When using towels, it is inadvisable to rub the skin; instead the skin should be dabbed dry. Frequent application of emollients is advised, especially shortly after bathing when skin is still moist. The preferable clothing worn by individuals suffering from CI is made up of cotton or silver‐based textiles. Additionally, the patients should be encouraged to cut their nails short in order to minimize the irritation of the skin during scratching episodes [141].
According to Schut et al. [142], the psychological interventions that aid patients with CI include habit reversal training (HRT), relaxation techniques (progressive muscle relaxation and autogenic training), and cognitive‐behavioral therapy (CBT). Educational programs focused on increasing coping abilities are also beneficial for those patients and their families [143–146]. Certain studies have also demonstrated that specialized or multidisciplinary itch clinics might be of great importance in managing patients with CI [147, 148].
Topical Therapy
Emollients are a mainstay of therapy for CI regardless of the cause. These substances leave a fine occlusive layer of non‐physiological lipids or oils (e.g. petrolatum or mineral oil) on the skin surface, resulting in the reduction of water loss [149]. Additionally, they may also contain humectants (e.g. urea, glycerol), physiological lipids (ceramides, cholesterol, and free fatty acids) and antipruritic substances. As a result, emollients replenish skin barrier, decrease inflammation, and alleviate itch. Recent studies have shown that prophylactic application of emollients in infants leads to decreased frequency of AD [150, 151]. In AD patients, emollients should be used liberally and frequently, in a minimum dose of 150–200 g per week in young children, and up to as high as 500 g per week in adults [152]. In acute flares they are poorly tolerated by the inflamed skin, so it is necessary to treat the exacerbation first. It was proven that the use of emollients with topical corticosteroids (TCs) results in reduction of itch in AD [153–155]. Moreover, emollients provided steroid‐sparing effect, which is useful in the context of a long‐term application. In uremic itch, several randomized, double‐blind trials were performed. According to Balaskas et al. [156] an oil‐in‐water emulsion containing 15% glycerol and 10% paraffin improved uremic xerosis, as well as itching. Castello and Milani [157] demonstrated that a lotion containing 10% urea and dexpanthenol successfully alleviated uremic xerosis and itch in HD patients. Chen et al. [158] reported the usefulness of gamma‐linolenic acid in 2.2% cream on refractory uremic itch.
Topical anesthetics, such as lidocaine, are sodium channel blockers that may inhibit abnormal activity in peripheral nerve endings [159]. Apart from topical lidocaine utilized in various itchy conditions [160], lidocaine‐prilocaine cream is used in experimentally induced itch [161] and notalgia paresthetica [162], whereas bath oil containing polidocanol and pramoxine 1% lotion was successfully evaluated in uremic itch [163, 164]. In a recent study, a lipoderm cream containing 10% ketamine, 5% amitriptyline, and 5% lidocaine was successfully evaluated on 96 patients with CI [165]. The proposed mechanism of action on peripheral nerve fibers was due to the blockade of sodium channels and N‐methyl‐D‐aspartate receptor.
Menthol (also termed mint camphor) is a cyclic monoterpene alcohol found as a major constituent in the essential oils of cornmint and peppermint [166]. Due to interaction with cold‐sensitive transient receptor potential channel (TRPM8), menthol exerts its cooling effect when inhaled, chewed, consumed, or applied locally on the skin. The antipruritic effect of menthol in humans was demonstrated by Bromma et al. [167]. In a study by Panahi et al. [168] itch due to exposure to sulfur mustard was significantly relieved after a topical application of combined 1% menthol and 1% phenol. Recently, it has been shown that cold stimulation, along with application of trans‐cinnamaldehyde and L‐menthol, relieved histamine‐induced itch in 13 healthy volunteers [169].
Camphor is a white, crystalline substance characterized by a strong odor and pungent taste derived from the wood of Cinnamomum camphora and other trees of laurel family [170]. As a result of a strong TRPV3 and transient TRPV1 activation, as well as inhibition of TRPA1, this substance exerts antipruritic effect [171]. Haught et al. [172] reported a case of HES‐induced itch successfully treated with a lotion containing 0.5% camphor and 0.5% menthol. In a recent study (n = 146), 16% of patients with epidermolysis bullosa utilized a topical combination of menthol, camphor, and eucalyptus oil with a mean effect on itch assessed as “a little reduction of itch”.[173].
Topical corticosteroids (CS) are widely used in a variety of disorders due to their immunosuppressive, anti‐inflammatory, and antiallergic effects exerted on primary and secondary immune cells, tissues, and organs [174]. Topical CS are prescribed in several cutaneous conditions presenting with CI, including AD [152], psoriasis [175], contact dermatitis [176], LP [177], CLE [178], bullous pemphigoid (BP) [179], lichen sclerosus [180], and others. Their usefulness in treating itch lies in their ability to suppress inflammatory processes underlying the pathogenesis of a dermatosis. In AD, wet‐wrap dressings with diluted corticosteroids may be applied for up to 14 days [152]. This method provides swift alleviation of symptoms, including itch. The prolonged use of topical CS should be weighed against their potential adverse effects, therefore those with favorable safety profiles are preferable (mometasone furoate, methylprednisolone aceponate, and fluticasone propionate).
Among topical calcineurin inhibitors (TCIs), tacrolimus 0.03% and 0.1% ointment, as well as pimecrolimus 1% cream, are currently available. These immunomodulators inhibit the synthesis of proinflammatory cytokines via binding to intracellular protein termed macrophillin‐12 [181]. As a result, the synthesis of both Th1 and Th2 cytokines is blocked (IL‐2, IL‐3, IL‐4, IL‐5, INF‐γ, TNF‐α). TCIs were successful in alleviating itch in e.g. AD [182], psoriasis [183], prurigo nodularis [184], or lichen sclerosus [185]. TCI are registered in patients with AD, both in adults and children over two years old. In contrast to a classic reactive approach of AD treatment, which is focused on managing exacerbation of the disease, a proactive long‐term approach was conceived. Firstly, intensive topical anti‐inflammatory therapy is instigated to obtain clearance of visible lesions. Subsequently, low‐dose intermittent application of anti‐inflammatory agents to previously affected skin areas is applied to prevent disease exacerbation. Studies have demonstrated that proactive therapy with 0.03% or 0.1% tacrolimus twice weekly is safe and effective in AD patients to sustain clinical remission [186
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