Guidelines

In cooperation with the European Dermatology Forum (EDF) and the European Academy of Dermatology and Venereology (EADV)

Abbreviations and explanations

AD^: Atopic dermatitis

AEP : Atopic eruption of pregnancy

CGRP: Calcitonin gene-related peptide

CKD : Chronic kidney disease

CNS: Central nervous system

CNPG: Chronic nodular prurigo

CP: Chronic pruritus (longer than 6 weeks)

CPG : Chronic prurigo

CSU: Chronic spontaneous urticaria

DIF: Direct immunofluorescence

ICP: Intrahepatic cholestasis of pregnancy

IFSI : International Forum on the Study of Itch

IIF: Indirect immunofluorescence

IL: Interleukin

Itch: Synonym of pruritus

NRS : Numerical rating scale

NSAID: Non-steroidal anti-inflammatory drugs

PAR: Proteinase-activated receptor

PBC: Primary biliary cirrhosis

PEP : Polymorphic eruption of pregnancy

PG: Pemphigoid gestationis

Pruritus: A skin sensation that elicits the urge to scratch

PUO: Pruritus of undetermined origin

PTH: Parathyroid hormone

PV: Polycythaemia vera

RCT: Randomised controlled trials

SSRI: Selective serotonin re-uptake inhibitors

TRP: Transient receptor potential

UP : Uremic pruritus

UV: Ultraviolet

VAS: Visual analogue scale

VIP: Vasoactive intestinal peptide

VRS^: Visual rating scale

Chronic pruritus (CP) is a frequent symptom in the general population and in many skin and systemic diseases (1). Due to its severity and the fact that it is frequently refractory to therapy, it causes a high burden and impairs quality of life. This guideline addresses all causes and types of CP including chronic prurigo. In its early stage, CP is considered a symptom of the underlying disease. However, with time, CP may develop its own dynamics that are no longer linked to the course of the underlying disease. In this stage, and much like chronic pain, this can be considered a distinct syndrome (CP syndrome) or even a disease in its own right. The observation that different patients with CP report similar severity, course and burden of CP despite the diversity of the underlying origins supports the view that CP requires independent consideration. Nevertheless, this guideline presents a diagnostic and therapeutic approach that is applicable to all types of CP. However, as a consequence of the diversity of possible underlying diseases, each form of CP should also be considered individually. Studies have demonstrated that early intervention in certain types of CP may lead to a significant improvement [e.g. therapy of polycythemia vera-associated aquagenic pruritus with janus kinase (JAK) inhibitors].

Still, there is a significant lack of randomised controlled trials (RCTs) investigating different types of CP in detail, which can be explained by the diversity and complexity of this symptom, the multifactorial aetiologies of pruritus and the lack of well-defined outcome measures, biomarkers and therapy targets. To complicate matters, RCTs exist for some types of pruritus, but with conflicting results. However, new therapies for improved medical care have been suggested and are summarised in this guideline. Expert recommendations are also provided. In addition, if the underlying cause is detected, disease-specific guidelines should be consulted [e.g. atopic dermatitis (AD) (2–5), urticaria (6), scabies (7), adult palliative care (8)]. The health care systems in many countries and their social economic situation with ever diminishing financial resources increase the need for guidelines. These recommendations are based on a consensus of participating countries, while also allowing for adaptation to country-specific treatment modalities and health care structures. Furthermore, it should be borne in mind that several topical and systemic therapies can only be prescribed “off-label” and require informed consent. If such “off-label” therapies cannot be initiated in the physician’s office, cooperation with a specialised centre for pruritus might be helpful. The guideline addresses all medical disciplines that work with patients suffering from CP.

This updated and revised guideline considers the Appraisal of Guideline Research and Evaluation Instrument (AGREE 2015) and the methods of the GRADE working group (www.gradeworkinggroup.org). All consented recommendations are written at the end of each section on treatment in Section 6.

The definitions presented in this guideline are based on the terminology defined by the International Forum for the Study of Itch (IFSI). The European participants of this guideline agreed to use this terminology. All contributors accept pruritus and itch to be synonymous. This guideline also defines pruritus/itch as a sensation that provokes the desire to scratch. Patients do not only scratch; they also rub, pinch or damage their skin with devices (all summarised from this point onward under the term scratching). In some diseases involving itch, patients’ scratching does not lead to skin damage (e.g. urticaria); in other diseases, scratching leads to a worsening of itch (e.g. urticaria factitia) and is accordingly avoided. These differences hinder scratching or scratch lesions from serving as common objective markers for the severity of itch.

According to the IFSI, CP is defined as pruritus lasting 6 weeks or longer (9). This is a practical distinction defined by clinicians in order to facilitate the decision to perform a diagnostic work-up. In some cases, pruritus may precede the diagnosis of the underlying disease by years (premonitory pruritus); in others, it is the early sign of a neoplastic disease such as Hodgkin lymphoma (paraneoplastic disease). In line with the IFSI, the term “pruritus sine materia” will not be used in this guideline (10). In patients with no identified underlying disease, the term “pruritus of unknown origin” or “pruritus of undetermined origin” (PUO) is used. The term “pruritus of unknown aetiology” should be avoided as in most clinically well-defined forms of pruritus the neurobiological mechanisms of CP are unknown [e.g. chronic kidney disease (CKD)-associated pruritus].

The IFSI classification comprises a clinical distinction of patients with Group I pruritus on primarily diseased/inflamed skin, Group II pruritus on normal skin and Group III pruritus with chronic secondary scratch lesions (9). According to this classification, the aetiology of CP is classified into categories as “dermatological”, “systemic”, “neurological”, “somatoform”, “mixed origin” and “others” (9). Neurological pruritus refers mostly to diseases involving the central and/or peripheral nervous system resulting in diseased or malfunctioning neurons firing action potentials with origins at any point along the afferent pathway (11, 12). In most cases, this is better described as neuropathic pruritus inducing an overlap of pain, pruritus and par- or dysaesthetic sensations. Somatoform pruritus is defined as pruritus where psychic, psychiatric and psychosomatic factors play a critical role in the onset, intensity, aggravation or persistence of the pruritus.

Data on the prevalence of CP is very limited. The prevalence of CP seems to increase with age (13), but epidemiological studies are lacking. It is estimated that about 60% of the elderly (over 65 years of age) suffer from mild to severe occasional pruritus every week (14), referred to as pruritus in the elderly. A population-based cross-sectional study in 19,000 adults showed that about 8–9% of the general population experienced acute pruritus, which was a dominant symptom across all age groups (15). Moreover, it was revealed that pruritus is strongly associated with chronic pain (16). Recent surveys indicate a point prevalence of CP to be around 13.5% in the general adult population (17, 18) and 16.8% in employees seeking early detection cancer screenings (19). The 12-month-prevalence of CP was 16.4% and its lifetime prevalence 22.0% in a German population-based cross-sectional study (17). All these data suggest a higher prevalence of CP in the general population than previously reported (17). For the first time, a recent study found a 12-month cumulative incidence of CP of 7% and incident pruritus was significantly associated with higher age (18). Multivariate analysis revealed eczema, dry skin, asthma, liver disease, an elevated body mass index and higher anxiety scores to be determinants of prevalent CP (18).

CP may be due to both dermatological and systemic diseases. However, the origin of pruritus is unknown in up to 20% of affected patients (1). For example, pruritus is present in all patients with AD and urticaria (20) and in about 80% of psoriatic patients (21, 22). Systemic diseases such as primary biliary cirrhosis (PBC) and CKD are associated with CP in 80–100% and 25–70%, respectively (23); however, the great variability of numbers may be explained by a lack of disease definition and prevalence estimates. The first representative cohort study investigating CP in haemodialysis patients showed 25.2% to suffer from CP (point prevalence), while the lifetime prevalence was 35.2% (24). Pruritus is a frequent symptom in patients with Hodgkin’s lymphoma, occurring in more than 30% of this patient group (1). In a retrospective study on 139 patients with CP, most cases of severe and long-lasting itch were found in patients with multiple systemic diseases and in patients with pruritus of unknown origin, while pruritus of the scalp and face was often a presenting symptom of psychiatric disease (25).

Only few studies have addressed the frequency of pruritus in primary care. According to the Australian BEACH Program, a continuous national study of general practice activity, pruritus was the presenting complaint for 0.6% of consultations, excluding perianal, periorbital or auricular pruritus (26). In the UK, the fourth national study of morbidity statistics from general practice (27) was conducted in 1991/1992 with 502,493 patients (1% sample of England and Wales), resulting in 468,042 person-years at risk. Pruritus and related conditions were present in 1.04% of consultations (male, 0.73%; female, 1.33%). In Crete, where patients with cutaneous disorders mostly present to hospitals rather than to primary care centres, PUO was diagnosed in 6.3% of 3,715 patients in 2003 (28). In Germany and the Netherlands the prevalence of pruritus as a reason for consultation in primary care resulted in approximately 0.7% of all consultations, most of these resulting in a diagnosis of skin disease (SESAM2 study from 1999–2000, unpublished data from the Dutch Transition project from 1995 to 2003) (29).

The reader is referred to Section 4.2 for a more detailed discussion of the epidemiology of CP in specific patient populations.

4.1.1.Chronic pruritus in lesional and non-lesional skin. CP may occur as a common symptom in patients with dermatoses with primary skin lesions and systemic, neurologic and psychiatric/psychosomatic diseases without primary skin lesions (9). In the 3 latter instances, the skin may appear normal or have skin lesions induced by scratching. In chronic and severe cases, patients can develop chronic prurigo (CPG), which may present as chronic nodular prurigo (CNPG) or other subtypes (30). In these cases, a clinical diagnosis is difficult to establish and diagnostics should be performed. Systemic diseases frequently accompanied by pruritus are summarised in Table I. In recent years, several entities of pruritus on inflamed and normal skin have been characterised in more detail. Some frequent patient populations and systemic diseases inducing CP are presented in the following sections.

4.1.2. Pruritus in kidney disease. The pathophysiology of CKD-associated pruritus is unknown. Implicated mechanisms have included direct metabolic factors: increased concentrations of divalent ions (calcium, magnesium), parathyroid hormone (PTH), histamine and tryptase, dysfunction of peripheral or central nerves, the involvement of opioid receptors (µ- and κ-receptors) and xerosis cutis (dry skin) have been suggested as likely candidates (31–39). Some data point to a possible role for micro-inflammation, which is relatively frequent in uraemia (31, 40). Two uremic toxins, p-cresylsulfate and indoxylsulfate, were recently suggested to be involved in the pathogenesis of CP in kidney disease (41).

One representative study on CP in 177 haemodialysis patients showed that 43.5% had normal looking skin (IFSI II), 37.9% had secondary scratch lesions including CPG (IFSI III) and 18.6% had a skin disease (IFSI I) (42).

4.1.3. Pruritus in hepatobiliary diseases (cholestatic pruritus). CP is a frequent symptom in patients with hepatobiliary disease and cholestasis due to mechanical obstruction, metabolic disorders or inflammatory diseases (43–45). It is termed cholestatic pruritus (ChP), although cholestasis is not a prerequisite of pruritus related to diseases of the liver. ChP may be quite severe and can even precede the diagnosis of, e.g. primary biliary cholangitis (PBC) by years (46, 47). Pruritus is less frequent in patients with infectious liver disease (hepatitis B or C) or toxic liver disease (e.g. alcohol-induced). The true prevalence of CP in hepatobiliary diseases is not known due to lacking epidemiological data. It seems that CP is most frequent in PBC, primary sclerosing cholangitis (PSC) and secondary sclerosing cholangitis (SSC). CP usually peaks in the evening and night, frequently presenting without any primary skin lesion but sometimes with secondary scratch lesions and CPG. It is often generalised, affecting palms and soles in the early stage (48).

It has recently been shown that increased serum autotaxin (ATX) [the enzyme that metabolises lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA)] levels, and thereby increased LPA levels, are specific for pruritus in cholestasis, including intrahepatic cholestasis of pregnancy and paediatric cholestatic disorders (44, 45, 47), but not for other forms of systemic pruritus (49). Rifampicin significantly reduced itch intensity and ATX activity in pruritic patients. The beneficial antipruritic action of rifampicin may be explained partly by pregnane X receptor (PXR)-dependent transcription inhibition of ATX expression (49). Successful treatment with µ-receptor opioid antagonists such as nalmefene and naltrexone supports the hypothesis that opioid receptors and a high opioid tone influences ChP (50).

4.1.4. Pruritus in metabolic and endocrine diseases. In endocrine disorders such as hyperthyroidism and diabetes mellitus, less than 10% of patients report pruritus (51, 52). In patients with hypothyroidism, pruritus is most probably driven by xerosis of the skin. Patients with primary hyperparathyroidism do complain of itch in a substantial number of cases (53). The pathophysiology of pruritus in primary hyperparathyroidism is not known. These patients often experience a lack of vitamin D and minerals (e.g. zinc etc.), which probably contributes to CP. Iron deficiency may be associated with CP (54). The mechanism for this is unknown. Iron overload as in haemochromatosis may lead to CP (55, 56). CP in metabolic and endocrine disease frequently occurs as generalised pruritus, but localised forms such as genital CP may occur, e.g. in diabetes mellitus (51, 57). The clinical picture is not specific, frequently accompanied by dry skin and sometimes showing secondary scratch lesions (IFSI III) (1).

4.1.5. Pruritus in malignancy. Several malignant disorders including tumours, bone marrow diseases, myeloproliferative and lymphoproliferative disorders may be accompanied by pruritus. The term “paraneoplastic pruritus” is used to describe pruritus in patients with cancer (58). The true frequency of this symptom in malignant disease is unclear and epidemiological data in this field are limited. One study in a cohort of cancer patients showed that 5.9% suffer from generalised itch (59). Gastrointestinal tumours and haematological malignancies were among the tumours that most commonly cause pruritus (59). Most of the patients affected do not exhibit specific dermatoses, but unaffected skin or non-specific eruptions with and without papules and excoriations. In general, the prevalence of pruritus in haematological malignancies is higher compared to non-haematological malignancies; it is estimated to be around 30% in Hodgkin lymphoma, around 15–50% in non-Hodgkin lymphoma and around 15–50% in polycythemia vera (PV) (58, 60). The mechanisms of pruritus in malignancy are still not understood. Several mediators and mechanisms have been discussed in the literature such as toxic products generated by the tumour itself, allergic reactions to compounds released and a direct affect on the brain or nerves (in brain tumours), the latter being referred to as neuropathic pruritus (14, 61). Recently, interleukin-31 (IL-31), a Th-2 cytokine, was found to be highly associated with itch in lymphoma and highly expressed in malignant T-cells (62). In PV, more than 50% of patients suffer from pruritus (60, 63, 64). Aquagenic pruritus with pinching sensations after contact with water is a characteristic but not necessary feature. It has been suggested that high levels of histamine released by the augmented numbers of basophilic granulocytes might trigger the itch (65). For PV this seems to be most pronounced in patients showing the JAK2 617V mutation (60, 66).

Pruritus in Hodgkin’s disease often starts on the legs and is most severe at night, but generalised pruritus soon ensues. Several factors such as secretion of leukopeptidases and bradykinin, histamine release and high IgE levels with cutaneous depositions may contribute to pruritus in lymphoma (67). Patients with carcinoid syndrome may experience pruritus in addition to flushing, diarrhoea and cardiac symptoms (68).

A recent population-based cohort study in 8,744 patients with CP showed that CP without concomitant skin changes is a risk factor for undiagnosed haematological and bile-duct malignancy (69). A nationwide Danish cohort study based on registry data showed a 1-year absolute cancer risk of 1.63%, and a 13% higher than expected number of both haematological and various solid cancers among patients with pruritus was found. This related in particular to haematological cancers, above all Hodgkin lymphoma (70); however, the study was unable to differentiate between acute and chronic itch.

4.1.6. Pruritus in infectious diseases. Acute or chronic pruritus may occur with skin infections and infestations, among which scabies is the most prominent example (71). Viral infections such as herpes simplex, herpes zoster and varicella can present with acute pruritus. CP may occur in 4% of herpes zoster patients, which is termed post-herpetic itch (1).

Some generalised infections are accompanied by pruritus. Above all, patients infected with human immunodeficiency virus (HIV) may develop CP, which can be the initial presentation of HIV infection. The true prevalence is not known but could be as high as 45% according to cross-sectional study (72). In a significant number of HIV patients itching has no detectable cutaneous or systemic cause; however, HIV patients are prone to develop pruritic papular eruption (PPE), a major cause of CP in African HIV patients (1, 73). There is evidence for a high association between prurigo and HIV infection, but regional variations need to be considered (73).

Whether toxocariasis infections lead to pruritus in a substantial number of patients remains to be confirmed (74). Pruritus has been reported in up to 15% of patients with chronic hepatitis C virus (HCV) infection and may be a presenting symptom (75).

4.1.7. Pruritus in neurological diseases. Space occupying lesions (tumours, abscesses, haemorrhage) of the nervous system and degenerative neurological diseases, e.g. multiple sclerosis, are rare causes of neuropathic pruritus with variable clinical presentation (76–79). Pruritus due to these neurological disorders may be the presenting symptom prior to diagnosis and could be transient, continuous or paroxysmal in nature (80). Entrapment syndromes of specific peripheral nerves such as notalgia paraesthetica, brachioradial pruritus, cheiralgia paraesthetica and meralgia paraesthetica present with pruritus localised to a specific anatomical area (81–85). A typical accompanying clinical finding is the presence of various paraesthetic sensations, including a feeling of electrical current, prickling, tingling, burning and numbness. A recently recognised clinical phenomenon is generalised pruritus triggered by a localised neurological disorder, e.g. brachioradial pruritus (86, 87). In a broader perspective, neuropathy of small cutaneous nerve fibres in dermatological disorders such as keloids, burns and post-zoster pruritus may also be classified under pruritus in neurological diseases (88–91). Analogously, pruritus in several systemic diseases associated with small fibre neuropathy is similarly included, the list being led by diabetes (92).

4.1.8. Pruritus in psychiatric diseases. It is estimated that at least 32% of psychiatric patients on a psychiatric ward report itch (93). A large population survey showed that adults with depression are twice as likely to experience itch (94) and that the severity of itch increases with symptoms of depression among adolescents (95). The pathophysiological background seems to correlate with production and interaction of neuropeptides such as serotonin (96). Individuals with anxiety tend to itch over time and this has implications for the therapeutic approach (97). Symptoms of obsessive compulsive disorder can manifest with CP, as seen in patients with skin picking (98, 99). “Scalp itch” is often a symptom of depression or a precursor to psychosis. CP can be a symptom in psychotic patients, manifesting as delusional parasitosis, a rare condition that is challenging to treat both for dermatologists and for psychiatrists (100). Overall, the psychiatric population is little studied with regard to skin symptoms, but it is now established that psychiatric morbidity contributes to the pathophysiology of CP in the absence of skin disease (101).

4.1.9. Drug-induced chronic pruritus. Drug-induced pruritus without visible skin lesions accounts for approximately 5% of adverse cutaneous reactions. Almost any drug may induce pruritus by various pathomechanisms (Table II) (102). Some may cause urticarial or morbilliform rashes presenting with acute pruritus. Furthermore, drug-induced hepatoxicity or cholestasis, as well as drugs that cause xerosis, photoallergy or phototoxicity may produce CP on normal skin (103). Increased release of pruritogens (histamine, serotonin, neuropeptides), neurological alterations and neuronal deposition in the skin have also been suggested, but the pathogenesis of drug-induced itch is not fully understood (104). Hydroxyethyl starch (HES), a compound used for fluid restoration, can induce generalised or localised CP in 12–42% of treated patients (105). Duration depends on the cumulative dose, usually persisting for an average of 15 months (after HES deposits in the tissues have been metabolised). In approximately two-thirds of HES-induced pruritus it is generalised and presents without any skin lesions (1, 102).

4.2.1. Chronic pruritus in the elderly. Only a small number of studies have investigated pruritus in the elderly. They are characterised by selection bias and differing endpoints (pruritic skin disease or itch). An American study of cutaneous complaints in the elderly identified pruritus as the most frequent, accounting for 29% of all complaints (106). A Turkish study in 4,099 elderly patients found that pruritus was the most common skin symptom, affecting 11.5% of patients. Women were more frequently affected (12.0%) than men (11.2%). Patients older than 85 years showed the highest prevalence (19.5%) and pruritus was present more frequently in winter months (12.8%) (107). In a Thai study, pruritic diseases were the most common skin complaint (41%) among the elderly, while xerosis was identified as the most frequent ailment (38.9%) in a total of 149 elderly patients (108).The exact mechanisms of CP in the elderly are unknown. Pathophysiological changes of the aged skin, decreased function of the stratum corneum, xerosis cutis, co-morbidities and polypharmacy may all contribute to its aetiology (109).

4.2.2. Chronic pruritus in pregnancy. There are no epidemiological studies assessing the prevalence of CP in pregnancy. Pruritus is the leading dermatological symptom in pregnancy, estimated to occur in about 18% of pregnancies (110). It can present as specific dermatoses of pregnancy [polymorphic eruption of pregnancy (PEP), pemphigoid gestationis (PG), intrahepatic cholestasis of pregnancy (ICP), atopic eruption of pregnancy (AEP)], but may also occur in other dermatoses coinciding by chance with pregnancy or in pre-existing dermatoses (110–113). Indeed, one of every 5 consultations for pruritus in pregnancy is not related to the specific dermatosis of pregnancy (114).

PEP is one of the most common gestational dermatoses, affecting around one in 160 pregnancies. While PG, PEP and ICP characteristically present in late pregnancy, AEP starts before the third trimester in 75% of cases (1, 111). ICP is characterised by severe pruritus without any primary skin lesions; however, secondary skin lesions occur due to scratching. It is more prevalent among native Indians in Chile (27.6%) and Bolivia (13.8%) depending on ethnic predisposition and dietary factors (115, 116). ICP has decreased in both countries, e.g. to 14% in Chile. ICP is more common in women of advanced maternal age, multiple gestations, a personal history of cholestasis on oral contraceptives and during winter months. Scandinavian and Baltic countries are also more affected (1–2%). In Western Europe and North America ICP is observed in 0.4–1% of pregnancies (115–117). PEP is one the most common gestational dermatoses, affecting about one in 160 pregnancies. While PG, PEP and ICP characteristically present in late pregnancy, AEP starts before the third trimester in 75% of cases (1, 111). ICP is characterised by severe pruritus without any primary skin lesions, but secondary skin lesions occur due to scratching. It is a hormonally triggered, reversible cholestasis occurring in late pregnancy (late second or third trimester) in genetically predisposed women. The prevalence is around 1%, but varies: it is higher in Scandinavia, South America and South Africa (118). The aetiopathogenesis is multifactorial and involves genetic, hormonal and environmental factors such as seasonal variability and dietary factors (119).

4.2.3. Chronic pruritus in children. There are no epidemiological studies assessing the prevalence of CP in children (1, 110). The spectrum of differential diagnosis of CP in children is wide (110, 120), but is dominated by skin diseases, in particular AD. The cumulative prevalence of AD is between 5% and 22% in developed countries. The German Atopic Dermatitis Intervention Study (GADIS) showed a significant correlation between the intensity and severity of pruritus in AD and sleeplessness (121, 122). Chronic spontaneous urticaria (CSU) is a source of pruritus in approximately 3% of children (123), for which a complete characterization of the disease is needed.

A Norwegian cross-sectional questionnaire-based population study in adolescents revealed a pruritus prevalence of 8.8%. Pruritus was associated with mental distress, gender, sociodemographic factors, asthma, rhinoconjunctivitis and eczema (95). Itching of mild to moderate severity may occur in acne (124, 125).

If children are aged > 6 years, the visual analogue scale (VAS), numerical rating scale (NRS) or verbal rating scale can be employed (126). In order to accurately assess the impact of CP in a child’s life, some recommended scales include Skindex-16, Skindex-Teen, infant’s dermatology life quality index (127), children’s dermatology life quality index (128) and ItchyQoL (129). Instruments that measure the effect of the families’ quality of life include the dermatitis family impact questionnaire (130). The course of advanced learning for the management of itch (CALM-IT) task force recommend a multidisciplinary and multidimensional approach for children CP (120).

It must be assumed that systemic causes of CP in children are mostly based on genetic diseases or systemic diseases, e.g. biliary atresia or hypoplasia, familial hyperbilirubinemia syndromes, polycystic kidney disease or CKD (1, 131). Drug-induced pruritus without any specific skin symptoms appears to be rare in children (1). Common medications associated with CP in adults play a minor role in children due to limited use at that age.

Patient history and clinical examination are key to clarifying the aetiology of pruritus, which in turn allows adequate treatment. A number of typical features in the patient history may be helpful and sometimes even diagnostic to identifying the cause of pruritus, e.g. duration, localisation, time course of pruritus and trigger factors, as well as a detailed personal and family history. To obtain this information from the patient, it is helpful to go through their history with a patient history-based algorithm (Fig. 1). The following questions can help to compile a patient history:

• Duration and onset of itch (“When did itch start?”) enables a differentiation between acute and CP (more or less than 6 weeks) (9).
• Localisation of pruritus (“Where does it itch?”) makes it possible to distinguish localised pruritus from generalized pruritus.

Localized pruritus is usually caused by itchy dermatosis, when it occurs at localisations where inflamed skin is already present. Localised itch on primarily non-inflamed skin is suggestive for neurological disease, especially when itch appears in an asymmetrical pattern (12, 92, 132–134): unilateral localized pruritus on the back is typical for notalgia paraesthetica, whereas itch on lateral aspects of the arms (especially the forearms) is characteristic for brachioradial pruritus. Both diseases have a neuropathic origin (81, 135, 136). Pruritus may occur in internal diseases, where it can occur in typical localisations, e.g. on the back and legs in CKD-associated pruritus (42, 137) and on the palms and soles in cholestatic pruritus. Localised vulvar pruritus can be a symptom of iron deficiency (138).

Generalised pruritus can be caused by itchy dermatosis even if the inflamed skin does not show generalised spread, e.g. in patients with psoriasis (139). However, generalised pruritus on primarily normal skin is highly suggestive for not only internal but also neuropathic or psychiatric diseases (140) or use of a drug that causes CP. Interestingly, in one study, whole-body pruritus was found more frequently in patients with dermatosis than in pruritus due to systemic disease (73).

• Intermittent pruritus can be distinguished from constant itch by asking “When does it itch?”. Intermittent pruritus can be a symptom of spontaneous urticaria. In patients with factitial urticaria, pruritus occurs intermittently, typically starting as localised itch and generalising with scratching. Constant pruritus is typical for internal diseases, e.g. renal or liver diseases or pruritus in patients with malignant lymphoma.
• The time course of pruritus (“When is itch at its maximum/minimum?”) can be indicative for a number of diseases: nocturnal generalised pruritus in association with chills, fatigue and B symptoms (weight loss, fever and nocturnal sweating) is suggestive of malignancy such as Hodgkin’s disease. Seasonal pruritus during wintertime (“winter pruritus”) is found in exsiccation eczema in the elderly.
• Identification of pre-existing skin diseases in the patient history is crucial, especially if pruritus on primarily inflamed skin is assumed. In such cases, a history of AD, psoriasis or lichen planus is suggestive that pruritus has occurred due to an exacerbation of the known disease. An atopic background should always be verified or excluded. It is not uncommon for an atopic disposition to be the only explanation for the onset of pruritus in patients with PUO. However, the most important question to classify pruritus regards skin condition at the time of initial onset of pruritus (“How did the skin look when itch first appeared?”): if pruritus first appeared on primarily diseased (inflamed) skin, pruritic dermatosis – which needs to be diagnosed – is causative. If pruritus appeared on normal looking skin [“pruritus on primarily non-diseased (non-inflamed) skin”], one should consider a systemic, neuropathic or psychiatric disease, drug side effects, pregnancy or dermatosis without visible skin changes (9).
• History of pruritus (“How did pruritus or the skin develop over time?”) shows the dynamic of the disease course. Trigger factors and the relationship between pruritus and specific activities can be important: pruritus appearing during physical activity can be caused by AD, cholinergic pruritus and cholinergic urticaria. Pruritus provoked by skin cooling after emerging from a warm shower/bath can be a sign of aquagenic pruritus, polycythaemia vera or xerosis cutis.
• Intensity and quality of itch (burning, painful, stinging, prickling) are best quantified with special tools that have been developed for the assessment of pruritus. For intensity, validated categorical or continuous monodimensional scales, such as the NRS or VAS, are most commonly used. The quality of pruritus is assessed in a descriptive way by use of itch questionnaires. A validated questionnaire for quality of life assessment is the ItchyQol (141).
• Knowledge of pre-existing internal diseases is of importance when pruritus on primarily non-inflamed skin is assumed. In a patient with chronic renal failure or cholestatic liver disease, the primary disease will initially be suspected to cause itch. Unfortunately, there are no defined laboratory cut-off values (e.g. blood creatinine levels) that are indicative for the causative role of an internal disease.
• A complete history includes documentation of medication use and change of medication in the preceding 12 months prior to the onset of pruritus. Drugs that typically provoke pruritus include opioids, retinoids, antibiotics and new drugs for cancer therapy, especially epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitors, as well as tyrosine kinase inhibitors. In patients with a history of previous surgery and infusion treatments, hydroxyethyl starch (HES) should be considered as a possible cause.
• Family history is indicative of familial skin diseases or internal disorders that are accompanied by itch. Finally, the personal environment may be instructive: if multiple family members are affected by new-onset of pruritus, scabies or other parasites should be considered.

Clinical examination of the patient should always include a thorough inspection of the entire skin including scalp, nails, oral cavity and anogenital region. While examining skin lesions, the distinction between primary and secondary skin lesions is of the utmost importance, since this allows a distinction between the 3 clinical presentations of pruritus as proposed by the IFSI classification (9).

If primary skin lesions such as macules/erythema, vesicles, papulo-vesicles, blisters, pustules or wheals are observable and, according to the patient history, have been present since the onset of itch, pruritus on primarily diseased (inflamed) skin can be diagnosed. Further investigations can be performed to determine the underlying dermatosis, including skin biopsy, microbiological investigations and, in certain cases, laboratory testing (e.g. IgE, indirect immunofluorescence).

Secondary skin lesions encompass excoriations, ulcerations, necrosis, crusts, papules, nodules, lichenification, atrophy and scars, as well as hyper- and hypo-pigmentation of the skin. In patients with CP these lesions are most likely caused by scratching. If a patient with CP reports that no skin lesions were visible at onset, pruritus on primarily non-diseased (non-inflamed) skin can be diagnosed. An internal disease, medications, pregnancy or specific skin diseases could be causative. Laboratory and radiological investigations, adapted to the patient history and pre-existing diseases, are mandatory to obtain a final diagnosis.

If a patient presents with extensive scratch lesions with a duration of many months or years (e.g. CPG, CPGN), pruritus with chronic secondary scratch lesions is diagnosed. The underlying cause may be a systemic, neurological, psychiatric or dermatological disease. Skin biopsy, laboratory and radiological investigations, as well as procedures suited to the patient’s history and pre-existing diseases will yield a final diagnosis.

In addition to examining the entire integument, a general physical examination should be performed in all patients with unclear pruritus, including palpation of abdominal organs and lymph nodes, and a rectal examination.

Expert recommendation: We recommend taking a detailed history of any patient with chronic pruritus. This should include general characteristics of pruritus (e.g. duration, time course, localisation, intensity and quality), knowledge of the personal history, including precise information on medication and family history. We recommend a complete dermatological examination.

Laboratory screening, clinical and technical approaches and investigations are summarised in Tables III and IV. All this helps to follow a diagnostic algorithm (Fig. 1).

It is important to establish an individual antipruritic therapy regimen that takes into account the age of the patient, pre-existing diseases, medications as well as the quality and intensity of CP. Elderly patients, pregnant women and children need special attention (see Sections 6.6.1, 6.6.2 and 6.6.3). As the care of patients with CP often extends over a long period, with initial uncertainty about the origin of the pruritus, frustration regarding the failure of past therapies and general psychological stress frequently occurs. Taking a careful history on the occurrence and characteristics of pruritus is very important (see Section 5.1). The diagnostic procedures and therapy should be discussed with the patient in order to achieve the best possible concordance and compliance.

As a first step, the patient should be informed about general pruritus-relieving measures (Table V). These include simple and helpful tips such as keeping room temperatures low and applying moisturisers to improve skin barrier and reduce itching. Although many patients report that cold showers reduce itch, no scientific studies have been performed to confirm this observation. On the other hand, brief hot showers have shown itch-relieving effects in experimental studies applying heat to chronic pruritus and atopic skin (142, 143). Also, lukewarm baths with colloidal oatmeal may restore skin barrier and sooth pruritus (144). Moisturisers with water and liquid paraffin base are used in soothing creams and emulsions. Several active ingredients are used in emollients suitable for dry skin. The effects of urea (5–10%) and glycerol (20%) on pruritus are the best studied (145, 146). Propylene glycol (20%) and lactic acid (1.5–5%) may also contribute to hydration of the skin and to a reduction in pruritus (147). In addition, propylene glycol and lactic acid have antimicrobial properties, making preservatives redundant. Another antipruritic agent with antimicrobial properties is potassium permanganate, which can be used as an active ingredient in baths.

Emollients containing N-palmitoylethanolamine (PEA) (0.3%), an endogenous lipid, have been shown to significantly improve skin barrier function (148) and weak to moderate antipruritic and analgesic effects in experimentally induced pain, pruritus and erythema by topical application (149, 150). In (non-vehicle controlled) clinical trials and case series, it proved to have antipruritic effects in CPG, AD, CKD-associated pruritus and PUO (151–153), as well as analgesic effects in postherpetic neuralgia (154). In a monocentric, double-blind RCT of 60 patients with AD it was shown that the preservation and loss of moisture (measured by transepidermal water loss) were greatly improved with a PEA containing cream compared to the vehicle (148); however, a vehicle-controlled study with 100 subjects did not show any significant difference between the lotion with and without PEA (155). Thus a PEA-containing topical can be considered an emollient therapy. Allergenic compounds (e.g. fragrances or preservatives) and irritant substances (e.g. surfactants) in emollients should be avoided.

Prior to further symptomatic therapy, the patient should undergo a careful diagnostic evaluation, as well as treatment for any underlying disease (Fig. 1, Tables III and IV). Pharmacologic interventions for specific pruritic diseases, e. g. AD and urticaria, should be performed according to the current guideline of the specific disease and the field’s Cochrane Group (6, 7, 156–161).

If pruritus continues to persist, consecutive or combined step-by-step symptomatic treatment is necessary (Table VI). Before considering systemic treatment, patient adherence to topical treatment, including skin care, needs to be ensured (162). Severe generalised CP often requires multiple treatment approaches, which may be administered alone or in different combinations and sometimes repeated. Some therapies are not approved for CP and can only be prescribed “off-label”, which requires separate informed consent.

Expert recommendation: We recommend the use of moisturisers and emollients depending on the status of the skin.

CP can be addressed by treating the underlying disease, e.g. specific treatments for underlying dermatoses, avoidance of contact allergens, discontinuation of implicated drugs, specific internal, neurological and psychiatric therapies, surgical treatment of an underlying tumour or transplantation of organs. Normally, there is sudden relief of pruritus when the underlying disease improves, e.g. when Hodgkin’s disease responds to chemotherapy or when a patient with PBC has received a transplant. For some underlying diseases, specific treatments have proven to be successful in relieving pruritus, even if the underlying disease is not treated. Aetiology-specific treatments act on a known or hypothetically assumed pathogenesis of pruritus in underlying diseases. Evidence of efficacy can be found in controlled studies for only a few of these treatments. Treatments for CP in specific diseases are presented in Tables VII–XI. When deciding the choice of treatment, consideration should be given to the level of evidence, side-effects, practicability, costs, availability of a treatment and individual factors such as patient age.

6.3.1. Local anaesthetics. Local anaesthetics (LA) are a heterogeneous group of compounds, e.g. benzocaine, lidocaine and polidocanol. They act via different groups of skin receptors, interfering with peripheral neural transmission of pruritus. Topical LA are widely used for the symptomatic treatment of localised forms of CP, such as neuropathic pruritus, CKD-associated pruritus, post-burn pruritus and paraneoplastic pruritus, as well as in the palliative care setting (163).

In experimental studies, LA exhibited only limited antipruritic effects in both histamine- and cowhage-induced pruritus, with short-term duration (10 min) after topical application (164, 165). Successful use in the treatment of localised forms of pruritus such as notalgia paraesthetica has been reported in case series (166, 167).

Polidocanol, an anionic surfactant with local anaesthetic properties, selectively reduces cowhage-induced pruritus via PAR-2 inhibition (168). It is commonly used in different galenic formulations, alone (polidocanol 2–10%) or in combination with other active substances (urea) to treat larger skin areas, i.e. atopic skin.

Topical 1% pramoxine hydrochloride has been shown to ameliorate CKD-associated pruritus in a double-blind, placebo-controlled study and can be used to treat larger skin areas, also in combination with other antipruritic compounds (lactic acid, hydrocortisone) (169).

Ethyl chloride spray, a topical cooling and anaesthetic agent, reportedly reduces histamine-induced itch in experimental studies and finds limited application in localised pruritus secondary to allergy skin testing (170).

Expert recommendation: We suggest the application of topical anaesthetics for localised pruritus including polidocanol for selected cases of generalised pruritus.

6.3.2. Zinc, menthol and camphor. Although zinc oxide has been used in dermatology for over 100 years due to its anti-inflammatory, antiseptic and antipruritic properties and its safety, there is only scarce literature on its effects. Prescriptions of zinc are frequent, with concentrations varying from 10–50% in creams, liniments, lotions, ointments and pastes that are useful in the treatment of pruritus, especially localised forms of pruritus, in children as well as in adults (171). Calamine, which is often found in cooling liniments, contains 98% zinc oxide (171). In an experimental study zinc oxide was shown to be as effective as moderate potency corticosteroid in suppressing contact dermatitis (172).

Menthol is an alcohol obtained from mint oils, or prepared synthetically. Applied to the skin and mucous membranes, it causes a sensation of coldness, followed by an analgesic effect (171). Menthol is used in dusting powders, liniments, lotions and ointments in concentrations from 1% to 10% (171). It has been shown to have a cooling effect for up to 70 min and to act as a counter-irritant (173). Menthol binds to the TRPM8 receptor (174), which belongs to the same TRP family of excitatory ion channels as TRPV1, the capsaicin receptor. These two receptors have been shown to occasionally co-exist in the same primary afferent neurons and promote thermo-sensations at a wide range of temperatures, 8–28°C and >42ºC, respectively (174). First studies showed that topicals containing the TRPM8 agonist combination or menthoxypropanediol ameliorate CP (175, 176).

Camphor, an essential oil-containing terpene, is soluble in alcohol (171). Applied to the skin, it causes a sensation of warmth followed by a mild degree of anaesthesia (171). Camphor has been used in dermatology for decades in liniments, lotions and ointments at concentrations ranging from 2% to 20%. It has been shown to specifically activate another constituent of the TRP ion channel family, namely TRPV3 (177). Camphor was recently demonstrated to activate the capsaicin receptor, TRPV1, while menthol also activates the camphor receptor, TRPV3. These findings illustrate the complexity of sensory perception and explain the efficacy of ointments containing both menthol and camphor (171).

Expert recommendation: We recommend topical application of menthol and its derivates. We suggest topical application of camphor or zinc.

6.3.3. Capsaicin. Capsaicin (trans-8-metyl-N-vanillyl-6-nonenamide) is the pungent agent of chilli peppers and is used as a pain-relieving medication (178). Topical application of capsaicin activates sensory C-fibres to release neurotransmitters that induce dose-dependent erythema and burning. After repeated applications of capsaicin, the burning fades due to tachyphylaxis and retraction of epidermal nerve fibres (178). However, pruritus recurs some weeks following discontinuation of therapy, indicating no permanent degeneration of the nerve fibres (179).

The greater the initial dose of capsaicin and the more frequent the applications, the sooner desensitization will appear and pruritus will disappear. The burning sensation accompanying topical treatment may be reduced by lidocaine or cooling of the skin (180–182). Unusual adverse effects include cough or sneezing due to inhalation of capsaicin from the skin or from the jar, as well as its effect on sensory nerve fibres in the mucous membranes (178). A lower concentration of capsaicin and less frequent applications will induce tachyphylaxis later, but may ensure better compliance. The concentration of capsaicin varies in different studies, but 0.025% capsaicin is well tolerated by most patients. If capsaicin is not available in this concentration as a standard drug, it can be produced using a lipophilic vehicle. Capsaicin is also readily soluble in alcohol (0.025% capsaicin in spir dil) suitable to treat burning scalp. A weaker concentration of 0.006% capsaicin is recommended for intertriginous skin, e.g. pruritus ani (183). High dose capsaicin treatment (8% patch) for neuropathic pruritus induced CP relief for up to 12 weeks and longer (184).

Topical capsaicin’s effects have been confirmed in controlled clinical trials for different pain syndromes and neuropathy, as well as notalgia paraesthetica (185), brachioradial pruritus (83), pruritic psoriasis (186, 187) and haemodialysis-related pruritus (188, 189). Case reports and case series described effects in hydroxyethyl starch-induced pruritus (190, 191), prurigo nodularis (191–194), lichen simplex (191, 193), nummular eczema (191), aquagenic pruritus (195) and psoralen and ultraviolet A (PUVA)-associated pruritus (196). High-concentration topical capsaicin for the treatment of postherpetic neuralgia and HIV neuropathy have been evaluated in a Cochrane review (197).

Expert recommendation: We suggest topical capsaicin for localized forms of CP.

6.3.4. Topical glucocorticosteroids. Topical glucocorticosteroids are the first line therapy for inflammatory dermatoses and the antipruritic effect they display has been attributed to an indirect consequence of their anti-inflammatory properties. Thus they are not currently recommended for the treatment of pruritus in the absence of a skin disease. Once- or twice-daily application of a medium or high potency glucocorticosteroid to the trunk and extremities or a low potency preparation on the face or intertriginous areas for approximately 1–3 weeks is recommended in the case of pruritic dermatoses (198). Prolonged use and application to large areas is to be avoided. Children, pregnant women and elderly patients are especially susceptible to the adverse effects of glucocorticosteroids and should be closely monitored (199, 200).

Some recent data hint at the possibility of an alternative mode of antipruritic action of glucocorticosteroids. Pruritus experimentally induced by histamine was significantly suppressed by topical hydrocortisone when compared to placebo (201). In another experimental model itch relief from nickel allergy provided by methylprednisolone aceponate was very rapid and preceded resolution of all other eczema findings, suggesting a direct antipruritic effect of the agent rather than just an indirect anti-inflammatory one (202).

Some studies suggest that topical corticosteroids such as betamethasone valerate are effective in CNPG (203, 204). Intralesional application in single nodules of CPG may be considered but there are no studies verifying the efficacy of this therapy.

Expert recommendation: We recommend application of topical glucocorticosteroids in CP associated with inflammatory dermatoses and CPG. We recommend against topical glucocorticosteroids in CP on non-inflamed skin. We recommend against long-term treatment with topical glucocorticosteroids.

6.3.5. Tacrolimus and pimecrolimus. The effects of the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus on pruritus are mediated both through their immunological and their neuronal properties (205). Paradoxically, while they can induce transient pruritus at the beginning of treatment, in the medium-term they may provide an alternative treatment for many causes of pruritus. An initial burning sensation upon application, which may be due to activation of TRPV1, can be a biomarker of antipruritic effect on individual patients with CP (206). TCIs are highly effective against pruritus in AD, and do not have the atrophying effects of topical corticosteroids on the skin (207, 208). Furthermore, 0.1% tacrolimus ointment is more effective at reducing symptoms of AD when compared with low-potency corticosteroids, 0.03% tacrolimus and 1% pimecrolimus cream (209). Clinical trials have shown benefit of both pimecrolimus and tacrolimus in seborrhoeic dermatitis, genital lichen sclerosus, intertriginous psoriasis and cutaneous lupus erythematosus and – only for tacrolimus – in resistant pruritus ani (210–218). Both substances can be used to treat localised forms of CP such as genital pruritus (219). In other diseases, the available data are limited to small case series, or individual cases, e.g. hand eczema (pimecrolimus), rosacea (tacrolimus), graft-versus-host disease (tacrolimus), vulval pruritus (tacrolimus) or Netherton’s syndrome (tacrolimus, pimecrolimus). Topical tacrolimus has been shown anecdotally to be effective in pruritus associated with systemic diseases such as PBC (220) and chronic renal insufficiency (221, 222). Despite early reports of efficacy of tacrolimus on CKD-associated pruritus, these observations have not been confirmed in a controlled study and so it is not recommended in these patients, although it may have some benefit in combination with systemic therapies (e.g. nalfurafine) (223–225).

Numerous clinical trials have demonstrated the safety of using TCIs routinely, in children as well as adults (209, 226). The transient burning upon application diminishes after 5–10 days of regular (e.g. twice-daily) application in most cases (227). Some patients may experience flushing upon taking alcohol; however, this can be blocked with acetylsalicylic acid (500 mg) taken in advance of drinking alcohol (208). Long-term studies are required to assess the risk of lymphoma in both adult and paediatric patients using TCIs; however, this seems to be extremely rare (228). In the elderly population TCIs are recommended for inflammatory skin diseases and, if effective, can be used indefinitely (229).

Expert recommendation: We suggest tacrolimus and pimecrolimus for the treatment of localized forms of CP.

6.3.6. Acetylsalicylic acid. Topical acetylsalicylic acid (acetylsalicylic acid/dichlormethane solution) has been described to have antipruritic effects in occasional patients with lichen simplex and CPG (230, 231). However, this beneficial effect could not be confirmed in experimentally induced itch with histamine (232).

Expert recommendation: We cannot make a recommendation with respect to topical acetylsalicylic acid for the treatment of CP.

6.3.7. Doxepin. The tricyclic antidepressant doxepin showed antipruritic effects when applied as a 5% cream in double-blind studies for treatment of AD (233), lichen simplex, nummular dermatitis and contact dermatitis (234). Topical doxepin therapy is not licensed and not used in any European country except for the UK (Xepin^©) (235–237).

6.3.8. Topical mast cell inhibitors. Pruritus in AD responds to topical sodium cromoglycate (238), which was confirmed by a placebo-controlled study (239). Comparison with vehicle showed that topical sodium cromoglycate (especially 4%) was effective in histamine-induced itch (240).

Expert recommendation: We suggest against the use of topical mast cell inhibitors for the treatment of CP.

6.4.1. Antihistamines. Antihistamines are the most widely used systemic antipruritic drugs in dermatology (241). Drugs that target the H1 receptor can effectively block the acute itch of cutaneous conditions as urticaria or insect bites, among others (242).

First-generation antihistamines, such as chlorpheniramine, clemastine, cyproheptadine, diphenhydramine, hydroxyzine, and promethazine are known to bind not only to H1-receptors, but also to muscarinic, α-adrenergic, dopamine or serotonin receptors and have a central sedative effect. Hydroxizine is the most commonly used first-generation antihistamine showing sedative, anxiolytic and antipruritic activities. In adult patients it is recommended as an antipruritic agent at a dosage of 25 mg at night, increasing to 25 mg 3 to 4 times a day if necessary. In children under 6 years the effective dose is up to 50 mg/day in divided doses, and 50–100 mg/day in children aged 6–12 years (243). However, the sedative effect of such antihistamines induce impaired sleep, interfering with the REM phase. A prospective cohort study recently suggested that its cumulative long-term use (and other cholinergic drugs) is associated with increased risk of dementia (244). Increased drowsiness may be problematic in the elderly (229). Due to these side effects, the use of sedative antihistamines is nowadays limited, and the dose modified accordingly, especially in vulnerable populations (245).

Second-generation antihistamines such as cetirizine, levocetirizine, loratadine, desloratadine, ebastine, fexofenadine, rupatadine or bilastine have minimal activity on non-histaminic receptors, little sedative effect, and a longer duration of action compared to the first generation (246). For the treatment of PUO, loratadine (10 mg), fexofenadine (180 mg) or cetirizine (10 mg) are helpful. Cetirizine may be preferred for its mild sedative properties (247). Oral cetirizine has been shown to be preferable in CP to narrowband (NB) ultraviolet B (UVB) phototherapy, for reasons of cost-effectiveness and time-saving (248).

In general, the non-sedative H1-receptor antagonists offer an effective reduction of CP in diseases associated with increased mast cell degranulation such as urticaria or mastocytosis (249). Rupatadine, a dual inhibitor of histamine H1 and PAF receptors, has been shown to significantly reduce the severity of pruritus in mastocytosis, as well as mosquito bite allergy and urticaria in both adults and children (250). In adult patients with confirmed mosquito-bite allergy, rupatadine 10 mg administered prophylactically has been shown to be effective in reducing subsequent wealing and skin pruritus (251). The newest antihistamine, bilastine, is highly selective for the H1 receptor. With properties of rapid onset, prolonged duration of action, no need for dose adjustment, and low potential for central nervous system (CNS) impairment or drug–drug interaction, bilastine is a front runner among other second-generation antihistamines in the management of chronic urticaria (252). European guidelines on urticaria (6) recommend second-generation anti H1-antihistamines as the first-line therapy for chronic spontaneous urticaria, starting at licensed doses and being increased to up to 4 times the dose if licensed doses fail to control the disease. Systemic H1-antihistamines are often employed to treat pruritus in AD. The older, sedating H1-antihistamines may be more useful for this indication especially in acute AD flares, improving sleep quality in the short term, although these are not recommended for long-term use in children (159). The European guideline on AD does not recommend the general use of any antihistamines for AD, since there is no high-level evidence that non-sedating antihistamines reduce itch in AD, or that sedating antihistamines are of benefit, except for aiding sleep (253, 254).

It is currently thought that pruritus in psoriasis is also not histamine-mediated, and therefore antihistamines are not routinely recommended (242). Recently, however, both sedating and non-sedating antihistamines have been shown to be moderately effective in reducing itch in patients with psoriasis, but further studies are needed on larger patient groups (255).

Antihistamines are widely used as first-line drugs for the treatment of CP associated with various systemic diseases such as chronic renal failure, cholestasis, hematopoetic diseases and thyroid disorders. However, conventional doses of antihistamines in the treatment of pruritus in internal diseases have not proven to be effective (246).

Antihistamines have been shown to be safe in specific populations. However, while there is no particular antihistamine that is universally effective for the treatment of pruritus, certain antihistamines [e.g. loratadine, cetirizine or rupatadine (256)] are thought to be safer for use in children, pregnancy and lactation, and so may be preferred in these patients (206). The use of first-generation antihistamines is to be avoided in pregnant women (257). For the paediatric management of pruritus, long-term use of first-generation antihistamines is not recommended (158, 159). The associated psychomotor impairment may impact the education and safety of children, and remains even while the child becomes used to the sedating effects (258). Second-generation antihistamines with appropriate dose adjustment are the first-line therapy for chronic urticaria in children (259).

Although identified in human skin, H2-receptors play a minor role in pruritus, and H2-receptor antagonists alone have no antipruritic effect (260, 261). A combination of H2-antihistamines and H1-antihistamines has been used in the treatment of pruritus in small trials, but the results are conflicting (260, 261). It has recently been found that H3- and H4-histamine receptors are involved in pruritus, with the H4 in particular being associated with mast cell function, as well as T cells, dendritic cells, monocytes and eosinophils (262). The efficacy of an H4 receptor antagonist is currently under research in clinical studies and may be available as an antipruritic therapy in the near future (263). There is pre-clinical evidence that local antagonism of the H3 receptor can induce scratching; therefore, new drugs that target the H3R are anticipated in the field, with the hope that more effective treatment of chronic pruritus can be offered to patients in the future (264).

A case series suggests that updosing of antihistamines may also be beneficial in CP (265).

Expert recommendation: We recommend treating CP in urticaria with non-sedating H1-antihistamines. We suggest non-sedating H1-antihistamines in CP in mastocytosis. We suggest non-sedating and/or sedating H1-antihistamines as an initial symptomatic therapy of CP.

6.4.2. Mast cell inhibitors. Ketotifen (1 mg twice daily), showed antipruritic effects in patients with CKD-associated pruritus, but less than gabapentin (266). Cromolyn sodium and placebo were compared in 62 haemodialysis patients and a significant decrease in itch was seen in the treatment group, but without effects on tryptase level (267).

Expert recommendation: We suggest against the use of systemic mast cell inhibitors for the treatment of CP.

6.4.3. Glucocorticosteroids. Systemic glucocorticoids (GCs) are commonly used to treat severe CP associated with inflammatory skin disease or systemic disease, supported only by limited clinical evidence. In clinical experience, pruritus ceases within approximately 30 min of i.v. glucocorticosteroids in the treatment of urticaria or drug-induced exanthema. Likewise, in AD, allergic contact dermatitis, dyshidrosis and bullous pemphigoid a rapid reduction in pruritus is observed, which can be explained by their high anti-inflammatory potency. Thus, while systemic glucocorticosteroids should not be considered as an antipruritic for long-term therapy, short-term use is possible in cases of severe pruritus in inflammatory skin diseases; however, they should not be used for a period of more than 2 weeks (268) due to their severe side-effects.

Severe, intractable lymphoma-related paraneoplastic CP can be successfully treated with short courses of systemic GCs (269). An improvement in cutaneous T-cell lymphoma-related pruritus via suppression of IL-31 production, which has been shown to correlate with pruritus severity, was reported using dexamethasone (270, 271).

Prednisone is the most commonly selected oral corticosteroid, initially at a daily dose ranging from 2.5 mg to 100 mg or more, usually starting at a dose of 30–40 mg daily. In exceptional cases i.v. methylprednisolone is used at a dose of 500 mg–1 g/day, due to its high potency and low sodium-retaining activity. It is important to remember that the dosage should be tapered in accordance with pruritus severity. Before discontinuing systemic therapy, one may change to topical corticosteroid therapy. Corticosteroids should be used with caution in children, the elderly and in patients with relevant metabolic disorders such as diabetes.

Expert recommendation: We suggest systemic glucocorticoids as a short-term treatment in selected cases of refractory CP, especially in paraneoplastic pruritus and palliative care.

6.4.4. Opioid receptor agonists and antagonists. Experimental and clinical observations have demonstrated that pruritus can be evoked or intensified by endogenous or exogenous μ-opioids (272). This phenomenon can be explained by activation of CNS opioid receptors, mainly μ-opioid receptors. Reversing this effect with μ-opioid antagonists thus leads to an inhibition of pruritus (154). The opposite is true for κ-opioids. Their binding to κ-opioid receptors leads to inhibition of pruritus (273).

Several clinical studies have demonstrated that different μ-opioid receptor antagonists may significantly diminish pruritus (43, 50, 274–278). In double-blind RCT, μ-opioid receptor antagonists such as nalmefene, naloxone and naltrexone have exhibited high antipruritic potency. For example, pruritus in chronic urticaria, AD and cholestatic pruritus has shown therapeutic response to nalmefene (10 mg twice daily) and naltrexone (50–100 mg/day) (279, 280). Controlled studies have also been performed in patients with CKD-associated pruritus (37, 38, 281, 282). Results were variable, ranging from significant reduction of pruritus to no response. Naltrexone (50 mg/day) was more effective than placebo on CP in patients with AD (283). Case reports have demonstrated efficacy of naltrexone in several pruritic dermatoses.

Nalfurafine, a preferential κ-opioid receptor agonist, was investigated in CKD-associated CP in two large RTCs (36, 284). Both trials demonstrated significant clinical benefit of nalfurafine in patients with CKD-associated pruritus (273) within the first 7 days of treatment. Similar outcomes in terms of results and adverse drug effects were obtained in an open-label long-term study with 5 mg nalfurafine given orally in 211 haemodialysis patients over a period of 52 weeks (285). In a RCT on 318 patients with refractory cholestatic pruritus nalfurafine (2.5 and 5.0 mg given orally per day) reduced itch significantly more than placebo as measured on a VAS scale (28.56 and 27.46 vs. 19.25) (286). The drug is currently licensed only in Japan.

Expert recommendation: We suggest mu-opioid receptor antagonists in refractory CP, especially in cholestatic pruritus.

6.4.5. Gabapentin and pregabalin. Gabapentin is an antiepileptic and anxiolytic drug also used in neuropathic pain and pruritus (287). The mechanisms of action of gabapentin, a 1-amino-methyl-cyclo-hexane acetic acid and a structural analogue of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), remain unclear. It is used in postherpectic neuralgia (288), especially with paroxys-mal pain or pruritus. Pilot studies have been performed for the treatment of pruritus caused by burns and wound healing in children demonstrating antipruritic effects of gabapentin (289). Double-blind RCTs were performed for CKD-associated pruritus (300 mg thrice weekly or 400 mg twice weekly after haemodialysis sessions) (290, 291) and cholestatic pruritus (292). Gabapentin was safe and effective for treating CKD-associated pruritus (293, 294). It was shown to be effective in 6 cases of brachioradial pruritus, but more disappointing in notalgia paraesthetica (295, 296). An anecdotal indication is cutaneous T-cell lymphoma (297).

Pregabalin is similar to gabapentin and a more recent drug. Its use has been suggested in a case of cetuximab-related pruritus, aquagenic pruritus and in CKD patients unable to tolerate gabapentin (298–300). A controlled trial demonstrated a significant antipruritic effect of pregabalin in patients on haemodialysis within one month (301). In another study on uremic itch, treatment with 75 mg of pregabalin given orally twice weekly in dialysis-dependent patients was compared either to ondansetron or placebo. While a significant effect of pregabalin could be documented, the use of ondansetron and placebo did not yield significant results (302). In an open study 30 patients with CNPG were treated with 75 mg pregabalin per day orally. Treatment improved itch in 76% of patients after a 3-month treatment course (303). Pregabalin 50 mg every other day or 10 mg doxepin given daily for 4 weeks in patients with CKD-associated pruritus led to a significant improvement of pruritus in both groups, but was significantly more effective in patients receiving pregabalin (304).

However, regarding the use of gabapentin or pregabalin an analysis by the US Renal Data System on a large cohort issued a caveat to the use of these drugs. Their use was associated with much higher hazards of altered mental status, falls and fractures (305).

Expert recommendation: We recommend gabapentin and pregabalin in neuropathic CP and in CKD-associated pruritus. We suggest gabapentin and pregabalin for refractory CP and PUO.

6.4.4. Antidepressants. Recent systematic reviews demonstrate evidence that antidepressants are effective particularly in refractory pruritus, pruritus in CKD, cholestasis or neoplasm (306), as well as in other forms of CP (307, 308). Psycho-emotional factors are known to modulate the “itch threshold” (309). Under certain circumstances, they can trigger or enhance CP (310). Itch is a strong stressor and can elicit psychiatric disease and psychological distress. Depressive disorders are present in about 10% of patients with CP (311) and have a clear correlation (312). Antidepressants probably also exert an effect on pruritus through their pharmacological action on serotonin and histamine (306).

The antipruritic action of serotonin reuptake inhibitors (SSRIs) does not start until after 2–3 weeks and the maximum effect is usually seen at 4–6 weeks after initiation of therapy (313); only escitalopram 10–40 mg/day might have a slightly shorter efficacy period. SSRIs such as paroxetine can have an antipruritic effect on patients with PV, psychogenic or paraneoplastic pruritus and other patients with chronic PUO (314, 315). Paroxetine (20 mg/day) has exhibited antipruritic effects in pruritus due to PV (316), paraneoplastic pruritus (317, 318) and psychiatric disease (315, 319). In two patients pruritus was induced by discontinuation of paroxetine treatment for depression (320). An RCT in pruritus of non-dermatologic origin confirmed the antipruritic effect of paroxetine (314). In a two-armed proof-of-concept study with paroxetine and fluvoxamine, patients with CP of dermatological origin reported a significant antipruritic effect (321). Sertraline proved effective in cholestatic pruritus both in adults (322) and children (323), as well as in CKD-associated pruritus (324, 325). In a recent double-blind RCT among 50 haemodialysis patients, sertraline was shown to be effective in reducing uremic pruritus (326), while Doxepin also showed positive effects in 7 patients (304). Doxepin may be administered in a dose from 25–50 mg/day.

Tricyclic antidepressants like doxepin (327) have been effective in urticaria, AD, cutaneous T-cell lymphoma, carcinoma en cuirasse and HIV-related pruritus. It shows almost identical effects compared with hydroxyzine (327). Amitriptyline 25 mg/day has shown a reduction in pruritus in patients with brachioradial pruritus. Trimeprazine and trimipramine are older antidepressants that exhibit some antipruritic effects in AD (328).

Mirtazapine 15–45 mg/ day is an atypical antidepressant, both noradrenergic and serotonergic, and has been shown to be effective in the treatment of CP (297, 329, 330). In brachioradial pruritus antidepressants showed moderate effects to decrease pruritus (331).

Side effects of antidepressants are common and include drowsiness, fatigue and headache, mostly initially, but also cardiovascular and gastrointestinal symptoms occur; therefore, caution should be shown in elderly patients (306). Recommended treatment doses for pruritus in malignant diseases are paroxetine 20–40 mg/day or mirtazapine 15–30 mg/day; for patients with cholestasis or CKD amitriptyline 25–50 mg/day or doxepin 25–20 mg/day.

Expert recommendation: We recommend selected antidepressants (e.g. paroxetine, mirtazapine, doxepin, amitryptiline) for psychogenic CP and for refractory CP, especially in malignant, cholestatic and chronic kidney disease.

6.4.7. Serotonin receptor antagonists. Due to the patho-physiological significance of serotonin in various diseases, e.g. kidney and liver diseases, serotonin receptor antagonists (of the 5-HT3 type) such as ondansetron (8 mg 1–3x/day), topisetron (5 mg/day) and granisetron (1 mg/day) have been used anecdotally to treat pruritus(332–338). Contradictory or negative results have been reported in partly controlled studies using ondansetron for cholestatic pruritus (332, 339, 340) and opioid-induced pruritus (341–343). An antipruritic effect was reported for ondansetron in CKD-associated pruritus (344). However, this could not be confirmed in subsequent controlled studies (345–347).

Expert recommendation: We recommend against serotonin receptor antagonists in the treatment of CP.

6.4.8. Thalidomide. A number of mechanisms for the antipruritic action of thalidomide have been proposed, including a central depressant effect (348), a local effect on proliferated neural tissue in PN (349) and antagonism of tumour necrosis factor-α (TNFα) (350).

The best results with thalidomide in CP have been achieved in PN. Several studies have shown a rapid decrease in pruritus on thalidomide (50–300 mg/day) (351, 352). In a very recent review the authors refer to how patients were started on higher doses of 200 mg or more daily in earlier studies (353). In the majority of studies since then, however, patients received an initial dose ranging from 50 to 200 mg/day, following which the dosage was tailored according to response or the development of side effects. A prospective open trial of thalidomide 100 mg/day, followed by NB-UVB (TL-01) showed a high response with minimal side effects (354). Likewise, good results have been seen in HIV-positive patients with PN (355). There is one randomised, double-blind cross-over trial of the successful treatment of CKD-associated pruritus with thalidomide (356). Thalidomide is teratogenic and there is a dose-related risk of neuropathy, especially in high daily doses (> 100 mg/day) (357). In most cases the peripheral neuropathy is reversible (353). Thalidomide could be considered particularly in a palliative setting (358).

The scarce information on lenalidomide, a more potent analogue of thalidomide, seems promising (359). More studies are needed to evaluate the effectiveness and tolerability of this analogue of thalidomide.

Expert recommendation: We suggest thalidomide for selected cases of refractory CP after informing the patient about teratogenicity and dose-related risk of neuropathy.

6.4.9. Leukotriene receptor antagonists and TNFα antagonists. Leukotriene receptor antagonists (e.g. montelukast) and TNFα antagonists influence the patho-genesis of AD. They have been used in combination with antihistamines as antipruritic therapy. Montelukast has also been used in several types of urticaria as well as in combination with antihistamines. A combination of H1-antihistamine with a leukotriene antagonist has been reported to alleviate pruritus in chronic urticaria (348).

Expert recommendation: We suggest against leukotriene receptor antagonists in the treatment of CP.

6.4.10. Cyclosporine, methotrexate, azathioprine and tacrolimus. Controlled clinical studies investigating the efficacy of systemic anti-inflammatory drugs on CP are scarce. Cyclosporine is the only drug that has been approved for the treatment of pruritus in AD (162). The effect of methotrexate and azathioprine on pruritus is mainly documented in retrospective case reports. All these therapies are associated with significant systemic toxicity and require careful patient monitoring. The choice of systemic therapy for CP depends on comorbidities (existing or prior neoplasms or cardiovascular disease), blood tests (haematology, liver and kidney function), age and history of alcohol abuse.

Pruritus in AD responds to treatment with cyclosporine as demonstrated in several double-blind controlled studies (162, 360, 361). Cyclosporine has also proved effective in pruritus associated with refractory chronic urticaria (362). Cyclosporine has been administered in PN for 24–36 weeks, using doses of 3.0–4.5 mg/kg/day. Improvement was observed in both pruritus and skin lesions after 2 weeks of treatment (363, 364). It seems likely that, in these diseases, cyclosporine acts on pruritus through its immunological effects. However, direct effects on nerve endings are also possible (365). Successful use of cyclosporine in non-immunological disease was reported in several studies, e. g. 10 patients with pruritus of senescence were treated with cyclosporine 5 mg/kg/day
for 8 weeks (366). All patients in this uncontrolled, open study responded. Case reports describe antipruritic effects in dystrophic epidermolysis bullosa-associated CP (367).

Methotrexate, licensed for psoriasis, has proved effective for psoriasis-associated pruritus (368). Patients with severe AD refractory to topical therapy may respond to methotrexate with greatly reduced pruritus (162, 369). In a retrospective report on 13 patients with CNPG, 10 markedly improved on methotrexate at doses of 7.5–20 mg once weekly for a minimum of 6 months (370). In a recent multicenter study, a 90% overall response rate was reported in 39 patients with difficult-to-treat prurigo using methotrexate with a median weekly dose of 15 mg (371).

Azathioprine, licensed as a corticosteroid-sparing drug for blistering diseases, has proved effective in pruritus associated with bullous pemphigoid in doses of 50–200 mg/day (372). Patients with severe AD refractory to topical therapy may respond to azathioprine with greatly reduced pruritus (162, 369). In a retrospective review 96 patients with life-altering CP who had previously responded to systemic steroids were reported. A daily azathioprine dose ranging from 25 to 275 mg resulted in relief of pruritus with a reduction in VAS from 9.2 prior to treatment to 1.6 post treatment. The mean duration of therapy in this study was 53 months and 33% of the patients were forced to discontinue treatment due to adverse drug effects (373).

Data on systemic treatment with tacrolimus in CP are sparse. Besides case reports (374), one open-label study on a sequential treatment with oral (6 weeks) and topical tacrolimus (11 weeks) in 12 patients with severe AD resulted in a substantial reduction in pruritus (375). In contrast to these results, a case series in 4 patients with AD treated with 5 mg tacrolimus twice daily for 14 months showed poor results in 3 of the patients (376).

Expert recommendation: We suggest cyclosporine, methotrexate and azathioprine for refractory CP associated with inflammatory dermatoses and CPG.

6.4.11. Neurokinin receptor 1 antagonist. Substance P (SP) plays a dominant role in pruritus induction after release from cutaneous sensory neurons. Via binding to the neurokinin 1 receptor (NK1R) on keratinocytes, blood vessels and mast cells, SP promotes inflammation and mast cell degranulation. Cutaneous SP levels are increased in conditions with hyperplasia of skin nerves (AD, PN). Accordingly, inhibition of the pruritogenic effects of SP by blocking the corresponding receptor may have antipruritic effects. Several case series and case reports suggest a positive role of the NK1R antagonist aprepitant in CP, e.g. cutaneous T-cell lymphoma, solid tumours, drug-induced pruritus, CP with atopic predisposition and CNPG (377–382). However, recent controlled trials including a randomized double-blind, placebo-controlled phase-II study using topical or systemic aprepitant failed to show a benefit compared to placebo (383–385). Serlopitant is a novel NK1R antagonist that can be administered for long-term therapy. RCTs demonstrated a significant effect on pruritus of CPG and was well tolerated (386, 387).

Expert recommendation: We suggest NKR1 antagonists such as serlopitant in refractory CP and CPG.

6.4.12. Biologics. Biologic therapies have burst onto the armamentarium to treat CP in certain cutaneous diseases. In addition, some biologic approaches have been developed to control CP alone. This is the case with omalizumab for CSU. This humanized recombinant monoclonal antibody binds specifically to the Cε3 domain of the immunoglobulin E (IgE) heavy chain. Omalizumab reduces the levels of free IgE and the density of the high-affinity IgE receptor, both of which are essential in mast cell and basophil activation and consequently degranulation (388). Omalizumab was approved in 2014 in Europe (300 mg) and the US (150 and 300 mg), administered subcutaneously every 4 weeks for recalcitrant chronic spontaneous urticaria refractory to H1-antihistamines in adults and children (aged 12 years and above). The itch severity score was the primary endpoint assessed in the phase III clinical trials. Omalizumab showed effective and rapid reduction of itch in a dose-dependent manner that was maintained over the treatment period. An improvement in the number of hives, need for emergency medication and quality of life of patients with chronic spontaneous urticaria, as well as good tolerance and safety profiles, were also reported (389–391). A clinically relevant response is seen within a few weeks of initial administration. Side effects are usually mild or moderate and include mainly headache, nasopharyngitis, myalgia and local symptoms at the injection site.

With regard to AD, monoclonal antibodies that block signalling of both IL-4 and IL-13, key T helper cell 2 (Th2) cytokines, are in development. Dupilumab, a fully human monoclonal antibody directed against the IL-4 receptor α (IL-4R α), has been shown to be efficient in controlling patients’ assessment of CP as measured by the pruritus NRS score at week 16, with a significant reduction of pruritus seen as early as week 1 (dupilumab 300 mg once a week) in severe adult AD patients in the phase 2b trial (392) A number of trials are currently ongoing with different targets such as IL-31, IL-22, TSLP and CRTH.

Pruritus-reducing effects of biologic treatment on psoriatic pruritus have been reported (393-401). One single report of cases referred to persistent CP (402). Secukinumab significantly improved CP in a phase 3 study (398). Ixekizumab showed long-term effects on CP in psoriasis in a phase 3 clinical trial and maintenance therapy sustained improvements in psoriasis severity over more than 1 year (397, 400). According to a systematic review anti-IL 17, JAK inhibitors, adalimumab, and apremilast are effective in reducing CP in psoriasis, with anti-IL-17 showing the largest effect in reducing psoriasis (401).

According to the different pathogenic mechanisms involved in pruritus, potential new monoclonal antibodies will be developed that, e.g. target Na V1.7, a voltage sensor for pain and itch relief (403). However, these developments lie in the future.

Expert recommendation: We suggest omalizumab for refractory CP in CSU and dupilumab for refractory CP in AD. We cannot make a recommendation with respect to the use of monoclonal antibodies in CP of other origin.

6.4.13. Physical treatment modalities. Physical treatments such as transcutaneous electrical (field) stimulation and acupuncture have been described for the treatment of CP (404, 405). Acupuncture is the oldest and best studied alternative option with evidence-based effect on pain, but much less evidence of its antipruritic effects. A few placebo-controlled experimental studies have shown that local treatment with acupuncture needling reduces histaminergic itch in healthy volunteers and allergen-induced itch in patients with AD (406–408). The effect of acupuncture on sensory innervation in the skin was investigated in 10 subjects that were treated with 10 acupuncture needles subcutaneously during twice-weekly 25-min sessions over 5 weeks and skin biopsies revealed reduced density of sensory nerve fibres (409). In a retrospective study, symptomatic relief of neuropathic pruritus (brachioradial CP, notalgia paresthetica, meralgia paresthetica) in 12 of 16 patients treated with acupuncture was reported (410). Relapse occurred in 37% of patients within 1–12 months following treatment. In a placebo-controlled study of 6 patients with intractable pruritus in CKD, electrical needle stimulation at the point of the elbow reduced severity, frequency and distribution of itch both day and night (410), while control treatment with superficial electrical stimulation was ineffective. Che-Yi et al. randomised 40 patients with refractory uremic pruritus into two groups: acupuncture needling was applied either unilaterally at the acupoint of the elbow or at a non-acupoint (control). The patients were treated 3 times weekly for 1 month. At the end of the treatment period and at 3 months follow-up, only the acupoint group showed a 50% reduction in pruritus (411). The rationale for the use of acupuncture in the treatment of itch, as well as its effects in uremic pruritus and allergic diseases has been reviewed (409, 412, 413).

A double-blind randomised placebo-controlled study in 30 patients with AD revealed that acupuncture achieved a significant reduction of itch (414). In another study in 40 patients with refractory UP, an acupuncture needle was inserted at the Quchi acupoint and then removed after 1 h. Patients undergoing this treatment showed a substantial improvement in itch compared to controls (411).

Transcutaneous electrical nerve stimulation (TENS), which activates electrically myelinated nerve fibres (α and δ), is widely used for the treatment of chronic pain (415). Fjellner & Hägermark studied the effect of TENS on CP of various origin in 41 patients for 5–47 days. Initially, TENS ameliorated pruritus in 63% of patients, but the effect declined over the course of therapy and was regarded as placebo (416).

Another technique, cutaneous field stimulation (CFS), was developed to electrically stimulate unmyelinated C-fibres at the dermo-epidermal junction in order to treat pruritus (417). In an experimental study on 21 subjects, the pruritus induced by histamine iontophoresis was completely abolished by CFS (417). In a controlled study, 27 atopic patients with CP were treated with CFS and TENS (418), CP was significantly surpressed for 7 h after cessation of CFS, but not after TENS.

In an open trial on 19 patients (16 patients with neuropathic pruritus and 3 patients with generalized pruritus) using CFS once daily for 25 min for 5 weeks, pruritus was reduced by 49% at the end of treatment (419). Skin biopsies revealed a significant reduction in epidermal nerve fibres following the treatment (419). In this study, pruritus relapsed gradually after discontinuation of CFS, indicating nerve fibre regeneration in the epidermis.

Expert recommendation: We cannot make a recommendation with respect to physical treatment for the treatment of CP.

UV-based therapy is well established for treating pruritus and utilizes UVB (290–320 nm) and UVA (320–400 nm). The light sources include broadband UVB (BB-UVB, 290–320 nm, peaks at 313 nm), narrowband UVB (NB-UVB, 311 nm), broadband UVA (320–400 nm, peaks at 355 nm) and UVA1 (340–400 nm, peaks at 365 nm) (420). Immunomodulatory effects due mostly to the release of anti-inflammatory neuropeptides, or the inhibition of pro-inflammatory mediators (e.g. IL-1, TNFα), make these different UV treatments particularly useful for treating pruritus associated with inflammatory dermatoses (421).

For the treatment of AD, phototherapy is a common and valid treatment, inhibiting pruritus by reducing numbers of nerve fibres in the epidermis and normalising the expression of axonal guidance molecules (e.g. nerve growth factor, semaphorin 3A) in atopic skin (422, 423). Treatment with phototherapy can improve, or even resolve, AD with remission of up to 6 months and no reported serious adverse effects in the short-term (5). Preference is given to UVA-1 and NB-UVB as modalities, since both have been found to be equally effective in improving pruritus of AD, although it is noted that NB-UVB has the dual advantage of less heat load and shorter duration of phototherapy (424, 425). Systemic PUVA has also been shown to effectively treat the itch of AD, but with side effects including burning, pain, nausea, headache, erythema and lentigenes (426). A study comparing bath-PUVA with NB-UVB found both to be very effective measures, reporting that relief from pruritus was usually achieved in the first 2 weeks, and consistently preceded the resolution of skin lesions (427).

UVB laser may be still more effective than NB-UVB, with localised AD and associated pruritus being successfully treated with 308-nm xenon chloride excimer laser (428).

Both AD and lichen amyloidosis have been successfully treated by combinations of NV-UVB with steroids or cyclosporine A (421).

For the treatment of CPG, PUVA, UVA1 and NB-UVB proved to be effective in a RCT, with PUVA and UVA1 superior to NB-UVB (429).

For many other skin diseases, a number of studies have demonstrated the efficacy of UV treatment, e.g. psoriasis, lichen planus, T-cell lymphoma, solar, chronic and idiopathic urticaria, as well as urticaria pigmentosa and folliculitis of pregnancy (421, 430). UVB mainly affects epidermal keratinocytes and Langerhans cells, due to its limited penetration into the skin. UVA1, in contrast, reaches to the dermis and therefore can affect T lymphocytes, mast cells and dermal dendritic cells, e.g. induces apoptosis of these cells (420). However, UVB-induced apoptosis of mast cells has been postulated to explain relief of pruritus (431). Furthermore, phototherapy leads to a reduction in CGRP-immunoreactive nerve fibres in the skin (432). No further benefit has been found by adding UVA in combination with NB-UVB phototherapy for the treatment of pruritic inflammatory skin disease (433). A novel treatment that has proven beneficial in pilot studies is a topical cream that filters solar UVB (434). This has the advantage of saving time, inconvenience and expense associated with traditional UV therapy.

Pruritus associated with mastocytosis can be treated with oral PUVA, although alleviation is only short-term, or with NB-UVB if PUVA is not tolerated (435).

UV phototherapy has been used with some success in conditions with pruritus on primarily non-inflamed or normal appearing skin. It has been particularly effective in many cases of CKD-associated pruritus (224, 436, 437). In an open pilot study using NB-UVB 14/20, CKD-associated pruritus patients responded well to treatment (438). Also in a recent study NB-UVB appeared to be effective in the reduction of CKD-associated pruritus (439). However, a later RCT failed to demonstrate a significant difference in the reduction of pruritus intensity in patients receiving NB-UVB compared with a control group (440). In another case NB-UVB treatment was unsuccessful, but BB-UVB helped (441). For end-stage renal disease BB-UVB is recommended at a frequency of 3 times per week, tapering to one or two maintenance sessions per week to achieve control of pruritus (442).

UV therapy has also been reported to be effective in a number of cases of pruritus associated with other systemic diseases, including hepatic and metabolic disorders, as well as malignancy (443). BB-UVB was found to reduce cholestatic-induced pruritus in 10/13 patients (444). In polycythemia vera, 8/10 patients responded to NB-UVB in an open study (445). In a single case report a patient with Hodgkin’s disease responded well to BB-UVB (446).

Aquagenic pruritus showed response to bath-PUVA therapy (447) and systemic PUVA (448, 449) for the duration of therapy. To treat aquagenic pruritus, PUVA was found to be superior to BB-UVB in 5 patients (450). Recently, two patients with aquagenic pruritus were reported to show a good, but transient response to NB-UVB (451). In HIV patients with pruritus, UVB produced significant relief of pruritus in an open study with 21 patients (33% primary pruritus, 66% eosinophilic folliculitis) (452). Phototherapy has been useful in treating idiopathic pruritus in some HIV patients, as well as HIV-associated dermatoses (453).

Common adverse effects of UVB phototherapy are tanning and erythema. Both UVA and UVB have been associated with skin ageing. The potential carcinogenic effect of phototherapy is of concern. In general, the use of UVB has shown no or little association with skin cancer and is considered a very safe treatment option (454, 455). However, studies of PUVA-treated patients and associated cancer risk have reported increased incidence of melanoma (particularly squamous cell carcinoma) and recommend careful selection of patients with rigorous follow-up (456, 457).

Expert recommendation: We suggest UVA and UVB (NB-UVB/BB-UVB) phototherapy for refractory CP in inflammatory skin diseases, cutaneous lymphoma CPG and selected cases of systemic pruritus (e.g. CKD-associated pruritus, cholestatic pruritus, aquagenic pruritus). We suggest UV phototherapy in combination with topical and/or systemic treatment, with the exception of calcineurin inhibitors and immunosuppressant drugs.

6.6.1. Treatment of chronic pruritus in the elderly. Elderly patients with CP require special attention, even though the general principles of treatment apply. The older patient with CP characteristically presents a mixed clinical picture of comorbidities and polypharmacy, including physical and cognitive limitations; some degree of xerosis cutis is omnipresent in most cases (458–460). Any underlying condition such as CKD, hepatobiliary disease or malignancies should be addressed primarily (460). Treatment is therefore challenging and needs to be tailored to each case.

The application of topical soothing agents and, if required, anti-inflammatory treatment are recommended for the management of xerosis. Fingernails should be kept short and soap should be avoided or restricted to the axilla, groin, scalp and soles, preferably using acidic pH soap. Furthermore, less frequent bathing, preferably in tepid water, and the avoidance of astringents and lactic acid (>5%) are also recommended. The application of petroleum-containing moisturisers immediately after bathing is helpful. More aggressive hydration might be necessary: after a 20-min soak, an effective moisturiser is applied on patted-dry skin, which is then covered with kitchen clingfilm (plastic wrap) or a moist garment. This technique is called the “soak and smear” method (458, 461). Oatmeal baths can also be useful, likely due to the anti-inflammatory properties of oatmeal (462). Other topical treatments with urea solutions, menthol, pramoxine, pimecrolimus, tacrolimus and topical amitriptyline-ketamine with lidocaine can be beneficial; however, topical corticosteroids should be avoided on elderly skin due to skin thinness.

Systemic treatment of CP in an elderly patient demands special caution. Second-generation non-sedating antihistamines may be useful, but first-generation sedating antihistamines should be avoided, as well as tricyclic antidepressants such as doxepin due to anticholinergic effects. Long-term systemic steroids should also be avoided, since impaired immunity and comorbidities are often present in the elderly patient (460). The antiepileptic drugs gabapentin and pregabalin are useful, but dizziness and sedation may occur with increasing dose. In elderly patients, lower dosages of gabapentin and pregabalin are usually sufficient to control CP. The tetracyclic antidepressant mirtazapine can be effective against nocturnal itch (463). SSRIs such as paroxetine and fluvoxamine are also effective in the elderly, but can exacerbate sexual dysfunction and insomnia (460). Sertraline is a good option for the treatment of cholestatic itch. The use of µ-opioid receptor antagonists and κ-opioid receptor agonists should be approached with caution as a result of hepatotoxicity, gastrointestinal symptoms and dizziness. Thalidomide might be a good option for the elderly patient with chronic itch (460). Successful use of cyclosporine was reported in several studies, e. g. 10 patients with pruritus of senescence were treated with cyclosporine 5 mg/kg per day for 8 weeks (366).

UV phototherapy is an option in the elderly; however, caution must be taken in case of increased photosensitivity or phototoxicity caused by multiple drug ingestion (229). Overall, phototherapy such as NB-UVB (TL01) is a good treatment option, since it can avoid further polypharmacy; however, skin cancer needs to be borne in mind. Phototherapy in the elderly depends on the patient’s mobility. In summary, treatment of pruritus in the elderly is primarily focused on efficient hydration of the skin. Caution should be shown with systemic therapy due to polypharmacy, interactions and adverse effects.

6.6.2. Treatment of chronic pruritus in pregnancy. Due to potential effects on the foetus, the treatment of pruritus in pregnancy requires prudent consideration of whether the severity of the underlying disease warrants treatment and careful selection of the safest treatments available. Topical corticosteroids are the most frequently used drugs for treating skin conditions and are prescribed to more than 6% of pregnant women (464). However, little is known about the effects of local corticosteroids on the foetus.

According to a very recent Cochrane review update, there are no causal associations between maternal exposure to topical corticosteroids of all potencies and pregnancy outcomes, including mode of delivery, congenital abnormalities, preterm delivery, fetal death and low Apgar score (465). A recent study showed a significantly increased risk of low birth weight in cases where more than 300 g of potent or very potent topical corticosteroids were applied over the course of the entire pregnancy (464). Systemic treatments such as systemic glucocorticosteroids, a limited number of antihistamines and UV phototherapy, e.g. UVA, may be necessary in severe and generalised forms of CP in pregnancy. UV phototherapy is a useful alternative therapy for pruritus during pregnancy that is refractory to steroids or antihistamines (421).

There is a lack of knowledge concerning the pharmacokinetics of the use of antihistamines during pregnancy. The use of first-generation antihistamines is to be avoided in pregnant women (257); on the other hand, they are also considered safe on the basis that they have already been prescribed for a very long time. Of the second-generation antihistamines, loratadine and cetirizine are the best studied (466). They can be prescribed after the first trimester in the case of well-considered indications. Administration immediately prior to or after birth must be avoided. NB as well as BB UVB phototherapy is safe; however, since folic acid levels may decrease with both (467), follow-up of folic acid levels is indicated. In summary, the treatment of pruritus in pregnancy is primarily focused on topical treatment in order to relieve CP, possibly complemented by UV phototherapy. Caution should be shown with systemic therapy due to possible effects on the foetus.

6.6.3. Treatment of chronic pruritus in children. The management of CP in children is based on the diagnosed systemic or skin condition. Nevertheless, some general considerations must be taken into account once topical or systemic drugs are used, such as the body volume/body surface area rate and the total weight. In addition, the licensed age for any drug must be taken into account. Individualised management is recommended.

Topical treatments for pruritus should be focussed on the cause if possible. Avoidance of the specific and non-specific provocation factors is necessary. Such factors include, e.g.: inhalants, microbial agents, foods, textiles, chemicals and emotional stress. The use of emollients in an attempt to preserve barrier function is always required. Low- (class 1, 2) to medium-strength (class 3) glucocorticosteroids may be administered in children. Topical immunomodulators are used for AD and pruritus in children aged 2 years and older, but in some European countries pimecrolimus, for instance, is licensed for use in children older than 3 months. Topical capsaicin is not used in children <10 years. New topical active principles are in development for CP in children, such as a 4% cutaneous emulsion of sodium cromoglicate (468) or a 2% topical ointment of crisaborole (phosphodiesterase-4 inhibitor) (469).

The dosages of systemic drugs need to be adjusted in children. The most common drugs used to control pruritus in AD and CSU in children is an H1-receptor inverse agonist. The common use of first-generation antihistamines (e.g. hydroxyzine dichlorhydrate) to avoid scratching during the night in AD has long been discussed based on the controversial role of histamine in dermatitis and on the defined adverse events, e.g. drowsiness and impaired attention. There is no mechanistic rationale for treating non-histaminergic pruritus-related AD with antihistamines (120). The treatment of CSU in infants and children is based on the use of second-generation H1-antihistamines according to the same algorithm recommended for adults (158, 470). Cetirizine, desloratadine, fexofenadine, levocetirizine and loratadine have been studied in children and their long-term safety has been well established in the paediatric population. Rupatadine has been recently approved for the treatment of CSU in children aged 2–11 years old based on a double-blind trial showing safe efficacy with respect to placebo at 1 mg/ml (256). Certain antihistamines (e.g. loratadine, ceterizine) are thought to be safer for use in children, and thus may be preferred in these patients (206). In children aged under 6 years the effective dose of hydroxyzine is up to 50 mg/day in divided doses, and 50–100 mg/day in children aged 6–12 years (243). In summary, for the paediatric management of pruritus, long-term use of first-generation antihistamines is not recommended (158, 208). The associated psychomotor impairment may impact the education and safety of children and persists even after the child has become accustomed to the sedating effects (258). Second-generation antihistamines with appropriate dose adjustment are first-line therapy for CP in children such as urticaria (259).

Other therapies could also be considered, such as UV phototherapy, but the indication and protocol should be carefully considered together with the family due to possible long-term photo damage to the skin. A retrospective analysis of children up to the age of 18 years suffering from AD and psoriasis suggests NB-UVB treatment (471). In children, longer follow-up is essential to determine the true carcinogenic risk of UV therapy. An adjuvant psychological intervention as well as an educational approach can also be highly useful in children (120).

Other systemic treatments such as cyclosporine are not licensed in children younger than 16 years due to a lack of clinical studies. They may be used in treatment-refractory cases (110).

In summary, the treatment of pruritus in children is primarily focused on treatment of the skin disease, especially AD. Topical corticosteroids, topical immunomodulators and some antihistamines can be administered in children, but national regulations must be considered. UV phototherapy may be initiated depending on the child’s skin type and age. Caution should be shown with systemic therapy due to the lack of data and off-label use in children.

The vicious itch–scratch cycle needs to be considered when a patient is treated for CP. The psychosomatic approach recognises the pruritus patient with regard to coping behaviour and possible stress attempts as cause or provocation factors in CP. Essentially, psychosomatic treatment could complement topical and systemic therapy and should be differentiated into unimodal psychological treatment and multimodal psychological treatment for CP (97). Depending on the factors involved, a unimodal (progressive muscular relaxation, autogenic training) or multimodal psychological approach is recommended (97). In addition to causal and symptomatic therapy, behavioural therapy to avoid scratching should be considered, e. g. conscious suppression of the reflex by intense concentration, distraction or alternative scratching techniques such as habit reversal (472). This is very important in patients with CPG who might show unconscious automatic scratching behaviour.

Adjuvant psychosocial programmes focused on CP are most effective in AD (122, 473–475). Such programmes include strategies for breaking the vicious circle of itching and scratching, relaxation and stress management techniques, as well as strategies for dealing with relapses. There are more than 10 RCTs showing slightly beneficial effects; these were recommended for treatment by a Cochrane review on psychological interventions (476). A similar educational programme was developed for patients with CP (477, 478). It is currently established for in-patient hospital treatment of patients with pruritic dermatoses using behavioural therapy in the context of an integrated psychosomatic treatment (479, 480). In patients with coexisting depression, psychotherapy in combination with psychotropic medication can be helpful even to treat CP of different aetiology (481). Most publications on psychotherapeutic/ psychopharmacologic interventions, however, refer to small groups or single case reports. In neurotic excoriations, combined psychopharmacotherapy is also often indicated (481–484). Internet-delivered (eHealth) self-management was investigated in recent years, mostly with cognitive behavioural interventions. Results demonstrate effects similar to face-to-face psychotherapy (485). Studies specifically for dermatologic patients are promising (486).

Expert recommendation: We recommend educational programs. We suggest relaxation and habit reversal techniques as a complementary treatment for managing CP.

• Chronic pruritus is frequent in medicine and needs a precise diagnostic work-up. Its management comprises treatment of the underlying disease, topical treatment modalities including symptomatic antipruritic treatment, UV phototherapy and systemic treatments.
• Sedative or non-sedating H1 antihistamines are suggested as an initial symptomatic therapy in severe CP and sleep loss. Studies on the systemic administration of higher doses of non-sedating antihistamines seem to be promising, but RCTs need to be conducted.
• Systemic glucocorticosteroids are not recommended for first-line treatment of CP, with the exception of extremely severe and acute cases of inflammatory dermatoses and as a short-term treatment in selected cases of refractory CP, especially in paraneoplastic pruritus and palliative care.
• UV phototherapy is recommended for refractory CP in inflammatory skin diseases, cutaneous lymphoma, CPG and selected cases of systemic pruritus (e.g. CKD-associated pruritus, cholestatic pruritus, aquagenic pruritus), especially in elderly pruritus patients or in case of contraindications for systemic therapy. We suggest UV phototherapy in combination with topical and/or systemic treatment, with the exception of calcineurin inhibitors and immunosuppressant drugs.
• Gabapentinoids (gabapentin, pregabalin) are recommended in neuropathic CP and in CKD-associated pruritus and suggested for the treatment of refractory CP and PUO.
• We suggest µ-opioid receptor antagonists in refractory CP, especially in cholestatic pruritus.
• Selected antidepressants are recommended for psychogenic CP and for refractory CP, especially in malignant, cholestatic and chronic kidney disease.
• Neurokinin receptor 1 antagonists like e.g. serlopitant can be recommended in refractory CP and CPG.
• Serotonin receptor antagonists are not recommended for the treatment of CP and CPG.

We thank Mrs Christine Schaefer for her help with editing, language correction and arranging the list of references.

Conflict of Interest: see Appendix S1.

Composition of the guideline group: Experts in the field from Europe. More than 30% are European Academy of Dermatology and Venereology (EADV) members.