Chronic Pruritus in the Absence of Skin Disease: Pathophysiology,Diagnosis and Treatment

Chronic pruritus arises not only from dermatoses, but also, in up to half of cases, from extracutaneous origins. A multitude of systemic, neurological, psychiatric, and somatoform conditions are associated with pruritus in the absence of skin disease. Moreover, pruritus is a frequently observed side effect of many drugs. It is therefore difficult for physicians to make a correct diagnosis. Chronic pruritus patients frequently present to the dermatologist with skin lesions secondary to a long-lasting scratching behavior, such as lichenification and prurigo nodularis. A structured clinical history and physical examination are essential in order to evaluate the pruritus, along with systematic, medical history-adapted laboratory and radiological tests carried out according to the differential diagnosis. For therapeutic reasons, a symptomatic therapy should be promptly initiated parallel to the diagnostic procedures. Once the underlying factor(s) leading to the pruritus are identified, a targeted therapy should be implemented. Importantly, the treatment of accompanying disorders such as sleep disturbances or mental symptoms should be taken into consideration. Even after successful treatment of the underlying cause, pruritus may persist, likely due to chronicity processes including peripheral and central sensitization or impaired inhibition at spinal level. A vast arsenal of topical and systemic agents targeting these pathophysiological mechanisms has been used to deter further chronicity. The therapeutic options currently available are, however, still insufficient for many patients. Thus, future studies aiming to unveil the complex mechanisms underlying chronic pruritus and develop new therapeutic agents are urgently needed.     

Treatments for chronic pruritus outside of the box

Patients with chronic pruritus are in desperate need of novel treatment options, as current therapeutic possibilities are often not effective, have a poor level of evidence and are mostly off‐label. In recent years, much effort has been put into the identification of potential targets for the treatment of chronic pruritus. More importantly, a number of promising new drugs that are aimed at treating pruritus in different conditions are currently in advanced stages of clinical trials. Here, current pharmacological developments leading to potential new drugs for the treatment of chronic pruritus within various conditions are summarized. Hopefully, these new approaches will result in effective and safe therapies for our patients with chronic pruritus associated with dermatological or non‐dermatological diseases in the near future.     

Research in practice: Substance P antagonism in chronic pruritus

Pruritus is an unpleasant sensation of the skin, which triggers a desire to scratch or rub. The chronic form (≥6 weeks’ duration) often occurs as a side effect of many diseases and is usually accompanied by a high loss in quality of life for patients, especially in cases in which the symptom is chronic without adequate treatment options. In recent years, the situation improved continuously, guidelines for chronic pruritus have been defined and standard medications have been proposed. For many reasons, there are still patients who are unable to obtain relief. New therapeutic approaches are therefore urgently needed. Blocking the neuropeptide substance P is a promising strategy; substance P mediates clinically relevant pro‐inflammatory effects by binding to the neurokinin 1 receptor (NK‐1R). This led us to hypothesize that NK‐1R antagonists are promising therapeutic options for chronic pruritus. Several international case series have meanwhile proven the antipruritic effect of the NK‐1R antagonist aprepitant for various forms of chronic pruritus. Initiation of clinical trials with new NK‐1R‐antagonists as a new therapeutic option continues this trend.     

Clinical management of pruritus

The care of patients with chronic pruritus as a symptom of a wide variety of underlying diseases continues to confront dermatologists with diagnostic and therapeutic challenges. However, a structured history and a physical examination may already substantially help in narrowing down the number of potential differential diagnoses. Apart form reducing the intensity of pruritus, identification and appropriate treatment of the underlying disease are important needs of patients. If these goals doesn't lead to improvement of itch, current guidelines provide a number of topical and systemic therapies for symptomatic treatment. Various skin lesions (for example, xerosis caused by irritant substances, secondary scratch lesions) prompt patients to consult a dermatologist, but most cases require an interdisciplinary therapeutic approach to identify potential internal medicine, neurologic, or psychosomatic aspects. Although great strides have been made in basic research, specific therapies are still rare, and a precise knowledge of the legal framework for the implementation of guidelines (for example, off‐label use) is essential. This CME article gives an overview of the causes of and treatment options for chronic pruritus and discusses both advances in basic research as well as progress in clinical knowledge.     

Causes,pathophysiology, and treatment of pruritus in the mature patient

Chronic itch is a common and debilitating health condition in the elderly. There are several common causes of itch in the mature population, such as skin xerosis, immunosenescence, and neuropathic changes. In addition, skin diseases, such as seborrheic dermatitis and stasis dermatitis, systemic conditions (end-stage renal disease and diabetes), or psychogenic derailments, such as depression, anxiety, and dementia, can all serve as triggers of pruritus. Polypharmacy, a common occurrence among the elderly population, may also serve as a cause of itch that may or may not be accompanied by dermatitis. Such medications as μ opioids and calcium channel blockers have been found to have a connection with pruritus in the advanced aging population.Determining the exact trigger for pruritus in the elderly may be especially challenging, because itch can be idiopathic in many cases. The role of treatments should not only take into account elimination of various underlying cutaneous, systemic, or psychogenic conditions associated with itch but also focus on the skin changes that are characteristic of the aging process. Development of such treatment options can be guided by elucidation of the mechanisms underlying the pathophysiology of itch in the geriatric population.     

Cholestatischer Pruritus

Pruritus is a common symptom of hepatobiliary disorders and may considerably diminish quality of life. Cholestatic pruritus exerts a circadian rhythm and is typically most severe in the evening hours and early at night. Itching is reported often to be most intense at the palms and the soles, but may also be generalized. The pathophysiological mechanisms of cholestatic pruritus have not been completely clarified. In the past, bile salts, histamine, progesterone metabolites and opioids have been discussed as potential causal substances; a correlation with itch intensity could never be proven. The enzyme autotaxin, which releases lysophosphatidic acid, has recently been identified as potential cholestatic pruritogen. Treatment aims to bind pruritogens in the gut lumen by resins such as cholestyramine, to modulate pruritogen metabolism by rifampicin and to influence central itch signaling by μ-opioid antagonists and selective serotonin re-uptake inhibitors. In cases of refractory pruritus experimental treatment options such as UV-therapy, extracorporeal albumin dialysis and nasobiliary drainage may be considered.     

Immunosuppressive therapy for autoimmune bullous diseases

Adjuvant immunosuppressive drugs are widely used to minimize corticosteroid-related adverse effects in the short-term and long-term management of cautoimmune bullous diseases. In bullous pemphigoid and pemphigus vulgaris, azathioprine and mycophenolate mofetil seem to be equally effective when used in combination with oral corticosteroids, but mycophenolate mofetil is less myelosuppressive and hepatotoxic. Due to a better safety profile, mycophenolate mofetil or enteric-coated mycophenolate sodium may gradually replace azathioprine as the first-line adjuvant of choice in the treatment of moderate to severe autoimmune bullous diseases, including epidermolysis bullosa acquisita and cicatricial pemphigoid. Cyclophosphamide still has a place in the treatment of severe relapsing autoimmune bullous diseases. Continuous oral cyclophosphamide provides optimal immunosuppression, but it also produces the highest cumulative dose. Several pulsed cyclophosphamide regimens have, therefore, been developed and are reported to be effective in severe forms of pemphigus. Randomized controlled studies are needed to compare the efficacy and safety of cyclophosphamide with newer treatment options, such as rituximab and immunoapheresis, and to define optimal dose ranges and duration of available immunosuppressive treatments in different stages of autoimmune bullous diseases.     

Aquagenic pruritus in an adolescent effectively managed with β‐alanine supplementation

Aquagenic pruritus is a rare debilitating condition, which can be idiopathic, iatrogenic, or associated with systemic disease. In idiopathic cases, treatment can be challenging as options are limited and of variable efficacy. Here, we report the case of a teenage boy with refractory idiopathic aquagenic pruritus effectively managed with administration of β‐alanine supplementation, a treatment gaining traction in lay media but not yet reported in the medical literature. This report adds to the limited options published for treatment of idiopathic aquagenic pruritus in pediatric patients.     

瘙痒介质及其受体的研究进展

瘙痒的产生是一个复杂的多因素作用的结果,其具体机制尚不完全清楚.研究已证实,瘙痒具有特异的神经传导通路,多种内源性物质与瘙痒的发病密切相关.近年来的研究表明,组胺4型受体、蛋白酶活化受体-2、白介素-31受体、神经激肽受体-1在皮肤无髓C神经纤维的表达可能介导瘙痒的发生,而神经营养素和神经生长因子及其受体则可能作为一种瘙痒敏感剂,促进瘙痒的形成与发展.这些化学介质及其受体在瘙痒发生的病理生理机制中并不是孤立地起作用,而是与神经细胞、免疫细胞及皮肤细胞紧密联系.     

Neurophysiology of pruritus

Neurophysiologic studies indicate that pruritus is a distinct sensation with its own neuronal pathways in the peripheral and central nervous system which are different from that of pain. Pruritus is a very disturbing sensation and most common skin-related symptom. Histamine was long considered to be the only mediator of pruritus. However, it has become evident that - besides histamine - a variety of neuromediators such as neurotrophins and neuropeptides as well as their receptors play an important role in pruritus. Neuromediators are produced by mast cells, keratinocytes and eosinophil granulocytes which are in close contact to sensory nerves. The discovery of these neurophysiological interactions opens new and promising therapeutic options for the treatment of pruritus.     

Neurophysiologie des Pruritus

Neurophysiologic studies indicate that pruritus is a distinct sensation with its own neuronal pathways in the peripheral and central nervous system which are different from that of pain. Pruritus is a very disturbing sensation and most common skin-related symptom. Histamine was long considered to be the only mediator of pruritus. However, it has become evident that – besides histamine – a variety of neuromediators such as neurotrophins and neuropeptides as well as their receptors play an important role in pruritus. Neuromediators are produced by mast cells, keratinocytes and eosinophil granulocytes which are in close contact to sensory nerves. The discovery of these neurophysiological interactions opens new and promising therapeutic options for the treatment of pruritus.     

Pruritus in the elderly

Pruritus is an unpleasant sensation leading to the desire to scratch. It is the most common symptom in dermatology, and various skin and systemic diseases can be associated with the presence of itching. Pruritus may also be provoked by numerous drugs. Although the exact epidemiologic data are still absent, it is generally accepted that elderly people frequently suffer from pruritus, and the problem of itching in this population remains a challenge for clinicians. The elderly often complain of numerous comorbidities that complicate the determination of the cause of pruritus, as well as its treatment. Physical and mental deprivation may complicate proper assessment of pruritus severity and negatively impair compliance with complex antipruritic therapies. Taking also into account heterogeneity of possible causes of pruritus, every patient with pruritus must be handled individually, regarding the diagnostic procedures and antipruritic therapy.     

Topical anti-itch therapy

Topical anti-itch therapy could be causative (antiviral, antimycotic, and/or antiparasitic preparations) or symptomatic. Symptomatic therapy includes substituting some other sensation by cooling, heating, and/or counterirritation, by anesthesia of sensory nerve endings with local anesthetics, blocking mediators of pruritus (to deplete substance P or to block acetylcholine release), and reducing inflammation of the skin with corticosteroids or topical immunomodulators (pimecrolimus and tacrolimus). In addition to drugs, the patient should be taught to use emollients and to avoid skin dryness and vasodilatation by contact with irritants. Topical anti-itch preparations can be recommended not only for treatment of localized pruritus, but also for therapy of generalized pruritus when general measures are not effective, systemic drugs are contraindicated, and/or as addition to causative or systemic therapy. Topical anti-itch preparations should be prescribed after the diagnosis is made and used as the first-choice treatment together with general measures.     

Pruritus in pregnancy and childhood--do we really consider all relevant differential diagnoses?

During pregnancy and also during childhood, pruritus can have manifold aetiologies and should therefore always be taken seriously. In pregnancy, pruritus is the main dermatological symptom, occurring in 18% of women. Pregnancy-specific dermatological diseases such as polymorphic eruption of pregnancy (PEP), Pemphigoid (Herpes) gestationis, Pruritus gravidarum are accompanied by severe pruritus and scratching. In children, it mainly occurs along with dermatoses but in rare cases with systemic diseases such as renal or liver failure. Mostly, it appears in the setting of atopic dermatitis (AD). Both groups of patients require therapeutic regimens of their own. The use of topical and systemic treatments depends on the underlying aetiology of the pruritus and the stage and status of the skin. Because of potential effects on the fetus, the treatment of pruritus in pregnancy requires prudent consideration of whether the severity of the underlying disease warrants treatment and selection of the safest treatments available. Systemic treatments such as systemic glucocorticosteroids, a restricted number of antihistamines and ultraviolet phototherapy may be necessary in severe and generalized forms of pruritus in pregnancy. In children, the physician has to consider that topically applied drugs may cause intoxication due to the different body volume/body surface proportion. The dosages of systemic drugs need to be adapted in children and ultraviolet phototherapy should be performed with caution due to possible longterm photo damage of the skin. In a two center approach, we wanted to highlight the major aetiologies of pruritus during pregnancy and in children and point out the mainstays of antipruritic therapy in these two challenging groups of patients according to our clinical experiences. For the future, it would be desirable for all disciplines involved (dermatologist, gynaecologist, paediatrician, general practitioner) to cooperate closely to expand the clinical and scientific knowledge of pruritus in these groups of pruritus patients.     

Schlafstörungen in der Dermatologie – eine umfassende Übersicht

Sleep is a normal physiological process that accounts for approximately one third of a person's life. Disruption of the normal sleep cycle, which maintains physiological homeostasis, can lead to pathology. It is not known whether sleep disturbance causes skin disease or skin disease causes sleep impairment, but a bidirectional influence is suspected. We have compiled the data from published articles on “sleep disorders in dermatology” in PubMed Central from July 2010 to July 2022 (with the option “full text available”) and provide an overview of sleep disorders associated with dermatological conditions and certain drugs used in dermatology as well as sleep disturbances for which some drugs used can cause itch or dermatological issues. Atopic dermatitis, eczema and psoriasis have been shown to be exacerbated by sleep problems and vice versa. Sleep deprivation, night-time pruritus and disrupted sleep cycles are often used to assess treatment response and quality of life in these conditions. Some medications used primarily for dermatological conditions have also been associated with alterations in the sleep-wake cycle. Addressing patients sleep disorders should be an integral part of the management of dermatological conditions. More studies are needed to further investigate the influence of sleep and skin disorders.     

What are new treatment concepts in systemic itch?

Chronic pruritus is a relevant symptom burden in various systemic diseases. It is most commonly observed in patients with chronic kidney disease, hepatobiliary and hematological disorders as well as adverse drug reaction. Recent basic research has unravelled novel treatment targets which are currently in preclinical phases, clinical trials or have already been licensed. While µ‐opioid receptor antagonists have been used since decades mainly in cholestatic pruritus, the k‐opioid receptor agonist nalfurafine has been licensed in Japan for chronic kidney disease‐associated pruritus (CKDaP) as well as cholestatic pruritus. Further κ‐opioid receptor agonists are currently investigated in various clinical trials including CKDaP. In recent years, the calcium channel blockers gabapentin and pregabalin have also been recognized as effective anti‐pruritus therapy in several internal diseases with the best evidence in chronic kidney disease‐associated pruritus. Neurokinin‐1 receptor antagonists have been investigated with variable benefit in CKDaP, solid tumors and lymphoproliferative disorders such as cutaneous T‐cell lymphoma, Sézary syndrome. Inhibitors of the ileal bile acid transporter (IBAT) represent a selective interruption of the enterohepatic circulation and are currently investigated in various hepatobiliary disorders associated with pruritus. The current development and testing of novel drugs in clinical trials offers hope to struggling physicians and suffering patients.     

Future treatment options for atopic dermatitis – Small molecules and beyond

Atopic dermatitis (AD) is a common eczematous skin disease with a chronic and relapsing course. Current therapeutic options for moderate to severe AD in children and adults are unsatisfactory. Along with the success of basic research to define pathogenesis-related targets, novel small molecule inhibitors and biologics for the treatment of AD have been developed.These compounds focus on the specific reduction of pruritus, interfere with the pro-allergic Th2-deviation of the immune system or inhibit inflammatory pathways in the skin. Based on studies registered at ClinicalTrials.gov we present novel treatment strategies of AD, their molecular mechanisms of action, and discuss the current status of the clinical results. As many of the new compounds target pathogenesis-related traits of the disease, we face a new era in the treatment and understanding of AD.