Chronic pruritus: principals of diagnostics and therapy

Chronic pruritus (starting from 6 weeks duration) is symptom of dermatological, internal, neurological or psychiatric disease. Identification and treatment of the underlying diseases is of great importance especially in the initial phase of chronic pruritus in order to prevent peripheral and central sensitization processes and thus chronification. Application of the redefined clinical classification, newly defined clinical algorithms and inquiry of clinical characteristics of pruritus is helpful in finding the underlying disease. In chronic pruritus existing for several years, clarifying the underlying origin is difficult and therapies are often ineffective. Next to conventional therapies such as antihistamines and corticosteroids, central effective substances can be applied preventing pruritus sensation on spinal or cerebral level.     

Interaktionen von Juckreiz und Schmerz

The discovery of specific pathways for the processing of itch has greatly enhanced our understanding of the physiology of pruritus. However, the complex interactions between itch and pain are only partly understood. This review focuses on the neurophysiological basis of itch under experimental and clinical conditions. Chronic inflammatory diseases can locally sensitize nerve endings and thereby contribute to itch. In addition, there is increasing evidence that also central processing of itch can be sensitized in pruritus patients. Interestingly, this pattern of peripheral and central sensitization in pruritus has striking similarities to the one observed in chronic pain patients. The presumed similarities in underlying sensitizing mechanisms between itch and pain has major therapeutic consequences as successful therapies for chronic pain might be used also in chronic itch.     

Interactions between itch and pain

The discovery of specific pathways for the processing of itch has greatly enhanced our understanding of the physiology of pruritus. However, the complex interactions between itch and pain are only partly understood. This review focuses on the neurophysiological basis of itch under experimental and clinical conditions. Chronic inflammatory diseases can locally sensitize nerve endings and thereby contribute to itch. In addition, there is increasing evidence that also central processing of itch can be sensitized in pruritus patients. Interestingly, this pattern of peripheral and central sensitization in pruritus has striking similarities to the one observed in chronic pain patients. The presumed similarities in underlying sensitizing mechanisms between itch and pain has major therapeutic consequences as successful therapies for chronic pain might be used also in chronic itch.     

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.     

Managing itch: Can we do better

Itch is a common problem and it can be debilitating. In the approach to managing chronic pruritic diseases, the key would be to identify the underlying cause and to adopt treatment specific to the condition. Unfortunately, in many cases, the cause/s can be occult. A careful examination for an underlying primary dermatosis is required, and repeated examinations at intervals may be needed. In generalized pruritus without a primary dermatosis, investigations to exclude a systemic disease are usually necessary. If the cause is still not determined, a trial of therapy may be very useful. The next step in the approach to chronic pruritus would be to use anti-pruritic agents specific to the type of pruritic disease. As we understand more about the patho-physiology of the various types of chronic pruritic diseases, we will be able to judiciously use treatment targeting the underlying mechanisms better and thereby achieve more favorable results. It is important to understand that itch is a sensation of multi-dimensional nature. In addition to its somatosensory aspect, it is closely linked to emotion and cognition. Very often, chronic pruritus originates from an organic disease but is amplified by the psychology of the patient. It is important to check if there are psycho-social issues that accompanies the presentation of chronic pruritus, and addressing them provides for a more effective and holistic management to the condition. A multi-disciplinary clinic would be suited to better address these aspects. Such a multi-disciplinary clinic would typically comprise a dermatologist, a nurse educator, a psychologist, a psychiatrist and medical social worker. In summary, our current clinical management of itch can be improved through careful identification of the underlying cause/s, using therapies specific for the disease and targeting the pathological mechanisms, and adopting a holistic approach to the clinical problem.     

Pruritus as a sign of systemic disease

Pruritus, as one of the most common clinical manifestations in medicine, has been recognized for many centuries. Defined as an unpleasant sensation resulting in the need to scratch, it is divided into acute and chronic stages, based on the duration of the clinical manifestation. Classically, pruritus is associated with cutaneous disorders; however, it may also accompany various systemic disorders, including renal, hepatic, hematologic, or oncologic, and be the first or solitary manifestation of an underlying systemic disease. Additionally, the clinical manifestation may occur as an adverse reaction to drug administration. The pathogenesis of itch is multifactorial, involving various neuromediators and cytokines, with a prominent role of peripheral and central nervous system in its development. Based on an underlying disorder, the affected patients present different clinical patterns of pruritus. Diagnostic approach is based on detailed history taking and physical examination. Frequently, additional diagnostic measures, including laboratory or imaging tests, are performed, especially when the cause of pruritus is unknown. Pruritus remains a challenging clinical manifestation with a significant importance for physicians managing systemic disorders.     

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.     

S2k Guidelines for the diagnosis and treatment of chronic pruritus – update – short version

Associated with a host of different diseases, pruritus is a cardinal symptom that poses an interdisciplinary diagnostic and therapeutic challenge. Over time, that symptom may progress independently of the initial cause, thus losing its function as a warning sign and turning into a clinically relevant disease of its own. In Germany, approximately 13.5 % of the general population are affected by chronic pruritus, with an incidence of 7 %. All forms of chronic pruritus require targeted treatment consisting of (a) diagnosis and management of the underlying disease, (b) dermatological treatment of primary or secondary (for example, dry skin, scratch lesions) symptoms, (c) symptomatic antipruritic treatment, and (d) psychological/psychotherapeutic treatment in case of an underlying or associated psychological or psychosomatic condition. Medical care of patients with chronic pruritus should therefore include an interdisciplinary approach, in particular with respect to diagnosis and therapy of the underlying disease as well as in terms of the management of treatment and adverse events. The objective of the present interdisciplinary guidelines is to define and standardize diagnostic and therapeutic procedures in patients with chronic pruritus. This is a short version of the current S2 guidelines on chronic pruritus. The long version may be found at www.awmf.org .     

Clinical classification of itch: a position paper of the International Forum for the Study of Itch

Chronic itch is a common and distressing symptom that arises from a variety of skin conditions and systemic diseases. Despite this, there is no clinically based classification of pruritic diseases to assist in the diagnosis and cost-effective medical care of patients with pruritus. The proposed classification focuses on clinical signs and distinguishes between diseases with and without primary or secondary skin lesions. Three groups of conditions are proposed: pruritus on diseased (inflamed) skin (group I), pruritus on non-diseased (non-inflamed) skin (group II), and pruritus presenting with severe chronic secondary scratch lesions, such as prurigo nodularis (group III). The next part classifies the underlying diseases according to different categories: dermatological diseases, systemic diseases including diseases of pregnancy and drug-induced pruritus, neurological and psychiatric diseases. In some patients more than one cause may account for pruritus (category "mixed") while in others no underlying disease can be identified (category "others"). This is the first version of a clinical classification worked out by the members of the International Forum for the Study of Itch. It is intended to serve as a diagnostic route for better evaluation of patients with chronic pruritus and aims to improve patients' care.     

Brachioradial pruritus: a case report and review of the literature

Brachioradial pruritus is an enigmatic pruritic sensation that characteristically involves the proximal lateral forearm of middle-aged women residing in tropical to temperate climates. There are often no associated cutaneous signs. The pathophysiology has been debated but is believed to involve UV radiation and/or cervical spine disease. We present a patient with brachioradial pruritus and a review of the literature. Brachioradial pruritus should be suspected in patients with intractable pruritus overlying the brachioradialis muscle of the forearm that is recalcitrant to standard therapies. These patients commonly report a history of chronic solar damage and/or cervical spine disease.     

Pruritus bei systemischen Erkrankungen

Chronic pruritus is a symptom of various internal disorders. In contrast to dermatological diseases, pruritus does not present with primary skin alterations in these patients. However, intense scratching may cause secondary skin changes such as abrasion, excoriation, prurigo nodularis, or in rare cases even scaring. The most common internal medicine causes for chronic pruritus are chronic kidney disease, hepatobiliary and hematological disorders as well as adverse drug reactions. Pruritus is less commonly seen in patients with endocrine or metabolic diseases, malabsorption syndromes, infectious diseases and solid tumors. The pathogenesis of pruritus in these disorders remains largely elusive, albeit preliminary insights have been gained for uremic and cholestatic pruritus. Antipruritic treatment is therefore symptomatic in most cases and may represent a clinical challenge. The calcium channel blockers gabapentin and pregabalin have the best proven efficacy in chronic kidney disease-associated pruritus. In Japan nalfurafine, a κ-opioid receptor agonist, has been licensed for this indication. UVB light may also attenuate uremic symptoms. In patients suffering from hepatobiliary disorders the sequestrant cholestyramine and the enzyme inducer rifampicin are effective. Furthermore, μ?opioid receptor antagonists and sertraline may be used to ameliorate cholestatic pruritus. So far, no randomized controlled trials have been performed for chronic itch in other internal medicine disorders. Antipruritic treatment is mainly based on effective therapy of the underlying disease.     

Pruritus – Pathophysiologie,Klinik und Therapie – Eine Übersicht

Pruritus is an unpleasant sensory perception of the skin associated with the desire to scratch. As a physiological nociception, pruritus leads to the removal of harmful agents such as parasites and plants from the skin surface. More often, pruritus occurs as a severe and therapy‐refractory symptom of various underlying dermatological and systemic diseases. Comparable to chronic pain, chronic pruritus worsens the general condition and may lead to physical and psychological exhaustion. Until the 1990s, pruritus had been regarded as an incomplete pain sensation. Only recently, itch was defined as a separate, pain‐independent sensation with its own mediators, spinal neurons and cortical areas. These observations led to the development of new therapeutic modalities. This paper gives an overview of itch pathophysiology, clinical types and therapies.     

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.     

Neurophysiological and neurochemical basis of modern pruritus treatment

Abstract:  Chronic pruritus of any origin is a frequent discomfort in daily medical practice, and its therapy is challenging. Frequently, the underlying origin may not be identified and symptomatic therapy is necessary. Conventional treatment modalities such as antihistamines often lack efficacy, and hence new therapeutic strategies are necessary. The neuronal mechanisms underlying chronic pruritus have been partly identified during the past years and offer new therapeutic strategies. For example, mast cell degranulation, activation of neuroreceptors on sensory nerve fibres and neurogenic inflammation have been identified to be involved in induction and chronification of the symptom. Accordingly, controlling neuroreceptors such as cannabinoid receptors by agonists or antagonists showed high antipruritic efficacy. Pruritus is transmitted to the central nervous system by specialized nerve fibres and sensory receptors. It has been demonstrated that pruritus and pain have their own neuronal pathways with broad interactions. Accordingly, classical analgesics for neuropathic pain (gabapentin, antidepressants) also exhibit antipruritic efficacy upon clinical use. In summary, these recent developments show that highlighting the basis of pruritus offers modern neurophysiological and neurochemical therapeutic models and the possibility to treat patients with refractory itching of different origin.     

German-Austrian-Swiss Consensus Conference on clinical practice in chronic graft-versus-host disease (GVHD): guidance for supportive therapy of chronic cutaneous and musculoskeletal GVHD

Supportive therapy plays a central role in the management of cutaneous and musculoskeletal manifestations of chronic graft-versus-host disease (cGVHD), either alone or in combination with systemic approaches. We present results from the German-Austrian-Swiss Consensus Conference on clinical practice in cGVHD, held in Regensburg, Germany, in November 2009. The intention was to achieve a consensus on current evidence-based treatment options as well as to provide guidelines for daily clinical practice. Skin is the most common organ involved in cGVHD. Its clinical presentation varies considerably. Patients may have pruritus, rash, pain, dyspigmentation and fibrotic or sclerodermatous lesions, often leading to contractures. Treatment options for supportive therapy in cutaneous cGVHD include topical therapies such as topical steroids and topical calcineurin inhibitors, as well as phototherapy and physiotherapy. The most relevant manifestation in musculoskeletal cGVHD is fasciitis which must be distinguished from sclerodermatous skin cGVHD. Physiotherapy is the mainstay of supportive treatment in fasciitis in cGVHD. Successful therapy of cutaneous and musculoskeletal cGVHD depends on interdisciplinary management to improve patients' quality of life.     

Rationelle symptomatische Therapie bei chronischem Pruritus

Chronic pruritus is a difficult-to-treat problem which accompanies many dermatologic and systemic diseases. Frequently, therapy is ineffective and prolongs the pruritus. Thus significant costs arise for the health system, which are clearly lowered by a rational therapy concept. Extensive knowledge about both topical and systemic therapy of pruritus has been acquired in recent years. Currently, new therapeutic approaches are available, which intervene in different pruritogenic mechanisms. Substances can block the cutaneous pruritus induction (e.g. antihistamines, leukotriene antagonists, cannabinoid agonists) or mediate central effects such as the inhibition of pruritus transmission via the spinal cord (e.g. naltrexone, gabapentin) or the suppression of the cerebral itch perception (e.g. antidepressants, neuroleptics). Usually combining several therapeutic principles is necessary in order to suppress chronic pruritus with lasting effect. The most effective approach is to gradually combine therapies, always considering both the medical and financial impacts.     

Role of neuroimmune circuits and pruritus in psoriasis

Psoriasis is a chronic inflammatory skin disease presenting with an array of clinical phenotypes, often associated with pruritus. Environmental and psychological stressors can exacerbate psoriasis symptoms and provoke flares. Recent studies suggest a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis in some patients with psoriasis that can result in immune dysregulation. The immune system, in turn, can communicate with the nervous system to induce, maintain or aggravate psoriasis. In the skin, peripheral sensory as well as autonomic nerves control release of inflammatory mediators from dendritic cells, mast cells, T cells or keratinocytes, thereby modulating inflammatory responses and, in case of sensory nerves, pruritus. In response to the environment or stress, cytokines, chemokines, proteases, and neuropeptides fluctuate in psoriasis and influence immune responses as well as nerve activity. Furthermore, immune cells communicate with sensory nerves which control release of cytokines, such as IL-23, that are ultimately involved in psoriasis pathogenesis. Nerves also communicate with keratinocytes to induce epidermal proliferation. Notably, in contrast to recent years the debilitating problem of pruritus in psoriasis has been increasingly appreciated. Thus, investigating neuroimmune communication in psoriasis will not only expand our knowledge about the impact of sensory nerves in inflammation and pruritus and give new insights into the impact of environmental factors activating neuroimmune circuits or of stress in psoriasis, but may also lead to novel therapies. This review summarizes the relevant literature on the role of neuroimmune circuits, stress and how the central HPA axis and its peripheral equivalent in the skin, impact psoriasis.     

Alternative therapy in pruritus

Because of its multitude of origins, the symptom complex of pruritus has a plethora of purported remedies and few therapeutic indications. Very few topical and systemic FDA approved medications have the indication of pruritus. Specific therapy still awaits a better definition of the exact physiologic events in chronic pruritus. Hence most medications actually focus on the central nervous system--the peripheral receptors--and the lack of specific physiologic targets has inhibited pharmacologic development. The resulting gap has opened the door to a variety of alternative therapies.     

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.     

Pruritus as a manifestation of systemic disorders

A significant internal disorder is present in only a limited number of patients with essential pruritus. The mechanisms for the production of pruritus in these disorders are poorly understood and frequently are unrelated to liberation of histamine. Proteolytic enzymes in lymphoproliferative disorders, bile acids in obstructive hepatobiliary disease, parathyroid hormone in chronic renal failure, and prostaglandins and kinins are but a few of the chemicals that may ultimately be responsible for the development of pruritus in these and other purely cutaneous disorders. Patients with essential pruritus should have a comprehensive physical and laboratory evaluation, but psychologic, environmental, and other factors must be considered when thorough clinical evaluation is unrewarding. Treatment should be directed towards elimination of the underlying alteration, control of the additional factors, and alleviation of the symptom.