Pathogenesis of pruritus

The pathogenesis of acute and chronic (> 6 weeks duration) pruritus is complex and involves in the skin a network of resident cells (e. g., mast cells, keratinocytes, sensory neurons) and transient inflammatory cells (e. g., eosinophils). Though pruritus and pain show overlapping mechanisms, recent studies have provided evidence that pruritus and pain pathogenesis differ in important points. In the skin, the sensory C‐nerve fibers have been investigated intensively. Several classes of histamine‐sensitive or histamine‐insensitve C‐fibers have been described. Epidermal and dermal sensory nerve fibres are now assumed to be of major importance in pruritus induction. They interact with keratinocytes, inflammatory cells such as T lymphocytes, eosinophils and basophils which have been shown to release multiple pruritogenic mediators (e.g., nerve growth factor, interleukin‐31) which lead to activation, sensitization and sprouting of skin nerves. Specific receptors have been discovered on cutaneous and spinal neurons to be exclusively involved in the processing of pruritic signals. Just recently, the gastrin‐releasing peptide receptor (GRPR) was identified on spinal neurons that are crucially involved in pruritus but not pain processing. Chronic pruritus is notoriously difficult to treat. Newer insights into the underlying pathogenesis of pruritus have enabled novel treatment approaches that target the pruritus‐specific pathophysiological mechanism. For example, kappa‐opioid receptor agonists and neurokinin‐1 antagonists have been found to relieve chronic pruritus.     

Clinical potential of Melanotan® (NDP-α-MSH) in skin protection – current status and future perspective

Non-histaminergic pruritus of any origin is difficult to treat and requires evaluation of new therapeutic strategies which were offered by recent neurophysiologic findings. For example, the discovery of opioid receptors on mast cells and nerve fibers enables the effective administration of opioid receptor antagonists. Up to now, 130 patients with pruritus of different origin were successfully treated with the oral opioidantagonist naltrexone. A significant therapeutic response was achieved under 50–150 mg daily in 66% of patients. In prurigo nodularis, naltrexone also contributed to healing of the skin lesions. Tachyphylaxis was infrequent, and adverse drug effects, in particular nausea, were of short duration. Only recently, the vanilloid receptor 1 (VR1) was demonstrated on nerve fibers and mast cells what explains the antipruritic efficacy of the topical application of capsaicin. Upon continual therapy with this VR1-ligand, neuropeptides are depleted and the nerve fiber is desensitized. A total of 53 patients with pruritus of different origin (prurigo nodularis, psoriasis, eczema, aquagenic pruritus, PUVA itch, hydroxyethyl starch-induced itch, and lymphoma) were selected to receive capsaicin four to six times daily in gradually increasing concentrations (0.025–0.1%). After cessation of the symptoms of neurogenic inflammation, all of the patients experienced a complete elimination of pruritus within 12 days. In addition, capsaicin largely contributed to healing of the skin lesions in prurigo nodularis.     

Neurophysiology of pruritus: interaction of itch and pain

The discovery of an itch-specific neuronal pathway, which is distinct from the pain-processing pathway, has clarified the neuronal basis for the itch sensation. Albeit being distinct, there are complex interactions between pain and itch. The inhibition of itch by pain is well known and can explain the antipruritic effect of scratching. However, the opposite effect also exists and has major clinical implications: inhibition of pain processing (eg, by spinal opioids) can generate itch. Conversely, blockade of spinal opioid receptors can be used as an antipruritic therapy. Moreover, the spinal processing of pain and itch can be modulated, resulting in a hypersensitivity or hyposensitivity to pain or itch: similar to chronic painful conditions, ongoing activity of pruriceptors can induce a spinal hypersensitivity for itch in patients with chronic pruritus. Therapeutic antipruritic approaches therefore should target both local inflammation and spinal sensitization of itch processing.     

Schmerzen und Jucken

Chronic pruritus and chronic pain are frequent symptoms of a variety of underlying diseases. Painful sensations usually suppress acute itching. In chronic states, both may be present in parallel and be a part of one event. Patients with chronic pruritus should be asked for the presence of pain, which can be identified and characterized using specific and validated questionnaires. The early detection of (neuropathic) pain in patients with chronic pruritus can be done using the PainDetect questionnaire. In general, patients suffering from both itch and pain have a highly impaired quality of life, high degree of objective health burden, need a more intensive health care and a complex analgetic and antipruritic therapy.     

β-endorphin modulates lipogenesis in human sebocytes

Proteinase-activated receptors are G-protein-coupled receptors with seven-transmembrane domains activated by serine proteinases. PAR-2 is a receptor for mast cell tryptase, house dust mite allergens, bacterial antigens and trypsin, for example, indicating a role of PAR-2 during inflammation and immune responses. In the skin, PAR-2 is expressed by keratinocytes, endothelial cells, certain immune cells and nerves, suggesting a broad regulatory role of proteases in the skin. Recently, PAR-2 has been demonstrated to be involved in neurogenic inflammation. Therefore, we examined whether neuronal PAR-2 may be involved in pruritus of human skin. The endogenous PAR-2 agonist tryptase was increased up to fourfold in atopic dermatitis (AD) patients. PAR-2 was markedly enhanced on primary afferent nerve fibres in skin biopsies of AD patients. Intracutaneous injection of endogenous PAR-2 agonists provoked enhanced and prolonged itch when applied intralesionally. Interestingly, itch upon mast cell degranulation prevailed despite local antihistamines in AD patients only. Thus, we identified enhanced PAR-2 signalling as a new link between inflammatory and sensory phenomena in AD patients. PAR-2 antagonists, thus, represent a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus.     

Antipruritic effects of pimecrolimus and tacrolimus

The development of topical calcineurin inhibitors resulted in a significant improvement in the treatment of inflammatory skin diseases such as atopic dermatitis. In addition, an excellent amelioration of pruritus could be observed. Other itchy dermatoses such as chronic irritative hand dermatitis, rosacea, graft-versus-host-disease, renal pruritus, lichen sclerosus, prurigo simplex, prurigo nodularis, scrotal eczema, and inverse psoriasis also have been treated successfully with pimecrolimus and tacrolimus. The antipruritic effect currently is believed to be related to the inhibition of inflammatory cytokines. Furthermore, recent investigations indicate a release of neuropeptides from sensory nerve fibers and degranulation of mast cells mediated by pimecrolimus and tacrolimus. Similar effects have been observed during capsaicin treatment. These findings may provide a possible explanation for initially observed calcineurin inhibitors related side-effects such as burning and pruritus. Moreover, the antipruritic potency may be related to a direct effect on nerve fibers leading to suppression of itch mediated by unknown mechanisms.     

Neurotropin inhibits both capsaicin-induced substance P release and nerve growth factor-induced neurite outgrowth in cultured rat dorsal root ganglion neurones

Background.  Neurotropin (NTP), a biological extract from rabbit skin inoculated with vaccinia virus, is an effective analgesic and anti-allergic agent, and has antipruritic effects in various dermatoses including eczema, dermatitis and urticaria. In patients receiving haemodialysis who have pruritus, NTP appears to exert its antipruritic effect by lowering the plasma levels of substance P (SP), but its underlying mechanisms are not fully understood.
Aim.  To investigate the antipruritic mechanisms of NTP.
Methods.  The effects of NTP on capsaicin-induced SP release from neonatal rat dorsal root ganglion (DRG) neurones were assessed by measuring SP concentrations in culture media by a competitive ELISA. The effects of NTP on nerve growth factor (NGF)-induced neurite outgrowth were assessed by measuring the length of the longest process of cultured DRG neurones. The neuronal cytotoxicity of NTP was determined using a methylthiazole tetrazolium cytotoxicity assay.
Results.  NTP dose-dependently inhibited capsaicin-induced release of SP from cultured DRG neurones, whereas NTP alone had no effect on SP release. Moreover, NTP dose-dependently inhibited NGF-induced neurite outgrowth in cultured DRG neurones. NTP had no observable cytotoxicity.
Conclusions.  These results suggest that NTP exerts its antipruritic effects by inhibiting both SP release and neurite outgrowth of cutaneous sensory nerves.     

Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases.

BACKGROUND: The perception of pruritus is modified by endogenous opiates via central opiate receptors in a histamine-independent manner. OBJECTIVE: The aim of this pilot study was to evaluate the efficacy and safety of naltrexone, an orally active opiate antagonist, in the treatment of severe, otherwise intractable pruritus of different origin in an open-label clinical trial. METHODS: A total of 50 patients with pruritus caused by internal diseases, hydroxyethyl starch, contact with water, cutaneous lymphoma, atopic dermatitis, xerosis cutis, macular amyloidosis, psoriasis, and other skin disorders as well as with pruritus of unknown origin were randomly selected to receive naltrexone 50 mg daily. The pruritus intensity was rated by the patients before and during therapy in a visual analogue scale. RESULTS: A significant therapeutic response was achieved in 35 of the 50 patients within 1 week (confidence limits of 0.55 and 0.82 at a confidence level of 0. 95). Naltrexone was of high antipruritic effect in 9 of 17 cases of prurigo nodularis and contributed to healing of the skin lesions. Tachyphylaxis was infrequent (6/50), occurred late, and could be counterbalanced by raising the dosage in 2 patients. Adverse drug effects were restricted to the first 2 weeks of treatment and included nausea (11/50), fatigue (3/50), dizziness, heartburn, and diarrhea (1/50 each). CONCLUSION: The study suggests that oral opiate antagonists might be a well-tolerated and effective therapy for pruritic symptoms in many diseases.     

Antipruritische Wirksamkeit einer hoch dosierten Antihistaminikatherapie

Background and objectives

The causal treatment of chronic pruritus is not always possible or effective necessitating symptomatic antipruritic therapy. Antihistamines are the only drugs approved for the treatment of chronic pruritus, but they are rarely effective at standard doses. The aim of this investigation was to describe the efficacy and safety of high-dosage antihistamine treatment in patients with chronic pruritus of different origin.

Patients

A total of 67 patients with chronic pruritus caused by different skin diseases or chronic pruritus of unknown origin were treated with levocetirizine 10 mg/fexofenadine 360 mg or levocetirizine 10 mg/fexofenadine 360 mg/azelastine 4 mg or desloratadine 20 mg per day.

Results

A therapeutic response was achieved in 43.8% of patients with a combination of two antihistamines, 68.4% of patients with three antihistamines and 76.9% of patients with high dosage desloratadine. The average reduction in pruritus was 57.5% (two antihistamines), 67.4% (three antihistamines) and 89% (desloratadine). Adverse drug effects were observed rarely.

Conclusions

The results of this case series suggest a high antipruritic effect in chronic pruritus by administration of high-dosage, non-sedating antihistamines. These results have to be confirmed in controlled trials. The combination was not more effective than the high dosage monotherapy. The latter one might be preferable due to unknown interactions and addition of side-effects in the combination therapy.     

Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus

Pruritus (itch) can be defined as an unpleasant cutaneous sensation associated with the immediate desire to scratch. Recent findings have identified potential classes of endogenous "itch mediators" and establish a modern concept for the pathophysiology of pruritus. First, there in no universal peripheral itch mediator, but disease-specific sets of involved mediators. Second, numerous mediators of skin cells can activate and sensitize pruritic nerve endings, and even modulate their growth. Our knowledge of itch processing in the spinal cord and the involved centers in the central nervous system is rapidly growing. This review summarizes the current information about the significance of neuron-skin interactions, ion channels, neuropeptides, proteases, cannabinoids, opioids, kinins, cytokines, biogenic amines, neurotransmitters, and their receptors in the pathobiology of pruritus. A deeper understanding of these circuits is required for the development of novel antipruritic strategies.     

Topical pimecrolimus and tacrolimus transiently induce neuropeptide release and mast cell degranulation in murine skin

BACKGROUND: The topical calcineurin inhibitors pimecrolimus and tacrolimus have been demonstrated to be an effective new anti-inflammatory therapy. The only clinically relevant side-effect reported is transient application site burning and stinging itch at the beginning of topical therapy. OBJECTIVES: In order to understand the underlying mechanism of this effect, we examined whether or not the compounds are able to stimulate neuropeptide release in normal murine skin as well as in a mouse model of experimentally induced irritant contact dermatitis. METHODS: Balb/c mice were treated with 1% pimecrolimus cream or 0.1% tacrolimus ointment. Untreated and corresponding vehicle-treated mice served as controls. Skin specimens were investigated by light, immunofluorescence and electron microscopy as well as enzyme-linked immunosorbent assay and polymerase chain reaction. RESULTS: Topical application of pimecrolimus and tacrolimus was followed by an initial release of substance P and calcitonin gene-related peptide from primary afferent nerve fibres in murine skin during the early inflammatory response. The release of the neuropeptides and their binding to mast cells (MCs) led to MC degranulation. Mediators of MCs such as histamine and tryptase may induce pruritus and burning by binding to the corresponding receptors (histamine receptor 1, proteinase-activated receptor 2) on sensory nerve fibres, which explains the initial side-effects during therapy with calcineurin inhibitors. CONCLUSIONS: It may be speculated that calcineurin inhibitors directly stimulate intracellular signalling pathways or bind to ion channels such as transient receptor potential vanilloid 1 or receptors involved in nociception.     

Putative neuronal mechanisms of sensitive skin

Abstract:  According to epidemiological studies, up to 50% of adults report facial sensitivity with various distinctive symptoms, such as prickling, burning, tingling, pain or itching. This is termed sensitive skin and represents a syndrome of physiological reactions rather than a disease entity. In this review, we discuss the currently available literature on this syndrome and describe the possible underlying neuronal pathomechanisms. The sensory receptors expressed on unmyelinated nerve fibres and keratinocytes involved in nociception, such as TRPV1 and endothelin receptors, are hypothesized to play a role in the induction of sensitive skin. Furthermore, we discuss the role of neurotrophins and the influence of stress on sensitive skin.     

Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors

BACKGROUND: Although some patients with psoriasis vulgaris also complain of severe pruritus, the data available regarding pruritus in psoriasis are sparse. OBJECTIVES: To clarify the mechanism and mediators involved in the pruritus of psoriasis vulgaris, we compared itch-associated factors in lesional skin from psoriatic patients vs. skin without pruritus quantitatively using a panel of histological and immunohistological parameters. PATIENTS AND METHODS: Biopsied specimens were obtained from 38 patients with psoriasis vulgaris who were divided into two groups according to the presence or absence of pruritus. RESULTS: When compared with psoriatic patients devoid of pruritus, lesional skin from patients with pruritus showed the following characteristic features: (i) a rich innervation both in the epidermis and in the papillary dermis; (ii) an increase in neuropeptide substance P-containing nerve fibres in perivascular areas; (iii) decreased expression of neutral endopeptidase in the epidermal basal layer as well as in the endothelia of blood vessels; (iv) many mast cells showing degranulating processes in the papillary dermis; (v) a strong immunoreactivity for nerve growth factor (NGF) throughout the entire epidermis and an increased NGF content in lesional skin homogenates; (vi) an increase in the expression of high-affinity receptors for NGF (Trk A) in basal keratinocytes and in dermal nerves; (vii) an increased population of interleukin-2-immunoreactive lymphocytes; and (viii) a strong expression of E-selectin on vascular endothelial cells. A significant correlation was observed between the severity of pruritus and protein gene product 9.5-immunoreactive intraepidermal nerve fibres, NGF-immunoreactive keratinocytes, expression of Trk A in the epidermis and the density of immunoreactive vessels for E-selectin. These findings indicate that possible pruritogenic mediators in psoriatic lesional skin are neurogenic factors including innervation, neuropeptide substance P, neuropeptide-degrading enzymes and NGF, activated mast cells, one or more cytokines and endothelial-leucocyte adhesion molecules. CONCLUSIONS: These data document for the first time itch-related local markers in psoriasis, and suggest complex and multifactorial mechanisms of pruritus in the disease. These results provide the groundwork for further studies to evaluate the efficacy of antipruritic treatment for psoriatic patients.     

Topical application of emollients prevents dry skin-inducible intraepidermal nerve growth in acetone-treated mice

In common dermatoses, such as atopic dermatitis (AD), a decline in skin barrier function often accompanies an increased severity of clinical symptomatology, including pruritus [1]. Skin barrier disruption alters epidermal innervation and increases nerve density in the skin [2]. These findings are indicative of increases in sensory receptors responsive to exogenous trigger factors, suggesting that hyperinnervation is partly responsible for intense itch sensations [2]. Therefore, the abnormal innervation associated with skin barrier dysfunction such as dry skin has been considered as a target of antipruritic therapy. Moreover, recent studies have demonstrated that epidermal innervation is probably regulated by a fine balance of nerve elongation factors (e.g., nerve growth factor (NGF), amphiregulin, gelatinase) [2] and nerve repulsion factors (e.g., semaphorin 3A (Sema3A), anosmin-1) [2] and [3]. Although many people use emollients daily to alleviate symptoms of clinically and subjectively dry skin [4], the effects of emollients on nerve fiber density and nerve growth activity in dry skin remain unclear. We therefore examined the anti-nerve growth effects of petrolatum and heparinoid cream in the epidermis of acetone-treated mice, an animal model of acute dry skin [5].     

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.     

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.     

Treatment of prurigo nodularis with topical capsaicin

BACKGROUND: Prurigo nodularis is an eruption of lichenified or excoriated nodules caused by intractable pruritus that is difficult to treat. Therefore the antipruritic efficacy of capsaicin seemed to be of particular interest because this alkaloid, extractable from red pepper, interferes with the perception of pruritus and pain by depletion of neuropeptides in small sensory cutaneous nerves. OBJECTIVE: The aim of this concentration- and regimen-ranging study was to evaluate the efficacy, safety, and practicability of capsaicin in the topical treatment of prurigo nodularis in a large series of patients. METHODS: A total of 33 patients with prurigo nodularis of various origins were selected to receive capsaicin (0.025% to 0.3%) 4 to 6 times daily for 2 weeks up to 10 months. The consecutive follow-up period was up to 6 months. In 7 patients, skin biopsy specimens were taken before, during, and after therapy and investigated histologically, immunohistochemically, and ultrastructurally. RESULTS: All 33 patients could be evaluated for efficacy. After cessation of the symptoms of neurogenic inflammation, such as burning sensations or erythema, all of them experienced a complete elimination of pruritus within 12 days. In addition, capsaicin largely contributed to the gradual healing of the skin lesions. After discontinuation of the therapy, pruritus returned in 16 of 33 patients within 2 months. At the ultrastructural level, no degenerative changes of cutaneous nerves could be found during or after capsaicin therapy. Depletion of substance P was demonstrated by confocal laser scanning microscopy thus confirming the specific effect of capsaicin in vivo. CONCLUSION: Topical treatment of prurigo nodularis with capsaicin proved to be an effective and safe regimen resulting in clearing of the skin lesions.     

Topische Cannabinoidagonisten

BACKGROUND: Chronic, therapy-resistant pruritus often fails to respond to standard measures so new therapeutic approaches are needed. Recently, the expression of cannabinoid receptors on cutaneous sensory nerve fibers was described, so cannabinoid agonists seem a rational therapeutic option for pruritus. PATIENTS: In an open application observation 22 patients with prurigo, lichen simplex and pruritus applied an emollient cream containing N-palmitoyl ethanolamine (PEA). RESULTS: In 14/22 patients a good antipruritic effect could be documented. The average reduction in itch was 86.4%. The therapy was well-tolerated by all patients; neither burning burn nor contact dermatitis was observed. CONCLUSIONS: Topical cannabinoid agonists represent an new effective and well-tolerated therapy for refractory itching of various origins. Creams with a higher concentration may be even more effective with broader indications.     

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 .