Treatment Of Chronic Itch Research Articles

Antipruritic Effect of Nalbuphine, a Kappa Opioid Receptor Agonist, in Mice: A Pan Antipruritic.

Antipruritic effects of kappa opioid receptor (KOR) agonists have been shown in rodent models of acute and chronic scratching (itchlike behavior). Three KOR agonists, nalfurafine, difelikefalin, and nalbuphine, are in clinical studies for antipruritic effects in chronic itch of systemic and skin diseases. Nalfurafine (in Japan) and difelikefalin (in the USA) were approved to be used in the treatment of chronic itch in hemodialysis patients. The FDA-approved nalbuphine has been used in clinic for over 40 years, and it is the only narcotic agonist that is not scheduled. We aimed to study (a) antiscratch activity of nalbuphine against TAT-HIV-1 protein (controls HIV transcription)-, deoxycholic acid (DCA, bile acid)-, and chloroquine (CQ)-induced scratching in a mouse model of acute itch; and (b) whether the effect of nalbuphine is produced via KORs. First, dose–responses were developed for pruritogens. Mice were pretreated with nalbuphine (0.3–10 mg/kg) and then a submaximal dose of pruritogens were administered and the number of scratching bouts was counted. To study if the antiscratch effect of nalbuphine is produced via KOR, we used KOR knock out mice and pharmacologic inhibition of KORs using nor-binaltorphimine, a KOR antagonist. For this aim, we used CQ as a pruritogen. We found that: (a) TAT-HIV-1 protein elicits scratching in a dose-dependent manner; (b) nalbuphine inhibits scratching induced by TAT-HIV-1, DCA, and CQ dose-dependently; and (c) nalbuphine inhibits scratching induced by CQ through KORs. In conclusion, nalbuphine inhibits scratching elicited by multiple pruritogens.

Qingpeng Ointment Ameliorates Inflammatory Responses and Dysregulation of Itch-Related Molecules for Its Antipruritic Effects in Experimental Allergic Contact Dermatitis.

The pathogenesis of itchy skin diseases including allergic contact dermatitis (ACD) is complicated and the treatment of chronic itch is a worldwide problem. One traditional Tibetan medicine, Qingpeng ointment (QP), has been used in treatment of ACD in China for years. In this study we used HPLC and LC/MS analysis, combined with a BATMAN-TCM platform, for detailed HPLC fingerprint analysis and network pharmacology of QP, and investigated the anti-inflammatory and antipruritic activities of QP on ACD induced by squaric acid dibutylester (SADBE) in mice. The BATMAN-TCM analysis provided information of effector molecules of the main ingredients of QP, and possible chronic dermatitis-associated molecules and cell signaling pathways by QP. In ACD mice, QP treatment suppressed the scratching behavior induced by SADBE in a dose-dependent manner and inhibited the production of Th1/2 cytokines in serum and spleen. Also, QP treatment reversed the upregulation of mRNAs levels of itch-related genes in the skin (TRPV4, TSLP, GRP, and MrgprA3) and DRGs (TRPV1, TRPA1, GRP, and MrgprA3). Furthermore, QP suppressed the phosphorylation of Erk and p38 in the skin. In all, our work indicated that QP can significantly attenuate the pathological alterations of Th1/2 cytokines and itch-related mediators, and inhibit the phosphorylation of MAPKs to treat the chronic itch.

Sensory TRP channels contribute differentially to skin inflammation and persistent itch

Although both persistent itch and inflammation are commonly associated with allergic contact dermatitis (ACD), it is not known if they are mediated by shared or distinct signaling pathways. Here we show that both TRPA1 and TRPV1 channels are required for generating spontaneous scratching in a mouse model of ACD induced by squaric acid dibutylester (SADBE), a small molecule hapten, through directly promoting the excitability of pruriceptors. TRPV1 but not TRPA1 channels protect the skin inflammation, as genetic ablation of TRPV1 function or pharmacological ablation of TRPV1-positive sensory nerves promotes cutaneous inflammation in the SADBE-induced ACD. Our results demonstrate that persistent itch and inflammation are mediated by distinct cellular and molecular mechanisms in a mouse model of ACD. Identification of distinct roles of TRPA1 and TRPV1 in regulating itch and inflammation may provide new insights into the pathophysiology and treatment of chronic itch and inflammation in ACD patients.

Psychological Interventions in the Treatment of Chronic Itch.

Patients with chronic itch suffer from higher levels of depression and anxiety than their healthy counterparts. Furthermore, psychological factors, such as stress, are known to aggravate itch. The mere act of thinking about itching can induce the sensation. Interventions like habit reversal training and arousal reduction have been shown to have positive effects on itch relief. Yet, there is still limited data on the psychological management to control the itch scratch cycle and a description of methods suitable to address itch. In this review, we describe different psychological interventions shown to be effective in the treatment of chronic itch. We also provide suggestions based on our experience of suitable interventions for patients with different types of itch.

Itch Management: Psychotherapeutic Approach.

A relationship between the intensity of itch and psychological factors like stress, coping, anxiety, and depression has often been shown in patients with skin diseases. Moreover, the biopsychosocial model of chronic itch nicely summarizes how psychological factors can contribute to a worsening or improvement of chronic itch. Thus, it is reasonable to consider psychological interventions in the treatment of chronic itch. In this chapter we focus on itch-scratch problems as well as stress and anxiety/depression as itch-increasing factors. We summarize the evidence of psychological interventions which can reduce these triggering factors. Hereby, we differentiate between unimodal and multimodal interventions, and emphasize that not every single intervention might help for all patients, but that a comprehensive anamnesis is needed in order to determine whether one or several psychological factors trigger itch in the particular patient.

Uremic Itch Management.

Uremic itch is a frequent and sometimes very tormenting symptom in patients with advanced or end-stage renal failure, with a strong negative impact on the quality of life. According to a representative study, the point prevalence of chronic itch is 25% in hemodialysis patients but may reach more than 50% in single cohorts depending on the country and dialysis efficacy. Not much is known regarding the pathogenesis of uremic itch. Besides parathyroid hormone, histamine, tryptase, and alteration of the calcium-phosphate metabolism have been suspected. More recently, derangements in the opioid system and an inflammatory condition have been investigated as suspected players in the pathogenesis of uremic itch, but remain unproven so far. Treatment of chronic itch in dialysis patients remains difficult. Besides topical application of rehydrating or immunomodulating compounds, such as γ-linolenic acid or tacrolimus treatment with nalfurafine may be helpful. Apart from that, gabapentin and pregabalin are promising drugs to alleviate uremic itch. In many cases, UVB phototherapy is effective in reducing the intensity of itch. When treating patients, one should take into account that most of the drugs available are not licensed for the treatment of itch. Therefore, a deliberate use of therapeutic options aiming for a good risk-benefit relation should be adopted. In very severe and refractory cases, patients suitable for renal transplantation might be switched to 'high urgency' status, as successful renal transplantation cures uremic pruritus in most of the cases.

Treatment of chronic itch in systemic disease. Current standards

Chronic itch (CI) is a frequent and sometimes tormenting symptom in many skin and systemic diseases. In systemic diseases, it mostly appears on primarily unaffected skin. As a sequelae of intense scratching, secondary skin lesions such as excoriations, scars, and prurigo nodularis may occur. Due to the lack of valid pathogenetic concepts and good clinical trials, the therapy of CI remains mostly symptomatic. In Europe almost all drugs used to treat CI are not approved for this indication. CI is frequent in patients with chronic kidney diseases in advanced stages. Gabapentin and pregabalin, anticonvulsants, and centrally acting calcium channel blockers have been shown to exert a profound effect in CI. Furthermore, UVB phototherapy has been proven to attenuate pruritus in uremic patients. Randomized controlled studies have recently shown that nalfurafine, a κ-opioid receptor agonist, is able to ameliorate itch in patients with uremic itch. In patients suffering from cholestatic itch, the anion exchange resin colestyramine and rifampicin are effective antipruritic drugs. Furthermore, µ-opioid receptor antagonists and sertraline may be used to alleviate CI in hepatic diseases. In refractory cases, naso-biliary drainage or albumin dialysis are effective invasive procedures. For the treatment of chronic itch in hematological diseases no controlled trials have been performed so far. The mainstay in these cases is to treat the underlying disease.

Gastrointestinal peptides and itch sensation.

To highlight the most recent advances regarding gastrointestinal peptides and their relation to chronic itch, with focus on gastrin-releasing peptide (GRP), substance P, and their respective receptors. GRP and its high-affinity GRP receptor (GRPR) have been identified as key regulators in the spinal cord itch pathway and may be involved in the maintenance of chronic itch sensation. Several neuropeptides including GRP, neuromedin B, and substance P regulate itch signals in a cooperative or inhibitory manner on the spinal level. Small clinical studies show that neurokinin 1 receptor antagonists might be of benefit in the treatment of chronic itch. Chronic itch is a burdensome clinical problem, for which no specific treatment is available. Studies on the mechanisms of pruriceptive sensation and its signaling to the central nervous system (CNS) via the spinal cord have elucidated a number of peptides that are implicated in the regulation of itch-specific signaling pathways. Among those, GRP and its high-affinity GRP receptor have been proposed as key elements in the itch-specific neuronal pathways.

New insights into the pathophysiology and treatment of chronic itch in patients with end‐stage renal disease, chronic liver disease, and lymphoma

Chronic itch associated with systemic diseases continues to be one of the most bothersome dermatological symptoms accompanying end-stage renal disease (ESRD), chronic liver diseases, and lymphoma. The International Forum for the Study of Itch has recently issued a consensus paper on different types of chronic pruritus, including pruritus in systemic diseases that can present with or without secondary skin changes.1Various types of itch have been described based on the origin of the itch, which could be skin-related, neuropathic, systemic, or psychogenic.2 At any given time patients with these systemic diseases may have more than one origin, for example, patients with end-stage renal disease (ESRD) could have neuropathic itch due to nerve fibers damage, as well as itch associated with skin inflammation such as perforating folliculitis. Itch adversely affects quality of life of patients, leading to sleep deprivation and depression that further augment itch. Chronic itch associated with systemic diseases range from mild to intractable, which is defined as a chronic itch state in which the cause cannot be removed or treated, and no relief or cure has been found in the generally accepted course of medical practice.3 In the last decade, there are significant advances in our understanding of specific itch neuronal pathways, mediators and relevant receptors, opening the field for development of new antipruritic strategies. The purpose of this review is to highlight the new findings related to the pathophysiological mechanisms and the treatment of itch associated with the most common systemic diseases including ESRD, chronic liver disease and lymphoma.