Emerging drugs for the treatment of chronic pruritic diseases

Chronic pruritus is non-histaminergic and mediated through a complex interplay of peripheral and central immune and neural pathways. Significant developments in the understanding of chronic pruritus have emerged and paved the way for new, emerging therapies. This review details the emerging drug landscape for chronic pruritus treatment, focusing on monoclonal antibody agents that target key cytokines and their receptors as well as small molecule agents that inhibit mediators of the immune and neural pathways. The article provides background regarding the currently available therapies and the rationale for the development of new agents based on the current market and recent scientific developments. Identification of new targets along neuroimmune itch pathways has allowed for the development of targeted drugs which can be utilized for effective therapy. As we enter a new era of chronic itch treatments, we face exciting prospects and challenges

Itch in Organs Beyond the Skin

The purpose of this review was to explore mechanisms, causes, and therapies of itchy conditions involving organs beyond the skin including the eyes, ears, nose, and genital region. Conditions which cause itch in these locations vary from skin diseases that extend to these areas (i.e., atopic dermatitis, seborrheic dermatitis, and psoriasis) to allergic conditions (i.e., allergic rhinitis and conjunctivitis) and to neuropathic conditions that relate to afferent nerve fiber damage (i.e., lumbosacral radiculopathies in genital disease) as well as some psychological components. Similar to the skin, itch in these locations involves a complex interaction between epithelial cells, unmyelinated C nerve fibers, and cytokines. There is also a significant component of neural sensitization phenomena. Mechanisms of itch beyond the skin are currently an understudied topic that affects millions of patients. Future research should be done in order to further understand the pathophysiology of itch in these body sites

Use of Butorphanol as Treatment for Cholestatic Itch

Pruritus is a debilitating symptom of cholestatic diseases such as primary biliary cholangitis and primary sclerosing cholangitis and often results in major reduction in quality of life for afflicted patients. Classic treatment options for the treatment of cholestatic pruritus include antihistamines, bile acid resins, serotonin reuptake inhibitors, and mu-opioid antagonists. Unfortunately, these drugs are not always successful in treating pruritus of cholestasis and may be associated with adverse effects. Recent advances in our understanding of itch pathophysiology have led to the use of butorphanol, a kappa-opioid agonist and mu-opioid antagonist, for the treatment of various forms of pruritus. Reports of butorphanol to treat cholestatic itch specifically are rare. To better understand the role of butorphanol in the treatment of cholestatic pruritus, including characterization of its side effect profile. We present a case series of eight adult patients with cholestatic disease who were treated with butorphanol in hopes of alleviating intractable pruritus. Patients were identified through a clinical data request form serviced by University of Miami Information Technology. Five out of eight patients (62.5%) reported successful reductions in itch severity after treatment with butorphanol, two patients reported no (or transient) change in itch severity, and one patient reported a paradoxical increase in itching. Side effects included somnolence, sedation, nausea, vomiting, and dizziness. Butorphanol was safe and leads to clinically significant symptomatic improvement. Clinicians should be aware of butorphanol as an off-label treatment option for pruritus of cholestasis. Further studies are needed to better characterize the effect of butorphanol on cholestatic itch

Chapter 43 - Treatment of itch in atopic dermatitis

Atopic dermatitis (AD) is a disease that affects millions of patients worldwide and is characterized by debilitating itch. The pathophysiology of pruritus in AD consists of multiple players, including pruritogens, unique receptors, and ion channels found on unmyelinated C-nerve fibers. The sensation of the itch is also perpetuated by the disrupted epidermal skin barrier characterizing this disease, as well as sensitization phenomena in both the peripheral and central nervous systems. Thankfully, treatment options for atopic itch are abundant. These range from topical therapies, to systemic immunomodulators, to systemic therapies, which attenuate itch transmission in the nervous system. Topical treatment of itch includes a variety of medications including corticosteroids, calcineurin antagonists, and phosphodiesterase-4 inhibitors. Systemic treatment includes oral prednisone, methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil. Moisturizing topical treatments remain one of the mainstays of treatment. Emerging therapies, such as novel monoclonal antibodies that are directed against itch mediators, such as interleukin-31, as well as drugs targeting the Janus kinase-STAT system, are promising treatments that will hopefully improve the lives of many patients

Dupilumab use in atopic dermatitis and beyond in skin diseases

Atopic dermatitis (AD) is a chronic inflammatory condition that affects 5–10% of adults and 9–18% of children and its pathology is rooted in the Th-2-mediated immune response. Dupilumab is a fully human IgG4 monoclonal antibody that targets the IL-4 receptor alpha subunit that is endogenously bound by the Th-2 cytokines IL-4 and IL-13. Successful clinical trials of dupilumab showing marked improvements in clinical signs of AD, patient reported symptoms and quality of life measures led to its approval for clinical use for moderate-to-severe AD in 2017. This review details the current body of evidence on the drug’s mechanism of action, pharmacology, clinical efficacy and safety as well as post market and real world use

Effects of Stress on Itch

Psychological stress and ensuing modulation of the immune and nervous systems can have a significant impact on itch. Stress can exacerbate itch and vice versa, resulting in a vicious cycle that can greatly impair a patient's quality of life. This review summarizes the association between stress and itch, elucidates the mechanism by which these two phenomena influence one another, and explores treatment modalities that aim to reduce stress-induced itch. A complete search of the PubMed and Google Scholar databases was completed and literature pertinent to this review was compiled. Both acute and chronic stress can significantly affect itch in healthy individuals and in those diagnosed with itchy skin diseases as well as systemic diseases, thus resulting in a vicious cycle in which stress exacerbates itch and vice versa. The mechanisms by which stress induces or aggravates itch include both central and peripheral activation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. Activation of these systems, in turn, affects the mast cells, keratinocytes, and nerves that secrete neuropeptides, such as substance P, nerve growth factor, acetylcholine, histamine, and itchy cytokines. A dysfunctional parasympathetic response is thought to be involved in the chronic stress/itch response. Brain structures associated with emotion, such as the limbic system and periaqueductal gray, which work on the descending facilitation of itch, play a significant role in stress-induced itch. As specific brain structures are associated with stress, drug treatments targeting these areas (ie, γ-aminobutyric acid–ergic drugs, serotonin and norepinephrine reuptake inhibitors) may help to modulate itch. Stress can also be combatted using nonpharmacologic treatments such as cognitive–behavioral therapies and stress-relieving holistic approaches (eg, yoga, acupuncture)

Practical Approach for the Diagnosis and Treatment of Chronic Pruritus

Chronic itch is a common condition that affects the quality of life of many patients and can often be difficult to treat. When managing a patient with itch, the first step requires identification of the underlying cause, which may be dermatologic or nondermatologic in nature. The process begins with a thorough history and physical examination, which may or may not be followed by laboratory tests and imaging. The appropriate treatment for each patient should be considered based on the diagnosis, severity of itch, and individual patient preference. Treatment options range from topical treatments, which may be indicated for more mild types of itch, to systemic treatments, which may be indicated for itch that is more ubiquitous and debilitating in nature. Within the last decade, developments in our understanding of itch pathophysiology has led to new treatment options on the horizon that consist of more targeted medications, including monoclonal antibodies and opioid modulators. •Chronic itch is a common and disruptive condition that affects the lives of many individuals.•Management of chronic itch depends upon the identification of an underlying etiology; if underlying causes cannot be identified, symptomatic control is necessary.•Treatment options range from topical to systemic medications, and appropriate drug choice depends upon severity of itch and individual patient preference.•Exciting treatments on the horizon include monoclonal antibodies as well as opioid modulators that serve as promising new treatment options for itch

Drug-Induced Pruritus Without Primary Rash

Drug-induced pruritus is a phenomenon in which the ingestion of a particular drug results in the sensation of pruritus without coexisting skin lesions. It is a common medical problem which accounts for about 5% of drug adverse reactions. Drugs most commonly known to cause this adverse event include mu-opioids, chloroquine, and hydroxyethyl starch. However, within the realm of oncology, many other new anticancer therapies have been shown to induce pruritus with and without rash. Not only does it cause significant distress, it also results in decreased compliance to treatment. Hence, it is of utmost importance for clinicians to be cognizant of drug-induced pruritus. This chapter aims to provide physicians with updated information on the topic, including prevalence, categorization, pathophysiology, diagnosis, and treatment of this phenomenon