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Tenenhaus M, Rennekampff HO. Promising Strategies for the Management of Burn-Wound-Associated Pruritus. EUROPEAN BURN JOURNAL 2025; 6:2. [PMID: 39982335 PMCID: PMC11843913 DOI: 10.3390/ebj6010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/23/2024] [Accepted: 01/16/2025] [Indexed: 02/22/2025]
Abstract
Patients who have been injured by burns often suffer from persistent and debilitating post burn pruritus. Despite a myriad of therapeutic interventions and medications, this complex condition remains particularly difficult to ameliorate. Recently, a new generation of antipruritic medications has demonstrated clinical success in managing pruritus in a number of dermatologic, nephritic and hepatic disease states, targeting unique aspects of the pruritic pathways. While specific trials demonstrating efficacy and safety are currently lacking, the purported mechanisms of action and similarities to the targeted inflammatory markers, pruritogens and neural pathways of these new medications, in concert with clinical evidence, hold promise for burn patients.
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Gabrielli F, Crepaldi E, Cavicchioli A, Rivi M, Costanzo AC, Cursaro C, Andreone P. Itching for Answers: A Comprehensive Review of Cholestatic Pruritus Treatments. Biomolecules 2024; 14:1227. [PMID: 39456160 PMCID: PMC11505983 DOI: 10.3390/biom14101227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/21/2024] [Accepted: 08/28/2024] [Indexed: 10/28/2024] Open
Abstract
Cholestasis is a clinical and laboratory syndrome indicating impaired bile production or excretion. One of the hallmark symptoms of cholestasis is pruritus. Itch can be severe and debilitating for patients, impacting their quality of life similarly to pain, and, in some cases, it can be refractory. Current therapies like anion exchange resins and rifampicin, offer partial relief but with side effects. Effective, well-tolerated treatments are urgently needed. This literature review examines existing options (bile acid sequestrants, antihistamines, opioid antagonists, sertraline, and rifampicin) and explores novel therapies (monoclonal antibodies, PPAR agonists, and bile-acid-based therapies). We analyze mechanisms, limitations, and adverse effects to aid clinicians and researchers. Novel approaches include monoclonal antibodies to inhibit bile recirculation and PPAR agonists targeting pruritus signaling. Despite the limited current options, ongoing research promises better treatments for cholestatic pruritus, addressing its distressing impact. In summary, cholestasis-associated pruritus poses a significant challenge with limited treatments. Advancements in understanding its pathophysiology offer hope for more effective therapies in the future.
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Affiliation(s)
- Filippo Gabrielli
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Internal and Metabolic Medicine, AOU of Modena-Baggiovara, 41126 Modena, Italy
| | - Eleonora Crepaldi
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Alessia Cavicchioli
- Internal and Metabolic Medicine, AOU of Modena-Baggiovara, 41126 Modena, Italy
| | - Marco Rivi
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Arianna Carmen Costanzo
- Department of Hepato-bilio-pancreatic Surgery and Liver Transplantation, Hautepierre Hospital, Avenue Molière, 67200 Strasbourg, France
| | - Carmela Cursaro
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Internal and Metabolic Medicine, AOU of Modena-Baggiovara, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
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Zhang P, Xiang S, Liu B, Wang X, Yang X, Ye C, Wang Z, Li Y, Zhou L, Wang C, Li H, Huang J, Peng A, Wang X, Wang D, Xiao J, Chen W, Cheng H, Mao N, Wang J, Yang L, Chen J. Randomized controlled trial of nalfurafine for refractory pruritus in hemodialysis patients. Ren Fail 2023; 45:2175590. [PMID: 36856148 PMCID: PMC9980412 DOI: 10.1080/0886022x.2023.2175590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023] Open
Abstract
Background: Chronic kidney disease-associated pruritus (CKD-aP) is very common and sometimes refractory to treatment in hemodialysis patients. In a trial conducted in Japan, nalfurafine, effectively reduced itching of treatment-resistant CKD-aP. Our present bridging study aimed to evaluate the efficacy and safety of nalfurafine in Chinese cohort with refractory CKD-aP.Methods: In this phase III, multicenter bridging study conducted at 22 sites in China, 141 Chinese cases with refractory CKD-aP were randomly (2:2:1) assigned to receive 5 μg, 2.5 μg of nalfurafine or a placebo orally for 14 days in a double-blind manner. The primary end point was the mean decrease in the mean visual analogue scale (VAS) from baseline.Results: A total of 141 patients were included. The primary endpoint analysis based on full analysis set (FAS), the difference of mean VAS decrease between 5 μg nalfurafine and placebo group was 11.37 mm (p = .041); the difference of mean VAS decrease between 2.5 μg and placebo group was 8.81 mm, but not statistically significantly different. Both differences were greater than 4.13 mm, which met its predefined success criterion of at least 50% efficacy of the key Japanese clinical trial. The per protocol set (PPS) analysis got similar results. The incidence of adverse drug reactions (ADRs) was 49.1% in 5μg, 38.6% in 2.5 μg and 33.3% in placebo group. The most common ADR was insomnia, seen in 21 of the 114 nalfurafine patients.Conclusions: Oral nalfurafine effectively reduced itching with few significant ADRs in Chinese hemodialysis patients with refractory pruritus.
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Affiliation(s)
- Ping Zhang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Kidney Disease Center, Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Kidney Disease Center, National Key Clinical Department of Kidney Diseases, Hangzhou, China,Institute of Nephrology, Zhejiang University, Hangzhou, China,Kidney Disease Center, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Shilong Xiang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Kidney Disease Center, Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Kidney Disease Center, National Key Clinical Department of Kidney Diseases, Hangzhou, China,Institute of Nephrology, Zhejiang University, Hangzhou, China,Kidney Disease Center, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Bicheng Liu
- Department of Nephrology, ZhongDa Hospital, Southeast University, Chongqing, China
| | - Xiaohui Wang
- Department of Nephrology, Fifth Hospital in Wuhan, Wuhan, China
| | - Xiaoping Yang
- Department of Nephrology, The First Affiliated Hospital of Shihezi University School of Medicine, Shihezi, China
| | - Chaoyang Ye
- Department of Nephrology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zunsong Wang
- Department of Nephrology, Shandong Province QianFoshan Hospital, Jinan, China
| | - Yanlin Li
- Department of Nephrology, Zhongshan Traditional Chinese Medicine Hospital, Guangzhou, China
| | - Li Zhou
- Department of Nephrology, West China Hospital of Sichuan University, Chengdu, China
| | - Caili Wang
- Department of Nephrology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Hongbo Li
- Department of Nephrology, Wuhan No.1 Hospital, Wuhan, China
| | - Jian Huang
- Department of Nephrology, Jinhua Municipal Central Hospital, Jinhua, China
| | - Ai Peng
- Department of Nephrology, Shanghai Tenth People’s Hospital, Shanghai, China
| | - Xiaoping Wang
- Department of Nephrology, The Central Hospital of Jinan, Jinan, China
| | - Deguang Wang
- Department of Nephrology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Jie Xiao
- Department of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenli Chen
- Department of Nephrology, The Central Hospital of Wuhan, Wuhan, China
| | - Hong Cheng
- Department of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Nan Mao
- Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jianqin Wang
- Department of Nephrology, Lanzhou University Second Hospital, Lanzhou, China
| | - Lin Yang
- Department of Nephrology, Yichang Central People’s Hospital, Yichang, China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Kidney Disease Center, Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Kidney Disease Center, National Key Clinical Department of Kidney Diseases, Hangzhou, China,Institute of Nephrology, Zhejiang University, Hangzhou, China,Kidney Disease Center, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China,CONTACT Jianghua Chen Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Hu M, Scheffel J, Elieh-Ali-Komi D, Maurer M, Hawro T, Metz M. An update on mechanisms of pruritus and their potential treatment in primary cutaneous T-cell lymphoma. Clin Exp Med 2023; 23:4177-4197. [PMID: 37555911 PMCID: PMC10725374 DOI: 10.1007/s10238-023-01141-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/12/2023] [Indexed: 08/10/2023]
Abstract
Primary cutaneous T-cell lymphomas (CTCL), which include mycosis fungoides (MF) and Sézary syndrome (SS), are a group of lymphoproliferative disorders characterized by clonal accumulation of neoplastic T-lymphocytes in the skin. Severe pruritus, one of the most common and distressing symptoms in primary CTCL, can significantly impair emotional well-being, physical functioning, and interpersonal relationships, thus greatly reducing quality of life. Unfortunately, effectively managing pruritus remains challenging in CTCL patients as the underlying mechanisms are, as of yet, not fully understood. Previous studies investigating the mechanisms of itch in CTCL have identified several mediators and their corresponding antagonists used for treatment. However, a comprehensive overview of the mediators and receptors contributing to pruritus in primary CTCL is lacking in the current literature. Here, we summarize and review the mediators and receptors that may contribute to pruritus in primary CTCL to explore the mechanisms of CTCL pruritus and identify effective therapeutic targets using the PubMed and Web of Science databases. Studies were included if they described itch mediators and receptors in MF and SS. Overall, the available data suggest that proteases (mainly tryptase), and neuropeptides (particularly Substance P) may be of greatest interest. At the receptor level, cytokine receptors, MRGPRs, and TRP channels are most likely important. Future drug development efforts should concentrate on targeting these mediators and receptors for the treatment of CTCL pruritus.
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Affiliation(s)
- Man Hu
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Hindenburgdamm 27, 12203, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Jörg Scheffel
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Hindenburgdamm 27, 12203, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Daniel Elieh-Ali-Komi
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Hindenburgdamm 27, 12203, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Marcus Maurer
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Hindenburgdamm 27, 12203, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Tomasz Hawro
- Department of Dermatology, Allergology and Venereology, Institute and Comprehensive Center for Inflammation Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany.
| | - Martin Metz
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Hindenburgdamm 27, 12203, Berlin, Germany.
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany.
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Pan M, Wang G, Zhou L, Xu Y, Yao L, Wu C, Mei C, Zhao Z, Sun D, Guan T, Chen Q, Shi M, Xu H, Zeng W, Li F, Yan R, Liu BC. Safety and effectiveness of HSK21542 for hemodialysis patients: a multiple ascending dose study. Front Pharmacol 2023; 14:1203642. [PMID: 37876731 PMCID: PMC10590914 DOI: 10.3389/fphar.2023.1203642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 09/22/2023] [Indexed: 10/26/2023] Open
Abstract
Background: HSK21542, a novel selective peripherally-restricted κ-opioid receptor agonist has been proven to be a safe and effective analgesic and antipruritic drug in both in vitro and in vivo studies. We aimed to evaluate its safety, pharmacokinetics and efficacy in hemodialysis patients over a 1-week treatment period, and to establish the optimal dosage for a further 12-week stage 2 trial. Methods: In this multiple ascending dose study, hemodialysis patients were randomly assigned to receive HSK21542 (0.05-0.80 μg/kg), or a placebo three times within 2.5 h at the end of each dialysis session for 1 week. Safety evaluations included reports of treatment-emergent adverse events (TEAEs); pharmacokinetics and efficacy outcomes were also assessed. Results: Among the 44 screened patients, 41 were enrolled and completed the trial. The overall incidence of TEAEs was higher in the HSK21542 group compared to the placebo group, with an incidence of 75.0%, 50.0%, 75.0%, and 88.9% in the range of 0.05-0.80 μg/kg. All TEAEs were grade 1 or 2 in severity. HSK21542 exhibited linear pharmacokinetics characteristics within the dose range 0.05-0.80 μg/kg, without drug accumulation after multiple-doses. Compared to the placebo, a significant decrease of the weekly mean Worst Itching Intensity Numerical Rating Scale was found in the HSK21542-0.30 μg/kg group (p = 0.046), but without significant improvement in the Skindex-16 score. Conclusion: HSK21542 was well tolerated in the dose range 0.05-0.80 μg/kg in hemodialysis patients. HSK21542-0.3 μg/kg exhibited promising efficacy in patients with moderate to severe pruritus and warrants a further Stage 2 trial. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04470154.
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Affiliation(s)
- Mingming Pan
- Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Guihua Wang
- Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Li Zhou
- Division of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Xu
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Li Yao
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
| | - Chaoqing Wu
- Department of Nephrology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Changlin Mei
- Division of Nephrology, The Second Affiliated Hospital Navy Medical University, Shanghai, China
| | - Zhanzheng Zhao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dong Sun
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Tianjun Guan
- Division of Nephrology, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Qinkai Chen
- Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ming Shi
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hui Xu
- Division of Nephrology, Xiangya Hospital of the Central South University, Changsha, China
| | - Weifang Zeng
- Sichuan Haisco Pharmaceutical Co., Ltd., Chengdu, China
| | - Fangqiong Li
- Sichuan Haisco Pharmaceutical Co., Ltd., Chengdu, China
| | - Rui Yan
- Department of Nephrology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Bi-Cheng Liu
- Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
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Misery L, Pierre O, Le Gall-Ianotto C, Lebonvallet N, Chernyshov PV, Le Garrec R, Talagas M. Basic mechanisms of itch. J Allergy Clin Immunol 2023; 152:11-23. [PMID: 37201903 DOI: 10.1016/j.jaci.2023.05.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/02/2023] [Accepted: 05/11/2023] [Indexed: 05/20/2023]
Abstract
Pruritus (or itch) is an unpleasant sensation leading to a desire to scratch. In the epidermis, there are selective C or Aδ epidermal nerve endings that are pruriceptors. At their other ends, peripheral neurons form synapses with spinal neurons and interneurons. Many areas in the central nervous system are involved in itch processing. Although itch does not occur solely because of parasitic, allergic, or immunologic diseases, it is usually the consequence of neuroimmune interactions. Histamine is involved in a minority of itchy conditions, and many other mediators play a role: cytokines (eg, IL-4, IL-13, IL-31, IL-33, and thymic stromal lymphopoietin), neurotransmitters (eg, substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, neuropeptide Y, NBNP, endothelin 1, and gastrin-releasing peptide), and neurotrophins (eg, nerve growth factor and brain-derived neurotrophic factor). Moreover, ion channels such as voltage-gated sodium channels, transient receptor potential vanilloid 1, transient receptor ankyrin, and transient receptor potential cation channel subfamily M (melastatin) member 8 play a crucial role. The main markers of nonhistaminergic pruriceptors are PAR-2 and MrgprX2. A notable phenomenon is the sensitization to pruritus, in which regardless of the initial cause of pruritus, there is an increased responsiveness of peripheral and central pruriceptive neurons to their normal or subthreshold afferent input in the context of chronic itch.
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Affiliation(s)
- Laurent Misery
- Laboratoire Interactions Neurones-Keratinocytes (LINK), University of Brest, Brest, France; Department of Dermatology and Venereology, University Hospital of Brest, Brest, France.
| | - Ophélie Pierre
- Laboratoire Interactions Neurones-Keratinocytes (LINK), University of Brest, Brest, France
| | - Christelle Le Gall-Ianotto
- Laboratoire Interactions Neurones-Keratinocytes (LINK), University of Brest, Brest, France; Department of Dermatology and Venereology, University Hospital of Brest, Brest, France
| | - Nicolas Lebonvallet
- Laboratoire Interactions Neurones-Keratinocytes (LINK), University of Brest, Brest, France
| | - Pavel V Chernyshov
- Department of Dermatology and Venereology, National Medical University, Kiev, Ukraine
| | - Raphaële Le Garrec
- Laboratoire Interactions Neurones-Keratinocytes (LINK), University of Brest, Brest, France
| | - Matthieu Talagas
- Laboratoire Interactions Neurones-Keratinocytes (LINK), University of Brest, Brest, France; Department of Dermatology and Venereology, University Hospital of Brest, Brest, France
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Trivella J, John BV, Levy C. Primary biliary cholangitis: Epidemiology, prognosis, and treatment. Hepatol Commun 2023; 7:02009842-202306010-00027. [PMID: 37267215 DOI: 10.1097/hc9.0000000000000179] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/10/2023] [Indexed: 06/04/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. The incidence and prevalence of PBC vary widely in different regions and time periods, and although disproportionally more common among White non-Hispanic females, contemporary data show a higher prevalence in males and racial minorities than previously described. Outcomes largely depend on early recognition of the disease and prompt institution of treatment, which, in turn, are directly influenced by provider bias and socioeconomic factors. Ursodeoxycholic acid remains the initial treatment of choice for PBC, with obeticholic acid and fibrates (off-label therapy) reserved as add-on therapy for the management of inadequate responders or those with ursodeoxycholic acid intolerance. Novel and repurposed drugs are currently at different stages of clinical development not only for the treatment of PBC but also for its symptomatic management. Here, we summarize the most up-to-date data regarding the epidemiology, prognosis, and treatment of PBC, providing clinically useful information for its holistic management.
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Affiliation(s)
- Juan Trivella
- Department of Medicine, Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Binu V John
- Department of Medicine, Division of Gastroenterology and Hepatology, Miami VA Medical System, Miami, Florida, USA
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Cynthia Levy
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
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Ebhohon E, Chung RT. Systematic review: efficacy of therapies for cholestatic pruritus. Therap Adv Gastroenterol 2023; 16:17562848231172829. [PMID: 37255856 PMCID: PMC10226044 DOI: 10.1177/17562848231172829] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 04/13/2023] [Indexed: 06/01/2023] Open
Abstract
Background Pruritus is a symptom of several cholestatic liver diseases (CLDs) that can impair health-related quality of life (HRQoL). Despite evidence-based guideline therapy, managing cholestatic pruritus (CP) remains challenging, thus making the need for newer, more effective therapeutic agents more evident. Objective Our study evaluated the efficacy of existing CP therapies. Design Systematic review. Data sources From inception until March 2023, we conducted a comprehensive search of MEDLINE, Cochrane, EMBASE, Scopus, ClinicalTrial.gov, and other sources, including pharmaceutical webpages and conference proceedings published in English that reported on CP interventions. Methods Two reviewers independently conducted screening and full-text review of articles with extraction conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The methodological quality of studies included in our qualitative synthesis was assessed by using the Cochrane ROBINS-I and ROBINS-II tools for interventional studies and the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The primary outcome assessed in our systematic review was the severity of CP after therapy. Results Of 3293 screened articles, 92 studies were eligible for inclusion in the qualitative synthesis. Some patients' HRQoL improved with evidence-based standard therapy. Others, particularly those with severe and refractory CP, often required conversion to or addition of experimental noninvasive (e.g., ondansetron) or extracorporeal liver support to alleviate CP. In addition, studies investigating a newer class drug, the ileal bile acid transporter inhibitor (IBATi), demonstrate its effectiveness in reducing serum bile acid and alleviating CP with sustained improvement noted in patients with the inherited childhood cholestatic disorders - progressive familial intrahepatic cholestasis and Alagille syndrome. Conclusion Our findings consolidate data on the efficacy of guideline-based approaches and newer therapies for CP. While the initial findings are promising, additional clinical trials will be needed to determine the full extent of IBATi's efficacy and potential use in treating other common CLDs. These results provide a foundation for future research and highlight the need for continued investigation into the management and treatment of CLDs.
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Affiliation(s)
| | - Raymond T. Chung
- Gastrointestinal Division, Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Ito H, Navratilova E, Vagnerova B, Watanabe M, Kopruszinski C, Moreira de Souza LH, Yue X, Ikegami D, Moutal A, Patwardhan A, Khanna R, Yamazaki M, Guerrero M, Rosen H, Roberts E, Neugebauer V, Dodick DW, Porreca F. Chronic pain recruits hypothalamic dynorphin/kappa opioid receptor signalling to promote wakefulness and vigilance. Brain 2023; 146:1186-1199. [PMID: 35485490 PMCID: PMC10169443 DOI: 10.1093/brain/awac153] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 03/08/2022] [Accepted: 03/31/2022] [Indexed: 11/13/2022] Open
Abstract
Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signalling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naïve mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus, a key node of the hypothalamic-pituitary-adrenal stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide delivered in drinking water over 4 days, disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of paraventricular nucleus KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of paraventricular nucleus KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signalling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signalling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism.
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Affiliation(s)
- Hisakatsu Ito
- Department of Pharmacology, University of Arizona, Tucson, USA
- Department of Anesthesiology, University of Toyama, Toyama, Japan
| | - Edita Navratilova
- Department of Pharmacology, University of Arizona, Tucson, USA
- Department of Collaborative Research, Mayo Clinic, Scottsdale, USA
| | | | - Moe Watanabe
- Department of Pharmacology, University of Arizona, Tucson, USA
| | | | | | - Xu Yue
- Department of Pharmacology, University of Arizona, Tucson, USA
| | - Daigo Ikegami
- Department of Pharmacology, University of Arizona, Tucson, USA
| | - Aubin Moutal
- Department of Pharmacology, University of Arizona, Tucson, USA
| | - Amol Patwardhan
- Department of Pharmacology, University of Arizona, Tucson, USA
| | - Rajesh Khanna
- Department of Pharmacology, University of Arizona, Tucson, USA
| | | | - Miguel Guerrero
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, USA
| | - Hugh Rosen
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, USA
| | - Ed Roberts
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, USA
| | - Volker Neugebauer
- Department of Pharmacology and Neuroscience and Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, USA
| | | | - Frank Porreca
- Department of Pharmacology, University of Arizona, Tucson, USA
- Department of Collaborative Research, Mayo Clinic, Scottsdale, USA
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Pharmacological Therapy of Pruritus in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Clin Gastroenterol 2023; 57:143-152. [PMID: 36598806 DOI: 10.1097/mcg.0000000000001797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
GOALS We aim to summarize the current management of pruritus in primary biliary cholangitis (PBC) by evaluating the efficacy and safety of pharmacological therapies. BACKGROUND Pruritus is a common symptom of PBC, and evidence regarding the most effective antipruritic agents available is lacking. New pharmacotherapy for PBC has shown promising antipruritic effects. STUDY We performed a systematic literature review and meta-analysis including all available double-blind, randomized, placebo-controlled clinical trials that evaluated the efficacy of pharmacotherapy for the symptomatic management of pruritus in PBC. Pruritus was assessed as either a change from baseline or a postintervention score. RESULTS We included 33 studies and 20 medications. Using the visual analog scale, cholestyramine did not significantly improve pruritus compared with placebo [standardized mean differences (SMD): -0.94, 95% CI: -2.05 to 0.17], whereas rifampin and nalfurafine hydrochloride both significantly improved pruritus (SMD: -3.29, 95% CI: -5.78 to -0.80; n=23 and SMD: -0.58, 95% CI: -1.04 to -0.12). In addition, Bezafibrate and linerixibat significantly improved pruritus (SMD: -1.05, 95% CI: -1.41 to -0.68; n=110 and SMD: -0.31, 95% CI: -0.62 to -0.04, respectively). This effect was also present within the subgroup analysis by pruritus scale, where both bezafibrate and linerixibat significantly improved pruritus compared with placebo (SMD: -1.09, 95% CI: -1.54 to -0.65; P <0.001; visual analog scale; as postintervention score and SMD: -0.31, 95% CI: -0.62 to -0.01; P =0.04; numeric rating scale; as a change from baseline score, respectively). CONCLUSIONS Bezafibrate and Linerixibat are potential second-line antipruritic medications for PBC, particularly those with moderate to severe pruritus.
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Mechanisms of pruritus in cholestasis: understanding and treating the itch. Nat Rev Gastroenterol Hepatol 2023; 20:26-36. [PMID: 36307649 DOI: 10.1038/s41575-022-00687-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/07/2022] [Indexed: 02/01/2023]
Abstract
Pruritus in cholestatic liver diseases can be a major burden and dramatically impair the quality of life of those affected. Here, we provide an update on the latest insights into the molecular pathogenesis of and novel therapeutic approaches for cholestasis-associated itch. Endogenous and exogenous small-molecule pruritogen candidates bind to their receptors on unmyelinated itch C-fibres in the skin. Candidate pruritogens in cholestasis include certain lysophospholipids and sulfated progesterone metabolites, among others, whereas total bile acid or bilirubin conjugates seem unlikely to have a dominant role in the pathogenesis of cholestasis-associated pruritus. Transmission of itch signals via primary, secondary and tertiary itch neurons to the postcentral gyrus and activation of scratch responses offer various targets for therapeutic intervention. At present, evidence-based treatment options for pruritus in fibrosing cholangiopathies, such as primary biliary cholangitis and primary sclerosing cholangitis, are the peroxisome proliferator-associated receptor (PPAR) agonist bezafibrate and the pregnane X receptor (PXR) agonist rifampicin. In pruritus of intrahepatic cholestasis of pregnancy, ursodeoxycholic acid is recommended and might be supported in the third trimester by rifampicin if needed. Alternatively, non-absorbable anion exchange resins, such as cholestyramine, can be administered, albeit with poor trial evidence. Liver transplantation for intolerable refractory pruritus has become an extremely rare therapeutic strategy.
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12
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Levy C, Kendrick S, Bowlus CL, Tanaka A, Jones D, Kremer AE, Mayo MJ, Haque N, von Maltzahn R, Allinder M, Swift B, McLaughlin MM, Hirschfield GM. GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. Clin Gastroenterol Hepatol 2022:S1542-3565(22)01021-7. [PMID: 36343847 DOI: 10.1016/j.cgh.2022.10.032] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 10/25/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND & AIMS GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). METHODS GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0-10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changes in mean worst daily itch (MWDI) score. RESULTS One hundred forty-seven patients received placebo (n = 36) or linerixibat (once daily: 20 mg, n = 16; 90 mg, n = 23; 180 mg, n = 27; twice daily: 40 mg, n = 23; 90 mg, n = 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P = .0424), 40 mg twice daily (P = .0105), and 90 mg twice daily (P = .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P = .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. CONCLUSIONS Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. CLINICALTRIALS gov ID: NCT02966834.
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Affiliation(s)
- Cynthia Levy
- Digestive Health and Liver Diseases, Miller School of Medicine, University of Miami, Miami, Florida, and Schiff Center for Liver Diseases, University of Miami, Miami, Florida
| | | | | | | | - David Jones
- Newcastle University, Newcastle, United Kingdom
| | - Andreas E Kremer
- Department of Gastroenterology and Hepatology, University of Zürich, Zürich, Switzerland; Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany
| | | | | | | | | | | | | | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada.
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13
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Abstract
Chronic pruritus is a classic symptom in patients with primary biliary cholangitis. It affects up to two-thirds of patients in the course of the disease. Efficient therapy consists of topical treatment combined with systemic options such as anion exchangers, rifampicin, bezafibrate, μ-opioid receptor antagonists, selective-serotonin receptor uptake inhibitors, and gabapentinoids. Future therapeutic approaches may contain the selective blockade of the enterohepatic cycle by inhibiting the ileal bile acid transporter, the agonism at κ-opioid receptors, and antagonism of the mas-related G protein-coupled receptor X4. As nondrug treatment, ultraviolet B therapy, albumin dialysis, and biliary drainage are available at specialized centers.
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Affiliation(s)
- Miriam M Düll
- Department of Medicine 1, Gastroenterology, Hepatology, Pneumology, Endocrinology, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Ulmenweg 18, 91054 Erlangen, Germany
| | - Andreas E Kremer
- Department of Gastroenterology and Hepatology, Universitäts Spital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland.
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14
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Paul B, Sribhashyam S, Majumdar S. Opioid signaling and design of analgesics. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2022; 195:153-176. [PMID: 36707153 PMCID: PMC10325139 DOI: 10.1016/bs.pmbts.2022.06.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Clinical treatment of acute to severe pain relies on the use of opioids. While their potency is significant, there are considerable side effects that can negatively affect patients. Their rise in usage has correlated with the current opioid epidemic in the United States, which has led to more than 70,000 deaths per year (Volkow and Blanco, 2021). Opioid-related drug development aims to make target compounds that show strong potency but with diminished side effects. Research into pharmaceuticals that could act as potential alternatives to current pains medications has relied on mechanistic insights of opioid receptors, a class of G-protein coupled receptors (GPCRs), and biased agonism, a common phenomenon among pharmaceutical compounds where downstream effects can be altered at the same receptor via different agonists. Opioids function typically by binding to an active site on the extracellular portion of opioid receptors. Once activated, the opioid receptor initiates a G-protein signaling pathway and/or the β-arrestin2 pathway. The proposed concept for the development of safe analgesics around mu and kappa opioid receptor subtypes has focused on not recruiting β-arrestin2 (biased agonism) and/or having low efficacy at the receptor (partial agonism). By altering chemical motifs on a common scaffold, chemists can take advantage of biased agonism as well as create compounds with low intrinsic efficacy for the desired treatments. This review will focus on ligands with bias profile, signaling aspects of the receptor and probe into the structural basis of receptor that leads to bias and/or partial agonism.
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Affiliation(s)
- Barnali Paul
- Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St Louis and Washington University School of Medicine, St Louis, MO, United States
| | - Sashrik Sribhashyam
- Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St Louis and Washington University School of Medicine, St Louis, MO, United States
| | - Susruta Majumdar
- Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St Louis and Washington University School of Medicine, St Louis, MO, United States.
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15
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Kong L, Shu X, Tang S, Ye R, Sun H, Jiang S, Li Z, Chai J, Fang Y, Lan Y, Yu L, Xie Q, Fu W, Wang Y, Li W, Qiu Z, Liu J, Shao L. SLL-627 Is a Highly Selective and Potent κ Opioid Receptor (KOR) Agonist with an Unexpected Nonreduction in Locomotor Activity. J Med Chem 2022; 65:10377-10392. [PMID: 35900351 DOI: 10.1021/acs.jmedchem.2c00014] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Undue central nervous system (CNS) side effects including dysphoria and sedation remain to be a challenge for the development of κ opioid receptor (KOR) agonists as effective and safe analgesics. On the basis of our previous work on morphinan-based KOR agonists, a series of 7α-methyl-7β-substituted northebaine derivatives were designed, synthesized, and biologically assayed. Among others, compound 4a (SLL-627) has been identified as a highly selective and potent KOR agonist both in vitro and in vivo, and its molecular basis was also examined and discussed. Besides low liability to conditioned place aversion (CPA) test, treatment of SLL-627 was associated with a nonreduction in locomotor activity, compared to most of the other arylacetamide- or morphinan-based KOR agonists which generally exhibited apparently sedative effects. This unexpected finding provides new insights to dissociate analgesia from sedation for future discovery of innovative KOR agonists.
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Affiliation(s)
- Linghui Kong
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Xuelian Shu
- CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science, No. 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Siyuan Tang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Rongrong Ye
- School of Chemical and Environmental Engineering, Shanghai Institute of Technology, No. 100 Haiquan Road, Shanghai 201418, China
| | - Huijiao Sun
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Shuang Jiang
- School of Pharmacy, Nanjing University of Chinese Medicine, No. 138, Xianlin Road, Nanjing 210023, China
| | - Zixiang Li
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Jingrui Chai
- CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science, No. 555 Zuchongzhi Road, Shanghai 201203, China
| | - Yun Fang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Yinjie Lan
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Linqian Yu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Qiong Xie
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Wei Fu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Yujun Wang
- CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science, No. 555 Zuchongzhi Road, Shanghai 201203, China
| | - Wei Li
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Zhuibai Qiu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China
| | - Jinggen Liu
- CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science, No. 555 Zuchongzhi Road, Shanghai 201203, China
| | - Liming Shao
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China.,State Key Laboratory of Medical Neurobiology, Fudan University, No. 138 Yixueyuan Road, Shanghai 200032, China
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16
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Cholestatic Itch: Our Current Understanding of Pathophysiology and Treatments. Am J Clin Dermatol 2022; 23:647-659. [PMID: 35900649 DOI: 10.1007/s40257-022-00710-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2022] [Indexed: 11/01/2022]
Abstract
Hepatic pruritus is common in liver conditions, including cholestasis and nonalcoholic fatty liver disease. The pruritus can be severe enough to diminish sleep and decrease quality of life. The pathophysiology likely involves many molecules and receptors, including bile acids, bilirubin, lysophosphatidic acid (LPA), endogenous opioids, and serotonin. Recent advances suggest a significant role of Mas-related G protein-coupled receptor X4 (MRGPRX4) and autotaxin/LPA as key players in cholestatic pruritus. Further research is needed to develop increasingly targeted therapies with greater efficacy, especially given that many patients report itch refractory to various treatments. Cholestyramine was the only US FDA-approved drug for cholestatic pruritus until recent approval of ileal bile acid transporter (IBAT) inhibitors for use in the pediatric cholestatic conditions, progressive familial intrahepatic cholestasis and Alagille syndrome. Both medications decrease the bile acid pool. IBAT inhibitors are under investigation for broader use, and targeting LPA receptors and MRGPR4 are additional attractive options.
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Kaplan A, Rosenblatt R. Symptom Management in Patients with Cirrhosis: a Practical Guide. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2022; 20:144-159. [PMID: 35313484 PMCID: PMC8928010 DOI: 10.1007/s11938-022-00377-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 02/14/2022] [Indexed: 12/03/2022]
Abstract
Purpose of the review
Though it is well known that cirrhosis is associated with significant morbidity and mortality, management of symptoms in cirrhosis can be difficult. This review serves to offer practical guidance in the management of liver-specific symptoms of cirrhosis as well as other symptoms with special hepatic considerations. Recent findings We discuss liver-specific symptoms and management, including ascites and refractory ascites, hepatic encephalopathy, pruritus, and muscle cramping. We also discuss the challenges of treating more generalized symptoms in cirrhosis, including pain, depression/anxiety, appetite, and fatigue. Medication management is, especially complex in this population given the altered metabolism of drugs, and we consider some strategies to approach this. Summary With the right tools, provided throughout this review, hepatologists should be well equipped to manage the nuanced liver-specific and generalized symptoms in patients with cirrhosis.
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Affiliation(s)
- Alyson Kaplan
- Department of Gastroenterology and Hepatology, New York Presbyterian, Weill Cornell Medicine, New York, NY USA
| | - Russell Rosenblatt
- Department of Gastroenterology and Hepatology, New York Presbyterian, Weill Cornell Medicine, New York, NY USA
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18
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Park JW, Kim JH, Kim SE, Jung JH, Jang MK, Park SH, Lee MS, Kim HS, Suk KT, Kim DJ. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics. Biomedicines 2022; 10:1288. [PMID: 35740310 PMCID: PMC9220082 DOI: 10.3390/biomedicines10061288] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.
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Affiliation(s)
- Ji-Won Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jung-Hee Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jang Han Jung
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Myoung-Kuk Jang
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sang-Hoon Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Myung-Seok Lee
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Hyoung-Su Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
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Yoshitani H, Ito J, Kozono H. Post-Marketing Surveillance Study of the Safety and Efficacy of Nalfurafine (Capsules 2.5 μg, Oral Dispersing Tablets 2.5 μg) in 1186 Patients with Chronic Liver Disease and Intractable Pruritus. Hepat Med 2022; 14:37-66. [PMID: 35530746 PMCID: PMC9075016 DOI: 10.2147/hmer.s352775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 03/08/2022] [Indexed: 11/23/2022] Open
Abstract
Background Nalfurafine (Remitch®, Toray Industries, Inc.) is a selective κ-receptor agonist approved in Japan for the improvement of pruritus in patients with chronic liver diseases (only when existing treatments bring insufficient efficacy) in May 2015. Methods A post-marketing Specific Drug Use Survey was conducted in Japan (March 1, 2016 to June 30, 2020) of the safety and efficacy of nalfurafine for the improvement of pruritus in patients with chronic liver disease. Results Among 1186 cases analyzed for safety, the incidence of adverse drug reactions was 9.4% (112/1186 cases), lower than 61.4% reported in pre-marketing surveillance (297/484 cases). No specific safety issues were found and no cases of concern for drug dependence identified. Efficacy (itch improvement) was demonstrated in 73.16% (815/1114 cases; 12-week analysis set) and in 85.67% (520/607; general assessment of itch improvement at 1-year analysis set). A significant difference was found in 4 items of itch improvement at 12 weeks and 8 items of itch improvement at 1 year. No noteworthy issues were identified. Mean Visual Analog Scale (VAS) values after 12 weeks and 1 year after the first dose were significantly lower than the baseline (p < 0.0001 for both treatment durations). Mean severity scores (Kawashima’s classification scheme) were significantly lower than the pretreatment score at 12 weeks and 1 year after the first dose (both p < 0.0001). No concerns were identified in the efficacy and safety of nalfurafine in patients with specific background, ie, the elderly (aged ≥ 65 years), those with renal impairment, and those on long-term treatment (≥ 365 days) compared with patients without corresponding background. Conclusion No new safety issues of concern or cases of insufficient efficacy were identified in this Specific Drug Use Survey of the safety and efficacy of nalfurafine for the improvement of pruritus in patients with chronic liver diseases.
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Affiliation(s)
- Hiroshi Yoshitani
- Pharmaceutical & Medical Device Vigilance Department, Toray Industries, Inc., Tokyo, Japan
| | - Junko Ito
- Pharmaceutical & Medical Device Vigilance Department, Toray Industries, Inc., Tokyo, Japan
| | - Hideki Kozono
- Pharmaceutical & Medical Device Vigilance Department, Toray Industries, Inc., Tokyo, Japan
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20
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Kawano T, Atsukawa M, Tsubota A, Shimada N, Toyoda H, Takaguchi K, Tani J, Morishita A, Hiraoka A, Mikami S, Ishikawa T, Okubo H, Watanabe T, Okubo T, Arai T, Hayama K, Itokawa N, Kondo C, Iwakiri K. Shorter pruritus period and milder disease stage are associated with response to nalfurafine hydrochloride in patients with chronic liver disease. Sci Rep 2022; 12:7311. [PMID: 35508514 PMCID: PMC9068920 DOI: 10.1038/s41598-022-11431-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/21/2022] [Indexed: 11/09/2022] Open
Abstract
Nalfurafine hydrochloride, a selective κ-opioid receptor agonist has been approved for pruritus in patients with chronic liver disease. However, not all patients respond to nalfurafine hydrochloride. The aim of this study was to clarify the efficacy of nalfurafine hydrochloride. The subjects were patients with chronic liver disease complicated by pruritus who were treated with nalfurafine hydrochloride between May, 2015, and May, 2021. The degree of pruritus was evaluated based on the Visual Analog Scale (VAS) score and the Kawashima's pruritus score. Nalfurafine hydrochloride 2.5 μg was orally administered once a day for 12 weeks. A decrease in the VAS score of ≥ 25 mm or the Kawashima's pruritus score of ≥ 1 scores was designated as relevant response. The former of ≥ 50 mm or the latter of ≥ 2 scores as remarkable response. The 326 patients who were evaluated the efficacy at 12 weeks. The median time suffering from pruritus to administration of nalfurafine hydrochloride was 4 months. The median VAS score improved from 70.0 mm before administration to 40.0 and 30.0 mm at 4 and 12 weeks of treatment, respectively. On multivariate analysis, shorter itching period and lower FIB-4 index value were extracted as the independent factors related to remarkable responder. On multivariate analysis, shorter itching period was extracted as the only independent factor related to relevant responder. In conclusion, this study suggested nalfurafine hydrochloride treatment markedly improves pruritus in patients with chronic liver disease. A short pruritus period and less-advanced fibrosis were associated with response to nalfurafine hydrochloride.
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Affiliation(s)
- Tadamichi Kawano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.
| | - Akihito Tsubota
- Core Research Facilities, The Jikei University School of Medicine, Tokyo, Japan
| | - Noritomo Shimada
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Joji Tani
- Department of Gastroenterology, Kagawa University Graduate School of Medicine, Kagawa, Japan
| | - Asahiro Morishita
- Department of Gastroenterology, Kagawa University Graduate School of Medicine, Kagawa, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Shigeru Mikami
- Department of Internal Medicine, Division of Gastroenterology, Kikkoman General Hospital, Noda, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Hironao Okubo
- Department of Gastroenterology, Juntendo University Nerima Hospital, Tokyo, Japan
| | - Tsunamasa Watanabe
- Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Taeang Arai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Korenobu Hayama
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Norio Itokawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Chisa Kondo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Katsuhiko Iwakiri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
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21
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Bailey AJM, Li HOY, Kirchhof MG. Novel Kappa-Opioid Receptor Agonist for the Treatment of Cholestatic Pruritus: Systematic Review. JMIR DERMATOLOGY 2022; 5:e30737. [PMID: 37632854 PMCID: PMC10648544 DOI: 10.2196/30737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 03/23/2022] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
| | - Heidi Oi-Yee Li
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Division of Dermatology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - Mark G Kirchhof
- Division of Dermatology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
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22
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Dervout C, Boulais N, Barnetche T, Nousbaum JB, Brenaut E, Misery L. Efficacy of Treatments for Cholestatic Pruritus: A Systemic Review and Meta-analysis. Acta Derm Venereol 2022; 102:adv00653. [PMID: 35088869 PMCID: PMC9609979 DOI: 10.2340/actadv.v102.310] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cholestatic itch is a disabling symptom that may be secondary to liver or biliary diseases. Management of cholestatic pruritus is complex. A systematic review and meta-analysis on the efficacy of treatments for cholestatic pruritus were performed. PubMed and Cochrane Library were searched using the algorithm “(hepatitis OR cholestatic OR liver) AND (pruritus OR itch) AND (management OR treatment OR treatments)” for 1975–2019. Of the 2,264 articles identified, 93 were included in a systematic review and 15 in a meta-analysis (studies evaluating pruritus with a visual analogue scale). Some treatments act by reducing levels of pruritogens in the enterohepatic cycle, others modify the metabolism or secretion of these pruritogens, or act on pruritus pathways. A further possible treatment is albumin dialysis. However, due to many heterogeneities in the reviewed studies it is difficult to identify and recommend an optimum treatment. Only 15 studies were included in the meta-analysis, due to the small number of randomized studies using a visual analogue scale.
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Affiliation(s)
| | | | | | | | - Emilie Brenaut
- Department of Dermatology, University Hospital, FR-29609 Brest, France.
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23
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Misery L, Brenaut E, Pierre O, Le Garrec R, Gouin O, Lebonvallet N, Abasq-Thomas C, Talagas M, Le Gall-Ianotto C, Besner-Morin C, Fluhr JW, Leven C. Chronic itch: emerging treatments following new research concepts. Br J Pharmacol 2021; 178:4775-4791. [PMID: 34463358 DOI: 10.1111/bph.15672] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/20/2021] [Accepted: 08/24/2021] [Indexed: 11/29/2022] Open
Abstract
Until recently, itch pathophysiology was poorly understood and treatments were poorly effective in relieving itch. Current progress in our knowledge of the itch processing, the numerous mediators and receptors involved has led to a large variety of possible therapeutic pathways. Currently, inhibitors of IL-31, IL-4/13, NK1 receptors, opioids and cannabinoids, JAK, PDE4 or TRP are the main compounds involved in clinical trials. However, many new targets, such as Mas-related GPCRs and unexpected new pathways need to be also explored.
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Affiliation(s)
- Laurent Misery
- LIEN, Univ Brest, Brest, France.,Department of Dermatology, University Hospital of Brest, Brest, France
| | - Emilie Brenaut
- LIEN, Univ Brest, Brest, France.,Department of Dermatology, University Hospital of Brest, Brest, France
| | | | | | - Olivier Gouin
- LIEN, Univ Brest, Brest, France.,INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France.,University of Paris, Paris, France
| | | | - Claire Abasq-Thomas
- LIEN, Univ Brest, Brest, France.,Department of Dermatology, University Hospital of Brest, Brest, France
| | - Matthieu Talagas
- LIEN, Univ Brest, Brest, France.,Department of Dermatology, University Hospital of Brest, Brest, France
| | | | - Catherine Besner-Morin
- LIEN, Univ Brest, Brest, France.,Department of Dermatology, University Hospital of Brest, Brest, France.,Division of Dermatology, McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, Canada
| | - Joachim W Fluhr
- LIEN, Univ Brest, Brest, France.,Department of Dermatology, University Hospital of Brest, Brest, France.,Department of Dermatology, Charité Universitätsmedizin, Berlin, Germany
| | - Cyril Leven
- LIEN, Univ Brest, Brest, France.,EA3878, FCRIN INNOVTE, groupe d'étude thrombose Bretagne Occidentale, Brest, France.,Department of Biochemistry and Pharmaco-Toxicology, University Hospital of Brest, Brest, France
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24
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Satoh T, Yokozeki H, Murota H, Tokura Y, Kabashima K, Takamori K, Shiohara T, Morita E, Aiba S, Aoyama Y, Hashimoto T, Katayama I. 2020 guidelines for the diagnosis and treatment of prurigo. J Dermatol 2021; 48:e414-e431. [PMID: 34314056 DOI: 10.1111/1346-8138.16067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 11/28/2022]
Abstract
Prurigo is a treatment-resistant skin disease characterized by multiple isolated papules/nodules that cause severe itch. Prurigo papules/nodules occur either as primary lesions or as secondary lesions due to persistent scratching. The fundamental concepts and classifications of prurigo have not been sufficiently established, and considerable confusion remains regarding this topic. Clinical guidelines for chronic prurigo in Japan were published in 2012 in an attempt to reduce confusion regarding the concepts of prurigo and to standardize laboratory tests and treatments. However, the diagnostic terms for prurigo and associated concepts have changed over time, and new forms of treatment are under development. We have, thus, updated and revised the guidelines to classify prurigo based on clinical forms and causes, and disease name classifications based on the clinical form have been further simplified, such as prurigo nodularis, prurigo chronica multiformis, and prurigo (not otherwise specified). Expressions for acute, subacute, and chronic forms are not used. These guidelines outline the current concepts and specify treatments for prurigo.
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Affiliation(s)
- Takahiro Satoh
- Department of Dermatology, National Defense Medical College, Tokorozawa, Japan
| | - Hiroo Yokozeki
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroyuki Murota
- Department of Dermatology, School of Medical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yoshiki Tokura
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kenji Takamori
- Juntendo Itch Research Center, Institute for Environmental and Gender-specific Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tetsuo Shiohara
- Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Eishin Morita
- Department of Dermatology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Setsuya Aiba
- Department of Dermatology, Tohoku University School of Medicine, Sendai, Japan
| | - Yumi Aoyama
- Department of Dermatology, Kawasaki Medical School, Kurashiki, Japan
| | - Takashi Hashimoto
- Department of Dermatology, National Defense Medical College, Tokorozawa, Japan
| | - Ichiro Katayama
- Department of Dermatology, Course of Integrated Medicine Graduate School of Medicine, Osaka University, Suita, Japan
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25
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Satoh T, Yokozeki H, Murota H, Tokura Y, Kabashima K, Takamori K, Shiohara T, Morita E, Aiba S, Aoyama Y, Hashimoto T, Katayama I. 2020 guidelines for the diagnosis and treatment of cutaneous pruritus. J Dermatol 2021; 48:e399-e413. [PMID: 34288036 DOI: 10.1111/1346-8138.16066] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 11/27/2022]
Abstract
The mechanisms underlying itch are not fully understood. Physicians usually encounter difficulty controlling itch in generalized pruritus. Since only a small percentage of patients with generalized pruritus respond to antihistamines (H1 receptor antagonists), a variety of itch mediators and mechanisms other than histaminergic signals are considered to be involved in itch for these non-responsive patients. In 2012, we created guidelines for generalized pruritus. Those guidelines have been updated and revised to make some of the definitions, diagnostic terms, and classifications more applicable to daily clinical practice. Cutaneous pruritus as designated in these guidelines is a disease characterized by itch without an observable rash. Generalized pruritus (without skin inflammation) is defined as the presence of itch over a wide area, and not localized to a specific part of the body. This entity includes idiopathic pruritus, pruritus in the elderly, symptomatic pruritus, pregnancy-associated pruritus, drug-induced pruritus, and psychogenic pruritus. Localized pruritus (without skin inflammation) represents fixed itch localized to a specific part of the body, and includes anogenital pruritus, scalp pruritus, notalgia paresthetica, and brachioradial pruritus. These guidelines outline the current concepts and specify the diagnostic methods/treatments for cutaneous pruritus.
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Affiliation(s)
- Takahiro Satoh
- Department of Dermatology, National Defense Medical College, Tokorozawa, Japan
| | - Hiroo Yokozeki
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroyuki Murota
- Department of Dermatology, School of Medical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yoshiki Tokura
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kenji Takamori
- Juntendo Itch Research Center, Institute for Environmental and Gender-specific Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tetsuo Shiohara
- Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Eishin Morita
- Department of Dermatology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Setsuya Aiba
- Department of Dermatology, Tohoku University School of Medicine, Sendai, Japan
| | - Yumi Aoyama
- Department of Dermatology, Kawasaki Medical School, Kurashiki, Japan
| | - Takashi Hashimoto
- Department of Dermatology, National Defense Medical College, Tokorozawa, Japan
| | - Ichiro Katayama
- Department of Dermatology, Course of Integrated Medicine Graduate School of Medicine, Osaka University, Suita, Japan
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26
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Yoshiji H, Nagoshi S, Akahane T, Asaoka Y, Ueno Y, Ogawa K, Kawaguchi T, Kurosaki M, Sakaida I, Shimizu M, Taniai M, Terai S, Nishikawa H, Hiasa Y, Hidaka H, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for Liver Cirrhosis 2020. J Gastroenterol 2021; 56:593-619. [PMID: 34231046 PMCID: PMC8280040 DOI: 10.1007/s00535-021-01788-x] [Citation(s) in RCA: 189] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023]
Abstract
The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.
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Affiliation(s)
- Hitoshi Yoshiji
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
| | - Sumiko Nagoshi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takemi Akahane
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshinari Asaoka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshiyuki Ueno
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Koji Ogawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takumi Kawaguchi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masayuki Kurosaki
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Isao Sakaida
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masahito Shimizu
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Makiko Taniai
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Shuji Terai
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroki Nishikawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoichi Hiasa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hisashi Hidaka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuaki Chayama
- The Japan Society of Hepatology, Kashiwaya 2 Building 5F, 3-28-10 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tetsuo Takehara
- The Japan Society of Hepatology, Kashiwaya 2 Building 5F, 3-28-10 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
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27
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Yoshiji H, Nagoshi S, Akahane T, Asaoka Y, Ueno Y, Ogawa K, Kawaguchi T, Kurosaki M, Sakaida I, Shimizu M, Taniai M, Terai S, Nishikawa H, Hiasa Y, Hidaka H, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for liver cirrhosis 2020. Hepatol Res 2021; 51:725-749. [PMID: 34231046 DOI: 10.1111/hepr.13678] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022]
Abstract
The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.
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Affiliation(s)
- Hitoshi Yoshiji
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan.,Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Sumiko Nagoshi
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Takemi Akahane
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoshinari Asaoka
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoshiyuki Ueno
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Koji Ogawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Takumi Kawaguchi
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Masayuki Kurosaki
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Isao Sakaida
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Masahito Shimizu
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Makiko Taniai
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Shuji Terai
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hiroki Nishikawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoichi Hiasa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hisashi Hidaka
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | | | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | | | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
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Sezaki H, Suzuki F, Fujiyama S, Kawamura Y, Hosaka T, Akuta N, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Kumada H. Two cases receiving retreatment with 12 weeks of glecaprevir and pibrentasvir for HCV genotype 2 infection who failed prior glecaprevir and pibrentasvir therapy. KANZO 2021; 62:357-362. [DOI: 10.2957/kanzo.62.357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
| | | | | | | | | | - Norio Akuta
- Department of Hepatology, Toranomon Hospital
| | | | | | | | | | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital
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Golpanian RS, Yosipovitch G, Levy C. Use of Butorphanol as Treatment for Cholestatic Itch. Dig Dis Sci 2021; 66:1693-1699. [PMID: 32556969 DOI: 10.1007/s10620-020-06392-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/03/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND 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. AIMS To better understand the role of butorphanol in the treatment of cholestatic pruritus, including characterization of its side effect profile. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Rachel Shireen Golpanian
- Department of Dermatology and Cutaneous Surgery, Itch Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Gil Yosipovitch
- Department of Dermatology and Cutaneous Surgery, Itch Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Cynthia Levy
- Division of Hepatology, Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, 1500 NW 12th Ave Ste 1101, Miami, FL, USA.
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30
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Abstract
Introduction: Pruritus is adisabling symptom common to cholestatic liver disorders. Its pathophysiology has not been completely elucidated and although multiple mediators have been identified, only lysophosphatidic acid (LPA) and its synthetizing enzyme autotaxin (ATX) appear to consistently correlate with symptom intensity. This review aims to summarize the most relevant safety and efficacy data regarding both standard and new medications utilized to treat pruritus in cholestatic liver disease.Areas covered: International societies like the AASLD and EASL recommend astepwise approach for the management of cholestatic itch. However, therapeutic response is variable. Cholestyramine is considered first-line, followed by rifampicin, naltrexone and sertraline. When used appropriately, these medications have afavorable adverse events profile with most side effects related to drug class and not to the underlying etiology of liver disease.Expert opinion: Although conventional therapies seem to be effective in aproportion of patients, asizable number of cases remain refractory and require the utilization of experimental treatments. Multiple potential targets, especially in the ATX-LPA axis have yet to be pharmacologically explored, with ongoing translational and clinical research. Novel drugs are currently being developed for the management of cholestatic itching with promising results and afavorable safety profile.
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Affiliation(s)
- Juan Trivella
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Cynthia Levy
- Division of Digestive Health and Liver Disease, University of Miami Miller School of Medicine, Miami, Florida, USA
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31
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Düll MM, Wolf K, Vetter M, Dietrich P, Neurath MF, Kremer AE. Endogenous Opioid Levels Do Not Correlate With Itch Intensity and Therapeutic Interventions in Hepatic Pruritus. Front Med (Lausanne) 2021; 8:641163. [PMID: 33937284 PMCID: PMC8079640 DOI: 10.3389/fmed.2021.641163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 03/18/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Chronic pruritus affects up to 70% of patients with immune-mediated hepatobiliary disorders. Antagonists of the μ-opioid receptor (MOR) and agonists of the κ-opioid receptor (KOR) are used to treat hepatic itch, albeit with limited success. An imbalance between ligands of MOR and KOR receptors has recently been suggested as a potential mechanism of hepatic pruritus. In this study, we therefore investigated systemic levels of important endogenous opioids such as β-endorphin, dynorphin A, Leu- and Met-enkephalin in plasma of a large cohort of well-characterized patients with immune-mediated cholestatic disorders, including patients with liver cirrhosis, and during effective anti-pruritic therapy. Methods: Plasma samples and clinical data were prospectively collected from well-characterized patients with primary/secondary sclerosing cholangitis (PSC/SSC), primary biliary cholangitis (PBC) and overlap syndromes suffering from pruritus (n = 29) and age-, gender- and disease-matched controls without pruritus (n = 27) as well as healthy controls (n = 20). General laboratory testing for hepatobiliary and renal function was performed. Levels of β-endorphin, dynorphin A, Leu- and Met-enkephalin were quantified in plasma by ELISA. Intensity of pruritus over the last week was evaluated using a visual analog scale (VAS, 0–10). Results: PBC and PSC patients with or without pruritus did neither differ in disease entity, disease stage, nor in the presence of cirrhosis. While both dynorphin A and β-endorphin concentrations were lower in pruritic patients compared to those without pruritus and healthy controls, the MOR/KOR ligand ratio was unaltered. No significant differences were observed for Leu- and Met-enkephalin concentrations. Opioid levels correlated with neither itch intensity nor stage of disease. Cirrhotic patients displayed higher concentrations of MOR agonist Leu-enkephalin and KOR agonist dynorphin A. Endogenous opioid levels remained largely unchanged after successful treatment with the potent anti-pruritic drugs rifampicin and bezafibrate. Conclusions: Endogenous opioid levels and the MOR/KOR ligand ratio neither correlate with itch intensity nor differentiate pruritic from non-pruritic patients with immune-mediated liver diseases. Thus, endogenous opioids may modulate signaling pathways involved in hepatic pruritus, but are unlikely to represent the major pruritogens in liver disease.
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Affiliation(s)
- Miriam M Düll
- Department of Medicine 1, University Hospital Erlangen and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Katharina Wolf
- Department of Medicine 1, University Hospital Erlangen and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Marcel Vetter
- Department of Medicine 1, University Hospital Erlangen and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Peter Dietrich
- Department of Medicine 1, University Hospital Erlangen and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.,Emil-Fischer-Zentrum, Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University Hospital Erlangen and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie DZI, Erlangen, Germany
| | - Andreas E Kremer
- Department of Medicine 1, University Hospital Erlangen and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
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Langedijk JAGM, Beuers UH, Oude Elferink RPJ. Cholestasis-Associated Pruritus and Its Pruritogens. Front Med (Lausanne) 2021; 8:639674. [PMID: 33791327 PMCID: PMC8006388 DOI: 10.3389/fmed.2021.639674] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
Pruritus is a debilitating symptom of various cholestatic disorders, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inherited progressive familial intrahepatic cholestasis (PFIC). The molecular mechanisms leading to cholestasis-associated pruritus are still unresolved and the involved pruritogens are indecisive. As a consequence of pruritus, patients suffer from sleep deprivation, loss of daytime concentration, auto-mutilation and sometimes even suicidal ideations. Current guideline-approved therapy of cholestasis-associated pruritus includes stepwise administration of several medications, which may alleviate complaints in some, but not all affected patients. Therefore, also experimental therapeutic approaches are required to improve patients' quality of life. This article reviews the current state of research on pruritogens and their receptors, and shortly discusses the most recent experimental therapies.
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Affiliation(s)
| | | | - Ronald P. J. Oude Elferink
- Amsterdam University Medical Centers, Tytgat Institute for Liver and Intestinal Research, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), University of Amsterdam, Amsterdam, Netherlands
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Hiraoka A, Onishi M, Koyama S, Kato M, Marui K, Murakami T, Onishi K, Adachi T, Matsuoka J, Ueki H, Yoshino T, Tsuruta M, Aibiki T, Okudaira T, Kuroda T, Iwasaki R, Suga Y, Miyata H, Ninomiya T, Hirooka M, Abe M, Matsuura B, Michitaka K, Hiasa Y. Factors Related to Sleeping Disorder Due to Pruritus in Patients with Chronic Liver Disease. Intern Med 2021; 60:3195-3203. [PMID: 34657905 PMCID: PMC8580778 DOI: 10.2169/internalmedicine.7129-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Objective This study evaluated cases of pruritus, which is known to be associated with sleep disorder, in chronic liver disease (CLD) patients. Methods Questionnaires were given to 339 enrolled CLD outpatients in winter (November 2019 to March 2020) and again in summer (April to October 2020) (median interval: 104 days). Relative changes in symptoms shown by a visual analogue scale (VAS) and Kawashima's pruritus score between winter and summer were evaluated in Study 1 (n=199), while Study 2 examined the clinical features of patients with sleep disorder based on the results of the second questionnaire (n=235, median age 70 years old; 141 men, liver cirrhosis 37%). Results Study 1. There was a significant relationship in VAS between daytime and nighttime for each season, as well as between winter and summer for each time period (p<0.001). A comparison of Kawashima's pruritus scores for the daytime and nighttime showed no significant seasonal differences (p=0.436 and 0.828, respectively). When Kawashima's score increased, so did the average VAS for both daytime (0:1:2:3:4=0.4±0.2:1.4±0.9:3.0±1.8:5.9±2.1:6.2±2.3) and nighttime (0:1:2:3:4=0.3±0.1:1.4±1.5:3.5±2.3:6.7±2.6:6.9±1.8) (p<0.001 for both). Study 2. Twenty subjects (8.5%) complained of sleep disorder. An elevated FIB-4 index (≥3.07) showed a good predictive value for sleep disorder (p<0.01). The cut-off for the daytime and nighttime VAS values for existing sleep disorder were 1.6 [area under the curve (AUC) 0.901] and 3.4 (AUC 0.931). The respective sensitivity, specificity, and positive and negative predictive values for sleep disorder based on Kawashima's score (≥2) were 0.85, 0.28, 0.10, and 0.95 for the daytime and 1.00, 0.29, 0.12, and 1.00 for the nighttime. Conclusion Intervention against pruritus is recommended in CLD patients with a high Kawashima's score (≥2) in any season, especially with an elevated FIB-4 index.
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Affiliation(s)
- Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Miho Onishi
- Department of Nursing, Ehime Prefectural Central Hospital, Japan
| | - Satsuki Koyama
- Department of Nursing, Ehime Prefectural Central Hospital, Japan
| | - Masaya Kato
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Kaori Marui
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Taisei Murakami
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Kei Onishi
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Tomoko Adachi
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Junko Matsuoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Hidetaro Ueki
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Takeaki Yoshino
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Miho Tsuruta
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Toshihiko Aibiki
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | | | - Taira Kuroda
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | | | - Yoshifumi Suga
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Hideki Miyata
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | | | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Japan
| | - Bunzo Matsuura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Japan
| | - Kojiro Michitaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Japan
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Cao D, Huang P, Chiu YT, Chen C, Wang H, Li M, Zheng Y, Ehlert FJ, Zhang Y, Liu-Chen LY. Comparison of Pharmacological Properties between the Kappa Opioid Receptor Agonist Nalfurafine and 42B, Its 3-Dehydroxy Analogue: Disconnect between in Vitro Agonist Bias and in Vivo Pharmacological Effects. ACS Chem Neurosci 2020; 11:3036-3050. [PMID: 32897695 DOI: 10.1021/acschemneuro.0c00407] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Nalfurafine, a moderately selective kappa opioid receptor (KOR) agonist, is used in Japan for treatment of itch without causing dysphoria or psychotomimesis. Here we characterized the pharmacology of compound 42B, a 3-dehydroxy analogue of nalfurafine and compared with that of nalfurafine. Nalfurafine and 42B acted as full KOR agonists and partial μ opioid receptor (MOR) agonists, but 42B showed much lower potency for both receptors and lower KOR/MOR selectivity, different from previous reports. Molecular modeling revealed that water-mediated hydrogen-bond formation between 3-OH of nalfurafine and KOR accounted for its higher KOR potency than 42B. The higher potency of both at KOR over MOR may be due to hydrogen-bond formation between nonconserved Y7.35 of KOR and their carbonyl groups. Both showed modest G protein signaling biases. In mice, like nalfurafine, 42B produced antinociceptive and antiscratch effects and did not cause conditioned place aversion (CPA) in the effective dose ranges. Unlike nalfurafine, 42B caused motor incoordination and hypolocomotion. As both agonists showed G protein biases, yet produced different effects on locomotor activity and motor incoordination, the findings and those in the literature suggest caution in correlating in vitro biochemical data with in vivo behavior effects. The factors contributing to the disconnect, including pharmacodynamic and pharmacokinetic issues, are discussed. In addition, our results suggest that among the KOR-induced adverse behaviors, CPA can be separated from motor incoordination and hypolocomotion.
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Affiliation(s)
- Danni Cao
- Center for Substance Abuse Research, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140, United States
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China
| | - Peng Huang
- Center for Substance Abuse Research, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140, United States
| | - Yi-Ting Chiu
- Center for Substance Abuse Research, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140, United States
| | - Chongguang Chen
- Center for Substance Abuse Research, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140, United States
| | - Huiqun Wang
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Mengchu Li
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Yi Zheng
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Frederick J. Ehlert
- Department of Pharmaceutical Sciences, Center of Health Sciences, University of California, Irvine, California 92697, United States
| | - Yan Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States
| | - Lee-Yuan Liu-Chen
- Center for Substance Abuse Research, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140, United States
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35
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Abstract
Chronic pruritus, defined as an unpleasant sensation resulting in a need to scratch that lasts more than 6 weeks, is a prevalent and bothersome symptom associated with both cutaneous and systemic conditions. Due to complex pathogenesis and profuse contributing factors, chronic pruritus therapy remains challenging. Regardless of the well-established antipruritic properties of classic pharmacotherapy (topical therapy, phototherapy and systemic therapy), these methods often provide insufficient relief for affected individuals. Owing to the growing interest in the field of pruritic research, further experimental and clinical data have emerged, continuously supporting the possibility of instigating novel therapeutic measures. This review covers the most relevant current modalities remaining under investigation that possess promising perspectives of approval in the near future, especially opioidergic drugs (mu-opioid antagonists and kappa-opioid agonists), neurokinin-1 receptor antagonists, biologic drugs, Janus kinase inhibitors, ileal bile acid transporter inhibitors, aryl hydrocarbon receptor agonists and histamine H4 receptor antagonists.
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Affiliation(s)
- Radomir Reszke
- Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, 1 Chalubinskiego Street, 50-368, Wrocław, Poland
| | - Piotr Krajewski
- Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, 1 Chalubinskiego Street, 50-368, Wrocław, Poland
| | - Jacek C Szepietowski
- Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, 1 Chalubinskiego Street, 50-368, Wrocław, Poland.
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36
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Arzneitherapie des chronischen Pruritus – Licht am Ende des langen Tunnels? Internist (Berl) 2020; 61:1076-1086. [DOI: 10.1007/s00108-020-00837-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Sanjel B, Shim WS. Recent advances in understanding the molecular mechanisms of cholestatic pruritus: A review. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165958. [PMID: 32896605 DOI: 10.1016/j.bbadis.2020.165958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/21/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023]
Abstract
Cholestasis, a condition characterized by an abnormal decrease in bile flow, is accompanied by various symptoms such as pruritus. Although cholestatic pruritus is a prominent condition, its precise mechanisms have largely been elusive. Recently, advancements have been made for understanding the etiology and pathogenesis of cholestatic pruritus. The current review therefore focuses on summarizing the overall progress made in the elucidation of its molecular mechanisms. We have reviewed the available animal models on cholestasis to compare the differences between them, characterized potential pruritogens involved in cholestatic pruritus, and have summarized the receptor and ion channels implicated in the condition. Finally, we have discussed the available treatment options for alleviation of cholestatic pruritus. As our understanding of the mechanisms of cholestatic pruritus deepens, novel strategies to cure this condition are awaited.
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Affiliation(s)
- Babina Sanjel
- College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Won-Sik Shim
- College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea.
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38
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Moderne systemische Therapie des Pruritus. Hautarzt 2020; 71:518-524. [DOI: 10.1007/s00105-020-04604-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Golpanian RS, Yosipovitch G. Current and emerging systemic treatments targeting the neural system for chronic pruritus. Expert Opin Pharmacother 2020; 21:1629-1636. [PMID: 32515664 DOI: 10.1080/14656566.2020.1775815] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
INTRODUCTION Pruritus is a debilitating symptom that significantly affects the quality of life of patients who suffer from it. Many current and emerging systemic treatments targeting the neural system have been successful in treating itch of various underlying etiologies. AREAS COVERED A complete search of the PUBMED and Google Scholar databases was completed and literature pertinent to current and emerging systemic anti-pruritic drugs which target the neural system was compiled. The purpose of this review is to give the reader with an overview of the current and emerging systemic therapeutic options which target the neural system for chronic pruritus. The authors then provide the reader with their expert perspectives on the future of these therapies. EXPERT OPINION Exciting new anti-pruritic therapies targeting the neural system which show promise include NK-1 inhibitors, opioid receptor modulators, and drugs targeting specific itch receptors such as Mrgpr, Nav1.7, and PAR2, as well as selective GABA modulators. Future studies should be conducted in order to fully understand these exciting therapeutic options.
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Affiliation(s)
- Rachel Shireen Golpanian
- Department of Dermatology and Cutaneous Surgery, and Itch Center, University of Miami Miller School of Medicine , Miami, FL, USA
| | - Gil Yosipovitch
- Department of Dermatology and Cutaneous Surgery, and Itch Center, University of Miami Miller School of Medicine , Miami, FL, USA
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Erickson S, Heul AV, Kim BS. New and emerging treatments for inflammatory itch. Ann Allergy Asthma Immunol 2020; 126:13-20. [PMID: 32497711 DOI: 10.1016/j.anai.2020.05.028] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/20/2020] [Accepted: 05/25/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To summarize recent therapeutic developments for chronic pruritus with a focus on allergic and type 2 inflammatory pathways. DATA SOURCES Literature search of PubMed, industry websites, and review of the ClinicalTrials.gov database. STUDY SELECTIONS Peer-reviewed publications and public disclosures by industry relating to chronic pruritus pathophysiology and therapeutics. RESULTS Histamine and immunoglobulin E remain primary targets for the treatment of itch in the setting of chronic urticaria. More recently, blockade of type 2 immune cell-associated cytokines, including interleukin (IL) 4, IL-13, and IL-31, and the epithelial cell-derived cytokines, specifically IL-33 and thymic stromal lymphopoietin, has and is revolutionizing the treatment of chronic pruritic dermatoses, such as atopic dermatitis and prurigo nodularis. Other novel targets include histamine receptor 4, Janus kinases, κ-opioid receptor, neurokinin 1 receptor, and phosphodiesterase 4. CONCLUSION Advances in our understanding of the neuroimmunology of chronic pruritus have led to the identification of new therapeutic targets and the rapid development of cutting-edge clinical trials. Although incredible advances have already been made, chronic itch continues to be an area of great unmet need.
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Affiliation(s)
- Stephen Erickson
- Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Aaron Ver Heul
- Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, Missouri
| | - Brian S Kim
- Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, Missouri; Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
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41
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Abstract
Abstract
Purpose of Review
Chronic pruritus represents a burdensome symptom in cholestatic liver disease. This review recommends a stepwise therapeutic approach, alongside with providing information on epidemiology, pathophysiology, and novel drug targets.
Recent Findings
Current epidemiological data emphasize chronic itch as a major symptom in immune-mediated liver diseases such as primary biliary cholangitis affecting up to 70% of patients with a significant number suffering from long-lasting and severe pruritus. κ-opioid receptor (KOR) agonists, PPAR agonists, and ileal bile acid transporter (IBAT) inhibitors are currently investigated for their anti-pruritic efficacy in clinical trials. Future therapies may target the autotaxin-lysophosphatidic acid-axis or the Mas-related GPCR MRGPRX4.
Summary
Cholestatic pruritus still remains a challenging symptom for patients and physicians. Using a stepwise approach including cholestyramine, rifampicin, bezafibrate, naltrexone, and sertraline, pruritus is often adequately manageable. KOR agonists and IBAT inhibitors are currently the most promising anti-pruritic drugs for cholestatic pruritus in development.
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42
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Abstract
Introduction: Treatment for chronic pruritus ranges from use of topical formulations to newer biologic agents. Targeting treatment to the underlying etiology is key in reducing the burden of disease while avoiding systemic or adverse effects.Areas covered: This review details the effective medical treatments used in various etiologies of chronic itch with a focus on the potential adverse effects and safety data available for each.Expert opinion: New drug developments in the areas of neural signaling and immune targeting show great promise for the future of chronic itch treatment. These new therapies broaden the available treatment options but also pose new considerations for safety and adverse effects.
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Affiliation(s)
- Kayla Fourzali
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery and Miami Itch Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Gil Yosipovitch
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery and Miami Itch Center, University of Miami Miller School of Medicine, Miami, FL, USA
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43
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Miyamoto Y, Oh T, Aihara E, Ando A. Clinical Profiles of Nalfurafine Hydrochloride for the Treatment of Pruritus Patients. Handb Exp Pharmacol 2020; 271:455-472. [PMID: 33201326 DOI: 10.1007/164_2020_400] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Nalfurafine hydrochloride is a selective kappa-opioid agonist that has antipruritic effects. Here we describe the clinical trials for treatment of uremic pruritus in dialysis patients and on hepatic pruritus in patients with chronic liver disease. Among cytochrome P-450 (CYP) isoforms in humans, CYP3A4 is the major isoform involved in metabolic decyclopropylmethylation of nalfurafine hydrochloride. Nalfurafine hydrochloride was found to be a substrate for P-glycoprotein (P-gp), but had no inhibitory effects on P-gp-mediated transport. The efficacy of oral nalfurafine hydrochloride at 2.5 and 5 μg for refractory pruritus in hemodialysis patients was observed within the first 7 days of treatment, and the effects persisted for the 52-week treatment period. Nalfurafine hydrochloride is also effective in the treatment of conventional refractory pruritus in peritoneal dialysis patients. Moreover, nalfurafine hydrochloride at 2.5 and 5 μg is effective for the treatment of refractory pruritus in chronic liver disease patients within the first 7 days of drug administration. In all the clinical trials, most adverse drug reactions (ADRs) were mild and resolved quickly and there was no clinical safety problem. Following 52 weeks of treatment, hemodialysis patients did not develop physical or psychological dependence, indicating no addiction risks. In summary, nalfurafine hydrochloride administered orally at doses of 2.5 and 5 μg was safe and effective for treatment of refractory pruritus in patients undergoing hemodialysis or peritoneal dialysis and in chronic liver disease patients.
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Affiliation(s)
- Yohei Miyamoto
- Clinical Research Department, Toray Industries, Inc., Tokyo, Japan.
| | - Takanori Oh
- Clinical Research Department, Toray Industries, Inc., Tokyo, Japan
| | - Eiji Aihara
- Clinical Research Department, Toray Industries, Inc., Tokyo, Japan
| | - Akihiro Ando
- Clinical Research Department, Toray Industries, Inc., Tokyo, Japan
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44
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Yosipovitch G, Berger T, Fassett MS. Neuroimmune interactions in chronic itch of atopic dermatitis. J Eur Acad Dermatol Venereol 2019; 34:239-250. [PMID: 31566796 PMCID: PMC7027518 DOI: 10.1111/jdv.15973] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 09/11/2019] [Indexed: 12/30/2022]
Abstract
Itch is a defining symptom of atopic dermatitis. Crosstalk between keratinocytes, the immune system and non‐histaminergic sensory nerves is responsible for the pathophysiology of chronic itch in atopic dermatitis. An expanding understanding of the contribution of the nervous system and its interaction with immune pathways in atopic itch are helping to identify new therapeutic strategies.
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Affiliation(s)
- G Yosipovitch
- Department of Dermatology and Cutaneous Surgery and Miami Itch Center, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - T Berger
- Department of Dermatology, School of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - M S Fassett
- Department of Dermatology, School of Medicine, University of California San Francisco, San Francisco, CA, USA
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45
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Fujino H, Tanaka M, Imamura M, Morio K, Ono A, Nakahara T, Murakami E, Kawaoka T, Takahashi S, Miki D, Tsuge M, Hiramatsu A, Aikata H, Hayes CN, Chayama K. Pruritus in patients with chronic liver disease and serum autotaxin levels in patients with primary biliary cholangitis. BMC Gastroenterol 2019; 19:169. [PMID: 31651244 PMCID: PMC6813053 DOI: 10.1186/s12876-019-1092-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 10/11/2019] [Indexed: 12/22/2022] Open
Abstract
Background Pruritus is a common symptom seen in patients with chronic liver disease. However, frequency and severity of pruritus in patients with chronic liver disease is unclear. We investigated frequency, severity and predictive factors of pruritus in these patients from a large cohort. Methods A total of 2477 patients with chronic liver disease without allergies or skin diseases were investigated for itch frequency and severity. Itch severity was self-assessed using pruritus scores using the numerical rating scale (NRS). Multivariate regression analysis was performed to identify factors associated with pruritus. Serum autotaxin levels were measured in patients with primary biliary cholangitis (PBC), and the relationship to liver fibrosis and pruritus was analyzed. Results The frequency of pruritus in patients with chronic liver disease was significantly higher than in subjects without liver disease (29.8 and 16.2%, respectively, P < 0.001). NRS was high in patients with chronic liver disease, especially in those with PBC, as is generally expected. Multivariate analysis identified lower albumin, higher eosinophil count, and etiology of PBC as independent factors associated with severe pruritus (≥5 points of NRS). In patients with PBC, serum autotaxin levels were significantly correlated with liver fibrosis markers such as platelet count and liver stiffness, and hepatobiliary enzymes such as total bilirubin, aspartate aminotransferase and alkaline phosphatase. However, no significant correlations between serum autotaxin levels and frequency and severity of pruritus were observed in patients with PBC. Conclusion The frequency of pruritus was high in patients with chronic liver disease. Reduction of liver function is associated with severe pruritus based on the large number of patients with chronic liver disease. Serum autotaxin is useful for assessing liver fibrosis and severity of cholangitis; however, it is not a predictive marker for severe pruritus in patients with PBC.
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Affiliation(s)
- Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Mio Tanaka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. .,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Shoichi Takahashi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
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46
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The Neuromodulatory Effect of Antipruritic Treatment of Chronic Prurigo. Dermatol Ther (Heidelb) 2019; 9:613-622. [PMID: 31512177 PMCID: PMC6828989 DOI: 10.1007/s13555-019-00321-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Indexed: 12/05/2022] Open
Abstract
Chronic prurigo is an extremely severe pruritic skin disease which presents with multiple, hyperkeratotic and erosive papules, nodules and/or plaques. Patients with this high-burden disease require effective therapies, but effective treatments with regulatory agency approval are currently lacking. Deeper understanding of the pathophysiology suggests that hypersensitive nerves play an important role in the development of chronic prurigo. Accordingly, a treatment with neuroactive substances which modulate hypersensitivity seems promising. Here, we review antipruritic therapies with a neuromodulative effect. Current treatment options, such as topical capsaicin or opioid-receptor modulators, and also novel and future treatment regimens, such as, for example, interleukin-31 antibodies and neurokinin-1 receptor antagonists, are discussed.
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47
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Kremer AE. What are new treatment concepts in systemic itch? Exp Dermatol 2019; 28:1485-1492. [DOI: 10.1111/exd.14024] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 08/02/2019] [Accepted: 08/23/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Andreas E. Kremer
- Department of Medicine 1 & Translational Research Center Friedrich‐Alexander‐University Erlangen‐Nürnberg Erlangen Germany
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48
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Ishikawa T, Hashimoto T, Munetsugu T, Yokozeki H, Satoh T. Increased β‐endorphin and autotaxin in patients with prurigo. JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY 2019. [DOI: 10.1002/cia2.12062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Affiliation(s)
- Takahiro Ishikawa
- Department of Dermatology National Defense Medical College Tokorozawa Japan
- Department of Dermatology, Graduate School Tokyo Medical and Dental University Tokyo Japan
| | - Takashi Hashimoto
- Department of Dermatology, Graduate School Tokyo Medical and Dental University Tokyo Japan
| | - Takichi Munetsugu
- Department of Dermatology National Defense Medical College Tokorozawa Japan
| | - Hiroo Yokozeki
- Department of Dermatology, Graduate School Tokyo Medical and Dental University Tokyo Japan
| | - Takahiro Satoh
- Department of Dermatology National Defense Medical College Tokorozawa Japan
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49
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Abstract
PURPOSE OF REVIEW Pruritus is a common extrahepatic symptom in various liver disorders, in particularly those with cholestatic features. This review summarizes epidemiology, pathophysiology, evidence-based therapeutic recommendations and currently investigated drugs for pruritus in hepatobiliary disorders. RECENT FINDINGS Recent epidemiological data suggest pruritus as a common and relevant symptom in immune-mediated liver diseases, i.e., primary biliary cholangitis (PBC) with over 70% affected patients, up to 56% suffering from chronic pruritus. The better pathophysiological understanding of hepatic pruritus has led to the identification of novel therapeutic targets, addressed in drug trials using KOR agonists, PPAR agonists, and ileal bile acid transporter inhibitors. Hepatic itch remains among the most agonizing symptoms for affected patients and a clinical challenge for physicians. Therapeutic recommendations include a guideline-based stepwise approach starting with cholestyramine, followed by rifampicin, naltrexone, and sertraline. Bezafibrate and ileal bile acid transporter inhibitors represent promising future anti-pruritic treatment options.
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Affiliation(s)
- Miriam M Düll
- Department of Medicine 1, Gastroenterology, Hepatology, Pneumology and Endocrinology, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, D-91054, Erlangen, Germany
| | - Andreas E Kremer
- Department of Medicine 1, Gastroenterology, Hepatology, Pneumology and Endocrinology, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, D-91054, Erlangen, Germany.
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50
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Abstract
Itch treatment is a major challenge in the dermatologist’s practice. We encounter patients suffering from pruritus on a regular basis, and often lack diverse treatment options to adequately respond to the patients’ needs. In the last 20 years, novel pathways have been investigated that were beyond the scope of histamine. Although most did not result in a molecule available on the Canadian market, it is interesting and important as health care providers to stay up to date with new neuronal pathways involved in itch transmission and potential new therapeutic options. In this review, we will discuss pathways targeted in new topical treatments such as antagonist of proteinase-activated receptor-2, the endocannabinoid system, neurotrophins and tropomyosin-related kinase A receptor, the transient receptor potential-vanilloid or transient receptor potential-melastatine ion channels. New systemic therapies are now focusing on antagonizing the neurokinin receptor, modulating the opioidergic system, or targeting itch cytokines such as interleukin-31.
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Affiliation(s)
| | - Laurent Misery
- Department of Dermatology, University Hospital Brest, France
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