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Meta-Analysis
. 2023 Apr 14;4(2023):CD008320.
doi: 10.1002/14651858.CD008320.pub4.

Pharmacological interventions for pruritus in adult palliative care patients

Christopher Boehlke  1 , Lisa Joos  2 , Bettina Coune  2 , Carola Becker  2 , Joerg J Meerpohl  3   4 , Sabine Buroh  5 , Daniel Hercz  6 , Guido Schwarzer  7 , Gerhild Becker  2
Affiliations
Meta-Analysis

Pharmacological interventions for pruritus in adult palliative care patients

Christopher Boehlke et al. Cochrane Database Syst Rev. .

Abstract

Background: This is the second update of the original Cochrane review published in 2013 (issue 6), which was updated in 2016 (issue 11). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is a burdening symptom. It can cause considerable discomfort and negatively affect patients' quality of life.

Objectives: To assess the effects of different pharmacological treatments compared with active control or placebo for preventing or treating pruritus in adult palliative care patients.

Search methods: For this update, we searched CENTRAL (the Cochrane Library), MEDLINE (OVID) and Embase (OVID) up to 6 July 2022. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data.

Selection criteria: We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients.

Data collection and analysis: Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta-analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE and created 13 summary of findings tables.

Main results: In total, we included 91 studies and 4652 participants in the review. We added 42 studies with 2839 participants for this update. Altogether, we included 51 different treatments for pruritus in four different patient groups. The overall risk of bias profile was heterogeneous and ranged from high to low risk. The main reason for giving a high risk of bias rating was a small sample size (fewer than 50 participants per treatment arm). Seventy-nine of 91 studies (87%) had fewer than 50 participants per treatment arm. Eight (9%) studies had low risk of bias in the specified key domains; the remaining studies had an unclear risk of bias (70 studies, 77%) or a high risk of bias (13 studies, 14%). Using GRADE criteria, we judged that the certainty of evidence for the primary outcome (i.e. pruritus) was high for kappa-opioid agonists compared to placebo and moderate for GABA-analogues compared to placebo. Certainty of evidence was low for naltrexone, fish-oil/omega-3 fatty acids, topical capsaicin, ondansetron and zinc sulphate compared to placebo and gabapentin compared to pregabalin, and very low for cromolyn sodium, paroxetine, montelukast, flumecinol, and rifampicin compared to placebo. We downgraded the certainty of the evidence mainly due to serious study limitations regarding risk of bias, imprecision, and inconsistency. For participants suffering from uraemic pruritus (UP; also known as chronic kidney disease (CKD)-associated pruritus (CKD-aP)), treatment with GABA-analogues compared to placebo likely resulted in a large reduction of pruritus (visual analogue scale (VAS) 0 to 10 cm): mean difference (MD) -5.10, 95% confidence interval (CI) -5.56 to -4.55; five RCTs, N = 297, certainty of evidence: moderate. Treatment with kappa-opioid receptor agonists (difelikefalin, nalbuphine, nalfurafine) compared to placebo reduced pruritus slightly (VAS 0 to 10 cm, MD -0.96, 95% CI -1.22 to -0.71; six RCTs, N = 1292, certainty of evidence: high); thus, this treatment was less effective than GABA-analogues. Treatment with montelukast compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (two studies, 87 participants): SMD -1.40, 95% CI -1.87 to -0.92; certainty of evidence: very low. Treatment with fish-oil/omega-3 fatty acids compared to placebo may result in a large reduction of pruritus (four studies, 160 observations): SMD -1.60, 95% CI -1.97 to -1.22; certainty of evidence: low. Treatment with cromolyn sodium compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (VAS 0 to 10 cm, MD -3.27, 95% CI -5.91 to -0.63; two RCTs, N = 100, certainty of evidence: very low). Treatment with topical capsaicin compared with placebo may result in a large reduction of pruritus (two studies; 112 participants): SMD -1.06, 95% CI -1.55 to -0.57; certainty of evidence: low. Ondansetron, zinc sulphate and several other treatments may not reduce pruritus in participants suffering from UP. In participants with cholestatic pruritus (CP), treatment with rifampicin compared to placebo may reduce pruritus, but the evidence is very uncertain (VAS: 0 to 100, MD -42.00, 95% CI -87.31 to 3.31; two RCTs, N = 42, certainty of evidence: very low). Treatment with flumecinol compared to placebo may reduce pruritus, but the evidence is very uncertain (RR > 1 favours treatment group; RR 2.32, 95% CI 0.54 to 10.1; two RCTs, N = 69, certainty of evidence: very low). Treatment with the opioid antagonist naltrexone compared to placebo may reduce pruritus (VAS: 0 to 10 cm, MD -2.42, 95% CI -3.90 to -0.94; two RCTs, N = 52, certainty of evidence: low). However, effects in participants with UP were inconclusive (percentage of difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). In palliative care participants with pruritus of a different nature, the treatment with the drug paroxetine (one study), a selective serotonin reuptake inhibitor, compared to placebo may reduce pruritus slightly by 0.78 (numerical analogue scale from 0 to 10 points; 95% CI -1.19 to -0.37; one RCT, N = 48, certainty of evidence: low). Most adverse events were mild or moderate. Two interventions showed multiple major adverse events (naltrexone and nalfurafine).

Authors conclusions: Different interventions (GABA-analogues, kappa-opioid receptor agonists, cromolyn sodium, montelukast, fish-oil/omega-3 fatty acids and topical capsaicin compared to placebo) were effective for uraemic pruritus. GABA-analogues had the largest effect on pruritus. Rifampin, naltrexone and flumecinol tended to be effective for cholestatic pruritus. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta-analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.

Keywords: *Palliative Care; Anesthetics [therapeutic use]; Anti-Inflammatory Agents, Non-Steroidal [therapeutic use]; Cholestasis [complications]; HIV Infections [complications]; Pruritus [*drug therapy, etiology, prevention & control]; Receptors, Opioid, kappa [agonists]; Renal Insufficiency, Chronic [complications]; Selective Serotonin Reuptake Inhibitors [therapeutic use].

PubMed Disclaimer

Conflict of interest statement

CB: none known. CB is an attending physician at University Hospital Basel.

LJ: none known

BC: none known

CaB: none known

JM: none known

SB: none known

GS: received personal consulting fees for ‘External statistical consultant of Roche Pharma AG, Grenzach‐Wyhlen, Germany‘

DH: none known

GB: none known. GB is a Medical Director, Department of Palliative Care, University of Freiburg.

This review does not comply with Cochrane’s Conflict of Interest Policy. Waldemar Siemens, who is listed in the Acknowledgements, was a member of the author team for the original review and the first update, before taking on a role at Roche. Following this, he checked the draft updated review text for factual errors and approved the submitted version. The review will therefore be updated again within 12 months of publication of this version with an author team that complies with the CoI Policy for Cochrane Library content 2020.

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Özaykan 2001 {published data only}
    1. Özaykan S, Mansur T, Gündüz S, Güney O. Comparison of ondansetron and cyproheptadine in treatment of uremic pruritus [Üremi kaşintisi olan hastlarda ondansetron ve siproheptadinin etkinliğinin karşılaştırılması]. Türkderm 2001;35:130-4.
Pakfetrat 2018 {published data only}
    1. Pakfetrat M, Malekmakan L, Hashemi N, Tadayon T. Sertraline can reduce uremic pruritus in hemodialysis patient: a double blind randomized clinical trial from Southern Iran. Hemodialysis International 2018;22:103-9. [DOI: 10.1111/hdi.12540] [PMID: ] - DOI - PubMed
Pauli‐Magnus 2000 {published data only}
    1. Pauli-Magnus C, Mikus G, Alscher DM, Kirschner T, Nagel W, Gugeler N, et al. Naltrexone does not relieve uremic pruritus: results of a randomized, double blind, placebo-controlled crossover study. Journal of the American Society of Nephrology 2000;11:514-9. [DOI: 10.1681/ASN.V113514] [PMID: ] - DOI - PubMed
Pederson 1980 {published data only}
    1. Pederson JA, Matter BJ, Czerwinski AW, Llach F. Relief of idiopathic generalized pruritus in dialysis patients treated with activated oral charcoal. Annals of Internal Medicine 1980;93(3):446-8. [DOI: 10.7326/0003-4819-93-3-446] [PMID: ] - DOI - PubMed
Peer 1996 {published data only}
    1. Peer G, Kivity S, Agami O, Fireman E, Silverberg D, Blum M, et al. Randomized crossover trial of naltrexone in uraemic pruritus. Lancet 1996;348(9041):1552-4. [DOI: 10.1016/s0140-6736(96)04176-1] [PMID: ] - DOI - PubMed
Podesta 1991a {published data only}
    1. Podesta A, Lopez P, Terg R, Villamil F, Flores D, Mastai R, et al. Treatment of pruritus of primary biliary cirrhosis with rifampin. Digestive Diseases and Sciences 1991;36(2):216-20. [DOI: 10.1007/BF01300759] [PMID: ] - DOI - PubMed
Pour‐Reza‐Gholi 2007 {published data only}
    1. Pour-Reza-Gholi F, Nasrollahi A, Firouzan A, Nasli Esfahani E, Farrokhi F. Low-dose doxepin for treatment of pruritus in patients on hemodialysis. Iranian Journal of Kidney Diseases 2007;1(1):34-7. [PMID: ] - PubMed
Ravindran 2020 {published data only}
    1. Ravindran A, Kunnath RP, Sunny A, Vimal B. Comparison of safety and efficacy of pregabalin versus gabapentin for the treatment of uremic pruritus in patients with chronic kidney disease on maintenance haemodialysis. Indian Journal of Palliative Care 2020;26(3):281-6. [DOI: 10.4103/IJPC.IJPC_212_19] [PMID: ] - DOI - PMC - PubMed
Rivory 1984 {published data only}
    1. Rivory JP, Maheut H. Favorable effect of nicergoline on pruritus in chronic hemodialysis patients. Role of a hyper-alphaadrenergicsystem? [Effet favorable de la nicergoline sur leprurit des hemodialyses chroniques. Role de l'hyperalphaadrenergie?]. Presse Medicale 1984;13(44):2704. [PMID: ] - PubMed
Rossi 2019 {published data only}
    1. Rossi GM, Corradini M, Blanco V, Mattei S, Fiaccadori E, Vaglio A, et al. Randomized trial of two after‑dialysis gabapentin regimens for severe uremic pruritus in hemodialysis patients. Internal and Emergency Medicine 2019;14:1341-6. [DOI: 10.1007/s11739-019-02175-4] [PMID: ] - DOI - PubMed
Shayanpour 2019 {published data only}
    1. Shayanpour S, Beladi Mousavi SS, Lakhaye Rizi P, Cheraghian B. The effect of the omega-3 supplement on uremic pruritus in hemodialysis patients; a double-blind randomized controlled clinical trial. Journal of Nephropathology 2019;8(2):1-5. [DOI: 10.15171/ jnp.2019.13]
Shirazian 2013 {published data only}
    1. Shirazian S, Schanler M, Shastry S, Dwivedi S, Kumar M, Rice K, et al. The effect of ergocalciferol on uremic pruritus severity: a randomized controlled trial. Journal of Renal Nutrition 2013;23(4):308-14. [DOI: 10.1053/j.jrn.2012.12.007] [PMID: ] - DOI - PubMed
Silva 1994 {published data only}
    1. Silva SR, Viana PC, Lugon NV, Hoette M, Ruzany F, Lugon JR. Thalidomide for the treatment of uremic pruritus: a crossover randomized double-blind trial. Nephron 1994;67(3):270-3. [DOI: 10.1159/000187978] [PMID: ] - DOI - PubMed
Silverberg 1977 {published data only}
    1. Silverberg DS, Iaina A, Reisin E, Rotzak R, Eliahou HE. Cholestyramine in uraemic pruritus. British Medical Journal 1977;1(6063):752-3. [DOI: ] [PMID: ] - PMC - PubMed
Sja'bani 1997 {published data only}
    1. Sja'bani M, Asdie AH. Effect of erythropoietin on pruritus, anemia and quality of life, in chronic hemodialyzed end stage renal disease patients [abstract]. In: ISN XIII International Congress of Nephrology; 1995 Jul 2-6; Madrid, Spain. 1995:501. [CENTRAL: CN-00509480]
    1. Sja'bani M, Asdie AH. Effect of erythropoietin on pruritus and quality of life in chronic hemodialyzed end stage renal disease patients [abstract]. Journal of Clinical Epidemiology 1997;50(Suppl 1):10S. [CENTRAL: CN-00550491]
Smith 1997a {published data only}
    1. Smith KJ, Skelton HG, Yeager J, Lee RB, Wagner KF. Pruritus in HIV-1 disease: therapy with drugs which may modulate the pattern of immune dysregulation. Dermatology 1997;195(4):353-8. [DOI: 10.1159/000245987] [PMID: ] - DOI - PubMed
Solak 2012 {published data only}
    1. Solak Y, Biyik Z, Atalay H, Gaipov A, Guney F, Turk S, et al. Pregabalin versus gabapentin in the treatment of neuropathic pruritus in maintenance haemodialysis patients: a prospective, crossover study. Nephrology 2012;17:710-7. [DOI: 10.1111/j.1440-1797.2012.01655.] [PMID: ] - DOI - PubMed
Somkearti 2021 {published data only}
    1. Somkearti P, Chuasuwan A. Efficacy and safety of oral zinc sulfate for uremic pruritus in ESRD patients: a double-blind, randomized controlled trial. Nephrology 2021;26(Suppl 1):p52. [EMBASE: 845422229]
Spencer 2015 {published data only}
    1. Mathur VS, Spencer RH, Illidge J, Stauffer JW, Munera C, Menzaghi F. Improvement of quality of life in hemodialysis patients with uremic pruritus as measured by the skindex-10 questionnaire: effect of a novel kappa opiod receptor agonist, CR845 [abstract no: TH-PO1040]. Journal of the American Societyof Nephrology 2016;27(Abstract Suppl):338A.
    1. Spencer R, Mathur VS, Tumlin JA, Stauffer JW, Menzaghi F. CR845, a novel kappa opiod receptor agonist reduces moderate-to-severe pruritus and improves quality of life in chronic kidney disease patients undergoing hemodialysis [abstract no: SA-PO1117]. Journal of the American Society of Nephrology 2015;26(Abstract Suppl):B9.
Subach 2001 {published data only}
    1. Subach RA, Radabaugh RS, Williams DK, Marx MA. Ondansetron versus diphenhydramine versus placebo for hemodialysis associated itching [abstract no: A1790]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):348A. [CENTRAL: CN-00447890]
Suwanpidokkul 2007 {published data only}
    1. Suwanpidokkul P, Chaiprasert A, Supasyndh O, Choovichian P, Luesuthiviboon L. Effects of gabanpentin and loratadine on uremic pruritus in hemodialysis patients: a randomized controlled trial [abstract no: F-PO896]. Journal of the American Society of Nephrology 2007;18(Abstracts):300A.
Tapia 1977 {published data only}
    1. Tapia L, Cheigh JS, David DS, Sullivan JF, Saal S, Reidenberg MM, et al. Pruritus in dialysis patients treated with parenteral lidocaine. New England Journal of Medicine 1977;296(5):261-2. [DOI: 10.1056/NEJM197702032960508] [PMID: ] - DOI - PubMed
    1. Tapia L, Cheigh JS, David DS, Sullivan JF, Saal S, Reindenberg MM, et al. Treatment of pruritus in dialysis patients with parenteral lidocaine [abstract]. Kidney International 1976;10(6):527. [CENTRAL: CN-00583216]
Tarng 1996 {published data only}
    1. Tarng DC, Cho YL, Liu HN, Huang TP. Hemodialysis-related pruritus: a double-blind, placebo-controlled, crossover study of capsaicin 0.025% cream. Nephron 1996;72(4):617-22. [DOI: 10.1159/000188949] [PMID: ] - DOI - PubMed
Terg 2002 {published data only}
    1. Terg R, Coronel E, Sordá J, Muñoz AE, Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis: a crossover, double blind, placebo-controlled study. Journal of Hepatology 2002;37(6):717-22. [DOI: 10.1016/s0168-8278(02)00318-5] [PMID: ] - DOI - PubMed
Tol 2010 {published data only (unpublished sought but not used)}
    1. Tol H, Atalay H, Guney I, Gokbel H, Altintepe L, Buyukbas S, et al. The effects of gabapentin therapy on pruritus, quality of life, depression and sleep quality in pruritic hemodialysis patients. Trakya Universitesi Tip Fakultesi Dergisi 2010;27(1):1-5. [EMBASE: 2010207038]
Turner 1994a {published data only}
    1. Turner IB, Rawlins MD, Wood P, James OF. Flumecinol for the treatment of pruritus associated with primary biliary cirrhosis. Alimentary Pharmacology & Therapeutics 1994;8(3):337-42. [DOI: 10.1111/j.1365-2036.1994.tb00297.x] [PMID: ] - DOI - PubMed
Turner 1994b {published data only}
    1. Turner IB, Rawlins MD, Wood P, James OF. Flumecinol for the treatment of pruritus associated with primary biliary cirrhosis. Alimentary Pharmacology & Therapeutics 1994;8(3):337-42. [DOI: 10.1111/j.1365-2036.1994.tb00297.x] [PMID: ] - DOI - PubMed
Van Leusen 1978 {published data only}
    1. Van Leusen R, Kutsch Lojenga JC, Ruben AT. Is cholestyramine helpful in uraemic pruritus? British Medical Journal 1978;1(6117):918-9. [DOI: 10.1136/bmj.1.6117.918-c] [PMID: ] - DOI - PMC - PubMed
Vessal 2010 {published data only}
    1. Vessal G, Sagheb MM, Shilian S, Jafari P, Samani SM. Effect of oral cromolyn sodium on CKD-associated pruritus and serum tryptase level: a double-blind placebo-controlled study. Nephrology Dialysis Transplantation 2010;25(5):1541-7. [DOI: 10.1093/ndt/gfp628] [PMID: ] - DOI - PubMed
Villamil 2005 {published data only}
    1. Villamil AG, Bandi JC, Galdame OA, Gerona S, Gadano AC. Efficacy of lidocaine in the treatment of pruritus in patients with chronic cholestatic liver diseases. American Journal of Medicine 2005;118(10):1160-3. [DOI: 10.1016/j.amjmed.2005.05.031] [PMID: ] - DOI - PubMed
Wikström 2005a {published data only}
    1. Wikström B, Gellert R, Ladefoged SD, Danda Y, Akai M, Ide K, et al. Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. Journal of the American Society of Nephrology 2005;16(12):3742-7. [DOI: 10.1681/ASN.200502015] [PMID: ] - DOI - PubMed
Wikström 2005b {published data only}
    1. Wikström B, Gellert R, Ladefoged SD, Danda Y, Akai M, Ide K, et al. Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. Journal of the American Society of Nephrology 2005;16(12):3742-7. [DOI: 10.1681/ASN.2005020152] [PMID: ] - DOI - PubMed
Wolfhagen 1997 {published data only}
    1. Wolfhagen FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 1997;113(4):1264-9. [DOI: 10.1053/gast.1997.v113.pm9322521] [PMID: ] - DOI - PubMed
Young 2009 {published data only}
    1. Young TA, Patel TS, Camacho F, Clark A, Freedman BI, Kaur M, et al. A pramoxine-based anti-itch lotion is more effective than a control lotion for the treatment of uremic pruritus in adult hemodialysis patients. Journal of Dermatological Treatment 2009;20(2):76-81. [DOI: 10.1080/09546630802441218] [PMID: ] - DOI - PubMed
Yue 2015 {published data only}
    1. Yue J, Jiao S, Xiao Y, Ren W, Zhao T, Meng J. Comparison of pregabalin with ondansetron in treatment of uraemic pruritus in dialysis patients: a prospective, randomized, double-blind study. International Urology and Nephrology 2015;47(1):161-7. [DOI: 10.1007/s11255-014-0795-x] [PMID: ] - DOI - PubMed
Zylicz 2003 {published data only}
    1. Zylicz Z, Krajnik M, Sorge AA, Costantini M. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. Journal of Pain and Symptom Management 2003;26(6):1105-12. [DOI: 10.1016/j.jpainsymman.2003.05.004] [PMID: ] - DOI - PubMed

References to studies excluded from this review

Afrasiabifar 2016 {published data only}
    1. Afrasiabifar A, Mehri Z, Hosseini N. Efficacy of topical application of sweet almond oil on reducing uremic pruritus in hemodialysis patients: a randomized clinical trial study. Iranian Red Crescent Medical Journal 2016;19(2):e34695.
Almasio 2000 {published data only}
    1. Almasio PL, Floreani A, Chiaramonte M, Provenzano G, Battezzati P, Crosignani A, et al. Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis. Alimentary Pharmacology & Therapeutics 2000;14(12):1645-52. - PubMed
Anggraini 2020 {published data only}
    1. Anggraini DI, Rihatmadja R, Yusharyahya SN. Comparison between moisturizing cream containing 10% urea and 10% lanolin in petrolatum in skin hydration improvement among elderly. Biomedical & Pharmacology Journal 2020;13(3):1513-21.
Aperis 2010 {published data only}
    1. Aperis G, Paliouras C, Zervos A, Arvanitis A, Alivanis P. The use of pregabalin in the treatment of uraemic pruritus in haemodialysis patients. Journal of Renal Care 2010;36(4):180-5. - PubMed
Aramwit 2012 {published data only}
    1. Aramwit P, Keongamaroon O, Siritientong T, Bang N, Supasyndh O. Sericin cream reduces pruritus in hemodialysis patients: a randomized, double-blind, placebo-controlled experimental study. BMC Nephrology 2012;13:119. - PMC - PubMed
Aymard 1980 {published data only}
    1. Aymard JP, Lederlin P, Witz F, Colomb JN, Herbeuval R, Weber B. Cimetidine for pruritus in Hodgkin's disease. British Medical Journal 1980;280(6208):151-2. - PMC - PubMed
Balaskas 1998 {published data only}
    1. Balaskas EV, Bamihas GI, Karamouzis M, Voyiatzis G, Tourkantonis A. Histamine and serotonin in uremic pruritus: effect of ondansetron in CAPD-pruritic patients. Nephron 1998;78(4):395-402. - PubMed
Bergasa 1991 {published data only}
    1. Bergasa NV, Jones EA. Management of the pruritus of cholestasis: potential role of opiate antagonists. American Journal of Gastroenterology 1991;86(10):1404-12. - PubMed
Bergasa 1992 {published data only}
    1. Bergasa NV, Talbot TL, Alling DW, Schmitt JM, Walker EC, Baker BL, et al. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992;102(2):544-9. - PubMed
Bergasa 1995 {published data only}
    1. Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Annals of Internal Medicine 1995;123(3):161-7. - PubMed
Bergasa 1999 {published data only}
    1. Bergasa NV, Alling DW, Talbot TL, Wells MC, Jones EA. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study. Journal of the American Academy of Dermatology 1999;41(3 Pt 1):431-4. - PubMed
Berman 1998 {published data only}
    1. Berman B, Flores F, Burke G 3rd. Efficacy of pentoxifylline in the treatment of pruritic papular eruption of HIV-infected persons. Journal of the American Academy of Dermatology 1998;38(6):955-9. - PubMed
Bigliardi 2007 {published data only}
    1. Bigliardi PL, Stammer H, Jost G, Rufli T, Büchner S, Bigliardi-Qi M. Treatment of pruritus with topically applied opiate receptor antagonist. Journal of the American Academy of Dermatology 2007;56(6):979-88. - PubMed
Bousquet 1989 {published data only}
    1. Bousquet J, Rivory JP, Maheut M, Michel FB, Mion C. Double-blind, placebo-controlled study of nicergoline in the treatment of pruritus in patients receiving maintenance hemodialysis. Journal of Allergy and Clinical Immunology 1989;83(4):825-8. - PubMed
Breneman 1992b {published data only}
    1. Breneman DL, Cardone JS, Blumsack RF, Lather RM, Searle EA, Pollack VE. Topical capsaicin for treatment of hemodialysis-related pruritus. Journal of the American Academy of Dermatology 1992;26(1):91-4. - PubMed
Castello 2011 {published data only}
    1. Castello M, Milani M. Efficacy of topical hydrating and emollient lotion containing 10% urea ISDIN® plus dexpanthenol (Ureadin Rx 10) in the treatment of skin xerosis and pruritus in hemodialyzed patients: an open prospective pilot trial. Giornale Italiano Di Dermatologia e Venereologia [Official Journal of the Italian Society of Dermatology and Sexually Transmitted Diseases] 2011;46(5):321-5. - PubMed
Chen 2006 {published data only}
    1. Chen YC, Chiu WT, Wu MS. Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus. American Journal of Kidney Diseases 2006;48(1):69-76. - PubMed
Datta 1966 {published data only}
    1. Datta DV, Sherlock S. Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis. Gastroenterology 1966;50(3):323-32. - PubMed
Davis 2003 {published data only}
    1. Davis MP, Frandsen JL, Walsh D, Andresen S, Taylor S. Mirtazapine for pruritus. Journal of Pain and Symptom Management 2003;25(3):288-91. - PubMed
Easton 1978 {published data only}
    1. Easton P, Galbraith PR. Cimetidine treatment of pruritus in polycythemia vera. New England Journal of Medicine 1978;299(20):1134. - PubMed
Fjellner 1979 {published data only}
    1. Fjellner B, Hagermark O. Pruritus in polycythemia vera: treatment with aspirin and possibility of platelet involvement. Acta Dermato-Venereologica 1979;59(6):505-12. - PubMed
Giovanetti 1995 {published data only}
    1. Giovannetti S, Barsotti G, Cupisti A, Dani L, Bandini S, Angelini D, et al. Oral activated charcoal in patients with uremic pruritus. Nephron 1995;70(2):193-6. - PubMed
Goicoechea 1999 {published data only}
    1. Goicoechea M, De Sequera P, Ochando A, Andrea C, Caramelo C. Uremic pruritus: an unresolved problem in hemodialysis patients. Nephron 1999;82(1):73-4. - PubMed
Goncalves 2010 {published data only}
    1. Goncalves F. Thalidomide for the control of severe paraneoplastic pruritus associated with Hodgkin's disease. American Journal of Hospice & Palliative Medicine 2010;27(7):486-7. - PubMed
Hegade 2017 {published data only}
    1. Hegade VS, Kendrick SFW, Dobbins RL, Miller SR, Thompson D, Richards D, et al. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet 2017;389(10074):1114-23. - PubMed
Hellier 1963 {published data only}
    1. Hellier FF. A comparative trial of trimeprazine and amylobarbitone in pruritus. Lancet 1963;1(7279):471-2. - PubMed
Jones 2005 {published data only}
    1. Jones EA, Zylicz Z. Treatment of pruritus caused by cholestasis with opioid antagonists. Journal of Palliative Medicine 2005;8(6):1290-4. - PubMed
Jones 2007 {published data only}
    1. Jones EA, Molenaar HA, Oosting J. Ondansetron and pruritus in chronic liver disease: a controlled study. Hepato-Gastroenterology 2007;54(76):1196-9. - PubMed
Juby 1994 {published data only}
    1. Juby LD, Wong VS, Losowsky MS. Buprenorphine and hepatic pruritus. British Journal of Clinical Practice 1994;48(6):331. - PubMed
Kato 2001 {published data only}
    1. Kato A, Takita T, Furuhashi M, Takahashi T, Watanabe T, Maruyama Y, et al. Polymethylmethacrylate efficacy in reduction of renal itching in hemodialysis patients: crossover study and role of tumor necrosis factor-alpha. Artificial Organs 2001;25(6):441-7. - PubMed
Korfitis 2008 {published data only}
    1. Korfitis C, Trafalis DT. Carbamazepine can be effective in alleviating tormenting pruritus in patients with hematologic malignancy. Journal of Pain and Symptom Management 2008;35(6):571-2. - PubMed
Kuypers 2004 {published data only}
    1. Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. A prospective proof of concept study of the efficacy of tacrolimus ointment on uraemic pruritus (UP) in patients on chronic dialysis therapy. Nephrology Dialysis Transplantation 2004;19(7):1895-901. - PubMed
Lysy 2003 {published data only}
    1. Lysy J, Sistiery-Ittah M, Israelit Y, Shmueli A, Strauss-Liviatan N, Mindrul V, et al. Topical capsaicin - a novel and effective treatment for idiopathic intractable pruritus ani: a randomised, placebo controlled, crossover study. Gut 2003;52(9):1323-6. - PMC - PubMed
Mansour‐Ghanaei 2006 {published data only}
    1. Mansour-Ghanaei F, Taheri A, Froutan H, Ghofrani H, Nasiri-Toosi M, Bagherzadeh AH, et al. Effect of oral naltrexone on pruritus in cholestatic patients. World Journal of Gastroenterology 2006;12(7):1125-8. - PMC - PubMed
Marquez 2012 {published data only}
    1. Marquez D, Ramonda C, Lauxmann JE, Romero CA, Vukelic VL, Martinatto C, et al. Uremic pruritus in hemodialysis patients: treatment with desloratidine versus gabapentin. Jornal Brasileiro Nefrologia 2012;34(2):148-52. - PubMed
Metze 1999a {published data only}
    1. Metze D, Reimann S, Beissert S, Luger T. Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases. Journal of the American Academy of Dermatology 1999;41:533-9. - PubMed
Montero 2006 {published data only}
    1. Montero JL, Pozo JC, Barrera P, Fraga E, Costán G, Domínguez JL, et al. Treatment of refractory cholestatic pruritus with molecular adsorbent recirculating system (MARS). Transplantation Proceedings 2006;38(8):2511-3. - PubMed
Müller 1998a {published data only}
    1. Müller C, Pongratz S, Pidlich J, Penner E, Kaider A, Schemper M, et al. Treatment of pruritus in chronic liver disease with the 5-hydroxytryptamine receptor type 3 antagonist ondansetron: a randomized, placebo-controlled, double-blind cross-over trial. European Journal of Gastroenterology & Hepatology 1998;10(10):865-70. - PubMed
Müller 1998b {published data only}
    1. Müller C, Pongratz S, Pidlich J, Penner E, Kaider A, Schemper M, et al. Treatment of pruritus in chronic liver disease with the 5-hydroxytryptamine receptor type 3 antagonist ondansetron: a randomized, placebo-controlled, double-blind cross-over trial. European Journal of Gastroenterology & Hepatology 1998;10:865-70. - PubMed
Pakfetrat 2014 {published data only}
    1. Pakfetrat M, Basiri F, Malekmakan L, Roozbeh J. Effects of turmeric on uremic pruritus in end stage renal disease patients: a double-blind randomized clinical trial. Journal of Nephrology 2014;27(2):203-7. - PubMed
Podesta 1991b {published data only}
    1. Podesta A, Lopez P, Terg R, Villamil F, Flores D, Mastai R, et al. Treatment of pruritus of primary biliary cirrhosis with rifampin. Digestive Diseases and Sciences 1991;36(2):216-20. - PubMed
Price 1998 {published data only}
    1. Price TJ, Patterson WK, Olver IN. Rifampicin as treatment for pruritus in malignant cholestasis. Supportive Care in Cancer 1998;6(6):533-5. - PubMed
Prieto 2004 {published data only}
    1. Prieto LN. The use of midazolam to treat itching in a terminally ill patient with biliary obstruction. Journal of Pain and Symptom Management 2004;28(6):531-2. - PubMed
Razeghi 2009 {published data only}
    1. Razeghi E, Eskandari D, Ganji MR, Meysamie AP, Togha M, Khashayar P. Gabapentin and uremic pruritus in hemodialysis patients. Renal Failure 2009;31(2):85-90. - PubMed
Rehman 2018 {published data only}
    1. Rehman IU, Wu DB, Ahmed R, Khan NA, Rahman AU, Munib S, et al. A randomized controlled trial for effectiveness of zolpidem versus acupressure on sleep in hemodialysis patients having chronic kidney disease-associated pruritus.. Medicine (Baltimore) 2018;97(31):e10764. - PMC - PubMed
Reig 2018 {published data only}
    1. Reig A, Sesé P, Parés A. Effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with suboptimal ursodeoxycholic acid response. American Journal of Gastroenterology 2018;113(1):49-55. - PubMed
Rifai 2006 {published data only}
    1. Rifai K, Hafer C, Rosenau J, Athmann C, Haller H, Peter Manns M, et al. Treatment of severe refractory pruritus with fractionated plasma separation and adsorption (Prometheus ®). Scandinavian Journal of Gastroenterology 2006;41(10):1212-7. - PubMed
Sadeghnejad 2021 {published data only}
    1. Sadeghnejad Z, Karampourian A, Borzou SR, Gholyaf M, Mohammadi Y, Hadadi R. The effect of ostrich oil as a complementary medicine on the severity of pruritus and quality of life in hemodialysis patients. Complementary Medicine Research 2021;28(40):40-5. - PubMed
Shavit 2013 {published data only}
    1. Shavit L, Grenader T, Lifschitz M, Slotki I. Use of pregabalin in the management of chronic uremic pruritus. Journal of Pain and Symptom Management 2013;45(4):776-81. - PubMed
Ständer 2009 {published data only}
    1. Ständer S, Böckenholt B, Schürmeyer-Horst F, Weishaupt C, Heuft G, Luger TA, et al. Treatment of chronic pruritus with the selective serotonin re-uptake inhibitors paroxetine and fluvoxamine: results of an open-labelled, two-arm proof-of-concept study. Acta Dermato-Venereologica 2009;89(1):45-51. - PubMed
Szepietowski 2005 {published data only}
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References to ongoing studies

NCT01852318 {unpublished data only}
    1. NCT01852318. Pregabalin for the treatment of uremic pruritus [A multicenter, double-blind, randomized, placebo and active-controlled study of pregabalin for the treatment of uremic pruritus]. clinicaltrials.gov/ct2/show/NCT01852318 (first received 13 May 2013).
NCT02032537 {unpublished data only}
    1. NCT02032537. Efficacy of calmmax cream in the management of chronic uremic pruritus. clinicaltrials.gov/ct2/show/NCT02032537 (first received 10 January 10 2014).
NCT02229929 {unpublished data only}
    1. NCT02229929. Safety and pharmacokinetics of iv CR845 in hemodialysis patients, and Its efficacy in patients with uremic pruritus. clinicaltrials.gov/ct2/show/NCT02229929 (first received 3 September 2014).
NCT02696499 {unpublished data only}
    1. NCT02696499. Treatment of uremic pruritus with PA101B [Treatment of uremic pruritus with inhaled PA101B in patients with end-stage renal disease requiring hemodialysis]. clinicaltrials.gov/ct2/show/NCT02696499 (first received 2 March 2016).
NCT02701166 {unpublished data only}
    1. NCT02701166. The effect of bezafibrate on cholestatic itch (FITCH) [The effect of bezafibrate on cholestatic itch]. clinicaltrials.gov/ct2/show/NCT02701166 (first received 8 March 2016).
NCT02811783 {unpublished data only}
    1. NCT02811783. Naloxone hydrochloride study for relief of pruritus in patients with MF or SS forms of CTCL. clinicaltrials.gov/ct2/show/NCT02811783 (first received 23 June 2016).
NCT03905330 {unpublished data only}
    1. NCT03905330. MRX-502: Randomized double-blind placebo-controlled phase 3 study to evaluate the efficacy and safety of maralixibat in the treatment of subjects with progressive familial intrahepatic cholestasis (PFIC) - MARCH-PFIC. clinicaltrials.gov/ct2/show/NCT03905330 (first received 5 April 2019).
NCT03995212 {unpublished data only}
    1. NCT03995212. Study to evaluate the safety and efficacy of oral CR845 (difelikefalin) in patients with primary biliary cholangitis (PBC) and moderate-to-severe pruritus. clinicaltrials.gov/ct2/show/NCT03995212 (first received 21 June 2019).
NCT04470154 {unpublished data only}
    1. NCT04470154. A study evaluating the safety, pharmacokinetics, and efficacy of HSK21542 injection in subjects undergoing hemodialysis. clinicaltrials.gov/ct2/show/NCT04470154 (first received 14 July 2020).
NCT04660773 {unpublished data only}
    1. NCT04660773. Narrow band UVB phototherapy versus pregabalin in treatment of refractory pruritus in ESRD. clinicaltrials.gov/ct2/show/NCT04660773 (first received 9 December 2020).
NCT04663308 {unpublished data only}
    1. NCT04663308. A study to evaluate efficacy and safety of an investigational drug named volixibat in patients with itching caused by primary sclerosing cholangitis (VISTAS). clinicaltrials.gov/ct2/show/NCT04663308 (first received 11 December 2020).
NCT04728984 {unpublished data only}
    1. NCT04728984. A mlti-site bridging study of nalfurafine hydrochloride orally disintegrating tablet. clinicaltrials.gov/ct2/show/NCT04728984 (first received 28 January 2021).
NCT04950127 {unpublished data only}
    1. NCT04950127. Global linerixibat itch study of efficacy and safety in primary biliary cholangitis (PBC) (GLISTEN). clinicaltrials.gov/ct2/show/NCT04950127 (first received 6 July 2021).
NCT04999787 {unpublished data only}
    1. NCT04999787. A clinical trial evaluating the efficacy, safety, and pharmacokinetics of HSK21542 injection in liver disease subjects with pruritus. clinicaltrials.gov/ct2/show/NCT04999787 (first received 11 August 2021).
NCT05075408 {unpublished data only}
    1. NCT05075408. To evaluate the efficacy and safety of nemolizumab for 12 weeks in participants with chronic kidney disease with associated severe pruritus (Nemo CKDaP). clinicaltrials.gov/ct2/show/NCT05075408 (first received 12 October 2021).
NCT05180968 {unpublished data only}
    1. NCT05180968. DIalysis Symptom COntrol-Pruritus Outcome Trial (DISCO-POT). clinicaltrials.gov/ct2/show/NCT05180968 (first received 6 January 2022).
NCT05341843 {unpublished data only}
    1. NCT05341843. Sertraline effect in uremic pruritis. clinicaltrials.gov/ct2/show/NCT05341843 (first received 22 April 2022).
NCT05342623 {unpublished data only}
    1. NCT05342623. A study to evaluate the safety and efficacy of difelikefalin in advanced chronic kidney disease patients with moderate-to-severe pruritus and not on dialysis. clinicaltrials.gov/ct2/show/NCT05342623 (first received 22 April 2022).

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