Effectiveness of difelikefalin in a new treatment algorithm for hemodialysis-associated pruritus: a prospective interventional study

Effectiveness of difelikefalin in a new treatment algorithm for hemodialysis-associated pruritus: a prospective interventional study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effectiveness of difelikefalin in a new treatment algorithm for hemodialysis-associated pruritus: a prospective interventional study Naoko Takahashi, Taku Yoshizawa, Junko Kumagai, Hideki Kawanishi, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6209685/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Jul, 2025 Read the published version in Renal Replacement Therapy → Version 1 posted You are reading this latest preprint version Abstract Background Since June 2009, our facility has been using an internally developed treatment algorithm that facilitates a comprehensive approach to address each cause of hemodialysis-associated pruritus (HAP), wherein oral nalfurafine, a selective κ-opioid receptor (KOR) agonist, is used for patients resistant to conventional treatments. Upon approval of intravenous difelikefalin, a new KOR agonist, in Japan in December 2023, we revised the treatment algorithm. Here, we evaluated the effectiveness of difelikefalin in the new treatment algorithm. Methods Nalfurafine was administered for 6 weeks or longer to 43 patients who were receiving maintenance hemodialysis at our facility in order to treat treatment-resistant HAP in accordance with the treatment algorithm. In 9 of the 43 patients, response to nalfurafine was considered poor based on the presence of moderate or severe daytime or nighttime pruritus according to the Shiratori severity score, or the numerical rating scale (NRS) ≥4, despite good adherence confirmed through history taking. For those 9 patients, the medicine was switched to difelikefalin in April 2024 and administered for 16 weeks. The primary endpoint was pruritus severity according to the Shiratori severity score and the NRS. The secondary endpoints were the frequency of itching, presence/absence of pruritus-related insomnia, satisfaction with treatment, and presence/absence of adverse events. Results The numbers of patients with moderate or severe pruritus according to the Shiratori severity score were 4 (44.0%) during the daytime and 6 (66.7%) at nighttime before the change to difelikefalin. However, at week 16 after the change, both had decreased to 0 (0.0%) (p < 0.01, p < 0.001, respectively). The median [interquartile range] of the NRS was 5 [ 4 , 7 ] before the change, which significantly decreased to 3 [ 2 , 3 ] at week 16 after the change (p < 0.005). The number of patients with insomnia due to pruritus was 4 (44.4%) before the change, which significantly decreased to 0 (0.0%) at week 16 after the change (p < 0.01). No adverse events were observed. Conclusions In the new HAP treatment algorithm, difelikefalin was suggested to be a useful and safe medicine for patients on hemodialysis who are resistant to conventional HAP treatment. Hemodialysis-associated pruritus Quality of life Treatment algorithm Shiratori severity score Numerical rating scale Difelikefalin Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Background Hemodialysis-associated pruritus (HAP) develops in 60–80% of patients on hemodialysis and is a serious complication associated with sleeping disorder and depression, which impairs quality of life as well as survival [ 1 – 11 , 12 ]. In phase 6 (2015–2018) of the Dialysis Outcomes and Practice Patterns Study, an international prospective multicenter observational study (cohort study) examining the prognosis of patients treated with hemodialysis and related clinical practice in Japan, the proportion of patients with pruritus was 74%, and the proportion of those with moderate or worse pruritus was 38% [ 8 ]. We conducted an online questionnaire survey of 485 Japanese patients treated with hemodialysis between late November and December 2022 and examined the proportion of patients with pruritus and its severity to reveal the status of HAP in Japan in recent years [ 13 ]. It was revealed that 378 patients (77.9%) experienced itching, indicating a proportion of patients with pruritus similar to those in previous reports. Of those 378 patients who experienced itching, 101 (26.7%) and 78 (20.6%) experienced moderate or worse itching during the daytime and nighttime, respectively, indicating that pruritus continues to bother many patients even when the severity of HAP appears to be less than previously reported. Causes of HAP are largely classified into (1) abnormalities due to renal failure and dialysis, (2) skin abnormalities due mainly to dry skin, and (3) abnormalities in the endogenous opioid balance in the skin and central nervous system (CNS) [ 14 – 16 ]. However, those factors are involved in a complex manner in the development of treatment resistance, and thus, a comprehensive approach that can also address each cause is necessary for the treatment of HAP [ 9 – 11 , 17 – 20 ]. Accordingly, our facility has been using an internally developed HAP treatment algorithm since June 2009, and its effectiveness was previously reported [ 21 , 22 ]. In this treatment algorithm, moisturizers, topical steroids, and oral antihistamines are used depending on the skin condition and the severity of pruritus, and when patients are resistant to conventional treatments, the selective κ-opioid receptor (KOR) agonist nalfurafine is orally administered to treat abnormalities in the endogenous opioid balance [ 23 – 25 ]. Once the pruritus is alleviated, use of weaker steroids, and reduction and withdrawal of steroids are attempted. Simultaneously, dialysis methods, medication, and test data are repeatedly reviewed, and guidance on skincare and lifestyle improvement are continuously provided. Injectable difelikefalin, a new KOR agonist, has been launched overseas, and its favorable effect on the alleviation of moderate-to-severe HAP has been reported in numerous studies [ 26 – 33 ]. Its favorable effect on the alleviation of pruritus was also reported in Japanese clinical studies [ 34 – 36 ], and difelikefalin was approved in December 2023 for HAP resistant to conventional treatments. Accordingly, we included difelikefalin in the revised treatment algorithm so that either nalfurafine or difelikefalin can be selected for conventional treatment-resistant HAP depending on other medications and patients’ will. The observation period to judge the effect of nalfurafine was 2–4 weeks in the previous version of the algorithm. However, in Japan, a 6-week randomized double-blind placebo-controlled study and the following 52‑week open‑label extension phase 3 study showed that the proportion of patients who continuously received difelikefalin from the double-blinded period and whose weekly mean nighttime Shiratori severity score decreased to ≤2 from the baseline score ≥3 was 55.3% at week 4, which markedly increased to 68.4% at week 6, followed by a gradual upward trend [ 36 ]. Thus, in the new algorithm, the observation period to judge the effect of nalfurafine or difelikefalin was set to 2–6 weeks, and when the response was judged poor, switching one medicine to the other or increasing the dose of nalfurafine was considered (Fig. 1 ). Here, we evaluated the effectiveness of difelikefalin for conventional treatment-resistant HAP in the new treatment algorithm. Methods Patients In accordance with the treatment algorithm, nalfurafine was administered for 6 weeks or longer to 43 patients who were receiving maintenance hemodialysis at our facility. In 9 (5 men and 4 women) of these 43 patients, the response to nalfurafine was considered poor based on the presence of moderate or worse daytime or nighttime pruritus assessed according to the Shiratori severity score [ 37 ] or ≥4 according to the numerical rating scale (NRS) [ 38 , 39 ], despite good adherence confirmed through history taking. Those 9 patients consented to having their medication switched from nalfurafine to difelikefalin, and were thus included as the subjects of this study. The median age [interquartile range (IQR)] was 70 [69, 71] years old, and the median duration of dialysis [IQR] was 47 [31, 71] months. Primary conditions were diabetes mellitus in 5 patients, chronic glomerulonephritis in 3 patients, and nephrosclerosis in 1 patient. Treatments for pruritus, other than nalfurafine, were moisturizers in 9 patients (100%), topical steroids in 9 patients (100%), other topical agents in 4 patients (44.4%), and oral antihistamines in 3 patients (33.3%). GABA analogues, although they were not included in the treatment algorithm, were used in 2 patients (22.2%). The baseline characteristics of patients are shown in Table 1 . Table 1 Patient characteristics. N = 9 Sex (male / female) 5 (55.6) / 4 (44.4) Age (years), median [IQR] 70 [69, 71] Duration of HD (months), median [IQR] 47 [31, 71] Primary illness of chronic kidney disease Diabetes mellitus 5 (55.6) Chronic glomerulonephritis 3 (33.3) Nephrosclerosis 1 (11.1) Dialysis method HD 0 (0) OHDF 6 (66.7) O/IHDF 2 (22.2) IHDF 1 (11.1) Dry weight, kg 65 7 (77.8) Laboratory data, median [IQR] Hb, g/dL 11.6 [10.3, 12.7] Alb, g/dL 3.3 [3.0, 3.5] Corrected Ca, mg/dL 8.6 [8.4, 9.1] IP, mg/dL 4 [3.1, 4.7] Whole PTH, pg/mL 68.1 [58.4, 96.3] β 2 -MG, mg/L 23.6 [18.4, 25.5] spKt/Vurea 1.86 [1.78, 1.88] Other anti-pruritic drugs Moisturizers 9 (100) Topical steroids 9 (100) Other topical drugs 4 (44.4) Oral antihistamines 3 (33.3) GABA analogues 2 (22.2) Data are presented as number (%), unless stated otherwise. IQR interquartile range, HD hemodialysis, OHDF online hemodiafiltration, O/IHDF online/intermittent infusion hemodiafiltration, IHDF intermittent infusion hemodiafiltration, Hb hemoglobin, Alb albumin, IP inorganic phosphorus, PTH parathyroid horomone, β 2 -MG β 2 -microglobrin, spKt/Vurea single-pool Kt/Vurea, GABA analogues gamma-aminobutyric acid analogues. Study design This is a single-center single-arm prospective interventional study involving light invasiveness. To avoid seasonal effects on pruritus, nalfurafine was switched to difelikefalin in all patients in April 2024, followed by 16-week observation. The doses of difelikefalin were 17.5 µg when the dry weight was <45 kg, and 25 µg when it was ≥45 kg and <65 kg. Anti-pruritic drugs and dialysis methods were not changed for 16 weeks after the start of difelikefalin treatment. The primary endpoint was the severity of pruritus according to the Shiratori severity score and the NRS. The daytime and nighttime Shiratori severity scores were assessed separately. The following 5-point scale was used to assess daytime pruritus: 0 (no symptoms: not itchy), 1 (very mild: bearable without scratching), 2 (mild: subsides with a little scratching), 3 (moderate: subsides with considerable scratching), and 4 (severe: does not subside with scratching, prompting further scratching). The following 5-point scale was used to assess nighttime pruritus: 0 (no symptoms: not itchy), 1 (very mild: slightly itchy at bedtime, but not requiring intentional scratching; no difficulty sleeping), 2 (mild: slight itching subsides with a little scratching; no difficulty sleeping), 3 (moderate: wakes up due to itching, can go back to sleep after scratching, and unintentional scratching occurs during sleep), and 4 (severe, can hardly sleep due to itching, requiring frequent scratching that worsens the itching). The integers 0–10 were used to express the severity by the NRS (0, not itchy; 10 worst imaginable itching). The secondary endpoints were the frequency of itching, presence/absence of pruritus-related insomnia, satisfaction with treatment, and presence/absence of adverse events. The following 5-point scale was used to assess the frequency of itching: not every day, once a day, a few times a day, 4 times or more a day, and always. The following 2-point scale was used to assess the onset of insomnia due to pruritus: present and absent. The following 5-point scale was used to assess the satisfaction with treatment: very satisfied, satisfied, neither satisfied nor dissatisfied, dissatisfied, and very dissatisfied. Statistical analysis Changes in continuous variables in a period from week 0 to week 16 were tested using the Friedman test (non-parametric). When significant differences were found, a pairwise comparison of each week with week 0 was performed, using the closed testing procedure. The test was performed from week 16 to the earlier timepoint, and stopped when there was no statistical significance. The Jonckheere–Terpstra test was used to analyze trends in the period from week 0 to week 16. Changes in discrete variables from week 0 to week 16 were tested using Cochran’s Q test. In all analyses, p < 0.05 was regarded as statistically significant. All statistical analyses were performed using SPSS ver. 29.0 for Windows (IBM Japan, Tokyo, Japan). Ethical approval This study was approved by the ethical review board of Tsuchiya General Hospital (approval number: E240122-3) and conducted in accordance with the principles of the Declaration of Helsinki. All participants enrolled in this study first provided oral consent and then a written consent form, which was stored with medical records. Results Severity of pruritus Before the change in medication, the numbers of patients with “no symptoms,” “very mild,” “mild,” “moderate,” and “severe” daytime pruritus according to the Shiratori severity score were 0 (0.0%), 3 (33.3%), 2 (22.2%), 3 (33.3%), and 1 (11.1%), respectively. After the change in medication, the numbers of patients with very mild or no symptoms increased, while those with mild or worse itching decreased. Specifically, the numbers of patients with “no symptoms,” “very mild,” “mild,” “moderate,” and “severe” daytime pruritus were 1 (11.1%), 6 (66.7%), 2 (22.2%), 0 (0.0%), and 0 (0.0%), respectively, at week 16 after the change in medication (p <0.01, Figure 2). Before the change in medication, the numbers of patients with “no symptoms”, “very mild”, “mild”, “moderate”, and “severe” nighttime pruritus were 0 (0.0%), 0 (0.0%), 3 (33.3%), 5 (55.6%), and 1 (11.1%), respectively. After the change in medication, the numbers of patients with very mild or no symptoms increased, while those with mild or worse itching decreased. Specifically, the numbers of patients with “no symptoms,” “very mild,” “mild,” “moderate,” and “severe” nighttime pruritus were 2 (22.2%), 5 (55.6%), 2 (22.2%), 0 (0.0%), and 0 (0.0%), respectively, at week 16 after the change in medication (p <0.001, Figure 3). The daytime Shiratori severity score decreased at week 16 after the change in medication in 7 patients (77.8%, Figure 4A). The nighttime Shiratori severity score decreased at week 16 after the change in medication in all 9 patients: a score of ³3 was observed in 6 patients before the change in medication, which decreased to 2 in 2 patients, 1 in 3 patients, and 0 in 1 patient at week 16 after the change in medication (Figure 4B). The median [IQR] NRS was 5 [4, 7] before the change in medication, which decreased to 3 [3, 4] at week 2 after the change in medication, and significantly decreased to 3 [2, 3] at week 16 after the change in medication (p < 0.01, Figure 5). The NRS was unchanged in 1 patient (11.1%), and decreased in 8 patients (88.9%) at week 16 after the change in medication (Figure 6). Frequency of pruritus The numbers of patients who experienced itching “not every day,” “once a day,” “a few times a day,” “4 times or more a day,” and “always” were 0 (0.0%), 0 (0.0%), 4 (44.4%), 3 (33.3%), and 2 (22.2%), respectively, before the change in medication, and 5 (55.6%), 1 (11.1%), 1 (11.1%), 1 (11.1%), and 1 (11.1%), respectively, at week 12 after the change in medication, indicating significant alleviation (p < 0.01). At week 16 after the change in medications, the numbers were 4 (44.4%), 1 (11.1%), 2 (22.2%), 1 (11.1%), and 1 (11.1%), respectively. The numbers of patients who experienced itching a few times a day or less showed an increasing trend while the numbers of patients who experienced itching 4 times a day or more showed a decreasing trend; however, the differences before and after the change in medication were not statistically significant. Insomnia due to pruritus The number of patients with insomnia due to pruritus was 4 (44.4%) before the change in medication, which significantly decreased to 1 (11.1%), 0 (0.0%), 0 (0.0%), 0 (0.0%), 1 (11.1%), and 0 (0.0%), at week 2, 4, 6, 8,12, and 16 after the change in medication, respectively (p < 0.01, Figure 7). Treatment satisfaction Before the change in medication, the numbers of patients whose satisfaction level with treatment was “very satisfied,” “satisfied,” “neither satisfied nor dissatisfied,” “dissatisfied,” and “very dissatisfied” were 0 (0.0%), 4 (44.4%), 3 (33.3%), 2 (22.2%), and 0 (0.0%), respectively. At week 16 after the change in medication, the numbers of patients whose satisfaction level with treatment was “very satisfied” and “satisfied” increased to 1 (11.1%) and 8 (88.9%), respectively, while the numbers of patients whose satisfaction level with treatment was “neither satisfied nor dissatisfied,” “dissatisfied,” or “very dissatisfied” all decreased to 0 (0.0%), indicating significant improvement (p < 0.05). Adverse events No adverse event was observed after the change to difelikefalin, and difelikefalin administration was continued for 16 weeks in all patients. Discussion In accordance with the new treatment algorithm, difelikefalin was administered to 9 hemodialysis patients whose response to >6-week oral nalfurafine was poor based on the presence of persistent moderate or worse pruritus. Pruritus was alleviated 16 weeks after the change in medication to difelikefalin. Decreases in the NRS score and in the nighttime Shiratori severity score were observed in 8 patients and all patients, respectively. Compared with other opioids, difelikefalin has higher selectivity to KORs and less of an effect on selective μ- opioid receptors that induce pruritus [40], suggesting the possibility that difelikefalin can alleviate pruritus in patients who respond poorly to nalfurafine. The numbers of patients with insomnia due to pruritus significantly decreased after the change in medication to difelikefalin, and no patients had insomnia due to pruritus at week 16. A nighttime Shiratori severity score of ³3, but not £2, indicates insomnia due to pruritus. A nighttime Shiratori severity score of ³3 was found in 6 patients before the change in medication, but the score decreased to £2 in all 6 patients (2 in 2 patients, 1 in 3 patients, and 0 in 2 patients), indicating no insomnia at week 16. A phase 3 study involving 168 patients in Japan also evaluated nighttime pruritus and quality of life (QOL) according to the Shiratori severity score, and found that the nighttime Shiratori severity score decreased after the start of difelikefalin treatment, an effect that was maintained until week 58. Also, in patients who had insomnia (score ³3) at baseline, 92.6% did not have insomnia (score £2) at week 58. Furthermore, a subgroup analysis showed that improvement in the NRS score was greater in the group with insomnia than in the group without insomnia [36]. Weiner et al. performed a post hoc analysis of a multicenter open-label, single-arm phase 3 study of 12-week difelikefalin treatment, involving 222 patients on hemodialysis in the U.S., Europe, and Asia (except Japan); they reported that difelikefalin reduced the severity of pruritus as assessed by the Worst Itch-Numerical Rating Scale (WI-NRS) and improved pruritus-related sleep quality as assessed by the Sleep Quality-Numerical Rating Scale (SQ-NRS), and there was a strong correlation between improvement of pruritus and improvement of sleep quality [41]. In addition, Fotheringham et al. conducted a multicenter open-label phase 3 study involving 197 patients in the U.S. and Europe, and reported significant decreases in the WI-NRS and SQ-NRS at week 12, as well as complete resolution in the SQ-NRS in 19.1% of patients at week 12 [42]. Taken together, those findings and ours suggest that difelikefalin alleviates nighttime pruritus, thereby improving sleep quality. There were no adverse events during the 16-week administration of difelikefalin. In a phase 3 study in Japan, the main treatment-related adverse events observed were constipation (2.4%), somnolence (2.4%), and dizziness (1.8%); the incidence of treatment-related adverse events associated with the CNS was low, and treatment-related insomnia, which is observed with nalfurafine treatment, was absent [36]. Difelikefalin, a low-molecular-weight synthetic peptide, is a KOR agonist that activates KORs in the skin, peripheral nerves, and immune cells, thereby regulating visceral pain, inflammatory pain, pruritus, and inflammatory signaling [27, 40]. Compared with other KOR agonists, difelikefalin was shown to have a more favorable safety profile and is better tolerated because of its physicochemical properties, including limited membrane permeability and delivery to the CNS [26-28, 35, 36, 43]. Because it has fewer adverse effects involving the CNS, difelikefalin is thought to be easy to use for aging patients on hemodialysis. In addition, difelikefalin is injectable, making it suitable for treatment of conventional treatment-resistant HAP in patients with poor or unreliable adherence to oral medications, which may help to prevent or resolve polypharmacy. Another advantage is that interaction with other medications via cytochrome P450 and adsorption do not have to be considered. There are several limitations in this study. First, this is a single-center study, involving a small number of patients. Second, it is a single-arm study wherein effectiveness was not compared between difelikefalin and nalfurafine, and thus, it is difficult to prove that difelikefalin is the most important factor in the alleviation of HAP. Third, a comprehensive approach addressing individual causes is required for treatment of HAP wherein multiple factors interplay in a complex manner, but it was difficult to examine the selection of medication and the role of skincare in this study. Lastly, changes in QOL associated with pruritus other than insomnia were not assessed. It is desirable to conduct a randomized controlled study involving more patients in order to examine the effect of long term use of difelikefalin on pruritus and related QOL. Conclusion Difelikefalin was suggested to be a useful and safe medicine in the new HAP treatment algorithm for patients on hemodialysis who are resistant to conventional HAP treatment. Abbreviations HAP hemodialysis-associated pruritus QOL quality of life CNS central nervous system KOR κ-selective opioid receptor NRS numerical rating scale IQR interquartile range WI-NRS worst itch-numerical score SQ-NRS sleep quality-numerical rating scale Declarations Ethics approval and consent to participate This study was conducted with the approval of the Institutional Review Board of Tsuchiya General Hospital (no. E240122-3). Prior verbal consent was obtained from all patients enrolled in this study. The fact that patients provided consent was recorded in their medical records. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors’ contributions NT established the new treatment algorithm for hemodialysis-associated pruritus, conceived the study, and wrote the first draft of the manuscript. TY contributed to the study design, coordinated the study, and performed the statistical analysis. JK, HK, ST, MM, and TM contributed to the study design and were involved in the writing of the first draft of the manuscript. All the authors read and approved the final version of the manuscript for submission. Acknowledgements The authors are grateful to all members of the medical staff who participated in this study. References Pisoni RL, Wikström B, Elder SJ, Akizawa T, Asano Y, Keen ML, et al. Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Transplant. 2006;21:3495-505. Narita I, Alchi B, Omori K, Sato F, Ajiro J, Saga D, et al. Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. 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Front Pharmacol. 2024;15:1476587. Ständer S, Fishbane S, Schaufler T, Ruessmann D, Morin I, Menzaghi F, et al. Chronic kidney disease-associated pruritus and quality of life with difelikefalin treatment: a post hoc analysis of phase 3 data using the Skindex-10 questionnaire. Clin Kidney J. 2024;17:sfae274. Narita I, Tsubakihara Y, Uchiyama T, Okamura S, Oya N, Takahashi N, et al. Efficacy and safety of difelikefalin in Japanese patients with moderate to severe pruritus receiving hemodialysis: a randomized clinical trial. JAMA Netw Open. 2022;5:e2210339. Narita I, Tsubakihara Y, Takahashi N, Ebata T, Uchiyama T, Marumo M, et al. Difelikefalin for hemodialysis patients with pruritus in Japan. NEJM Evid. 2023;2:EVIDoa2300094. Narita I, Tsubakihara Y, Takahashi N, Ebata T, Uchiyama T, Marumo M, et al. Long‑term efficacy and safety of difelikefalin in moderate‑to‑severe pruritus in Japanese hemodialysis patients: a 52‑week open‑label extension period of a phase 3 trial. Ren Replace Ther. 2024;10:42. Shiratori A. Therapeutic outcomes of the use of mequitazine (LM-209) in severe dermatological diseases. Nishinihon J Dermatol. 1983;45:470-3 (in Japanese). Phan NQ, Blome C, Fritz F, Gerss J, Reich A, Ebata T, et al. Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus. Acta Derm Venereol. 2012;92:502-7. Yosipovitch G, Reaney M, Mastey V, Eckert L, Abbé A, Nelson L, Clark M, et al. Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis. Br J Dermatol. 2019;181:761-9. Albert-Vartanian A, Boyd MR, Hall AL, Morgado SJ, Nguyen E, Nguyen VP, et al. Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential? J Clin Pharm Ther. 2016;41:371-82. Weiner DE, Schaufler T, McCafferty K, Kalantar-Zadeh K, Germain M, Ruessmann D, et al. Difelikefalin improves itch-related sleep disruption in patients undergoing haemodialysis. Nephrol Dial Transplant. 2024;39:1125-37. Fotheringham J, Guest J, Latus J, Lerma E, Morin I, Schaufler T, et al. Impact of difelikefalin on the health‑related quality of life of haemodialysis patients with moderate‑to‑severe chronic kidney disease‑associated pruritus: a single‑arm intervention trial. Patient. 2024;17:203-13. Deeks ED. Difelikefalin: first approval. Drugs. 2021;81:1937-44. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 08 Jul, 2025 Read the published version in Renal Replacement Therapy → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6209685","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":432673207,"identity":"ac3287f9-5513-455b-b3b3-486834107d4a","order_by":0,"name":"Naoko Takahashi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFklEQVRIie3RMUvEMBTA8fcI9BwCrimC/QoJB3ceIn6VKw63OomgQ6WQSZwrJ9xXqLjolvLASXGtULBy0LkuolBFW8Wp1XMTyR8y5MGPkATAZvujYQAGQOBBXu8k+xg1qz32RUJpfknAEQ35PLizISwnD9F+5nnTUO+VFXnDHlclnmfApu1uFDDmxpeFirNEp4kmdRHyvsCrAvDEtBJ5Nwc3dwhj4b+TgMaSuFx50QQYjduJYew5f6XNWeTrbVM1pP+E3xPHPdXkB6mvwTgNGYgfyGB0fERbceqH4lpPVEzOzhrqgnfexeD89vCRNmbR5L7crdY9eUNnKepsVXW8WFtL9dcYrqKFBfTymoAnFic2m832r3sDjwBuQygL1N4AAAAASUVORK5CYII=","orcid":"","institution":"Akane-Foundation Omachi Tsuchiya Clinic","correspondingAuthor":true,"prefix":"","firstName":"Naoko","middleName":"","lastName":"Takahashi","suffix":""},{"id":432673208,"identity":"79d31b45-5a65-42f3-8610-0ccfbb7445db","order_by":1,"name":"Taku Yoshizawa","email":"","orcid":"","institution":"Akane-Foundation Omachi Tsuchiya Clinic","correspondingAuthor":false,"prefix":"","firstName":"Taku","middleName":"","lastName":"Yoshizawa","suffix":""},{"id":432673214,"identity":"766cbf06-61ee-48e4-9f8f-8c324b66d9c8","order_by":2,"name":"Junko Kumagai","email":"","orcid":"","institution":"Akane-Foundation Omachi Tsuchiya Clinic","correspondingAuthor":false,"prefix":"","firstName":"Junko","middleName":"","lastName":"Kumagai","suffix":""},{"id":432673216,"identity":"34753067-bb41-4e76-8421-5ad8fb43b72b","order_by":3,"name":"Hideki Kawanishi","email":"","orcid":"","institution":"Tsuchiya General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Kawanishi","suffix":""},{"id":432673217,"identity":"174a60d1-0c62-4be3-b57b-a3ce31aedacd","order_by":4,"name":"Shinichiro Tsuchiya","email":"","orcid":"","institution":"Tsuchiya General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shinichiro","middleName":"","lastName":"Tsuchiya","suffix":""},{"id":432673218,"identity":"31fb8788-a3ba-4160-ab14-4b69ea591948","order_by":5,"name":"Misaki Moriishi","email":"","orcid":"","institution":"Akane-Foundation Nakajima Tsuchiya Clinic","correspondingAuthor":false,"prefix":"","firstName":"Misaki","middleName":"","lastName":"Moriishi","suffix":""},{"id":432673220,"identity":"e87627dd-bf8b-4364-afee-36160fc85eb1","order_by":6,"name":"Takao Masaki","email":"","orcid":"","institution":"Hiroshima University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takao","middleName":"","lastName":"Masaki","suffix":""}],"badges":[],"createdAt":"2025-03-12 07:38:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6209685/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6209685/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s41100-025-00653-4","type":"published","date":"2025-07-08T15:56:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79680713,"identity":"ba26c71d-463d-4f3c-9212-d65716439887","added_by":"auto","created_at":"2025-04-01 12:47:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":812931,"visible":true,"origin":"","legend":"\u003cp\u003eNew treatment algorithm for hemodialysis‒associated pruritus.\u003c/p\u003e","description":"","filename":"Binder11.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6209685/v1/79b9cabff9f87cdbecb04c58.jpg"},{"id":79680712,"identity":"9150b842-7056-4cfe-b3ae-c79a93ddfbda","added_by":"auto","created_at":"2025-04-01 12:47:45","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1332737,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in the number and proportion of patients by daytime Shiratori severity score.\u003c/p\u003e","description":"","filename":"Binder12.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6209685/v1/77a13801b3748d692cf3ea5a.jpg"},{"id":79678922,"identity":"06ca7854-abb0-43bd-9d3d-ff35aa25a929","added_by":"auto","created_at":"2025-04-01 12:31:45","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1373389,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in the number and proportion of patients by nighttime Shiratori severity score.\u003c/p\u003e","description":"","filename":"Binder13.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6209685/v1/5b8ea476b3c58653def77699.jpg"},{"id":79680711,"identity":"92e2fe84-de7d-483e-94e5-8be0a1d95e7b","added_by":"auto","created_at":"2025-04-01 12:47:45","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":258195,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in the Shiratori severity score in individual patients. (A) Daytime. (B) Nighttime.\u003c/p\u003e","description":"","filename":"Binder14.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6209685/v1/ac91a37f82e3e785a7f51c60.jpg"},{"id":79678917,"identity":"7ca3be11-d058-4e46-b2b3-beb46a0580ca","added_by":"auto","created_at":"2025-04-01 12:31:45","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":194495,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in the numerical rating scale.\u003c/p\u003e","description":"","filename":"Binder15.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6209685/v1/2ed725f72a860965779e515c.jpg"},{"id":79678919,"identity":"9bbae364-ff73-40bc-a544-c0e740345855","added_by":"auto","created_at":"2025-04-01 12:31:45","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":397433,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in the numerical rating scale in individual patients.\u003c/p\u003e","description":"","filename":"Binder16.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6209685/v1/0a4fca782dbf7e2e78cbbae7.jpg"},{"id":79680191,"identity":"0d49acf0-03de-41b4-8bab-52aa941588c0","added_by":"auto","created_at":"2025-04-01 12:39:45","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":265456,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in the number and proportion of patients with/without insomnia due to pruritus.\u003c/p\u003e","description":"","filename":"Binder17.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6209685/v1/9b9d8bb0d907a0f8b3ea497b.jpg"},{"id":86699245,"identity":"337411a3-cee1-4a38-9e60-dd463bbbb2d6","added_by":"auto","created_at":"2025-07-14 16:04:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5256796,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6209685/v1/e09610b1-7e83-4ac7-a389-fc4ad1b93b63.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effectiveness of difelikefalin in a new treatment algorithm for hemodialysis-associated pruritus: a prospective interventional study","fulltext":[{"header":"Background","content":"\u003cp\u003eHemodialysis-associated pruritus (HAP) develops in 60\u0026ndash;80% of patients on hemodialysis and is a serious complication associated with sleeping disorder and depression, which impairs quality of life as well as survival [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In phase 6 (2015\u0026ndash;2018) of the Dialysis Outcomes and Practice Patterns Study, an international prospective multicenter observational study (cohort study) examining the prognosis of patients treated with hemodialysis and related clinical practice in Japan, the proportion of patients with pruritus was 74%, and the proportion of those with moderate or worse pruritus was 38% [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe conducted an online questionnaire survey of 485 Japanese patients treated with hemodialysis between late November and December 2022 and examined the proportion of patients with pruritus and its severity to reveal the status of HAP in Japan in recent years [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. It was revealed that 378 patients (77.9%) experienced itching, indicating a proportion of patients with pruritus similar to those in previous reports. Of those 378 patients who experienced itching, 101 (26.7%) and 78 (20.6%) experienced moderate or worse itching during the daytime and nighttime, respectively, indicating that pruritus continues to bother many patients even when the severity of HAP appears to be less than previously reported.\u003c/p\u003e \u003cp\u003eCauses of HAP are largely classified into (1) abnormalities due to renal failure and dialysis, (2) skin abnormalities due mainly to dry skin, and (3) abnormalities in the endogenous opioid balance in the skin and central nervous system (CNS) [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, those factors are involved in a complex manner in the development of treatment resistance, and thus, a comprehensive approach that can also address each cause is necessary for the treatment of HAP [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Accordingly, our facility has been using an internally developed HAP treatment algorithm since June 2009, and its effectiveness was previously reported [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In this treatment algorithm, moisturizers, topical steroids, and oral antihistamines are used depending on the skin condition and the severity of pruritus, and when patients are resistant to conventional treatments, the selective κ-opioid receptor (KOR) agonist nalfurafine is orally administered to treat abnormalities in the endogenous opioid balance [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Once the pruritus is alleviated, use of weaker steroids, and reduction and withdrawal of steroids are attempted. Simultaneously, dialysis methods, medication, and test data are repeatedly reviewed, and guidance on skincare and lifestyle improvement are continuously provided.\u003c/p\u003e \u003cp\u003eInjectable difelikefalin, a new KOR agonist, has been launched overseas, and its favorable effect on the alleviation of moderate-to-severe HAP has been reported in numerous studies [\u003cspan additionalcitationids=\"CR27 CR28 CR29 CR30 CR31 CR32\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Its favorable effect on the alleviation of pruritus was also reported in Japanese clinical studies [\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], and difelikefalin was approved in December 2023 for HAP resistant to conventional treatments. Accordingly, we included difelikefalin in the revised treatment algorithm so that either nalfurafine or difelikefalin can be selected for conventional treatment-resistant HAP depending on other medications and patients\u0026rsquo; will. The observation period to judge the effect of nalfurafine was 2\u0026ndash;4 weeks in the previous version of the algorithm. However, in Japan, a 6-week randomized double-blind placebo-controlled study and the following 52‑week open‑label extension phase 3 study showed that the proportion of patients who continuously received difelikefalin from the double-blinded period and whose weekly mean nighttime Shiratori severity score decreased to \u0026le;2 from the baseline score \u0026ge;3 was 55.3% at week 4, which markedly increased to 68.4% at week 6, followed by a gradual upward trend [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Thus, in the new algorithm, the observation period to judge the effect of nalfurafine or difelikefalin was set to 2\u0026ndash;6 weeks, and when the response was judged poor, switching one medicine to the other or increasing the dose of nalfurafine was considered (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Here, we evaluated the effectiveness of difelikefalin for conventional treatment-resistant HAP in the new treatment algorithm.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eIn accordance with the treatment algorithm, nalfurafine was administered for 6 weeks or longer to 43 patients who were receiving maintenance hemodialysis at our facility. In 9 (5 men and 4 women) of these 43 patients, the response to nalfurafine was considered poor based on the presence of moderate or worse daytime or nighttime pruritus assessed according to the Shiratori severity score [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] or \u0026ge;4 according to the numerical rating scale (NRS) [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], despite good adherence confirmed through history taking. Those 9 patients consented to having their medication switched from nalfurafine to difelikefalin, and were thus included as the subjects of this study. The median age [interquartile range (IQR)] was 70 [69, 71] years old, and the median duration of dialysis [IQR] was 47 [31, 71] months. Primary conditions were diabetes mellitus in 5 patients, chronic glomerulonephritis in 3 patients, and nephrosclerosis in 1 patient. Treatments for pruritus, other than nalfurafine, were moisturizers in 9 patients (100%), topical steroids in 9 patients (100%), other topical agents in 4 patients (44.4%), and oral antihistamines in 3 patients (33.3%). GABA analogues, although they were not included in the treatment algorithm, were used in 2 patients (22.2%). The baseline characteristics of patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male / female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (55.6) / 4 (44.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years), median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 [69, 71]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of HD (months), median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 [31, 71]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary illness of chronic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (55.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic glomerulonephritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNephrosclerosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (11.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis method\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOHDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (66.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO/IHDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (22.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIHDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (11.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDry weight, kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (22.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;45, \u0026gt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (77.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory data, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.6 [10.3, 12.7]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlb, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.3 [3.0, 3.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorrected Ca, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.6 [8.4, 9.1]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIP, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 [3.1, 4.7]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhole PTH, pg/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.1 [58.4, 96.3]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eβ\u003csub\u003e2\u003c/sub\u003e-MG, mg/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.6 [18.4, 25.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003espKt/Vurea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.86 [1.78, 1.88]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther anti-pruritic drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoisturizers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTopical steroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther topical drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (44.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOral antihistamines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGABA analogues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (22.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eData are presented as number (%), unless stated otherwise. \u003cem\u003eIQR\u003c/em\u003e interquartile range, \u003cem\u003eHD\u003c/em\u003e hemodialysis, \u003cem\u003eOHDF\u003c/em\u003e online hemodiafiltration, \u003cem\u003eO/IHDF\u003c/em\u003e online/intermittent infusion hemodiafiltration, \u003cem\u003eIHDF\u003c/em\u003e intermittent infusion hemodiafiltration, \u003cem\u003eHb\u003c/em\u003e hemoglobin, \u003cem\u003eAlb\u003c/em\u003e albumin, \u003cem\u003eIP\u003c/em\u003e inorganic phosphorus, \u003cem\u003ePTH\u003c/em\u003e parathyroid horomone, \u003cem\u003eβ\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e-MG\u003c/em\u003e β\u003csub\u003e2\u003c/sub\u003e-microglobrin, \u003cem\u003espKt/Vurea\u003c/em\u003e single-pool Kt/Vurea, \u003cem\u003eGABA\u003c/em\u003e analogues gamma-aminobutyric acid analogues.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eThis is a single-center single-arm prospective interventional study involving light invasiveness. To avoid seasonal effects on pruritus, nalfurafine was switched to difelikefalin in all patients in April 2024, followed by 16-week observation. The doses of difelikefalin were 17.5 \u0026micro;g when the dry weight was \u0026lt;45 kg, and 25 \u0026micro;g when it was \u0026ge;45 kg and \u0026lt;65 kg. Anti-pruritic drugs and dialysis methods were not changed for 16 weeks after the start of difelikefalin treatment.\u003c/p\u003e \u003cp\u003eThe primary endpoint was the severity of pruritus according to the Shiratori severity score and the NRS. The daytime and nighttime Shiratori severity scores were assessed separately. The following 5-point scale was used to assess daytime pruritus: 0 (no symptoms: not itchy), 1 (very mild: bearable without scratching), 2 (mild: subsides with a little scratching), 3 (moderate: subsides with considerable scratching), and 4 (severe: does not subside with scratching, prompting further scratching). The following 5-point scale was used to assess nighttime pruritus: 0 (no symptoms: not itchy), 1 (very mild: slightly itchy at bedtime, but not requiring intentional scratching; no difficulty sleeping), 2 (mild: slight itching subsides with a little scratching; no difficulty sleeping), 3 (moderate: wakes up due to itching, can go back to sleep after scratching, and unintentional scratching occurs during sleep), and 4 (severe, can hardly sleep due to itching, requiring frequent scratching that worsens the itching). The integers 0\u0026ndash;10 were used to express the severity by the NRS (0, not itchy; 10 worst imaginable itching).\u003c/p\u003e \u003cp\u003eThe secondary endpoints were the frequency of itching, presence/absence of pruritus-related insomnia, satisfaction with treatment, and presence/absence of adverse events. The following 5-point scale was used to assess the frequency of itching: not every day, once a day, a few times a day, 4 times or more a day, and always. The following 2-point scale was used to assess the onset of insomnia due to pruritus: present and absent. The following 5-point scale was used to assess the satisfaction with treatment: very satisfied, satisfied, neither satisfied nor dissatisfied, dissatisfied, and very dissatisfied.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eChanges in continuous variables in a period from week 0 to week 16 were tested using the Friedman test (non-parametric). When significant differences were found, a pairwise comparison of each week with week 0 was performed, using the closed testing procedure. The test was performed from week 16 to the earlier timepoint, and stopped when there was no statistical significance. The Jonckheere\u0026ndash;Terpstra test was used to analyze trends in the period from week 0 to week 16. Changes in discrete variables from week 0 to week 16 were tested using Cochran\u0026rsquo;s Q test. In all analyses, p \u0026lt; 0.05 was regarded as statistically significant.\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using SPSS ver. 29.0 for Windows (IBM Japan, Tokyo, Japan).\u003c/p\u003e \u003c/div\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthical approval\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the ethical review board of Tsuchiya General Hospital (approval number: E240122-3) and conducted in accordance with the principles of the Declaration of Helsinki. All participants enrolled in this study first provided oral consent and then a written consent form, which was stored with medical records.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSeverity of pruritus\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore the change in medication, the numbers of patients with “no symptoms,” “very mild,” “mild,” “moderate,” and “severe” daytime pruritus according to the Shiratori severity score were 0 (0.0%), 3 (33.3%), 2 (22.2%), 3 (33.3%), and 1 (11.1%), respectively. After the change in medication, the numbers of patients with very mild or no symptoms increased, while those with mild or worse itching decreased. Specifically, the numbers of patients with “no symptoms,” “very mild,” “mild,” “moderate,” and “severe” daytime pruritus were 1 (11.1%), 6 (66.7%), 2 (22.2%), 0 (0.0%), and 0 (0.0%), respectively, at week 16 after the change in medication (p\u0026nbsp;\u0026lt;0.01, Figure 2). Before the change in medication, the numbers of patients with “no symptoms”, “very mild”, “mild”, “moderate”, and “severe” nighttime pruritus were 0 (0.0%), 0 (0.0%), 3 (33.3%), 5 (55.6%), and 1 (11.1%), respectively. After the change in medication, the numbers of patients with very mild or no symptoms increased, while those with mild or worse itching decreased. Specifically, the numbers of patients with “no symptoms,” “very mild,” “mild,” “moderate,” and “severe” nighttime pruritus were 2 (22.2%), 5 (55.6%), 2 (22.2%), 0 (0.0%), and 0 (0.0%), respectively, at week 16 after the change in medication (p\u0026nbsp;\u0026lt;0.001, Figure 3). The daytime Shiratori severity score decreased at week 16 after the change in medication in 7 patients (77.8%, Figure 4A). The nighttime Shiratori severity score decreased at week 16 after the change in medication in all 9 patients: a score of ³3 was observed in 6 patients before the change in medication, which decreased to 2 in 2 patients, 1 in 3 patients, and 0 in 1 patient at week 16 after the change in medication (Figure 4B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe median [IQR] NRS was 5 [4, 7] before the change in medication, which decreased to 3 [3, 4] at week 2 after the change in medication, and significantly decreased to 3 [2, 3] at week 16 after the change in medication (p\u0026nbsp;\u0026lt;\u0026nbsp;0.01, Figure 5). The NRS was unchanged in 1 patient (11.1%), and decreased in 8 patients (88.9%) at week 16 after the change in medication (Figure 6).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFrequency of pruritus\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe numbers of patients who experienced itching “not every day,” “once a day,” “a few times a day,” “4 times or more a day,” and “always” were 0 (0.0%), 0 (0.0%), 4 (44.4%), 3 (33.3%), and 2 (22.2%), respectively, before the change in medication, and 5 (55.6%), 1 (11.1%), 1 (11.1%), 1 (11.1%), and 1 (11.1%), respectively, at week 12 after the change in medication, indicating significant alleviation (p\u0026nbsp;\u0026lt;\u0026nbsp;0.01). At week 16 after the change in medications, the numbers were 4 (44.4%), 1 (11.1%), 2 (22.2%), 1 (11.1%), and 1 (11.1%), respectively. The numbers of patients who experienced itching a few times a day or less showed an increasing trend while the numbers of patients who experienced itching 4 times a day or more showed a decreasing trend; however, the differences before and after the change in medication were not statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInsomnia due to pruritus\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe number of patients with insomnia due to pruritus was 4 (44.4%) before the change in medication, which significantly decreased to 1 (11.1%), 0 (0.0%), 0 (0.0%), 0 (0.0%), 1 (11.1%), and 0 (0.0%), at week 2, 4, 6, 8,12, and 16 after the change in medication, respectively (p\u0026nbsp;\u0026lt;\u0026nbsp;0.01, Figure 7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment satisfaction\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore the change in medication, the numbers of patients whose satisfaction level with treatment was “very satisfied,” “satisfied,” “neither satisfied nor dissatisfied,” “dissatisfied,” and “very dissatisfied” were 0 (0.0%), 4 (44.4%), 3 (33.3%), 2 (22.2%), and 0 (0.0%), respectively. At week 16 after the change in medication, the numbers of patients whose satisfaction level with treatment was “very satisfied” and “satisfied” increased to 1 (11.1%) and 8 (88.9%), respectively, while the numbers of patients whose satisfaction level with treatment was “neither satisfied nor dissatisfied,” “dissatisfied,” or “very dissatisfied” all decreased to 0 (0.0%), indicating significant improvement (p\u0026nbsp;\u0026lt;\u0026nbsp;0.05).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAdverse events\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo adverse event was observed after the change to difelikefalin, and difelikefalin administration was continued for 16 weeks in all patients.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn accordance with the new treatment algorithm, difelikefalin was administered to 9 hemodialysis patients whose response to\u0026nbsp;\u0026gt;6-week oral nalfurafine was poor based on the presence of persistent moderate or worse pruritus. Pruritus was alleviated 16 weeks after the change in medication to difelikefalin. Decreases in the NRS score and in the nighttime Shiratori severity score were observed in 8 patients and all patients, respectively. Compared with other opioids, difelikefalin has higher selectivity to KORs and less of an effect on selective\u0026nbsp;\u0026mu;- opioid receptors that induce pruritus [40], suggesting the possibility that difelikefalin can alleviate pruritus in patients who respond poorly to nalfurafine.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe numbers of patients with insomnia due to pruritus significantly decreased after the change in medication to difelikefalin, and no patients had insomnia due to pruritus at week 16. A nighttime Shiratori severity score of\u0026nbsp;\u0026sup3;3, but not\u0026nbsp;\u0026pound;2, indicates insomnia due to pruritus. A nighttime Shiratori severity score of\u0026nbsp;\u0026sup3;3 was found in 6 patients before the change in medication, but the score decreased to\u0026nbsp;\u0026pound;2 in all 6 patients (2 in 2 patients, 1 in 3 patients, and 0 in 2 patients), indicating no insomnia at week 16. A phase 3 study involving 168 patients in Japan also evaluated nighttime pruritus and quality of life (QOL) according to the Shiratori severity score, and found that the nighttime Shiratori severity score decreased after the start of difelikefalin treatment, an effect that was maintained until week 58. Also, in patients who had insomnia (score\u0026nbsp;\u0026sup3;3) at baseline, 92.6% did not have insomnia (score\u0026nbsp;\u0026pound;2) at week 58. Furthermore, a subgroup analysis showed that improvement in the NRS score was greater in the group with insomnia than in the group without insomnia [36]. Weiner et al. performed a post hoc analysis of a multicenter open-label, single-arm phase 3 study of 12-week difelikefalin treatment, involving 222 patients on hemodialysis in the U.S., Europe, and Asia (except Japan); they reported that difelikefalin reduced the severity of pruritus as assessed by the Worst Itch-Numerical Rating Scale (WI-NRS) and improved pruritus-related sleep quality as assessed by the Sleep Quality-Numerical Rating Scale (SQ-NRS), and there was a strong correlation between improvement of pruritus and improvement of sleep quality [41]. In addition, Fotheringham et al. conducted a multicenter open-label phase 3 study involving 197 patients in the U.S. and Europe, and reported significant decreases in the WI-NRS and SQ-NRS at week 12, as well as complete resolution in the SQ-NRS in 19.1% of patients at week 12 [42]. Taken together, those findings and ours suggest that difelikefalin alleviates nighttime pruritus, thereby improving sleep quality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere were no adverse events during the 16-week administration of difelikefalin. In a phase 3 study in Japan, the main treatment-related adverse events observed were constipation (2.4%), somnolence (2.4%), and dizziness (1.8%); the incidence of treatment-related adverse events associated with the CNS was low, and treatment-related insomnia, which is observed with nalfurafine treatment, was absent [36]. Difelikefalin, a low-molecular-weight synthetic peptide, is a KOR agonist that activates KORs in the skin, peripheral nerves, and immune cells, thereby regulating visceral pain, inflammatory pain, pruritus, and inflammatory signaling [27, 40]. Compared with other KOR agonists, difelikefalin was shown to have a more favorable safety profile and is better tolerated because of its physicochemical properties, including limited membrane permeability and delivery to the CNS [26-28, 35, 36, 43]. Because it has fewer adverse effects involving the CNS, difelikefalin is thought to be easy to use for aging patients on hemodialysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition, difelikefalin is injectable, making it suitable for treatment of conventional treatment-resistant HAP in patients with poor or unreliable adherence to oral medications, which may help to prevent or resolve polypharmacy. Another advantage is that interaction with other medications via cytochrome P450 and adsorption do not have to be considered.\u003c/p\u003e\n\u003cp\u003eThere are several limitations in this study. First, this is a single-center study, involving a small number of patients. Second, it is a single-arm study wherein effectiveness was not compared between difelikefalin and nalfurafine, and thus, it is difficult to prove that difelikefalin is the most important factor in the alleviation of HAP. Third, a comprehensive approach addressing individual causes is required for treatment of HAP wherein multiple factors interplay in a complex manner, but it was difficult to examine the selection of medication and the role of skincare in this study. Lastly, changes in QOL associated with pruritus other than insomnia were not assessed. It is desirable to conduct a randomized controlled study involving more patients in order to examine the effect of long term use of difelikefalin on pruritus and related QOL.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDifelikefalin was suggested to be a useful and safe medicine in the new HAP treatment algorithm for patients on hemodialysis who are resistant to conventional HAP treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehemodialysis-associated pruritus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eQOL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003equality of life\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecentral nervous system\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eKOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eκ-selective opioid receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enumerical rating scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWI-NRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eworst itch-numerical score\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSQ-NRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esleep quality-numerical rating scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted with the approval of the Institutional Review Board of Tsuchiya General Hospital (no. E240122-3). Prior verbal consent was obtained from all patients enrolled in this study. The fact that patients provided consent was recorded in their medical records.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors’ contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNT established the new treatment algorithm for hemodialysis-associated pruritus, conceived the study, and wrote the first draft of the manuscript. TY contributed to the study design, coordinated the study, and performed the statistical analysis. JK, HK, ST, MM, and TM contributed to the study design and were involved in the writing of the first draft of the manuscript. All the authors read and approved the final version of the manuscript for submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to all members of the medical staff who participated in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePisoni RL, Wikstr\u0026ouml;m B, Elder SJ, Akizawa T, Asano Y, Keen ML, et al. Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Transplant. 2006;21:3495-505. \u003c/li\u003e\n\u003cli\u003eNarita I, Alchi B, Omori K, Sato F, Ajiro J, Saga D, et al. Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int. 2006;69:1626-32. \u003c/li\u003e\n\u003cli\u003eKimata N, Fuller DS, Saito A, Akizawa T, Fukuhara S, Pisoni RL, et al. Pruritus in hemodialysis patients: results from the Japanese Dialysis Outcomes and Practice Patterns Study (JDOPPS). Hemodial Int. 2014;18:657-67. \u003c/li\u003e\n\u003cli\u003eRemakrishnan K, Bond TC, Claxton A, Sood VC, Kootsikas M, Agnese W, et al. Clinical characteristics and outcomes of end-stage renal disease patients with self-reported pruritus symptoms. Int J Nephrol Renovasc Dis. 2014;7:1-12.\u003c/li\u003e\n\u003cli\u003eMathur VS, Lindberg J, Germain M, Block G, Tumlin J, Smith M, et al. ITCH National Registry Investigators: a longitudinal study of uremic pruritus in hemodialysis patients. Clin J Am Soc Nephrol. 2010;5:1410-9. \u003c/li\u003e\n\u003cli\u003eShirazian S, Aina O, Park Y, Chowdhury N, Leger K, Hou L, et al. Chronic kidney disease-associated pruritus: impact on quality of life and current management challenges. Int J Nephrol Renovasc Dis. 2017;10:11-26.\u003c/li\u003e\n\u003cli\u003eGrochulska K, Ofenloch RF, Mettang T, Weisshaar E. Mortality of haemodialysis patients with and without chronic itch: a follow-up study of the German Epidemiological Hemodialysis Itch Study (GEHIS). Acta Derm Venereol. 2019;99:423-8.\u003c/li\u003e\n\u003cli\u003eSukul N, Karaboyas A, Csomor PA, Schaufler T, Wen W, Menzaghi F, et al. Self-reported pruritus and clinical, dialysis related, and patient-reported outcomes in hemodialysis patients. Kidney Med. 2020;3:42-53.\u003c/li\u003e\n\u003cli\u003eLopes MB, Karaboyas A, Sukul N, Tsuruya K, Al Salmi I, Asgari E, et al. Utility of a single itch-related question and the Skindex-10 questionnaire for assessing pruritus and predicting health-related quality of life in patients receiving hemodialysis. Kidney Med. 2022;4:100476.\u003c/li\u003e\n\u003cli\u003eAhdoota RS, Kalantar-Zadeh K, Burtonc JO, Lockwood MB. Novel approach to unpleasant symptom clusters surrounding pruritus in patients with chronic kidney disease and on dialysis therapy. Curr Opin Nephrol Hypertens. 2022;31:63-71.\u003c/li\u003e\n\u003cli\u003eSukul N, Zhao J, Pisoni RL, Walpen S, Schaufler T, Asgari E, et al. Pruritus in hemodialysis patients: longitudinal associations with clinical and patient-reported outcomes. Am J Kidney Dis. 2023;82:666-76.\u003c/li\u003e\n\u003cli\u003eThompson J, Kammerer J, Boshears T, Oliveira J, Johansen KL, Kovar A, et al. Chronic kidney disease-associated pruritus burden: a patient survey study. Kidney Med. 2024;6;100900.\u003c/li\u003e\n\u003cli\u003eTakahashi N, Yoshizawa T. The status of hemodialysis‒associated pruritus: internet-based questionnaire survey report. J Jpn Soc Dial Ther. 2024;57:111-22 (in Japanese).\u003c/li\u003e\n\u003cli\u003eHashimoto T, Yosipovitch G. Itching as a systemic disease. J Allergy Clin Immunol. 2019;144:375-80.\u003c/li\u003e\n\u003cli\u003eKim BS, Inan S, St\u0026auml;nder S, Sciascia T, Szepietowski JC, Yosipovitch G. Role of kappa-opioid and mu-opioid receptors in pruritus: peripheral and central itch circuits. Exp Dermatol. 2022;31:1900-7.\u003c/li\u003e\n\u003cli\u003eWieczorek A, Krajewski P, Kozioł-Gałczyńska M, Scepietowski JC. Opioid receptors expression in the skin of hemodialysis patients suffering from uremic pruritus. J Eur Acad Dermatol Venereol. 2020;34:2368-72.\u003c/li\u003e\n\u003cli\u003eSimonsen E, Komenda P, Lerner B, Askin N, Bohm C, Shaw J, et al. Treatment of uremic pruritus: a systematic review. Am J Kidney Dis. 2017;70:638-55.\u003c/li\u003e\n\u003cli\u003eSuzuki H, Omata H, Kumagai H. Recent advances in treatment for uremic pruritus. Open J Nephrol. 2015;5:1-13. \u003c/li\u003e\n\u003cli\u003eMettang T, Kremer AE. Uremic pruritus. Kidney Int. 2015;87:685-91.\u003c/li\u003e\n\u003cli\u003eYosipovitch G. Chronic kidney disease\u0026ndash;associated pruritus, still a vexing problem. NEJM Evid. 2023;2:EVIDe2300227.\u003c/li\u003e\n\u003cli\u003eTakahashi N, Yoshizawa T, Kumagai J, Kawanishi H, Moriishi M, Masaki T, et al. Response of patients with hemodialysis-associated pruritus to new treatment algorithm with nalfurafine hydrochloride: a retrospective survey-based study. Ren Replace Ther. 2016;2:27.\u003c/li\u003e\n\u003cli\u003eTakahashi N, Yoshizawa T, Kumagai J, Kawanishi H, Tsuchiya S, Moriishi M, et al. Effectiveness of a treatment algorithm for hemodialysis-associated pruritus in terms of changes in medications. Ren Replace Ther. 2021;7:24.\u003c/li\u003e\n\u003cli\u003eKumagai H, Saruta T, Matsukawa S, Utsumi J. Prospects for a novel \u0026kappa;-opioid receptor agonist, TRK-820, in uremic pruritus. Itch: basic mechanisms and therapy. New York: Marcel Dekker; 2004. p. 279-86. \u003c/li\u003e\n\u003cli\u003eKumagai H, Ebata T, Takamori K, Muramatsu T, Nakamoto H, Suzuki H. Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a phase III, randomized, double-blind, placebo-controlled study. Nephrol Dial Transplant. 2010;25:1251-7.\u003c/li\u003e\n\u003cli\u003eKumagai H, Ebata T, Takamori K, Miyasato K, Muramatsu T, Nakamoto H, et al. Efficacy and safety of a novel ĸ-agonist for managing intractable pruritus in dialysis patients. Am J Nephrol. 2012;36:175-83.\u003c/li\u003e\n\u003cli\u003eFishbane S, Jamal A, Munera C, Wen W, Menzaghi F, KALM-1 Trial Investigators. A phase 3 trial of difelikefalin in hemodialysis patients with pruritus. N Engl J Med. 2020;382:222-32.\u003c/li\u003e\n\u003cli\u003eLipman ZM, Yosipovitch G. An evaluation of difelikefalin as a treatment option for moderate-to-severe pruritus in end stage renal disease. Expert Opin Pharmacother. 2021;22:549-55.\u003c/li\u003e\n\u003cli\u003eTopf J, Wooldridge T, McCafferty K, Sch\u0026ouml;mig M, Csiky B, Zwiech R, et al. Efficacy of difelikefalin for the treatment of moderate to severe pruritus in hemodialysis patients: pooled analysis of KALM-1 and KALM-2 phase 3 studies. Kidney Med. 2022;4:100512.\u003c/li\u003e\n\u003cli\u003eRastogi A, Fishbane S, Lerma E. Difelikefalin for the treatment of moderate-to-severe pruritus associated with chronic kidney disease on hemodialysis. Expert Rev Clin Pharmacol. 2023;16:387-400.\u003c/li\u003e\n\u003cli\u003eRami H. Mahmoud MO, Yosipovitch G. Intravenous difelikefalin for the treatment of hemodialysis pruritus. Expert Rev Clin Immunol. 2024;20:31-7.\u003c/li\u003e\n\u003cli\u003eXue G, Yuan H, Fan D, Yang Y, Ma C, Liu J, et al. Efficacy and safety of difelikefalin in the treatment of hemodialysis patients with pruritus: a meta-analysis and systematic review. Clin Nephrol. 2024;101:155-63.\u003c/li\u003e\n\u003cli\u003eCai X, Wu G, Lin Y, Yang L. Difelikefalin in the treatment of hemodialysis patients with pruritus: a systematic review and meta-analysis. Front Pharmacol. 2024;15:1476587.\u003c/li\u003e\n\u003cli\u003eSt\u0026auml;nder S, Fishbane S, Schaufler T, Ruessmann D, Morin I, Menzaghi F, et al. Chronic kidney disease-associated pruritus and quality of life with difelikefalin treatment: a post hoc analysis of phase 3 data using the Skindex-10 questionnaire. Clin Kidney J. 2024;17:sfae274.\u003c/li\u003e\n\u003cli\u003eNarita I, Tsubakihara Y, Uchiyama T, Okamura S, Oya N, Takahashi N, et al. Efficacy and safety of difelikefalin in Japanese patients with moderate to severe pruritus receiving hemodialysis: a randomized clinical trial. JAMA Netw Open. 2022;5:e2210339.\u003c/li\u003e\n\u003cli\u003eNarita I, Tsubakihara Y, Takahashi N, Ebata T, Uchiyama T, Marumo M, et al. Difelikefalin for hemodialysis patients with pruritus in Japan. NEJM Evid. 2023;2:EVIDoa2300094.\u003c/li\u003e\n\u003cli\u003eNarita I, Tsubakihara Y, Takahashi N, Ebata T, Uchiyama T, Marumo M, et al. Long‑term efficacy and safety of difelikefalin in moderate‑to‑severe pruritus in Japanese hemodialysis patients: a 52‑week open‑label extension period of a phase 3 trial. Ren Replace Ther. 2024;10:42.\u003c/li\u003e\n\u003cli\u003eShiratori A. Therapeutic outcomes of the use of mequitazine (LM-209) in severe dermatological diseases. Nishinihon J Dermatol. 1983;45:470-3 (in Japanese).\u003c/li\u003e\n\u003cli\u003ePhan NQ, Blome C, Fritz F, Gerss J, Reich A, Ebata T, et al. Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus. Acta Derm Venereol. 2012;92:502-7.\u003c/li\u003e\n\u003cli\u003eYosipovitch G, Reaney M, Mastey V, Eckert L, Abb\u0026eacute; A, Nelson L, Clark M, et al. Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis. Br J Dermatol. 2019;181:761-9.\u003c/li\u003e\n\u003cli\u003eAlbert-Vartanian A, Boyd MR, Hall AL, Morgado SJ, Nguyen E, Nguyen VP, et al. Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential? J Clin Pharm Ther. 2016;41:371-82.\u003c/li\u003e\n\u003cli\u003eWeiner DE, Schaufler T, McCafferty K, Kalantar-Zadeh K, Germain M, Ruessmann D, et al. Difelikefalin improves itch-related sleep disruption in patients undergoing haemodialysis. Nephrol Dial Transplant. 2024;39:1125-37.\u003c/li\u003e\n\u003cli\u003eFotheringham J, Guest J, Latus J, Lerma E, Morin I, Schaufler T, et al. Impact of difelikefalin on the health‑related quality of life of haemodialysis patients with moderate‑to‑severe chronic kidney disease‑associated pruritus: a single‑arm intervention trial. Patient. 2024;17:203-13.\u003c/li\u003e\n\u003cli\u003eDeeks ED. Difelikefalin: first approval. Drugs. 2021;81:1937-44.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hemodialysis-associated pruritus, Quality of life, Treatment algorithm, Shiratori severity score, Numerical rating scale, Difelikefalin","lastPublishedDoi":"10.21203/rs.3.rs-6209685/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6209685/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSince June 2009, our facility has been using an internally developed treatment algorithm that facilitates a comprehensive approach to address each cause of hemodialysis-associated pruritus (HAP), wherein oral nalfurafine, a selective κ-opioid receptor (KOR) agonist, is used for patients resistant to conventional treatments. Upon approval of intravenous difelikefalin, a new KOR agonist, in Japan in December 2023, we revised the treatment algorithm. Here, we evaluated the effectiveness of difelikefalin in the new treatment algorithm.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eNalfurafine was administered for 6 weeks or longer to 43 patients who were receiving maintenance hemodialysis at our facility in order to treat treatment-resistant HAP in accordance with the treatment algorithm. In 9 of the 43 patients, response to nalfurafine was considered poor based on the presence of moderate or severe daytime or nighttime pruritus according to the Shiratori severity score, or the numerical rating scale (NRS) \u0026ge;4, despite good adherence confirmed through history taking. For those 9 patients, the medicine was switched to difelikefalin in April 2024 and administered for 16 weeks. The primary endpoint was pruritus severity according to the Shiratori severity score and the NRS. The secondary endpoints were the frequency of itching, presence/absence of pruritus-related insomnia, satisfaction with treatment, and presence/absence of adverse events.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe numbers of patients with moderate or severe pruritus according to the Shiratori severity score were 4 (44.0%) during the daytime and 6 (66.7%) at nighttime before the change to difelikefalin. However, at week 16 after the change, both had decreased to 0 (0.0%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). The median [interquartile range] of the NRS was 5 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] before the change, which significantly decreased to 3 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] at week 16 after the change (p \u0026lt; 0.005). The number of patients with insomnia due to pruritus was 4 (44.4%) before the change, which significantly decreased to 0 (0.0%) at week 16 after the change (p \u0026lt; 0.01). No adverse events were observed.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn the new HAP treatment algorithm, difelikefalin was suggested to be a useful and safe medicine for patients on hemodialysis who are resistant to conventional HAP treatment.\u003c/p\u003e","manuscriptTitle":"Effectiveness of difelikefalin in a new treatment algorithm for hemodialysis-associated pruritus: a prospective interventional study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-01 12:31:41","doi":"10.21203/rs.3.rs-6209685/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"903b907f-99b0-4f5d-881a-48e37c126545","owner":[],"postedDate":"April 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T15:58:39+00:00","versionOfRecord":{"articleIdentity":"rs-6209685","link":"https://doi.org/10.1186/s41100-025-00653-4","journal":{"identity":"renal-replacement-therapy","isVorOnly":false,"title":"Renal Replacement Therapy"},"publishedOn":"2025-07-08 15:56:51","publishedOnDateReadable":"July 8th, 2025"},"versionCreatedAt":"2025-04-01 12:31:41","video":"","vorDoi":"10.1186/s41100-025-00653-4","vorDoiUrl":"https://doi.org/10.1186/s41100-025-00653-4","workflowStages":[]},"version":"v1","identity":"rs-6209685","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6209685","identity":"rs-6209685","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}