Difelikefalin in the Treatment of Chronic Kidney Disease-Associated Pruritus: A Systematic Review

Abstract

Chronic kidney disease-associated pruritus (CKD-aP) is a chronic condition that significantly reduces the quality of life of patients with end-stage renal disease. The etiology is not fully understood, but imbalance in the activity of the opioid pathways, including downregulation of the kappa-opioid receptor, may contribute to itching sensation. Difelikefalin is a selective, peripherally acting kappa-opioid receptor (KOR) agonist. Recently, difelikefalin has been approved as a first drug for the treatment of pruritus associated with chronic kidney disease (CKD) in adult hemodialysis patients. A systematic review of currently available clinical trials was performed to assess the efficacy and safety of difelikefalin in patients with uremic pruritus. A literature review was conducted in May 2022 based on the PRISMA 2020 guidelines. The analyzed clinical trials showed that difelikefalin was effective in reducing pruritus in patients as assessed by the Worst Itching Intensity Numerical Rating Scale. Improvement in quality of life assessed on the basis of the Skindex score and the 5-D itch scale was also noticed. The most commonly reported side effects were mild and included nausea, vomiting, dizziness, and diarrhea. Due to its proven efficacy and good safety profile, difelikefalin is a promising drug for the treatment of pruritus in patients with chronic kidney disease.

Serum Level of Protein-Bound Uraemic Toxins in Haemodialysis Patients with Chronic Kidney Disease-Associated Pruritus: Myths and Facts

“…This situation leads to different choices among doctors in clinical practice, and effects are often unsatisfactory and difficult to achieve. Nevertheless, it should be emphasized that difelikefalin is the first drug approved in August 2021 by the Food and Drug Administration (FDA) and in April 2022 by the European Medicines Agency (EMA) for the treatment of moderate-to-severe pruritus associated with CKD in adults undergoing haemodialysis [ 49 ]. Due to its efficacy and acceptable safety profile, it should be currently regarded as the primary treatment in a group of HD patients with refractory itch sensation [ 49 , 50 ].…”

Contrasting Evolution After Withdrawal of Long-Term Administration of Difelikefalin for CKD-Associated Pruritus

“…Its approval was based on demonstrated superiority over placebo, as assessed by the Worst Itch Numeric Rating Scale (WI-NRS), in KALM-1 and KALM-2, two 12-week prospective trials. 5 , 6 However, guidelines for managing long-term administration of DFK are not currently available.…”

Endogenous Opioid Imbalance as a Potential Factor Involved in the Pathogenesis of Chronic Kidney Disease-Associated Pruritus in Dialysis Patients

“…For example, KOR agonists such as nalfurafine have been shown to reduce the severity of pruritus when administered to patients with CKD-aP [ 38 ]. KOR agonist—selective and peripherally acting difelikefalin is the first drug to have been approved by the FDA and EMA for the treatment of CKD-aP [ 39 ]. However, some dialysis patients do not respond to available therapies or their improvement is not sufficient.…”