Intravenous difelikefalin for the treatment of hemodialysis pruritus

ABSTRACTIntroduction Patients with chronic kidney disease (CKD) undergoing hemodialysis often experience significant itch secondary to their condition and a subsequent reduction in their overall quality of life. Current treatments are underwhelming, necessitating the search for new, effective therapeutic options to combat itch in this population.Areas Covered The purpose of this review is to explore the available data for the use of intravenous difelikefalin in patients with CKD undergoing hemodialysis. The pathophysiology of CKD-associated itch is multifactorial, with one proposed mechanism involving an imbalance in the endogenous opioid system, favoring upregulation of itch-activating μ-opioid receptors (MORs) and downregulation of itch-inhibiting κ-opioid receptors (KORs). Dysregulation of the immune system is also involved. Difelikefalin is a recent FDA approved treatment that functions as peripherally acting KOR agonist, targeting this imbalance in the endogenous opioid system seen in CKD patients with itch and having an anti-inflammatory effect on immune cells. Clinical data on intravenous difelikefalin is promising regarding its ability to reduce itch in CKD patients on hemodialysis and improve patient quality of life, with few, mild adverse side effects.Expert Opinion As intravenous difelikefalin becomes more widely used in the clinical setting, further studies assessing long-term efficacy and safety will be needed.KEYWORDS: Difelikefalintreatmentchronic kidney diseaseend stage renal diseasehemodialysisitchpruritusopioid Article highlights Pruritus is a commonly reported and debilitating symptom experienced by patients with chronic kidney disease, particularly patients with advanced CKD or end-stage renal disease requiring dialysis.This patient population experiences upregulation of itch activating μ-opioid receptors (MORs) and downregulation of itch-inhibiting κ-opioid receptors (KORs) as well as a higher ratio of the itch activating ligand B-endorphin to the itch inhibiting ligand dynorphin-A.Difelikefalin targets this endogenous opioid system imbalance through its mechanism of action as a peripheral KOR agonist.Preclinical studies using mouse, rat, and rabbit models found difelikefalin to be safe and efficacious.Recent clinical trials have demonstrated the superior efficacy of difelikefalin in treating pruritus in this patient populations and improving overall patient quality of life, with few, mild adverse effects reported.With the increasing use of intravenous difelikefalin in clinical practice, additional studies assessing long-term efficacy and safety will be needed.Declaration of interestsG Yosipovitch serves as an advisory board member for Abbvie, Arcutis, BMS, Cara Therapuetics, GSK. Escient Health, Eli Lilly, Galderma, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Sanofi, TreviTherapeutics, and Vifor; G Yosipovitch receives grants/research funding from Eli Lilly, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Galderma, Escient, Sanofi Regeneron, and Celldex; G Yosipovitch is an investigator for Regeneron Pharmaceuticals, Inc. and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresOne reviewer is a consultant for CARA and CSL-Vifor, companies that produce and promote Difelikefalin. A separate reviewer is a speaker and part of advisory boards for CSL VIfor for Difelikefalin.Scientific accuracy reviewCara Therapeutics provided a scientific accuracy review at the request of the journal editor.Additional informationFundingThis paper was not funded.