By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

The FDA has approved the first-in-class selective kappa opioid receptor (KOR) agonist for the treatment of moderate-to-severe pruritus in adults undergoing hemodialysis (i.e., uremic pruritus). Difelikefalin is a synthetic peptide marker. It received a breakthrough therapy designation and priority review. It is marketed as Korsuva.


Difelikefalin can be prescribed to treat moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis.1 Difelikefalin has not been studied for use in peritoneal dialysis and is not recommended for use in this population.1


The recommended dose is 0.5 mcg/kg given by intravenous bolus into the venous line of the dialysis circuit at the end of each hemodialysis treatment.1 Difelikefalin is available as a single dose (65 mcg in a 1.3 mL vial).


Difelikefalin is the first approved pharmacological treatment for uremic pruritus. In clinical trials, difelikefalin improved itch intensity and itch-related quality of life, including sleep.1-3 Difelikefalin produces no detectable activity at mu or delta opioid receptors that might be associated with dependency.2


Adverse reactions reported with greater frequency than placebo were diarrhea (9% vs. 5.7%), dizziness (6.8% vs. 3.8%), nausea (6.6% vs. 4.5%), gait disturbance (including falls; 6.6% vs. 4.5%), mental status change (3.1% vs. 1.4%), and hyperkalemia in subjects on concomitant opioids (11.7% vs. 6.2%).1


KORs are believed to play an important role in chronic pruritus.4 Therefore, KORs are a reasonable target for pharmacological intervention. The efficacy of difelikefalin was evaluated in two randomized, double-blind, placebo-controlled, 12-week trials in adults (≥ age 18 years) with moderate-to-severe pruritus undergoing hemodialysis.1,2 Subjects (n = 378 in Trial 1, n = 472 in Trial 2) were randomized to difelikefalin or placebo three times weekly. Efficacy was based on the percentage of subjects achieving a 4-point or greater improvement from baseline in the weekly mean of the daily 24-hour, 11-point, Worst Itch Numeric Rating Scale (WI-NRS) score at week 12. Baseline was defined as the mean of the scores collected during the seven days before randomization. Rating of itch ranged from 0 (no itch) to 10 (worst itch imaginable). Percentages achieving efficacy endpoint were 40% vs. 21% in Trial 1 (baseline mean, 7.1 ± 1.5) and 37% vs. 26% in Trial 2 (baseline mean, 7.2 ± 1.4) for difelikefalin and placebo, respectively. Reduction in itch was observed by week 4 and sustained through week 12.


Pruritus is highly prevalent in patients with chronic kidney disease and end-stage renal disease.5 It affects more than 60% of patients on hemodialysis, with 20% to 40% experiencing moderate-to-severe pruritus.2 Pruritus is associated with worse quality of life, poor sleep, depression, and higher mortality rates.5 The pathogenesis is poorly understood, with various proposed mechanisms involved, including immune-mediated effect, increase in the level of histamine, eosinophils and mast cells, peripheral nervous system dysfunction, and imbalance in mu and kappa receptor activity.5 Current off-label pharmacologic interventions include oral antihistamines and gabapentin/pregabalin, with limited and some benefit, respectively.5,6 Difelikefalin provides a new agent that targets KOR and is the only FDA-approved drug for this condition. An oral form of difelikefalin is under evaluation. The cost for difelikefalin was unavailable at the time of this review.


  1. Cara Therapeutics, Inc. Difelikefalin prescribing information. August 2021.
  2. Fishbane S, Jamal A, Munera C, et al. A phase 3 trial of difelikefalin in hemodialysis patients with pruritus. N Engl J Med 2020;382:222-232.
  3. Fishbane S, Mathur V, Germain MJ, et al. Randomized controlled trial of difelikefalin for chronic pruritus in hemodialysis patients. Kidney Int Rep 2020;5:600-610.
  4. Phan NQ, Lotts T, Antal A, et al. Systemic kappa opioid receptor agonists in the treatment of chronic pruritus: A literature review. Acta Derm Venereol 2012;92:555-560.
  5. Shirazian S, Aina O, Park Y, 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.
  6. Rayner HC, Larkina M, Wang M, et al. International comparisons of prevalence, awareness, and treatment of pruritus in people on hemodialysis. Clin J Am Soc Nephrol 2017;12:2000-2007.