Clinical Pearls & Morning Reports
Published January 15, 2020
Chronic kidney disease–associated pruritus, also known as uremic pruritus, is a common, distressing, and underrecognized condition. Fishbane et al. conducted a double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of difelikefalin in adult patients undergoing hemodialysis who had moderate-to-severe pruritus. Read the Original Article here.
Q: What causes chronic kidney disease-associated pruritus?
A: The pathogenesis of chronic kidney disease–associated pruritus is incompletely understood. Several hypotheses have been proposed, including metabolic disturbances, dysregulated immune response, and imbalances in the endogenous opioid system, with peripherally distributed kappa opioid receptors potentially playing a role.
Q: What is difelikefalin and how does it work?
A: Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by means of activation of kappa opioid receptors on peripheral neurons and immune cells. The hydrophilic small-peptide structure restricts passive diffusion across membranes, thereby limiting access to kappa opioid receptors in the central nervous system.
A: The primary outcome was the percentage of patients with an improvement (decrease) of at least 3 points from baseline at week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS; scores range from 0 to 10, with higher scores indicating greater itch intensity). Difelikefalin resulted in significant improvements, as compared with placebo, in the primary outcome. At week 12, the estimated percentage of patients who had an improvement (decrease) of at least 3 points from baseline on the WI-NRS was significantly greater in the difelikefalin group than in the placebo group (49.1% vs. 27.9%; relative risk, 1.65; 95% confidence interval, 1.26 to 2.14; P<0.001). The treatment effect was rapid (evident by week 1) and persisted throughout the 12 weeks of treatment. All secondary outcomes in the prespecified testing hierarchy showed significant improvement with difelikefalin as compared with placebo. The most common adverse events in patients receiving difelikefalin were diarrhea, dizziness, and vomiting; these events were generally mild to moderate in severity and resolved without evident clinical consequence.
A: In findings that were consistent with the pharmacologic and physicochemical properties of difelikefalin, there was no evidence of abuse or development of physical dependence during the 12-week trial. The authors observed no events of dysphoria or hallucination, both of which are well-documented adverse events that have been associated with centrally acting kappa opioid receptor agonists. Assessments over longer durations (ongoing in an open-label phase of the present trial) as well as ongoing trials including patients from other regions will help support the generalizability of this treatment.