Kappa-opioid agonist · dialysis itch
Difelikefalin is a small synthetic peptide made of four D-amino acids attached to a piperidine group. It activates kappa-opioid receptors but was designed to stay largely outside the brain. It is approved to treat moderate-to-severe itch caused by chronic kidney disease in adults on hemodialysis, given intravenously through the dialysis circuit.
Kappa-opioid receptors are one branch of the body's opioid system and are considered important in regulating itch, including the itch that accompanies chronic kidney disease. Difelikefalin is a selective agonist at these receptors and was designed to have limited entry into the brain, which is why it is described as peripherally restricted. The FDA label states plainly that how kappa activation produces the itch benefit is not known. More than 99% of the drug circulating in the blood is the unchanged molecule, and it is not broken down by the liver's main CYP enzymes.
In dialysis patients it leaves mostly in feces, with smaller shares in urine and dialysate, and a dialysis session lowers its blood level by roughly 70 to 80%.
Human evidence centers on two 12-week placebo-controlled phase 3 trials in hemodialysis patients with moderate-to-severe itch. In KALM-1 (378 patients), 49% on difelikefalin versus 28% on placebo had at least a 3-point drop on a 0-to-10 worst-itch scale, with better itch-related quality of life; diarrhea, dizziness and vomiting were more common on the drug1.
A pooled analysis of KALM-1 and KALM-2 (851 patients) found a 3-point drop in 51% versus 35% and a 4-point drop in 39% versus 23%, with benefit from the first week2. On the label's primary measure, a 4-point or greater improvement, results were 40% versus 21% in the first trial and 37% versus 26% in the second3.
In rats, the drug increased urine output through a pathway that a brain-delivered blocker substantially reduced, suggesting some central action despite its peripheral design4. An oral version showed no meaningful benefit over placebo for itch in notalgia paresthetica, and that trial was stopped5.
The FDA approved difelikefalin as Korsuva in 2021 for moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis; it has not been studied in, and is not recommended for, peritoneal dialysis. The European Union has authorised it as Kapruvia6.
In the placebo-controlled trials the most common reactions were diarrhea, dizziness, nausea, gait disturbances including falls, high blood potassium, headache, sleepiness and mental-status changes. The label warns that dizziness, sleepiness, mental-status changes or unsteady gait occurred in 17% of treated patients versus 12% on placebo, with sleepiness more frequent after age 65, and that sedating drugs, antihistamines and opioids may add to these effects. Patients are advised not to drive until they know how it affects them.
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