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Evidence: HighPeptideFDA ApprovedKappa opioid agonistFDA-approved 2021 · KorsuvaKidney-disease itch

Difelikefalin

A peripherally restricted kappa opioid agonist that eases itch in people on hemodialysis

Difelikefalin is a selective kappa opioid receptor agonist with limited entry into the brain. Approved as Korsuva in 2021, it is injected into the dialysis line after each session for moderate-to-severe itch caused by chronic kidney disease.

At a Glance Read Research →
Overview

What is it?

Itch caused by chronic kidney disease is common in people on hemodialysis and can be distressing enough to harm quality of life. Kappa opioid receptors help modulate itch. Difelikefalin activates them while staying largely outside the central nervous system, and it does not act on the mu receptors through which morphine-like opioids work.

In KALM-1, 49.1% of patients given difelikefalin after dialysis had a drop of at least 3 points in their worst-itch score at 12 weeks, against 27.9% on placebo. A Japanese trial found a similar benefit at 4 weeks, and pooled phase 3 data linked itch relief to better quality of life.

Two studies addressed the opioid question directly: in recreational drug users its liking scores were lower than pentazocine's, and stopping it abruptly in dialysis patients produced no withdrawal signs. It is not a controlled substance in the US. An oral form has been tested for other itchy conditions.

Structured data

At a Glance

Every value in this table is printed from the Grey Peptides dataset, the same record the compound explorer and comparison tool read, so the three can never disagree.

ClassA peripherally restricted, selective kappa opioid receptor agonist; FDA-approved as Korsuva in 2021 for moderate-to-severe itch from chronic kidney disease in adults on hemodialysis.
FormulaC36H53N7O6
Molecular weight679.8 g/mol
Half-life23 to 31 hours in hemodialysis patients, before dialysis
Label dose0.5 mcg/kg (after each hemodialysis session, intravenous)
US statusFDA Approved
Evidence levelHigh
Last reviewed2026-10-02

Educational information, not medical advice. The doses on this page come from approved labels, published studies and, where no study exists, amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.

Interactive

Half-Life: How Much Remains

The dataset records a half-life of 23 to 31 hours in hemodialysis patients, before dialysis for Difelikefalin. After each half-life, half of what was in the circulation is gone, so about 3% remains after five. Real clearance varies with the person, the dose, the route and kidney or liver function; this is arithmetic on a published figure, not a dosing tool.

Time since a single dose
ElapsedTimeRemaining
1 half-life27 h50% remaining
2 half-lives2.2 days25% remaining
3 half-lives3.4 days12.5% remaining
4 half-lives4.5 days6.25% remaining
5 half-lives5.6 days3.125% remaining
Evidence

Published Research

The studies behind difelikefalin, read from their PubMed abstracts.

Human2020

KALM-1: 378 patients on hemodialysis

Difelikefalin 0.5 µg/kg three times a week for 12 weeks gave a drop of at least 3 points in worst-itch score in 49.1% against 27.9% on placebo, and a 4-point drop in 37.1% against 17.9%; diarrhoea, dizziness and vomiting were more common.

PMID: 31702883
Human2023

Japan: 178 patients

After 4 weeks, the itch score fell 2.06 points against 1.09 on placebo; treatment-related adverse events occurred in 15% against 3%, mostly gastrointestinal.

PMID: 38320524
Human2024

Itch relief and quality of life, 914 patients

In pooled phase 3 data, quality-of-life scores improved more on difelikefalin than placebo, and most in those whose itch fell by at least 3 points.

PMID: 39421431
Human2022

Abuse potential in drug users

In 44 recreational drug users, high intravenous doses produced lower drug-liking scores than pentazocine, and no greater wish to take it again than placebo.

PMID: 34708917
Human2023

No withdrawal on stopping

In 30 dialysis patients randomized to continue or stop after three weeks, withdrawal scores did not differ; abrupt stopping produced no signs of physical withdrawal.

PMID: 37128642
Human2023

Oral form in notalgia paresthetica

In 125 patients with this nerve-related back itch, oral difelikefalin 2 mg twice daily lowered itch by 4.0 points against 2.4 over 8 weeks, but secondary outcomes did not support the result.

PMID: 36780675
Safety

Side Effects & Contraindications

Reported Side Effects

From the studies above.

● Diarrhoea, dizziness and vomiting (KALM-1)
● Constipation and abdominal discomfort (Japan trial)
● Headache and dizziness with the oral form

Contraindications & Cautions

Warnings from the Korsuva label (DailyMed, effective August 26, 2025).

● Dizziness, sleepiness, mental status changes and unsteady walking
● Caution with driving or operating machinery until the effect is known
● Not studied in peritoneal dialysis
● Tested athletes — see the Sport (WADA) row below
Questions

Frequently Asked Questions

?What is difelikefalin?

A kappa opioid receptor agonist with limited entry into the brain, sold as Korsuva for moderate-to-severe itch caused by chronic kidney disease in adults on hemodialysis.

?Is difelikefalin an opioid like morphine?

It acts on kappa opioid receptors rather than mu receptors. It is not a controlled substance in the US, showed low abuse potential in drug users, and stopping it caused no withdrawal in dialysis patients.

?How well does it work?

In KALM-1, 49.1% had a clinically meaningful drop in itch at 12 weeks against 27.9% on placebo.

Bibliography

References

  1. [fda] US FDA, Drugs@FDA (openFDA): KORSUVA (difelikefalin), NDA 214916, original approval August 23, 2021, prescription. Read October 2, 2026.
  2. [fda-pi] FDA. Korsuva (difelikefalin) injection US prescribing information (DailyMed set 0c7b81f2-0fd3-47cb-8b0f-185e07f19c87, effective August 26, 2025). Read October 2, 2026.
  3. [clinical-trial] Fishbane S, et al. "A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus." N Engl J Med, 2020;382(3):222-232. PMID: 31702883.
  4. [clinical-trial] Narita I, et al. "Difelikefalin for Hemodialysis Patients with Pruritus in Japan." NEJM Evid, 2023;2(11):EVIDoa2300094. PMID: 38320524.
  5. [pubmed] Ständer S, et al. "Chronic kidney disease-associated pruritus and quality of life with difelikefalin treatment: a post hoc analysis of phase 3 data using the Skindex-10 questionnaire." Clin Kidney J, 2024;17(10):sfae274. PMID: 39421431.
  6. [clinical-trial] Shram MJ, et al. "Evaluation of the abuse potential of difelikefalin, a selective kappa-opioid receptor agonist, in recreational polydrug users." Clin Transl Sci, 2022;15(2):535-547. PMID: 34708917.
  7. [clinical-trial] Spencer RH, et al. "Assessment of the physical dependence potential of difelikefalin: Randomized placebo-controlled study in patients receiving hemodialysis." Clin Transl Sci, 2023;16(9):1559-1568. PMID: 37128642.
  8. [clinical-trial] Kim BS, et al. "Phase 2 Trial of Difelikefalin in Notalgia Paresthetica." N Engl J Med, 2023;388(6):511-517. PMID: 36780675.

Sources & Citations

Studies were read from their PubMed records; regulatory sources are listed below, read October 2, 2026.

Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Consult a licensed healthcare provider before making health decisions.

Last reviewed: 2026-10-02