Difelikefalin

CR845, Korsuva (US, Australia, Canada), Kapruvia (EU/UK)

Cognitive & neuro

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Note on this profile. Difelikefalin is an approved prescription medicine given intravenously at the end of haemodialysis sessions. This page explains the published science. Oral programmes for other itch conditions were discontinued after failed trials. Community or self-directed use is essentially none documented.

Summary

Class: Synthetic tetrapeptide (four D-amino acids: D-Phe-D-Phe-D-Leu-D-Lys) with a 4-aminopiperidine-4-carboxylic acid cap; a peripherally restricted, selective kappa-opioid receptor agonist
Mechanism: Activates kappa-opioid receptors on peripheral sensory nerves and immune cells to suppress itch signalling and inflammation, while barely entering the brain, so it avoids the sedation, euphoria and dysphoria of brain-acting opioids
Routes studied: Intravenous bolus (approved); oral tablets (investigational, discontinued); subcutaneous (early studies)
Half-life: ~23–31 hours in people on haemodialysis (cleared substantially by dialysis); ~2 hours in people with normal kidneys
Storage: Single-dose vials at room temperature; clinic use only
Regulatory status: Approved medicine (US 2021, EU 2022, UK, Canada, Australia); oral form not approved anywhere

Doses are as reported in studies or by the community — never recommendations.

1What it is

Difelikefalin is a small peptide built entirely from D-amino acids, the mirror-image forms that human enzymes cannot cut, which is why it survives in the blood for hours. It is charged and water-loving, so it does not cross the blood-brain barrier to any meaningful degree. That combination gives a kappa-opioid that works on the body but not the mind.

Chronic kidney disease-associated pruritus (CKD-aP) affects a large fraction of people on dialysis and is miserable, under-treated and linked to poor sleep, depression and higher mortality. Difelikefalin was the first drug approved specifically for it: FDA approval came in August 2021 (Korsuva), the EU followed in April 2022 (Kapruvia), and Canada, Australia and others after. A tablet version was tested for itch in notalgia paresthetica, atopic dermatitis and non-dialysis kidney disease; after the notalgia paresthetica Phase 2/3 (KOURAGE-1) Part A failed in June 2024, the developer stopped all difelikefalin development.

2How it's thought to work

Kappa-opioid receptors sit on peripheral sensory neurons and on immune cells such as keratinocytes, macrophages and T cells. Activating them inhibits itch-transmitting neurons and reduces release of pro-inflammatory cytokines.

Uraemic itch is thought to involve an imbalance between mu-opioid (pro-itch) and kappa-opioid (anti-itch) tone, along with inflammation and neuropathy; a peripheral kappa rebalances this without the risks of brain-acting opioids.

Because the molecule is excluded from the brain, the classic kappa side effects (dysphoria, hallucination, sedation) are largely absent, though dizziness and somnolence still occur more than with placebo.

A kappa-opioid agonist built to stay out of the brain: it carries charges that stop it crossing the blood-brain barrier. It acts on peripheral nerve endings and immune cells to relieve itch, without the sedation and dysphoria central kappa agonism causes.Schematic — not to scale

3What the research shows

Pruritus in haemodialysis patients

KALM-1 (378 patients, US) reported that 51% of difelikefalin-treated patients achieved at least a 3-point improvement on the 0–10 worst-itch scale at 12 weeks versus 28% with placebo (Fishbane 2020, NEJM). KALM-2 (473 patients, international) confirmed the result (54% vs 42%) †. Pooled analyses showed improvements in itch-related quality of life and sleep. Open-label extensions to 52 weeks showed sustained effect. [1]

Graded A (negative)

Oral difelikefalin for notalgia paresthetica

A Phase 2 trial of 2 mg twice daily reported a modest but significant itch reduction (Kim 2023, NEJM). The subsequent Phase 2/3 KOURAGE-1 Part A (2024) did not show a meaningful separation from placebo and the programme was halted. [3]

Graded A (negative/mixed)

Oral difelikefalin for atopic dermatitis and non-dialysis CKD

A Phase 2 in atopic dermatitis did not meet its primary endpoint overall, though a subgroup with moderate-to-severe itch and limited skin involvement appeared to respond; Phase 3 was not pursued. A Phase 2 in stage 3–5 CKD not on dialysis showed signals but was not advanced †.

Graded A (small)

Post-operative pain (IV)

Early Phase 2 trials after abdominal and bunion surgery showed pain reduction versus placebo, the original intended indication before the itch programme took priority (Menzaghi 2015 and related abstracts) †.

4Reported side effects and interactions

Literature-reported

Diarrhoea (around 9%), dizziness (7%), nausea, gait disturbance including falls (7%), hyperkalaemia, headache, somnolence and mental-status change. Falls and dizziness are the clinically important ones in a frail dialysis population. No evidence of euphoria, dependence or withdrawal; it is not a controlled substance in the US. Dialysis removes roughly 70–80% of the drug, which is why it is given after the session.

Community-reported

none documented.

Theoretical. additive sedation and dizziness with centrally acting drugs; kappa agonism could in principle cause diuresis (a known kappa effect) but this was not a clinical issue.

Interactions. no pharmacokinetic interactions established (not metabolised by CYP enzymes). The label advises caution with sedating antihistamines, opioids and other CNS depressants because of additive dizziness and somnolence.

Markers researchers commonly monitor

Per label and trial practice:

Marker	Why it's watched
Worst Itch Numeric Rating Scale (WI-NRS)	the primary efficacy measure; a 3-point drop on 0–10 is the standard responder threshold.
Serum potassium	hyperkalaemia was reported more often than placebo in a population already prone to it.
Falls and gait assessment	the main safety issue in dialysis patients.
Sleep quality (e.g. 5-D itch or Skindex-10)	secondary outcomes in trials.
Dialysis adequacy (Kt/V)	affects drug clearance; relevant to exposure.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Supplied as a ready-to-use solution (65 µg/1.3 mL vials); the dialysis nurse draws up a weight-based volume and injects it into the venous line of the dialysis circuit during or after rinse-back. No patient handling occurs and the calculator does not apply.

6Commonly studied alongside

Compared indirectly with gabapentin, pregabalin and nalfurafine (a non-peptide kappa agonist approved in Japan for the same indication). Studied alongside standard dialysis care, emollients and antihistamines. No research-peptide co-use is documented.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	FDA-approved August 2021 (Korsuva) for moderate-to-severe CKD-associated pruritus in adults on haemodialysis; not a controlled substance
European Union	EMA-authorised April 2022 (Kapruvia), same indication
United Kingdom	MHRA-licensed (Kapruvia); NICE recommended it in 2023 †
Australia	TGA-registered (Korsuva) †
South Africa	Not registered †
Sport (WADA)	Not prohibited; kappa agonists are not on the Prohibited List and the molecule has no central effect

8Open questions

Why oral difelikefalin failed in notalgia paresthetica after a positive Phase 2, and whether oral kappa agonism can work for any itch condition.
Benefit in peritoneal dialysis patients, who were not included in the pivotal trials.
Whether the itch improvement translates into mortality or hospitalisation benefit.

9References

1Fishbane S et al. (2020). A phase 3 trial of difelikefalin in hemodialysis patients with pruritus (KALM-1). NEJM. PubMed · DOI
2Wooldridge TD et al. (2020). Efficacy and safety of difelikefalin for moderate-to-severe CKD-associated pruritus: a global phase 3 study in hemodialysis patients (KALM-2). J Am Soc Nephrol (abstract) [verify full publication]. DOI
3Kim BS et al. (2023). Difelikefalin for the treatment of notalgia paresthetica. NEJM. PubMed
4Fishbane S et al. (2022). Safety and tolerability of difelikefalin for the treatment of moderate to severe pruritus in hemodialysis patients: pooled analysis from the phase 3 clinical trial program. Kidney Med [verify]. PubMed · DOI
5Deeks ED (2021). Difelikefalin: first approval. Drugs. PubMed · DOI
6Korsuva US prescribing information (2021, current); EMA Kapruvia EPAR (2022). PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

Not enough data yet. 0 of the 50 members needed have logged this compound for 4+ weeks. We don't show anything below 50, so no one can be identified.

11Page history

31 Oct 2026Profile published — awaiting medical review

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