Difelikefalin is a synthetic D-amino acid tetrapeptide (MW ~714.9 g/mol) that acts as a selective peripheral kappa-opioid receptor (KOR) agonist. It was FDA-approved in August 2021 (Korsuva) for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis. Difelikefalin was specifically designed to not cross the blood-brain barrier, thereby providing peripheral kappa-opioid agonism without the central dysphoric and psychotomimetic effects associated with centrally acting kappa agonists.
Category: Pain / Kappa-Opioid Agonist. Evidence rating: A (strong human clinical data).
Clinical status: FDA-approved (Korsuva for CKD-associated pruritus in hemodialysis patients, August 2021)
Difelikefalin selectively activates kappa-opioid receptors (KOR) on peripheral sensory neurons, immune cells, and keratinocytes. Peripheral KOR activation on sensory neurons inhibits the release of pruritogenic neuropeptides (substance P, CGRP) and reduces neuronal excitability through…
Safety considerations: Common (>=5%): diarrhea (9%), dizziness (7%), nausea (5%), gait disturbances (3%), hyperkalemia, mental status changes; Dizziness and somnolence are the most common CNS-related events but are generally mild; may be related to peripheral vestibular effects rather than central penetration; No evidence of abuse potential, physical dependence, or withdrawal symptoms; not a scheduled controlled substance.
Reviewed by the PeptideAtlas Editorial Team.
| Molecular weight | ~714.9 g/mol |
|---|---|
| CAS number | 1024828-77-0 |
| Half-life | ~23-31 hours (hemodialysis patients) |
| Bioavailability | 100% (intravenous) |
| Production method | synthetic |
| Anti-doping status | not-listed |
| US regulatory status | FDA-approved (Korsuva, August 2021) for moderate-to-severe CKD-associated pruritus in adults undergoing hemodialysis. Not a controlled substance. |
Difelikefalin is designed to not cross the blood-brain barrier. It is composed of D-amino acids making it highly hydrophilic and resistant to transport across the BBB. This means it activates kappa-opioid receptors only in the periphery, avoiding the central dysphoric, psychotomimetic, and addictive effects associated with centrally acting opioids.
Currently, difelikefalin is only approved for CKD-associated pruritus in hemodialysis patients. Clinical trials are investigating oral formulations for other pruritic conditions including atopic dermatitis and primary biliary cholangitis, but these are not yet approved indications.
Difelikefalin (0.5 mcg/kg) is given as an intravenous bolus injection into the venous line of the dialysis circuit at the end of each hemodialysis session (3 times per week). It is administered by a healthcare provider, not self-injected.