Pruritus (Chronic Itch)
Persistent itching that significantly impacts quality of life. CKD-associated pruritus affects up to 40-70% of haemodialysis patients. Difelikefalin, a peripherally-restricted kappa opioid receptor agonist, is specifically approved for moderate-to-severe pruritus in adults on haemodialysis.
Technical Context
Pruritus is mediated by unmyelinated C-fibres (distinct from but overlapping with nociceptive C-fibres) expressing pruriceptors — receptors activated by histamine, proteases (PAR-2), cytokines (IL-31, IL-4, IL-13), neuropeptides (substance P, CGRP), bile acids, and opioids (mu-opioid agonists are pruritogenic; kappa-opioid agonists are antipruritic). Afferent signals travel via the spinothalamic tract to the thalamus and somatosensory cortex. CKD-associated pruritus affects 40-70% of haemodialysis patients and is associated with: uraemic toxin accumulation, immune dysregulation (micro-inflammation, elevated IL-31), altered opioid balance (relative mu-opioid excess/kappa-opioid deficit in skin), and neuropathy. Difelikefalin addresses the opioid imbalance mechanism: selective peripheral kappa-opioid receptor agonism restores the mu/kappa balance, reducing pruritogenic signalling without CNS effects. The KALM-1 and KALM-2 Phase III trials demonstrated significant improvement in itch intensity (Worst Itch NRS) and itch-related quality of life.