• Brian S Kim, Robert Bissonnette, Kristine Nograles, Catherine Munera, Nilam Shah, Alia Jebara, Joshua Cirulli, Joana Goncalves, Mark Lebwohl, and KOMFORT Trial Investigators.
• From the Kimberly and Eric J. Waldman Department of Dermatology (B.S.K., M.L.), the Mark Lebwohl Center for Neuroinflammation and Sensation (B.S.K.), the Marc and Jennifer Lipschultz Precision Immunology Institute (B.S.K.), and the Friedman Brain Institute (B.S.K.), Icahn School of Medicine at Mount Sinai, New York; Innovaderm Research, Montreal (R.B.); and Cara Therapeutics, Stamford, CT (K.N., C.M., N.S., A.J., J.C., J.G.).
• N. Engl. J. Med. 2023 Feb 9; 388 (6): 511517511-517.

BackgroundNotalgia paresthetica is a neuropathic disorder characterized by pruritus in a circumscribed region of the upper back. Difelikefalin, a selective kappa opioid receptor agonist, has shown efficacy in other chronic pruritic conditions and is being investigated for the treatment of notalgia paresthetica.MethodsIn this phase 2, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, patients with moderate-to-severe pruritus caused by notalgia paresthetica to receive 2 mg of oral difelikefalin or placebo twice daily for 8 weeks. The primary outcome was the change from baseline at week 8 in the weekly mean score on the daily Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). The secondary clinical outcomes were itch-related quality-of-life and itch-related sleep measures.ResultsA total of 126 patients were enrolled; 62 patients were assigned to receive difelikefalin, and 63 were assigned to receive placebo. One patient who had been assigned to receive difelikefalin withdrew consent before the first dose and is not included in the main analyses. The mean baseline WI-NRS score was 7.6 (indicating severe itch) in each group. The change from baseline in the weekly mean WI-NRS score at week 8 was -4.0 points in the difelikefalin group and -2.4 points in the placebo group (difference in change, -1.6 points; 95% confidence interval, -2.6 to -0.6; P = 0.001). The results for the secondary outcomes generally did not support those of the primary analysis. Headache, dizziness, constipation, and increased urine output occurred more frequently in the difelikefalin group than in the placebo group.ConclusionsAmong patients with notalgia paresthetica, oral treatment with difelikefalin resulted in modestly greater reductions in itch intensity scores than placebo over a period of 8 weeks but was associated with adverse events. Larger and longer trials are needed to assess the efficacy and safety of difelikefalin treatment in this disorder. (Funded by Cara Therapeutics; KOMFORT ClinicalTrials.gov number, NCT04706975.).Copyright © 2023 Massachusetts Medical Society.

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