Oral Difelikefalin for Notalgia Paresthetica: What Happened After KOMFORT?

An early study of oral difelikefalin reduced itch scores in diagnosed notalgia paresthetica. Its later development program stopped after a larger dose-finding study reported no meaningful benefit over placebo.¹²

What did KOMFORT find?

The 2023 phase-two trial tested 2 mg twice daily for eight weeks. 125 adults received treatment, 62 taking difelikefalin and 63 placebo; another randomized participant withdrew before dosing.¹

The primary measure was the weekly average of daily worst-itch ratings, on a 0–10 scale. Scores fell 4.0 points versus 2.4: adjusted difference −1.6 points (95% confidence interval −2.6 to −0.6).¹

Missing week-eight ratings in 14 versus eight participants were imputed statistically, assuming missingness could be explained by observed data. Sleep and itch-related quality-of-life results did not establish a corresponding advantage. Adverse events caused treatment discontinuation in 12/62 versus 4/63. Cara funded and analyzed the trial; several authors were company employees.¹

What happened in the later study?

KOURAGE-1 Part A randomized 214 adults to 0.25, 1 or 2 mg twice daily, or placebo, for eight weeks. Its primary endpoint was the proportion achieving at least a four-point improvement in weekly itch ratings, rather than the first trial’s average change.²³

On June 12, 2024, Cara reported no meaningful clinical benefit at any dose and announced that it would discontinue the notalgia program. This was a company announcement filed with the SEC², not a peer-reviewed full trial report. It did not provide group response rates or confidence intervals.²

The registry records the study as terminated for that reason, with no posted results tables.³

Isn’t difelikefalin already approved?

The current US KORSUVA label, revised July 2025, covers an intravenous injection for moderate-to-severe kidney-disease-associated itch in adults undergoing hemodialysis. Administration is through the dialysis circuit at the end of a session.⁴

That approval does not cover an oral tablet for notalgia paresthetica. Route, dose and diagnosis belong in the prescription discussion; an injection’s approval cannot substitute for evidence supporting a different formulation and condition.⁴

What can you bring to a review?

Bring the actual study name or dated headline, alongside a list of treatments you have tried and why each stopped. Note changes in itch, sleep and daily activities separately. Ask: “Does newer evidence change what you would recommend for my diagnosed condition?”

“Your First Thirty Days, and the Next Twelve Weeks” in Skin, Head to Toe includes a dated treatment-and-reaction log and puts a clinician’s plan first. Use that record for the appointment; its skin-care calendar is not a schedule for trying an experimental medicine.