Over an 8-week period, treatment with oral difelikefalin leads to modest itch reduction in patients with notalgia paresthetica, according to study findings published in The New England Journal of Medicine.
Notalgia paresthetica, a neuropathic itch disorder, is thought to be caused by damage to thoracic spinal nerves and is resistant to many traditional antipruritic therapies. Difelikefalin is a selective kappa opioid receptor agonist, which had been associated with itch suppression in itch involving peripheral sensory neurons. Currently, difelikefalin is approved by the US Food and Drug Administration (FDA) as an injection for the treatment of moderate to severe itch in adults with kidney disease, undergoing hemodialysis.
For the study, researchers sought to assess the efficacy of difelikefalin for the treatment of notalgia paresthetica.
They conducted a randomized, double-blind, placebo-controlled trial (KOMFORT; ClinicalTrials.gov Identifier: NCT04706975) at 28 sites in North America. Patients (N=126) with notalgia paresthetica were randomly assigned in a 1:1 ratio to receive 2 mg oral difelikefalin (n=62) or placebo (n=63) twice daily for 8 weeks following a 2-week run-in period. Prior to the first dose of difelikefalin, 1 patient withdrew consent. After the active treatment phase, patients could continue or switch to difelikefalin for 4 weeks during an open-label extension period.
The primary efficacy outcome was daily 24-hour Worst Itch Numeric Rating Scale (WI-NRS) score from 0-10 with 0 classified as “no itch” and 10 classified as “worst itch imaginable.”
Secondary outcomes were itch-related quality of life and itch-related sleep measures.
Recipients of difelikefalin and placebo recipients had the following characteristics:
- mean age 59.3±12.4 and 60.2±11.8 years;
- 77% and 67% were women;
- 79% and 89% were White;
- they had body mass indexes (BMIs) of 29.7±5.8 and 28.7±5.2 kg/m2;
- they had been experiencing notalgia paresthetica symptoms for 8.9±10.4 and 8.2±7.4 years; and
- WI-NRS scores were 7.6±1.4 and 7.6±1.4 points at baseline, respectively.
Between baseline and week 8, the least-squares mean difference (LSMD) in WI-NRS scores were -4.0 points among difelikefalin recipients compared with -2.4 points among placebo recipients. These group changes were significantly different, favoring difelikefalin (LSMD, -1.6; 95% CI, -2.6 to -0.6 points; P =.001).
No significant group differences in the change in Skindex-ten scores (LSMD, -1.4; 95% CI, -6.7 to 3.9) or Sleep Disturbance scores (LSMD, 0.6; 95% CI, -6.6 to 7.7) were observed.
Discontinuation prior to week 8 occurred among 14 difelikefalin and 6 placebo recipients and 48 from the difelikefalin and 55 from the placebo groups entered the open-label extension period.
The rates of adverse events were 56% among the difelikefalin group compared with 51% among the placebo group. The most common adverse events in the difelikefalin cohort were nausea (13%), abdominal pain (11%), headache (11%), dizziness (11%), constipation (10%), and increased urine output (8%). No laboratory, electrocardiographic, or vital sign abnormalities were observed during this study.
The major limitation of this study was the short duration.
Researchers noted that over an 8-week period, compared with placebo, treatment with difelikefalin led to a modestly greater reduction in itch intensity in patients with notalgia paresthetica.
“Larger and longer trials are required to determine the effect and risks of difelikefalin treatment in this disorder,” they concluded.
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Kim BS, Bissonnette R, Nograles K, et al. Phase 2 trial of difelikefalin in notalgia paresthetica. N Engl J Med. Published online February 9, 2023. doi:10.1056/NEJMoa2210699