Oral Drug Shows Benefit for Notalgia Paresthetica in Mid-Stage Trial

A selective kappa opioid receptor agonist in patients with notalgia paresthetica led to "modestly" greater improvements in itchiness over placebo, but was associated with adverse events, a randomized phase II trial showed.

At 8 weeks, improvements in average itchiness was significantly greater with oral difelikefalin (Korsuva) versus placebo on the Worst Itch Numeric Rating Scale (WI-NRS), a 0-to-10 scale that ranges from no itch to worst itch imaginable.

On average, patients on difelikefalin -- which is currently approved as an injection for chronic kidney disease (CKD)-associated pruritus -- experienced 4-point reductions in WI-NRS scores, as compared with 2.4-point reductions with placebo (P=0.001), reported Brian Kim, MD, MTR, of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues.

Yet secondary clinical outcomes including itch-related quality-of-life and sleep measures "generally did not support those of the primary analysis," the group wrote in the New England Journal of Medicine.

Three times as many patients discontinued difelikefalin due to adverse events (AEs) compared with placebo (19% vs 6%). Overall, AEs were reported in 56% of participants in the difelikefalin group and 51% of the control group, with dizziness, constipation, urine output, and headaches being more common with difelikefalin.

"Larger and longer trials are required to determine the effect and risks of difelikefalin treatment in this disorder," the group concluded.

Notalgia paresthetica is a neuropathic disorder characterized by pruritus in a circumscribed region of the upper back.

"It has been speculated that notalgia paresthetica is caused by damage to the cutaneous branches of the dorsal rami of the thoracic spinal nerves," Kim and colleagues explained. "Excessive scratching often leads to pigmentary changes or lichenification of the area. The condition is resistant to numerous treatments. Traditional antipruritic therapies such as antihistamines and topical glucocorticoids have been ineffective. Neuromodulators such as topical capsaicin or gabapentinoids may have some value in reducing symptoms, but side effects may reduce adherence."

Currently, no treatments are approved specifically for the condition.

"For those who experience chronic itch of any kind, relief can sometimes seem unattainable," Kim said in a news release. "The encouraging results achieved in this trial could reenergize the field and mark an important step toward improving symptoms of itch for patients with notalgia paresthetica."

The phase II study included 125 adults with notalgia paresthetica enrolled at 28 sites in North America. They were randomized 1:1 to difelikefalin (2 mg) or matching placebo twice daily for 8 weeks. Patients had an average age of 60 years.

In order to be included in the study, patients needed to report experiencing chronic pruritus as a result of their notalgia paresthetica for at least 6 months prior to enrollment, and had to be experiencing a baseline level of pruritus categorized as moderate to severe, representing WI-NRS scores of 5 points or above. In the study, the mean duration of notalgia paresthetica was more than 8 years.

More than 80% of the patients were white, and more than 70% were women. The researchers said an imbalance in the number of Black patients between groups (16% for the study group vs 6% for the placebo group) resulted by chance.

Mean baseline WI-NRS scores were 7.6 in each group, with most patients categorized as having severe itch. Baseline Skindex-10 scores were 38.6 on the 0-to-60 scale for both groups, and mean scores on the 100-point Sleep Disturbance Subscale were 40.3 in the study arm and 38.7 in the placebo arm.

For secondary outcomes, no significant differences were seen in average change from baseline to week 8 in the Skindex-10 total score between the difelikefalin and placebo groups (-20.1 vs -18.7 points). Similar reductions on the Sleep Disturbance Subscale were also observed for both groups at week 8 (-15.7 vs -16.3, respectively).

Kim and his fellow researchers noted, however, that Skindex-10 has not been validated in this patient population, and that while many chronic pruritic conditions are associated with poor sleep, sleep was not greatly impaired at baseline in the trial, a finding "consistent with results of a 2020 report, which suggested that itch associated with notalgia paresthetica occurs more often during the daytime than at night."

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