By Mary Beth Nierengarten
March 16, 2023
The Science Explained Article In Brief A new study study found that difelikefalin reduced the intensity of pruritis in patients with notalgia paresthetica, but it did have some adverse events. The study author suggests the therapy could be used for other neuropathies that include less severe burning and stinging.
A new agent modestly reduced the intensity of itchiness in patients with notalgia pasethical, but it also was associated with adverse events including headache, dizziness, constipation, and increased urine output, according to a phase 2 study in the Feb. 9 New England Journal of Medicine .
The study looked at the efficacy and safety of difelikefalin to reduce itch in patients with moderate to severe pruritis caused by notalgia paresthetica, a condition characterized by overactive nerves in the skin on the upper back that leads to chronic itch.
Difelikefalin is a selective kappa opioid receptor agonist that has shown efficacy for treating pruritus in other conditions. It was approved in 2021 for intravenous use for moderate-to-severe pruritis in adults undergoing hemodialysis, and phase 2 trials have shown its efficacy as an oral agent to treat pruritis in patients with chronic kidney disease and those with atopic dermatitis.
The lead study author, Brian S. Kim, MD, director of the Mark Lebwohl Center for Neuroinflammation and Sensation and director of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, said the results show that notalgia paresthetica can be treated and offer hope that it will be approved as the first therapy for this condition.
He underscored the importance of this for patients, particularly since many are unlikely to even know that notalgia paresthetica is a clear diagnosis.
Although the study only looked at patients with moderate to severe cases, he said patients with mild notalgia paresthetica likely also would respond to difelikefalin. He cautioned, however, about the potential limitations of the drug for some patients.
“Patients who have side effects from the medication may have to come off of it,” he said.
Study Details The double-blind, placebo-controlled trial included 126 patients from 28 cites in North America enrolled between February 2021 and March 2022. The patients, aged 18 to 80 years, had at least a six-month history of chronic pruritus caused by notalgia paresthetica and were considered candidates for systemic therapy. At baseline, all patients had moderate to severe itching with a score of 5.0 or higher on the Worst Itch Numeric Rating Scale (WI-NRS). At baseline, the mean WI-NRS score was 7.6, indicating severe itch.
“Larger and longer studies are needed to further demonstrate difelikefalin safety and efficacy in this patient population.”—DR. ELINA ZAKIN
“Although it was shown to be slightly better than placebo, the side effect profile may preclude widespread adoption of difelikefalin.”—DR. AHMET HOKE
Patients were randomized to difelikefalin 2 mg (n=62) or placebo (n=63) and treated twice daily for eight weeks. No topical agents affecting pruritus were permitted.
The primary endpoint of the study was the change from baseline at week eight in the weekly mean of the daily WI-NRS scales: scores range from zero to 10 (no itch to worst itch). Secondary outcomes looked at itch-related sleep and quality-of-life measures.
At eight weeks, patients treated with difelikefalin showed a modest but significant reduction in itch compared to patients in the placebo group (p =0.001). No significant differences between the two groups were found in measures for sleep and quality of life.
Patients in the difelikefalin group experienced more mild to moderate adverse events—headache, dizziness, constipation, and increased urine output—than the placebo group (56 vs. 51 percent). Adverse events reported in both groups included nausea and abdominal pain. Twelve patients (19 percent) in the difelikefalin group discontinued the trial most often because of dizziness, nausea, and abdominal pain.
Dr. Kim said the results suggest that difelikefalin could be used for other neuropathies that include burning and stinging, but it probably would be used less for conditions with more severe pain. He said the contraindications for severe pain are unclear, but he suspected it could counteract the effects of narcotics, such as morphine and opioids.
A phase 3 trial is in the works, he said.
Experts Weigh In Elina Zakin, MD, assistant professor of neurology at the NYU Grossman School of Medicine, said having several therapeutic avenues to offer patients is crucial. “Improving the quantity of options we provide to our patients as we counsel them about the management of their neuropathic pain and symptoms in general is very important,” she said, adding that a multimodal approach is generally required to manage these conditions.
Dr. Zakin noted the intensity of symptoms was reduced in patients treated with difelikefalin, but it also increased the chance of side effects. As with all treatments, she said, it is paramount for clinicians to discuss side effect profiles with their patients.
When discussing the current study, Dr. Zakin also said clinicians should talk to patients about the study's limitations, including the small sample size and relatively short follow-up period.
“Larger and longer studies are needed to further demonstrate difelikefalin safety and efficacy in this patient population,” she said.
Ahmet Hoke, MD, PhD, FAAN, professor of neurology and neuroscience and director of the Merkin Peripheral Neuropathy and Nerve Regeneration Center at Johns Hopkins School of Medicine, underscored the need for new medications to treat bothersome symptoms of peripheral neuropathies, such as itch and pain, but said he “isn't sure if difelikefalin is that medication.”
“Although it was shown to be slightly better than placebo, the side effect profile may preclude widespread adoption of difelikefalin,” he said, noting that dizziness and nausea were among the main reasons why some patients treated with difelikefalin quit the trial.
Further limiting the widespread use of difelikefalin, according to Dr. Hoke, is the fact that itch, although debilitating, is not common in most peripheral neuropathies, such as diabetic peripheral neuropathy. Medications such as gabapentinoids and some anti-depressants to treat these other types of neuropathic pain and discomfort work well in up to 60 to 70 percent of people, although the side effects of these drugs also limit widespread use.
“The need for a selective kappa opioid receptor agonist to block the itch receptors is limited in most peripheral neuropathies,” he said.
