Advances in pruritus therapeutics: It’s Greek to us

By Warren R. Heymann, MD, FAAD
June 19, 2024
Vol. 6, No. 25

Every dermatologist encounters maddeningly pruritic patients at their wit’s end. Our deficient understanding of and treating dermatology’s essential symptom is even more exasperating. The following is the abstract from the incisive article by Vander Does et al, entitled “How to get rid of itching,” (1) which provides a succinct current overview of pruritus:

Itch is an unpleasant sensation arising from a variety of dermatologic, neuropathic, systemic, and psychogenic etiologies. Various itch pathways are implicated according to the underlying etiology. A variety of pruritogens, or itch mediators, as well as receptors have been identified and provide potential therapeutic targets. Recent research has primarily focused on targeting inflammatory cytokines and Janus kinase signaling, protease-activated receptors, substance P and neurokinin, transient receptor potential-vanilloid ion channels, Mas-related G-protein-coupled receptors (MRGPRX2 and MRGPRX4), the endogenous opioid and cannabinoid balance, and phosphodiesterase 4. Periostin, a newly identified pruritogen, should be further explored with clinical trials. Drugs targeting neural sensitization including the gabergic system and P2X3 are other potential drugs for chronic itch. There is a need for more targeted therapies to improve clinical outcomes and reduce side effects.

This commentary will focus on the opioid receptors mu and kappa. Kappa-opioid receptors (KORs) and mu-opioid receptors (MORs) have been implicated in suppressing and promoting itch, respectively, by acting on both the peripheral and central nervous systems. KOR agonism and MOR antagonism represent important mechanisms with the potential to suppress itch in the periphery, the spinal cord, and the brain. The mechanisms by which these agents modulate pathways to alleviate itch is actively being researched; there is evidence demonstrating that KORs have anti-inflammatory effects, possibly via downregulation of proinflammatory cytokine expression and release. (2) It should be noted that there are black box warnings for nalbuphine including risk of addiction, abuse, and misuse; respiratory depression; and risks from concomitant use with benzodiazepines and central nervous system depressants. There are no black box warnings for difelikefalin (DFK), according to ePocrates (accessed Oct. 1, 2023).

Nalbuphine is a kappa-opioid receptor agonist and a partial mu-opioid receptor antagonist. Nalbuphine is FDA-indicated for moderate to severe pain where the patient requires an opioid agent, and other alternative treatments have been insufficient. (3) Although studies have shown efficacy in itch associated with prurigo nodularis and chronic kidney disease (CKD) (1), this drug will not be discussed further in this commentary because pain is the only approved indication.

DFK (brand name Korsuva) is a KOR agonist whose intravenous use was approved in the U.S. in 2021 for treating moderate-to-severe pruritus in adults with CKD undergoing hemodialysis (HD). (4) This commentary concentrates on new studies exploring the use of oral DFK, notably for CKD, atopic dermatitis (AD), and notalgia paresthetica (NP). (The drug has also been studied in primary biliary cholangitis.) Please note that I have no conflict of interest regarding the development or use of DFK.

Yosipovitch et al evaluated DFK efficacy and safety in reducing itch in subjects with non-dialysis-dependent CKD and those undergoing HD in a phase 2, double-blind, randomized, placebo-controlled, dose-finding study. Non-dialysis-dependent CKD (stage 3-5) and HD subjects with moderate-to-severe pruritus were enrolled. Subjects were equally randomized to oral DFK (0.25, 0.5, or 1.0 mg) or placebo once daily for 12 weeks. The primary end point was the change in the weekly mean Worst Itching Intensity Numeric Rating Scale (WI-NRS) score at week 12. Two hundred sixty-nine subjects were randomized. DFK 1.0 mg significantly reduced weekly mean WI-NRS scores versus placebo at week 12 (P = .018), with numerical reductions observed with DFK 0.25 and 0.5 mg. At week 12, 38.6% of subjects receiving DFK 1.0 mg achieved a complete response (WI-NRS 0-1) versus 14.4% receiving placebo. DFK resulted in approximately 20% improvement in itch-related quality-of-life (QOL) measures. The most common treatment-emergent adverse events were dizziness, falls, constipation, diarrhea, gastroesophageal reflux disease, fatigue, hyperkalemia, hypertension, and urinary tract infection. The authors concluded that oral DFK significantly reduced itch intensity in stage 3-5 CKD and hemodialysis patients with moderate-to-severe pruritus, supporting the continued development of oral DFK for advanced CKD patients. (5)

Guttman-Yassky et al evaluated DFK on pruritus intensity and pruritus- and immune-related biomarkers in subjects with moderate to severe AD-related pruritus. They performed a phase 2 clinical trial investigating oral DFK 0.25, 0.5, and 1.0 mg efficacy and safety in subjects with moderate to severe AD-related pruritus. A biomarker substudy evaluated the effects of DFK on the expression of pruritus, TH2-associated genes, and skin barrier-related genes. In the clinical trial (N = 401), all DFK doses reduced itch versus placebo; however, the results were not statistically significant at week 12. In a subgroup of subjects in the trial with mild to moderate skin inflammation and moderate to severe itch (itch-dominant AD phenotype), DFK reduced itch at week 12 versus placebo. In the biomarker substudy, DFK downregulated the expression of key pruritus-related genes (e.g., IL-31 and TRPV1) and the AD phenotype (e.g., CCL17). Gene set variation analysis confirmed that DFK downregulated pruritus-related genes and TH2 pathways, but not placebo. DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism-associated genes. To summarize, DFK treatment reduced itch in subjects with moderate to severe AD-related pruritus, particularly those with an “itch-dominant” AD phenotype, and had an impact on the expression of pruritus, TH2-associated genes, and skin barrier-related genes. The authors concluded that DFK is a promising therapy for AD-related pruritus, warranting further clinical studies. (6)

Kim et al investigated the use of oral DFK for NP in a phase 2, double-blind, placebo-controlled trial, by randomly assigning, patients with moderate-to-severe pruritus caused by NP (n=62) to receive 2 mg of oral DFK or placebo (n=63) twice daily for 8 weeks. The primary outcome was the change from baseline at week 8 in the weekly mean score on the WI-NRS. Secondary clinical outcomes were itch-related QOL and itch-related sleep measures. Each group had a mean baseline WI-NRS score of 7.6 (indicating severe itch). The change from baseline in the weekly mean WI-NRS score at week 8 was -4.0 points in the DFK group and -2.4 points in the placebo group (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 DFK group than in the placebo group. The authors concluded that in patients with NP, oral treatment with DFK resulted in modestly greater reductions in itch intensity scores than placebo over a period of 8 weeks but was associated with adverse events. They suggest that larger and longer trials are needed to assess the efficacy and safety of DFK treatment in this disorder. (7)

Many pathways are worthy of exploration in treating pruritus, as noted in our DWI&I discussion of the anti-IL-31 antibody nemolizumab (8) scheduled for release in 2024. Further studies will determine if oral DFK will follow in nemolizumab’s footsteps. We are all itching to know (you knew I couldn’t resist)!

Point to Remember: Recent studies on the oral kappa-opioid receptor difelikefalin demonstrate benefit in treating pruritus in several dermatoses such as atopic dermatitis, notalgia paresthetica, and chronic kidney disease. More extensive studies are warranted to determine if the drug earns a respected role in our therapeutic armamentarium in battling pruritus.

Our experts’ viewpoints

Gil Yosipovitch, MD, FAAD
Professor, Stiefel Chair of Medical Dermatology
Director Miami Itch Center
Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery
Miller School of Medicine, University of Miami

Kappa opioids difelikafelin and nalfurafine (available only in Japan and Korea) and kappa opioids with mu antagonism such as nalbuphine or butorphanol share rapid effective treatment for chronic severe itch of different etiologies by primarily targeting the neural system, thereby reducing neural sensitization of itch. I doubt that their anti-pruritic effect in inflammatory skin diseases such as eczema would be as robust as targeted anti-cytokine drugs. Nevertheless, these drugs will add to our treatment armamentarium especially with the hopeful approvals of the oral formulations. Their adverse effects are mainly mild, affecting the central nervous system (dizziness) and the GI tract (diarrhea). Dermatologists concerned about the addictive potential of these opioids should be assured that these classes of medications have minimal or no abuse potential. Although butorphanol, a mixed kappa agonist and mu antagonist, has been classified as a class IV-controlled substance, Nalbuphine, which has similar properties, is not categorized as a controlled substance. In my experience of using butorphanol for more than 20 years I rarely experienced any abuse potential, although there are limited reports in the literature. All told, I am looking forward to seeing these medications made available for relief of many types of chronic itchy conditions.

Brian S. Kim, MD, MTR, FAAD
Vice Chair of Research, Icahn School of Medicine
Director, Mark Lebwohl Center for Neuroinflammation and Sensation
Mount Sinai Health System

The efficacy of kappa agonists such as difelikefalin and nalbuphine (also a mu antagonist), along with the historical use of butorphanol (a mixed kappa agonist/mu antagonist, pioneered by Gil Yosipovitch) for pruritus, strongly support these pathways as targets in pruritus. In addition to validation across multiple small molecule entities, they have demonstrated efficacy or potential utility across several indications including atopic dermatitis, notalgia paresthetica, prurigo nodularis, and uremic pruritus in the setting of dialysis. Further, these medications have been used across a number of routes of delivery including intravenous, oral, and intranasal. Taken together, kappa agonists, alone or in combination with mu antagonism, are a highly promising class of anti-pruritic therapeutics with the potential for broad efficacy. Regarding addictive potential for difelikefalin, studies have shown low potential for abuse. Further, this pathway is known for dysphoria centrally, not the euphoria of mu agonists such as morphine.

1. Vander Does A, Ju T, Mohsin N, Chopra D, Yosipovitch G. How to get rid of itching. Pharmacol Ther. 2023 Mar;243:108355. doi: 10.1016/j.pharmthera.2023.108355. Epub 2023 Feb 3. PMID: 36739914.

2. Kim BS, Inan S, Ständer S, Sciascia T, Szepietowski JC, Yosipovitch G. Role of kappa-opioid and mu-opioid receptors in pruritus: Peripheral and central itch circuits. Exp Dermatol. 2022 Dec;31(12):1900-1907. doi: 10.1111/exd.14669. Epub 2022 Sep 23. PMID: 36054458; PMCID: PMC10087456.

3. Larsen D, Maani CV. Nalbuphine. 2023 May 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30484997.

4. Deeks ED. Difelikefalin: First Approval. Drugs. 2021 Nov;81(16):1937-1944. doi: 10.1007/s40265-021-01619-6. PMID: 34674115.

5. Yosipovitch G, Awad A, Spencer RH, Munera C, Menzaghi F. A phase 2 study of oral difelikefalin in subjects with chronic kidney disease and moderate-to-severe pruritus. J Am Acad Dermatol. 2023 Aug;89(2):261-268. doi: 10.1016/j.jaad.2023.03.051. Epub 2023 Apr 12. PMID: 37059302.

6. Guttman-Yassky E, Facheris P, Da Rosa JC, Rothenberg-Lausell C, Del Duca E, David E, Estrada Y, Liu Y, Bose S, Chowdhury M, Munera C, Goncalves J, Nograles K, Kim BS, Lebwohl M. Oral difelikefalin reduces moderate to severe pruritus and expression of pruritic and inflammatory biomarkers in subjects with atopic dermatitis. J Allergy Clin Immunol. 2023 Jul 13:S0091-6749(23)00888-6. doi: 10.1016/j.jaci.2023.06.023. Epub ahead of print. PMID: 37453614.

7. Kim BS, Bissonnette R, Nograles K, Munera C, Shah N, Jebara A, Cirulli J, Goncalves J, Lebwohl M; KOMFORT Trial Investigators. Phase 2 Trial of Difelikefalin in Notalgia Paresthetica. N Engl J Med. 2023 Feb 9;388(6):511-517. doi: 10.1056/NEJMoa2210699. PMID: 36780675.

8. Kim BS in Heymann WR. The 2020 vision for nemolizumab in atopic dermatitis. Dermatology World Insights and Inquiries. 2020, vol 2, no 10. https://staging.aad.org/dw/dw-insights-and-inquiries/2020-archive/march/nemolizumab-in-atopic-dermatitis

---