Itching for More: Treatment Options Continue to Expand for Itch and Pain

Gil Yosipovitch, MD, remembers a time when he could almost count on one hand the number of dermatologists who were willing to work on itch. 

“The majority were not interested in that field,” Yosipovitch said. “I was preaching to an empty crowd.” 

The first World Congress on Itch in 2001 drew approximately 80 people. Yosipovitch, a professor of dermatology at the University of Miami Miller School of Medicine, recalls half-empty rooms for courses on itch American Academy of Dermatology (AAD) meetings. Now, those courses have people outside waiting to get in. Last November’s World Congress on Itch drew 500 attendees. 

“I’m not alone anymore because the field has gotten recognition,” Yosipovitch said. “The FDA understands, and industry understands. There is a need.”

That need, of course, translates to immense growth potential in the field of dermatology.

“To put it in perspective, psoriasis has approximately a 1% incidence and currently comprises about a $28 billion market,” Brian S. Kim, MD, MTR, FAAD, vice chair of research for the Icahn School of Medicine at Mount Sinai’s Department of Dermatology, told Practical Dermatology. “Itch can result from dozens of conditions, so the incidence is much, much higher. You can only imagine how big the frontier of itch is, and we have finally woken up to it.”

Indeed, Yosipovitch and colleagues studied 50,552 individuals from 20 countries last year and reported the worldwide prevalence of pruritus to be 39.8%.¹ This figure was surprising to Yosipovitch.

Of course, itch and pain often go hand in hand, so while itch may be receiving more attention, much of the work being done in that area likely will generate positive solutions for pain as well. 

“The dogma was once that if you have itch, you cannot have pain because two sensory modalities, in the same period of time, would inhibit one another,” Yosipovitch said. “Now, we know that is incorrect. We better understand the concept of neurosensitization, its impact on chronic itch conditions where the narrow system is overactive, and the subsequent potential for certain types of drugs to work on both itch and pain.”

THE LATEST

The US Food and Drug Administration (FDA) approval this summer of injectable nemolizumab for treatment of adults with prurigo nodularis was a major step forward in the world of itch. Nemolizumab is the first approved monoclonal antibody specifically inhibiting the signaling of IL-31.² Kim said it is a positive progression that builds on the success of dupilumab and JAK inhibitors such as ruxolitinib. 

“Several years ago, IL-31 was the first cytokine that really opened up the field of itch as a neuroimmune disorder, meaning that immune factors can cause itch directly,” he said. “We refer to IL-31 as the first pruritogen. We now finally have a drug entering the clinic for it. It is not just an anti-inflammatory drug; it is really a true anti-itch drug, blocking itch at the neuroimmune interface.” 

Nemolizumab also has been studied for the treatment of atopic dermatitis, with promising results that could lead to another FDA approval.³

For their part, JAK inhibitors have demonstrated considerable itch reduction in various dermatological diseases in a relatively short time compared with conventional pruritus treatments.⁴ Unlike steroids, Kim explained, topical JAK inhibitors such as ruxolitinib restore the health of the skin 

“There is no topical JAK inhibitor resistance or rebound because the skin becomes much more resistant to subsequent inflammation,” he said.

Ruxolitinib 1.5% cream is FDA-approved for short-term and non-continuous treatment of mild-to-moderate atopic dermatitis in non-immunocompromised patients aged 12 years and older for whom the disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.⁵ In studies, it has demonstrated rapid improvement in itch in patients with mild-to-moderate atopic dermatitis, a benefit that was sustained for 8 weeks.⁶

Other topical JAK inhibitors that have been used for itch relief in atopic dermatitis, psoriasis, and other diseases include tofacitinib (FDA approved only for ulcerative colitis and three types of arthritis) and delgocitinib (approved for inflammatory skin conditions in Japan).⁴ Oral JAK inhibitors for itch relief include abrocitinib and upadacitinib, both of which are FDA approved for treatment of atopic dermatitis.⁴

“Clinical trial data on upadacitinib, including head-to-head trials showing its superiority over dupilumab,⁷ demonstrate that upadacitinib has a remarkable ability to significantly reduce itch in patients with moderate-to-severe atopic dermatitis,” Christopher Bunick, MD, FAAD, an associate professor of dermatology at Yale School of Medicine, told Practical Dermatology. “This itch reduction is often very quick in onset, within hours to days, and long-term data show itch reduction is sustained over time. The recent LEVEL-UP trial results for period 1, using the stringent composite EASI-90 plus itch NRS 0/1 endpoint, reinforced the superiority of upadacitinib in clearing skin and reducing itch burden in atopic dermatitis patients.”

While Kim noted that the TYK2 pathway is not a proven itch target in the way that JAK1 is, the TYK2 inhibitor deucravacitinib may impact itch.

“Recent published data from phase 3 POETYK trials on deucravacitinib showed it is effective in reducing itch in psoriasis patients, often beginning in just 1 to 2 weeks; this itch reduction is reflected in PSSD symptom score improvements,” Bunick noted.⁸

The IL-4 and IL-13 antagonist dupilumab, meanwhile, has been FDA approved for atopic dermatitis since 2017, and it was approved for treating prurigo nodularis in 2022.⁹ Its success in reducing pruritus in atopic dermatitis has generated interest regarding its potential application in various other pruritic conditions.¹⁰

Another systemic drug that could be approved soon for treatment of atopic dermatitis is lebrikizumab. 

“That will work extremely well, and I suspect off-label use would be affected,” Yosipovitch said. Other important potential upcoming approvals could include dupilumab for treatment of chronic pruritus of unknown origin and the BTK inhibitor remibrutinib for treatment of chronic spontaneous urticaria.

“Remibrutinib probably does not directly target the nervous system in the way that some of these other drugs do,” Kim said, “but it definitely targets the mast cell, which is almost the next-best thing in many ways for itch. It will definitely be important for chronic urticaria and potentially for other conditions as well.” 

Yosipovitch concurred that this approach could help with other types of chronic itch, noting that remibrutinib is just the beginning of a new area of treatments in development for chronic itch targeting. 

 “The field is hot, and a better understanding of what is occurring mechanistically is leading to new developments,” he added, explaining that 

the FDA approvals of topical roflumilast for the treatment of atopic dermatitis, seborrheic dermatitis, and plaque psoriasis were important milestones as well. 

“There has always been an unmet need for topical therapies for itch,” Yosipovitch said. “The addition of roflumilast to the armamentarium provides a strong alternative to good old topical steroids.”

Opioid agonists and antagonists are another drug area developing therapies for itch. Yosipovitch and Kim both agreed that kappa opioid receptors have shown promise, despite an oral formulation of difelikefalin failing in its phase 3 trials. 

“I believe difelikefalin really works, but patients unfortunately will not see that drug,” Kim said. Still, researchers remain interested in developing other drugs to agonize kappa opioid receptors. 

“The idea of inhibiting the narrow system via kappa opioids is a valid and clear target,” Yosipovitch said. “There are two pathways of itch in different diseases: a narrow immune pathway, and a pathway targeting the nerves. The nerves transmit itch. We are a bit behind there, however, and drug development takes time.”

Several other drugs targeting different treatment pathways itch are in the pipeline. Kim mentioned one drug that blocks both IL-31 and IL-13, and another that has both an IL-4 receptor and IL-31 blocker. Yosipovitch noted the development of a drug that targets the G-protein coupled receptor MRGPRX2. 

“Transcriptomic studies indicate that this receptor is highly expressed in patients with chronic itch, so that drug is exciting,” he said. “It is undergoing clinical trials for chronic spontaneous urticaria and most probably will be studied for other conditions as well.”

STEROIDS

Traditional steroids still impact itch to a certain degree, even if opinions regarding their utilization vary. 

Yosipovitch still prescribes steroids and says resistance is not as common as some may think, though there are other drawbacks. 

“Applying steroids all over the body is difficult when there is extensive involvement,” he said. “Additionally, steroids sometimes have significant side effects, so you need to be very careful. You cannot put a high-potency steroid on the face, even if it’s very itchy.”

Kim once was a proponent of steroids but said he view has changed significantly. 

“I have come to the conclusion that topical steroids are almost invariably iatrogenic to some degree,” he explained. “We were always selecting the lesser evil. Steroids are potently anti-inflammatory, but they also potently have adverse effects on many cell types. They thin your skin and cause your blood vessels to dilate and pop out, both of which are very much counterproductive in the long term to controlling inflammation. I’m not so sure that steroid resistance is even what is really happening in many cases; I think the adverse effects of steroids on the skin make it more susceptible to inflammation in the future. Steroids have been the main weapon for dermatologists and still are. I used to think steroids were benign if used sparingly and dangerous if misused. Now, I think it’s a spectrum with a very narrow benign window, if any I’m not so sure it’s ever truly benign.”

OTHER SOLUTIONS

Not all traditional treatments are obsolete, of course. Matthew Zirwas, MD, founder of the Bexley Dermatology Research Clinic, said the most underutilized drug for itch is oral mirtazapine, perhaps because it is better known as an anti-depressant. 

“I explain to patients, ‘you are not depressed,’” Zirwas told Practical Dermatology. “We are not treating depression. This drug works for depression because it helps nerve endings work better in people’s brains. You have a problem with the nerve endings in your skin, and it is going to help those nerve endings to work better as well.’”

Yosipovitch said that compounding treatments is another strategy. He has published research, for example, on a combination of topical ketamine-amitriptyline-lidocaine for chronic pruritus.¹¹ “That is the most robust treatment that I give for itch,” he said, “because it really numbs the skin for hours.”

One itch treatment that is rising in popularity is an over-the-counter, topical, strontium-based serum that recently became available in a formulation specifically intended for scalp use. “It is really effective for neuropathic itch—brachioradial pruritus, lichen amyloidosis, notalgia paresthetica,” Zirwas said.

Yosipovitch also has found success using silicone-based creams, among other options. “As dermatologists, we need to be open-minded and explore new things for our patients,” he said. “I am always in a learning process because I believe that is the way we can advance treatments. I am very hopeful that there are many new pathways to target itch beyond just the immune system.”

MECHANISM

Understanding the mechanisms of itch has been critical in developing many of these solutions. Researchers have only scratched the surface in terms of utilizing genetics to address itch, but already the vast potential can be seen. 

“Itch, as a symptom, has not really been explored in terms of genetic studies,” Kim said. “Genetic studies typically screen for mutations associated with dementia or cardiovascular disease, for example, and then researchers find correlations. Itch, however, is not something that has really been tracked. People have asked, ‘If itch is so important, why have we not found any mutations that cause it?’ That is a backward question; because itch was not considered important to begin with, we could not find any mutations for it. You need to have those clinical data in your sets, otherwise, you cannot correlate them to mutations.” 

The other issue, Kim said, is that most genetic studies are biased toward loss of function. 

Progress has been made, however. Yosipovitch and colleagues earlier this year published a study identifying the key role of B-type natriuretic peptide (BNP) in chronic itch severity and identifying certain types of itch through blood testing.¹² “BNP has been associated with congestive heart failure, but finding that it is highly associated with itch—particularly chronic pruritus of unknown origin—was very interesting,” Yosipovitch said. He and colleagues also reported on periostin, an extracellular matrix and matricellular protein that binds to several types of integrins that transduce its signals, and its role in itch sensation through direct integrin-mediated stimulation of nerve fibers and interaction with immune and nonimmune cells.¹³

“It can activate both the immune system but it also can activate the nerve end usage, which is very powerful,” Yosipovitch said.

‘A GOOD TIME FOR THIS FIELD’

Yosipovitch has been called “The Godfather of Itch.” He does not like the moniker. 

“I am just one messenger in the field,” he said, “and 20 years down the road, people might not even remember my name. But the field itself will be well-addressed.”

The field of itch still has a long way to go. Kim noted that dupilumab has been on the market for 7 years and still has only an approximate 10% market penetration. 

“Only about one in 10 patients who should get dupilumab are getting it, which is wild because that drug is as safe as it gets,” Kim said. “The efficacy-to-safety coefficient on dupilumab compares favorably even to Tylenol and aspirin, and yet it is not widely enough utilized.”

Kim said a colleague, Dr. Daniel Butler, recently posited on social media that the problem with itch is that the superpower of the dermatologist is their eyes, and itch betrays the eyes. 

“Itch is essentially the Achilles’ tendon of the dermatologist in that way,” Kim said, “because it is actually a big, big problem, but it is not well suited to the strength of any physician.”

Awareness on the part of both patients and clinicians will be of the utmost importance as the field of itch continues to evolve. While it may be slow, progress is being made. Dupilumab might not be widely utilized yet, but its impact in drug development was massive. 

“Before dupilumab,” Yosipovitch said, “there were no targeted treatments. We would use immunosuppressants or bombard patients with systemic steroids that were not specific to their disease. We could affect itch, but there were side effects. Now, we have drugs that are extremely safe and effective. It is a good time for this field, and hopefully it will continue this way.” -by Jason Mazda

Disclosures:

Dr. Bunick reports serving as a consultant for several companies that manufacture JAK/TYK2 inhibitors, including AbbVie, BMS, Pfizer, Sanofi-Regeneron, and Takeda. 

Dr. Kim reports being co-founder of Alys Pharmaceuticals; he also reports having served as a consultant for 23andMe, ABRAX Japan, AbbVie, Amgen, Attovia Therapeutics, Cara Therapeutics, Clexio Biosciences, Eli Lilly and Company, Escient Pharmaceuticals, Evommune, Galderma, LEO Pharma, Micreos, Novartis, Pfizer, Recens Medical, Regeneron, Sanofi, Septerna, Teva, Trevi Therapeutics, Triveni Bio, and WebMD; he reports having stock in ABRAX Japan, Alys Pharamaceuticals, Attovia Therapeutics, Locus Biosciences, Recens Medical, and Triveni Bio; and he reports holding a patent for the use of JAK1 inhibitors for chronic pruritus.. 

Dr. Yosipovitch reports serving as an advisory board member for Arcutis, Abbvie, Amgen, Eli Lilly, Galderma, GSK, Escient , LEO Pharma, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi; he also reports serving as an investigator for Abbvie, Eli Lilly, Kiniksa Pharmaceuticals, LEO Pharma, Regeneron Pharmaceuticals, Inc., and Sanofi; and he reports having received grants and research funding from Pfizer, Eli Lilly, Novartis, and Escient. 

Dr. Zirwas reports serving as a consultant for Advanced Derm Solutions. 

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