A Hidden Crisis: The Need for Treatments in Notalgia Paresthetica

A quiet crisis, whose true impact is only realized by those afflicted, the unmet need in notalgia paresthetica is not fully understood but wreaks havoc on patients as the medical community looks to the future for a potential treatment.

With the incidence and prevalence not fully elucidated, partly as a byproduct of lacking an approved treatment, notalgia paresthetica poses a unique challenge for dermatologists, anesthesiologists, primary care, and medicine in general.¹

First described by a Russian neurologist in 1934,² notalgia paresthetica is a chronic cutaneous neuropathy with characteristics including localized pruritus and associated dysesthesias as well as sensations of pain, numbness, and tingling within the middle or upper back. For some patients, these symptoms can be mild and manageable, but for others the pain, numbness, and tingling, which is often described as a burning sensation, can be so severe it disrupts nearly all aspects of life.

“I have a really wide range of patients, from those whose back occasionally bothers them twice a week, to a patient who felt like jumping off a bridge because of the incredible itch in her back that was driving her crazy,” described Pamela Weinfeld, MD, a dermatologist with Dermatology and Skin Care Associates in Massachusetts, in an interview with HCPLive. “Then there are patients who experience everything in between, like those who are itchy multiple times a day or only in certain situations, like at night before going to sleep, which keeps them up at night. Some patients experience it very occasionally. So, I think there's a very, very wide range.”

A condition with no treatments approved by the US Food and Drug Administration (FDA), notalgia paresthetica finds itself in limbo as a lack of knowledge surrounding the true prevalence and etiology of the disease prevents the medical community from developing therapeutic agents. In an interview with HCPLive, Raj Chovatiya, MD, PhD, assistant professor of dermatology and director of Center for Eczema and Itch at Northwestern University, purported the possibility far more patients than suspected deal with notalgia paresthetica, but a lack of education and clinician awareness can often end the journey to treatment in early stages or before it can begin.

“A challenge of this condition is that people may come directly to their healthcare providers seeking care, but there are also people who probably don't. They may be lost in the system, someone may have told them it has nothing to do with dermatology,” Chovatiya said. “Even if people are actually trying to use ICD codes and electronic health records to see how prevalent this condition is, it may not even be coded at the time of visit because there aren't any specifically approved treatments for it. So, it may not even look like those encounters are happening for it either. It leads to a really confusing situation where it's hard to make estimates based on some of the conventional ways we use to estimate things like psoriasis or eczema through health claims or electronic health records.”

Although the community waits eagerly for its first FDA-approved therapy, a diagnosis of notalgia paresthetica is not without options for symptom management. In fact, the prevalence of the disease, combined with the experience of dermatologists in treating similar conditions, has left patients with a multitude of treatment options with varying efficacy, safety, and evidence base sizes.

“So, dermatologists can diagnose it and we have been diagnosing it for a very long time very quickly. The problem has been how do you treat it? How do you counsel patients, and this is why not having an FDA drug in this space is very problematic for patients because it's hard to know what to prescribe for them or treat them,” said Chris Bunick, MD, PhD, associate professor of dermatology at Yale School of Medicine, in an interview.

Current Options for Symptom Management

Although current treatments have proven useful and anecdotal evidence suggests they are effective for many patients, some dermatologists argue, because the true prevalence of the disease is unknown, the need for an FDA-approved therapy limits their ability to effectively manage symptoms of notalgia paresthetica patients. According to the dermatologists interviewed for this feature, most first attempts at management feature topical steroids, capsaicin, or botulinum toxin injections, with other therapies such as topical analgesics making up the majority of the treatment options for patients with notalgia paresthetica. However, while these treatments have produced varying degrees of effectiveness, they are not without potential drawbacks.

Among the first treatment options exercised for notalgia paresthetica, use of capsaicin patches and topical capsaicin has been examined in a number of trials and studies. In these studies, the treatment effects ranged from widely. An oral option, gabapentin has also found a home as a treatment option for symptom mitigation in notalgia paresthetica but carries a safety profile concerning to some. Among the bevvy of other pharmacological options with limited efficacy and reproducibility are oxcarbazepine, tacrolimus, and amitriptyline.¹

In her interview, Weinfeld, who published a case report in 2007 on use of botulinum toxin type A in nostalgia paresthetica, 3 described seeing success in numerous patients with the intradermal therapy, with one patient regularly travelling from Pennsylvania to Massachusetts to receive injections.

Although other pharmacologic and non-pharmacologic options exist, notalgia paresthetica continues to present a treatment challenge for many patients, in part due to its still unknown etiology. The potential for the condition to be caused by nerve compression occurring as a result of degenerative spine issues has led to many advocating for physical therapy as an avenue for symptom relief.¹

Despite the options available, the lack of conclusive data and dedicated trials limits the applicability of anecdotal evidence and individual case reports.

“Just because some things work for some patients, some things don't work, and hopefully having a therapy that's maybe a little more targeted to some of the mechanisms involved in notalgia paresthetica that might work better,” Bunick added.

Even with some of the aforementioned treatment options showing promise, the list of companies who have sought to conduct or sponsor trials examining treatment options for nostalgia paresthetica is small. In her interview, Weinfeld pointed to the overwhelming cost of conducting trials and the potential lack of return given the uncertainty surrounding the size of the patient population and unmet need.

“To do a clinical trial costs so much money. I mean, it's just not worth it for an indication if they think it's not a large enough indication. I think companies get really interested in curing cancer. When someone says, I have an itch on my back spending $100 million on a clinical trial is just not going to see the see the return for them,” Weinfeld noted.

Phase 2 Trial Renews Hope

In early February 2023, the community received renewed hope with the publishing of results from a phase 2 trial in the New England Journal of Medicine.⁴ The trial, which examined the selective kappa opioid receptor agonist difelikefalin as a treatment for notalgia paresthetica, returned results indicating the therapy could one day be the long-awaited agent to receive FDA approval for this patient population.

“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,” said principal Brian Kim, MD, vice chair of Research for the Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai.⁵

Approved by the FDA for treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis in August 2021,⁶ difelikefalin was examined as a potential treatment for notalgia paresthetica in the phase 2, double-blind, placebo-controlled KOMFORT trial.

In the KOMFORT trial, a total of 126 patients with moderate-to-severe pruritus caused by notalgia paresthetica were randomized in a 1:1 ratio to receive 2 mg oral difelikefalin or placebo twice daily for 8 weeks. With a primary outcome of interest defined as change from baseline to week 8 in weekly mean score on the Worst Itch Numeric Rating Scale (WI-NRS). At baseline, each cohort had a mean WI-NRS score of 7.6, which investigators noted was indicate of severe itch.⁴

Upon analysis, the change from baseline to week 8 in the weekly mean WI-NRS score was -4.0 points in the difelikefalin group and -2.4 points in the placebo group (difference in change, -1.6 points [95% CI, -2.6 to -0.6]; P = .001), with a significantly greater proportion of patients achieving a 4-point improvement or greater in WI-NRS score at week 8 (41% vs 18%; P = .007). Additionally, use of difelikefalin was associated with a significantly greater proportion of patient achieving a complete response relative to placebo therapy (22% vs 5%; P <.01).⁴

When assessing the safety profile of the agent in this patient population, investigators pointed out headache, dizziness, constipation, and increased urine output occurred more frequently in the difelikefalin group. Investigators also pointed out 14 patients in the difelikefalin group and 6 patients in the placebo group discontinued the trial before 8 weeks.⁴

In an interview with HCPLive, Kim called attention to criticisms of the magnitude of benefit translated by a placebo-corrected 1.6-point mean difference in WI-NRS observed in the trial. Kim was quick to point out, because notalgia paresthetica is a form of neuropathic itch, they were unable to adjust for the impact of a potential placebo in the trial and the overall reduction in WI-NRS demonstrated in the trial offer the most insight into the potential of difelikefalin in this patient population.

“If you look at the difference in how many people reach the 4-point reduction in the treatment group compared with what is seen in the placebo group, that is what we should be focusing on because the patients don't go ‘Gee, I know I feel a lot better. But I want to know how much I feel better compared to the average of the placebo population’,” Kim remarked. “We define a 4-point reduction as clinically meaningful, which it's a big reduction. A lot of people say you can't reach that and when you look at the difference between those 2 groups, that is incredibly powerful.”

In a statement, Cara Therapeutics noted plans for a registrational phase 2/3 program of oral difelikefalin. This program will include an 8-week, phase 2 dose-finding trial followed by 2 identical phase 3 studies.⁷

References

1. ^{Robinson C, Downs E, De la Caridad Gomez Y, et al. Notalgia Paresthetica Review: Update on Presentation, Pathophysiology, and Treatment. Clin Pract. 2023 Feb 19;13(1):315-325. doi: 10.3390/clinpract13010029. PMID: 36826171; PMCID: PMC9955802.}
2. ^{Šitum M, Kolić M, Franceschi N, Pećina M. NOTALGIA PARESTHETICA. Acta Clin Croat. 2018 Dec;57(4):721-725. doi: 10.20471/acc.2018.57.04.14. PMID: 31168209; PMCID: PMC6544103.}
3. ^{Weinfeld PK. Successful Treatment of Notalgia Paresthetica With Botulinum Toxin Type A. Arch Dermatol. 2007;143(8):980–982. doi:10.1001/archderm.143.8.980}
4. ^{Kim BS, Bissonnette R, Nograles K, et al. Phase 2 trial of Difelikefalin in Notalgia paresthetica. New England Journal of Medicine. 2023;388(6):511-517. doi:10.1056/nejmoa2210699}
5. ^{Mount Sinai Health System. New formulation of FDA-approved drug shows encouraging results for treating a common itch condition. Mount Sinai Health System. https://www.mountsinai.org/about/newsroom/2023/new-formulation-of-fda-approved-drug-shows-encouraging-results-for-treating-a-common-itch-condition. Published February 8, 2023. Accessed March 28, 2023.}
6. ^{Cara Therapeutics and VIFOR Pharma announce U.S. FDA approval of Korsuva™ (difelikefalin) injection for the treatment of moderate-to-severe pruritus in hemodialysis patients. Cara Therapeutics. https://ir.caratherapeutics.com/news-releases/news-release-details/cara-therapeutics-and-vifor-pharma-announce-us-fda-approval. Published August 23, 2021. Accessed March 28, 2023.}
7. ^{Cara Therapeutics announces results from the KOMFORT phase 2 trial of oral Difelikefalin for the treatment of pruritus in notalgia paresthetica published in the New England Journal of Medicine. Cara Therapeutics. https://ir.caratherapeutics.com/news-releases/news-release-details/cara-therapeutics-announces-results-komfort-phase-2-trial-oral. Published February 8, 2023. Accessed March 28, 2023.}