As understanding of neurogenic rosacea’s pathophysiology evolves, signs point to its being both a manifestation of overall rosacea pathology and a distinct subtype warranting its own treatment strategy. This conundrum notwithstanding, experts told Medscape Dermatology that many dermatologists should expand their comfort level regarding effective treatments for neurogenic rosacea — particularly those that are commonly used in psychiatry.

Neurogenic rosacea (NR), characterized by symptoms such as erythematous flushing and severe burning and stinging that do not respond to regular treatments, was first proposed as a separate rosacea subtype in 2011. However, controversy persists over whether this is the case continues, and a professional consensus regarding its definition is lacking.

The complexity of rosacea pathophysiology and dramatic individual variation in presentation make it difficult to determine whether NR constitutes a subtype of rosacea or a pathophysiological and clinical manifestation at the extreme end of the rosacea spectrum, said Benjamin Ungar, MD, assistant professor of dermatology and director of the Rosacea & Seborrheic Dermatitis Clinic in the Icahn School of Medicine at Mount Sinai in New York. “But it’s probably the latter,” he said.

Nevertheless, Ungar told Medscape Medical News that as researchers’ understanding of the intricate relationship between neurogenic inputs and inflammatory pathways in rosacea has grown, “it’s probably not fair to say in many cases that it’s purely one or the other, but that they’re both contributing.” Part of the neurogenic contribution likely involves oxidative stress triggering innate immune and nerve responses in the skin, leading to recruitment of adaptive immune responses, many of which also signal to neural mechanisms, he said. “This is not a linear process,” Ungar added, “but a complex web of inputs and responses.”

Another Set of Building Blocks

From stinging and burning to flushing, said Neal Bhatia, MD, director of clinical dermatology at Therapeutics Clinical Research in San Diego, many rosacea symptoms have similar neurogenic and neurovascular triggers and pathways. “To say that rosacea is only coming from a neurogenic basis is incomplete. Rather than making a separate classification, we are actually looking at another set of building blocks.”

In patients who are genetically susceptible to rosacea, Bhatia said, environmental triggers such as heat, alcohol, and ultraviolet exposure activate transient receptor potential vanilloid (TRPV) receptors in the skin and eyes to release neurotransmitters such as substance P and calcitonin gene-related peptide (CGRP). According to the Calgary Guide to Understanding Disease, resulting epithelial irritation activates the sensory nervous system, leading to burning and stinging symptoms of rosacea. TRPV receptors also release bradykinin and nitric oxide, which spur vasodilation, leading to erythema, flushing, and edema in rosacea.

Mast cell degranulation and release of histamine and proinflammatory cytokines in response to TRPV channel activation further amplify vasodilation and local immune responses, Bhatia explained. Rosacea triggers also activate the toll-like receptor 2 pathway, in which kallikrein-related peptidase 5 cleaves cathelicidin LL-37, leading to angiogenesis and telangiectasia formation. 

Altogether, NR pathophysiology constitutes a vicious cycle wherein TRP channel hypersensitivity drives exaggerated, prolonged vasodilation in response to mild environmental stimuli, according to a review of NR management published in 2025.

Neurovascular Overlap

The fact that traditional rosacea treatments fail in NR provides strong rationale for its being a separate subtype, said Christopher G. Bunick, MD, PhD, associate professor of dermatology with the Program in Translational Biomedicine at Yale University School of Medicine in New Haven, Connecticut. On the other hand, he said that within neurovascular bundles, the fact that dysregulation can affect nerves, blood vessels, or both structures suggests an overlapping neurovascular element in NR.

Perhaps the best evidence of the connection between vascular and neurologic pathways in NR, said Bunick, comes from the topical vasoconstrictor oxymetazoline (Rhofade). Because oxymetazoline produces slightly less rebound redness around 12 hours post-application than does brimonidine (Mirvaso), Bunick told Medscape Medical News, prescribers generally prefer oxymetazoline.

As more patients have used oxymetazoline long-term, he added, physicians have learned that a year of daily use can reduce patients’ everyday baseline redness. In the phase 3 REVEAL trial, which evaluated oxymetazoline cream for treating persistent facial erythema in patients with rosacea, the proportions of patients who achieved a second-grade or greater composite improvement from baseline in clinician- and patient-assigned erythema scores at week 52 were 36.7% and 43.4%, respectively. These results suggest that at least part of the neurovascular mechanism in NR can be reprogrammed with certain medications, Bunick said.

A Clinical Diagnosis

With rosacea itself almost certainly underdiagnosed, said Ungar, pinpointing the prevalence of NR is difficult. Patients do not always seek care for, or recognize neurologic symptoms as part of, rosacea, he said. “In broad strokes, neurogenic rosacea is fairly common and largely underdiagnosed.”

Because no specific tests or markers can identify NR, added Bhatia, there is little ongoing research that is unique to this entity. Bunick said he sees only a few patients per year with NR, and its rarity may explain the paucity of research.

Diagnostic criteria from both the global Rosacea Consensus panel and the National Rosacea Society, which reflect a shift from subtype-based to phenotype-based diagnosis and treatment, can help in diagnosing NR, said Ungar. Whether clinicians use these phenotypic criteria explicitly or not, he added, diagnosing NR requires considering patients’ clinical features together.

Bunick added that the clinical presentation of NR — featuring stark, full-cheek redness, as shown in the 2010 article in which Scharschmidt and colleagues proposed the NR subtype — is often unmistakable and may support considering it a unique subtype. “That is not your typical papulopustular or vascular rosacea presentation,” he said.

Somewhat similarly, Ungar said that although physicians should ask patients about common NR comorbidities such as migraine and complex regional pain syndrome, affected patients tend to volunteer this information. “Those components are not subtle, he explained.

Often, added Bhatia, the pain, burning, and/or pruritus that patients with NR experience can be much more severe than the observed erythema. Therefore, he said, what patients see as erythema may not reflect disease activity accurately.

Off-Label Strategies Required

Because NR typically resists approved rosacea treatments, said Ungar, off-label treatments, often applied through trial and error, are crucial. “Nothing is effective across the board,” he said.

For the burning and stinging of NR, experts have recommended neuroleptic agents (such as gabapentin or pregabalin), tricyclic antidepressants, and pain-modifying antidepressants (such as duloxetine). Other agents such as memantine, systemic antibiotics, and topical ketamine may help in selected cases, according to Scharschmidt and colleagues.

Regarding migraine medications, said Ungar, CGRP inhibitors may represent the most promising option for NR. In a small nonrandomized trial published in 2024, three monthly 140 mg doses of erenumab (Aimovig) reduced the mean number of days participants experienced moderate-to-severe flushing and moderate-to-severe erythema by 6.9 and 8.1, respectively.

Among experimental treatments, inhibiting TRPV1 activation with topical agents can reduce neuronal hyperresponsiveness and relieve burning or stinging sensations, according to authors of a small randomized clinical trial published in 2016.

Agents recommended for patients with NR who experience prominent flushing and telangiectasias include beta blockers, topical alpha-adrenergic agonists, and calcium channel blockers. Laser and light-based therapies also appear more effective in this group. Additionally, botulinum toxin injections have shown promise in reducing facial erythema and flushing.

Considering the pathophysiological overlap between neurogenic and vascular rosacea, Bunick said, “You may have to treat both in order to have long-lasting, high success rates. I would be interested in seeing more combination therapies trying to hit both the neurological and vascular elements at the same time — such as oxymetazoline and gabapentin — to see if you get higher degrees of neurovascular reprogramming.”

Expanding Dermatologists’ Comfort Zone

Among the neuropsychiatric agents above, said Bunick, dermatologists are likely comfortable with gabapentin, which they commonly prescribe for shingles pain, and perhaps pregabalin. Beyond these medications, Ungar added, most dermatologists likely will defer to neurologists.

Getting dermatologists to become more comfortable with additional neuropsychiatric agents will be challenging, Ungar said, noting that comfort with prescribing a particular medication comes from experience. Interested dermatologists may benefit from speaking with colleagues who have more experience regarding dosages, treatment duration, and appropriate expectations for neuropsychiatric agents, he said.

Although insurers tend to balk at newer, more expensive medications such as CGRP inhibitors, Ungar added, cases requiring such drugs are rare in dermatology and require the same approach as other off-label treatments — exhausting prior options and providing insurers with relevant medical literature.

One reason dermatologists experience pushback regarding NR treatments, added Bunick, is that insurers still see rosacea as a cosmetic disease. “They don’t want to cover for the on-label therapies, let alone off-label therapies,” he said. “That remains an incredibly big barrier to getting rosacea patients adequate care.” As a workaround, he said, patients can pay cash prices for off-label rosacea treatments at compounding pharmacies, where available.

In the next few years, said Ungar, translational efforts underway likely will help characterize more fully what is driving the neurogenic process, thereby providing additional insights into potential NR treatments. “And that might lead to major advances in treatment based on a rational approach of understanding what's driving the disease,” he said.

The better researchers elucidate the inflammation and neurovascular dysregulation involved in NR, Bunick added, the more likely insurers will understand that rosacea is a medical disease, and one that remains difficult to control.

Bunick reported having no relevant financial relationships. Ungar reported being a consultant, researcher, and/or speaker for AbbVie, Arcutis Biotherapeutics, Bristol Myers Squibb, Botanix Pharmaceuticals, Castle Biosciences, Fresenius Kabi, Galderma, Incyte, Johnson & Johnson, LEO Pharma, Eli Lilly, Pfizer, Primus Pharmaceuticals, RAPT Therapeutics, Sanofi, Sun Pharma, UCB, Veradermics, and VRG Therapeutics. Bhatia reported being affiliated with AbbVie, Advanced Derm Solutions, Almirall, Arcutis Biotherapeutics, Beiersdorf, Galderma, Journey, La Roche-Posay, LEO Pharma, Ortho Dermatologics, Sagimet Biosciences, Skinfix, and Sun Pharma.

John Jesitus is a Denver-based freelance medical writer and editor.