Why Antihistamines Fall Short in Chronic Itch
In this special conference coverage from the 2026 Elevate-Derm RAPIDS Conference, dermatology NP Victoria Garcia-Albea sits down with Gil Yosipovitch, MD, to unpack how APPs should approach itchy patients. Yosipovitch draws a sharp line between acute and chronic itch: acute itch often has a histamine component, but the chronic itch that causes real suffering is largely non-histaminergic.
He explains that the nerve fibers transmitting chronic itch are driven mainly by proteinase-activated receptor two (PAR2), and possibly PAR1 in some cases, and they simply don't respond to histamine. That makes reflexive antihistamine prescribing unnecessary for these patients. The one exception Yosipovitch allows is using a sedating antihistamine to help a sleepless patient rest — but he notes those agents carry a lot of side effects and that better options exist.
A Sensible Workup — Not a Million-Dollar One
Yosipovitch is emphatic that chronic itch doesn't warrant an exhaustive, expensive workup. He starts with history-taking to flag red flags like weight loss or systemic symptoms that might point toward lymphoma or other underlying disease. His basic labs include CBC with differential, CMP, liver function tests, and creatinine.
He notes that kidney disease at stages three and four—not just dialysis patients—can drive itch, so a creatinine of 2.4 could be the culprit. Liver dysfunction, including fatty liver, can also cause itch beyond classic cholestatic pruritus. He checks thyroid function to rule out hyperthyroidism as a driver, and in selected cases adds a chest X-ray and abdominal ultrasound (or CT) to rule out underlying malignancy. He also flags HIV testing, noting chronic itch is common in HIV even without low CD counts.
History should include travel and a review for parasites. Scabies came up repeatedly — Yosipovitch notes it affects hundreds of millions of people a year and warns that biologics have changed how it presents. Because type 2 cytokines fight parasites, he has seen scabies rashes look totally different in patients on agents like nemolizumab or dupilumab. His caution: don't reach for a biologic in what is actually scabies, and don't miss the diagnosis.
Emerging Biomarkers: BNP and Periostin
Yosipovitch introduces two emerging biomarkers. BNP (brain natriuretic peptide), long associated with heart failure, kidney and cardiac disease, is also a neuropeptide highly associated with itch — particularly in the elderly, in chronic pruritus of undetermined origin, in prurigo nodularis, and even in some atopic dermatitis patients. In some patients, it correlated well with itch intensity, though he stops short of calling it a validated biomarker yet. Insurance coverage remains a barrier.
Periostin, an extracellular matrix protein secreted by fibroblasts and keratinocytes, is tied to type 2 inflammation and amplifies the scratch cycle — more periostin drives more type 2 cytokines, and vice versa. Work with a veterinary medicine colleague showed periostin also acts directly on nerve fibers via the alpha-beta-integrin receptor, making it a 'double whammy' for itch. Periostin is found in prurigo nodularis nodules and correlates strongly with itch intensity. Yosipovitch is excited about the potential for an anti-periostin or anti-receptor drug, noting that blocking it in mice stopped their itching — though he stresses his greater respect for the human data.
Is Itch Contagious? The Brain Connection
Yosipovitch describes a phenomenon many clinicians recognize: audiences start scratching during his talks. A German study showed that videos of crawling ants and insect bites induced scratching in healthy subjects, and his own team’s work nearly 20 years ago showed atopic patients were even more susceptible to these visual cues—scratching in areas where no itch had been induced.
His original hypothesis, that this mirrored the mirror-neuron mechanism of contagious yawning, turned out to be wrong. Instead, the phenomenon involves reward and striatal brain regions that amplify the urge to scratch. He tells the story of a dermatologist in Fayetteville, North Carolina, who holds the Guinness record for backscratchers — more than 1,200 — and wanted to donate the collection to his clinic. Yosipovitch declined, reasoning that displaying them would only cue more patients to scratch.
Topical Tools: A Compounded Trio and Careful Capsaicin
Yosipovitch shares his go-to topical concoction for neuropathic-type itch: 10% ketamine, 5% lidocaine, and 5% amitriptyline in a lipoderm-based vehicle that penetrates the epidermis, available only through a compounding pharmacy. Building on early Mayo Clinic reports (which used lower concentrations), he developed a stronger formulation and has collaborated for years with a compounding pharmacist in Philadelphia. He calls it his most robust anti-pruritic topical.
Safety caveats matter. Systemic absorption is minimal, but he does not recommend applying it to more than 20% body surface area at once, and he warns against swallowing it — one patient did and experienced a dissociative state from the ketamine. The concept comes from the neuropathic pain field, and he has also studied IV ketamine for severe neuropathic itch, later validated by his former fellow Dr. Quattra, though that carries systemic effects unlike the topical.
On capsaicin, Yosipovitch is more measured. His early work paired it with EMLA, which blocks sodium channels and adds benefit while easing the burning that comes from substance P release via the TRPV1 pathway. The catch: 'no gain without pain' — patients need high-concentration application for the first two weeks, and many can't tolerate it long enough. He warns strongly against use near the eyes and genital area (it penetrated even his gloves), and notes an intriguing finding that African American / skin of color patients showed no effect, so he doesn't recommend it for them.