Substance P serum levels and NK1 receptor expression were elevated in chronic prurigo patients, but a randomized trial of topical aprepitant (an NK1 receptor antagonist) failed to outperform placebo for itch reduction, despite both groups improving over 50%.
>50% itch reduction — in both groupsBoth topical aprepitant (-35.2 VAS) and placebo (-38.1 VAS) reduced itch intensity by more than 50% over 28 days, with no significant difference (p=0.76), highlighting the challenge of strong placebo responses in itch trials.
What the researchers found
Biomarker findings confirmed substance P/NK1R involvement:
- Substance P serum levels were increased in chronic prurigo patients compared to controls
- NK1R expression was higher in lesional versus non-lesional skin
Clinical trial results (randomized, placebo-controlled, split-sided, double-blind):
- Topical aprepitant reduced itch intensity by >50% from baseline by day 28 (VAS change: -35.2)
- Placebo vehicle also reduced itch by >50% (VAS change: -38.1)
- No significant difference between groups (p=0.76)
- Overall clinical scores improved in both groups with no significant between-group difference (p=0.32)
The strong placebo response in the split-sided design likely obscured any treatment effect.
Why it matters
Chronic prurigo is a common and distressing condition with limited treatment options. This study provides important evidence at two levels: the biomarker data confirms that substance P and NK1R are legitimate therapeutic targets in this disease, while the negative clinical trial result reveals a critical methodological lesson — split-sided trial designs may not work for systemic conditions where treating one side can affect the other through circulating neuropeptides. This informs future trial design for neuropeptide-targeted itch therapies.
How the study worked
The study had two components: (1) A case-control biomarker analysis comparing substance P serum levels and cutaneous NK1R expression between chronic prurigo patients and healthy controls, and between lesional and non-lesional skin within patients. (2) A randomized, placebo-controlled, split-sided (one side of body gets drug, other gets placebo), double-blind proof-of-concept trial of topical aprepitant in chronic prurigo patients. Primary outcome was pruritus intensity measured by visual analogue scale (VAS) at day 28.
What this study cannot tell us
The split-sided trial design is a major limitation — applying drug to one side and placebo to the other may not control for systemic effects of topical absorption or for psychological effects of knowing some part of the body is being treated. The sample size is not specified in the abstract but was likely small for a proof-of-concept study. Topical drug penetration to reach NK1R on nerve fibers may have been insufficient. The >50% improvement in both groups suggests a strong placebo effect or natural disease fluctuation. The 28-day duration may be too short for a chronic condition.
How to read the evidence
This is a randomized, double-blind, placebo-controlled proof-of-concept trial — a well-designed study. However, the split-sided design introduces potential contamination between treatment sides, and the small sample size limits power. The biomarker data is observational (case-control). Overall, this provides moderate evidence for substance P involvement but negative clinical evidence for topical NK1R blockade.
When this study was published
Published in 2018, this study is about 7 years old. Since then, oral NK1R antagonists (like serlopitant and tradipitant) have been tested in larger trials for chronic pruritus with more promising results.
The bigger picture
Substance P has been implicated in itch for decades, and systemic NK1 receptor antagonists (like oral serlopitant) have shown more promising results in chronic itch than this topical approach. The failure of topical aprepitant doesn't disprove the substance P-itch connection — it more likely reflects that topical delivery can't adequately block NK1R in the relevant nerve fibers, or that the split-sided design allowed systemic placebo effects to contaminate results. Oral NK1R antagonists for chronic prurigo and other itch conditions continue to be developed and tested.
Questions still open
- Would oral or injectable NK1 receptor antagonists be more effective than topical formulations for chronic prurigo?
- Could a parallel-group trial design (separate patient groups rather than split-sided) reveal a treatment effect that the split-sided design missed?
- Is the elevated serum substance P a cause of chronic prurigo or a consequence of chronic scratching and skin damage?
Common questions
What is substance P and why does it cause itching?
If substance P causes the itch, why didn't the NK1 blocker work?
Read the original research
Role of Substance P and Its Receptor Neurokinin 1 in Chronic Prurigo: A Randomized, Proof-of-Concept, Controlled Trial with Topical Aprepitant.
Acta dermato-venereologica, 98(1), 26-31
Citation
Ohanyan, Tatevik; Schoepke, Nicole; Eirefelt, Stefan; Hoey, Gert; Koopmann, Witte; Hawro, Tomasz; Maurer, Marcus; Metz, Martin. (2018). Role of Substance P and Its Receptor Neurokinin 1 in Chronic Prurigo: A Randomized, Proof-of-Concept, Controlled Trial with Topical Aprepitant.. Acta dermato-venereologica, 98(1), 26-31. https://doi.org/10.2340/00015555-2780