Scratching the surface: NK-1 inhibitors for chronic itch—Promise or placebo?

Chronic pruritus (CP) remains a significant therapeutic challenge across dermatologic and systemic diseases. The neuropeptide substance P and its receptor, neurokinin-1 receptor (NK1R), have emerged as pivotal mediators in the pathogenesis of itch.¹ The meta-analysis by Ho et al.² provides a timely and comprehensive synthesis of the current clinical evidence supporting the efficacy of systemic NK1R antagonists—particularly serlopitant and aprepitant—in alleviating CP. The authors conducted a rigorous literature review spanning multiple databases and clinical trial registries. Their final analysis incorporated 20 studies (13 RCTs, 2 non-RCTs, and 5 grey literature reports) with a total of 2876 patients. This broad inclusion enhances the generalizability of the findings and reflects the real-world application of NK1R-targeting therapies. However, the pooled analysis revealed a modest albeit statistically significant reduction in pruritus scores with systemic NK1R antagonists compared to placebo (SMD: −0.44; p = 0.002). Importantly, the odds of achieving a clinically meaningful 4-point improvement in itch severity were higher in the treatment 33.9% of patients meeting this threshold, compared to 24.7% in the placebo arm. These results are significantly less impressive than those of other anti-pruritic drugs that are not biologics or JAK inhibitors, where we expect higher itch reductions. For example, Kappa opioid difelikefalin, approved in the United States and Europe, achieved a 4-point NRS reduction in studies ranging from 42% to 64%.^{3, 4}

Subgroup analyses offer important insights for clinical practice. Notably, serlopitant and aprepitant demonstrated superior antipruritic effects compared to placebo, with aprepitant exhibiting a larger effect size (SMD: −1.55). However, the wide confidence interval suggests considerable variability and potential heterogeneity in the studies examining aprepitant. Interestingly, although initially the use of aprepitant was recommended for malignancy-associated pruritus, the analysis found greater efficacy in nonmalignant dermatologic inflammatory conditions. These findings echo the pathophysiological understanding that substance P, released from sensory neurons, contributes to neurogenic inflammation and directly activates mast cells and keratinocytes—both of which are key contributors to itch propagation in the skin. Blocking NK1R, antagonists may disrupt this cascade and provide symptom relief.

Although the authors suggest that NK-1 inhibitors are effective, the overall effect sizes, while statistically significant, are modest. This may reflect heterogeneity in study populations, treatment durations, and disease etiologies. Second, the inclusion of grey literature—while helpful in reducing publication bias—introduces variability in study quality. Additionally, the duration of treatment and sustainability of antipruritic effects remain unclear in many trials.

Moreover, most studies assessed short- to medium-term outcomes, and the long-term safety and efficacy of NK1R antagonists have not been well established. Adverse effect profiles, especially with repeated or prolonged use, require further elucidation. Furthermore, although both serlopitant and aprepitant demonstrated efficacy, neither agent is currently FDA-approved specifically for chronic pruritus; furthermore, the off-label extremely high cost of using aprepitant is limiting their routine clinical adoption.

Nonetheless, this meta-analysis strengthens the argument for considering NK1R antagonists in the therapeutic armamentarium for CP, particularly in refractory cases of dermatologic origin. The stratified efficacy suggests that patient selection—guided by pruritus aetiology—will be crucial in optimizing outcomes. It also underscores the need for future research to refine dosing regimens, identify predictive biomarkers of response and explore combination approaches with other antipruritic agents such as gabapentinoids or JAK inhibitors.

In conclusion, systemic NK1R antagonists, especially serlopitant and aprepitant, show modest efficacy in reducing chronic itch, with the greatest benefit observed in nonmalignant skin conditions. As our understanding of the neuroimmune mechanisms of pruritus expands, NK1R antagonism may be effective in some types of chronic itch.

Gil Yosipovitch: Advisory board consultant: Abbvie, Arcutis,Almiral, Amgen, Attovia, Celldex, Escient Health, Eli Lilly, Galderma, LEO Pharma, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Vifor, GSK, Celldex and Maruho; Investigator and research support: Eli Lilly, LEO Pharma, Novartis, Pfizer, Galderma, Escient, Regeneron, Sanofi, Celldex, Kiniksa, Pfizer and Abbvie.