GOTHENBURG, SWEDEN – Patients with longstanding chronic pruritus refractory to the full array of conventional therapies had a high response rate to a neurokinin-1 receptor antagonist in a proof-of-concept study.
"To the best of our knowledge, this is the first clinical report demonstrating that targeting the neuropeptide substance P via applying the NK-1 receptor antagonist aprepitant is an effective approach for the treatment of chronic pruritus," Dr. Sonja Ständer said at the annual congress of the European Academy of Dermatology and Venereology.
She reported on 20 patients, mean age 67 years, with an average 61-month duration of pruritus refractory to antihistamines, topical and systemic steroids, cyclosporine, and/or UV phototherapy.
Participants were placed on oral aprepitant at 80 mg once daily for 1 week, with no other anti-pruritic therapy allowed. Sixteen of the 20 patients responded with a significant reduction in itching. Mean values on a daily self-rated pruritus visual analog scale improved from 8.4 points on the 0-10 scale at baseline to 4.9 points after a week on aprepitant (Emend).
Four patients reported complete or nearly complete relief, eight others had a 40%-60% reduction in pruritus, and four patients had a modest 10%-30% improvement. Four others were nonresponders, according to Dr. Ständer of the University Hospital, Münster, Germany.
Responses varied considerably depending upon the presumed pathophysiology of a patient’s pruritus. The best results were seen in the 10 patients with an atopic predisposition and in the 13 with prurigo nodularis and scratch lesions. The seven patients whose pruritus was thought to be caused by underlying systemic disease, such as diabetes or chronic kidney disease, had a far more modest mean 24% reduction in pruritus. However, those who had uremic pruritus, caused by chronic kidney disease as well as an atopic predisposition, fared much better on aprepitant, with a mean 50% reduction in pruritus.
Side effects were limited to mild nausea, drowsiness, and vertigo in three patients.
Aprepitant is approved for the prevention of chemotherapy-induced nausea and vomiting, as well as postoperative nausea and vomiting. The rationale for studying this antiemetic as a potential therapy for chronic pruritus lies in the fact that as an NK-1 receptor antagonist, aprepitant inhibits substance P. And studies in both animals and humans indicate substance P is an important mediator of itch.
Substance P binds to the NK-1 receptor, which is expressed in the skin and the central nervous system. When substance P binds to NK-1 receptors on mast cells, it triggers mast cell degranulation, with release of pruritus-inducing tumor necrosis factor–alpha, histamine, leukotriene B4, and prostaglandin D2. And when substance P binds to NK-1 receptors on keratinocytes, it stimulates production of interleukin-1–alpha and –beta, interleukin-8, and other proinflammatory cytokines, Dr. Ständer explained.
Previous studies indicate chronic pruritus patients with prurigo nodularis or an atopic predisposition are characterized by particularly high levels of substance P in the skin – and these were just the patients with the greatest response to aprepitant in this initial study, she added. Based upon the encouraging results of this pilot study, a randomized, controlled study is planned.
Dr. Ständer declared having no relevant financial interests.