Antipruritic Effect of Topical Ketamine, Amitriptyline, and Lidocaine

Phase 2

Terminated

Conditions: Pruritus

Interventions: Drug: Ketamine Hydrochloride
Drug: Amitriptyline Hydrochloride
Combination Product: Ketamine hydrochloride, Amitriptyline hydrochloride, and Lidocaine hydrochloride
Drug: Lipoderm Cream
Drug: Lidocaine Hydrochloride

Registration Number: NCT03096444

Lead Sponsor: Gil Yosipovitch

Brief Summary: The purpose of this study is to examine the antipruritic efficacy of topical ketamine, amitriptyline, lidocaine, and a tri-combination of ketamine, amitriptyline and lidocaine (hereafter referred to as "KeAmLi") using non-histaminergic itch provocations in healthy volunteers. The primary outcome is itch reduction (AUC) between the vehicle and active treatment (KeAmLi-combo). Secondary outcomes include modality-specific analgesic properties of the topically applied ketamine, amitriptyline, lidocaine, and KeAmLi-combo to controlled quantitative thermal and mechanical stimuli, which can improve our understanding of the mechanism of action of these substances in the context of topical therapy.

Detailed Description: This is a double-blind, vehicle-controlled study to evaluate the antipruritic efficacy of topical ketamine, amitriptyline, lidocaine, and a tri-combination of ketamine, amitriptyline and lidocaine (hereafter referred to as "KeAmLi") using non-histaminergic itch provocations in healthy volunteers. Each participant will be pre-treated with the vehicle and 4 active topical creams, over two study visits (3 treatments on the 1st visit and 2 treatment on the 2nd visit). Each treatment will be applied to the randomized forearm test area for 30 minute, and then sensory testing will be performed. Sensory testing includes thermal and mechanical stimuli, and itch induction using the plant cowhage. These tests will reveal mechanistic information and potential cellular and molecular targets for improved antipruritic and analgesic therapies.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 13

Inclusion Criteria

Healthy subjects (absence of disease) between 18 and 50 years of age.
Must be in general good health with no disease or physical conditions that would impair evaluation of itch and pain perception.
No history of chronic itch or pain.
Must abstain from the use of any systemic or topical anti-histamine, steroid, or pain relief medications 48 hours prior to the study visits.
Must abstain from the use of moisturizers on the arms the day of study visit.

Exclusion Criteria

Individuals under 18 or over 50 years of age.
Inability to complete the required measures.
The presence of an itchy skin disease or a painful condition.
Diagnosis of diseased that would affect itch or pain perception (e.g. neuropathies).
Currently enrolled in any investigational study in which the subject is receiving any type of drug, biological, or non-drug therapy.
Use of oral, topical analgesics, or other medications known to interfere with itch or pain perception 48 hours prior to the study visits (e.g. antihistamines, anesthetics, anti-inflammatories, opioids, neuroleptics, etc.).
Use of emollients on the volar aspects of the forearms arms on the day of the study visit.
Use of anti-depressants, anti-psychotics, and illicit drugs.
Known history of neuropathy, uremia, uncontrolled thyroid disease, and diabetes mellitus.
Known history of anaphylactic shock, or allergy to cowhage and/or known adverse reactions to lidocaine (or other local anesthetics of the amide type), ketamine or amitriptyline.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Topical ketamine	Ketamine Hydrochloride	Topical ketamine 10% will be applied to one four 4 x 4 cm predefined skin areas on the ventral forearms during one of two study visits. The pre-treatment will occur under topical occlusion for 30 minutes to allow the ointment to be adsorbed. Following this, residual ointment will be removed and sensory testing, strictly within the pretreated area, will commence.
Topical amitriptyline	Amitriptyline Hydrochloride	Topical amitriptyline 5% will be applied to one four 4 x 4 cm predefined skin areas on the ventral forearms during one of two study visits. The pre-treatment will occur under topical occlusion for 30 minutes to allow the ointment to be adsorbed. Following this, residual ointment will be removed and sensory testing, strictly within the pretreated area, will commence.
Topical KeAmLi combo	Ketamine hydrochloride, Amitriptyline hydrochloride, and Lidocaine hydrochloride	Topical KeAmLi-combo (ketamine 10%, amitriptyline 5%, and lidocaine 5%) will be applied to one four 4 x 4 cm predefined skin areas on the ventral forearms during one of two study visits. The pre-treatment will occur under topical occlusion for 30 minutes to allow the ointment to be adsorbed. Following this, residual ointment will be removed and sensory testing, strictly within the pretreated area, will commence.
Topical vehicle	Lipoderm Cream	Topical vehicle (PCCA Lipoderm) will be applied to one four 4 x 4 cm predefined skin areas on the ventral forearms during one of two study visits. The pre-treatment will occur under topical occlusion for 30 minutes to allow the ointment to be adsorbed. Following this, residual ointment will be removed and sensory testing, strictly within the pretreated area, will commence.
Topical lidocaine	Lidocaine Hydrochloride	Topical lidocaine 5% will be applied to one four 4 x 4 cm predefined skin areas on the ventral forearms during one of two study visits. The pre-treatment will occur under topical occlusion for 30 minutes to allow the ointment to be adsorbed. Following this, residual ointment will be removed and sensory testing, strictly within the pretreated area, will commence.

Primary Outcome Measures

Name	Time	Method
Peak Itch Intensity Between the Vehicle and Active Treatments (Individual and KeAmLi-combo).	10 minutes	Peak itch intensity between the vehicle and 4 other active treatments (individual ketamine, amitriptyline, or lidocaine, and KeAmLi-combo). Itch intensity was measured on a 100mm scale visual analog scale for 10 minutes. 0 was weighted with "no itch" and 100 was weighted with "most itch imaginable".

Secondary Outcome Measures

Name	Time	Method
Thermal Threshold Detection (Warmth and Heat Pain)	3 minutes	Two standardized quantitative sensory tests are performed to measure warmth detection threshold (assesses the threshold of which warmth sensation is first detected) and heat pain threshold (assesses the threshold at which heat pain sensation is first detected). Measured in change in celsius.
Mechanical Thresholds (Mechanical Detection and Pain).	5 minutes	Assess mechanical detection and pain thresholds using von Frey filaments stimulators (measured in force mN) to calculate the final threshold as the geometric mean of five series of ascending and descending stimuli.