Antipruritic Effect of Topical Ketamine, Amitriptyline, and Lidocaine

Study Overview
=================
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.

Official Title
-----------------
Antipruritic Effect of Topical Ketamine, Amitriptyline, and Lidocaine

Conditions
-----------------
Pruritus

Intervention / Treatment
-----------------
* Drug: Ketamine Hydrochloride
* Drug: Amitriptyline Hydrochloride
* Drug: Lidocaine Hydrochloride
* Combination Product: Ketamine hydrochloride, Amitriptyline hydrochloride, and Lidocaine hydrochloride
* Drug: Lipoderm Cream


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The antipruritic effect of 4 topical treatments and 1 vehicle treatment will be explored in each subject. Study visit 1 will consist of testing 3 topical formulations, and study visit 2 will test the remaining 2 topical formulations in each subject.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topical KeAmLi combo<br>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. | Combination Product: Ketamine hydrochloride, Amitriptyline hydrochloride, and Lidocaine hydrochloride<br>* 2g of topical KeAmLi-combo (ketamine 10%, amitriptyline 5%, and lidocaine 5%) will be applied for 30 minutes on one 4x4cm area on the volar forearm in one of two study visits.<br>* Other names: Topical KeAmLi combo;|
| Experimental: Topical ketamine<br>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. | Drug: Ketamine Hydrochloride<br>* 2g of topical 10% Ketamine will be applied for 30 minutes on one 4x4cm area on the volar forearm in one of two study visits.<br>* Other names: Topical ketamine;|
| Experimental: Topical amitriptyline<br>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. | Drug: Amitriptyline Hydrochloride<br>* 2g of topical 5% Amitriptyline will be applied for 30 minutes on one 4x4cm area on the volar forearm in one of two study visits.<br>* Other names: Topical amitriptyline;|
| Experimental: Topical lidocaine<br>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. | Drug: Lidocaine Hydrochloride<br>* 2g of topical 5% Lidocaine will be applied for 30 minutes on one 4x4cm area on the volar forearm in one of two study visits.<br>* Other names: Topical lidocaine;|
| Placebo Comparator: Topical vehicle<br>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. | Drug: Lipoderm Cream<br>* 2g of topical vehicle (Lipoderm) will be applied for 30 minutes on one 4x4cm area on the volar forearm in one of two study visits.<br>* Other names: Topical vehicle;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Itch Intensity Between the Vehicle and Active Treatments (Individual and KeAmLi-combo). | 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. | 10 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thermal Threshold Detection (Warmth and Heat Pain) | 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. | 3 minutes | 
| Mechanical Thresholds (Mechanical Detection and Pain). | 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. | 5 minutes |