Pruritus
Conditions
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.
Interventions
DRUGKetamine Hydrochloride
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.
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.
DRUGLidocaine Hydrochloride
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.
COMBINATION_PRODUCTKetamine hydrochloride, Amitriptyline hydrochloride, and Lidocaine hydrochloride
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.
DRUGLipoderm Cream
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.
Sponsors
Gil Yosipovitch
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy subjects (absence of disease) between 18 and 50 years of age. 2. Must be in general good health with no disease or physical conditions that would impair evaluation of itch and pain perception. 3. No history of chronic itch or pain. 4. Must abstain from the use of any systemic or topical anti-histamine, steroid, or pain relief medications 48 hours prior to the study visits. 5. Must abstain from the use of moisturizers on the arms the day of study visit.
Exclusion criteria
1. Individuals under 18 or over 50 years of age. 2. Inability to complete the required measures. 3. The presence of an itchy skin disease or a painful condition. 4. Diagnosis of diseased that would affect itch or pain perception (e.g. neuropathies). 5. Currently enrolled in any investigational study in which the subject is receiving any type of drug, biological, or non-drug therapy. 6. 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.). 7. Use of emollients on the volar aspects of the forearms arms on the day of the study visit. 8. Use of anti-depressants, anti-psychotics, and illicit drugs. 9. Known history of neuropathy, uremia, uncontrolled thyroid disease, and diabetes mellitus. 10. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Topical KeAmLi Combo/Ketamine/Amitriptyline/Lidocaine/Vehicle Each participant will receive topical cream treatments applied for 30 minutes to 5 separate 4 x 4 cm predefined skin areas on the ventral forearms.
The 5 topical treatments are:
Topical KeAmLi Combo: Ketamine hydrochloride, Amitriptyline hydrochloride, and Lidocaine hydrochloride: 2g of topical KeAmLi-combo (ketamine 10%, amitriptyline 5%, and lidocaine 5%) Topical ketamine: 10% Topical amitriptyline: 5% Topical lidocaine: 5% Topical vehicle: PCCA Lipoderm cream | 13 |
| Topical KeAmLi Combo/Ketamine/Amitriptyline/Lidocaine/Vehicle Each participant will receive topical cream treatments applied for 30 minutes to 5 separate 4 x 4 cm predefined skin areas on the ventral forearms.
The 5 topical treatments are:
Topical KeAmLi Combo: Ketamine hydrochloride, Amitriptyline hydrochloride, and Lidocaine hydrochloride: 2g of topical KeAmLi-combo (ketamine 10%, amitriptyline 5%, and lidocaine 5%) Topical ketamine: 10% Topical amitriptyline: 5% Topical lidocaine: 5% Topical vehicle: PCCA Lipoderm cream | 65 |
| Total | 78 |
Baseline characteristics
| Characteristic | Topical KeAmLi Combo/Ketamine/Amitriptyline/Lidocaine/Vehicle |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 |
Outcome results
Primary
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.
Time frame: 10 minutes
Population: All subjects received 5 topical cream treatments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topical KeAmLi Combo | Peak Itch Intensity Between the Vehicle and Active Treatments (Individual and KeAmLi-combo). | 62.7 Intensity score | Standard Deviation 29.00397851 |
| Topical Ketamine | Peak Itch Intensity Between the Vehicle and Active Treatments (Individual and KeAmLi-combo). | 63.1 Intensity score | Standard Deviation 30.11218341 |
| Topical Amitriptyline | Peak Itch Intensity Between the Vehicle and Active Treatments (Individual and KeAmLi-combo). | 69.2 Intensity score | Standard Deviation 29.52725816 |
| Topical Lidocaine | Peak Itch Intensity Between the Vehicle and Active Treatments (Individual and KeAmLi-combo). | 65.8 Intensity score | Standard Deviation 33.80866222 |
| Topical Vehicle | Peak Itch Intensity Between the Vehicle and Active Treatments (Individual and KeAmLi-combo). | 61.9 Intensity score | Standard Deviation 33.95207784 |
Secondary
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.
Time frame: 5 minutes
Population: All subjects received treatment with the 5 topical cream formulations. Quantitative sensory testing was performed on each area of treated skin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Topical KeAmLi Combo | Mechanical Thresholds (Mechanical Detection and Pain). | Mechanical Detection Threshold | 3.519376956 mN | Standard Deviation 0.122225324 |
| Topical KeAmLi Combo | Mechanical Thresholds (Mechanical Detection and Pain). | Mechanical Pain Threshold | 152.3293608 mN | Standard Deviation 90.32609423 |
| Topical Ketamine | Mechanical Thresholds (Mechanical Detection and Pain). | Mechanical Detection Threshold | 3.464204768 mN | Standard Deviation 0.16205246 |
| Topical Ketamine | Mechanical Thresholds (Mechanical Detection and Pain). | Mechanical Pain Threshold | 135.9 mN | Standard Deviation 121.5234567 |
| Topical Amitriptyline | Mechanical Thresholds (Mechanical Detection and Pain). | Mechanical Detection Threshold | 3.573423965 mN | Standard Deviation 0.141531726 |
| Topical Amitriptyline | Mechanical Thresholds (Mechanical Detection and Pain). | Mechanical Pain Threshold | 152.4768146 mN | Standard Deviation 114.1149716 |
| Topical Lidocaine | Mechanical Thresholds (Mechanical Detection and Pain). | Mechanical Pain Threshold | 126.9 mN | Standard Deviation 106.9414678 |
| Topical Lidocaine | Mechanical Thresholds (Mechanical Detection and Pain). | Mechanical Detection Threshold | 3.546037659 mN | Standard Deviation 0.157416303 |
| Topical Vehicle | Mechanical Thresholds (Mechanical Detection and Pain). | Mechanical Detection Threshold | 3.525692637 mN | Standard Deviation 0.169487169 |
| Topical Vehicle | Mechanical Thresholds (Mechanical Detection and Pain). | Mechanical Pain Threshold | 148.7138273 mN | Standard Deviation 104.3418768 |
Secondary
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.
Time frame: 3 minutes
Population: All subjects received treatment with the 5 topical cream formulations. Quantitative sensory testing was performed on each area of treated skin.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Topical KeAmLi Combo | Thermal Threshold Detection (Warmth and Heat Pain) | Warm Detection Threshold | 33.6 Degrees celsius | Standard Deviation 0.303939003 |
| Topical KeAmLi Combo | Thermal Threshold Detection (Warmth and Heat Pain) | Heat Pain Threshold | 39.8 Degrees celsius | Standard Deviation 2.401845207 |
| Topical Ketamine | Thermal Threshold Detection (Warmth and Heat Pain) | Warm Detection Threshold | 34.0 Degrees celsius | Standard Deviation 1.10853976 |
| Topical Ketamine | Thermal Threshold Detection (Warmth and Heat Pain) | Heat Pain Threshold | 40.0 Degrees celsius | Standard Deviation 2.2098072 |
| Topical Amitriptyline | Thermal Threshold Detection (Warmth and Heat Pain) | Warm Detection Threshold | 33.9 Degrees celsius | Standard Deviation 0.649150223 |
| Topical Amitriptyline | Thermal Threshold Detection (Warmth and Heat Pain) | Heat Pain Threshold | 40.0 Degrees celsius | Standard Deviation 2.80388162 |
| Topical Lidocaine | Thermal Threshold Detection (Warmth and Heat Pain) | Heat Pain Threshold | 39.4 Degrees celsius | Standard Deviation 2.305045253 |
| Topical Lidocaine | Thermal Threshold Detection (Warmth and Heat Pain) | Warm Detection Threshold | 33.7 Degrees celsius | Standard Deviation 0.389004867 |
| Topical Vehicle | Thermal Threshold Detection (Warmth and Heat Pain) | Warm Detection Threshold | 33.8 Degrees celsius | Standard Deviation 0.577436619 |
| Topical Vehicle | Thermal Threshold Detection (Warmth and Heat Pain) | Heat Pain Threshold | 39.7 Degrees celsius | Standard Deviation 2.227588606 |