L-menthol as a Topical Counter-irritant to TRPA1-induced Neurogenic Inflammation and Pain

Study Overview
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Brief Summary
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The aim of this study is to quantitatively characterize the effects of L-menthol as a topical counter-irritant on cutaneous pain and hyperalgesia provoked by topical application of the TRPA1-agonist trans-cinnamaldehyde (CA) in healthy human volunteers.

Detailed Description
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This study is designed as an experimental model in healthy humans.

Official Title
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High-concentration L-menthol as a Counter-irritant to TRPA1-induced Neurogenic Inflammation, Thermal and Mechanical Hyperalgesia Caused by Trans-cinnamaldehyde

Conditions
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Inflammation, Pruritus, Hyperalgesia

Intervention / Treatment
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* Other: Topical L-menthol 40%
* Other: Vehicle, topical ethanol 96%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 healthy men and women aged 18-50 years willing to abstain from alcohol, nicotine, caffeine and pain medication 24 hours before experimental sessions Exclusion Criteria: Pregnancy Skin disorders (e.g. contact eczema) Chronic pain conditions Drug addiction defined as the use of cannabis, opioids or other drugs Previous neurologic, musculoskeletal or mental illnesses Lack of ability to cooperate

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


Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Vehicle, topical ethanol 96%<br>Exposure: 10 % topical trans-cinnamaldehyde [CAS Number: 14371-10-9] Vehicle: 96% ethanol | Other: Vehicle, topical ethanol 96%<br>* Organic solvent CAS Number: 64-17-5<br>|
| Experimental: Topical L-menthol 40%<br>Exposure: 10 % trans-cinnamaldehyde [CAS Number: 14371-10-9] Intervention: 40% l-menthol [CAS Number: 2216-51-5] Vehicle: 96% ethanol | Other: Topical L-menthol 40%<br>* Naturally occurring local anaesthetic, counterirritant and TPRM8-agonist. CAS Number: 2216-51-5<br>* Other names: Menthol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spontaneous pain intensity [self-reported on a visual analog scale] | Rating of the overall pain intensity on a visual analog scale (VAS ranging from No pain = 0, to worst imaginable pain =10) once every minute | 0-20 minutes with a sampling frequency of 1/1 min | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurogenic inflammation [Measured by Laser speckle flowmetry in a 3x3 cm area] | Speckle contrast flowmetry (MoorFLPI, Moor Instruments, Devon, UK). The assessment is conducted with a 30-cm distance between the head of the laser and the application area with an exposure time of 8.3ms. Single frame images are analyzed on appertaining software (MoorFLPI Review V 4.0, Moor Instruments), upon which the arithmetic mean flux (arbitrary units) is calculated. The longitudinal analysis of the spatial dispersion of neurogenic inflammation is performed using the line histogram tool. A 7-cm line centered in the area of application was placed longitudinally along the volar forearm and the perfusion intensity is recorded every 2.5 mm. | 20-25 minutes post induction | 
| Heat hyperalgesia | Heat pain threshold assessments is performed with a Medoc Pathway (Medoc Ltd, Ramat Yishay, Israel) equipped with a 3 × 3 cm advanced thermal stimulator probe where the baseline temperature was set to 32 °C. Ramp stimuli of 1 °C/s are delivered and the subjects are asked to identify the heat pain threshold upon which the temperature is returned to the baseline at a rate of 5 °C/s. The test result is calculated as the arithmetic mean of the outcome from three repeated stimuli. Heat hyperalgesia is considered to be a significant drop in heat pain threshold | 25-27.5 minutes post induction | 
| Mechanical hyperalgesia | To evaluate the mechanical pain threshold (MPT) an electronic von Frey transducer and an electronic coVAS connected to a SENSE-Box setup is used (both items: Somedic, Hörby, Sweden). Five ramp stimuli from 0-110 g at a rate of 5g/1 sec with the default stimulus probe is conducted at different locations within the application area. The subjects are instructed to continuously rate the perceived pain on the coVAS ranging from No pain (0) to worst imaginable pain (10). The arithmetic mean of the VAS scores yields three MPTs (fixed to VAS = 0.5, 1 and 2) and an area-under-the-curve (AUC). | 27.5-30 minutes post induction |