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

Primary Purpose

Inflammation, Pruritus, Hyperalgesia

Status
Completed
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Topical L-menthol 40%
Vehicle, topical ethanol 96%
Sponsored by
Aalborg University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Inflammation

Eligibility Criteria

18 Years - 50 Years (Adult)Accepts Healthy Volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Placebo Comparator

    Experimental

    Arm Label

    Vehicle, topical ethanol 96%

    Topical L-menthol 40%

    Arm Description

    Exposure: 10 % topical trans-cinnamaldehyde [CAS Number: 14371-10-9] Vehicle: 96% ethanol

    Exposure: 10 % trans-cinnamaldehyde [CAS Number: 14371-10-9] Intervention: 40% l-menthol [CAS Number: 2216-51-5] Vehicle: 96% ethanol

    Outcomes

    Primary Outcome Measures

    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

    Secondary Outcome Measures

    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.
    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
    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).

    Full Information

    First Posted
    January 8, 2016
    Last Updated
    January 11, 2016
    Sponsor
    Aalborg University
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02653703
    Brief Title
    L-menthol as a Topical Counter-irritant to TRPA1-induced Neurogenic Inflammation and Pain
    Official Title
    High-concentration L-menthol as a Counter-irritant to TRPA1-induced Neurogenic Inflammation, Thermal and Mechanical Hyperalgesia Caused by Trans-cinnamaldehyde
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    January 2016
    Overall Recruitment Status
    Completed
    Study Start Date
    October 2014 (undefined)
    Primary Completion Date
    December 2014 (Actual)
    Study Completion Date
    December 2014 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Aalborg University

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    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
    This study is designed as an experimental model in healthy humans.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Inflammation, Pruritus, Hyperalgesia

    7. Study Design

    Primary Purpose
    Basic Science
    Study Phase
    Not Applicable
    Interventional Study Model
    Crossover Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    14 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Vehicle, topical ethanol 96%
    Arm Type
    Placebo Comparator
    Arm Description
    Exposure: 10 % topical trans-cinnamaldehyde [CAS Number: 14371-10-9] Vehicle: 96% ethanol
    Arm Title
    Topical L-menthol 40%
    Arm Type
    Experimental
    Arm Description
    Exposure: 10 % trans-cinnamaldehyde [CAS Number: 14371-10-9] Intervention: 40% l-menthol [CAS Number: 2216-51-5] Vehicle: 96% ethanol
    Intervention Type
    Other
    Intervention Name(s)
    Topical L-menthol 40%
    Other Intervention Name(s)
    Menthol
    Intervention Description
    Naturally occurring local anaesthetic, counterirritant and TPRM8-agonist. CAS Number: 2216-51-5
    Intervention Type
    Other
    Intervention Name(s)
    Vehicle, topical ethanol 96%
    Intervention Description
    Organic solvent CAS Number: 64-17-5
    Primary Outcome Measure Information:
    Title
    Spontaneous pain intensity [self-reported on a visual analog scale]
    Description
    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
    Time Frame
    0-20 minutes with a sampling frequency of 1/1 min
    Secondary Outcome Measure Information:
    Title
    Neurogenic inflammation [Measured by Laser speckle flowmetry in a 3x3 cm area]
    Description
    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.
    Time Frame
    20-25 minutes post induction
    Title
    Heat hyperalgesia
    Description
    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
    Time Frame
    25-27.5 minutes post induction
    Title
    Mechanical hyperalgesia
    Description
    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).
    Time Frame
    27.5-30 minutes post induction

    10. Eligibility

    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    50 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    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

    12. IPD Sharing Statement

    Plan to Share IPD
    Undecided
    Citations:
    PubMed Identifier
    24664788
    Citation
    Olsen RV, Andersen HH, Moller HG, Eskelund PW, Arendt-Nielsen L. Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans-cinnamaldehyde in healthy volunteers. Eur J Pain. 2014 Oct;18(9):1333-42. doi: 10.1002/j.1532-2149.2014.494.x. Epub 2014 Mar 25.
    Results Reference
    background
    PubMed Identifier
    25792226
    Citation
    Hojland CR, Andersen HH, Poulsen JN, Arendt-Nielsen L, Gazerani P. A human surrogate model of itch utilizing the TRPA1 agonist trans-cinnamaldehyde. Acta Derm Venereol. 2015 Sep;95(7):798-803. doi: 10.2340/00015555-2103.
    Results Reference
    background
    PubMed Identifier
    15931068
    Citation
    Namer B, Seifert F, Handwerker HO, Maihofner C. TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol. Neuroreport. 2005 Jun 21;16(9):955-9. doi: 10.1097/00001756-200506210-00015.
    Results Reference
    background
    PubMed Identifier
    18440147
    Citation
    Namer B, Kleggetveit IP, Handwerker H, Schmelz M, Jorum E. Role of TRPM8 and TRPA1 for cold allodynia in patients with cold injury. Pain. 2008 Sep 30;139(1):63-72. doi: 10.1016/j.pain.2008.03.007. Epub 2008 Apr 25.
    Results Reference
    background
    PubMed Identifier
    23963768
    Citation
    Andersen HH, Olsen RV, Moller HG, Eskelund PW, Gazerani P, Arendt-Nielsen L. A review of topical high-concentration L-menthol as a translational model of cold allodynia and hyperalgesia. Eur J Pain. 2014 Mar;18(3):315-25. doi: 10.1002/j.1532-2149.2013.00380.x. Epub 2013 Aug 20.
    Results Reference
    background
    PubMed Identifier
    25861788
    Citation
    Leslie TA, Greaves MW, Yosipovitch G. Current topical and systemic therapies for itch. Handb Exp Pharmacol. 2015;226:337-56. doi: 10.1007/978-3-662-44605-8_18.
    Results Reference
    background
    PubMed Identifier
    8520097
    Citation
    Heyneman CA. Topical nonsteroidal antiinflammatory drugs for acute soft tissue injuries. Ann Pharmacother. 1995 Jul-Aug;29(7-8):780-2. doi: 10.1177/106002809502907-822.
    Results Reference
    background
    PubMed Identifier
    27260636
    Citation
    Andersen HH, Gazerani P, Arendt-Nielsen L. High-Concentration L-Menthol Exhibits Counter-Irritancy to Neurogenic Inflammation, Thermal and Mechanical Hyperalgesia Caused by Trans-cinnamaldehyde. J Pain. 2016 Aug;17(8):919-29. doi: 10.1016/j.jpain.2016.05.004. Epub 2016 May 31.
    Results Reference
    derived

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

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