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

Inflammation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02653703
• Other study ID #: N-20130005
• Status: Completed
• Phase: N/A
• First received: January 8, 2016
• Last updated: January 11, 2016
• Start date: October 2014
• Est. completion date: December 2014

Study information

• Verified date: January 2016
• Source: Aalborg University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Danish Medicines Agency
• Study type: Interventional

Clinical Trial 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.

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Hyperalgesia
• Inflammation
• Neurogenic Inflammation
• Pruritus

Intervention

Other:
• Topical L-menthol 40%
Naturally occurring local anaesthetic, counterirritant and TPRM8-agonist. CAS Number: 2216-51-5
• Vehicle, topical ethanol 96%
Organic solvent CAS Number: 64-17-5

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Aalborg University

References & Publications (7)

Andersen HH, Olsen RV, Møller 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. Review. — View Citation

Heyneman CA. Topical nonsteroidal antiinflammatory drugs for acute soft tissue injuries. Ann Pharmacother. 1995 Jul-Aug;29(7-8):780-2. Review. — View Citation

Højland 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. — View 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. Review. — View 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. — View Citation

Namer B, Seifert F, Handwerker HO, Maihöfner C. TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol. Neuroreport. 2005 Jun 21;16(9):955-9. — View Citation

Olsen RV, Andersen HH, Møller 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No

External Links

•   FDA-statement on topical anti-irritants