Mechanism of Human Cold Pain Perception - Involvement of TRPA1, TRPM8, Nav1.7 and Nav1.8

Human Cold Pain - a Single-group, Randomized, Placebo-controlled, Adaptive, Factorial Crossover Trial

Animal studies suggest that the transient receptor potential ion channels TRPM8 and TRPA1 are cold sensors and that sodium channels Nav1.8 and Nav1.7 are essential for detecting pain induced by cold temperatures. This study aims to validate these findings in humans.

Study Overview

• Status: Completed
• Conditions: Pain
• Intervention / Treatment: Other: Room temperature; Other: Cold temperature; Drug: Lidocain; Drug: PF-05105679; Drug: A967079; Drug: PF-05089771; Drug: PF-06305591

Detailed Description

It is essential for human survival to be able to perceive potentially harmful cold. The perception of slight cooling in animals depends on the ion channel TRPM8, but this may represent a largely separate mechanism from painful cold. In mice, TRPM8 and TRPA1 appear to be involved, but also the sodium channels Nav1.7 and Nav1.8, through their temperature-dependent function. These receptors might be redundant, so that failure of individual receptors only leads to no or only a partial reduction in the detection of cold.

Since results obtained in animals do not always translate to humans, the investigators want to clarify whether TRPM8, TRPA1, Nav1.7 and Nav1.8 are involved in the perception of cold pain in humans.

In order to induce cold pain experimentally, an increasingly cooled solution (down to 3°C) is injected into the skin, and the inhibitors for the mentioned targets are added individually and in combination.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age between 18 and 70 years
• Full legal capacity

To ensure an equal number of each sex in the study population, only volunteers of one sex will be included as soon as the number of subjects with the other sex has reached half of the calculated sample size.

Exclusion Criteria:

• Participant of another study, ongoing or within the last 4 weeks
• Medication intake (except contraception) or drug abuse
• Female subjects: Positive pregnancy test or breastfeeding
• Body temperature above 38°C, diagnostically verified
• Known allergic diseases, in particular asthmatic disorders and skin diseases
• Sensory deficit, skin disease or hematoma of unknown origin in physical examination of the test site

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Room temperature injection; Pain induced by intradermal injection of fluid with room temperature.	Other: Room temperature; Room temperature injection
Placebo Comparator: Cold temperature injection 1; Pain induced by intradermal injection of increasingly cold fluid down to 3°C.	Other: Cold temperature; Cold temperature injection
Active Comparator: Cold temperature injection with lidocain; Pain induced by intradermal injection of increasingly cold fluid down to 3°C including lidocain (unspecific sodium channel blocker).	Other: Cold temperature; Cold temperature injection; Drug: Lidocain; Unspecific sodium channel blocker; Other Names: Unspecific sodium channel blocker
Placebo Comparator: Cold temperature injection 2; Pain induced by intradermal injection of increasingly cold fluid down to 3°C.	Other: Cold temperature; Cold temperature injection
Experimental: Cold temperature injection with PF-05105679; Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05105679 (specific TRPM8 antagonist).	Other: Cold temperature; Cold temperature injection; Drug: PF-05105679; Specific antagonist of the TRPM8 ion channel; Other Names: Specific TRPM8 antagonist
Experimental: Cold temperature injection with A-967079; Pain induced by intradermal injection of increasingly cold fluid down to 3°C including A-967079 (specific TRPA1 antagonist).	Other: Cold temperature; Cold temperature injection; Drug: A967079; Specific antagonist of the TRPA1 ion channel; Other Names: Specific TRPA1 antagonist
Experimental: Cold temperature injection with PF-05089771; Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05089771 (specific Nav1.7 antagonist).	Other: Cold temperature; Cold temperature injection; Drug: PF-05089771; Specific antagonist of the Nav1.7 sodium channel; Other Names: Specific Nav1.7 antagonist
Experimental: Cold temperature injection with PF-06305591; Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-06305591 (specific Nav1.8 antagonist).	Other: Cold temperature; Cold temperature injection; Drug: PF-06305591; Specific antagonist of the Nav1.8 sodium channel; Other Names: Specific Nav1.8 antagonist
Experimental: Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591; Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05105679 (TRPM8)-, A-967079 (TRPA1)-, PF-05089771 (Nav1.7)-, PF-06305591 (Nav1.8)- antagonist.	Other: Cold temperature; Cold temperature injection; Drug: PF-05105679; Specific antagonist of the TRPM8 ion channel; Other Names: Specific TRPM8 antagonist; Drug: A967079; Specific antagonist of the TRPA1 ion channel; Other Names: Specific TRPA1 antagonist; Drug: PF-05089771; Specific antagonist of the Nav1.7 sodium channel; Other Names: Specific Nav1.7 antagonist; Drug: PF-06305591; Specific antagonist of the Nav1.8 sodium channel; Other Names: Specific Nav1.8 antagonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC Pain3°C	The primary outcome variable is the area under the curve (AUC) of pain ratings over a limited duration of the infusion period, i.e. from 120-150 seconds (last 30 seconds of the cold stimulus).	Through study completion, on average 90 minutes.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC Pain	The secondary outcome variable is the area under the curve (AUC) of pain ratings over the full duration of the infusion period (full 150 seconds of the cold stimulus).	Through study completion, on average 90 minutes.

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Study Chair: Michael JM Fischer, Medical University of Vienna

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2023
• Primary Completion (Actual): September 1, 2023
• Study Completion (Actual): September 1, 2023

Study Registration Dates

• First Submitted: June 28, 2023
• First Submitted That Met QC Criteria: July 6, 2023
• First Posted (Actual): July 7, 2023

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Psychophysics; Human physiology; Sensory neuron; Cold perception; Transient receptor potential ion channels; Voltage-gated sodium channels
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Membrane Transport Modulators; Anesthetics, Local; Voltage-Gated Sodium Channel Blockers; Lidocaine; Sodium Channel Blockers
• Other Study ID Numbers: EK Nr: 1164/2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All raw data will be shared with other researches upon reasonable request.
• IPD Sharing Time Frame: As soon as the study is published.
• IPD Sharing Access Criteria: Access will be granted to other researchers as well as clinicians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No