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

Early Phase 1

Completed

• Conditions: Pain
• Interventions: Other: Room temperature; Other: Cold temperature; Drug: PF-06305591; Drug: Lidocain; Drug: A967079; Drug: PF-05105679; Drug: PF-05089771

• Registration Number: NCT05935280
• Lead Sponsor: Medical University of Vienna

Brief Summary

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.

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 Timeline

• Study First Submitted: 2023-06-28
• Study First Submitted QC: 2023-07-06
• Study Start: 2023-07-07
• Study First Posted: 2023-07-07
• Primary Completion: 2023-09-01
• Study Completion: 2023-09-01
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-13
• Last Update Posted: 2024-03-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 36

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Room temperature injection	Room temperature	Pain induced by intradermal injection of fluid with room temperature.
Cold temperature injection with PF-05105679	Cold temperature	Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05105679 (specific TRPM8 antagonist).
Cold temperature injection 1	Cold temperature	Pain induced by intradermal injection of increasingly cold fluid down to 3°C.
Cold temperature injection with lidocain	Cold temperature	Pain induced by intradermal injection of increasingly cold fluid down to 3°C including lidocain (unspecific sodium channel blocker).
Cold temperature injection with PF-06305591	PF-06305591	Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-06305591 (specific Nav1.8 antagonist).
Cold temperature injection with lidocain	Lidocain	Pain induced by intradermal injection of increasingly cold fluid down to 3°C including lidocain (unspecific sodium channel blocker).
Cold temperature injection with PF-05089771	Cold temperature	Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05089771 (specific Nav1.7 antagonist).
Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591	Cold temperature	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.
Cold temperature injection 2	Cold temperature	Pain induced by intradermal injection of increasingly cold fluid down to 3°C.
Cold temperature injection with A-967079	Cold temperature	Pain induced by intradermal injection of increasingly cold fluid down to 3°C including A-967079 (specific TRPA1 antagonist).
Cold temperature injection with A-967079	A967079	Pain induced by intradermal injection of increasingly cold fluid down to 3°C including A-967079 (specific TRPA1 antagonist).
Cold temperature injection with PF-06305591	Cold temperature	Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-06305591 (specific Nav1.8 antagonist).
Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591	A967079	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.
Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591	PF-05089771	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.
Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591	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.
Cold temperature injection with PF-05105679	PF-05105679	Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05105679 (specific TRPM8 antagonist).
Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591	PF-05105679	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.
Cold temperature injection with PF-05089771	PF-05089771	Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05089771 (specific Nav1.7 antagonist).

Primary Outcome Measures

Name	Time	Method
AUC Pain3°C	Through study completion, on average 90 minutes.	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).

Secondary Outcome Measures

Name	Time	Method
AUC Pain	Through study completion, on average 90 minutes.	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).

Trial Locations

Locations (1)

Medical University of Vienna; 🇦🇹 Vienna, Austria