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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

EARLY_PHASE1

Total Enrollment

36 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-07-07

Study Completion Date

2023-09-01

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Pain

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SINGLE_GROUP

This study is a randomized, placebo-controlled, crossover trial. The factors determining the conditions varied within individuals are 'TRPM8 inhibitor', 'TRPA1 inhibitor', 'Nav1.7 inhibitor', 'Nav1.8 inhibitor' each with the levels 'inhibitor' or 'control'. The design allows estimating the effect size caused by each factor alone, as well as the fractional inhibition achieved when all four channels are blocked. In a separate condition, the hypothesized action of lidocaine against nerve conduction, thus including cold-induced activity, is intended as positive control.

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Room temperature injection

Pain induced by intradermal injection of fluid with room temperature.

Group Type PLACEBO_COMPARATOR

Room temperature

Intervention Type OTHER

Room temperature injection

Cold temperature injection 1

Pain induced by intradermal injection of increasingly cold fluid down to 3°C.

Group Type PLACEBO_COMPARATOR

Cold temperature

Intervention Type OTHER

Cold temperature injection

Cold temperature injection with lidocain

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including lidocain (unspecific sodium channel blocker).

Group Type ACTIVE_COMPARATOR

Cold temperature

Intervention Type OTHER

Cold temperature injection

Lidocain

Intervention Type DRUG

Unspecific sodium channel blocker

Cold temperature injection 2

Pain induced by intradermal injection of increasingly cold fluid down to 3°C.

Group Type PLACEBO_COMPARATOR

Cold temperature

Intervention Type OTHER

Cold temperature injection

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).

Group Type EXPERIMENTAL

Cold temperature

Intervention Type OTHER

Cold temperature injection

PF-05105679

Intervention Type DRUG

Specific antagonist of the TRPM8 ion channel

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).

Group Type EXPERIMENTAL

Cold temperature

Intervention Type OTHER

Cold temperature injection

A967079

Intervention Type DRUG

Specific antagonist of the TRPA1 ion channel

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).

Group Type EXPERIMENTAL

Cold temperature

Intervention Type OTHER

Cold temperature injection

PF-05089771

Intervention Type DRUG

Specific antagonist of the Nav1.7 sodium channel

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).

Group Type EXPERIMENTAL

Cold temperature

Intervention Type OTHER

Cold temperature injection

PF-06305591

Intervention Type DRUG

Specific antagonist of the Nav1.8 sodium channel

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.

Group Type EXPERIMENTAL

Cold temperature

Intervention Type OTHER

Cold temperature injection

PF-05105679

Intervention Type DRUG

Specific antagonist of the TRPM8 ion channel

A967079

Intervention Type DRUG

Specific antagonist of the TRPA1 ion channel

PF-05089771

Intervention Type DRUG

Specific antagonist of the Nav1.7 sodium channel

PF-06305591

Intervention Type DRUG

Specific antagonist of the Nav1.8 sodium channel

Interventions

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Room temperature

Room temperature injection

Intervention Type OTHER

Cold temperature

Cold temperature injection

Intervention Type OTHER

Lidocain

Unspecific sodium channel blocker

Intervention Type DRUG

PF-05105679

Specific antagonist of the TRPM8 ion channel

Intervention Type DRUG

A967079

Specific antagonist of the TRPA1 ion channel

Intervention Type DRUG

PF-05089771

Specific antagonist of the Nav1.7 sodium channel

Intervention Type DRUG

PF-06305591

Specific antagonist of the Nav1.8 sodium channel

Intervention Type DRUG

Other Intervention Names

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Unspecific sodium channel blocker Specific TRPM8 antagonist Specific TRPA1 antagonist Specific Nav1.7 antagonist Specific Nav1.8 antagonist

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Maximum Eligible Age

70 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes