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

NCT05935280 | Completed Early Phase 1

• 1 other identifier: EK Nr: 1164/2023
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Pain

Keywords

Psychophysics; Human physiology; Cold perception; Transient receptor potential ion channels; Voltage-gated sodium channels; Sensory neuron

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• AUC Pain

  Through study completion, on average 90 minutes.

Study Arms (9)

Room temperature injection

PLACEBO COMPARATOR

Pain induced by intradermal injection of fluid with room temperature.

Other: Room temperature

Cold temperature injection 1

PLACEBO COMPARATOR

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

Other: Cold temperature

Cold temperature injection with lidocain

ACTIVE COMPARATOR

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

Other: Cold temperature; Drug: Lidocain

Cold temperature injection 2

PLACEBO COMPARATOR

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

Other: Cold temperature

Cold temperature injection with PF-05105679

EXPERIMENTAL

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05105679 (specific TRPM8 antagonist).

Other: Cold temperature; Drug: PF-05105679

Cold temperature injection with A-967079

EXPERIMENTAL

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including A-967079 (specific TRPA1 antagonist).

Other: Cold temperature; Drug: A967079

Cold temperature injection with PF-05089771

EXPERIMENTAL

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05089771 (specific Nav1.7 antagonist).

Other: Cold temperature; Drug: PF-05089771

Cold temperature injection with PF-06305591

EXPERIMENTAL

Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-06305591 (specific Nav1.8 antagonist).

Other: Cold temperature; Drug: PF-06305591

Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591

EXPERIMENTAL

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; Drug: PF-05105679; Drug: A967079; Drug: PF-05089771; Drug: PF-06305591

Interventions

Room temperature OTHER

Room temperature injection

Room temperature injection

Cold temperature OTHER

Cold temperature injection

Cold temperature injection 1; Cold temperature injection 2; Cold temperature injection with A-967079; Cold temperature injection with PF-05089771; Cold temperature injection with PF-05105679; Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591; Cold temperature injection with PF-06305591; Cold temperature injection with lidocain

Lidocain DRUG

Unspecific sodium channel blocker

Also known as: Unspecific sodium channel blocker

Cold temperature injection with lidocain

PF-05105679 DRUG

Specific antagonist of the TRPM8 ion channel

Also known as: Specific TRPM8 antagonist

Cold temperature injection with PF-05105679; Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591

A967079 DRUG

Specific antagonist of the TRPA1 ion channel

Also known as: Specific TRPA1 antagonist

Cold temperature injection with A-967079; Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591

PF-05089771 DRUG

Specific antagonist of the Nav1.7 sodium channel

Also known as: Specific Nav1.7 antagonist

Cold temperature injection with PF-05089771; Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591

PF-06305591 DRUG

Specific antagonist of the Nav1.8 sodium channel

Also known as: Specific Nav1.8 antagonist

Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591; Cold temperature injection with PF-06305591

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Medical University of Vienna: lead

Study Sites (1)

Medical University of Vienna

Vienna, 1090, Austria

Location

Related Publications (1)

• Resch FJ, Heber S, Shahi F, Zauner M, Ciotu CI, Gleiss A, Sator S, Fischer MJM. Human cold pain: a randomized crossover trial. Pain. 2025 Jun 1;166(6):1406-1417. doi: 10.1097/j.pain.0000000000003503. Epub 2024 Dec 17.

  PMID: 39693244 DERIVED

MeSH Terms

Conditions

Pain

Interventions

Cold Temperature; A 967079; PF-05089771

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Temperature; Thermodynamics; Physical Phenomena; Weather; Atmosphere; Environment; Ecological and Environmental Phenomena; Biological Phenomena; Meteorological Concepts; Environment and Public Health

Study Officials

• Michael JM Fischer

  Medical University of Vienna

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: June 28, 2023
• First Posted: July 7, 2023
• Study Start: July 7, 2023
• Primary Completion: September 1, 2023
• Study Completion: September 1, 2023
• Last Updated: March 15, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ANALYTIC CODE
• Time Frame: As soon as the study is published.
• Access Criteria: Access will be granted to other researchers as well as clinicians.

Locations

AU (1)