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

Study Overview
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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.

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.

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

Conditions
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Pain

Intervention / Treatment
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* Other: Room temperature
* Other: Cold temperature
* Drug: Lidocain
* Drug: PF-05105679
* Drug: A967079
* Drug: PF-05089771
* Drug: PF-06305591


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Voltage-gated sodium channels, Sensory neuron, Psychophysics, Human physiology, Cold perception, Transient receptor potential ion channels