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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Room temperature injection | Placebo Comparator | Pain induced by intradermal injection of fluid with room temperature. |
|
| Cold temperature injection 1 | Placebo Comparator | Pain induced by intradermal injection of increasingly cold fluid down to 3°C. |
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| 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). |
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| Cold temperature injection 2 | Placebo Comparator | Pain induced by intradermal injection of increasingly cold fluid down to 3°C. |
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| 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). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Room temperature | Other | Room temperature injection |
| |
| 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. |
| 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. |
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Inclusion Criteria:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Michael JM Fischer | Medical University of Vienna | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Medical University of Vienna | Vienna | 1090 | Austria |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39693244 | Derived | 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. |
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All raw data will be shared with other researches upon reasonable request.
As soon as the study is published.
Access will be granted to other researchers as well as clinicians.
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| ID | Term |
|---|---|
| D010146 | Pain |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D003080 | Cold Temperature |
| C560402 | A 967079 |
| C000618268 | PF-05089771 |
| ID | Term |
|---|---|
| D013696 | Temperature |
| D013816 | Thermodynamics |
| D055585 | Physical Phenomena |
| D014887 | Weather |
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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.
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| 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). |
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| 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). |
|
| 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). |
|
| 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. |
|
| Cold temperature |
| Other |
Cold temperature injection |
|
| Lidocain | Drug | Unspecific sodium channel blocker |
|
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| PF-05105679 | Drug | Specific antagonist of the TRPM8 ion channel |
|
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| A967079 | Drug | Specific antagonist of the TRPA1 ion channel |
|
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| PF-05089771 | Drug | Specific antagonist of the Nav1.7 sodium channel |
|
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| PF-06305591 | Drug | Specific antagonist of the Nav1.8 sodium channel |
|
|
| D001272 |
| Atmosphere |
| D004777 | Environment |
| D055669 | Ecological and Environmental Phenomena |
| D001686 | Biological Phenomena |
| D008685 | Meteorological Concepts |
| D004778 | Environment and Public Health |