PainEarly Phase 1NCT05935280
Mechanism of Human Cold Pain Perception - Involvement of TRPA1, TRPM8, Nav1.7 and Nav1.8
A Early Phase 1 study testing Room temperature, Cold temperature and Lidocain in people with Pain, run by Medical University of Vienna at 1 site in Austria.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Pain
- What is being tested?
- Room temperature, Cold temperature and Lidocain
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 36 participants
- Where
- 1 siteAustria
- Study dates
- 7 Jul 2023to 1 Sep 2023
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Human Cold Pain - a Single-group, Randomized, Placebo-controlled, Adaptive, Factorial Crossover Trial
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.
Read the 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.
- Conditions
- Pain
- Being tested
- Room temperature, Cold temperature, Lidocain, PF-05105679, A967079
- Keywords
- Psychophysics, Human physiology, Cold perception, Transient receptor potential ion channels, Voltage-gated sodium channels, Sensory neuron
- Medical subject headings
- Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Room temperatureOther
Room temperature injection
Cold temperatureOther
Cold temperature injection
LidocainDrug
Also called Unspecific sodium channel blocker
Unspecific sodium channel blocker
PF-05105679Drug
Also called Specific TRPM8 antagonist
Specific antagonist of the TRPM8 ion channel
A967079Drug
Also called Specific TRPA1 antagonist
Specific antagonist of the TRPA1 ion channel
PF-05089771Drug
Also called Specific Nav1.7 antagonist
Specific antagonist of the Nav1.7 sodium channel
PF-06305591Drug
Also called Specific Nav1.8 antagonist
Specific antagonist of the Nav1.8 sodium channel
| Study group | Role | What they receive |
|---|---|---|
| Room temperature injection | Placebo comparator | Pain induced by intradermal injection of fluid with room temperature. Receives: Other: Room temperature |
| Cold temperature injection 1 | Placebo comparator | Pain induced by intradermal injection of increasingly cold fluid down to 3°C. Receives: 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). Receives: Other: Cold temperature; Drug: Lidocain |
| Cold temperature injection 2 | Placebo comparator | Pain induced by intradermal injection of increasingly cold fluid down to 3°C. Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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. Receives: Other: Cold temperature; Drug: PF-05105679; Drug: A967079; Drug: PF-05089771; Drug: PF-06305591 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Through study completion, on average 90 minutes.
Secondary outcomes (1)
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).
Measured: Through study completion, on average 90 minutes.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jul 2023
- Study start7 Jul 2023
- Primary completion1 Sep 2023
- Study completion1 Sep 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for PainStudies of the same condition, open and under way.
- More trials run by Medical University of ViennaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Single group
- 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 blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medical University of Vienna
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Stefan Heber, Medical University of Vienna
- Investigators
- Michael JM Fischer, Study chair, Medical University of Vienna
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05935280
- Sponsor's protocol ID
- EK Nr: 1164/2023
- Status last verified
- Mar 2024
- First submitted
- 28 Jun 2023
- Last updated
- 15 Mar 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All raw data will be shared with other researches upon reasonable request.
Publications
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.
PubMed 39693244
Study at a glance
From the registry record, last updated by the sponsor on 15 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Human Cold Pain - a Single-group, Randomized, Placebo-controlled, Adaptive, Factorial Crossover Trial
- ClinicalTrials.gov ID
- NCT05935280
- Acronym / sponsor ID
- EK Nr: 1164/2023
- Conditions
- Pain
- Keywords
- Psychophysics, Human physiology, Cold perception, Transient receptor potential ion channels, Voltage-gated sodium channels, Sensory neuron
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- Medical University of ViennaUniversity, hospital or other
- Study start
- 7 Jul 2023 (actual)
- Primary completion
- 1 Sep 2023 (actual)
- Study completion
- 1 Sep 2023 (actual)
- First posted
- 7 Jul 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 9
- 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.
| Arm | Type | Receives |
|---|---|---|
| Room temperature injection | Placebo comparator | Other: Room temperaturePain induced by intradermal injection of fluid with room temperature. |
| Cold temperature injection 1 | Placebo comparator | Other: Cold temperaturePain induced by intradermal injection of increasingly cold fluid down to 3°C. |
| Cold temperature injection with lidocain | Active comparator | Other: Cold temperature, Drug: LidocainPain induced by intradermal injection of increasingly cold fluid down to 3°C including lidocain (unspecific sodium channel blocker). |
| Cold temperature injection 2 | Placebo comparator | Other: Cold temperaturePain induced by intradermal injection of increasingly cold fluid down to 3°C. |
| Cold temperature injection with PF-05105679 | Experimental | Other: Cold temperature, Drug: PF-05105679Pain induced by intradermal injection of increasingly cold fluid down to 3°C including PF-05105679 (specific TRPM8 antagonist). |
| Cold temperature injection with A-967079 | Experimental | Other: Cold temperature, Drug: A967079Pain induced by intradermal injection of increasingly cold fluid down to 3°C including A-967079 (specific TRPA1 antagonist). |
| Cold temperature injection with PF-05089771 | Experimental | Other: Cold temperature, Drug: PF-05089771Pain 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 | Other: Cold temperature, Drug: PF-06305591Pain 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 | Other: Cold temperature, Drug: PF-05105679, Drug: A967079, Drug: PF-05089771, Drug: PF-06305591Pain 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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Room temperatureRoom temperature injection | Other | Room temperature injection |
| Cold temperatureCold temperature injection | Other | 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 |
| LidocainAlso: Unspecific sodium channel blockerUnspecific sodium channel blocker | Drug | Cold temperature injection with lidocain |
| PF-05105679Also: Specific TRPM8 antagonistSpecific antagonist of the TRPM8 ion channel | Drug | Cold temperature injection with PF-05105679, Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591 |
| A967079Also: Specific TRPA1 antagonistSpecific antagonist of the TRPA1 ion channel | Drug | Cold temperature injection with A-967079, Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591 |
| PF-05089771Also: Specific Nav1.7 antagonistSpecific antagonist of the Nav1.7 sodium channel | Drug | Cold temperature injection with PF-05089771, Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591 |
| PF-06305591Also: Specific Nav1.8 antagonistSpecific antagonist of the Nav1.8 sodium channel | Drug | Cold temperature injection with PF-05105679, A-967079, PF-05089771, PF-06305591, Cold temperature injection with PF-06305591 |
Primary outcome
AUC Pain3°C
Time frame: 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).
1 secondary outcome
AUC Pain
Time frame: Through study completion, on average 90 minutes.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Mar 2024.
- Derived from this study: PubMed 39693244Resch 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.
- Individual participant dataSharing planned: Yes. All raw data will be shared with other researches upon reasonable request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael JM Fischer study chair
Medical University of Vienna
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Room temperature, Cold temperature and Lidocain in people with Pain, run by Medical University of Vienna at 1 site in Austria.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Austria. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
AUC Pain3°C (time frame: Through study completion, on average 90 minutes.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05935280, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Mar 2024.