Clinical trial NCT06971250: Peripheral KV7 Activation for Pain Relief
Official title: Peripheral KV7 Activation for Pain Relief - A Randomized, Placebo-Controlled Crossover Microdosing Trial Using Flupirtine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Pain
Keywords: KV7 potassium channels
Flupirtine
Pain modulation
Peripheral analgesia
Experimental pain model
Capsaicin
Microdosing
non-opioid pain treatment
heat pain
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2025-05-14
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This study uses a randomized, placebo-controlled, single-visit crossover design in healthy volunteers. Each participant receives multiple intradermal injections in a predefined sequence, with each injection acting as its own control. A balanced Williams design ensures equal distribution of intervention order. The interventions include capsaicin with or without Flupirtine (multiple doses) and heated fluid injections with or without Flupirtine. Pain intensity is measured every 5 seconds using numeric rating scales. The model is optimized for within-subject comparisons of localized, short-duration nociceptive responses and permits precise analysis of peripheral analgesic effects without systemic drug exposure.
Primary purpose: BASIC_SCIENCE

Brief summary: The goal of this clinical trial is to learn if the drug Flupirtine can safely lower pain when used in tiny amounts directly in the skin. The study will test whether Flupirtine works by activating specific nerve channels in the skin called KV7 potassium channels. These channels help control how pain signals travel to the brain.

The main questions the study aims to answer are:

* Does Flupirtine lower pain caused by capsaicin, the active ingredient in chili peppers?
* Does Flupirtine lower pain caused by heat?

Researchers will compare Flupirtine to a placebo (a look-alike injection that does not contain any drug) to see if Flupirtine lowers pain better than the placebo.

Participants will:

* Receive tiny skin injections that contain either Flupirtine, capsaicin, heat, or placebo
* Rate their pain on a scale from 0 (no pain) to 100 (worst pain imaginable)
* Complete all study procedures during one visit that lasts about 1 hour

Only a small amount of Flupirtine will be used in this study-less than 1/800 of the usual dose. The drug is injected into the skin, not taken by mouth. Because of this, the risk of side effects is extremely low.

This study includes healthy adults between the ages of 18 and 70. It does not include people who are pregnant, taking medications, or who have skin or nerve problems.

The goal is to find out if Flupirtine can be used in the future to treat pain in a new way-by working directly in the skin and not in the brain. This could help avoid side effects like tiredness or dizziness.

The study is sponsored by the Medical University of Vienna and follows all safety and ethical rules.

Detailed description: This randomized, placebo-controlled crossover clinical trial investigates whether a very small (microdose) amount of the drug Flupirtine, when injected directly into the skin, can reduce pain caused by chemical and heat-based stimuli. The research is based on the hypothesis that activating KV7 potassium channels in peripheral sensory nerves can lower pain without involving the central nervous system (brain and spinal cord), potentially offering a new class of non-opioid analgesics with fewer side effects.

Background and Rationale

Pain is the leading reason why people seek medical care. While several types of pain medications exist-such as non-opioid and opioid analgesics, antidepressants, anticonvulsants, and local anesthetics-many have limitations due to side effects, addiction risks, or limited effectiveness in certain pain types. New strategies for safe, targeted pain relief are urgently needed.

Recent research highlights KV7 channels, a group of voltage-gated potassium channels, as promising targets for pain modulation. These channels are expressed in peripheral sensory neurons, including nociceptors in the skin. When activated, they make it less likely for the neuron to send pain signals to the brain. Preclinical studies in animals have shown that activating these channels-particularly the KV7.2/7.3 subtypes-can reduce pain.

Flupirtine, a previously approved non-opioid analgesic, is known to activate KV7 channels. Although it was withdrawn from the market due to rare cases of liver toxicity after long-term, high-dose systemic use, its mechanism of action remains of high scientific interest. Importantly, prior studies suggest that Flupirtine's pain-relieving effects may occur, at least in part, through peripheral activation of KV7 channels.

In this study, Flupirtine is used at doses over 800 times lower than those associated with any systemic toxicity, and is applied locally into the skin to restrict its action to the peripheral nervous system. This "microdosing" strategy is intended to eliminate systemic exposure while retaining local analgesic potential.

Study Objectives

Primary Objective 1:

To test whether pain caused by intradermal injection of 7.6 ng capsaicin (a TRPV1 agonist) is reduced by co-injection of 7.6 µg Flupirtine.

Primary Objective 2:

To test whether pain caused by a slow, intradermal injection of heated fluid (up to \~52°C) is reduced by co-injection of 124 µg Flupirtine.

Secondary Objectives:

* To explore dose-response relationships for lower doses of Flupirtine (0.5 µg, 1.2 µg, 3.0 µg) in the capsaicin pain model.
* To observe pain patterns across all injection types in a within-subjects crossover design.

Study Design

This is a two-part, single-visit, crossover trial in healthy adult volunteers. The study uses a Williams design to balance for injection sequence and period effects.

Each participant undergoes:

* 7 intradermal bolus injections: 1 unblinded familiarization with capsaicin, followed by 6 blinded, randomized injections containing capsaicin ± varying doses of Flupirtine or placebo.
* 4 intradermal slow infusions: 1 unblinded familiarization with room-temperature fluid, followed by 3 blinded, randomized heat infusions with or without Flupirtine.

Each injection site is separated by at least 3 cm on alternating volar forearms. All injections are performed under sterile conditions.

Pain is rated by participants every 5 seconds on a 0-100 numerical scale. Pain ratings continue until the participant reports zero pain for 30 seconds. Pain Area Under the Curve (Pain AUC) is calculated using the trapezoidal rule and serves as the primary outcome.

The total Flupirtine dose per subject across all injections is 136.3 µg, which is less than 0.14 mg, well below known toxicity thresholds. The vehicle for injection is synthetic interstitial fluid with 0.5% DMSO and 0.1% polysorbate 80.

Safety Considerations

Flupirtine's known risk profile includes liver toxicity only after prolonged, high-dose systemic use (200-600 mg daily for \>14 days). This study uses:

* A single dose of \<0.14 mg
* Local intradermal administration, not systemic
* No follow-up dosing

These differences make hepatotoxicity highly unlikely. In addition, no local tissue toxicity is expected, as previous injectable formulations (e.g., Katadolon inject) contained over 100 mg per 3 mL with no reported injection-site damage.

The other injected agent, capsaicin, is widely used in experimental pain research. The dose (7.6 ng in 50 µL) is much lower than in similar studies and causes only brief burning pain with no lasting effects.

Adverse events (AEs) and serious adverse events (SAEs) will be recorded. These may include:

* Mild local skin reactions (e.g., redness, itch)
* Injection site bleeding
* Rare allergic reactions

No follow-up visits are planned, but participants are informed to report any delayed symptoms.

Statistical Analysis

Primary analyses will be performed on the per-protocol set to ensure integrity of the crossover design. Supplementary intention-to-treat analyses will also be performed.

Statistical models include:

* Linear mixed models with injection type (fixed), injection period (fixed), and subject (random)
* Covariate adjustment for insertion pain
* No multiplicity correction, as both objectives are treated as independent

Sample size calculations are based on prior published data (Heber et al. 2019; unpublished heat data). A total of 32 participants will be recruited to allow for 5% dropout and balanced sex representation.

Implications and Future Directions

If successful, this study could support the development of new peripherally acting pain medications based on KV7 activation. Such drugs might avoid central nervous system side effects (like sedation or dizziness) and could represent an important alternative or supplement to current pain therapies-especially for localized inflammatory or neuropathic pain.

Furthermore, a better understanding of peripheral pain pathways could guide drug development that avoids opioid use and its associated risks.

Study Location

All procedures take place at the Department of Anesthesia, Intensive Care Medicine, and Pain Medicine at the Medical University of Vienna.

Ethics and Registration

The study has been reviewed and approved by the local Ethics Committee. It is conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP), and GDPR regulations.

Participants receive full information and provide written informed consent before taking part. Participation is voluntary, and withdrawal is possible at any time without giving a reason.

Results will be submitted for publication in a peer-reviewed journal and presented at relevant scientific conferences. Identifiable data will not be disclosed.

Eligibility criteria: 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 examination of the test site

Primary outcomes:
measure: Pain intensity over time (area under the curve, AUC) after intradermal capsaicin or heat stimulus ± Flupirtine
timeFrame: Immediately post-injection, up to 3 minutes on Day 1
Secondary outcomes:
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
Study officials:
References:
citation: Heber S, Resch F, Ciotu CI, Gleiss A, Heber UM, Macher-Beer A, Bhuiyan S, Gold-Binder M, Kain R, Sator S, Fischer MJM. Human heat sensation: A randomized crossover trial. Sci Adv. 2024 Sep 6;10(36):eado3498. doi: 10.1126/sciadv.ado3498. Epub 2024 Sep 4.
citation: Heber S, Gold-Binder M, Ciotu CI, Witek M, Ninidze N, Kress HG, Fischer MJM. A Human TRPA1-Specific Pain Model. J Neurosci. 2019 May 15;39(20):3845-3855. doi: 10.1523/JNEUROSCI.3048-18.2019. Epub 2019 Mar 12.
citation: Heber S, Ciotu CI, Hartner G, Gold-Binder M, Ninidze N, Gleiss A, Kress HG, Fischer MJM. TRPV1 antagonist BCTC inhibits pH 6.0-induced pain in human skin. Pain. 2020 Jul;161(7):1532-1541. doi: 10.1097/j.pain.0000000000001848.