The Role of NaV1.8 in Human Pain Models

The Role of NaV1.8 in Human Pain Models - a Randomized, Placebo-controlled Crossover Microdosing Trial

This study aims to understand how NaV1.8, a specific type of sodium channel found in peripheral nerves, contributes to different types of pain in humans. To address this, suzetrigine, a highly selective blocker of the NaV1.8 channel, is used. While current pain medications often have side effects that limit their use, NaV1.8 is a promising target for new, non-opioid pain treatments because it is primarily located in the nerves that send pain signals to the brain.

This study is a randomised, placebo-controlled double-blind crossover microdosing trial. This means that very small, safe amounts of the drug are injected directly into the skin of healthy volunteers to observe its effects locally. This approach ensures the drug works only at the injection site with negligible exposure to the rest of the body.

Healthy volunteers will undergo six different types of brief, controlled pain tests to see which ones are reduced by blocking NaV1.8.

These tests are as follows:

• Electrical stimulation: Brief electrical pulses delivered onto the skin.
• Mechanical stimulation: A standardised "pin-prick" stimulation of the skin.
• Chemical stimulation: An injection of fluid containing capsaicin (the active component of chilli peppers) superficially into the skin.
• Heat stimulation: An injection of hot fluid superficially into the skin.
• Cold stimulation: An injection of cold fluid superficially into the skin.
• Acid stimulation: An injection of acidic fluid superficially into the skin.

By comparing the effects of suzetrigine against a placebo and a standard local anaesthetic (lidocaine), the study will help determine which specific pain modalities critically depend on NaV1.8.

Study Overview

• Status: Recruiting
• Conditions: Pain; Acute Pain; Healthy Volunteer Study
• Intervention / Treatment: Drug: Suzetrigine; Drug: Lidocaine (drug); Drug: Control Solution

Detailed Description

Study Objective:

The primary objective of this trial is to evaluate the analgesic efficacy of selective NaV1.8 inhibition across multiple established experimental human pain models. While selective NaV1.8 inhibitors like suzetrigine have demonstrated success in clinical trials for acute post-surgical pain, it remains unknown whether their efficacy is modality-specific in humans. This study seeks to bridge that gap by testing mechanical, electrical, chemical, and thermal pain induction.

Study Design:

This is a randomised, placebo-controlled double-blind crossover microdosing trial involving healthy volunteers. To isolate the role of NaV1.8 without systemic side effects, the study utilises an intracutaneous microdosing approach. Suzetrigine (1 µM) is administered via local injection, providing an effective local concentration while resulting in a total dose (~1.53 µg) that is approximately 32,000-fold lower than therapeutic oral doses.

Methodology and Pain Modalities:

Participants will receive injections of suzetrigine, a positive control (lidocaine 2 mM), or a negative (vehicle) control at separate, randomised sites on the volar forearms. Subjective pain will be rated on a numerical scale of 0 to 100.

The following six modalities will be tested:

• Electrical Stimulation: Epicutaneous delivery of 5-pulse trains (0.6 ms duration) at 1.5 minutes post-injection.
• Mechanical Stimulation: Suprathreshold pin-prick stimulation using a standardised device at 1.5 minutes post-injection.
• Chemical Stimulation: Intradermal injection of 7.6 ng capsaicin to trigger a transient burning pain sensation.
• Heat Stimulation: A defined, non-hazardous intradermal heat stimulus with increasing temperature from 23°C to 52°C over 150 seconds.
• Cold Stimulation: A defined, non-hazardous intradermal cold stimulus with decreasing temperature from 23°C to 4°C over 150 seconds.
• Acid stimulation: A defined, non-hazardous intradermal acid stimulus delivering a linear pH decrease from 7.2 to 5.4 over 110 seconds.

Hypotheses:

The primary hypotheses are that selective NaV1.8 inhibition will significantly reduce pain scores (or the area under the curve for prolonged stimuli) compared to the vehicle control for each of the six modalities. The secondary hypothesis is that the degree of pain reduction will differ significantly across the various modalities, indicating a modality-specific profile for NaV1.8 in human sensory processing.

Safety and Rationale:

Suzetrigine (marketed as Journavx in the US) has been extensively tested in phase II and III trials and was found to be well-tolerated with no significant CNS or cardiovascular adverse effects. The microdosing model used here further minimises risk by ensuring negligible systemic exposure. Findings from this study will provide critical guidance for the development of future sodium channel inhibitors and the selection of clinical models for testing.

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Felix J. Resch, PhD; Phone Number: +43 1 40160 31419; Email: felix.resch@meduniwien.ac.at
• Study Contact Backup: Name: Michael J.M. Fischer, Professor; Phone Number: +43 1 40160 31410; Email: michael.jm.fischer@meduniwien.ac.at

Study Locations

• Austria
  • State of Vienna
    • Vienna, State of Vienna, Austria, 1090
      • Recruiting
      • Medical University of Vienna
      • Contact: Felix J. Resch, PhD; Phone Number: +43 1 40160 31419; Email: felix.resch@meduniwien.ac.at
      • Contact: Michael J.M. Fischer, Professor; Phone Number: +43 1 40160 31410; Email: michael.jm.fischer@meduniwien.ac.at
      • Principal Investigator: Michael J.M. Fischer, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria

• Age between 18 and 70 years
• Full legal capacity 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
• Verified body temperature above 38°C
• Known allergic diseases, in particular asthmatic disorders
• Limited accessibility of forearms (e.g. orthopedic cast)
• Sensory deficit, skin disease or hematoma at the forarms

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Suzetrigine; Participants receive intracutaneous injections of suzetrigine at a concentration of 1 µM before or during experimental pain induction across six different modalities (electrical, mechanical, capsaicin, acid, heat, and cold).	Drug: Suzetrigine; A selective NaV1.8 inhibitor. It is administered at a concentration of 1 µM via intracutaneous injection at the site of pain induction. The total dose per subject is 1.53 µg.
Active Comparator: Lidocaine; Participants receive intracutaneous injections of lidocaine (positive control) at a concentration of 2 mM before or during experimental pain induction across three out of six different modalities (electrical, mechanical, capsaicin).	Drug: Lidocaine (drug); A non-selective NaV inhibitor. It is administered at a concentration of 2 mM via intracutaneous injection at the site of pain induction. The total dose per subject is 120 µg.
Placebo Comparator: Control solution; Participants receive intracutaneous injections of control solution (negative control) before or during experimental pain induction across six different modalities (electrical, mechanical, capsaicin, heat, and cold).	Drug: Control Solution; A control solution mimicking extracellular fluid. It is administered via intracutaneous injection at the site of pain induction.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Intensity: Electrical stimulation	Metric: Numerical Rating Scale (0-100; 0=No pain, 100=Worst imaginable pain). Calculation: The average of all provided pain ratings divided by the number of delivered stimuli (maximum of 23 stimuli). If a subject stops the test upon reaching a rating of 30, the average is calculated based on the actual number of stimuli delivered.	1.5 minutes post-injection.
Geometric Mean Pain Intensity: Mechanical stimulation	Metric: Numerical Rating Scale (0-100; 0=No pain, 100=Worst imaginable pain). Calculation: The geometric mean of the pain ratings recorded from three standardized mechanical stimuli (3.6N force).	1.5 minutes post-injection.
Area Under the Curve (AUC): Capsaicin injection	Metric: Numerical Rating Scale (0-100; 0=No pain, 100=Worst imaginable pain). Calculation: The AUC of pain ratings provided every 5 seconds, starting from the time of injection until a consecutive rating of 0 is maintained for 30 seconds.	From injection until 0 pain for 30 seconds.
Area Under the Curve (AUC): Acid injection	Metric: Numerical Rating Scale (0-100; 0=No pain, 100=Worst imaginable pain). Calculation: The AUC of pain ratings provided every 5 seconds during the pH decrease from 7.2 to 5.4.	110 seconds
Area Under the Curve (AUC): Heat injection	Metric: Numerical Rating Scale (0-100; 0=No pain, 100=Worst imaginable pain). Calculation: The AUC of pain ratings provided every 5 seconds during the temperature increase from 23°C to 52°C.	150 seconds
Area Under the Curve (AUC): Cold injection	Metric: Numerical Rating Scale (0-100; 0=No pain, 100=Worst imaginable pain). Calculation: The AUC of pain ratings provided every 5 seconds during the temperature decrease from 23°C to 4°C.	150 seconds

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Michael J.M. Fischer, Professor, Medical University of Vienna

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2026
• Primary Completion (Estimated): October 12, 2026
• Study Completion (Estimated): October 12, 2026

Study Registration Dates

• First Submitted: March 28, 2026
• First Submitted That Met QC Criteria: March 28, 2026
• First Posted (Actual): April 6, 2026

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 25, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Electrical stimulation; Microdosing; Nociception; Suzetrigine; VX-548; NaV1.8 Inhibitor; Sodium Channel Blocker; Selective NaV1.8 Antagonist; Intracutaneous injection; Experimental Pain Models; Human Pain Models; Capsaicin-induced pain; Thermal pain (Heat and Cold); Mechanical pain; Acid-induced pain
• Additional Relevant MeSH Terms: Neurologic Manifestations; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Picornaviridae Infections; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Acute Pain; Common Cold; Organic Chemicals; Anilides; Amides; Aniline Compounds; Amines; Acetanilides; Lidocaine; Pharmaceutical Preparations
• Other Study ID Numbers: EK1933/2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD), including pain ratings, time- stamped injection responses, and basic demographics (age, sex), will be shared alongside the publication of the primary results. Only data used in the main publication and relevant supplementary analyses will be included.
• IPD Sharing Time Frame: IPD will be made available at the time of publication of the primary results article, as a supplementary file.
• IPD Sharing Access Criteria: All individuals who have access to the published article will be able to access the individual participant data (IPD) and supporting information as supplementary material. No special request or data use agreement is required.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes