The Role of NaV1.8 in Human Pain Models

Overview

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 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.