The Role of NaV1.8 in Human Pain Models

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.

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