RM1 Project 1 - tAN Naloxone

Early Phase 1

Recruiting

• Conditions: Analgesia
• Interventions: Drug: Naloxone; Drug: Saline

• Registration Number: NCT05490134
• Lead Sponsor: Medical University of South Carolina

Brief Summary

This two-visit, randomized, double-blind, sham-controlled trial, uses a novel naloxone blockade model in 136 individuals to determine whether the analgesic effects of a 30-minute transcutaneous auricular neurostimulation (tAN) intervention are mediated through a release of endogenous opioids. Analgesic effects of four various stimulation interventions will be measured (auricular vagus, auricular trigeminal, combination, or sham) while varying the type of intravenous (IV) infusion (either naloxone or saline) a participant is administered to determine whether the analgesic effects are mitigated by pharmacological opioid receptor blockade.

Detailed Description

The demand for chronic pain treatment has demonstrated an unprecedented increase over the last several decades, in part contributing to an unsustainable surge in opioid prescriptions. Countless patients were escalated to prolonged, high-dose opioid regimens over years of treatment. By 2014, 5.4% of US adults were estimated to use prescription opioids on a long-term basis. As the harms of opioid proliferation became increasingly clear, a dramatic paradigm shift occurred in which these drugs came to be seen as often more dangerous than beneficial for chronic pain. New clinical guidelines highlighted the risks of high-dose regimens as well as limited benefits, particularly insufficient analgesia, associated with long-term use. According to this new perspective, the preferred therapeutic modality for many patients is to significantly reduce, or even completely stop, using opioids.

Stimulation of the auricular branch of the vagus nerve (ABVN) has demonstrated additional benefits for reducing the need for opioids for pain as well as lessening opioid withdrawal symptoms. Clinical trials of ABVN stimulation as an adjunctive treatment for pain have noted decreased intake of tramadol, remifentanil, morphine, as well as naproxen plus tramadol. A pioneering study of electrical stimulation at the cymba conchae in eight persons with opioid use disorder found significantly reduced withdrawal symptoms: first, decreases in anxiety, craving for opioids, chills, nausea; second, reduced bone and joint pain. Results in follow-up clinical trials bolstered the efficacy of ABVN stimulation for opioid withdrawal. More recently, an open-label trial of simultaneous ABVN and trigeminal stimulation found reduced withdrawal symptoms and decreased need for morphine maintenance in newborns with neonatal opioid withdrawal syndrome (see Preliminary Studies, below). This method of simultaneous vagal and trigeminal stimulation via the external ear is known as transcutaneous auricular neurostimulation (tAN), as the targets of electrical stimulation include the ABVN and auriculotemporal nerve (ATN), which is a branch of the mandibular division of the trigeminal nerve. Electrodes applied to select dermatome regions can target ear neural structures and deliver non-invasive VNS and TNS.

Use of tAN devices for pain relief is an attractive alternative to pharmacologic and opioid-based approaches because it is safe and effective and presents no addiction liability. In order to increase clinical adoption and optimize efficacy of these devices, the mechanism of action must be fully characterized.

This study is investigating the anti-pain mechanism behind tAN in a healthy cohort. This study begins to understand whether the anti-pain effects are driven by a release of endogenous opioids - and will accomplish this by administering tAN during aμ-opioid receptor blockade (via naloxone IV). Administering tAN concurrently with IV Naloxone or Saline (control) will allow us to better understand what underlying mechanism drives the analgesic effects of tAN, and whether the blockade of opioid receptors blocks the anti-pain effects of tAN.

Study Timeline

• Study First Submitted: 2022-08-02
• Study First Submitted QC: 2022-08-03
• Study First Posted: 2022-08-05
• Study Start: 2023-03-22
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-09
• Last Update Posted: 2024-12-12
• Primary Completion: 2027-01-01
• Study Completion: 2027-10-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 136

Inclusion Criteria

• Age 18-65
• Have the capacity and ability to provide one's own consent and sign the informed consent document

Exclusion Criteria

• Contraindicated for MRI.
• Any current or recent untreated medical, neurological, or psychiatric conditions
• Metal implant devices in the head, heart or neck.
• History of brain surgery.
• History of myocardial infarction or arrhythmia, bradycardia.
• Personal or family history of seizure or epilepsy or personal use of medications that substantially reduce seizure threshold (e.g., olanzapine, chlorpromazine, lithium).
• Personal history of head injury, concussion, or self-report of moderate to severe traumatic brain injury.
• Individuals suffering from frequent/severe headaches.
• Individuals with a reported history of psychosis or mania, or individuals who are actively manic or psychotic.
• Regular or recent pain medication use
• Moderate to severe alcohol or substance use disorder.
• Psychotropic or cardiac medicines that may interact with naloxone
• Positive urine drug screen for opiate use
• Females who are pregnant or lactating

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
ABVN Only Stimulation	Saline	30 minutes of ABVN Only stimulation (15Hz stimulation of cymba conchae).
Combination (ABVN + ATN) Stimulation	Saline	30 minutes of Combo stimulation (stimulation of both the 15Hz cymba conchae and 100HZ adjacently anterior to the tragus)
ATN Only Stimulation	Saline	30 minutes of ATNS Only stimulation (100Hz stimulation adjacently anterior to the tragus)
Sham Stimulation	Saline	30 minutes of Sham (15Hz stimulation of the earlobe)
ABVN Only Stimulation	Naloxone	30 minutes of ABVN Only stimulation (15Hz stimulation of cymba conchae).
Combination (ABVN + ATN) Stimulation	Naloxone	30 minutes of Combo stimulation (stimulation of both the 15Hz cymba conchae and 100HZ adjacently anterior to the tragus)
ATN Only Stimulation	Naloxone	30 minutes of ATNS Only stimulation (100Hz stimulation adjacently anterior to the tragus)
Sham Stimulation	Naloxone	30 minutes of Sham (15Hz stimulation of the earlobe)

Primary Outcome Measures

Name	Time	Method
Thermal Pain Thresholds	Change from Baseline Pain Threshold at Post-Stimulation Timepoint	Using a quantitative sensory testing paradigm, the investigators will systematically determine information on thermal pain tolerance thresholds (degrees celsius) using a 30 × 30 mm thermode attached to the left forearm of participants.

Trial Locations

Locations (1)

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States