tAN with Naloxone for Pain Relief

Overseen By Bashar Badran, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Medical University of South Carolina

Must not be taking: Pain medications, Psychotropic, Cardiac

Disqualifiers: Seizure, Epilepsy, Psychosis, Mania, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 1 day

136 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach for pain relief using transcutaneous auricular neurostimulation (tAN). Researchers aim to determine if this method reduces pain by triggering the body’s natural painkillers, known as endogenous opioids. Participants will receive one of four ear stimulations and either naloxone (a medicine that blocks opioids) or a saline solution to assess its effect on pain relief. Those with frequent or severe headaches or who regularly use pain medication might not be suitable for this study. As an Early Phase 1 trial, this research focuses on understanding how this new treatment works in people, offering participants the chance to be among the first to experience this innovative approach.

Will I have to stop taking my current medications?

The trial requires that participants do not use regular or recent pain medications and avoid psychotropic or cardiac medicines that may interact with naloxone. If you are taking these types of medications, you may need to stop them to participate.

What prior data suggests that this transcutaneous auricular neurostimulation is safe for pain relief?

Research shows that naloxone, a key component of this trial's treatment, is generally safe in medical settings. Widely used to reverse opioid overdoses, it has been extensively tested in people. Studies indicate that naloxone can cause withdrawal symptoms in those dependent on opioids, but these symptoms are expected and manageable. Otherwise, naloxone does not appear to pose major risks, even for pregnant women, according to some studies.

The transcutaneous auricular neurostimulation (tAN) aspect of the trial is relatively new. As this trial is in its early stages, limited data exists on its tolerability. However, early trials like this one typically focus on safety, so any side effects will be closely monitored. If early tests find the tAN treatment unsafe, the trial will be adjusted or stopped. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for pain relief typically involve medications like opioids, NSAIDs, or acetaminophen, which can have significant side effects or risk of dependency. Researchers are excited about these investigational treatments because they offer a non-invasive approach using transcutaneous auricular nerve (tAN) stimulation combined with naloxone. This method targets pain by stimulating specific nerves in the ear, potentially reducing pain perception without the side effects associated with traditional medications. Additionally, the use of naloxone, commonly known for reversing opioid overdoses, might enhance the pain relief effect by blocking certain pain pathways. This novel approach could provide an alternative pain management strategy with fewer risks.

What evidence suggests that this trial's treatments could be effective for pain relief?

Research shows that transcutaneous auricular neurostimulation (tAN) might relieve pain by activating the body's natural painkillers, known as endogenous opioids. This method stimulates certain nerves in the ear to potentially reduce pain. In this trial, participants will be assigned to different treatment arms: ABVN Only Stimulation, ATN Only Stimulation, Sham Stimulation, or Combination (ABVN + ATN) Stimulation. Researchers use naloxone to determine if these natural painkillers are active, as naloxone blocks opioid effects. Although direct data on this specific treatment is limited, the concept relies on well-known mechanisms of pain relief. Early indications suggest that this method might mimic the body's natural ability to manage pain. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for individuals aged 18-65 who can consent to participate. It's not suitable for those with a history of head injury, drug use, or certain medical conditions like heart issues or seizures. Pregnant women and people on specific medications that could interact with naloxone are also excluded.

Inclusion Criteria

I can make my own medical decisions and sign consent forms.

Exclusion Criteria

I regularly use pain medication.

I have had a heart attack or an irregular heartbeat.

I am not pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a 30-minute transcutaneous auricular neurostimulation (tAN) intervention with either naloxone or saline infusion to assess analgesic effects

1 day

2 visits (in-person)

Follow-up

Participants are monitored for changes in thermal pain thresholds post-stimulation

1 week

What Are the Treatments Tested in This Trial?

Interventions

• tAN Naloxone

Trial Overview

The study tests if the pain relief from a 30-minute ear neurostimulation (tAN) is due to the body's own opioids. Participants will receive either naloxone, which blocks opioid effects, or saline as a control while undergoing one of four types of tAN interventions.

How Is the Trial Designed?

Group I: Sham Stimulation Experimental Treatment 2 Interventions

30 minutes of Sham (15Hz stimulation of the earlobe)

Group II: Combination (ABVN + ATN) Stimulation Experimental Treatment 2 Interventions

30 minutes of Combo stimulation (stimulation of both the 15Hz cymba conchae and 100HZ adjacently anterior to the tragus)

Group III: ATN Only Stimulation Experimental Treatment 2 Interventions

30 minutes of ATNS Only stimulation (100Hz stimulation adjacently anterior to the tragus)

Group IV: ABVN Only Stimulation Experimental Treatment 2 Interventions

30 minutes of ABVN Only stimulation (15Hz stimulation of cymba conchae).

tAN Naloxone is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Naloxone for:

• Emergency treatment of known or suspected opioid overdose

Approved in European Union as Naloxone for:

• Emergency treatment of opioid overdose

Approved in Canada as Naloxone for:

• Emergency treatment of opioid overdose

Who Is Running the Clinical Trial?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

Published Research Related to This Trial

A survey of 3,255 patients indicated that transdermal buprenorphine is effective for managing chronic pain, with 81% of respondents reporting good or very good pain relief, especially beneficial for those with stable cancer and non-cancer pain.

Adverse effects were generally mild and similar to other opioids, with only 4% experiencing local erythema and 1% pruritus, suggesting that the buprenorphine patch may be a safer alternative for patients who have had side effects from oral pain medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine TDS: use in daily practice, benefits for patients. Radbruch, L.[2022]

In a study involving 445 patients with chronic pain, buprenorphine patches significantly reduced pain intensity and improved sleep duration compared to placebo, indicating their efficacy as a pain management option.

The buprenorphine transdermal system was well-tolerated, with a low incidence of side effects, particularly constipation, and over half of the patients expressed a desire to continue treatment, highlighting its potential as a safe alternative to conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Transdermal buprenorphine for treatment of chronic tumor and non-tumor pain]. Likar, R., Griessinger, N., Sadjak, A., et al.[2022]

Buprenorphine/naloxone has a unique pharmacology that provides a ceiling effect on its cardio-respiratory depressant properties, making it potentially safer than other opioids, especially at higher doses.

Data from various safety monitoring systems indicate that buprenorphine/naloxone has a favorable safety profile compared to other opioids and psychotropic drugs, suggesting it may reduce the risk of overdose-related morbidity and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Question About the Safety of Buprenorphine/Naloxone and Benzodiazepine Drugs. Howland, RH.[2015]

Extended-release naltrexone (XR-NTX) is effective in treating opioid use disorder (OUD), providing patients with the opportunity to reclaim their identity and participate more fully in society, as reported by 19 participants in a qualitative study.

Despite its benefits, patients faced challenges in adjusting to the absence of opioid effects, which could lead to emotional difficulties and increased use of non-opioid substances, highlighting the need for additional support and a comprehensive treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients' experiences of continued treatment with extended-release naltrexone: a Norwegian qualitative study. Marciuch, A., Brenna, IH., Weimand, B., et al.[2022]

A qualitative study involving 36 opioid users revealed that while naloxone is recognized for its life-saving benefits, users also reported negative effects such as severe withdrawal symptoms and a tendency to reuse opioids quickly after an overdose reversal.

Many participants expressed concerns that naloxone might encourage riskier drug use behaviors in others, highlighting the need for better education on naloxone's effects and strategies to manage withdrawal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"A Blessing and a Curse:" Opioid Users' Perspectives on Naloxone and the Epidemic of Opioid Overdose. Kline, A., Mattern, D., Cooperman, N., et al.[2021]

The nonpeptidic delta opioid receptor agonist (+/-) TAN-67 showed strong agonistic activity in lab tests but had weak pain-relieving effects in mice, prompting further investigation into its individual components.

The (-) TAN-67 compound specifically activated delta1 receptors and produced significant pain relief, while the (+) TAN-67 variant caused pain behaviors, indicating that the two enantiomers have very different effects on pain modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacological profile of delta opioid receptor ligands, (+) and (-) TAN-67 on pain modulation. Nagase, H., Yajima, Y., Fujii, H., et al.[2019]

In a study involving 42 healthy participants, the naloxone auto-injector (NAI) was significantly more effective than the intranasal delivery system (NXN) for administering naloxone during a simulated opioid overdose, with 90.5% success for NAI compared to 0% for NXN before training.

After training, 100% of participants successfully used NAI, while only 57.1% could use NXN, highlighting that NAI is easier to use and requires less training for effective administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery. Edwards, ET., Edwards, ES., Davis, E., et al.[2020]

The nonpeptide delta opioid receptor agonist TAN-67 significantly enhances the pain-relieving effects of low-dose morphine, indicating its potential to improve morphine efficacy in pain management.

The mechanism of TAN-67's action appears to involve the activation of central delta 1 opioid receptors, as its effects were blocked by specific delta receptor antagonists, suggesting a complex interaction between mu and delta opioid receptors in modulating pain relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a highly selective nonpeptide delta opioid receptor agonist, TAN-67, on morphine-induced antinociception in mice. Suzuki, T., Tsuji, M., Mori, T., et al.[2019]

The naloxone auto-injector (EZVIO™), approved by the FDA in 2014, is designed for easy use by anyone, including laypersons, to rapidly administer naloxone during an opioid overdose, potentially saving lives.

This device is safe and portable, requiring minimal instruction for use, and should be made widely available to individuals who may encounter opioid users, emphasizing the importance of quick response in overdose situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of the safety and ease of use of the naloxone auto-injector for the reversal of opioid overdose. Merlin, MA., Ariyaprakai, N., Arshad, FH.[2020]

The study found that the FDA-approved 4-mg nasal spray and autoinjector delivered higher plasma concentrations of naloxone compared to an improvised nasal naloxone device (INND), even after two administrations of the INND.

Using the 4-mg nasal spray resulted in the quickest and most effective absorption of naloxone, making it a more reliable option for treating opioid overdoses compared to the INND.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the Pharmacokinetic Properties of Naloxone Following the Use of FDA-Approved Intranasal and Intramuscular Devices Versus a Common Improvised Nasal Naloxone Device. Krieter, PA., Chiang, CN., Gyaw, S., et al.[2021]

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