Trans-auricular Nerve Stimulation as an Innovative Approach to the Treatment of Pain in Pediatric Patients Suffering From Sickle Cell Disease

Overview

The goal of this study is to evaluate the effects of transauricular vagus and trigeminal nerve stimulation on the treatment of pain in children with Sickle Cell Disease. * The primary objective is to determine the feasibility of using a tAN device to treat pain in pediatric participants with SCD by assessing the completion rate, stimulation tolerability, and acceptability of the intervention measures. * The secondary objective is to assess the preliminary efficacy of using a tAN device as a remedy for pain in pediatric SCD subjects by analyzing inflammatory serum biomarker levels, the Functional Status Scale (FSS), the Wong-Baker FACES questionnaire, tracking analgesic consumption, and other assessments.

Detailed description

The vagus nerve, the body's longest cranial nerve, extends from the brainstem to deep regions of the gastrointestinal tract and plays a vital role in regulating parasympathetic activity across multiple organ systems, including the cardiovascular, respiratory, immune, and nervous systems. Since the early 2000s, vagal nerve stimulation (VNS) has been explored as a therapeutic tool across various diseases, particularly for pain management. VNS can reduce pain by three primary mechanisms: 1) suppressing systemic inflammation, 2) modulating central pain-processing pathways, and 3) alleviating depressive symptoms, which are known to intensify the experience of pain.

Sickle cell disease (SCD) is a genetic blood disorder caused by a point mutation in the β-globin gene, resulting in the production of abnormal hemoglobin (HbS). This leads to polymerization of hemoglobin under low-oxygen conditions, which causes red blood cells to become rigid and sickle-shaped. These malformed cells damage blood vessels and adhere to endothelial surfaces, resulting in vaso-occlusion and impaired blood flow. The subsequent ischemia-reperfusion injury provokes widespread inflammation and produces both acute pain episodes and chronic pain syndromes, often beginning in childhood and persisting throughout life.

The current standard for managing SCD-related pain often involves chronic opioid use, which can lead to dependence, tolerance, and serious side effects. Given the ongoing opioid crisis, there is an urgent need for non-pharmacologic alternatives that are safe, effective, and scalable.

This study proposes the use of transcutaneous auricular vagal nerve stimulation (taVNS) as well as trigeminal auricular nerve stimulation (TAN) -non-invasive methods that stimulates vagal afferents and branches of the trigeminal nerve through the ear-to treat pain in pediatric patients with SCD. taVNS is notable for its excellent safety profile, with minimal to no adverse effects reported in clinical studies. It is a multimodal pain management tool, acting simultaneously on immune, neurologic, and psychological pathways that contribute to pain in SCD.

The innovative aspect of this study lies in its application of a non-invasive, neuroimmune-modulating therapy in a pediatric population with complex pain needs. By potentially reducing the frequency and severity of pain episodes and thereby decreasing reliance on opioids, tAN could transform the clinical approach to pain management in SCD. Ultimately, this research aims to provide a safe, sustainable, and accessible intervention that addresses both the biological and psychosocial dimensions of pain in children and adolescents with SCD.

Interventions

• Device tAN device
  Sparrow Link tAN device from Spark Biomedical, a non-invasive, adhesive earpiece placed over branches of the trigeminal nerve and vagus nerve near the tragus and mastoid around the ear. The stimulation level is titrated by the investigator to a perceptible but comfortable intensity. Patients cannot adjust the settings themselves, though adjustments can be made upon request. The device consists of a disposable earpiece connected by a cable to a battery-powered controller (3 AAA batteries). It em

Primary outcome measures

• Feasibility: Completion Rate [Time frame: Through study completion (an average of 3-7 days)]
• Stimulation tolerability [Time frame: Baseline, everyday throughout the study (an average of 3-7 days)]
• Acceptability of intervention [Time frame: Baseline, everyday throughout the study (an average of 3-7 days)]

Secondary outcome measures (5)

• Wong-Baker FACES [Time frame: Baseline, everyday throughout the study (an average of 3-7 days)]
• Functional Status Scale(FSS) [Time frame: Baseline, everyday throughout the study (an average of 3-7 days)]
• Change in Interleukin 6 (IL-6) levels [Time frame: Baseline, end of the study (an average of 3-7 days)]
• Change in MCP-1 [Time frame: Baseline, end of the study (an average of 3-7 days)]
• Change in Tumor necrosis factor (TNF-α) [Time frame: Baseline, end of the study (an average of 3-7 days)]

Eligibility criteria

Inclusion criteria

• Diagnosis of sickle-cell anemia (HbSS)
• Normal outer ear anatomy and intact skin for tAN placement
• Hospitalized for a pain crisis and experiencing pain as a result of SCD
• Patients must have had at least one prior hospitalization for a sickle cell pain crisis in the past

Exclusion criteria

• History of seizures
• History of uncontrolled psychiatric illness
• Repeated episodes of autonomic instability (apnea or bradycardia) that are not self-resolving
• Cardiomyopathy
• Diagnosis of Acute Chest Syndrome
• Unrepaired congenital anomalies affecting the cardiovascular or respiratory system
• Hemodynamically unstable patients
• Females who are pregnant or lactating. Subjects who refuse a pregnancy test.
• Women of childbearing potential, not using adequate contraception as per the investigator's judgment, or not willing to comply with contraception for the duration of the study
• Patients with a history of surgery within the last 3 months
• Patients who suffered from a stroke within the last 3 months
• Patient admitted with a fever or who develops a fever throughout their hospitalization
• Patients whose disease-modifying therapy (HU, chronic transfusions, etc.) and/or pain medications (gabapentin, pregabalin, etc.) have not yet reached a steady dose
• Patients who have had 3 or more hospitalizations for acute pain crises in a given year

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Children's Hospital of Atlanta: Eagelston — Atlanta

Identifiers

NCT: NCT07090668 · STUDY00008398

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗