Sickle cell disease (SCD) pain can lead to frequent hospitalization and reliance on opioid medications. Trans-auricular vagal nerve stimulation (taVNS) is a non-invasive neuromodulation technique that delivers low-level electrical stimulation to the cymba conchae of the ear—a region innervated exclusively by the auricular branch of the vagus nerve (ABVN). Stimulation of the ABVN activates brainstem nuclei such as the nucleus tractus solitarius and locus coeruleus, modulating autonomic tone, suppressing pro-inflammatory cytokines (e.g., IL-6, TNF-α), and engaging descending inhibitory pain pathways. Clinically, taVNS has been used in chronic inflammatory and neurologic disorders such as epilepsy, migraine, depression, rheumatoid arthritis, and systemic lupus erythematosus. Here we describe a pilot clinical trial evaluating the feasibility, tolerability and efficacy of taVNS in SCD patients hospitalized for an acute pain crisis in a pediatric facility.

This controlled, single-blind feasibility study will enroll 20 individuals aged 7-18 years with SCD, intact outer ear anatomy, at least one prior hospitalization for SCD pain crisis, currently hospitalized for a SCD acute pain crisis. Individuals with a diagnosis of chronic pain are included. Each participant serves as their own control, with pain scores, opioid use, and length of stay of the current taVNS-treated admission compared to a previous admission without taVNS occurring within a year. The Sparrow Link taVNS device is applied to the ear via a disposable earpiece on the cymba conchae, for a minimum of 2 hours and maximum of 24 per day throughout the hospitalization. Intensity is titrated between 20–35 units (2.0–3.5 mA equivalent), based on patient-reported sensory feedback and comfort, by a pediatric anesthesiologist. Feasibility is assessed daily through completion rates, patient self-reported stimulation tolerability (using the Wong-Baker FACES Pain Rating Scale and Functional Status Scale [FSS]), and intervention acceptability. Preliminary efficacy endpoints include daily pain assessment via Wong-Baker FACES, FSS, and a Visual Analog Scale, along with daily tracking of analgesic consumption (medications, dosages, bowel movements, and laxative use). Inflammatory biomarkers, including IL-6, MCP-1, and TNF-α, will be analyzed from plasma collected at the start and end of hospitalization, with a minimum of 3 and maximum of 7 days between the first and second sample collections.

At time of writing, one 18 yo female with HbSS was enrolled and treated for 7 days of an inpatient hospitalization for acute on chronic pain., with pain scores consistently 8-9/10 despite high doses of methadone and IV hydromorphone. TAVNS was initiated on day 14 of hospitalization. Stimulation intensity was titrated from 20 to 35 over the course. Daily wear times ranged from 5.2 hours (Day 1) to 16.7 hours (Day 5). Notable reductions in pain were observed during stimulation: minimum FACES scores were 4 (Day 1), 5 (Days 2–4), 3 (Day 5), 4 (Day 6), and 1 (Day 7). After Day 5, the patient reported mild device-related discomfort attributed to prolonged use, prompting a reduced wear time on Day 6 (8.8 hours). Despite this, analgesic benefit persisted. The patient qualitatively reported feeling more relaxed during stimulation, noting that her chronic lower back discomfort completely resolved and her knees felt “looser” and more flexible. She consistently requested continued use of the device each day, citing noticeable symptom relief. No adverse physiological effects such as bradycardia, skin irritation, or dizziness were observed.

Here we describe a novel use of taVNS to reduce pain in hospitalized patients with SCD. Our first patient tolerated the device well on moderate settings and did not experience any significant adverse effects. Given the first subject's complex pain diagnosis, prolonged hospital stay, and difficulty reducing pain scores on opioids prior to the taVNS device, the reduction in pain scores when the device was in place was considered promising. We anticipate completing enrollment within 6 months. Inflammatory biomarkers will be assessed at the end of the study to prevent batch effects and may be useful in identifying subgroups of patients likely to respond to taVNS. These findings will be crucial in informing subsequent randomized controlled trials of taVNS as a novel approach to pain management in SCD.

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2025
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