Transcutaneous Auricular Neurostimulation (tAN): A Novel Adjuvant Treatment in Neonatal Opioid Withdrawal Syndrome

Abstract

Maternal opioid use during pregnancy is a growing national problem and can lead to newborns developing neonatal opioid withdrawal syndrome (NOWS) soon after birth. Recent data demonstrates that nearly every 15 min a baby is born in the United States suffering from NOWS. The primary treatment for NOWS is opioid replacement therapy, commonly oral morphine, which has neurotoxic effects on the developing brain. There is an urgent need for non-opioid treatments for NOWS. Transcutaneous auricular neurostimulation (tAN), a novel and non-invasive form of electrostimulation, may serve as a promising alternative to morphine. tAN is delivered via a multichannel earpiece electrode worn on and around the left ear, targeting two cranial nerves-the vagus and trigeminal nerves. Prior research suggests that auricular neurostimulation exerts an anxiolytic effect on the body by releasing endogenous opioids and reduces withdrawal symptoms in adults actively withdrawing from opioids. In this first-in-human prospective, open-label trial, we investigated tAN as an adjuvant to morphine therapy in eight infants >33 weeks gestational age suffering from NOWS and receiving oral morphine treatment. Infants received tAN for 30 min 1 h before receiving a morphine dose. tAN was delivered at 0.1 mA below perception intensity at two different nerve targets on the ear: Region 1, the auricular branch of the vagus nerve; and Region 2, the auriculotemporal nerve. tAN was delivered up to four times daily for a maximum of 12 days. The primary outcome measures were safety [heart rate monitoring, Neonatal Infant Pain Scale (NIPS), and skin irritation] and morphine length of treatment (LOT). tAN was well-tolerated and resulted in no unanticipated adverse events. Comparing to the national average of 23 days, the average oral morphine LOT was 13.3 days (median 9 days) and the average LOT after tAN initiation was 7 days (median 6 days). These preliminary data suggest that tAN is safe and may serve as a promising alternative adjuvant for treating NOWS and reducing the amount of time an infant receives oral morphine.

Keywords: bioelectronic medicine; morphine; neonatal opioid withdrawal syndrome (NOWS); non-invasive neuromodulation; opioids; tAN; transcutaneous auricular neurostimulation.

Figure 1

Incorporation of transcutaneous auricular neurostimulation (tAN) therapy with scheduled morphine therapy.

Figure 2

The Roo™ therapy system. (A) The clinician application connects an iOS device to the patient controller using bluetooth low energy. The application allows a clinician to start a communication session with a Patient Controller to adjust therapy parameters, view diagnostic logs, and event history. (B) The Patient Controller delivers electrical stimulation to the earpiece via a removable cable. Clinicians can modulate therapy intensity by pressing up/down buttons and check therapy status with LED lights. (C) The earpiece (skin-facing side) delivers electrical stimulation via four metallic electrodes covered in hydrogel and surrounded with adhesive hydrocolloid (black region). (D) Hypothesized auricular dermatomes. ATN, auriculotemporal nerve; ABVN, auricular branch of the vagus nerve; GAN, greater auricular nerve. Modified from Butt et al. (2020). (E) The Roo system provides stimulation in a bipolar configuration forming stimulation channels/circuits between pairs of electrodes. The system has two channels: Channel 1 is formed between the electrode in Region 1 (ABVN) and the lower electrode in Region 3, and Channel 2 is formed between the electrode in Region 2 (ATN) and the upper electrode in Region 3. (F) Roo system on a neonate.

Figure 3

Individual and combined subjects daily finnegan neonatal abstinence scoring tool (FNAST) value and morphine dose plots. Daily morphine dose 2 days before, during, and 2 days post-tAN therapy. Gray shaded region indicates when tAN therapy was administered. Panel (A) represents individual subject morphine dose and (B) represents mean daily morphine dose across the entire cohort. In (B) the green dash line indicates the Finnegan score threshold requiring a change in morphine dose, the solid green line indicates mean FNAST scores, and the solid blue line indicates mean morphine dose. The number of days on oral morphine before the start of tAN therapy varied across all subjects but was accounted for in total morphine LOT. Data are means ± standard error of the means.

Figure 4

Schematic of hypothesized tAN innervation with central targets. Roo delivers individually tailored electrical stimulation targeting auricular cranial nerve branches of the ABVN (Vagus) and ATN (Trigeminal) nerves. These nerves send afferent signals to the NTS and TCC. The information is processed in the medulla and relayed to higher regions which may lead to the release of endogenous opioids (endorphins) and alleviation of opioid withdrawal symptoms. ABVN, auricular branch of the vagus nerve; Amyg, amygdala; Arc, arcuate nucleus; ATN, auriculotemporal nerve; LC, Locus coeruleus; NAC, nucleus accumbens; NTS, nucleus tractus solitarius; PB, parabrachial nucleus; PFC, prefrontal cortex; TCC, trigeminocervical complex; VTA, ventral tegmental.