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.

Delivering transcutaneous auricular neurostimulation (tAN) to improve symptoms associated with opioid withdrawal: results from a prospective clinical trial

“…This evidence suggests that tAN may target, in many cases, the underlying cause of addiction: depression, PTSD, trauma, and overall mental dysfunction (Koob 2020 ). Additionally, in a prospective, open-label trial, tAN demonstrated to be a safe and effective adjuvant treatment to oral morphine therapy in infants suffering from neonatal opioid withdrawal syndrome (Jenkins et al 2021 ).…”

“…The proposed mechanism for tAN is based on pre-clinical and clinical research suggesting that the therapeutic effects of vagus and trigeminal nerve stimulation are related to increased parasympathetic activation and release of endogenous opioids (endorphins) (Jenkins et al 2021 ). tAN therapy targets stimulation of the left AVBN and ATN.…”

“…Furthermore, tAN demonstrated significant improvements related to symptoms of depression and PTSD. Nearly half of patients experienced a clinically meaningfully reduction in depression symptoms, and approximately one-third of patients experienced a clinically Table 3 Change in PHQ-9 and PCL-5 scores at Day 5 in the population without data imputation 1 Excludes one participant with score over 2 standard deviations above the mean 2 Two-tailed, paired t-test 3 Defined as at least a 5-point decrease for PHQ-9 and at least a 10-point decrease for PCL-5 (Jenkins et al 2021). tAN demonstrated acute significant reductions in heart rate and significant increases in R-R interval.…”

Transcutaneous auricular Vagus Nerve Stimulation and Median Nerve Stimulation reduce acute stress in young healthy adults: a single-blind sham-controlled crossover study

“…We recently demonstrated that tcVNS reduced traumatic stress in several markers derived from ECG, RSP, BP, SCG, PPG, and EDA signals (Gazi et al, 2020 , 2021b , c ; Gurel et al, 2020a , b ); manifestations of opioid withdrawal (Gazi et al, 2022a ); and modulates stress-relevant limbic regions (Wittbrodt et al, 2020 , 2021 ). taVNS has been similarly shown to effectively modulate vagal afferents (Nonis et al, 2017 ; Badran et al, 2018b ; Yakunina et al, 2018 ), demonstrating promising results in neonate opioid withdrawal (Jenkins et al, 2021 ), Long COVID mental burden (Badran et al, 2022 ), and depression-related neural activity (Dietrich et al, 2008 ). While not studied as extensively as VNS, tMNS is another PNS modality recently shown to reduce BP in hypertensive participants (Bang et al, 2018 ).…”

Electrical stimulation of the trigeminal nerve improves olfaction in healthy individuals: A randomized, double-blind, sham-controlled trial

“…To date, TNS has shown promise in the treatment of numerous neuropsychiatric conditions [ 33 ] including depression [ 34 ], posttraumatic stress disorder [ 35 ], epilepsy [ 36 ] and migraine [ 37 ]. Additionally, there are three commercially available and FDA-cleared TNS Devices: 1) the Monarch eTNS system, which administers stimulation during sleep for the treatment of adolescent attention deficit hyperactivity disorder (ADHD) [ 38 ], 2) the Cefaly device for migraine, and 3) the Sparrow Therapy System for opioid withdrawal symptom relief [ 39 ]. Although TNS has shown recent potential as a neuromodulation technique for both laboratory and at-home applications, its effects on smell function have yet to be explored.…”