Transcutaneous Auricular Neurostimulation (tAN) to Mitigate Withdrawal Behaviors in Neonates With Opioid Withdrawal
Phase: NA
Conditions: Neonatal Abstinence Syndrome
Sponsor: Spark Biomedical, Inc.

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PROTOCOL TITLE: 
 
Transcutaneous Auricular Neurostimualtion (tAN) To Mitigate Withdrawal Behaviors In Neonates With 
Opioid Withdrawal  
 
PRINCIPAL INVESTIGATOR: 
 
Dorothea D. Jenkins, M.D. 
 
 
 

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1.0 
Objectives / Specific Aims 
 
The overall aim of this proposed effort is to test transcutaneous auricular neurostimulation (tAN) as a 
therapeutic for opioid withdrawal and neonatal abstinence syndrome (NAS).  
We hypothesize that tAN delivered for up to 60 minutes during peak withdrawal (1h before next morphine 
dose) will be safe, well tolerated and will decrease Finnegan withdrawal scores and shorten the length of 
morphine treatment compared with historical data. 
 
Aim 1: Determine the safety and feasibility of auricular neurostimulation therapy in neonates with 
opioid withdrawal or NAS.  
We hypothesize that auricular neurostimulation is safe and tolerable in both a single session, and 12-day 
treatment course. Furthermore, we believe target engagement can be validated by measuring stimulation-
induced reductions in heart rate. Milestone: No adverse events of bradycardia (HR < 80 bpm), 
worsening of swallowing or feeding, skin irritation, or elevation of Neonatal Infant Pain Scores. 
 
Aim 2: Demonstrate that auricular neurostimulation therapy in opioid withdrawing or NAS 
neonates reduces the Finnegan and/or WAT-1 scores from pre- to post-stimulation. We have used 
ear electrodes for taVNS in a similar stuy (#67997). However, in this prospective, open-label study we 
will use a novel, non-significant risk auricular neurostimulation device and ear electrodes to study 20 
opioid withdrawing or NAS neonates at the Medical University of South Carolina. We aim to show a 
clinically-meaningful reduction in Finnegan scores, the routine assessment that includes 21 signs of 
withdrawal (Finnegan 1992). Alternatively, in infants who receive both opioids and benzodiazepine 
analgesics, we aim to show a clinically-meaningful reduction in Withdrawal Assessment Tool (WAT-1) 
scores, which is a validated, 11 item/12 point scale used to monitor opioid withdrawal in pediatric patients 
(Franck 2008). In the study, we will deliver up to 60 minutes of tAN 1 hour prior to each morphine 
administration, up to 4 times per day for up to 12 days. If morphine is weaned off at or before 10 days, a 
weaning phase for tAN will begin on the following day for 2 days: tAN Weaning Day 1: deliver tAN 
twice  tAN Weaning Day 2: deliver tAN once We will assess each patient with standard Finnegan scores 
and/or WAT-1 before and after stimulation, and monitor use of morphine throughout the study. We 
expect a 25% reduction in Finnegan/WAT scores from before to after sessions of auricular 
neurostimulation.  
 
Drs. Jenkins and Badran have an IRB-approved protocol (#67997) for studying the use of 
transcutaneous auricular vagus nerve stimulation (taVNS) for improving oromotor function in 
newborns. In our taVNS protocol we use an ear clip electrode to devlier the stimuatlion, but this electrode 
has the disadvantage of becoming displaced with head turning, burping etc. Therefore, we propose to use 
Spark Biomedical company’s non-invasive, auricular neurostimulation device in this study to treat opioid 
withdrawal symptoms of babies with NAS. This device will be placed in the ear (similar to a hearing aid) 
and will target trigeminal and vagal nerve branches. Stimulation will be delivered transcutaneously via a 
hydrogel interface similar to the standard EMG and EKG leads we currently use in #67997. This device 
has proven to be safe across many indications with the only side effect being skin irritation. Spark 
Biomedical is curenlty working on FDA clearance for adult opioid withdrawal based on predicate devices 
(K173861, DEN170018). This product will be regulated as a Class II medical device by the FDA.  

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2.0 
Background 
NAS is a condition in which infants undergo withdrawal after exposure to prescription or non-prescription 
opioids such as morphine, methadone or heroin in utero (Finnegan 1992). The withdrawal is characterized 
by hyperirritability of the central nervous system and respiratory, gastrointestinal, and autonomic symptoms 
(Finnegan 1992). These symptoms usually appear within 24 to 72 hours after birth. Opioid withdrawal is 
characterized by CNS dysfunction with loss of glutamate homeostasis,  glutathione dysregulation and 
oxidative stress(McCLure EA e tal, 2014)  leading to poor neuronal health and clinical symptoms of 
hyperirritability, hypertonicity, tremors, high-pitched crying, tachypnea, gastrointestinal symptoms, 
sweating, temperature elevation, sneezing and nasal congestion, and poor feeding, emesis, and loose 
stools.  
 
From 2000 to 2012 there was a five-fold increase in the number of babies born with opioid withdrawal due 
to Neonatal Abstinence Syndrome (NAS, Patrick SW, et al., 2015). It is estimated that one baby is born 
every 25 minutes addicted to opiates (Patrick, et al. 2012). In 2012, term infants being treated for NAS 
stayed on average 16.9 days (compared to 2.1 days for other newborns), often in a neonatal intensive 
care unit (NICU). The length of stay has increased to 25 days in a neonatal intensive care unit (NICU) at 
an average treatment cost of $66K (Barlow 2017, Sanlorenzo 2018). Hospital costs totaled $1.5 billion, 
with 81% paid by state Medicaid programs (Patrick, et al. 2015). Despite improved recognition of NAS and 
early implementation of treatment (both pharmacologic and non-pharmacologic), One of the most 
important reasons for the difficulty in managing slow withdrawal in neonates is polydrug dependency of 
the mother, as opiates plus another substance of abuse has become increasingly common (Grim, 2013).  
 
Currently, treatment consists of either morphine or methadone, occasionally in combination with clonidine 
or phenobarbital, but with inability to truly tailor treatment to the mothers substance(s) of abuse (Bio, et al. 
2011; Hudak, et al. 2012). In addition, oral morphine or methadone have unwanted and harmful side effects 
in the infant (Sublett 2013). Other drugs including clonidine and phenobarbital are also used as adjuncts 
when needed (Sublett 2013). Iatrogenic opioid dependence is also a problem in sick neonates and infants, 
90% of whom require prolonged analgesics for sedation for mechanical ventilation, cardiac procedures, 
and conditions such as sepsis and pulmonary hypertension (Franck, et al., Pain, 2013). As opioid 
withdrawing or NAS babies are already under oxidative stress from opioid withdrawal and/or their 
undelying condition, a non-pharmacological treatment protocol would greatly benefit these 
vulnerable patients, potentially decreasing the need for additional drugs and shortening their 
hospital stay. 
 
Alternative non-pharmacologic approaches 
Auricular acupuncture (Filipelli 2012; Raith 2014) has recently been studied as an adjunctive therapy for 
NAS newborns. Non-insertive acupuncture (NIA) using traditional needles (Filipelli 2012) or a handheld 
laser (Raith 2014) was applied to the ear of newborns with NAS resulting in some of the babies 
becoming more relaxed during their course of treatment. While more in-depth studies are needed to 
evaluate NIA as an effective adjunct therapy for NAS newborns, the early results show promise of 
tapping into the auricular neural pathways for treating NAS. 
A more controlled, repeatable method of neurostimulation may provide effective treatment for 
opioid withdrawal in neonates. 

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Neurostimulation and Opioid Withdrawal. Transcutaneous neural stimulation to treat opioid 
withdrawal in adults has been studied with promising results (Miranda 2017). In the study, an FDA-
cleared auricular stimulation device was used to stimulate the areas in the brain involved in fear, pain, 
and nociception. Clinical opioid withdrawal scale (COWS) scores, which measure the severity of opioid 
withdrawal (Wesson 2003), were recorded before and after auricular neurostimulation. After just 20 
minutes of stimulation, the COWS scores were reduced by 60% and by 85% after 60 minutes of 
stimulation. No rescue medications were required. After 5 days on neurostimulation therapy, patients 
exhibited 97% reduction in COWS scores. As a result of this study, the authors concluded that auricular 
stimulation is associated with a reduction in opioid withdrawal scores. 
3.0 
Intervention to be studied  
The Auricular Branch of the Vagus Nerve. The vagus nerve 
efferently projects to the esophagus, trachea, lungs, heart, pancreas, 
stomach, intestines; and afferently projects to the nucleus tractus 
solitarius (NTS) and other brain regions (Frangos 2015). Activation of 
the NTS plays an important role in modulating cardiopulmonary 
function (Groves 2005, Sluka 2003, Lilei 2013), neuroplasticity 
(Porter 2011, Engineer 2011), systemic inflammation (Koopman 
2016), and epilepsy (Cutsforth 2017). Recently, several studies 
examined the function of the auricular branch of the vagus nerve 
(ABVN), as potential non-invasive method to stimulate the NTS and 
associated structures. The ABVN is a sensory branch of the vagus 
nerve and exclusively innervates the outer ear cymba concha region 
(Figure 1). Through anatomical cadaver studies (Peuker 2002), and 
animal (Gao 2010, Nomura 1984)/human (Frangos 2015) 
physiological studies, there is clear evidence that the ABVN has 
direct modulatory projections to the NTS. Thus, the ABVN serves as 
a non-invasive access point to the brain and central nervous system 
to deliver information, as similar to the cervical vagus nerve. 
Dual nerve stimulation. Sensation of pain is transcended throughout 
both vagus (Page 2008) and trigenimal (Pecikoza 2018) nerve pathways. While vagus nerve stimulation 
has been the subject of many studies, trigeminal nerve stimulation is a newer target, particularly for pain 
treatment and blocking opioid receptors (Abd-Elsayed 2015, Sayegh 2016). Electrical stimulation has been 
shown to successfully treat adults for opioid withdrawal (Meade 2010, Han 1992) by blocking opioid 
receptors. We hypothesize that having the ability to stimulate both the vagus nerve and trigeminal nerve, 
we will be able to saturate opioid receptors and block the effects of withdrawal from opioids such as 
morphine. By blocking a significant amount of opioid receptors through stimulating both the vagus 
and trigeminal nerves, we postulate that transcutaneous auricular neurostimulation (tAN) will 
enable non-pharmacological treatment of opioid withdrawal. 
 
Based on evidence that auricular neurostimulation reduces opioid withdrawal severity in adults, 
our team’s experience in an ongoing clinical study of auricular neurostimulation to improve 
oromotor function in newborns (#67997), we propose to use an auricular neurostimulation device, 
specifically to fit newborns, to treat opioid withdrawal and NAS patients. 
Figure 1: Dermatome 
representations of sensory nerve 
innervations of the outer ear. The 
auricular branch of the vagus 
nerve innervates 100% of the 
cymba concha (red region). 

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Device Description. The “Roo” (Figure 2C) is a non-invasive, battery-operated, prescription device 
designed to transcutaneously stimulate nerves on and/or around the auricle. Electrical stimulation is 
delivered through an ergonomically designed Earpiece (Figure 2A). The Earpiece is a disposable 
component that includes a single flexible circuit board with over molded silicone. The Earpiece contains 
four embedded hydrogel electrodes (Figure 2B), for stimulation of the ABVN and auricular temporal 
branch of trigeminal nerve nerve (ATN). To ensure sufficient skin-contact, the surface surrounding the 
hydrogel electrodes is covered with a medical grade adhesive. The system includes an External Pulse 
Generator (EPG, Figure 2A) that produces a current-controlled, biphasic stimulation output. The EPG 
and the Earpiece are connected to each other via a cable. The Roo device is based on the adult Phoenix 
System, but will fit neoantes and infants.  
A 
B 
 
 
C 
Figure 2. (A) Phoenix System (adult), External Pulse Generator and Earpiece. (B) Phoenix System, 
Patient contacting side of the Earpiece. (C) Roo device, fit for infant use. 
The earpiece is worn around and inside the ear. The four electrodes are positioned to stimulate three 
key dermatome regions (Figure 3, below). These regions are adjacent to several cranial nerves (V, VII, 
IX, X) and occipital nerves. In particular, the electrodes are located in the concha cymba (Figure 3, 
Region 1), on the temporomandibular join region, just anterior to the tragus (Figure 3, Region 2), and 
behind the auricle (Figure 3, Region 3).  

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Initial use. During first use, Dr. Badran will program the device with the study team and set the 
stimulation intensity to just below the perceptual threshold.  
4.0 
Study Endpoints  
Safety Outcomes: 1) Skin irritation, assessed by staff daily. 2) NIPS pain scores recorded during 
treatment. 
Efficacy Outcomes: 1) Finnegan scores before and after tAN will be recorded at each session or WAT-1 
scores will be recorded with hands on care . 2) Duration of morphine weaning. 3) Length of stay 
We will also collect data on developmental outcomes from a short motor test in the nursery and from 
routine clinic visits to the NICU high-risk follow-up clinic up to 24months. 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
 
Inclusion criteria: Neonates or infants with opioid withdrawal or NAS who have withdrawal scores 
requiring morphine replacement therapy. They must be clinically stable, on minimal respiratory support 
(Continuous positive airway pressure (CPAP), nasal cannula, or room air), >33 weeks gestational age at 
enrollment, and currently receiving replacement therapy for opioid dependence. 
 
Exclusion criteria:  
1) Unstable infants or those requiring significant respiratory support.  
2) Repeated episodes of autonomic instability (apnea or bradycardia) which are not self-resolving * 
3) Infants <33weeks gestation at enrollment. 
4) Major unrepaired congenital anomalies  
5) Cardiomyopathy  
 

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*Preterm infants commonly have short periods of shallow or absent breathing or lower heart rate termed 
apnea and bradycardia, respectively, and most are being treated for these physiologic manifestations of 
prematurity with caffeine, an effective central stimulant. Infants are on cardiorespiratory monitors through 
the nursery stay with recording devices to capture events and play them back. However, nearly all of 
these events are self resolving, meaning the infant resolves the breathing pause or bradycardia on their 
own. Infants who require repeated episodes of stimulation to come out of these events are defined as 
unstable. Similarly, infants on significant respiratory support are not stable, and will not be eligible. 
 
Stable neonates who are dependent on opioids, such as after ECMO, severe illness or brain injury, will 
be included in this study, as these neonates represent a population in which tAN could minimize 
withdrawal while not adding to burden of pharmacotherapies. Congenital syndromes may be included if 
the infants do not have major, unrepaired anomalies.  
 
6.0 
Number of Subjects 
 
Total Planned Enrollment: 20  
 
Up to twenty neonates will be enrolled in this prospective, open-label safety and feasibility trial. The 
experimental paradigm consists of up to 60 minutes of tAN at the peak withdrawal time 1 hour before 
usual morphine dose every 3h, before feeding, up to 4 times per day, and up to 12 days or until 
morphine is weaned off. If morphine is weaned off at or before 10 days, a weaning phase for tAN will 
begin on the following day for 2 days: 
 
tAN Weaning Day 1: deliver tAN twice  
 
tAN Weaning Day 2: deliver tAN once 
 
 
All consented participants will receive the active stimulation condition.   
 
7.0 
Setting 
This study will be conducted in the neonatal intensive care nurseries at MUSC. 
 
8.0 
Recruitment Methods 
Prospective participants will be identified by Dr. Jenkins at the neonatal intensive care units (Level II and 
III), and checked for potential inclusion. Clinical teams will mention the study to parents and refer them to 
Dr. Jenkins if they are interested in participating. 
 
9.0 
Consent Process 
Dr. Jenkins will approach parents of stable infants in the nursery who meet inclusion criteria, for 
participation in the study, using the IRB approved consent form. Electronic Consent will be used for 
situations when the parent (or Legally Authorized Representative) is at another hospital and cannot travel 
to MUSC to provide consent in person. We will use the approved REDcap system to obtain consent. Dr. 
Jenkins or other approved study personnel will go over the entire consent document on the phone with 

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the parent to ensure comprehension and to confirm identity. Parent will be given a copy of the 
completed, signed consent form in person or by email or fax. 
 
10.0 
Study Design / Methods 
 
After obtaining consent and describing this procedure to the parents and all members of the baby’s care 
team, we will first deliver stimulation per our protocol in #67997 to determine the perceptual threshold. 
We will use the identical method for determining the intensity for PT, which has proven to be safe as in 
our taVNS study in infant feeding. We will start with 0.2mA with a 250μs, 5Hz in vagus and 100Hz in 
trigeminal nerve area, and gradually increase the intensity of the TENS unit until the baby can first feel 
something in their ear. We will use the facial expression change, fidgety movements to determine when 
the infants feel the stimulation, as in the taVNS study. This intensity will be recorded as the perceptual 
sensory threshold (PT). The procedure is detailed below.  
 
Determination of Perceptual Threshold 
1. Electrode clip will be placed on the left tragus in an enrolled infant at rest. Starting at 0.2mA at 
5Hz in vagus and 100Hz in trigeminal nerve area, we will deliver 5 seconds of pulses, and 
increase by 0.1mA until the perceptual threshold is achieved by observation of the infant’s facial 
expression, fidgety movements. This will be termed the perceptual threshold. 
2. We will decrease the microcurrent by ~0.1mA below the perceptual threshold and administer this 
as the taVNS treatment dose 1h before the morphine dose and before the infant is feeding, every 
3h, for 60 minutes, up to 4 times per day. Current will then be held constant while pulse width and 
frequency will be set at 250µs and 5Hz in vagus area and 100Hz in trigeminal nerve area, 
respectively.  
3. Finnegan scores will be rated before and immediately after the taVNS treatment, and per usual 
clinical protocol. WAT-1 scores will also be rated during tAN treatment per usual clinical protocol.  
4. Physiological data will be monitored continuously as measured by the echocardiogram (ECG).  
5. Neonatal Infant Pain Scale (NIPS) data collected at beginning and the end of treatment session. 
The NIPS rating scale currently in use in the nursery is included in this submission.  
 
taVNS Protocol 
These studies will be conducted in the Shawn Jenkins Children’s Hospital’s Neonatal Intensive Care Unit 
(NICU).  
 
Participants will receive tAN stimulation to their left ear via electrodes attached to the ear. The stimulation 
intensity we will use for tAN will be ~0.1mA less than PT or each infant. We will recalibrate the PT daily, 
and then deliver that current intensity for each session that day administered every 3h, starting 1h before 
the morphine dose. The current will be on for 5 minutes, off for 10 seconds, for up to 60 minutes total 
each session, up to 4 times per day, for up to 12 days or until morphine is weaned off. If morphine is 
weaned off at or before 10 days, a weaning phase for tAN will begin on the following day for 2 days. tAN 
Weaning Day 1: deliver tAN twice. tAN Weaning Day 2: deliver tAN once. 
 

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The nurses will score the NAS using the Finnegan scale before and after the treatment. The Withdrawal 
Assessment Tool (WAT-1) will also be used to assess infant withdrawal symptoms before and after 
treatment in infants receiving benzodiazepines and opioids (Franck 2008, 2013). The WAT-1 is an 11 
item/12 point scale to monitor withdrawal and is routinely performed by nurses 3 times per 12 hour shift 
with hands on care. 
 
Prior to beginning the study, Drs. Jenkins and Badran will perform an in-depth in service with the charge 
nurses of the neonatal nurseries, a limited pool of 10 nurses. They will also in-service the neonatal 
nurses at their staff meetings to introduce them to the study, the rationale, the protocol and the 
equipment. Most nurses are familiar with ear electrode stimulation from the taVNS-paired feeding study 
conducted over the past 18 months.   
 
 
A short developmental test, the STEP, will be performed while the infant is stil in the nursery and at the 
first neonatal high-risk developmental clinic (outpatient) follow-up visit. 
 
Safety Monitoring   
 
Prior to determination of the daily sensory threshold of the infant by the study coordinator or research 
assistant, an initial pain level will be recorded using the NIPS. The nurse or other staff may decrease the 
current intensity or stop stimulation entirely if the infant shows signs of distress or an increase in NIPS 
score >3 above baseline. As opioid withdrawing infants frequently have higher NIPS, we will only halt or 
adjust stimulation if the NIPS is 3 greater than their baseline. The nursing staff routinely measure and 
record the NIPS throughout the day. We will monitor the relationship of increased NIPS scores to the up 
to 60 minute stimulation period daily.  
 
Switching from left to right ear in case of left ear difficulties 
Skin redness at the site of tAN attachment to the ear is possible after treatment, but is expected to be 
transient. In order to prevent injury to the skin in contact with the device, each day the left ear will be first 
examined for redness or other medical device placement prior to attaching the tAN earpiece. If there is 
skin redness or any emergent medical needs at the site of attachment to the ear prior to each day’s 
treatment, we will switch the site of stimulation to the right ear until redness or emergent medical needs 
on left ear are resolved.   
 
 
Estimated Difficulties, Limitations and Time Frames 
Estimated Difficulties: Many of the initial difficulties surrounding taVNS in humans, such as feasibility, 
were accomplished in the taVNS-feeding pilot trial at MUSC by Jenkins and Badran that were approved 
by IRB 1. Electrode placement: The ear electrode is easy to fit to the infant’s ear and much less likely to 
become dislodged due to head movement than the ear electrodes used in our taVNS infant feeding 
study. However, we will make sure the staff feel comfortable placing the electrodes and be on call to 
assist with electrode placement as needed for night shift nurses.  The program will be either on or off 
switch for nurses to activate, but will have ability to decrease stimulation current as needed.  

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Limitations: Finnegan scores may not show a difference acutely with tAN treatment, but may lead to 
faster morphine weaning. However, this is not a randomized study, and we will not be able to determine 
if this is significant, as it will have to be compared with historical control data already collected and 
analyzed in Pro # 63667. Nevertheless, we will show feasibility and safety, and gather data for a larger 
randomized study. 
Estimated Time Frames. We plan on completing enrollment in this study over a 6-12 month period. 
 
 
12.0 
Data Management  
Limited demographic and personal health history data will be collected for the study. All screening data will 
be identified only by study number except for the consent form and a master enrollment file, which will be  
kept in a binder a the locked office, and password protected, respectively, per the requirements of the IRB.  
All infants will be withdrawing from opioids, and will have had urine or meconium drug screens per clinical 
protocol. Also all fetal drug exposures will be a matter of clinical record, and not obtained for this study. 
We will not be doing any drug screening for this study. Study records will be kept confidential. However, 
as we will only have substance use information which is included in the clinical record and already 
known/reported to social services, we will not obtain a certificate of confidentiality.  
Power Calculation: N/A. This is a convenience sample. We estimate we can enroll up to 20 patients 
within 12 months.  
Statstical Analysis: tAN Finnegan scores obtained before and after will be compared within subjects by 
paired test. 
 
13.0 
Provisions to Monitor the Data to Ensure the Safety of Subjects  
Drs. Jenkins and Badran will ensure confidentiality of the subject data, monitor and review adverse 
events, and minimize possible risks associated with tAN procedures.  
Regarding informed consent, participants are fully advised on the research procedures to be used, the 
amount of time required of them, the possible risks and benefits of the procedures, their right to refuse 
participation in the study without prejudice, their right to terminate participation at any moment without 
prejudice, and the name and telephone number of the principal investigator. All subjects will be required 
to have capacity to consent.  
Regarding confidentiality, subjects are informed that the information they provide will be kept strictly 
confidential, with access limited to the research staff. Participation in the study will be treated as 
confidential, as will all records. The identity of subjects will be protected with alphanumeric codes. All 
data will be kept in locked file cabinets or in password-protected files on secure servers with access by 
study team members only.   
 Spark biomedical personnel will receive de-identified patient data via our clinical trial agreement under 
the SBIR. Spark biomedical personnel may review identified patient data on site visits. 
We do not anticipate any adverse events to occur in this study, however the experienced research team 
has a long standing record of recording and reporting unanticipated adverse events to the IRB.  
 

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14. Withdrawal of Subjects 
If any parent wishes to withdraw their infant from treatment, we will immediately terminate the tAN 
sessions, but still continue to collect information on the morphine dosing and length of stay. If a parent 
wishes to withdraw from the study entirely, then no further data will be collected on the patient, but safety 
and treatment data up to that point will be retained under deidentified study number. 
 
15.0 
Risks to Subjects 
tAN is another form of taVNS using transcutaneous electrical nerve stimulation (TENS) of the auricular 
branches of the vagus and trigeminal nerves that innervate the ear. Although this novel therapeutic 
modality is still in the development and optimization process, risks are a combination of those to be 
expected by both the peripheral TENS and taVNS, which has been safely used in neonates and infants 
at MUSC by the study team: Heart rate decrease, discomfort and skin irritation. 
Theoretical risks associated with neuromodulation of the parasympathetic nervous system via taVNS 
would also be applicable in the administration of noninvasive tNS, including reduction of heart rate. In the 
taVNS study we observe a transient 10% decrease of baseline HR with onset of stimulation and rapid 
rebound within 60 seconds. We have seen no epsidsodes of bradycardia related to taVNS stimulation 
and expect none in this protocol. 
TENS devices are FDA approved for pain relief and are available over the counter. The main risks 
associated with TENS is that stimulation may result in discomfort. The unit used in this studies is an FDA 
510(k) cleared electrical stimulator that meets the rigorous electrical standards of the FDA. Skin irritation, 
redness, or inflammation may occur under the stimulating electrodes if TENS current is delivered for a 
prolonged period of time, but is not expected with up to 60 minutes of stimulation, similar to the duration 
of taVNS in protocol #67997.  
Given the minimal risk both of these already FDA approved methods, we expect tAN like taVNS, will be a 
very safe procedure.  
Risk of loss of confidentiality: We will assign study numbers to each participant, keep CRF and 
consent forms in locked cabinets in locked offices. Database files with names and contact information will 
be password protected and stored on the MUSC Pediatric server. All other data files related to this study 
will be identified by participant number only, without link to standard identifiers. We will publish the 
aggregate data only.  
Unknown Risks: TENS stimulation of peripheral nerves is FDA approved and is considered very safe. 
Although tAN is essentially TENS on the ear, it is still an experimental procedure that has not been 
approved by the FDA to improve outcome of infants with opioid withdrawa symptoms. Therefore, there 
may be risks and discomforts that we are not aware of.  
16.0 
Potential Benefits to Subjects or Others 
tAN delivered at the peak time of withdrawal between doses of morphine may decrease behavioral 
scores on the Finnegan scale, and enable faster weaning of morphine or adjunctive medications 
and possibly earlier discharge from hospital. The treatment could potentially help avoid escalation 

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of morphine doses. tAN may also decrease scores on the WAT-1 scale. However, there may be no 
direct benefit to the participant, but we will gain knowledge about tAN in infants, and this information 
may help develop strategies to improve treatment of opioid withdrawal and NAS. 
 
17. Sharing of results with subjects: Individual study results will be known to parents and care 
providers, as this is an open label study. Overall study results will not be shared with subjects unless 
they request it. 
 
18.0 
Drugs or Devices   
The electrode and TENS device will be stored in Dr Jenkins’ office, the Research Clinical Trial lab 
at Shawn Jenkins Children’s Hospital or the Brain Stimulation Laboratory, and brought to the 
bedside of enrolled subjects. Charge nurses and staff will be inserviced on use of the TENs unit, 
and the study team, Dr. Jenkins or Dr Badran will be available for questions about use of the 
device.  
This non significant risk device, similar to taVNS used in Pro # 67997, 89851, 73767, and 86291. 
 
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