Auricular Percutaneous Electrical Nerve Field Stimulation (PENFS) Using the BRIDGE Device for Post-Operative Pain Control in Patients Undergoing Liver Transplantation
Phase: NA
Conditions: Liver Failure, Liver Diseases, Alcoholic, Liver Diseases, Pain, Postoperative, Transplant; Failure, Liver, Liver Cirrhosis, Biliary
Sponsor: Duke University

 
 
 
 
 
Auricular Percutaneous Electrical Nerve Field Stimulation (PENFS) using the BRIDGE device for Post-
Operative Pain Control in Patients Undergoing Liver Transplantation 
NCT03265249 
Document Date: 09/24/2020 
 

Purpose of the Study 
Pain after liver transplantation is unavoidable but it often has significant consequences for patients 
during their recovery. Opioid medications are the cornerstone of all pain control plans post-liver 
transplantation; nonetheless, they come at a cost with multiple side effects and potential serious 
adverse effects. Opioids have a profound impact on postoperative gastrointestinal (GI) motility via 
activation of the µ-opioid receptors of the small and large intestines. Slowed gastrointestinal motility 
causes discomfort, pain, and nausea. In fact, opioid medications have been shown to increase the 
incidence of postoperative ileus which can result in delayed time to return of bowel function, longer 
hospital stays, increased incidence of complications, and decreased patient satisfaction. With the use of 
a novel Auricular Percutaneous Electrical Nerve Field Stimulation (PENFS): the BRIDGE device 
(manufactured by Key Electronics [Jeffersonville, IN, USA] and distributed by Innovative Health Solutions 
[Versailles, IN, USA]), pain perception in post-operative patients may be modulated. There is ample data 
on the efficacy of auricular acupuncture and various transcutaneous auricular neurostimulation devices 
for acute pain relief, including post-operative pain. However, the novelty of this device is in using 
alternating currents of stimulation over a large field and with higher voltage in order to influence central 
pain areas.This has the potential to reduce the use of opioid medications, which in turn will reduce the 
incidence of postoperative ileus and reduce patient need for and dependence on narcotic pain 
medications. This can have an enormous economic impact due to decreased length of hospital stays for 
patients who undergo liver transplantation. The aim of the current project is to investigate the 
effectiveness this new, FDA cleared device in reducing or preventing post liver transplantation opioid 
use with improved pain control.If effective, this alternative approach may revolutionize post-operative 
pain management and have a substantial impact on health care costs and morbidity. In addition, opioid 
reduction could potentially lessen the national crisis of opioid addiction. The BRIDGE device has recently 
been approved by the U.S. Food & Drug Administration for use in accupuncture. 
 
Background & Significance 
Liver transplantation has become the standard treatment for many metabolic and end-stage liver 
diseases but remains one of the most complex abdominal surgeries. As such, liver transplantation is a 
growing field with more than 7,500 liver transplants performed in the US in 2016. Many of the 
complications associated with liver transplantation that lengthen hospitalization are related to 
postoperative pain control. Opioid medications are the standard of care and foundation for post-liver 
transplantation pain control and are associated with many side effects including prolonged post-
operative ileus, delayed return of bowel function leading to a longer interval before reinitiating enteral 
nutrition, nausea, and extended time to getting up and out of bed. 
Postoperative pain management has been a challenge since the field of surgery was invented. 
Nonetheless, acupuncture has been around since ancient times to help control pain of many types, as 
have opioid-based medications. Modern scientific approaches have validated the use of acupuncture, 
electroacupuncture, and transcutaneous electric acupoint stimulation (TEAS) for reducing pain scores 
and opioid use after surgery. A meta-analysis by Wu and colleagues found that acupuncture and related 
techniques caused lower utilization of opioid pain medications in the postoperative setting, with the 
most significant opioid reduction seen in patients treated with TEAS. The stimulation of the external ear 
may have particular benefit. A study by Greif et al. evaluated electrical stimulation to a point 3cm 

anterior to the auricular tragus, a site often used by German anesthesiologists to reduce pain 
requirements. They found that those patients having auricular stimulation were able to tolerate more 
painful sensory stimulation before needing rescue narcotics. 
A potentially more effective approach to auricular neurostimulation involves field stimulation of 
multiple points across the ear with alternating current. The BRIDGE device (Innovative Heath Solutions, 
IN, USA) is an externally placed, FDA-cleared device that delivers percutaneous electrical stimulation 
with alternating frequencies to branches of cranial nerves (V, VII, IX, and X) through the external ear via 
a field effect (Fig 1). Preliminary, unpublished animal data indicates that neurostimulation with this 
device leads to a significant decrease in baseline firing of amygdala neurons and pain perception 
through attenuation of spinal neurons and neurons in the central amygdala. Clinically, the BRIDGE 
device has been shown to reduce pain and symptom associated with opioid withdrawal. In that study, 
there was an 85% reduction in symptoms after just one hour of stimulation. The cymba concha region of 
the external ear receives 100% of the afferent auricular vagal nerve distribution through the auricular 
branch of the vagus nerve. Vagal nerve stimulation (VNS) thus is one possible mechanism of the anti-
nociceptive effects noted. In humans, the implantable VNS is documented to improve a variety of pain 
conditions and overall wellbeing. VNS also has demonstrated anti-nociceptive effects by inhibition of 
sensory neurons in the brainstem based on animal models. 
There is now increasing data on non-invasive transcutaneous VNS of the auricle. Human studies indicate 
increased pain threshold and reduced pain sensitivity through activation of central pain modulation 
mechanisms. A fMRI study in healthy adults revealed reduced activity in limbic brain regions and 
improved wellbeing. A central relay station for several cranial nerve signals including cranial nerves V, 
VII, IX, and X is the brainstem nucleus tractus solitarius (NTS).  All of these cranial nerves have 
projections to the external ear where stimulation occurs. The NTS integrates afferent input and relays 
information to other brain regions such as the periaqueductal gray (PAG), hypothalamus and limbic 
regions (amygdala etc) which process behavioral and emotional responses to sensations. The PAG is a 
major pain center in the CNS and integrates somatic and autonomic responses to pain stimuli. 
Stimulation of PAG suppresses nociceptive transmission from the spinal cord and PAG. Notably, 
descending pain inhibition is involved in the anti-nociceptive effects of electroacupuncture in rats. 
Auricular neurostimulation is a potential novel and non-invasive method of pain control following liver 
transplantation in a growing patient population with the probability of significant impact on economics 
and morbidity. We propose a pilot study to investigate the effects of auricular neurostimulation in 
patients receiving a liver transplantation. We will investigate the effects of auricular neurostimulation 
with this novel device and compare it to the current standard of care for pain management following 
liver transplantation. 
The BRIDGE device is an FDA-approved (510(k)140530) and commercially available device manufactured 
by Key Electronics (Jeffersonville, IN, USA) and distributed by Innovative Health Solutions (Versailles, IN, 
USA). BRIDGE is an ambulatory, neurological device which consists of a battery powered, externally 
affixed generator with 4 wire leads attached to 3 electrode/needle arrays and one single point needle. 
The arrays are designed to produce a field effect similar to surgically implanted peripheral 
neurostimulators. One BRIDGE device per patient will be used in this study. The electrodes will be placed 
percutaneously in the external ear with the help of a transilluminator to visualize the neurovascular 

bundles. The BRIDGE device has recently been approved by the U.S. Food & Drug Administration for use 
in accupuncture. 
 
Design & Procedures 
This is a prospective, randomized study to determine the efficacy of the BRIDGE device in reducing pain 
and opioid use in patients following liver transplantation. Subjects will be randomized in a 1:1 ration to 
one of the below groups: 
Group 1: BRIDGE device will be placed by a physician prior to start of the surgery with standard of care 
pain control analgesia 
Group 2: Subjects will receive the standard of care pain control analgesia 
Subjects will be randomized using the blinded envelope method. The manufacturer will provide the 
researchers with one device per package and each package will have a serial number. The devices will be 
stored in the manufacturer’s packaging and stored in a locked office in the Division of Abdominal 
Transplant Surgery and in the primary investigators office, only accessible by research 
coordinators/personnel. A labeled folder for each patient with all questionnaires (0-10 numerical pain 
scale, BAI, PONV, ASP-POQ-R, and symptom surveys) needed for the entire study will also be stored 
similarly. A team member will ask the subject to complete the pre-operative questionnaires and hand 
the device (numbered with serial #) to one of the certified MDs or advance practice providers for 
placement. A device accountability log will be maintained. 
a)   Rationale: Neurostimulation via acupuncture, electroacupuncture, and transcutaneous electric 
acupoint stimulation have proven to be beneficial for pain control in healthy humans when applied to 
the auricular area. This new device uses field stimulation of the auricular with alternating frequencies 
and the use of positive and negative current to prevent nerve saturation.  This allows better and more 
effective stimulation to modulate central pain pathways. Preclinical studies have already demonstrated 
efficacy and clinical studies have demonstrated also demonstrated efficacy and safety. We now propose 
the use of this technique in to more effectively manage pain after liver transplantation. 
b)   Experimental Design: After prescreening and informed consent, patients will be enrolled in the trial. 
The BRIDGE device will be applied after the transplant team determines subject eligible for liver 
transplantation but prior to the start of the surgical procedure.  The 0-10 numeric pain rating scale and 
Beck Anxiety Inventory (BAI) scores will be measured prior to placement of the device, while VAS, 
Postoperative Nausea and Vomiting Intensity scale (PONV), Revised American Pain Society Patient 
Outcome Questionnaire (APS-POQ-R), and daily symptoms surveys will be measured on device days 1-5. 
All patients will receive a standard pain control regimen while hospitalized. 
 
Selection of Subjects 
Patients currently or awaiting listing for a liver transplant will be prescreened by study personnel prior 
to their clinic. A member of the clinical care team known to the potential subject will introduce the 
study and/or study personnel once initial eligibility is confirmed. All patients eligible for liver 

transplantation will be assessed for eligibility and potential study participation. All transplant patients 
undergo social and psychological evaluation prior to transplant. The clinical and study team will address 
any cognitive issues prior to transplant. Subjects that signed consent greater than 1 month prior to 
transplant will be contacted at the time of transplant notification to confirm continued desire to 
participate. Patients with liver failure may also experience liver encephalopathy that would impair their 
ability to consent. For subjects experiencing hepatic encephalopathy we will consent their legally 
authorized representative prior to transplantation. Subjects will be re-evaluated following the liver 
transplant procedure for consent appropriateness. We anticipate enrolling 35 participants in each 
group, for a total of 70 subjects. We will exclude pregnant females form this study as part of clinical 
standard of care for liver transplantation. 
Inclusion criteria: 
≥18 years of age but < 70 years of age 
Actively listed for isolated liver transplantation 
Subject or legally authorized representative able to sign informed consent 
Not currently treated with opioids or any medications that may interact with opioids 
English speaking 
Willing and able to participate and consent to this study 
Exclusion criteria: 
Diagnosis of acute liver failure or primary sclerosing cholangitis (PSC) 
Anticipated that the subject will require a new roux-en-y hepaticojejunostomy 
Current use of opioid use or other substance abuse. 
Chronic pain disorders 
Need for regional anesthesia (regional nerve blocks or epidurals) 
Adhesive allergy/sensitivity 
Subject admitted to the ICU at the time of transplant 
Pregnancy 
Subjects who meet eligibility and sign the consent form will be eligible to be enrolled into the study at 
the time of transplant. All eligible subjects will be recruited from Duke Transplant clinics or during 
hospital admission prior to transplant. 
 
 
 
 

Study Interventions 
Technical Details 
Subjects will prospectively complete the following questionnaires at different time points during the 
study (see Table 1 for timeline): 
Patients will be asked to rate their average level of pain in the past week on an 11-point scale (0-10) at 
baseline and at every time point as listed in table 1 
Beck Anxiety Inventory (BAI): 21-item self-report inventory for measuring the severity of anxiety with 
high internal consistency. Each of the 21-items is rated on a 4-point Likert scale indicating how much 
each symptom bothered the patient in the previous month. This is a reliable and validated self-reported 
measure of anxiety.  This will be performed at baseline, visit 7 and visit 10. 
Postoperative Nausea and Vomiting Intensity scale (PONV): This is a 4-item questionnaire that is a valid, 
reliable, and responsive measure of clinically important postoperative nausea and vomiting. This will be 
performed at baseline, visit 2, 3, 4 and visit 9. 
Revised American Pain Society Patient Outcome Questionnaire (APS-POQ-R): This questionnaire 
measures 6 aspects of patient quality including 1) pain severity and relief, 2) impact of pain on activity, 
sleep, and negative emotions, 3) side effects of treatment, 4) helpfulness of information about pain 
treatment, 5) ability to participate in pain treatment decisions, and 6) use of nonpharmacological 
strategies. This is a reliable, validated, and feasible questionnaire with high internal consistency. This will 
be performed at visit 3, 4 and 5. 
Daily symptom surveys: Post-operative days 0-6, patients will complete a sheet with 16 questions about 
pain intensity, nausea, vomiting, and mobility. This will be performed at each visit starting at visit 4 
through visit 9. 
Patients will receive general anesthesia and post-operative analgesia per standard of care for liver 
transplantation. 
Screen failures: 
Subjects that are unable to complete visit 2 assessments, within the allotted window, will be a screen 
failure. Follow-up assessments will not be performed on screen failure subjects. However, subjects 
randomized to the device may continue to wear the device through the 120 hours regardless of screen 
fail status.   
Auricular Neurostimulation Application: 
The electrodes will be placed percutanesously in the external ear with the help of a transilluminator to 
visualize the neurovascular bundles. Three electrodes will be placed on the ventral and one on the 
dorsal aspect of the ear. The electrodes will be taped and secured behind the ear next to the generator 
itself which is secured to the skin with adhesive. The entire device may be covered by longer hair. Device 
placement training of all physicians, research personnel and advanced practice providers will be 
performed. After completing the baseline assessments above, the BRIDGE device will then be placed on 
the right ear prior to any premedication. 

  
The BRIDGE Surgical kit consists of: (1) An alcohol swab, (2) prep and stay swab, (3) round fixation 
plasters, (4) fixation plasters to fasten the generator, (5) Steri-strip adhesive vial, (6) Sterile wire harness 
pack, (7) Generator, (8) Tweezers, (9) Surgical marker, (10)Transilluminator. 
Bridge Placement Details: 
The neurostimulator placement will be performed as directed and per training protocol instructions 
Before neurostimulator placement, the subject should be advised that some discomfort is normal at first 
but should report if the discomfort persists or gets worse after a few minutes. The patients should be 
advised that they may feel a slight pulsing sensation and perhaps a warming sensation in the ear to 
which the electrodes are affixed. The pulsing and warming sensation may disappear after approximately 
5 minutes. If the discomfort level increases, the offending electrode can be slightly repositioned until the 
patient’s discomfort level decreases to an acceptable level. If there is continued discomfort in one 
specific electrode, it may be removed by cutting the lead. 
The electrodes will be placed percutaneously in the external ear with the help of a transilluminator to 
visualize the neurovascular bundles. Three electrodes will be placed on the ventral and one on the 
dorsal aspect of the ear. The exact location of the implantation may vary slightly from person to person 
but is determined by both knowledge of auricular neuro-anatomy and visualization of the neurovascular 
bundles by transillumination. The electrodes will be taped and secured behind the ear next to the 
generator itself which is secured to the skin with adhesive. The placement of the devices is within 
standard of care by properly trained medical doctors and advance practice providers. 
The device will then be activated. 
Device placement will take approximately 5 minutes. The patient will remain at rest for the next 5 
minutes. Care will be taken not to interfere with standard pre-operative procedures. If the electrodes 
become dislodged a qualified practitioner will re-apply them. 
Subject will then undergo surgery as per standard of care. The patient’s anesthesiologist will be 
informed ahead of time of the device placement. Anesthesiologist and operative room staff will be 
instructed to avoid manipulating the device while moving the patient or during the procedure. 
Patients will be advised not to manipulate the device or immerse the device in water as it is water 
resistant but not water proof. If showering or washing hair, they should place a dry wash cloth or plastic 
covering over the area to protect the device. If the electrodes become dislodged a qualified practitioner 
will re-apply them. 
 
Intraoperative and Postoperative Protocol 
In those randomized to have the BRIDGE device, neurostimulation will be delivered below sensation 
threshold continuously for 120 hours, the duration of the device battery. The anesthesiology team will 
be informed of participation in the study prior to BRIDGE application. It will be discussed that any use of 
regional anesthesia or NSAIDs are not permitted in this study. If the anesthesiologist believes the patient 
has contraindications to other methods of analgesia or anesthesia, or if it may be in the patient’s best 

interest to incorporate regional anesthetic techniques, the patient will be excluded from the study. 
Operating room staff will be instructed to avoid manipulating the device while moving the patient or 
during the procedure. The device does not interfere with any monitoring routinely used in the operating 
room. 
All patients will undergo general anesthesia per standard of care. There will be no intraoperative or 
postoperative use of regional pain therapies (i.e. epidural anesthesia, tranversus abdominis plan blocks); 
anesthetic plan will otherwise be per treating physician. Once the procedure is over and the patient is 
extubated and transferred to the postoperative care unit, both groups (those with the device and those 
without) will continue to receive postoperative pain control per standard of care, as determined by the 
anesthesia and surgical teams. During the hospitalization, the postoperative pain control in all patients 
(both groups) will be per standard of care (opioids) per the adult liver transplant protocol. 
Postoperative ileus will be measured by need for nasogastric decompression for >48 hours; again, these 
events are routinely documented in the medical record as part of routine medical care. Time to sitting 
up in a chair and time to walking will be determined based on patient symptom surveys. Diet will be 
advanced as determined by the primary care team. Once the patients are able to tolerate oral intake, 
oral opioid medications will be started as needed. Escalation of this oral pain regimen will be noted but 
will not warrant exclusion from the study. Patients needing additional pain control with regional 
anesthesia techniques will be excluded from the study at that time. Patients will be discharged from the 
hospital once discharge criteria are met as determined by the treating physician. All patients will receive 
a standard narcotic pain medication prescription at discharge. The patients will receive an information 
sheet upon discharge with study and device information as well as contact information for study team 
members. 
All patients will receive a phone call on device day 30 by the study coordinator, PI, or co-PI. At this time, 
the patients will again be asked to complete the numerical pain scale, BAI, symptom survey, and PONV 
score via telephone, and will be asked if he or she is still requiring narcotic pain medication, or if a refill 
of the narcotic pain medication was needed. 
Device Removal 
The study investigators, PI, or co-PI will remove the device after 120 hours of stimulation. The date and 
time of device removal will be recorded. If the patient is at home after 5 days, then the patient will be 
asked to remove it and to bring it to the next clinic appointment for proper disposal. If a device falls off 
completely, it should not be reapplied. If individual electrodes are dislodged, they can be reapplied with 
household adhesive tape.  If a patient requests withdrawal from the study or removal of the device 
before the 5-day device life has expired, time of removal will be recorded. 
 
Risk/Benefit Assessment 
Overall risks/ discomforts involved are very minimal – Rare (event rate 1% - < 5%) 
Possible risks/discomforts may involve: 
Discomfort upon insertion of the electrodes for < 5 minutes - Rare (event rate 1% - < 5%) 

Discomfort at the lead placement site > 5 minutes – Rare (1 % - < 5%) 
Bleeding at the electrode site if the neurovascular bundle is penetrated - Rare (event rate 1% - < 5%) 
Localized discomfort if the electrodes should become dislodged during the wearing of the device - Rare 
(event rate 1% - < 5%) 
Localized dermatitis - Rare (event rate 1% - < 5%) 
Drop in blood pressure - Rare (event rate 1% - < 5%) 
Syncope (fainting) - Rare (event rate 1% - < 5%) 
Adverse effects to supporting personnel 
Skin piercing with percutaneous needles - Rare (event rate 1 % - < 5%) 
There are numerous, possible direct and long-term benefits to the subjects in this study. The results of 
this study may provide important insights to the medical field regarding a new, non-pharmacologic 
therapy that could improve pain control and quality of life for patients undergoing liver transplantation. 
If effective, a significant decrease or prevention in post-operative opioid use would be a major 
breakthrough in healthcare.  This treatment would then have the potential to be extrapolated to other 
post-operative settings and populations. 
 
Data Analysis & Statistical Considerations 
This randomized study and the subjects will be randomized 1:1 ratio to the treatment groups.  The 
primary efficacy endpoint is opioid usage after surgery in the two groups, and the related secondary 
endpoint is pain score in the two groups at the end of surgery. Normality possible transformations to 
attain normality of these variables will be assessed. These variables will be analyzed using either a two-
sample t-test or non-parametric Wilcoxon test, depending on whether the outcomes are normal or non-
normal.  Analysis will be conducted under Intent-To-Treat (ITT), and any missing outcome will be 
imputed under missing at random (MAR) using multiple imputation methods. In addition, complete case 
analysis will be conducted. Continuous outcomes, adjusted for covarites, will be examined using 
regression analysis. Significance of the results will be examined at a two-tailed 0.05 alpha level. 
Other secondary outcomes are: postoperative nausea and vomiting, postoperative ileus, postoperative 
immobility, length of hospital stay, incidence of ileus and time to return of bowel function, time to 
physical function, complications, and re-hospitalization. Continuous variables here will be analyzed using 
two-sample t-test or non-parametric Wilcoxon test, depending on whether the variables are normal or 
non-normal; categorical variables will be compared using chi-squared tests; time to event analysis will 
be examined using Kaplan-Meier curves. In addition, adjusted continuous outcomes will be examined 
using regression analysis; adjusted dichotomous outcomes will be examined using logistic regression; 
and adjusted time-to-event analysis will be examined using Cox proportional models. These analyses are 
exploratory, and significance will be assessed with and without adjusting for multiple testing. 
  

Adverse events of this trial are infections and complications. Rates of infections and complications 
between the groups will be examined using Fisher’s exact test or Chi-squared test. 
Power: At the least (without any research funding) 25 subjects each will be randomized to the treatment 
groups. At alpha = 0.05 and 80% power and 25 subjects randomized to treatment groups, we should be 
able to observe effect size of about 0.81 between the two groups on the outcome of opioid usage; if we 
secure external funding, we should be able to randomize at least 32 subjects to each of the treatment 
groups.  With 32 subjects in each groups, at alpha = 0.05 and 80% power, we should be able to observe 
effect size of 0.71 between the two groups. If we assume a 20% dropout rate, with the above sample 
sizes, we would observe effect sizes between .69 and 0.80 (Cohen, 1988). 
Analysis will be conducted using statistical software SAS 9.4 (SAS Institute, Inc., Cary, NC).