Percutaneous Auricular Neuromodulation for Postoperative Analgesia: A Randomized, Participant- and Observer-Masked, Sham-Controlled Pilot Study
Phase: NA
Conditions: Postoperative Pain, Acute
Sponsor: University of California, San Diego

Official Title:  Percutaneous Auricular Neuromodulation for 
Postoperative Analgesia:  A Randomized, Participant- and 
Observer-Masked, Sham-Controlled Pilot Study 
 
 
 
NCT:  05521516 
 
 
 
Document date:  May 20, 2022 
 

 
 
 
UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN 
Instructions for completing the Research Plan are available on the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 9/30/2013 
1. 
PROJECT TITLE 
Percutaneous Auricular Neuromodulation for Postoperative Analgesia:  A Randomized, 
Participant- and Observer-Masked, Sham-Controlled Pilot Study 
 
2. 
PRINCIPAL INVESTIGATOR  
Brian Ilfeld, MD, MS 
 
3. 
FACILITIES 
UCSD health system:  Thornton Hospital, Jacobs Medical Center, Hillcrest Medical Center, KOP 
 
4. 
ESTIMATED DURATION OF THE STUDY 
Three years (1 month preparation, 24 months enrollment, 11 months publication prior to closure) 
 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
The moderate-to-severe pain many patients experience following surgery is often treated with 
opioids, which are associated with side effects such as nausea/vomiting, sedation, and respiratory 
depression (and a risk of abuse, dependence, and diversion).  Potent site-specific analgesia with 
fewer side effects may be provided with peripheral nerve blocks.  However, these too have limitations 
such as a duration of action measured in hours, while the pain from surgery is usually measured in 
days or weeks.  Peripheral nerve stimulation or “neuromodulation” is an alternative method of pain 
control involving the introduction of electrical current to stimulate various nerves that do not carry 
pain sensations, but which then decreases communication between pain fibers and the spinal cord 
and/or brain.  Placing small electrodes specifically in the area of the ear is called “auricular 
neuromodulation” and is theorized to function by stimulating various cranial and peripheral nerves 
that influence a part of the brain called the “limbic system” which is involved with many aspects of 
behavior including responses to stress.  A device that delivers auricular neuromodulation, the 
“Bridge” system, is approved by the US FDA for use to reduce symptoms associated with opioid 
withdrawal for up to 5 days.  However, one prospective and two published retrospective studies 
suggest that it may provide postoperative analgesia as well.  The device itself is relatively simple to 
apply; has few contraindications, side effects, or adverse events; and has no potential for 
dependence, abuse, or diversion.  Therefore, it has the potential to concurrently improve analgesia 
and decrease or even negate opioid requirements following surgery, only without the limitations of 
opioids and peripheral nerve blocks.  The purpose of this pilot study is to explore the possibility of 
treating postoperative pain with percutaneous auricular neuromodulation, optimize the study protocol, 
and estimate the treatment effect in preparation for developing a subsequent definitive clinical trial. 
 
6. 
SPECIFIC AIMS 
The proposed study will be a randomized, participant- and observer-masked, sham-controlled, 
parallel-arm, human participants pilot study with two primary aims: 
 
Specific Aim 1:  To determine the feasibility and optimize the protocol for a subsequent clinical 
trial that will compare the addition of percutaneous auricular neuromodulation to usual and 
customary analgesia following moderate-to-severely painful surgical procedures. 
 

 
 
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Specific Aim 2:  To estimate the treatment effect of adding percutaneous auricular 
neuromodulation to usual and customary analgesia on pain and opioid consumption following 
various surgical procedures.  This will provide an idea of the optimal surgical procedures 
amenable to this analgesic technique and allow determination of the required sample size of a 
subsequent definitive clinical trial. 
 
Hypothesis 1:  Auricular neuromodulation decreases pain in the 5 days following moderate-to-
severely painful surgical procedures currently treated with a single-injection peripheral nerve 
block. 
 
Hypothesis 2:  Auricular neuromodulation decreases opioid use in the 5 days following moderate-
to-severely painful surgical procedures currently treated with a single-injection peripheral nerve 
block. 
 
 
7. 
BACKGROUND AND SIGNIFICANCE 
The moderate-to-severe pain many patients experience following surgery is often treated with 
opioids, which are associated with side effects such as nausea/vomiting, sedation, and respiratory 
depression (and a risk of abuse, dependence, and diversion).  Potent site-specific analgesia with 
fewer side effects may be provided with peripheral nerve blocks.  However, these too have limitations 
such as requiring an anesthesiologist for administration, a duration of action measured in hours, and 
rendering the target area/limb insensate. 
 
An analgesic alternative with few associated limitations is neuromodulation.  Below the foramen 
magnum, this technique is based on Melzack and Wall’s “gate control theory” in which electric current 
stimulates large-diameter afferent peripheral nerves that subsequently interrupt communication (the 
“gate”) from small-diameter pain fibers to the central nervous system at the level of the spinal cord.2  
In contrast, the mechanism of action for nerves above the foramen magnum is multifactorial and less 
well elucidated, although indirect “gating” has been hypothesized.1  Functional MRI studies suggest 
that stimulation of one part of the ear—the “cymba conchae” just posterior to the crus of the helix—
results in activation of the primary somatosensory cortex, amygdala, fornix, thalamus and insula; and 
deactivation of the hippocampus and hypothalamus.2  However, the peri-auricular innervation is very 
complex with contributions from cranial nerves V (auriculotemporal branch of the mandibular nerve), 
VII (posterior auricular branch of the facial nerve), IX (glossopharyngeal nerve) and X (auricular 
branch of the vagus nerve) as well as the occipital and great auricular nerves from the 2nd and 3rd 
cervical levels.3  Stimulation of different anatomic locations results in differing effects, although all 
sites are believed to influence the limbic system which is involved with many aspects of behavior, 
including responses to stress.3 
 
Additional possible mechanisms for auricular neuromodulation are multifactorial, complex, and only 
partially understood.1  They include the modulation of serotonergic, noradrenergic, and 
endorphinergic pathways with associated release of serotonin, norepinephrine, and endogenous 
opioids such as beta-endorphins.4  Vagal stimulation further chemically modulates nociceptive (pain) 
processing, anxiety, and depression.5,6  Many neurotransmitters are influenced, such as increasing 
gamma-aminobutyric acid (GABA) which can lead to anxiolysis.7  Complex neuropathways exist from 
the auricle to the brainstem, higher brain structures, the spinal cord, and finally to multiple organs via 
spinal nerves.1  Given the large number of effects auricular stimulation produces, it is unsurprising 
that it has multiple therapeutic uses, including treating neurological (e.g. epilepsy), inflammatory, and 

 
 
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cardiovascular disorders; metabolic syndromes; psychiatric symptoms and disorders (e.g., anxiety, 
depression, autism);8 as well as multiple pain conditions.7 The auricular neuromodulation device 
proposed in the current study—the NSS-2 Bridge—is FDA cleared to reduce symptoms associated 
with opioid withdrawal.9-11  Three small uncontrolled retrospective and prospective studies suggest 
that this device may also provide analgesia and/or decreases opioid use following surgery.12-14  The 
proposed mechanisms for these findings are, unsurprisingly, multifactorial.  
 
Anti-nociceptive mechanisms.  As noted previously, stimulation of the vagus nerve chemically 
modulates nociceptive (pain) processing, anxiety, and depression.5,6  In addition, vagus stimulation 
results in anti-inflammatory effects which is hypothesized to counteract pain hypersensitivity.1  Unlike 
in the peripheral nervous system below the foramen magnum, A-beta afferent fibers of the auricle 
and pain-conducting A-delta and C nerves throughout the body do not originate in the same location.  
Therefore, a direct “gating” mechanism is not possible with stimulation of cranial nerves.  However, 
an indirect gating mechanism is theorized since afferent cranial nerve fibers end in the lower medulla 
(specifically the nucleus of the solitary tract);15,16 which itself interacts with other areas of the 
brainstem involved in pain processing.17  Additionally, a more traditional spinal cord gating 
mechanism might occur with auricular stimulation of the occipital and great auricular nerves, both 
originating from cervical roots 2 and 3.18  Both of these indirect and direct gating mechanisms may 
function by producing descending inhibitory impulses and stimulating encephalin-containing 
interneurons which impede ascending nociceptive signals within the spinal cord.19-21  It is probable 
that traditional auricular acupuncture shares these mechanisms;22 but since electrical stimulation of 
the auricle has demonstrated a positive correlation between current intensity and analgesia,23-25 it is 
possible that electrical auricular stimulation will provide superior analgesia to traditional acupuncture, 
as has been previously reported.26  Importantly, multiple studies demonstrate that neurologic effects 
of auricular stimulation outlast the stimulation itself, suggesting a mechanism for the prolonged 
analgesia reported in clinical use.26,27 
 
Indeed, auricular neuromodulation has been reported to provide analgesia and/or decrease 
supplemental analgesic requirements for a plethora of indications, including chronic pain states26,28-30 
and acute migraine31 and intra-procedure pain during in vitro fertilization,32 intraoperative anesthetic 
requirements,33 and postoperative pain following anterior cruciate ligament reconstruction,34 
laparoscopic nephrectomy,35 tonsillectomy,36 and hysterectomy.37   In contrast, auricular 
neuromodulation failed to provide benefits following gynecological surgery,38 and molar tooth 
extraction.21  Several prospective and retrospective series involving the NSS-2 Bridge system 
suggest possible analgesic improvements following gastric bypass,12 kidney donor surgery,13 and 
Cesarean delivery.14 
 
The NSS-2 Bridge (Masimo, Irvine, CA) is a small, single-use, drug-
free, non-surgical, battery-powered stimulator that is adhered 
directly to the skin behind the ear [figure].  Three electrodes and one 
ground are introduced through the skin with tiny integrated solid-bore 
needles which do not require pretreatment with intra-dermal anesthesia 
(e.g., lidocaine skin wheal).  The device is FDA cleared to reduce 
symptoms associated with opioid withdrawal and functions for up to 5 
days.9-11  Opioid withdrawal symptoms include anxiety, insomnia, 
muscle aches, nausea, and vomiting, all of which are frequent 
following surgery.39  There are only three relative contraindications to 
use:  concurrent use of another neuromodulation device (e.g., cardiac 

 
 
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pacemaker), bleeding disorder or anticoagulation, and skin abnormality at the treatment site such as 
psoriasis vulgaris.  Treatment-emergent adverse events (19,312 skin punctures in total) included 
minor bleeding at the skin (0.91%), dermatitis (0.91%), and significant pain during placement 
(0.17%).11  A zero incidence of syncope, infections, and side effects was observed.11  The FDA 
determined the NSS-Bridge to have a Class II risk designation, a class that includes surgical gloves 
and sphygmomanometers (blood pressure cuffs).  With its ease of insertion, low risk of adverse 
events, lack of side effects, prolonged duration of action, and simple removal, auricular 
neuromodulation has the very real possibility of replacing opioid analgesics—the standard of 
care for the past 100 years—that would completely revolutionize postoperative analgesia, as 
we know it. 
 
Device risk catagorization.  Treatment of postoperative pain is not currently an FDA cleared 
indication.  However, the investigators believe the Bridge to be a nonsignificant risk device 
regardless of the indication (e.g., opioid withdrawal symptoms, analgesia, antiemetic).  Per the 
FDA, a significant risk device is one that “presents a potential for serious risk to the health, 
safety, or welfare of a subject.” 
 
Of the risks of the Bridge device, “minor bleeding” at the skin (0.91%) included as little as a single 
drop of blood; but regardless, any bleeding is less serious than most childhood scratches and is 
treated with simple pressure.  There is no risk of hemorrhage, and we do not believe this risk rises 
to the level of a “serious risk to the health, safety, or welfare” of a patient.  Similarly, the risk of 
dermatitis (0.91%) is due to the adhesive on the bandages used to hold in the leads and the unit 
behind the ear—it is a similar adhesive to that used for “Band-Aids”.  If any dermatitis occurs, the 
unit can simply be removed, and the dermatitis resolves without treatment.  Therefore, we do not 
believe this rises to the level of a “serious risk to the health, safety, or welfare” of a patient.  The 
0.17% incidence of “significant pain during placement” involved patients in opioid-withdrawal 
having the leads inserted with no analgesic added.  Patients in opioid-withdrawal experience 
hyperalgesia and yet the incidence was only 0.17%.  Our postsurgical patients will have been 
provided opioids as part of their surgical care to provide analgesia preoperatively for regional 
peripheral nerve block administration, intraoperative and postoperative pain, and to decrease 
sympathetic response during intubation for patients having a general anesthetic.  We therefore 
anticipate the risk of severe pain to be far lower than 0.17%—most-likely zero.  The standard of 
care pain medication for surgery is expected to provide sufficient analgesia for placement of the 
device. 
 
Per the FDA, non-significant risk devices “include most daily-wear contact lenses and lens 
solutions, ultrasonic dental scalers, and Foley catheters [emphasis added].”  There is no know 
incidence of infection with the Bridge device.  In contrast, a Foley catheter—determined to be a 
nonsignificant risk device by the FDA—has an overall infection incidence of 10.5% (15.5% in 
women); and a urinary tract infection can develop into pyelonephritis with significant morbidity and 
mortality [Saint et al. JAMA Intern Med. 2018;178(8):1078-85].  So, if the FDA has designated the 
Foley catheter with its 10.5% incidence of infection as a nonsignificant risk device, we believe that 
the Bridge with no known infections in over 19,000 lead insertions to also be a nonsignificant risk 
device. 
 
Therefore, we do not believe that an IDE is required for the currently-described investigation.  
Consequently, we propose a randomized, participant- and observer-masked, sham-controlled, 
parallel-arm clinical pilot study to demonstrate feasibility and optimize the protocol as well as 

 
 
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estimate the treatment effect to allow the design and power of subsequent definitive multicenter, 
randomized, controlled clinical trials.  The primary hypotheses are that percutaneous peripheral 
nerve stimulation decreases pain and opioid use in the 5 days following moderate-to-severely 
painful surgical procedures currently treated with a single-injection peripheral nerve block. 
 
 
8. 
PROGRESS REPORT 
N/A 
 
 
9. 
RESEARCH DESIGN AND METHODS 
 
This will be a single-center (UCSD), randomized, participant- and observer-masked, sham-controlled, 
parallel-arm human participants pilot study. 
 
Enrollment.  Participants will be consenting adults undergoing various surgical procedures usually 
resulting in moderate-to-severe postoperative pain and treated with single-injection peripheral nerve 
blocks.  Study inclusion will be proposed to eligible patients prior to surgery.  If a patient desires 
study participation, written, informed consent will be obtained using a current UCSD IRB-approved 
ICF.  The study population of interest includes women and men of all races, ethnicity, sexual identity, 
and socioeconomic status.  Inclusion and exclusion criteria are listed in section #10 below. 
 
Preoperative Procedures.  Following written, informed consent, we will record baseline 
anthropometric information (age, sex, height, weight, current pain level).  Participants will have their 
single-injection peripheral nerve block administered using ropivacaine 0.5% with epinephrine 
(standard at UCSD) prior to undergoing their surgical procedure per standard of care.  A “successful” 
regional block will be defined as sensory- and motor-block onset in all expected nerve distributions 
within the 30 minutes following the local anesthetic injection.  Participants with a successful regional 
block and undergo the anticipated surgical procedure will be randomized and continue within the 
study. 
 
Treatment Group Assignment.  Each participant will be randomized to one of two treatment groups:  
Active (Experimental) or Sham treatment.  There are sham devices produced that are identical to 
active devices, only they do not deliver electrical current.  Randomization will be stratified by surgical 
procedure, in block sizes of 2.  The computer-generated randomization list will be created by the 
University of California San Diego Investigational Drug Service in a 1:1 treatment group ratio using 
opaque envelopes opened only after successful peripheral nerve block administration and the 
participant underwent the anticipated surgical procedure.  The active and sham stimulators are 
indistinguishable in appearance, and therefore investigators, participants, and all clinical staff other 
than the individual who opens the randomization envelope and chooses a sham or active device will 
be masked to treatment group assignment for the duration of the data collection period. 
 
Study intervention.  The NSS-2 Bridge device will be affixed to the ear and activated prior to 
discharge from the recovery room (Experimental).  There is currently no consensus regarding the 
placement on the ipsilateral or contralateral ear relative to the surgical procedure (if sided).  
Therefore, we will apply the device to the side that the participant sleeps on least, to optimize comfort 
in bed and sleep. 
 

 
 
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Postoperative course.  In addition to the experimental device and single-injection peripheral nerve 
block, participants will receive standard-of-care oral and intravenous postoperative analgesics which 
can include acetaminophen, ibuprofen, ketorolac, and opioids (this is surgeon- and patient-
dependent).  Therefore, all patients of this study—regardless of the treatment arm they are 
randomized to—will continue to receive current usual and customary analgesia:  all will receive the 
same combination of acetaminophen, ibuprofen, ketorolac, opioids, and a single-injection peripheral 
nerve block as they would regardless of study participation.  Prior to discharge, participants and their 
caretakers will be provided with verbal instructions regarding the care of the stimulator, and the 
telephone and pager numbers of an investigator available at all times during the first 5 days of 
treatment.  The instructions for the stimulator are few:  (1) you can shower, but use a shower cap to 
cover the stimulator; (2) there are no controls so there is nothing that needs to be adjusted; (3) the 
device will run out of power after 5 days; (4) we will call you every day to answer any questions you 
might have and describe how to remove the device as that time approaches. 
 
Participants will be discharged when ready, as determined by standard criteria by the masked 
surgical service.  Participants will be discharged home with their NSS-2 Bridge in situ and a 
prescription for immediate-release oral opioid, preferably oxycodone 5 mg tablets, taken for 
breakthrough pain.  Participants will be contacted by telephone for end point collection beginning on 
postoperative day 1.  The NSS-2 Bridge devices will be removed by patients or their caretakers at 
home on postoperative day 5.  Similar to perineural catheters,135 this procedure encompasses simply 
removing the small dressings (the electrodes remain adhered to the dressings and therefore do not 
require a separate extraction step), removing the stimulator from behind the ear with simple traction, 
and discarding all components (these are disposable, single-use devices). 
 
At the conclusion of the study, participants will be informed of the main results in lay-person language 
by either email or the U.S. Postal Service. 
 
 
Outcome measurements (end points).  We have selected outcome measures that have 
established reliability and validity, with minimal inter-rater discordance, and are recommended for 
pain-related clinical trials by the Initiative on Methods, Measurement, and Pain Assessment in 
Clinical Trials (IMMPACT) consensus statement.  All data collection will be through standard UCSD 
nursing/therapy EPIC notes and patient interviews in-person during hospitalization or via a telephone 
call.  Postoperatively, surgical endpoints will be recorded such as surgical duration and tourniquet 
duration (if applicable).  All pain scores will be measured using the Numeric Rating Scale (0: no pain, 
10: worst imaginable pain). 
 
 
Primary end points:  This is an exploratory pilot study to assist in planning a subsequent definitive 
trial and we therefore have no data analysis plan.  The two primary outcomes will be (1) the mean of 
the “average” pain recorded on postoperative days 1-5 measured with the Numeric Rating Scale 
(“average” pain is included in the Brief Pain Inventory pain domain); and (2) the cumulative opioids 
consumed from recovery room discharge until postoperative day 5, as measured in oral oxycodone 
equivalents. 
 
 
 

 
 
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Summary of post-enrollment assessments (color added for clarity) 
Time Point: 
Postoperative Days 
1 
2 
3 
4 
5 
6 
7 
8 
Opioid consumption 
• 
• 
• 
• 
• 
• 
• 
• 
Average Pain [NRS] 
• 
• 
• 
• 
• 
• 
• 
• 
Worst Pain [NRS] 
• 
• 
• 
• 
• 
• 
• 
• 
Brief Pain Inventory, Short 
Form 
 
• 
 
• 
 
• 
 
• 
Sleep disturbances (#) 
previous night 
• 
• 
• 
• 
• 
• 
• 
• 
Masking Assessment 
• 
 
 
 
 
 
 
 
 
    
 
10. 
HUMAN PARTICIPANTS 
We will recruit a convenience sample with a maximum of 150 participants.  Selection for inclusion 
will not be based on race, ethnicity, sexual identity, or socioeconomic status.  There will be no 
participants from vulnerable populations, such as pregnant women, children, or prisoners. 
 
Inclusion criteria: (1) undergoing one of the surgical procedures listed below as a primary 
procedure (not revision); (2) analgesic plan includes a single-injection peripheral nerve block with a 
long-acting local anesthetic [may be waived for hip arthroplasty]; and (3) age 18 years or older. 
 
a.  septoplasty [infraorbital nerve block] 
b.  laparoscopic cholecystectomy [transversus abdominis nerve block] 
c.  laparoscopic sleeve gastrectomy [transversus abdominis nerve block] 
d.  non-mastectomy breast surgery [paravertebral nerve block] 
e.  percutaneous nephrolithotomy [erector spinae plane nerve block] 
f.   inguinal hernia repair [transversus abdominis nerve block] 
g.  knee arthroplasty [adductor canal nerve block] 
h.  hip arthroplasty [pericapsular nerve group block] 
i.   shoulder acromioclavicular joint repair, labral repair, subacromial decompression, or 
Bankart repair (without rotator cuff repair) [interscalene nerve block] 
j.   orthopedic hardware removal anticipated to be at least moderately painful postoperatively 
[various peripheral nerve blocks] 
 

 
 
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Exclusion criteria: (1) concurrent use of another electric stimulator (e.g., cardiac pacemaker); (2) 
bleeding disorder; (3) anticoagulation; (4) skin abnormality at the treatment site; (5) psoriasis 
vulgaris; (5) morbid obesity as defined by a body mass index > 40 (BMI=weight in kg / [height in 
meters]2); (6) history of opioid abuse; (7) inability to communicate with the investigators or hospital 
staff; (8) pregnancy; (9) bilateral or multi-stage surgical procedures; (10) incarceration; (11) chronic 
opioid or tramadol use (daily use within the 2 weeks prior to surgery and duration of use > 4 weeks); 
and (12) neuro-muscular deficit of the surgical area/limb. 
 
11. 
RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH 
The investigators will need to know in advance which patients would like to participate in order to 
have an investigator and research coordinator present on the day of surgery.  The investigators 
therefore need to contact potential participants prior to their pre-surgery visit and request a waiver of 
consent for recruitment purposes.  We will scan the upcoming surgery schedule (which we have 
access to being anesthesiologists—we use this schedule daily for medical purposes), identify 
patients having the types of surgical procedures specified for this study, look in their electronic 
records to determine eligibility, and if eligible either call the potential participants ourselves or provide 
the name and contact information to a research coordinator to contact the potential participants. 
 
1.  These procedures are minimal risk to the potential participants as we are anesthesiologists who 
will be viewing these records even without study participation in preparation for surgery and 
postoperative analgesia planning.  There is no information that an anesthesiologist would not view 
regardless of the existence of the study. 
 
2.  A waiver of consent would not adversely affect the rights and welfare of the potential participants 
as we are anesthesiologists who will be viewing these records even without study participation in 
preparation for surgery and postoperative analgesia planning.  There is no information that an 
anesthesiologist would not view regardless of the existence of the study. 
 
3.  This clinical trial could not be practicably carried out without the waiver because many relatively 
healthy ambulatory patients are not seen in preop clinic; or, they are seen just 1-2 days prior to their 
date of surgery.  The investigators will need to know in advance which patients would like to 
participate in order to have an investigator and research coordinator present on the day of surgery.  
In addition, we need to bring participants to the surgical center 15 minutes earlier than regularly-
scheduled in order to record baseline measurements. 
 
4.  After participants are contacted, if they would like to participate they will receive written, informed 
consent using an IRB-approved informed consent form. 
 
These procedures would also include access to PHI, so we request a partial waiver of HIPAA 
authorization to be granted: 
 
1.  Identifiers will include the potential participant’s date of surgery, surgeon, name, phone number, 
and email address (to send ICF if patient is interested in participation).  This information will be 
recorded in hard-copy format and destroyed using a paper shredder (or in the locked UCSD PHI 
disposal stations) following contact with the patient.  If the patient does not participate, then there will 
be no record of PHI whatsoever.  If the patient does participate, then PHI will be protected as 
described in #16 below. 

 
 
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2.  This clinical trial could not be practicably carried out without the waiver because many relatively 
healthy ambulatory patients are not seen in preop clinic; or, they are seen just 1-2 days prior to their 
date of surgery.  The investigators will need to know in advance which patients would like to 
participate in order to have an investigator and research coordinator present on the day of surgery.  
In addition, we need to bring participants to the surgical center 15 minutes earlier than regularly-
scheduled in order to record baseline measurements. 
 
3.  The privacy risk to individuals whose PHI will be used is minimal since, as anesthesiologists at 
UCSD caring for ambulatory surgery patients, we use the surgery schedule daily in the normal 
course of our work caring for patients; and we will not record any PHI other than date of surgery, 
surgeon, name, contact phone numbers, and email address—and, these will be destroyed following 
use.  The anticipated benefit to participants is a chance of improving their postoperative pain control 
if they are randomized to active stimulation. 
 
4.  PHI that will be used includes date of surgery, surgeon, name, contact phone numbers, email 
address, basic anthropometric data such as height and weight, past medical and surgical history, and 
the surgical schedule itself.  Only coinvestigators will access this PHI, and the only people they might 
share it with are research coordinators actively participating in this research who understand PHI 
procedures and to appropriately destroy the hard copy of date/surgeon/name/contact numbers/email 
address after use. 
 
Patients meeting inclusion and exclusion criteria will be presented with the study, and prospective 
study participants desiring additional information will be required to give permission for a research 
coordinator to contact them to adhere to HIPAA requirements.  The study protocol will be reviewed 
with interested prospective participants in detail; and for participants desiring participation, written, 
informed consent will be obtained prior to any measurements, data collection, and/or interventions.  
The method of documenting consent will be using written informed consent forms approved by the 
local Institutional Review Board. 
 
12. 
INFORMED CONSENT 
Candidates who meet inclusion and exclusion criteria and desire study enrollment will be scheduled 
to arrive the day of surgery 15 minutes earlier than normal to allow for written informed consent and 
baseline information collection.  Written informed consent will be attained prior to any measurements 
or procedures prior to surgery.  When participants present for surgery, research coordinators will 
provide and attain written informed consent.  This will occur in private patient care areas, so that 
participants may feel comfortable asking questions of the research coordinator. 
We do not foresee any issues relevant to the mental capacity of the potential human participants.  
Written, informed consent will be attained prior to any study procedures or measurements; and 
participants will not receive procedure-related sedation until following the written, informed consent 
process is completed.  Participants will be provided privacy and time for decision making both in the 
study description/explanation telephone call to an investigator or research coordinator, as described 
above; and also the morning of the initial treatment using a private patient care area to again review 
the study, informed consent form, and answer any remaining questions.  As noted previously, 
participants may speak with an investigator by telephone from initial contact through the morning of 

 
 
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treatment; and will have access during and following the treatment(s) with cellular phone and pager 
numbers provided upon discharge. 
This study protocol has follow-up data-collection telephone calls a maximum of 8 days following the 
initial study treatment, so repeated informed consent following the initial consent is unnecessary, as 
opposed to multi-year, longer-term clinical trials.  Surrogate consent will not be accepted; therefore, if 
human participants cannot provide consent on their own, they will not be offered study enrollment.  
Consent by an individual’s Legally Authorized Representative is unacceptable for study enrollment. 
Following informed consent and the signing of the UCSD IRB-approved ICF and HIPAA documents, 
these documents will be copied, and the copy placed in the patient’s medical record.  The participant 
will be provided a copy along with the Participants’ Bill of Rights. 
 
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
Patients can decline enrollment.  If they do so, they will still receive the standard-of-care 
postoperative analgesia. 
 
14. 
POTENTIAL RISKS 
Potential risks include minor bleeding at the skin (0.9%), dermatitis (0.9%), and significant pain 
during placement (less than 0.1%).  In addition, there is the risk of infection and loss of confidentiality.  
The following study procedures will be done to maintain confidentiality of this study:  hard copies will 
be kept in locked medical offices and the locked Investigational Drug Service’s files.  Any digitized 
records containing personal health information will be stored as password-protected and encrypted 
files. 
 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
The procedural risks involved with the intervention will be managed according to the complication: 
 
- minor bleeding at the skin (0.9%):  pressure would be held until bleeding ceased 
- dermatitis (0.9%):  the device would be removed 
- significant pain during placement (far less than 0.17%):  The participant could opt to not have it 
placed and be removed from study participation 
- infection (theoretical:  none reported to date):  We would remove the device and possibly prescribe 
oral antibiotics, depending on the severity of the infection. 
 
During use, placement of the device may restrict some normal activities such as bathing and 
brushing/arranging hair.  While the device is water resistant, participants will be verbally instructed to 
avoid submerging it and should use a shower cap when showering.  The small wires could get pulled 
out accidentally, so participants will need to brush/arrange hair with care.  And, while we will place 
the device on whichever ear participants prefer, it may be less comfortable sleeping on the side with 
the device if a participant sleeps on both sides during the night. 
 
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
We request a partial waiver of HIPAA authorization to be granted as explained above in section #11. 
Identifiers will include the potential participant’s date of surgery, surgeon, name, phone number, and 
email address (to send ICF if patient is interested in participation).  This information will be recorded 
in hard-copy format and destroyed using a paper shredder (or in the locked UCSD PHI disposal 
stations) following contact with the patient.  If the patient does not participate, then there will be no 

 
 
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record of PHI whatsoever.  If the patient does participate, then PHI will be protected as described 
below: 
 
The following study procedures will be done to maintain confidentiality of this study:  hard copies will 
be kept in a locked medical office. Only the investigators will have access to the records.  Any 
electronic records with patient identifiers will be password protected according to UCSD IT 
recommendations and policies.  No patient identifiers will be used in reporting data from the study.  
Every effort will be made to assure protection of patient privacy. 
 
This study will require access to the medical record of patients who have consented to participate as 
participants.  The privacy of these patients will be protected in the manner described below: 
1. Specific consent will be obtained from each patient to permit examination of his or her medical 
record.  
2. Information obtained during the study will be de-identified with study specific identifiers that do 
not permit recognition of any participants’ personal information.  
3. All information gathered will be stored in a locked cabinet which is inside a locked room which 
will be accessible only to registered study investigators.   
4. Any data gathered stored on portable electronic media (e.g. flash drives) will be stored in this 
cabinet when not in use. 
5. Any digitized records will be stored in encrypted files on password-protected computers. 
6. No photographs will be taken. 
 
17. POTENTIAL BENEFITS 
Participants may or may not receive these benefits:  decreased pain, opioid consumption, sleep 
disturbances, and pain-induced physical and emotional dysfunction. 
 
Possible benefits to others:  Future patients may benefit if it is determined that auricular 
neuromodulation decreases the incidence and severity of pain following moderately painful surgeries, 
as well as exposure to opioids during the postoperative period. Finding an effective non-opioid 
analgesic would be a tremendous step forward in helping future patients. 
 
18. RISK/BENEFIT RATIO 
While there are risks involved in the placement and use of the NSS-2 Bridge devices, they are 
relatively rare and not catastrophic when they do occur.  With its ease of insertion, low risk of adverse 
events, lack of side effects, prolonged duration of action, and simple removal, auricular 
neuromodulation has the very real possibility of replacing opioid analgesics—the standard of care for 
the past 100 years—that would completely revolutionize postoperative analgesia, as we know it. 
 
19. EXPENSE TO PARTICIPANT 
None 
 
20. COMPENSATION FOR PARTICIPATION 
None 
 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Principal Investigator and Co-investigators are board-certified anesthesiologists with fellowship 
training in regional anesthesia and acute pain who place peripheral nerve blocks and manage acute 

 
 
Biomedical IRB Application Instructions 
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pain on a regular basis.  All hold a license to practice medicine in California, have medical privileges 
at the UC Medical Centers, and will be responsible for the overall management of this study. 
 
Investigators:  Brian Ilfeld, MD, MS; John Finneran, MD; Engy Said, MD; Rodney Gabriel, MD, MS; 
and Matthew Swisher, MD, MS. 
 
Baharin Abdullah is the current Program Manager of the Division of Regional Anesthesia and Acute 
Pain Medicine, and will therefore be performing regulatory work, consenting participants, and 
collecting data. 
 
22. BIBLIOGRAPHY 
 
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Lechner S, Klonowski W, Varoneckas G, Szeles JC: Current Directions in the Auricular Vagus Nerve 
Stimulation I - A Physiological Perspective. Front Neurosci 2019; 13: 854 
2. Frangos E, Ellrich J, Komisaruk BR: Non-invasive Access to the Vagus Nerve Central Projections via 
Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul 2015; 8: 624-36 
3. Mercante B, Deriu F, Rangon CM: Auricular Neuromodulation: The Emerging Concept beyond the 
Stimulation of Vagus and Trigeminal Nerves. Medicines (Basel) 2018; 5 
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Neurophysiol 2010; 27: 130-8 
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with reduction in signs and symptoms of opioid withdrawal: a multisite, retrospective assessment. Am J 
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12. Ahmed BH, Courcoulas AP, Monroe AL, Gourash WF, Chelly JE: Auricular nerve stimulation using the 
NSS-2 BRIDGE device to reduce opioid requirement following laparoscopic Roux-en-Y gastric bypass. 
Surg Obes Relat Dis 2021; 17: 2040-2046 
13. Chelly JE, Monroe AL, Planinsic RM, Tevar A, Norton BE: Auricular field nerve stimulation using the 
NSS-2 BRIDGE((R)) device as an alternative to opioids following kidney donor surgery. J Complement 
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Neurosci 2000; 85: 1-17 

 
 
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16. Groves DA, Bowman EM, Brown VJ: Recordings from the rat locus coeruleus during acute vagal nerve 
stimulation in the anaesthetised rat. Neurosci Lett 2005; 379: 174-9 
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branch of the vagus nerve): a transganglionic HRP study in the cat. Brain Res 1984; 292: 199-205 
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auricular nerve stimulation via the tragus in the rat involve spinal cervical sensory afferent pathways. Brain 
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19. Oleson T: Auriculotherapy stimulation for neuro-rehabilitation. NeuroRehabilitation 2002; 17: 49-62 
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for pain relief. Expert Rev Med Devices 2007; 4: 23-32 
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auricular electroacupuncture has no effect on pain and analgesic consumption after third molar tooth 
extraction. Anesth Analg 2007; 104: 542-7 
22. Kotani N, Hashimoto H, Sato Y, Sessler DI, Yoshioka H, Kitayama M, Yasuda T, Matsuki A: Preoperative 
intradermal acupuncture reduces postoperative pain, nausea and vomiting, analgesic requirement, and 
sympathoadrenal responses. Anesthesiology 2001; 95: 349-56 
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Chronic Pain Management. Curr Pain Headache Rep 2015; 19: 54 
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Heinze G, Kress HG: The short- and long-term benefit in chronic low back pain through adjuvant electrical 
versus manual auricular acupuncture. Anesth Analg 2004; 98: 1359-64, table of contents 
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30. Napadow V, Edwards RR, Cahalan CM, Mensing G, Greenbaum S, Valovska A, Li A, Kim J, Maeda Y, 
Park K, Wasan AD: Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular 
vagal afferent nerve stimulation. Pain Med 2012; 13: 777-89 
31. Garcia RG, Lin RL, Lee J, Kim J, Barbieri R, Sclocco R, Wasan AD, Edwards RR, Rosen BR, Hadjikhani 
N, Napadow V: Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal 
afferent nerve stimulation in migraine patients. Pain 2017; 158: 1461-1472 
32. Sator-Katzenschlager SM, Wolfler MM, Kozek-Langenecker SA, Sator K, Sator PG, Li B, Heinze G, Sator 
MO: Auricular electro-acupuncture as an additional perioperative analgesic method during oocyte 
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35. Likar R, Jabarzadeh H, Kager I, Trampitsch E, Breschan C, Szeles J: [Electrical point stimulation (P-
STIM) via ear acupuncture: a randomized, double-blind, controlled pilot study in patients undergoing 
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23. FUNDING SUPPORT FOR THIS STUDY 
Departmental funding and Bridge units donated by the manufacturer:  Masimo. 
 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
Not applicable 
 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
Not applicable 
 
26. IMPACT ON STAFF 
There will be no appreciable impact on nursing staff as the study intervention will take fewer than 5 
minutes while the patient is in the recovery room, and will not add to recovery room stay duration; 
and will not require any attention from the recovery room nursing staff. 
 
27. CONFLICT OF INTEREST 
None 
 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
Not applicable 
 
29. OTHER APPROVALS/REGULATED MATERIALS 
Not applicable 
 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY 
ASSESSMENT 
Not applicable:  surrogate consent will not be accepted.