Effectiveness of Electrical Neurostimulation as an Opioid-Sparing Alternative in the Treatment of Cyclic Vomiting Syndrome.
Phase: NA
Conditions: Cyclic Vomiting Syndrome
Sponsor: Medical College of Wisconsin

PROJECT TITLE: 
Effectiveness of Electrical Neurostimulation as an Opioid-Sparing Alternative in the 
Treatment of Cyclic Vomiting Syndrome. 
PI NAME 
Venkatesan, Thangam 
CO-PI NAME(s) 
Bhandari, Sanjay 
Co-Investigators 
Segon, Ankur 
Katja, Kovacic 
NCT#: NCT04721171
Document Date: 02/18/2019

 
Aims and Objectives (limit - 1 page)  
 
Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder (FGID) 
characterized by episodic nausea, vomiting and severe abdominal pain in majority (80%) of 
patients. Most patients also have a migraine headache, photophobia, phonophobia and 
lethargy during an episode. The pathophysiology of CVS is not known but is thought to be a 
migraine diathesis given the overlap between the two syndromes. Various factors such as 
mitochondrial DNA polymorphisms, genetic variants in the cannabinoid receptor genes and 
and calcitonin gene-related peptide (CGRP) are thought to play key roles.  
 
CVS is common and affects 2% of the population in the US. The disorder is disabling, and 
healthcare costs associated with CVS hospitalizations in adults are staggering, amounting to 
$200 million dollars bi-annually.  Due to sub-optimal therapies, hospitalized patients are 
usually treated empirically with IV fluids, anti-emetics, benzodiazepines and opioids for the 
intense abdominal pain. Unfortunately, opiate therapy in CVS is fraught with problems and is 
a risk factor for recurrent hospitalizations (preliminary data) as well as non-response to 
prophylactic therapy. Additionally, use of opioids is associated with dependence, withdrawal, 
addiction, overdose and even death. Hence, there is a critical need for safe, opiate-sparing 
strategies to treat pain associated with CVS episodes. Neurostimulation via a novel auricular 
percutaneous electrical nerve field stimulation (PENFS) device has recently emerged as a safe 
and non-invasive therapy for the treatment of pain, nausea and vomiting disorders. This 
therapy was recently FDA-approved for the symptoms of opioid withdrawal. Preliminary data 
indicates that PENFS modulates peripheral vagal nerve signaling, likely also modulating the 
trigeminal pathway from the external ear to the brainstem.  
 
We hypothesize that 1) PENFS is a safe, non-invasive opioid-sparing alternative therapy 
for the severe abdominal pain, nausea and vomiting associated with CVS. We also 
hypothesize that 2) PENFS reduces length of stay (LOS), and improves patient 
satisfaction. We propose the following specific aim: 
 
Aim 1. Investigate the efficacy of PENFS compared to a sham in hospitalized patients 
with CVS 
Objective 1:  
a. Demonstrate reduction in abdominal pain, nausea and vomiting using validated 
tools. 
b. Obviate or reduce the need for opioids.  
c. Reduce length of hospital stay and improve patient satisfaction. 
 
This approach will specifically address the current opioid problem using a novel, non-
invasive neurostimulation therapy with proven efficacy for opioid withdrawal. Long-
term, it may improve health care outcomes and significantly reduce overall health care costs. 
 
 

 
 
 (A) Significance  
 
Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder (FGID) 
that is characterized by episodic nausea, vomiting and abdominal pain and is a significant 
health care problem.1, 2 It affects 2% of the U.S. population and imposes an enormous burden 
on patients and the health care system.3 Due to the recalcitrant nature of the disease, patients 
have high rates of health care utilization with multiple emergency department visits and 
hospitalizations. These in turn lead to school and work absenteeism, job loss, divorce, and 
disability.4 The economic impact of CVS is staggering  amounting to  > $200 million over 2 
years, based on a nationwide study.5 
 
CVS is associated with multiple comorbid conditions such as migraine headaches, 
autonomic dysfunction, anxiety and depression, which further contribute to disease severity. 
A personal and family history of migraine is present in 87% of patients.6,7 CVS is considered 
a migraine equivalent given the striking similarities between the two disorders such as 
periodicity, response to medications like amitriptyline and triptans and common symptoms 
such as nausea, vomiting, photo- and phono-sensivtivity8. Both migraine and CVS are also 
triggered by sleep deprivation and stress.9 A recent brain imaging study demonstrates 
similarities in functional connectivity of the insular region in CVS and migraine, further 
solidifying the link between these disorders10. These data suggest that CVS and migraine 
share similar pathophysiology and potential for a common therapeutic avenue. 
 
Opioid use in CVS and the critical need for opioid sparing therapy 
 
Given the lack of knowledge about pathophysiology and evidence-based therapies, patients 
are often hospitalized to treat symptoms of CVS. During an episode, patients present with 
severe vomiting and abdominal pain and are treated empirically with IV fluids, antiemetics, 
benzodiazepines, and opioids. Estimates of opioid use range from 23%-27% in adults with 
CVS.4, 11 Patients are often dissatisfied with the level of analgesia as recurrent opioid use 
results in tolerance and dependence. This often undermines the physician-patient relationship 
and patients even leave against medical advice out of frustration with what they perceive as 
ineffective care.5, 12 This can lead to worse outcomes including recurrent hospitalizations, 
morbidity and increased health care costs.  
 
Preliminary data from a study by our group reveals that of 101 patients hospitalized with 
CVS at Froedtert Hospital, chronic opioid therapy is associated with a two-fold increased 
risk of hospitalization (RR 2.22, CI 1.1-4.4, P=0.02) and three-fold increase in hospital 
length of stay (LOS) (RR 3.43, CI 1.26-9.34, P=0.01).13 In a study of 132 CVS patients, 
opioid use was associated with non-response to amitriptyline (53% vs 15%, p<0.05), a 
prophylactic therapy used in CVS.14 This in turn was associated with increased frequency 
and duration of CVS episodes per year and increased number of hospitalizations/emergency 

 
department (ED) visits at baseline (18% vs 15.2%, p<0.05).  Hence there is an urgent need 
for an opioid-sparing, non-invasive strategy to treat CVS symptoms. 
 
In summary, CVS is common and disabling and is associated with significant health care 
costs. Much of this burden can be tied to iatrogenic opioid overuse, resulting in chronic 
opioid use and high risk of addiction and health care utilization. Understanding the 
pathophysiology of CVS and development of novel therapies are urgently needed. Further, 
similar to other disorders with rampant opioid use, there is a critical need for opioid-
sparing therapy in CVS to negate the devastating short and long-term effects of opioid 
use. Our proposed project using a novel, non-invasive device to treat CVS will also address 
the current opioid crisis. 
 
 
Auricular neurostimulation: a novel treatment modality in CVS 
The major role of the arousal neurocircuitry in nausea and vomiting is well established.15, 16 
Similar to migraines, stress and neuronal excitability may trigger CVS episodes. Various 
neurostimulation modalities have emerged as therapy for gastrointestinal disorders and 
migraines but most options are invasive.17, 18  The effects are believed to be mediated via 
increased vagal afference to the brainstem nucleus tractus solitarius (NTS) and modulation 
of the trigemino-autonomic reflex, influencing higher cortex.19-21 Tracing studies confirm 
that the ear contains branches of four cranial nerves (CN V, VII, IX, X) that project to the 
NTS, providing a conduit for stimulation of NTS22, 23. Animal and human data show that 
transcutaneous stimulation of the vagus nerve (CN X) in the ear transmits signals to the NTS 
and improves migraine, presumably via modulation of trigemino-cervical complex (TCC).24, 
25 Neuroimaging studies show that this therapy modulates brainstem and limbic brain regions 
such as the amygdala, a region involved in stress and fear signaling.26, 27 This arousal 
network is activated by perturbation of homeostasis28 such as in stress-triggered CVS. 
Auricular neurostimulation may thus alter emetic signals through NTS activation, 
modulating the TCC and limbic regions.  
 
More recently, the Bridge device, a non-invasive percutaneous electrical 
nerve field stimulation (PENFS) applied to the external ear, has 
demonstrated efficacy in treating pain, nausea and vomiting in opioid 
addiction (Fig. 1).29 A large, randomized sham-controlled trial also 
demonstrated significant improvement in abdominal pain, well-being 
and disability in adolescent FGIDs.30 Based on neuronal tracing studies, 
PENFS likely modulates the vagus and the trigeminal nerves which 
project to the external ear.22, 23 Branches of these nerves converge in the 
brainstem NTS and signal to higher brain regions (amygdala, 
hypothalamus). Recent data has also shown that PENFS modulates 
neurons of the central amygdala and improves visceral sensitivity in an animal model.31 We 
propose that the neurostimulation of cranial nerves through the PENFS device will alleviate 
Fig 1: Bridge device  

 
CVS symptoms by modulating the neurocircuitry pathway involved in the pathogenesis of the 
disease.  
 
 
 
 
 
 
B) Innovation, Novel Technology and/or Novel Approach 
 
PENFS: a novel technology for the treatment of CVS  
The Bridge device (PENFS) is a novel technology that is designed to treat pain and also 
improves other symptoms such as nausea and vomiting. The Bridge device has recently been 
approved by the FDA for treating opioid withdrawal symptoms including pain, nausea, 
vomiting, insomnia and agitation.32 Most recently, it has also been shown to be a safe and 
effective therapeutic option for adolescents with abdominal pain-related functional 
gastrointestinal disorders, resulting in reduction in abdominal pain and global symptom 
imrovement.30 If our study shows the efficacy of the Bridge device compared to sham in 
mitigating pain, nausea and vomiting, it will have the potential to transform the clinical care 
of CVS patients with the advent of an innovative, opiate sparing, non-invasive technology. 
Further, our purposed device through its effectiveness in resolution of symptoms will 
improve patient satisfaction, reduce hospital LOS and overall health care costs. More 
importantly, it will address the current opioid crisis that affects patients with CVS and 
potentially can be applied to other chronic disorders associated with pain. 
 
 
In summary, our study attempts to shift the current clinical practice paradigm in CVS and 
enhance our understanding of the pathophysiology through the use of PENFS device as a 
novel, non-invasive approach in mitigating the detrimental effects from opioids in CVS. 
Additionally, this device can also be used in the treatment of other chronic pain disorders.  
 
(C) Approach, Feasibility, and Environment 
 
Aim 1: Investigate the efficacy of PENFS in adults admitted with cyclic vomiting 
syndrome 
 
Methods 
Inclusion/Exclusion Criteria. We will enroll 80 adults between the ages of 18-65 years 
with a diagnosis of CVS (based on Rome IV diagnostic criteria).33 This study will only 
include patients who are admitted to Froedtert Hospital with an episode of CVS. Exclusion 

 
criteria includes developmental delays, non-English speaking patients, pregnancy, any 
implanted electrical device or any significant dermatological/infectious condition of the ear.  
 
Randomization. Subjects will be randomized to the intervention group (receiving the 
Bridge device) or control group (receiving an identical sham device lacking electrical 
charge) in 1:1 ratio. The auricular neurostimulator device will be placed on the subject’s ear 
upon presentation to the hospital. The device delivers low voltage (3.2), continuous 
stimulation for 5 days (around the clock) in alternating frequencies (1-10Hz) with an impulse 
interval of 100ms/2 sec. The neurostimulators (for both treatment arms) will be placed by a 
certified MD/APP/RN inside the patient’s room. All patients will be allowed to receive 
rescue medications after implantation of the device if the symptoms do not improve with the 
device or at patient’s request. 
 
We have performed a sample size calculation based on prior data. At a significance level 
of 0.05 and 80% power, we estimate a sample size of 40 participants per group to detect the 
minimum standardized effect size of 0.64 using two-sided tests, using prior data. We will 
compare the different variables (average daily reduction in abdominal pain, nausea/vomiting 
scores, average daily use/frequency/dosage of rescue medications (opiates, antiemetics and 
sedatives between PENFS vs sham device. 
 
Outcomes. Primary outcome will include the change in abdominal pain and concurrent opioid 
use.  Abdominal pain will be assessed daily through Visual Analog Scale with the score 
ranging from 0 to 10, with 0 being the least and 10 being the worst pain. The need for opiates 
will be assessed through- (a) the time taken by the subject from the time of admission to the 
first felt need accompanied by the actual administration of opiates (IV hydromorphone or 
morphine), (b) daily frequency and total dosage of opiates received. Secondary outcomes will 
include- (a) severity of daily nausea and vomiting assessed through the Index for Nausea, 
Vomiting and Retching (INVR); (b) the need for other rescue medications (which include 
antiemetics like ondansetron, promethazine & metoclopramide; benzodiazepines like 
lorazepam; antihistaminics like diphenhydramine, etc.), (c) hospital LOS and (d) survey on 
patient satisfaction. While all other outcomes will be assessed daily, LOS and patient 
satisfaction will be assessed at the time of discharge (Table 1). All variables will be compared 
between the subjects in intervention arm versus control arm.  
 
We hypothesize that PENFS will effectively mitigate the abdominal pain, nausea and 
vomiting associated with CVS episodes, obviate or reduce the need for opiates and 
simultaneously improve healthcare outcomes including LOS and patient satisfaction.  
 
                Table 1. Study Protocol 
 
Admission 
(0 hours) 
2 hours 
post -
placement 
24 
hrs. 
Daily 5 days* Discharge 
Screening & 
Consent 
x 
 
 
 
 
 

 
Demographics 
x 
 
 
 
 
 
Neurostimulator 
(PENFS) vs 
sham 
x 
x 
x 
x 
x 
 
Rome IV 
questionnaire33 
x 
 
 
 
 
 
INVR (vomiting 
scale; daily 
during 
therapy)34  
x 
x 
x 
x 
x 
x 
Abdominal pain 
(Visual 
Analogue Scale) 
x 
x 
x 
x 
x 
x 
Need for opiates 
and other rescue 
medications 
x 
x 
x 
x 
x 
x 
Length of stay 
 
 
 
 
 
x 
Patient 
Satisfaction 
Survey 
 
 
 
 
 
x 
          
INVR=Rhodes Index of Nausea, Vomiting & Retching; CGRP= Calcitonin Gene-Related 
Peptide 
* questionnaires will be completed as an outpatient if patient is already discharged  
 
Statistical Analysis: Summary statistics, such as mean, median, standard deviation and range 
will be used as a first step to examine data. To satisfy parametric assumptions, we may perform 
transformations with justifications if possible and otherwise use non-parametric tests. For any 
binary outcomes, we will use Chi-square or Fisher’s exact tests to compare the proportions 
between the two groups. We will compare the different variables (average daily reduction in 
abdominal pain, nausea/vomiting scores, average daily use/frequency/dosage of rescue 
medications (opiates, antiemetics and sedatives) between PENFS vs sham device.  
Data analyses will be performed using SAS version 9.4 (SAS institute, Cary, NC).  
 
Potential Pitfalls: This pilot data is both safe and non-invasive and will help us better 
understand the pathophysiology underlying CVS symptoms. The proposed device is non-
invasive and currently utilized at our institution. The PI is certified in the PENFS placement 
and has already used it in some of her patients with success. We thus expect no feasibility or 
safety issues. Potential risks generally would include bleeding or infection at the puncture 
site, pain at the application site, or skin irritation at the site of application.  
 
Feasibility: Recruitment should not pose a problem as the PI (Dr. Venkatesan) has the largest 
cohort of patients with CVS in the nation. Further in our experience, CVS sufferers are also 
highly motivated to enroll in studies and trial new therapies The PI also works closely with the 
Cyclic Vomiting Syndrome Association, who will advertise the study on their website and 

 
through email and supports this project. Co-PI (Dr. Bhandari) and Dr. Kovacic have worked 
extensively with the PI and published collaboratively in the field. Dr. Segon, the Section Chief, 
along with Dr. Bhandari, both hospitalists, are aware and will oversee all the logistics 
regarding the admissions and the study, as CVS patients are typically admitted under 
Hospitalist service. In a recent neurostimulation trial conducted by Dr. Kovacic, a high degree 
of compliance and a low dropout rate (12%) was observed despite a sham-controlled study 
design. Patient satisfaction with this non-pharmacological therapy was extremely high.  
 
In summary, this proposal will evaluate a novel, safe and non-invasive therapy for a 
debilitating and prevalent disorder with few established treatment options.  Demonstrating that 
this therapy is effective in treating and preventing CVS via neuromodulation will allow us to 
apply for extramural funding and expand our studies to a larger number of CVS patients and 
possibly other conditions.   
 
 
 
(D) Special Emphasis  
 
Patients who are admitted to the hospital with a CVS episode typically suffer from intense 
abdominal pain.35 Opiates with anxiolytic properties are therefore particularly effective in 
controlling symptoms in patients with CVS. Consequently, patients admitted with a CVS 
episode frequently require treatment with intravenous opioids. The addictive potential of 
narcotic pain medications is well known. As with other acute painful conditions, the use of 
opioids during a CVS episode may be followed by ongoing use of opioids. Also, withdrawal 
from opiates may be equivalent to a panic trigger for another exacerbation for a CVS 
episode. Therefore, patients are often reluctant to give up using opiates on an ongoing basis. 
Ongoing use of opioids in turn leads to disease coalescence with opioid dependence and 
withdrawal leading to recurrent episodes of CVS exacerbation.11 Escalating use of opiates 
can also lead to narcotic bowel syndrome which is characterized by worsening bouts of 
abdominal pain induced by opioid-induced bowel dysfunction.36  
 
The main focus of our study is to replace the need for intravenous opiates during a CVS 
episode with a non-invasive and safe device that can be placed with ease and does not 
require specific expertise.  
 
 

 
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Hejazi RA, Lavenbarg TH, Foran P, et al. Who are the nonresponders to standard 
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Babic T, Browning KN. The role of vagal neurocircuits in the regulation of nausea and 
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Hornby PJ. Central neurocircuitry associated with emesis. Am J Med 2001;111 Suppl 
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Yuan H, Silberstein SD. Vagus Nerve Stimulation and Headache. Headache 2017;57 Suppl 
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35. 
Fleisher DR, Gornowicz B, Adams K, et al. Cyclic Vomiting Syndrome in 41 adults: the 
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36. 
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quiz 1121-2. 
 
 
 

 
CTSI Support  
 
The CTSI's infrastructure provides an optimal framework for accomplishing the aims of our 
study. This study will utilize number of CTSI research support services.  
 
Our project involves collaboration between different CTSI member organizations, including 
the Medical College of Wisconsin ((PIs-Dr. Venkatesan, Dr. Bhandari) and Co-I-Dr. Segon), 
and Children’s Hospital of Wisconsin (Dr. Kovacic). Through this unique consortium of 
CTSI member institutions, we will have the ability to share research resources, technology, 
knowledge, and expertise to achieve our project's goals.   
 
The IRB reviewer of the CTSI will be consulted to assist in fulfilling the appropriate 
research regulatory requirements in order to accomplish the study in a safe and ethical 
manner. We will also utilize the services of the translational research unit (TRU) and the 
Clinical Trials Office (CTO) for sample collection and storage and assistance with 
coordination of various study related activities. These CTSI services, along with the inter-
institutional collaboration fostered by the CTSI, are critical for the success of this project. 
 
 

 
Project Timeline and Future Plans  
Timeline – Provide a detailed timeline/project plan for the project. Project must demonstrate its 
ability to be completed in 12 months.  
 
Dates 
Plan 
Feasibility 
Feb-2019 
Obtain IRB approval  
Working on logistics such as 
training personnel in placement 
of the device, communicating 
with/aligning hospitalists/ 
nurses regarding project 
IRB submission in progress  
Dr. Ankur Segon is Chief of the 
Hospitalist Section and will assist 
with  
the logistics of conducting the 
study. 
 
March 2019 
Enroll 12 patients/month in the 
study (allowing for attrition 
rates) 
Approximately 180 patients with  
CVS get admitted each year  
 
Dr Bhandari and Dr Segon 
including Hospitalist fellows will 
conduct the study 
 
April 2019 
Enroll 12 patients/month in the 
study (allowing for attrition 
rates) 
Approximately 180 patients with  
CVS get admitted each year  
 
Dr Bhandari and Dr Segon 
including Hospitalist fellows will 
conduct the study 
 
May-June 
2019-  
Analysis and data reporting 
Statistician (Rebekah Walker)  
from DOM will provide statistical  
support. 
 
   
Future Plans – Explain how pilot funding will be used for conducting research activities that 
will lead to future extramural grant funding (i.e. NIH, NSF) and ultimately to 
tangible clinical improvements.  
This study will enable us to collect preliminary data to study the efficacy of this non-
invasive device to treat pain and other symptoms in CVS and understand the underlying 
pathophysiology. We intend to submit an R01 proposal for a larger multi-center to the 
NIH.  The PI, Dr. Venkatesan is currently chairing the committee that has been charged with 
developing guidelines for the management of CVS in adults in collaboration with the 
American Neurogastroenterology and Motility Society (ANMS), which is slated for 

 
publication this year. As such, she has collaborative relationships with multiple faculty from 
various centers in the US and this will provide the framework for such multicenter trials.  
 
This project aims to study the effectiveness of a safe and novel therapy and elucidate the 
pathophysiology of CVS will change the treatment paradigm from one of trial and error to an 
evidence-based approach. This will significantly improve the lives of many patients who 
suffer from this debilitating illness.