Empower Opioid Misuse Theranova Study for Veterans With Chronic Pain
Phase: NA
Conditions: Chronic Pain, Opioid Use
Sponsor: University of California, San Francisco

Empower Opioid Misuse & Chronic Pain (RAP_EOM) 
NCT04184362 
5/1/2023 
 
 
 
Contents: 
 
• 
Study Protocol 
• 
Statistical analysis plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Protocol  
This pilot study aims to examine the feasibility, acceptability, and preliminarily examine efficacy of 
transcutaneous electrical nerve stimulation (TENS) at the ulnar nerve, in reducing opioid craving and use 
and decreasing pain. Opioid prescribing for chronic pain has increased dramatically over the past several 
decades, with devastating public health consequences, including high rates of opioid misuse and overdose 
deaths. Safe nonpharmacological treatments are urgently needed. Preclinical studies have shown that 
peripheral nerve stimulation at the ulnar nerve (ulnar aspect of the palm) through acupuncture or electrical 
stimulation directly regulates the mesolimbic dopaminergic pathway and reduces addictive behaviors. In 
addition, neurostimulation at acupressure points may reduce some types of chronic pain. Empower 
(TheraNova, LLC) is a non-invasive, portable TENS device that provides electrical stimulation at the 
ulnar nerve, which may reduce cravings and improve pain. We propose a single-blind, randomized 
controlled trial to examine the feasibility and to preliminarily examine efficacy of Empower in reducing 
opioid craving and opioid use in Veterans with chronic non-cancer pain (NCP). Aims are to examine the 
feasibility and acceptability of Empower and preliminarily examine its efficacy in reducing cravings, 
decreasing opioid use, and reducing pain when used at the ulnar nerve. Up to thirty veterans with chronic 
NCP and opioid misuse will be recruited. On Days 1- 7, participants will undergo baseline monitoring, 
and on Days 8-21, participants will undergo daily neurostimulation at ulnar nerve (n=15) or a control 
acupoint on the dorsal bicep (n=15). Study procedures will occur at home over 3 weeks, through secure 
two-way video or phone conference, with outcome assessments occurring at Days 0, 7, and 21. Pain 
scores, craving, and opioid use will be measured daily Days 0-21. Our goal is to provide an intervention 
that, alone or in conjunction with current treatments, reduces craving and reduces reliance on opioids in 
high-risk chronic pain patients.  
 
PROCEDURE  
In this proof-of-concept study, we will use a single-blind, randomized controlled design to assess 
feasibility, acceptability, and preliminarily examine efficacy of Empower in reducing opioid craving, 
opioid use, and pain levels in 30 Veterans with chronic NCP and opioid misuse. After screening, 
participants will undergo a 7-day no-treatment Baseline Monitoring Period, during which they will 
complete daily self-report measures of craving and pain. Participants will then take home the Empower 
device over a 14-day intervention period, during which they will receive neurostimulation at the ulnar 
nerve (n=15) or neurostimulation at a different anatomical location (Dorsal bicep) (n=15), twice daily, for 
15 min on each side of the body (30 min per treatment; 60 min total per day). Study procedures will occur 
over 3 weeks, with in-clinic assessments occurring at or around Days 0, 7, 14, and 21. Primary outcomes 
include: opioid craving, prescribed and nonprescribed opioid use, and pain scores; and qualitative and 
quantitative measures of usability and acceptability at treatment end. Exploratory outcomes include self-
reported depression levels, activity scores, and health-related quality of life, and the association between 
pain scores and craving levels over time.  
The total duration of participant participation will be three weeks. At screening, self-report and 
interviewer data will be reviewed to determine participant eligibility. Medical conditions, psychiatric 
history, and medication list will be collected through review of participants’ VA medical records. 
Participants will complete the MINI Neuropsychiatric Inventory. Urine toxicology panels may be 
completed through either VA lab urine drug screen or urine drug screen home test kits for participants at 
Days 0, 7, and 21. During pandemic times, if a participant is already scheduled for an essential visit to the 
hospital and lab, then they may optionally take the test at the lab. However, due to pandemic restrictions, 
we will also offer at home test kits for participants who will not be attending the VA site for an essential 

visit. To encourage self-monitoring during treatment sessions, participants may optionally self-monitor 
heart rate variability, through their own at-home heart rate monitors or through provision of 
commercialized heart rate monitoring apps. Interested participants will be informed that they may 
optionally monitor heart rate before, during, or after treatment sessions at Days 0, 7, 14, and 21, from 
home. Readings will be collected via encrypted message, de-identified and stored in the password 
protected database.  
A urine pregnancy test in women ages 18-50 who do not confirm a reliable method of birth control at 
screening will also be completed at screening (Day 0), either in the VA lab or at home. The results of at 
home urine pregnancy test can be shared securely via encrypted email through a photo image of the home 
test. We will obtain informed verbal consent to communicate with each participant’s medical provider to 
confirm eligibility after verbal consent. Participants who meet all inclusion criteria and none of the 
exclusion criteria will be enrolled in the study.  
The first week (Days 0-7) will be the Baseline Monitoring Phase, in which baseline measures of craving, 
and pain are completed daily (see below). On Day 7, participants will be randomized to use the Empower 
device at the ulnar nerve (Treatment Group, n=15) or at the bicep (Sham Group, n=15). The subsequent 
two weeks will be the Treatment Phase, followed by the Post-Treatment Completion visit at the end of the 
two- week Treatment Phase. Throughout the study, the participant will complete daily surveys on the 
Empower app on the provided smartphone and weekly Qualtrics-based questionnaires. The participant 
will be asked to complete surveys as close as possible to awakening. During the Treatment Phase only, 
the participant will self-administer a 30-minute treatment two times daily. The participant will be asked to 
administer treatments approximately 12 hours apart, if possible. The smartphone will have daily 
notifications to remind the participant to complete surveys and treatments.  
The study will include three clinic visits:  
1) Enrollment and start of Baseline Phase (Day 0),  
2) Completion of the Baseline Phase and start of the Treatment Phase (Day 7, ± 5 days to account for 
scheduling/ weekends), and  
3) Study Completion (14 ± 5 days after Visit 2).  
At Baseline (Day 0), the participant will be given the smartphone with Empower app and trained on 
smartphone and app use. The participant will then be sent home with the smartphone and instructions for 
use. They will record craving levels and pain levels daily on the Empower app. On Day 7, the study team 
will use a secure two-way video or telephone conference app to randomize participants into one of two 
groups (treatment condition (palm) or control condition (dorsal bicep) in a 1:1 ratio according to a 
computer-generated code provided by the study biostatistician using randomization software. Participants 
will be randomized in blocks of random size ranging between 4 and 6 to ensure equal numbers in each 
group and to maintain relative balance between groups as the study progresses. After enrolling a 
participant into the study, all study materials and devices will be securely delivered to the participant. 
When the receipt of the materials is confirmed with the participant, study staff will coordinate a tutorial 
on how to use the device using secure two-way video or telephone conferencing. Once participants 
demonstrate an understanding for how to use the Empower Neuromodulation System at their designated 
site, they will then undergo their first self-administered electrostimulation session under study staff 
supervision.  
Starting on Day 8, all participants will self-administer neurostimulation via Empower upon awakening 
(immediately following completion of the Empower App self-reports) and again approximately 12 hours 
later. Treatment Condition: Participants will complete a 15-min electrical stimulation application via 

Empower on one palm (ulnar nerve acupoint) followed by an additional 15-min stimulation on the 
opposite palm (30 min per session, 60 min per day). Control Condition: Empower will deliver equal 
electrical current to the dorsal aspect of the bicep for equal time duration as the Treatment condition.  
Surveys administered through Qualtrics will be conducted through secure two-way conferencing or 
encrypted e-mailed to participants through Qualtrics. The e-mails will contain no health information and 
will only contain the link to the survey in which a participant will submit their responses, and what week 
of the study they are in. The survey links will be anonymized as to not retrieve any IP address information 
from participants and will also be de-identified and participants will be entering their subject ID numbers 
rather than any identifiable information. The e-mail will be sent from a no-reply Qualtrics server. At the 
final assessment day, after the participant has completed their last self-administered treatment session, the 
clinical research staff will determine if any adverse effects (AEs), serious adverse effects, SAEs, or 
UADEs or other side effects have occurred during the study. The participant will also complete the 
weekly measures along with the usability survey on Qualtrics. 
 
Statistical Analysis Plan 
Prior to analysis, all data will be examined for anomalous and missing values and described in detail. To 
address missing data, we will perform a sensitivity analysis using a “copy reference” approach, under 
which missing-at-random data in either condition is imputed. The description of the data is a key aspect of 
this work as it informs future studies. Aim 1: Measures of feasibility, including proportion of those 
eligible among those screened, proportion enrolled among those eligible, enrollment rate, study retention, 
adherence to the baseline monitoring period, adherence to the treatment and control conditions, study 
completion rate, and potential adverse effects will be calculated. We will also passively collect data about 
participant usage patterns (compliance and electrical current). Qualitative data examining acceptability 
will be analyzed using an iterative, inductive process. We will meet approximately biweekly to conduct 
multiple reviews to identify prominent themes and develop coding templates based on new data emerging 
from interviews and using grounded theory methodologies. Mean quantitative acceptability data will be 
calculated, with a target of SUS ≥ 70 and CSQ ≥ 24. Lower scores would lead to revision of product 
design or other features to improve acceptability. 
 
Aims 2-3 and Exploratory Aims: Outcome measures will be examined with a series of parallel statistical 
models, estimated via maximum likelihood, using planned contrasts between the Empower active ulnar 
nerve treatment condition, the control condition, and the baseline monitoring period. Analyses of in-clinic 
assessments will compare outcome measures at Days 0, 7, 14, and 21. Given the limited number of 
assessment points, the most parsimonious model will be a general linear model for each outcome 
measure. For the daily measures, we will use multilevel modeling to compare changes in variables over 
days between the treatment and control condition/baseline monitoring period. Analyses will be performed 
with SPSS.