Addressing Opioid Use Disorder With an External Multimodal Neuromodulation Device: Development and Clinical Evaluation of DuoTherm for Opioid-Sparing Pain Relief in Acute and Chronic Low Back Pain
Phase: NA
Conditions: Opioid Use, Low Back Pain
Sponsor: MMJ Labs LLC

ClinicalTrials.gov  NCT04491175 
SPIRIT Table: eProtocol M-Stim for LBP Opioid & Pain Reduction 
Administrative 
Description 
Title 
Multimodal Mechanical Stimulation to Reduce Opioids for Low Back 
Pain: A Randomized Clinical Trial 
An Outpatient, Double-blinded Randomized Trial Comparing the Impact 
of DuoTherm™ Mechanical Stimulation (M-Stim) Versus TENS on Opioid 
Prescribing and Use for Low Back Pain 
Trial 
Registration 
ClinicalTrials.gov  NCT04491175 
Protocol Version NIH funded protocol submitted 5/29/2019 to FDA Q191165  
IRB Protocol Submission Date: 8/10/2019  
Protocol Amendment Number: 4 
Authors: A.B.,K.S.,L.L. 
Revision Chronology: 
1) 8/10/2019 Original [COVID delay] 
2) 4/21/2022 FDA recommended modifications from Q191165 
incorporated to protocol: increased sample size to 60 opioid 
naïve acute (for 3 months) and 100 chronic (with 6 months 
followup); Replaced Sham with LG Smart TENS and added a 
blinding assessment; Outcome measures of PROMIS Pain 
Interference , Pain Intensity, Depression to be measured weekly 
the first month. 
3) 6/8/2022 – Final survey design reduced daily diary reporting to 1 
month due to budget constraints of longer follow up. Depression 
and Catastrophizing only as baseline; weekly NRS Pain 
Interference (3) PROMIS Pain Interference (2) and Pain Intensity 
collected until 3 months for all; Monthly surveys added past 
month NRS, Blinding assessment to monthly survey at 3 months 
and after for those started in chronic strata. 
Added “source” for each opioid use case to DOSE tool collecting 
opioid formulation, dose, and number of pills.  
4) 5/5/23; Added “Do you think you will need surgery” and “do you 
think you will need epidural” questions, and “did you get surgery” 
and “did you get an epidural” to monthly. 
5) 7/13/2023 New Location added 

 
Funding 
National Institute on Drug Abuse, R44DA049631, R44DA058952 
Roles and 
Responsibilities 
Principal Investigator: Amy Baxter MD, responsible for study design, 
overall project oversight, and compliance. Study Coordinator: Jena 
Slaski, responsible for daily operation, protocol adherence and patient 
coordination at Kaizo Health Centers. Lindsey Cohen assisted Dr. Baxter 
with initial study design, ongoing recruitment recommendations, pain 
measure decision-making, study flow creation. M. Louise Lawson PhD 
(Deceased), responsible for initial power analysis, statistical support for 
study design, revisions after FDA. Dr. Kevin Swartout PhD, responsible for 
programming of data collection instruments, ongoing support of data 
collection tool and dataset, database consolidation; Jessica Allia 
Williams PhD, responsible for statistical analysis of completed dataset. 
All apart from Dr. Lawson reviewed the manuscript. 
Introduction 
Low back pain (LBP) affects nearly 40% of adults, contributing to 
significant reductions in quality of life and productivity. The opioid 
epidemic, largely driven by prescriptions for pain, has created an urgent 
need for effective non-pharmacological pain treatments. Existing options 
such as TENS devices may provide acute relief, but are not available as 
an opioid substitute. A multimodal approach, combining mechanical 
stimulation, heat, cold, and acupressure, holds promise for reducing 
both acute and chronic pain and opioid prescribing.  
Background and 
rationale for the 
study 
Between 25 and 50% of patients presenting with acute or exacerbated 
chronic LBP (a/cLBP) receive prescriptions for opioids. ALBP progresses 
to chronic in 40% of those with moderate to severe pain (4 out of 10 on a 
0 – 10 Numeric Rating Scale). Opioid pain relief is no better than placebo 
at 6 weeks after presentation, but increases the risk of cLBP and 
persistent use (5% of opioid naïve). Providing a multimodal low back pain 
device could reduce opioid prescribing or use compared to TENS; 
providing any device could reduce opioid prescribing and use compared 
to contemporaneous prescribing practices. 
Objectives 
Primary Objective, Opioids: To determine whether the use of a 
multimodal neuromodulatory mechanical stimulation (M-Stim) device 
(DuoTherm) can reduce opioids 30% compared to TENS in those with 
moderate to severe back pain.  

Co-Primary Objective, Acute Pain: To determine whether multimodal 
M-Stim reduces Pain Intensity 30% more than TENS in the first 10 days 
after presenting for treatment. 
Co-Primary Objective, Chronic Pain: To determine whether multimodal 
M-Stim reduces disability 30% more than TENS at 6 months. 
Study Design 
 
A randomized, double-blind controlled trial with 3- (aLBP) or 6- month 
(cLBP) follow-up. 
Study Setting 
The study will be conducted at mixed physical therapy/chiropractic 
practices in Washington, DC, Maryland, and Virginia, which offer 
demographic and economic diversity. These clinics provide an ideal 
environment, with frequent follow-ups and ongoing therapy but no on-
site access to opioid prescribers. 
Eligibility 
Criteria 
Inclusion Criteria: 
- Male or female adults aged 18-90 presenting for treatment of acute or 
chronic low back pain  
- Self report of moderate to severe LBP of 4 or greater out of 10 on a 0-10 
Numeric Rating Scale. 
- Acute: pain duration <3 months not using opioids for the current 
exacerbation of low back pain 
- Chronic: Pain duration >=3 months with or without ongoing opioid use 
- Capacity to understand risks and benefits (informed consent). 
- Smartphone for Qualtrics web-based platform use 
Exclusion Criteria: 
- Radicular pain likely reflecting a surgical or mechanical problem 
- Inability to apply or use the device 
- Sensitivity to cold or vibration (e.g Raynaud’s or Sickle Cell Disease) 
- Diabetic neuropathy rendering a patient unable to determine if the 
device is too hot 
- New neurologic deficits, skin lesions over the low back area 
- A contraindication to any medication for pain management that would 
impact analgesic use record 

- Pacemaker 
Intervention 
 
The experimental arm DuoTherm is a novel multimodal low back pain 
relief device incorporating 8 harmonic vibration patterns of mechanical 
stimulation (M-Stim) including neuromodulatory frequencies, 5 intensity 
levels, and optional heat, cold, and pressure delivered through a 
sculpted metal plate attached with a belt and controlled by buttons on 
the belt. Patients will be instructed to use the device at least daily for 30 
minutes. The active control is a prescription 4-lead 8-channel TENS unit 
(LG Smart) with variable intensity.  
Participants will be instructed to use the device for a minimum of 30 
minutes a day. Both M-Stim and LG Smart TENS groups will receive a 
standard pain management regimen typically used for low back pain 
standardized across all clinicians participating in the study. Participants 
will keep the devices and be instructed to use them for pain as needed 
during the duration of the study.   
Outcomes 
Opioid Use Primary Outcome:  
Prior use: For patients with prior or ongoing opioid use, a 30% reduction 
in MME (Milligram Morphine Equivalents) between the first 14 days and 
the last 14 days of daily diary recordings using the DOSE data collection 
tool.   
Opioid naïve: 30% reduction of those receiving an opioid prescription 
“prescribed to me for this event” 
Secondary outcomes: Use days; total MME and use past 7 days in the 
opioid naïve; use days by those with more severe pain using the NIH 
Research Taskforce definitions; and prescribing compared to a 
contemporaneous national LBP population (25%). 
Pain Primary Outcome: 
Chronic: 30% lower disability at 6 months using PROMIS Pain 
Interference for those with ongoing pain >3 months 
Acute: 30% lower NRS 0-10 “pain now” from entry to 10 days for those 
presenting with an episode of pain starting within the past 2 weeks 
Secondary Outcomes: Change in disability for those with >=57.7 
PROMIS Pain Interference; restoration of function to normal (PI=50); 

integrated analysis with common criteria for restoration of function with 
multifidus stimulation surgery. 
Participant 
Timeline 
 
Initial Visit 
Daily x 
28 days 
Weekly for 
3 months 
Monthly for 
3 months 
Monthly 
4 - 6 
months 
Consent, Enrollment, 
Randomization 
ALBP, 
CLBP 
 
 
 
 
Minimum Dataset, Pain 
Catastrophizing Sullivan, 
PROMIS Depression, 
Physical Function 
ALBP, 
CLBP  
 
 
 
 
NRS (at that moment & 
past 24 hours)   
ALBP, 
CLBP 
ALBP, 
CLBP 
ALBP, 
CLBP 
ALBP, 
CLBP  
 CLBP 
NRS after 30 minutes 
ALBP, 
CLBP 
 
 
 
 
NRS Past week 
 
 
ALBP, 
CLBP 
ALBP, 
CLBP 
CLBP 
NRS Past month 
 
 
 
ALBP, 
CLBP 
CLBP 
PROMIS Pain Intensity, 
Pain Interference 
ALBP, 
CLBP 
 
ALBP, 
CLBP 
ALBP, 
CLBP 
CLBP 
Dose, Opioid formulation, 
number Source (DOSE 
tool), other analgesics 
ALBP, 
CLBP 
ALBP, 
CLBP 
ALBP, 
CLBP 
ALBP, 
CLBP 
CLBP 
Device usage  
 
ALBP, 
CLBP 
ALBP, 
CLBP 
ALBP, 
CLBP 
CLBP 
Sample Size 
To estimate the M-Stim intervention effect size, a retrospective study of 
59 cLBP patients on chronic opioids (100% prolonged opioid use) 
reported a 28% reduction in MME after spinal stimulator 
implantation,[40] reducing MME 26.2(SD32.8) compared to 5.8(SD34.2) 
for those with conventional treatment (effect size 0.60. A priori, we would 
be able to detect an effect size of 1 (meaning a difference of 1 standard 
deviation) with 94% power and alpha of .03 using a Wilcoxon Mann 
Whitney test with 30 in each group. With this effect size for a two-sided 
significance of 0.05, 17 participants per group would detect a 30% 
prescribing reduction, while 50 participants on chronic opioids per 
treatment group would provide 85.4% power to detect a 30% reduction in 
MME. Given the 20% in a previous study by Jamieson et al, we increased 
the cLBP sample to 50 in each group. 

We planned to recruit 60 aLBP participants who had never taken opioids 
for their back pain, and 100 cLBP without a new prescription but with or 
without chronic opioid for cLBP. 
Recruitment 
 
Patients were recruited from Kaizo Health Centers in Landover and 
Fairfax, through direct referrals, flyers, and digital content like social 
posts and emails targeting local populations. Flyers were also distributed 
at three local pain clinics.  
Randomization 
After eligibility screening and informed consent, a 4-digit participant ID 
and the intervention allocation were randomly assigned  by the survey 
software to either the DuoTherm or LG Smart TENS group within acute 
and chronic arms. A copy of the informed consent was  emailed to the 
participant. 
Blinding 
(masking) 
 
Participants were blinded to which device powered the study hypothesis, 
and blinded to their assigned intervention until after documenting initial 
NRS pain intensity. Success of blinding the study device (M-Stim) versus 
the active control (TENS) was tested at months 3-6 with prompts, “select 
which group you think you were in (control or treatment)” and “How 
confident are you (0 = Least Confident ... 100 = Most Confident).”  
The protocol statistician and study coordinator knew the intervention 
assignments during enrollment but did not conduct statistical analysis. 
The PI and treating chiropractor were blinded to allocation during 
enrollment, with the PI accessing data only after study completion. The 
analyzing statistician was blinded to device assignment until completion 
of data cleaning and initial analysis. 
Data Collection 
Methods 
 
Site coordinators entered identification and contact information after 
informed consent on a tablet, then recorded weight, height, and duration 
to confirm acute or chronic follow-up duration, then participants took the 
tablet to record pain intensity on a 0-10 NRS now and past 24 hours. 
While using the device for 30 minutes, participants completed 7-day pain 
intensity NRS, NIH Back Pain Research Minimum Dataset, including 
PROMIS measures of Physical Function, Pain Interference, Depression, 
and Catastrophizing via the Sullivan Catastrophizing scale, Injury 
Mechanism, prior treatments, exercise and athletic status. 
 
Participants were prompted to record analgesic use, pain, and device 
use daily for a month on the web-based platform, then weekly, with the 
monthly surveys adding Pain Interference. All surveys asked about 

analgesic use. Due to the anticipated heterogeneity of opioid 
formulations, a skip-logic data collection instrument algorithm was 
created with robust options for Dose per pill (34), Opioid formulations, 
e.g. hydrocodone, hydromorphone etc. (15) and the Source (DOSE tool, 
Supplement 2).  Sources included “prescribed to me for this event”, 
“prescribed to me for another event”, “given to me by a family member”, 
“given to me by a friend”, “given to me by an acquaintance or stranger”, 
or “purchased from someone without a prescription”. These were 
converted to a total milligram morphine equivalent (MME) for analysis. 
Participants recorded when they used their device, duration of use, and 
any additional pain relief modalities (exercise, stretching, bath, hot tub, 
therapy, massage). Patients were asked to record any thermal use or 
therapy cycle or channel as appropriate to their device. 
Participants verbally endorsing pain for less than three months (acute) 
were entered into a 3 month follow-up program, or 6 months (chronic) for 
those for whom back pain had been an ongoing problem for more than 3 
months. 
Statistical 
Methods 
Statistical analysis was performed with masked intervention allocation 
by a statistician new to the project to determine differences in primary 
and secondary outcomes.  
An intention-to-treat analysis included all participants meeting inclusion 
criteria. Summary statistics (means, standard deviations, proportions) 
were calculated using T-tests and Chi-squared tests. Opioid prescribing 
differences were calculated with raw percent of change and relative 
risks. Diary entries and item-level data were analyzed for missing data to 
assess the need for imputation. Relative risks were calculated for MME 
and opioid use days between intervention groups, with paired T-tests 
used to compare first two and last two weeks of MME in those who used 
opioids during the study. A linear regression assessed BMI's interaction 
with opioid use, calculating marginal effects with standard errors via the 
Delta Method. Data analysis was performed using STATANow/SE 18.5. 
For pain outcomes, in addition to the above methods, missing 10 day 
NRS-1 data will be imputed using forward fill and KNN. A neural network 
will be created to determine factors contributing to 13 week Pain 
Interference, with iterative modeling to reduce mean absolute error. 
Graphs with r-squared for predictors will be generated. 

Data Monitoring 
Data collection was conducted through an app that tracked daily pain, 
opioid use and device usage. Monitoring included weekly enrollment 
review by the protocol statistician to assess comprehension of the data 
collection tool. Adverse events were reported as per protocol. 
Obtained data was stored on password-protected network drives made 
accessible solely to the listed investigators. Data analysis will only be 
conducted in secure rooms with restricted access. These rooms will only 
be accessible to investigators. Patient samples will not be obtained. The 
Institutional Review Board reserves the right to audit any research files to 
assure the quality of any data used in this research 
Safety/Harm 
Q191165/S001 FDA ruled Non-significant Risk 18-Sept 2019. Risks are 
minimal, similar to those associated with a handheld massager or 
standard heat/cold therapy. Patients will be screened for sensitivity to 
cold or vibration. Any significant adverse events will be reported to the 
IRB and NIH within 24 hours. Device-related adverse events will be 
documented and reported. 
Auditing 
Periodic auditing will be conducted by the Institutional Review Board 
(IRB) to ensure compliance with protocol and safety regulations, and by 
site visits by the PI. 
Ethics Approval 
This trial has received ethics approval from the Kaizo Clinical Research 
Institute IRB and is registered under NCT04491175. 
Protocol 
Amendments 
Revision Chronology: 
1) 8/10/2019 Original  
[COVID delay] 
2) 4/21/2022 Incorporated FDA recommended modifications from 
Q191165 incorporated to protocol: increased sample size to 60 
opioid naïve acute and 100 chronic (with 6 months followup); 
Replaced Sham with LG Smart TENS active control with 8 pre-
programmed patterns to correspond with 8 pre-set DuoTherm 
therapy cycles and added blinding assessment. Outcome 
measures of PROMIS Pain Interference , Pain Intensity, 
Depression to be measured weekly the first month. We extended 
the follow-up from one week for acute pain to 3 months for acute 
pain and 6 months for chronic pain.  
3) 6/8/2022 – Final survey design reduced daily diary reporting to 1 
month due to budget constraints of longer follow-up. Depression 
and Catastrophizing only as baseline; weekly NRS Pain 
Interference (3) PROMIS Pain Interference (2) and Pain Intensity 
collected until 3 months for all; “Past month NRS” added to 

monthly surveys added past month NRS, Blinding assessment for 
additional 3 months for those started in chronic strata. 
Added “source” for each opioid use case to DOSE tool collecting 
opioid formulation, dose, and number of pills.  
We intended to use evaluate change in MME over time for chronic 
opioid users. The FDA recommended requiring participants on 
opioids maintain dosage and frequency. As we did not have 
access to prescribing records, and opioid reduction was a desired 
outcome measure, we evaluated opioid use for the first two 
weeks versus the last two of those endorsing prior opioid use. We 
extended the baseline and follow-up Pain Intensity 
measurements to one month rather than one week. 
3a) 8/31/22 – Site Visit. PI noted staff using “will not fit” criteria 
rather than BMI of 30 from pilot study. New device fits variable 
BMI, based on abdominal girth. Retained “if device fits”, 
exclusion criteria using BMI changed to BMI >50, noting 
controversy in using BMI as exclusion criteria. 
4) 5/5/23; Added “Do you think you will need surgery” and “do you 
think you will need epidural” questions, and “did you get surgery” 
and “did you get an epidural” to monthly. 
5) 7/13/2023 New Location added 
Stratification by chronicity versus opioid use status: enrollment strata 
were based on verbal endorsement of duration and no acute opioid use 
for back pain. Initial evaluation of registration data after enrollment was 
complete revealed 16 of 60 in the “acute” strata reported a duration 
longer than three months, and half in each chronicity strata no prior 
opioids for LBP.  In consultation with Clinical Trials.gov, we pooled the 
data and included both opioid and pain outcomes as a single  
NCT04491175 registry with two different publications and analyses.         
Informed 
Consent 
Informed consent will be obtained from each participant after screening. 
Participants will be informed about the voluntary nature of the study, with 
a HIPAA form for confidentiality. Consent will be documented via 
selecting ‘continue’ on the digital consent form. 
Confidentiality 
Patient data will be stored on password-protected network drives. All 
data will be de-identified using a unique study ID for each participant. 
Confidential records will be stored in secure, restricted-access rooms. 
Declaration of 
interests 
The principal investigator has financial conflict of interest from design 
and research into the DuoTherm device, and creating a company to 

develop the device with NIH SBIR funding. The collaborators declare no 
financial or personal conflicts of interest related to this study. 
Dissemination 
Policy 
Results will be disseminated through peer-reviewed journals, 
conferences, and possibly through NIH publications, ensuring that both 
positive and negative outcomes are reported. 
Ancillary and 
Post-Trial Care 
Patients will receive standard care post-trial and may keep their devices 
if found beneficial. Participants will be provided referrals for ongoing care 
as needed. 
Publication Plan 
High impact journal, with presentation at the IASP or similar pain-related 
conference.