Virtual Reality Treatment in a Methadone Maintenance Treatment Program for Chronic Pain and Opioid Use Disorder
Phase: NA
Conditions: Chronic Pain, Opioid Use Disorder
Sponsor: Albert Einstein College of Medicine

VIRTUAL REALITY TREATMENT IN A METHADONE MAINTENANCE TREATMENT 
PROGRAM FOR CHRONIC PAIN AND OUD: A PILOT RANDOMIZED CONTROLLED TRIAL 
 
IRB number: 2022-14257 
NCT05546749 
 
Documents updated 04/20/2023 
 

VIRTUAL REALITY TREATMENT IN A METHADONE MAINTENANCE TREATMENT 
PROGRAM FOR CHRONIC PAIN AND OUD: A PILOT RANDOMIZED CONTROLLED TRIAL 
(VR-OUD PILOT)
Protocol V 1.6
BACKGROUND
A. Opioid use disorder (OUD) is highly associated with comorbid chronic pain. Opioid use disorder, 
a condition affecting 2 million persons in the United States, is defined by a pattern of opioid use with 
significant personal, professional, and social consequences. In addition to being highly associated with 
health outcomes such as overdose related to opioid use, OUD is also highly related to poor general health, 
low quality of life, and debilitating chronic pain.1,2 Among patients receiving medications for OUD, over 
half report at least moderate chronic pain, and more than a quarter report at least severe chronic pain.3–5 
Evidence suggests that poorly controlled chronic pain may impact OUD outcomes, likely mediated 
through increased opioid craving to relieve pain and/or reduce depression and anxiety symptoms.5–8
B. New and innovative treatments for chronic pain are needed. Despite the burden of chronic pain, 
established treatments are ineffective, laden with severe side effects, or inaccessible. Opioid therapy is 
common but ineffective for the treatment of chronic pain and, moreover, carries significant risk of severe 
adverse events including overdose.9,10 For these reasons, non-pharmacologic treatment for chronic pain is 
recommended by numerous clinical practice guidelines. However, numerous barriers, including local 
availability and perceived lack of efficacy, impede access to non-pharmacologic treatment options.11 For 
these reasons, studies of new and innovative treatments are needed.
C. Barriers and facilitators to non-pharmacologic treatment for chronic pain among persons with 
OUD. Accessing non-pharmacologic treatment among persons with OUD is further compounded by 
several unique barriers, including stigma and federal requirements requiring persons to visit MMTPs daily 
or very regularly.12–16 Integrating on-site non-pharmacologic treatments for chronic pain into MMTPs is 
an innovative strategy to reduce systemic and logistical barriers to treatment of chronic pain and has the 
potential to reduce stigma.17,18
C. VR treatments for chronic pain. VR treatments represent a relatively new and highly innovative 
treatment paradigm for chronic pain. VR treatments already have established efficacy in mood disorders, 
anxiety, phobias, and acute pain.19,20 Multiple systematic reviews have established that VR interventions 
for the treatment of chronic pain are promising, but interventions to date are heterogenous and further 
study is needed to demonstrate efficacy.21–23 For example, immersive VR in a virtual environment tends 
to be associated with higher pain reduction and greater satisfaction.24–26 Relevant to this application, the 
immersive VR intervention (RelieVRx) proposed for use in the current study was tested in a sample of 
179 adults with chronic low back pain and shown to be effective in an 8-week trial in reducing pain and 
improving sleep, mood, and stress; most changes persisted up to 3 months.27,28 
D. VR treatments have been used in substance use disorders, and early evidence suggests VR 
treatments can be effective in OUD. A recent systematic review concluded that VR treatments can 
provide benefits in substance use disorder treatment, mainly owing to the ability of a therapeutic, 
immersive environment.29 In persons with nicotine addiction and alcohol use disorder, VR treatments 
found mixed to positive results on a number of nicotine and alcohol outcomes, including decreased 
craving.30–39 A recent non-randomized pilot study of a VR meditative intervention with 15 persons on 
methadone for OUD showed reductions in pain, opioid craving, anxiety, and depression in addition to 
reduced saliva cortisol, and changes in brain activation in the postcentral gyrus region of the brain on pain 
related tasks.40
E. Immersive mindfulness VR can lead to improved pain and OUD outcomes through its targeted 
effects on stress and inflammation. Mindfulness exercises have been associated with a myriad of 
positive outcomes that are relevant to the current study, including improved quality of life, pain 
interference, mood and anxiety symptoms, sleep quality, opioid craving, and opioid use.41–49 We propose 
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these positive outcomes work through targeted effects on stress and inflammation, as mindfulness 
therapies have been associated with reductions in both patient reported stress and inflammation and in 
biomarkers linked to stress (such as cortisol) and inflammation (such as C-reactive protein and cytokine 
levels).45,50–52 Reductions in both stress and inflammation, in turn, are associated with improved pain and 
OUD outcomes.53–56
F. Summary. Chronic pain is highly prevalent in patients with OUD, and new and innovative treatments 
and onsite treatment paradigms are needed. We propose an innovative, on-site immersive mindfulness VR 
treatment targeting stress and inflammation to improve pain and OUD outcomes. The proposed trial will 
be the first pilot RCT study of VR treatment in a methadone maintenance treatment program (MMTP), 
and has the potential for widespread application.
STUDY DESIGN
Overview. In a 6-week pilot RCT, we will assess the feasibility and preliminary efficacy of an immersive 
mindfulness VR treatment (RelieVRx) versus a non-immersive sham VR control (sham VR) for the 
treatment of pain and OUD. We will recruit 40 adults with OUD and chronic pain enrolled in an MMTP 
and randomize 1:1 to RelieVRx vs sham VR. Over 6 weeks, participants in both groups will participate in 
20-30 minute VR sessions twice per week at the MMTP. Over the course of the study, the research team 
will conduct pain and psychological assessments at baseline, 3 weeks, and at the study conclusion at 6 
weeks. We will also explore changes in stress and inflammatory saliva and blood biomarkers at baseline, 
3 weeks and 6 weeks. To assess feasibility, we will examine recruitment and retention and assess patient 
satisfaction. Our preliminary efficacy co-primary outcomes are (1) change in pain intensity and (2) 
change in opioid craving between treatment groups at 6 weeks. Secondary outcomes will include changes 
in pain interference, physical functioning, depression, anxiety, sleep quality, illicit opioid use, and 
prescription opioid use. In a separate aim, we will also explore changes in stress and inflammatory 
markers over the course of the trial.
Setting and Participants. We will recruit and conduct study visits at one Montefiore Opioid Treatment 
Program (OTP). Montefiore has the largest network of OTPs in New York State. Three of the five 
Montefiore OTPs comprise the Montefiore Division of Substance Abuse (DoSA) Wellness Centers; in 
total, these sites serve approximately 3,000 individuals. Electronic health data indicates that of 945 people 
with a chronic pain diagnosis who are on methadone for OUD, 555 (59%) are Male, mean age is 58.3, 
566 (60%) are Hispanic, 170 (18%) are Black, and 140 (15%) are White. 
Participants: We will enroll 40 participants. As the narration of the VR device is only provided in 
English at this time, we require English proficiency for this pilot trial. Inclusion criteria: 1) ≥18 years 
old, 2) English proficiency; 3) receiving methadone treatment for DSM-5 confirmed OUD in the 
Montefiore network for at least 12 weeks, with no dose change in 14 days to ensure treatment stability; 4) 
chronic pain of at least moderate pain severity (score  ≥4 on the Pain, Enjoyment of Life, and General 
Activity (PEG) scale);57 5) willingness to participate in all study components; and 6) ability to provide 
informed consent, assessed using consent teach-back. Exclusion criteria: 1) conditions that could make 
participation in VR hazardous or cause adverse effects (current or prior diagnosis of epilepsy, seizure 
disorder, dementia, or migraines, any medical condition predisposing to nausea or dizziness, 
hypersensitivity to flashing light or motion), 2) conditions that could prevent proper use of the VR 
headset (stereoscopic vision or severe hearing impairment, or injury to eyes, face, or neck that prevents 
use of the VR headset), and 3) acute exacerbation of psychiatric conditions that preclude the ability to 
participate in the study. Pregnant patients are NOT excluded from the trial as there are no 
contraindications to their use of a VR device, but we are not specifically targeting pregnant patients for 
this study nor are we testing for pregnancy.
Recruitment, Screening, and Randomization. Recruitment will be active and passive in the OTP. 
Based on our team’s prior DoSA trials and the scope of this current project, we anticipate enrolling 1-2 
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participants weekly. Research staff will enroll from one DoSA site for the duration of the trial; we will 
plan our recruitment strategy in conjunction with other IMPOWR-ME trials as to not recruit from the 
same pool of patients at a site at the same time. We expect retention of approximately 85% based on our 
groups prior DoSA trials.58,59 Screening: After obtaining written consent, we will administer a screening 
questionnaire. Potentially eligible subjects will then complete a written informed consent process 
including discussion of procedures and risks and benefits before being randomized. Consent will occur in 
a private area of the OTP. Randomization: Randomization will occur using block randomization (blocks 
of 4) to two 
conditions in a 1:1 
ratio. 
Description of 
intervention and 
control. Both 
intervention and 
control arms will 
utilize a Pico G2 
head-mounted VR 
device with pre-
installed software. 
RelieVRx 
incorporates 
evidence-based 
principles of 
cognitive behavioral 
therapy and 
mindfulness to 
provide pain 
neuroscience 
education and to 
train users on 
evidence-based pain 
and stress 
management 
strategies with 
interactive and 
immersive exercises 
and experiences. In 
total, RelieVRx 
combines 
biopsychosocial 
pain education, 
diaphragmatic 
breathing training, 
relaxation exercises, 
and executive functioning and attentional games to strengthen pain coping skills. RelieVRx is typically 
delivered in a 56-day program through daily virtual experiences, with each experience lasting between 2 
and 16 minutes; in this pilot study, we will conduct in-office virtual experiences twice weekly. Each 
session will last about 20-30 minutes and go through 1-5 virtual experiences. The sham VR control is a 
non-immersive set of 56 daily virtual experiences, tuned to the length of the RelieVRx. Control 
participants will similarly experience 1-5 virtual experiences in each 20-30 session.
Table 1. Overview of Data Collection
Domain
Measure
Source
Feasibility Outcomes
Percent screened
Proportion of total participants contacted who are screened
RL
Percent consented
Proportion of total participants screened who consent
RL
Percent retained
Proportion of total participants consented who complete 
study
RL
Patient satisfaction
Global impression of change scale60
S
Preliminary Efficacy Outcomes and Covariates
Pain intensity (co-
primary)
PEG,57 PROMIS Pain Intensity subscale61
S
Opioid craving (co-
primary)
Opioid Craving Visual Analog Scale62
S
Quality of life
PROMIS Physical Functioning, PROMIS PROPr Fatigue, 
Cognitive Function, Social Function61
S
Stress
Perceived stress scale63,64
S
Pain interference
PROMIS Pain Interference Subscale,61 PEG57
S
Pain history and 
characteristics
Pain screening questions, Michigan pain body map65, use 
of medications and treatments, chronic pain acceptance,66 
pain self-efficacy67, pain catastrophizing68
S
Mood symptoms
PROMIS PROPr Depression, Anxiety61
S
Sleep quality
PROMIS Sleep Disturbance 6A + Sleep Duration69
S
Illicit opioid use and 
substance use
Modified Addiction severity index70, Narcan use and 
overdose 
S
Prescription opioid use
Opioid prescriptions, including methadone dose
S, EMR, 
PMP
Sociodemographics
Age, gender, insurance, race/ethnicity, education, marital 
status, socioeconomic status, social support71, social risk 
assessment questionnaire
S
Perceived discrimination
Adapted perceived discrimination scale71
S
Mindfulness
Mindful attention awareness scale72
S
Technology Attitudes
VR Knowledge, Media and Technology Use and Attitudes 
subscale73
S
Stress and Inflammation Outcomes
Cortisol
Morning salivary cortisol, serum morning cortisol
L
C-reactive protein
Serum CRP
L
Cytokine panel
Serum cytokines
L
Before/After VR Surveys
Pain
Pain intensity score
S
Mood
Brief Mood Introspection Scale74
S
Mindfulness
State Mindfulness Scale75
S
Immersion & Distraction
Adapted Immersion Scale76, Adapted Distraction Scale76
S
RL: Recruitment logs; S: Surveys; EMR: Electronic Medical Record; PMP: Prescription Monitoring Program; 
L: Lab tests
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Data sources, measures, and management. Study assessments will take place onsite at the OTP at 
weeks 0, 3, and 6 and last 30-60 minutes. Participants will receive $50 compensation at each study 
assessment. We will track the number of patients screened, eligible, consented, and retained. During 
assessments, participants will answer surveys and submit saliva and blood. In addition, we will extract 
information from the Montefiore EMR, SMART EMR (methadone dosage), and from the New York 
State Prescription Monitoring Program (PMP). Study measures are listed in Table 1; where possible we 
align our measures with IMPOWR CDEs and with IMMPACT recommendations for study of chronic 
pain.77 All measures will be examined at each study visit, at 0, 3 and 6 weeks. All study assessment data 
will be managed in REDCAP, a well-established, HIPAA-compliant web-based surveying platform and 
database.78 During twice weekly VR sessions, we will also conduct before and after surveys to ask about 
experiences during VR exercises not taking more than 5 minutes; these will be paper based, scanned, and 
uploaded to Montefiore BOX, a HIPAA-compliant online cloud storage service. A portion of blood will 
also be bio-banked to facilitate future biomarker analyses. We will conduct an optional qualitative 
interview exploring experiences in the trial at the conclusion of the trial; participant interviews will be 
recorded and transcribed for analysis.
Informed Consent. The RA will screen all potential participants for inclusion and exclusion criteria in a 
private area of the MMTP. First, we will obtain written consent to administer a screening questionnaire. 
Screening questionnaire questions will focus on inclusion and exclusion criteria, pain history, and also 
ask about prior use of virtual reality devices. The initial screening questionnaire will take 15 minutes. 
Participants will not be reimbursed for the screening questionnaire. Written consent and the initial 
screening questionnaire will occur in a private area of the MMTP.
Potentially eligible subjects will then complete a written informed consent process with HIPAA 
authorization including discussion of procedures and risks and benefits before being randomized. Consent 
will occur in a private area of the OTP. The RA will perform consent teach-back to assure that 
participants are aware of the details of the consent. Participants who give consent and are randomized will 
then complete the first study visit at a convenient time. Participants will be reimbursed $50 for their 
participation at each study assessment. If they choose to participate in the optional qualitative component, 
they will be reimbursed an additional $30.
Tests and procedures, including blood draws and saliva samples, performed at study assessments will not 
be billed to participants.
Patient privacy protection. We will strip patients’ protected health information from all data before 
conducting analyses. As in prior studies we have conducted, we will have a “name-based” and an “ID-
based” identification system that will remain separate. In the name-based system, all documents that
have patient identifiers will be filed together. Some of these documents will have participants’
signatures (e.g., consent forms). In the ID-based system, all documents that do not include
identifying information or signatures will use participants’ unique study IDs (rather than names)
and will be filed together. All forms will contain either a “name-based” or an “ID-based” identifier,
but never both. There will be only one electronic document that links participants’ names to their
study IDs; only the study staff will have access to this document, which will be password protected and 
kept on password-protected servers.
Study data will be kept in a password-protected, encrypted file on password-protected servers that are 
backed up daily. No one but the study team will have access to study data.  Publication or presentation of 
study results will not include information that would allow for identification of providers or patients.
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Analytic plan. Feasibility: Feasibility outcomes will be measured as proportions. Preliminary Efficacy: 
To examine the association between treatment arm and the co-primary outcomes, we will use separate 2-
level mixed-effects linear regression model with the treatment arm as a mixed effect with participant-
specific random intercepts to account for hierarchical data. The difference in trends of pain intensity and 
opioid craving will be represented by the time-by-arm interaction. For secondary outcomes and stress and 
inflammation exploratory outcomes, we will use a similar strategy; where outcomes are dichotomous, we 
will use 2-level mixed effects logistic regression models.
We will use thematic analysis to analyze transcripts in the qualitative study.
Power analysis. The primary purpose of this study is to test feasibility and to generate preliminary data 
for a future R01 application. We are able to enroll 40 participants in the pilot RCT given our resources 
and given the time of this study. We base our conservative power analysis on t-tests of change in our pain 
intensity preliminary efficacy outcome and use effect size estimates from a study of RelieVRx.27 In that 
study, the pre-post difference in pain intensity was 2.2 in the treatment group and 1.2 in the control group. 
Given the effect size of d=0.49, and 20 participants in each arm, we will have 70% power to detect a 
difference of this magnitude or larger. We expect to have greater statistical power using mixed effects 
linear regression models with repeated measures over time.
Risks/Benefits. We expect the major risks to be associated with the VR technology. VR can sometimes
cause “cybersickness” in some patients, especially when playing or experiencing fast moving games or 
videos. RelieVRx is a much less intense program designed to minimize these sensations. In the clinical 
trial of RelieVRx, about 10% of participants reported some nausea and/or motion sickness, but these 
symptoms were temporary and none decided to terminate their use of the technology because of adverse 
events. In our preliminary data of 20 patients, no patients have reported any issues with cybersickness. 
Nonetheless, this will be an important risk to discuss with patients.
Another risk is breach of confidentiality of patient data. Such a breach is unlikely, because all
study staff will be trained in confidentiality and secure data management, and the data collected
as part of this study will be stripped of protected health information.
In the major clinical trials of RelieVRx, both intervention and sham VR groups had reduced pain at the 
end of the trial, with the magnitude being larger in the intervention arm. However, this trial is shorter and 
some of the parameters are not the same, including the number of weeks of the intervention. Therefore, it 
is possible, but not certain, participants will receive a direct benefit.
Data Safety Monitoring Plan. Monitoring of recruitment and retention, adverse events, protocol 
deviations, and protocol violations will be ongoing by the Principal Investigator. Additionally, the PI and 
co-investigators will meet every 2 months in person to discuss recruitment, retention, data quality, and 
any adverse events. Together, they will make corrective plans as necessary. No interim analyses are 
planned for this pilot trial.
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