Neural Mechanisms of Immersive Virtual Reality in Chronic Pain

Study Overview
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Brief Summary
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This project examines, in chronic pain, the mechanisms of immersive virtual reality compared to the mechanisms of placebo hypoalgesia. The potential of developing new non-pharmacological premises for low-risk interventions for pain management is high.

Detailed Description
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Virtual reality (VR) has been seen as an intervention for alleviating clinical chronic (and acute) pain. An approach to pain management utilizing VR presents opportunities for reducing pain and suffering by using immersive, aesthetic, and multisensory stimulation. Investigator will analyze the behavioral and neural mechanisms of active VR against sham VR as two methods that investigate descending pain modulation. Thus, the central hypothesis is that those who respond to placebos will likely respond to active VR. If VR-induced analgesia depends upon the release of endogenous opioids. In this project, the investigators will determine the effects of VR at the neural and clinical levels directly for TMD participants, inviting participants from an existing Colloca Lab-based cohort phenotyped for diagnosis, grade, and low/high impact pain profiles and prospective TMD participants in collaboration with Johns Hopkins University. These participants have agreed to be recontacted for further research. Investigator will determine the role of the opioid tone (AIM1). In Aim 1, the investigators will determine the role of the endogenous opioid tone for VR-induced hypoalgesia in TMD participants using VR, tonic painful stimuli, and naloxone given intranasally with established mu-opioid receptor occupancy to determine how the opioid tone shapes VR-induced hypoalgesia.

Official Title
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Neural Mechanisms of Immersive Virtual Reality in Chronic Pain

Conditions
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Pain, Virtual Reality, Placebo, Temporomandibular Disorder

Intervention / Treatment
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* Behavioral: Active Virtual Reality
* Behavioral: sham Virtual Reality
* Other: No Intervention
* Drug: Naloxone
* Other: Saline
* Other: Natural history


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age (18-88 years) English speaker (written and spoken) Temporal Mandibular Disorder (TMD) for at least 3 months Exclusion Criteria: Present or past degenerative neuromuscular disease Cardiovascular, neurological diseases, pulmonary abnormalities, kidney disease, liver disease, history of cancer within past 3 years Cervical pain other than TMD related (e.g. stenosis, radiculopathy) Any personal (or family first degree) history of mania, schizophrenia, or other psychoses Severe psychiatric condition (e.g., schizophrenia, bipolar disorders, autism) leading to hospitalization within the last 3 years. Use of antidepressants, ADHD medication, non-over-the-counter painkillers, methadone, benzodiazepines, barbiturates, and/or narcotics during the past 3 months Lifetime alcohol/drug dependence or alcohol/drug abuse in the past 3 months Pregnancy or breastfeeding Color-blindness Pain in jaw or temple in last 3 months due to toothache or infection Any facial trauma that has occurred in the last 6 weeks History of severe facial trauma in the last 3 months Impaired or uncorrected hearing Conditions that would interfere with the VR mask placement (e.g. trauma, burn, infection) Known history of severe motion sickness High blood pressure or symptomatic low blood pressure History of fainting History of angioedema Failed drug test (testing for opiates, cocaine, methamphetamines, amphetamines, and THC)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 88 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: AIM 1: This is a double-blinded, randomized, between- and within-subjects design (3 X 3) with TMD participants randomly assigned to one of three groups. The three groups are 1. Naloxone group 2. Saline group 3. Natural history group, in which participants will not be given any drugs. Within-subjects factor: All three groups will go through the following 3 conditions:1. Active VR (theBlu); 2. Sham VR; 3. No-VR.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Naloxone<br>NARCAN® Naloxone Nasal Spray will be used to determine how the opioid tone shapes VR-induced hypoalgesia. Participants will be stratified for sex and then randomized to naloxone (The dose of naloxone will be 4 mg, so 0.1 mL of 40 mg/ml naloxone solution given intranasally) or saline (0.1 mL 0.9% sodium chloride intranasally), respectively. Investigators, staff, and participants will be blinded to the treatment options. | Behavioral: Active Virtual Reality<br>* Participants will be assigned to an immersive VR environment.<br>* Other names: Active VR;Behavioral: sham Virtual Reality<br>* Participants will be assigned to a sham VR environment without the immersive experience.<br>* Other names: Sham VR;Other: No Intervention<br>* Participants will experience tonic pain tolerance tests without exposure to any environments.<br>Drug: Naloxone<br>* 4mg of Naloxone will be administered (0.1 mL of 40 mg/ml naloxone solution given intranasally). A random allocation sequence will be independently generated by the UM Pharmacy. The Principal investigator will call for each experiment.<br>* Other names: Naloxone Hydrochloride/Narcan Intranasal;|
| Sham Comparator: Saline<br>Saline group, where participants will be given saline solution (4mg) via an identical spray device. Participants will be stratified for sex and then randomized to saline arm (The dose of saline will be (0.1 mL 0.9% sodium chloride intranasally), respectively. Investigators, staff, and participants will be blinded to the treatment options. | Behavioral: Active Virtual Reality<br>* Participants will be assigned to an immersive VR environment.<br>* Other names: Active VR;Behavioral: sham Virtual Reality<br>* Participants will be assigned to a sham VR environment without the immersive experience.<br>* Other names: Sham VR;Other: No Intervention<br>* Participants will experience tonic pain tolerance tests without exposure to any environments.<br>Other: Saline<br>* Intranasal Normal Saline (0.1 mL 0.9% sodium chloride) will be administered shortly before beginning the fMRI experiment. A random allocation sequence will be independently generated by the UM Pharmacy. The Principal investigator will call for each experiment.<br>* Other names: Placebo, Sodium chloride;|
| Other: Natural History<br>Natural history group, where participants will not be given any drugs. Participants will be stratified for sex and then randomized to the Natural History group. | Behavioral: Active Virtual Reality<br>* Participants will be assigned to an immersive VR environment.<br>* Other names: Active VR;Behavioral: sham Virtual Reality<br>* Participants will be assigned to a sham VR environment without the immersive experience.<br>* Other names: Sham VR;Other: No Intervention<br>* Participants will experience tonic pain tolerance tests without exposure to any environments.<br>Other: Natural history<br>* Participants will not be provided Naloxone or Saline.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ischemic pain endurance | Increments in experimental ischemic pain endurance will be assessed using a timer (minutes of tolerance) | one session lasting from 2 to 3 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ischemic pain rating | Increments in experimental ischemic pain endurance will be assessed using Visual Analogue Scale (VAS) (self-reported numbers) anchored from 0=no pain to 100=maximum tolerable pain. The VAS will be used every 10 seconds during the ischemic pain endurance task | one session lasting from 2 to 3 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VR, Naloxone, Observation, TMD volunteers