Neural Mechanisms of Immersive Virtual Reality in Chronic Pain

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.

Study Overview

• Status: Recruiting
• Conditions: Pain; Virtual Reality; Temporomandibular Disorder; Placebo
• Intervention / Treatment: Behavioral: Active Virtual Reality; Behavioral: sham Virtual Reality; Other: No Intervention; Drug: Naloxone; Other: Saline; Other: Natural history

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 259
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Rachel Massalee, MS; Email: rmassalee@umaryland.edu
• Study Contact Backup: Name: Research Coordinator; Phone Number: 410-706-5975; Email: NRSCollocaLab@umaryland.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201-1512
      • Recruiting
      • Luana Colloca
      • Contact: Luana Colloca, MD,PhD,MS; Phone Number: 301-364-8089; Email: Colloca@umaryland.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Naloxone; 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; Participants will be assigned to an immersive VR environment.; Other Names: Active VR; Behavioral: sham Virtual Reality; Participants will be assigned to a sham VR environment without the immersive experience.; Other Names: Sham VR; Other: No Intervention; Participants will experience tonic pain tolerance tests without exposure to any environments.; Drug: Naloxone; 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.; Other Names: Naloxone Hydrochloride/Narcan Intranasal
Sham Comparator: Saline; 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; Participants will be assigned to an immersive VR environment.; Other Names: Active VR; Behavioral: sham Virtual Reality; Participants will be assigned to a sham VR environment without the immersive experience.; Other Names: Sham VR; Other: No Intervention; Participants will experience tonic pain tolerance tests without exposure to any environments.; Other: Saline; 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.; Other Names: Placebo, Sodium chloride
Other: Natural History; 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; Participants will be assigned to an immersive VR environment.; Other Names: Active VR; Behavioral: sham Virtual Reality; Participants will be assigned to a sham VR environment without the immersive experience.; Other Names: Sham VR; Other: No Intervention; Participants will experience tonic pain tolerance tests without exposure to any environments.; Other: Natural history; Participants will not be provided Naloxone or Saline.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Investigators: Principal Investigator: Luana Colloca, MD/PHD/MS, University of Maryland Baltimore School of Nursing

Publications and helpful links

General Publications

• Colloca L. The Placebo Effect in Pain Therapies. Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:191-211. doi: 10.1146/annurev-pharmtox-010818-021542. Epub 2018 Sep 14.
• Honzel E, Murthi S, Brawn-Cinani B, Colloca G, Kier C, Varshney A, Colloca L. Virtual reality, music, and pain: developing the premise for an interdisciplinary approach to pain management. Pain. 2019 Sep;160(9):1909-1919. doi: 10.1097/j.pain.0000000000001539. No abstract available.
• Colloca L, Raghuraman N, Wang Y, Akintola T, Brawn-Cinani B, Colloca G, Kier C, Varshney A, Murthi S. Virtual reality: physiological and behavioral mechanisms to increase individual pain tolerance limits. Pain. 2020 Sep 1;161(9):2010-2021. doi: 10.1097/j.pain.0000000000001900.
• Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci. 1999 Jan 1;19(1):484-94. doi: 10.1523/JNEUROSCI.19-01-00484.1999.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2021
• Primary Completion (Anticipated): October 31, 2027
• Study Completion (Anticipated): November 30, 2027

Study Registration Dates

• First Submitted: April 6, 2021
• First Submitted That Met QC Criteria: April 14, 2021
• First Posted (Actual): April 20, 2021

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Naloxone; Observation; VR; TMD volunteers
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Stomatognathic Diseases; Jaw Diseases; Craniomandibular Disorders; Mandibular Diseases; Myofascial Pain Syndromes; Chronic Pain; Temporomandibular Joint Disorders; Temporomandibular Joint Dysfunction Syndrome; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Naloxone
• Other Study ID Numbers: HP-00095888

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: At this time, there is neither intent nor plan to share IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes