Neural Correlates of Hypoalgesia Driven by Observation

NCT ID: NCT03897998

Last Updated: 2025-06-25

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 182 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-01
• Study Completion Date: 2025-12-31

Brief Summary

Placebo effects held an ambivalent place in health care for at least two centuries. On the one hand, placebos are traditionally used as controls in clinical trials to correct for biases and the placebo response is viewed as an effect to be factored out in order to isolate and accurately measure the effects of the treatment. On the other hand, there is scientific evidence that placebo effects represent fascinating psychoneurobiological events involving the contribution of distinct central nervous as well as peripheral physiological mechanisms that influence pain perception and clinical pain symptoms and substantially modulate the response to pain therapeutics. Therefore, placebo effects have shifted from being a challenge for clinical trials to a resource to trigger the reduction of pain based on endogenous mechanisms that can be activated in the brain to promote hypolagesia, self-healing, and well-being. This is relevant in acute pain settings given that chronic opioid users die within approximately 2.5 years of being prescribed their first opioid medication to treat acute pain.

The overall hypothesis is that observational learning influences neural pain modulation and cognition systems, including processes associated with mentalizing (the ability to cognitively understand mental states of others), empathy (the ability to share an emotional experience), and expectancy (the anticipation of a benefit). The objective is to determine the brain mechanisms of observationally-induced analgesia using brain mapping approaches that target changes in blood oxygenation and oscillatory activity in the brain, thus enabling investigators to draw inferences about the localization and extent of neurobiological activation underlying hypoalgesia driven by observation. Therefore, the investigators designed innovative experiments using pharmacological fMRI, EEG, and combined EEG-fMRI measurements.

Detailed Description

Analgesic effects can also occur without formal conditioning and direct prior experience because crucial information necessary to build up expectations of analgesia can be acquired through observation of a therapeutic benefit in others. Placebo analgesic effects following the observation of a benefit in another person are similar in magnitude to those induced by directly experiencing an analgesic benefit. These observations emphasize that contextual cues substantially modulate the individual placebo analgesic effects.

In this project, the investigators propose a compelling research agenda to explore the neural mechanisms of hypoalgesia driven by observation as a foundation for future development of novel nonpharmacological pain therapies using pharmacological functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and combined EEG/fMRI. It builds on a decade of experience in placebo research in PI Colloca's lab and with University of Maryland collaborators experienced in brain mapping and pain research. In Aim 1, the investigators will determine the role of endogenous opioids on the neural mechanisms of observationally-induced hypoalgesia by using the opioid antagonist naloxone in a functional Magnetic Resonance Imaging (fMRI) setting. In Aim 2, the investigators will identify the impact of empathy by exploring how being in the immersive environment can enhance observationally-induced analgesia. In Aim 3, the investigators will leverage the EEG/fMRI to determine the neural EEG/fMRI transient changes that could co-occur when socially-induced expectations are violated.

Conditions

Pain; Virtual Reality; Placebo

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Naloxone

NARCAN® Naloxone Nasal Spray will be used to block placebo effects during the fMRI experiment. 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.

Group Type: ACTIVE_COMPARATOR

Naloxone

Intervention Type: DRUG

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.

Saline

Saline will be used as a sham comparator for blocking placebo effects during the fMRI experiment. 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.

Group Type: SHAM_COMPARATOR

Saline

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: OTHER

Other Intervention Names

Naloxone Hydrochloride/Narcan Intranasal; Sodium chloride

Eligibility Criteria

Inclusion Criteria

• Age (18-55 years old)
• English speaker (written and spoken)

Exclusion Criteria

• Cardiovascular, neurological diseases, pulmonary abnormalities, kidney disease, liver disease, degenerative neuromuscular disease, or history of cancer within past 3 years
• Any history of chronic pain disorder or currently in pain
• Severe psychiatric condition (e.g. schizophrenia, bipolar disorders, mania, autism) and /or psychiatric condition leading to treatment and/or hospitalization within the last 3 years.
• Personal history of mania, schizophrenia, or other psychoses
• Nasal Polyps
• Chronic intranasal drug use ( e.g., intranasal decongestants; antihistamines)
• Lifetime alcohol/drug dependence, or alcohol/drug abuse in past 3 months
• Use of antidepressants, ADHD medication, non-over-the-counter painkillers, methadone, benzodiazepines, barbiturates, and/or narcotics during the past 3 months
• Pregnancy or breast feeding
• Color-blindness
• Impaired, uncorrected hearing
• Left handed
• Allergies or sensitivities to creams, lotions, or food coloring
• Any non-organic implant or any non-removable metal device (e.g., pacemaker, cochlear implants, stents, surgical clips, non-removable piercings)
• Any prior eye injury or the potential of a foreign body in the eye (e.g., worked in metal fields)
• Persistent functional impairment due to a head trauma
• Fear of closed spaces
• Any other contraindications for MRI (e.g., large tattoos on head and neck)
• Previously participated in other "Pain Perception in the Brain" Studies in Colloca lab Failed drug test (testing for opiates, cocaine, methamphetamines, amphetamines, and THC)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Maryland, Baltimore

OTHER

Sponsor Role: lead

Responsible Party

Luana Colloca

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Luana Colloca, MD/PhD/MS

Role: PRINCIPAL_INVESTIGATOR

University of Maryland Baltimore School of Nursing

Locations

University of Maryland

Baltimore, Maryland, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Research Coordinator

Role: CONTACT

NRSCollocaLab@umaryland.edu

410-706-5975

Adria Suhr

Role: CONTACT

asuhr@umaryland.edu

Facility Contacts

Luana Colloca

Role: primary

colloca@umaryland.edu

301-364-8089

Adria Suhr

Role: backup

asuhr@umaryland.edu

4107065975

References

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.

Reference Type: BACKGROUND

PMID: 30216744 (View on PubMed)

Schenk LA, Krimmel SR, Colloca L. Observe to get pain relief: current evidence and potential mechanisms of socially learned pain modulation. Pain. 2017 Nov;158(11):2077-2081. doi: 10.1097/j.pain.0000000000000943. No abstract available.

Reference Type: BACKGROUND

PMID: 29035916 (View on PubMed)

Benedetti F, Pollo A, Colloca L. Opioid-mediated placebo responses boost pain endurance and physical performance: is it doping in sport competitions? J Neurosci. 2007 Oct 31;27(44):11934-9. doi: 10.1523/JNEUROSCI.3330-07.2007.

Reference Type: BACKGROUND

PMID: 17978033 (View on PubMed)

Other Identifiers

HP-00085382

Identifier Type: -

Identifier Source: org_study_id