PainPhase 2NCT03897998
Neural Correlates of Hypoalgesia Driven by Observation
A Phase 2 study testing Naloxone and Saline in people with Pain and Virtual Reality, run by University of Maryland, Baltimore at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Pain, Virtual Reality, Placebo
- What is being tested?
- Naloxone and Saline
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 211 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Nov 2021to 31 Dec 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Age (18-65 years old)
- English speaker (written and spoken)
Who cannot join
- 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)
Show all 19Show fewer
- 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)
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Maryland
Baltimore, Maryland, 21201-1512
About this study
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.
Read the 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
- Being tested
- Naloxone, Saline
- Keywords
- Naloxone, fMRI, EEG, Observation, Healthy Volunteers
- Medical subject headings
- Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NaloxoneDrug
Also called Naloxone Hydrochloride/Narcan Intranasal
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.
SalineOther
Also called Sodium chloride
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.
| Study group | Role | What they receive |
|---|---|---|
| Naloxone | Active comparator | 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. Receives: Drug: Naloxone |
| Saline | Sham comparator | 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. Receives: Other: Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Neural responses
Blood oxygenation level dependent (BOLD) responses will allow the identification of relative activation/deactivation in the brain as result of events (e.g. painful stimulations) that will be given during the experiment and the treatment administration.
Measured: Two days
Secondary outcomes (1)
Pain ratings
Participants will rate painful and non-painful stimulations on a Visual Analogue Scale raging from 0=no pain to 100= maximum unbearable pain.
Measured: Two days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Apr 2019
- Study start1 Nov 2021
- Primary completion31 Dec 2025
- Study completion31 Dec 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for PainStudies of the same condition, open and under way.
- More trials run by University of Maryland, BaltimoreThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This will be a 2 (group: naloxone vs. saline) X 2 (condition: placebo vs. control) double-blind mixed experimental design with group as the between-subjects factor and condition as the within-subjects factor. Each participant will be randomly assigned to either the naloxone or the saline group.
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 211 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Maryland, Baltimore
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Luana Colloca, University of Maryland, Baltimore
- Investigators
- Luana Colloca, MD/PhD/MS, Principal investigator, University of Maryland Baltimore School of Nursing
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03897998
- Sponsor's protocol ID
- HP-00085382
- Status last verified
- Apr 2026
- First submitted
- 29 Mar 2019
- Last updated
- 16 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: At this time, there is neither intent nor plan to share IPD.
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.
PubMed 30216744Schenk 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.
PubMed 29035916Benedetti 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.
PubMed 17978033
Study at a glance
From the registry record, last updated by the sponsor on 16 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neural Correlates of Hypoalgesia Driven by Observation
- ClinicalTrials.gov ID
- NCT03897998
- Acronym / sponsor ID
- HP-00085382
- Conditions
- Pain, Virtual Reality, Placebo
- Keywords
- Naloxone, fMRI, EEG, Observation, Healthy Volunteers
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 211 participants (actual)
- Lead sponsor
- University of Maryland, BaltimoreUniversity, hospital or other
- Study start
- 1 Nov 2021 (actual)
- Primary completion
- 31 Dec 2025 (actual)
- Study completion
- 31 Dec 2025 (actual)
- First posted
- 1 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- This will be a 2 (group: naloxone vs. saline) X 2 (condition: placebo vs. control) double-blind mixed experimental design with group as the between-subjects factor and condition as the within-subjects factor. Each participant will be randomly assigned to either the naloxone or the saline group.
| Arm | Type | Receives |
|---|---|---|
| Naloxone | Active comparator | Drug: NaloxoneNARCAN® 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. |
| Saline | Sham comparator | Other: SalineSaline 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Age (18-65 years old)
- English speaker (written and spoken)
Key exclusion criteria (19 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NaloxoneAlso: Naloxone Hydrochloride/Narcan Intranasal4mg 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. | Drug | Naloxone |
| SalineAlso: Sodium chlorideIntranasal 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 | Saline |
Primary outcome
Neural responses
Time frame: Two days
Blood oxygenation level dependent (BOLD) responses will allow the identification of relative activation/deactivation in the brain as result of events (e.g. painful stimulations) that will be given during the experiment and the treatment administration.
1 secondary outcome
Pain ratings
Time frame: Two days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Apr 2026.
- Background: PubMed 30216744Colloca 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.
- Background: PubMed 29035916Schenk 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.
- Background: PubMed 17978033Benedetti 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.
- Individual participant dataSharing planned: No. At this time, there is neither intent nor plan to share IPD.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Luana Colloca, MD/PhD/MS principal investigator
University of Maryland Baltimore School of Nursing
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Naloxone and Saline in people with Pain and Virtual Reality, run by University of Maryland, Baltimore at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Neural responses (time frame: Two days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03897998, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Apr 2026.