PainEarly Phase 1NCT04650841
The Role of the Opioid System in Placebo Effects on Pain and Social Rejection
A Early Phase 1 study of Pain and Rejection, run by Trustees of Dartmouth College at 1 site in United States.
Trial summary
The current study probes the involvement of the opioid system in placebo effects on social pain, using the opioid antagonist naloxone. 60 participants who recently experienced an unwanted breakup will experience rejection-related stimuli and receive painful heat and pressure stimuli during fMRI scanning. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Pain, Rejection, Placebo Effect
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Sep 2026to 1 Mar 2027
- Phase
- Early Phase 1
- Are there results?
- Not yet: the study is under way
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 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Adults aged 18-55 years
- No current psychiatric or major neurological diagnosis
- No reported substance abuse within the last six months
- Are capable of performing experimental tasks (e.g., are able to read, able to cooperate with fMRI examination)
- Are fluent or native speakers of English
- No current or recent history of pathological pain or reported neurological disorders.
Show all 9Show fewer
- Having abstained from alcohol and substance use for 48 hours
- Passed fMRI safety screener
- Experienced a recent unwanted breakup of a romantic relationship
Who cannot join
- Current presence of pain
- Current or past history of primary psychiatric disorder
- Current or past history of psychoactive substance abuse or dependence
- Dementias
- Movement disorders except familial tremor
- CNS infection
Show all 27Show fewer
- CNS vasculitis, inflammatory disease or autoimmune disease
- CNS demyelinating disease (e.g. multiple sclerosis)
- Space occupying lesions (mass lesions, tumors)
- Congenital CNS abnormality (e.g. cerebral palsy)
- Seizure disorder
- History of closed head trauma with loss of consciousness
- History of cerebrovascular disease (stroke, TIAs)
- Abnormal MRI (except changes accounted for by technical factors or UBOs)
- Neuroendocrine disorder (e.g., Cushings disease)
- Uncorrected hypothyroidism or hyperthyroidism
- Current or past history of cancer; Recent history (within two years) of myocardial infarction, severe cardiovascular disease, or currently active cardiovascular disease (e.g. angina, cardiomyopathy)
- Uncontrolled hypertension or hypotension
- Chronic pain syndromes
- Chronic fatigue syndromes
- Subjects unable to tolerate the scanning procedures (e.g., claustrophobia)
- Prior treatment within the last month with any of the following: antidepressants, mood stabilizers, glucocorticoids, opiates
- Prior treatment with any of the following: antipsychotics, isoniazid, centrally active antihypertensive drugs (e.g. clonidine, reserpine)
- Metal in body or prior history working with metal fragments (e.g., as a machinist)
- For women, pregnancy
- Any other contraindications for MRI examination (e.g., metallic implants such as pacemakers, surgical aneurysm clips, or known metal fragments embedded in the body)
- Claustrophobia
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
Dartmouth College
Hanover, New Hampshire, 03755
Bethany Hunt, BA, bethany.j.hunt@dartmouth.edu
About this study
The current study probes the involvement of the opioid system in placebo effects on social pain, using the opioid antagonist naloxone. 60 participants who recently experienced an unwanted breakup will experience rejection-related stimuli and receive painful heat and pressure stimuli during fMRI scanning. Participants will be randomized to receive either a naloxone or saline nasal spray, and be informed that the spray is either saline, or an effective pain and negative emotion reducing agent.
Read the detailed description
Background:
Loss of close relationships is one of the most aversive life events. An unwanted romantic breakup leads to a 20% risk of developing depression within a month, a dramatic increase in depression risk. The investigators recently identified brain pathways mediating placebo effects on physical heat pain and the social pain associated with an unwanted breakup, including common involvement of dlPFC-PAG pathways and vmPFC. Other recent studies have identified rejection-related opioidergic activity in these circuits that may reflect endogenous regulatory mechanisms. This experiment probes the involvement of the opioid system in placebo effects on social pain, using the opioid antagonist naloxone.
Design:
Extending the investigator's previous design, participants who recently experienced an unwanted breakup will submit pictures of their ex-partners, places associated with strong memories of the partner, and written descriptions of memories that evoke rejection and social pain. Participants will 1) experience rejection-related stimuli and 2) receive painful heat and pressure stimuli in separate runs during fMRI scanning. FMRI scans after Control and Placebo treatment-nasal spray with suggestions of efficacy for emotion and pain-will be performed in a 2-session within-person counterbalanced design. Participants will be randomized into two groups that receive either (1) 4mg naloxone nasal spray or (2) saline in the nasal spray in both sessions, implementing a 2 x 2 (Placebo/Control x Saline/Naloxone) design.
- Conditions
- Pain, Rejection, Placebo Effect
- Being tested
- Placebo Cream with Naloxone, Control Cream with Naloxone, Placebo Cream with Saline, Control Cream with Saline
- Medical subject headings
- Pain, Rejection, Psychology
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Placebo Cream with NaloxoneDrug
Participants will be informed that the spray is an effective pain and negative emotion reducing agent.
Control Cream with NaloxoneDrug
Participants will be informed that the spray is saline.
Placebo Cream with SalineDrug
Participants will be informed that the spray is an effective pain and negative emotion reducing agent.
Control Cream with SalineDrug
Participants will be informed that the spray is saline.
| Study group | Role | What they receive |
|---|---|---|
| Naloxone Group | Experimental | Participants will receive 4mg naloxone nasal spray. Receives: Drug: Placebo Cream with Naloxone; Drug: Control Cream with Naloxone |
| Saline Group | Experimental | Participants will receive saline in the nasal spray. Receives: Drug: Placebo Cream with Saline; Drug: Control Cream with Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Intervention effects on pain ratings
Pain ratings will be given on a 0-100 scale. 0 being "no pain at all" and 100 being "most pain imaginable in the context of this study."
Measured: Immediately after pain stimuli
Intervention effects on negative affect ratings
Rejection ratings will be given on a 0-100 scale. 0 being "not rejected at all" and 100 being "very rejected."
Measured: Immediately after rejection stimuli
Brain: Pain signature response
A priori regions of interest response from the brain (fMRI) patterns to the pain.
Measured: Immediately after pain stimuli
Brain: Rejection signature response
A priori regions of interest response from the brain (fMRI) patterns to rejection. The investigators will utilize a multivariate brain pattern developed and published in Woo et al., 2014, Nature Communications. This is a rejection-selected pattern of brain activity.
Measured: Immediately after rejection stimuli
Skin conductance
Skin conductance response (SCR) will be recorded during the task.
Measured: Immediately after pain/rejection stimuli
Heart rate
Heart rate will be recorded during the task.
Measured: Immediately after pain/rejection stimuli
Secondary outcomes (2)
Whole-brain maps of intervention effects
Standard resting-state images will be acquired for exploratory analyses. Exploratory brain analysis will include univariate voxel-wise maps comparing participant groups with a threshold of q < 0.05, False Discovery Rate (FDR) corrected.
Measured: Immediately after pain/rejection stimuli
Rejection Sensitivity Questionnaire
A measure of sensitivity to actual or perceived rejection with ratings on a 6-point Likert scale ranging from "very unconcerned" - "very concerned." Higher scores indicate more reaction sensitivity.
Measured: Within 2 weeks before first fMRI scan
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Dec 2020
- Study start1 Sep 2026 (estimated)
- Primary completion1 Mar 2027 (estimated)
- Study completion1 Mar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PainStudies of the same condition, open and under way.
- 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
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Trustees of Dartmouth College
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Tor Wager, Trustees of Dartmouth College
- Investigators
- Tor D Wager, PhD, Principal investigator, Dartmouth College
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04650841
- Sponsor's protocol ID
- 230136
- Status last verified
- Dec 2025
- First submitted
- 17 Nov 2020
- Last updated
- 9 Dec 2025
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The investigators are strongly committed to contributing to open and reproducible science. All MRI and behavioral data will be submitted to the NIMH Data Archive (NDA) according to the terms and conditions outlined on their website (https://ndar.nih.gov/contribute\_data\_sharing\_regimen.html ) and with OpenFMRI. The investigators will ensure that our IRB has approved our Data Sharing Plan. The investigators will use an informed consent document that permits subjects to allow sharing of de-identified (face removed) MRI and fMRI data with open-sharing repositories, including the NDA and OpenFMRI databases. The consent form will stipulate that: "Scientists can use my information, without personal identifiers, for any kind of genetic research."
Study at a glance
From the registry record, last updated by the sponsor on 9 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Role of the Opioid System in Placebo Effects on Pain and Social Rejection
- ClinicalTrials.gov ID
- NCT04650841
- Acronym / sponsor ID
- 230136
- Conditions
- Pain, Rejection, Placebo Effect
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Trustees of Dartmouth CollegeUniversity, hospital or other
- Study start
- 1 Sep 2026 (estimated)
- Primary completion
- 1 Mar 2027 (estimated)
- Study completion
- 1 Mar 2027 (estimated)
- First posted
- 3 Dec 2020 (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.
The current study probes the involvement of the opioid system in placebo effects on social pain, using the opioid antagonist naloxone. 60 participants who recently experienced an unwanted breakup will experience rejection-related stimuli and receive painful heat and pressure stimuli during fMRI scanning. Participants will be randomized to receive either a naloxone or saline nasal spray, and be informed that the spray is either saline, or an effective pain and negative emotion reducing agent.
Detailed description
Background:
Loss of close relationships is one of the most aversive life events. An unwanted romantic breakup leads to a 20% risk of developing depression within a month, a dramatic increase in depression risk. The investigators recently identified brain pathways mediating placebo effects on physical heat pain and the social pain associated with an unwanted breakup, including common involvement of dlPFC-PAG pathways and vmPFC. Other recent studies have identified rejection-related opioidergic activity in these circuits that may reflect endogenous regulatory mechanisms. This experiment probes the involvement of the opioid system in placebo effects on social pain, using the opioid antagonist naloxone.
Design:
Extending the investigator's previous design, participants who recently experienced an unwanted breakup will submit pictures of their ex-partners, places associated with strong memories of the partner, and written descriptions of memories that evoke rejection and social pain. Participants will 1) experience rejection-related stimuli and 2) receive painful heat and pressure stimuli in separate runs during fMRI scanning. FMRI scans after Control and Placebo treatment-nasal spray with suggestions of efficacy for emotion and pain-will be performed in a 2-session within-person counterbalanced design. Participants will be randomized into two groups that receive either (1) 4mg naloxone nasal spray or (2) saline in the nasal spray in both sessions, implementing a 2 x 2 (Placebo/Control x Saline/Naloxone) design.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Naloxone Group | Experimental | Drug: Placebo Cream with Naloxone, Drug: Control Cream with NaloxoneParticipants will receive 4mg naloxone nasal spray. |
| Saline Group | Experimental | Drug: Placebo Cream with Saline, Drug: Control Cream with SalineParticipants will receive saline in the nasal spray. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- Adults aged 18-55 years
- No current psychiatric or major neurological diagnosis
- No reported substance abuse within the last six months
- Are capable of performing experimental tasks (e.g., are able to read, able to cooperate with fMRI examination)
- Are fluent or native speakers of English
Key exclusion criteria (27 listed)
- Current presence of pain
- Current or past history of primary psychiatric disorder
- Current or past history of psychoactive substance abuse or dependence
- Dementias
- Movement disorders except familial tremor
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 |
|---|---|---|
| Placebo Cream with NaloxoneParticipants will be informed that the spray is an effective pain and negative emotion reducing agent. | Drug | Naloxone Group |
| Control Cream with NaloxoneParticipants will be informed that the spray is saline. | Drug | Naloxone Group |
| Placebo Cream with SalineParticipants will be informed that the spray is an effective pain and negative emotion reducing agent. | Drug | Saline Group |
| Control Cream with SalineParticipants will be informed that the spray is saline. | Drug | Saline Group |
Primary outcome
Intervention effects on pain ratings
Time frame: Immediately after pain stimuli
Pain ratings will be given on a 0-100 scale. 0 being "no pain at all" and 100 being "most pain imaginable in the context of this study."
Intervention effects on negative affect ratings
Time frame: Immediately after rejection stimuli
Rejection ratings will be given on a 0-100 scale. 0 being "not rejected at all" and 100 being "very rejected."
Brain: Pain signature response
Time frame: Immediately after pain stimuli
A priori regions of interest response from the brain (fMRI) patterns to the pain.
Brain: Rejection signature response
Time frame: Immediately after rejection stimuli
A priori regions of interest response from the brain (fMRI) patterns to rejection. The investigators will utilize a multivariate brain pattern developed and published in Woo et al., 2014, Nature Communications. This is a rejection-selected pattern of brain activity.
Skin conductance
Time frame: Immediately after pain/rejection stimuli
Skin conductance response (SCR) will be recorded during the task.
Heart rate
Time frame: Immediately after pain/rejection stimuli
Heart rate will be recorded during the task.
2 secondary outcomes
Whole-brain maps of intervention effects
Time frame: Immediately after pain/rejection stimuli
Rejection Sensitivity Questionnaire
Time frame: Within 2 weeks before first fMRI scan
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Dec 2025.
- Individual participant dataSharing planned: Yes. The investigators are strongly committed to contributing to open and reproducible science. All MRI and behavioral data will be submitted to the NIMH Data Archive (NDA) according to the terms and conditions outlined on their website (https://ndar.nih.gov/contribute_data_sharing_regimen.html ) and with OpenFMRI. The investigators will ensure that our IRB has approved our Data Sharing Plan. The investigators will use an informed consent document that permits subjects to allow sharing of de-identified (face removed) MRI and fMRI data with open-sharing repositories, including the NDA and OpenFMRI databases. The consent form will stipulate that: "Scientists can use my information, without personal identifiers, for any kind of genetic research."
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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.
Tor D Wager, PhD principal investigator
Dartmouth College
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study of Pain and Rejection, run by Trustees of Dartmouth College 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 9 inclusion and 27 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: opening soon, as of the sponsor's last update on 9 Dec 2025. 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. 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?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Tor D Wager, PhD (603-646-2196, Tor.D.Wager@Dartmouth.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Intervention effects on pain ratings (time frame: Immediately after pain stimuli). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 9 Dec 2025; AzTrials last refreshed its copy on 8 Nov 2026.