The Role of the Opioid System in Placebo Effects on Pain and Social Rejection

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Pain; Rejection; Placebo Effect
• Intervention / Treatment: Drug: Placebo Cream with Naloxone; Drug: Control Cream with Naloxone; Drug: Placebo Cream with Saline; Drug: Control Cream with Saline

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 Type: Interventional
• Enrollment (Estimated): 60
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Tor D Wager, PhD; Phone Number: 603-646-2196; Email: Tor.D.Wager@Dartmouth.edu

Study Locations

• United States
  • New Hampshire
    • Hanover, New Hampshire, United States, 03755
      • Dartmouth College
      • Contact: Bethany Hunt, BA; Email: bethany.j.hunt@dartmouth.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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.
• Having abstained from alcohol and substance use for 48 hours
• Passed fMRI safety screener
• Experienced a recent unwanted breakup of a romantic relationship

Exclusion Criteria:

• 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
• 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Naloxone Group; Participants will receive 4mg naloxone nasal spray.	Drug: Placebo Cream with Naloxone; Participants will be informed that the spray is an effective pain and negative emotion reducing agent.; Drug: Control Cream with Naloxone; Participants will be informed that the spray is saline.
Experimental: Saline Group; Participants will receive saline in the nasal spray.	Drug: Placebo Cream with Saline; Participants will be informed that the spray is an effective pain and negative emotion reducing agent.; Drug: Control Cream with Saline; Participants will be informed that the spray is saline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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."	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."	Immediately after rejection stimuli
Brain: Pain signature response	A priori regions of interest response from the brain (fMRI) patterns to the pain.	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.	Immediately after rejection stimuli
Skin conductance	Skin conductance response (SCR) will be recorded during the task.	Immediately after pain/rejection stimuli
Heart rate	Heart rate will be recorded during the task.	Immediately after pain/rejection stimuli

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	Within 2 weeks before first fMRI scan

Collaborators and Investigators

• Sponsor: Trustees of Dartmouth College
• Investigators: Principal Investigator: Tor D Wager, PhD, Dartmouth College

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: November 17, 2020
• First Submitted That Met QC Criteria: November 24, 2020
• First Posted (Actual): December 3, 2020

Study Record Updates

• Last Update Posted (Estimated): December 9, 2025
• Last Update Submitted That Met QC Criteria: December 2, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Social Behavior; Pain; Rejection, Psychology; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Alkaloids; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Inorganic Chemicals; Chlorine Compounds; Heterocyclic Compounds, 4 or More Rings; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Sodium Compounds; Chlorides; Hydrochloric Acid; Naloxone; Sodium Chloride
• Other Study ID Numbers: 230136

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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."

• IPD Sharing Time Frame: All data will be de-identified prior to sharing. Raw data will be submitted to NDA within one year from the end of data collection or 6 months from the acceptance date of the first primary study manuscript on the full dataset (excluding methods development papers), whichever is later. Analyzed data/maps of statistical results and models accompanying each paper will be submitted to NDA/OpenFMRI when the primary study manuscript is accepted.

IPD Sharing Access Criteria

These data would generally be made available to any qualified investigator for neuroimaging studies only including:

i. Research on any brain phenomenon; ii. Neuroimaging research on non-disease traits (intelligence, behavioral traits); iii. Methods development research.

The requesting investigator must provide documentation of local IRB approval.

These data would not be made available to:

i. Any criminal justice organization, because data may not be used for any criminal justice applications; ii. Any commercial entity, because use of the data is limited to not-for-profit organizations and data may not be used for any commercial purposes.

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