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

NCT ID: NCT04650841

Last Updated: 2025-12-09

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-09-01
• Study Completion Date: 2027-03-01

Brief 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. 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.

Conditions

Pain; Rejection; Placebo Effect

Study Design

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

Study Groups

Naloxone Group

Participants will receive 4mg naloxone nasal spray.

Group Type: EXPERIMENTAL

Placebo Cream with Naloxone

Intervention Type: DRUG

Participants will be informed that the spray is an effective pain and negative emotion reducing agent.

Control Cream with Naloxone

Intervention Type: DRUG

Participants will be informed that the spray is saline.

Saline Group

Participants will receive saline in the nasal spray.

Group Type: EXPERIMENTAL

Placebo Cream with Saline

Intervention Type: DRUG

Participants will be informed that the spray is an effective pain and negative emotion reducing agent.

Control Cream with Saline

Intervention Type: DRUG

Participants will be informed that the spray is saline.

Interventions

Placebo Cream with Naloxone

Participants will be informed that the spray is an effective pain and negative emotion reducing agent.

Intervention Type: DRUG

Control Cream with Naloxone

Participants will be informed that the spray is saline.

Intervention Type: DRUG

Placebo Cream with Saline

Participants will be informed that the spray is an effective pain and negative emotion reducing agent.

Intervention Type: DRUG

Control Cream with Saline

Participants will be informed that the spray is saline.

Intervention Type: DRUG

Eligibility Criteria

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

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

Sponsors

Trustees of Dartmouth College

OTHER

Sponsor Role: lead

Responsible Party

Tor Wager

Diana L. Taylor Distinguished Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tor D Wager, PhD

Role: PRINCIPAL_INVESTIGATOR

Dartmouth College

Locations

Dartmouth College

Hanover, New Hampshire, United States

Countries

United States

Central Contacts

Tor D Wager, PhD

Role: CONTACT

Tor.D.Wager@Dartmouth.edu

603-646-2196

Facility Contacts

Bethany Hunt, BA

Role: primary

bethany.j.hunt@dartmouth.edu

Other Identifiers

230136

Identifier Type: -

Identifier Source: org_study_id