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

Overview

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.

Interventions

• 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.
• 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.

Primary outcome measures

• Intervention effects on pain ratings [Time frame: Immediately after pain stimuli]
• Intervention effects on negative affect ratings [Time frame: Immediately after rejection stimuli]
• Brain: Pain signature response [Time frame: Immediately after pain stimuli]
• Brain: Rejection signature response [Time frame: Immediately after rejection stimuli]
• Skin conductance [Time frame: Immediately after pain/rejection stimuli]
• Heart rate [Time frame: Immediately after pain/rejection stimuli]

Secondary outcome measures (2)

• 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]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Triple blind

Primary purpose

Basic science

Study locations

United States · 1 center

• Dartmouth College — Hanover

Identifiers

NCT: NCT04650841 · 230136

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗