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

Study Overview
=================
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.

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

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


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

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 |