How Stress Alters Opioid Drug Effects (OPIOIDREWARD)

How Distress Alters Opioid Drug Effects and Abuse Liability

The main objective of the study is to test the hypothesis that opioid drug effects vary as a function of pre-drug affective state. Specifically, it is hypothesized that social stress induction enhances opioid drug wanting compared a non-stress control condition.

Study Overview

• Status: Completed
• Conditions: Drug Effect; Motivation; Stress Reaction; Misuse, Opioid
• Intervention / Treatment: Drug: Placebo; Behavioral: Control State Induction; Drug: Oxycodone; Behavioral: Stress State Induction

Detailed Description

Healthy participants complete four experiment sessions in a placebo-controlled, double-blind, randomized repeated-measures psychopharmacological study. Participants completed four combinations of pre-drug state induction (social stress or no-stress) and drug (intravenous oxycodone or saline).

Temporary and reversible social stress is induced using the Repeatable Social Stress Test (ReSST) which enables repeated administrations of stress-inductions. Across four sessions participants experience two carefully tailored tasks to provoke the experience of social evaluative threat and two non-stressful control tasks.

After each state inductions, participants receive an injection of opioid drug or saline. After a drug absorption phase and viewing of a state reinstatement video designed to evoke a mild form of social evaluative threat participants perform a drug-self-administration test to determine the potency of a second dose.

Self-reported affect, mental and physiological state and drug effects are assessed throughout the session.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0317
    • University of Oslo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Mentally and physically healthy
• Body mass index (BMI) in the healthy range (18.5 < BMI < 30)
• Normal or corrected vision
• Had received an opioid drug at least once in their lifetime (to ensure no severe adverse or allergic reactions).

Exclusion Criteria:

• Any significant physical health problem (e.g., heart, lung, kidney, liver, and other conditions)
• Current or past substance use problems
• Current mental health problems
• Past mental health problems beyond mild episodic anxiety or depression
• Social anxiety or fear of public speaking
• Past or current chronic pain
• Pregnancy or breastfeeding
• Recent use of any contraindicating medications
• Prior difficulty in providing blood samples.

All exclusion criteria required a 'yes' or 'no' response from participants. Participants were also asked to report any illnesses or medical conditions that were not covered by the questions in the clinical interview. Mental health and substance use were assessed during the clinical interview using the Mini-International Neuropsychiatric Interview (MINI). The interview required binary responses to questions regarding a wide range of psychological symptoms relevant for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) and ICD-10 (International Classification of Diseases) psychiatric disorders. Interviewers then used the pre-defined cut offs relevant to the severity of symptoms for each psychiatric disorder to assist the clinical judgement.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo_Control; Control state induction: Participants answer simple questions about their color or music preferences in a hybrid (zoom-lab) session with a friendly experimenter (The Repeatable Social Stress Test (ReSST) control conditions). Drug administration: A sampling dose of intravenous (i.v.) saline administered over 15 seconds through a venous catheter after the state induction. 45 minutes later participants receive the second dose of saline (0-100% of the initial sampling dose) determined by a behavioral self-administration task.	Drug: Placebo; Pure saline was administered as the placebo condition. Based on body weight, the study nurse/anesthetist adjusted the (unknown) content in two syringes by removing enough fluid to reach a volume that would result in a dose equivalent of 3.1mg/70kg (0,043 mg/ml pr kg) should the syringes contain oxycodone. The first dose was administered 5 minutes after the state induction task. The second dose was adjusted according to the performance on the self-administration task (but maximum 100% of the first dose) and administered 45 later.; Other Names: Saline; Behavioral: Control State Induction; Two different control tasks matched to the stress conditions on key parameters outlined in the protocol.; Other Names: ReSST (Repeatable Social Stress Test): Control
Active Comparator: Oxycodone_Control; Control state induction: Participants answer simple questions about their color or music preferences in a hybrid (zoom-lab) session with a friendly experimenter. (The Repeatable Social Stress Test (ReSST) control conditions). Drug administration: A sampling dose of i.v. oxycodone administered over 15 seconds through a venous catheter after the state induction. 45 minutes later participants receive the second dose of oxycodone (0-100% of the initial sampling dose) determined by a behavioral self-administration task.	Behavioral: Control State Induction; Two different control tasks matched to the stress conditions on key parameters outlined in the protocol.; Other Names: ReSST (Repeatable Social Stress Test): Control; Drug: Oxycodone; 3.1mg oxycodone/70 kg body weight was administered as the main drug intervention. Based on body weight, the study nurse/anesthetist adjusted the (unknown) content in two syringes by removing enough fluid to reach a volume that would result in a dose equivalent of 3.1mg/70kg (0,043 mg/ml pr kg) should the syringes contain oxycodone. The first dose was administered 5 minutes after the state induction task. The second dose was adjusted according to the performance on the self-administration task (but maximum 100% of the first dose) and administered 45 later.
Active Comparator: Placebo_Stress; State induction: Stress The Repeatable Social Stress Test (ReSST) was used to induce psychosocial stress (mock job talk in stress session 1 and singing task in stress session 2). Drug administration: A sampling dose of i.v. saline administered over 15 seconds through a venous catheter after the state induction. 45 minutes later participants receive the second dose of saline (0-100% of the initial sampling dose) determined by a behavioral self-administration task.	Drug: Placebo; Pure saline was administered as the placebo condition. Based on body weight, the study nurse/anesthetist adjusted the (unknown) content in two syringes by removing enough fluid to reach a volume that would result in a dose equivalent of 3.1mg/70kg (0,043 mg/ml pr kg) should the syringes contain oxycodone. The first dose was administered 5 minutes after the state induction task. The second dose was adjusted according to the performance on the self-administration task (but maximum 100% of the first dose) and administered 45 later.; Other Names: Saline; Behavioral: Stress State Induction; ReSST is an in-house hybrid online-lab implementation of two stress induction paradigms based on the Trier Social stress test (TSST) and Iowa Social Singing Stress Test (I-SSST). The set-up was tailored to allow repeated stress induction without diminishing effects that allowed for an online experiment panel. Stress and control state inductions were administered every-other session. The singing version of the stress test was always administered last as it was deemed more stressful during piloting.; Other Names: ReSST (Repeatable Social Stress Test): Stress
Experimental: Oxycodone_Stress; State induction: Stress ReSST was used to induce psychosocial stress (mock job talk in stress session 1 and singing task in stress session 2). Drug administration: A sampling dose of i.v. oxycodone administered over 15 seconds through a venous catheter after the state induction. 45 minutes later participants receive the second dose of oxycodone (0-100% of the initial sampling dose) determined by a behavioral self-administration task.	Drug: Oxycodone; 3.1mg oxycodone/70 kg body weight was administered as the main drug intervention. Based on body weight, the study nurse/anesthetist adjusted the (unknown) content in two syringes by removing enough fluid to reach a volume that would result in a dose equivalent of 3.1mg/70kg (0,043 mg/ml pr kg) should the syringes contain oxycodone. The first dose was administered 5 minutes after the state induction task. The second dose was adjusted according to the performance on the self-administration task (but maximum 100% of the first dose) and administered 45 later.; Behavioral: Stress State Induction; ReSST is an in-house hybrid online-lab implementation of two stress induction paradigms based on the Trier Social stress test (TSST) and Iowa Social Singing Stress Test (I-SSST). The set-up was tailored to allow repeated stress induction without diminishing effects that allowed for an online experiment panel. Stress and control state inductions were administered every-other session. The singing version of the stress test was always administered last as it was deemed more stressful during piloting.; Other Names: ReSST (Repeatable Social Stress Test): Stress

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amount of oxycodone self-administered in the behavioral drug wanting task relative to the first sampling dose (0-125%).	The number corresponds to the achieved cursor placement on a vertical electronic scale indicated desired effect intensity from second dose relative to the first (sampling) dose. Cursor placement depends on the amount of effort exerted (keyboard presses) and the task difficulty adapted to performance. The task ended abruptly after 2 minutes.	Single measure: final task result ~22 minutes after sampling dose
Self-report of oxycodone wanting relative to the first sampling dose (0-125 %)	Self-reported target effect intensity was indicated on a vertical scale at the onset of the behavioral drug wanting task before the effortful part of the task. Anchors visible to to participants were: "no effect/drug", "half the effect", "same effect", "a little stronger effect than the first drug dose". Numerically the scale anchors were 0-125 (VAS) where 100 corresponded to the "same effect".	Single measure: ~20 minutes after sampling dose
Self-reported drug wanting from "drug effects questionnaire".	Drug effects questionnaire (DEQ) take again item indicated on a 0-100 electronic Visual analogue scale (VAS) at two survey timepoints after the drug administration. Anchors were 'neutral' and 'very much'. Average rating was used.	From the drug administration until the start of the self-administration task (~15 minutes)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stress response 2: increase in physiological stress measured by heart rate (beats per minute: BMP) induced by the primary stress induction.	Heart rate change during the state induction compared to the time period before state induction.	Data from 20 minutes before to 20 minutes after the middle of the stress induction were used to estimate the heart rate increase
Stress response 3: change in endocrine stress response measured by cortisol induced by the primary stress induction.	Estimates of plasma cortisol levels changes from the baseline (2 blood samples) to the samples after the state induction (4 blood samples).	Throughout the experiment session (~3 hours, 6 samples)
Changes in positive and negative affect after the state manipulations (induction and reinstatement) and drug administrations	Select items from the PANAS based on pilot data. Baseline measures are collected several times before the state induction. Items were rated on a 0-100 Visual Analogue Scale (VAS). Negative affect (mood) items = "distressed", "anxious", "vulnerable", "irritable" Positive affect (mood) items = "good", "happy", "confident", "safe", "relaxed" Composite ratings from all measures collected throughout each session (k=11 measures) will be reported as descriptive information.	From immediately before to immediately after the state induction (~20 minutes)
Drug effects questionnaire (DEQ)	Drug effect, liking and disliking was measured using items from the Drug Effects Questionnaire (DEQ; 'Feel effect', 'Like effect', 'Dislike effect') measured on an electronic 0-100 VAS, anchors 'neutral' and 'very much'.	From the drug administration until the start of the self-administration task (~15 minutes)
Side effects	To assess the overall drug- and side effects, the following items were collected on a 0-100 electronic VAS: feeling high, blunted and dizzy. Additional items will be explored and reported where relevant and in the supplementary materials (feeling good, euphoric, indifferent, safe, dry mouth, nauseous, "not like myself").	From the drug administration until the start of the self-administration task (~15 minutes)
Stress response 1: increase in self-reported stress to the primary stress induction and subsequent stress reinstatement (as compared to control tasks).	Change in ratings on the item "feeling stressed" measured on a 0-100 Visual Analogue Scale (VAS) The following items were collected to assess stress effects: anxious, self-conscious, embarrassed, vulnerable, happy, relaxed, irritable, confident, shaky, distressed, flushed face, heart palpitations, stomach discomfort, dizzy (to stress on a 0-100 VAS) and report this in the supplementary materials.	From the measure before state induction until the end of the state induction (~20 minutes).

Collaborators and Investigators

• Sponsor: University of Oslo
• Collaborators: Oslo University Hospital; Linkoeping University
• Investigators: Principal Investigator: Siri Leknes, PhD, University of Oslo; Principal Investigator: Marie Eikemo, PhD, University of Oslo

Publications and helpful links

Helpful Links

• Time locked preregistration prior to data collection

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2021
• Primary Completion (Actual): April 28, 2022
• Study Completion (Actual): April 28, 2022

Study Registration Dates

• First Submitted: June 7, 2024
• First Submitted That Met QC Criteria: July 1, 2024
• First Posted (Actual): July 3, 2024

Study Record Updates

• Last Update Posted (Actual): July 5, 2024
• Last Update Submitted That Met QC Criteria: July 2, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Fractures, Bone; Wounds and Injuries; Narcotic-Related Disorders; Opioid-Related Disorders; Fractures, Stress; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Oxycodone
• Other Study ID Numbers: 802885; https://osf.io/bcxv8 (Other Identifier: OSF)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized information (non sensitive) will be shared on the Open Science Framework (OSF) at the time of publication.
• IPD Sharing Time Frame: The data will be released with the publication. The code, protocol, and supplementary materials have been released in the project repository.
• IPD Sharing Access Criteria: none. For conditional access to health/sensitive data following publication contact the corresponding author (marie.eikemo@psykologi.uio.no) A data use agreement may also be required.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Study Data/Documents

1. Analytic Code
   Information comments: Project directory where study relevant documentation can be found and data will be uploaded.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No