How Does the Opioid System Shape Stress and Social Behaviour in Men and Women and What Role Does Childhood Unpredictability Play?

N/ANot Yet RecruitingNCT07778511

Sara L. Kroll72 enrolled

Overview

The study aims to investigate sex differences in the effect of mu-opioid receptor (MOR) activation on stress response and social behaviour modulated by early life stress.

While opioid use disorder presents a rising public health concern, the underlying neurobiological mechanisms of substance use are not well understood. In animal studies, activation of the Mu Opioid Receptor (MOR) system has been shown to have stress-buffering effects and to decrease affiliative behaviour, which is in line with addiction models postulating impaired stress response and poor social interactions to be risk indicators for addiction pathogenesis. In humans however, this has not been consistently found. Importantly, behavioural pharmacology studies have often been restricted to male test subjects or have been underpowered. Therefore, a significant knowledge gap remains regarding sex-specific differences in MOR activation. The additional impact of chronic stress in the form of early life stress significantly affects brain development, in turn shaping stress reactivity and affiliative behaviour in later life. This forms the basis of the research question of the present study, whether sex and childhood unpredictability modulate the effects of MOR activation on stress response and social interaction behaviour. The prototypical opioid morphine will be used to activate the MOR. Participants will receive the study medication on two separate visits in a randomised, counterbalanced order. Afterwards, participants will conduct computer-based stress and social interaction tasks. Learning more about individual differences in MOR activation and its effects on stress and social behaviour can help to uncover vulnerability and risk factors for opioid use disorder and improve personalised treatment opportunities.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Enrollment

Conditions

Stress Early Life Stress Sex Differences Opioid

Interventions

MorphineDRUG

Sevredol 10mg, oral single-dose administration

PlaceboDRUG

identical in appearance to active drug, containing no active substance (mannitol), oral one-time administration

Eligibility

Sex: ALLMin age: 18 YearsMax age: 40 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Age 18-40 years * Ability to read, understand, and provide written informed consent in German * Proficiency in German * Able to give blood samples (no blood- or needle-related phobia) * Good health as determined by medical history, ECG, and clinical assessment of lab tests. Lab tests will include potassium, creatinine, hemoglobin, glucose, calcium, BUN, complete blood count, total bilirubin, AST, ALT, and GGT. The final decision will be according to the judgment of the study physician. * Females must have a negative urine pregnancy test (hCG) at inclusion and at the start of each study session. Females of childbearing potential who are sexually active and have not been surgically sterilized must agree to use an adequate method of birth control during the study. * Prior experience with medical opioids (at least one experience with prescription opioids such as oxycodone, morphine, hydromorphone, fentanyl, hydrocodone, codeine, or dihydrocodeine) and paracetamol. * Body mass index (BMI) between 19 and 30 kg/m2 Exclusion Criteria: * Any current instable medical or neurological condition * Any clinically significant psychiatric disorder (i.e., psychotic and stress-related disorders) including a diagnosis of substance use disorder (defined in DSM-5 terms as Moderate or Severe). Participants will be screened using the Structured Clinical Interview - SCID for DSM-5). If indication is obtained that a clinically significant psychiatric disorder may be present, a full SCID will be carried out by appropriately trained staff. * Significant adverse reaction to prior opioid or paracetamol exposure * Reporting any illegal drug use \>15 life-time occasions and regular drug use during the last three months incl. the test period (except for nicotine and alcohol) * Any current use of CNS-active medications. * Current use of opioid analgesics, opioid use for \> 6 weeks (lifetime), or within the three months prior to study enrollment. * Fagerström Test of Nicotine Dependence (FTND) Score \> 5 (strong nicotine dependence) * Heavy alcohol use based on the Alcohol Use Disorder Identification Test (AUDIT) * Lifetime diagnosis of cardiac disease. * Clinically significant laboratory or ECG abnormality that could be a safety issue in the study * Acute or chronic respiratory issues (e.g., cold, flu, asthma, etc.) * Lifetime diagnosis of liver or kidney disease including moderate or severe renal impairment (creatinine clearance \< 50 ml/min) * Lifetime diagnosis of schizophrenia, bipolar disorder, obsessive-compulsive disorder, or autism spectrum disorder according to DSM-5 * Diagnosis of a current episode of depression based on DSM-5 criteria * Current diagnosis of a moderate or severe substance use disorder according to DSM-5 * Daily cannabis consumption in the past three months * Use of psychotropic medication within the last 7 days * Participation in other pharmacological studies within the last 2 months * Alcohol use within the last 24 hours controlled by breathalyzer * Unable to provide a negative urine drug screen (cannabinoids, amphetamines, opiates and opioids, benzodiazepines, and cocaine). * Positive pregnancy test or nursing (self-report) * For women: irregular menstrual cycle or menopause

Locations (1)

University Hospital of Psychiatry Zurich

Zurich, Switzerland

Outcomes

Primary Outcomes

Self-report of subjective stress during stress exposure

Sex-specific differences in the stress relieving effects of morphine compared to placebo. Subjective stress response will be measured by differences between self- and other condition in ratings using a 1-7 Visual Analogue Scale (VAS) with the anchors "not at all" (1) to "very much" (7) for the items "How secure do you feel?" and "How stressed do you feel?" throughout the stress task.

Time frame: During the experimental stress task

Endocrinological markers of stress response

Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by changes in plasma concentrations of cortisol and endocannabinoids (2-AG, AEA, PEA, SEA, OEA).

Time frame: Throughout the experiment sessions (baseline and approx. 10, 20, 30, 60 and 105 minutes after stress onset, 6 samples).

Psychophysiological stress response of heart rate measured by electrocardiogram

Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by differences between self and other condition in heart rate (beats per minute).

Time frame: During the experimental stress task

Psychophysiological stress response of heart rate variability measured by electrocardiogram

Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by differences between self and other condition in heart rate variability.

Time frame: During the experimental stress task

Psychophysiological measure of sympathetic activity

Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by differences between self and other condition in skin conductance response (SCR).

Time frame: During the experimental stress task

Changes in self-reported subjective stress over time

Central Contacts

Sara L Kroll, Dr. phil.

CONTACT

+41 (0)58 384 34 13 saraliane.kroll@bli.uzh.ch

Ella L Sommer

CONTACT

+41 (0)58 384 26 01 ella.sommer@bli.uzh.ch

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Subjective differences in experiencing social interaction

Sex-specific differences in morphine effects on subjective pleasantness ratings measured by VAS scales (1-100) during the social approach/avoidance task and affective touch task with higher ratings indicating more pleasantness.

Time frame: During the experimental tasks

Behavioural differences of social approach and avoidance

Sex-specific differences in morphine effects on behavioural measures (measured by number of button presses) during the social approach/avoidance task.

Time frame: During the experimental task

Psychophysiological cardiac markers of social interaction measured by heart rate using electrocardiogram

Sex-specific differences in morphine effects on heart rate (beats per minute) during the social approach/avoidance task and the affective touch task.

Time frame: During the experimental tasks

Psychophysiological cardiac markers of social interaction measured by heart rate variability using electrocardiogram

Sex-specific differences in morphine effects on heart rate variability during the social approach/avoidance task and the affective touch task.

Time frame: During the experimental tasks

Psychophysiological measure of sympathetic activity during social interaction

Sex-specific differences in morphine effects on skin conductance response (SCR) during the social approach/avoidance task and the affective touch task.

Time frame: During the experimental tasks.

State anxiety over time

Sex-specific differences in morphine effects on changes in state anxiety measured by the State-Trait Anxiety Inventory (STAI) score. Scores can range from 20 -80 with higher scores indicating greater anxiety

Time frame: Throughout the experimental sessions (from before stress induction to approx. 10, 30, 60, and 105 minutes after stress onset, 6 times).

Drug Effects Questionnaire (DEQ)

Sex-specific differences in drug effects will be measured using the Drug Effects Questionnaire (DEQ; subjective experiences are reported of "feeling the drug", "feeling high", "drug liking" and "disliking", and "desire to take the drug again") measured on an electronic 0-100 VAS, anchors "not at all" and "extremely".

Time frame: Throughout the experimental sessions (immediately after drug administration until approx. 3 hours after study medication administration, 7 times).

Drug concentration

Differences in concentration of the study drug in blood between the two test sessions.

Time frame: Throughout the experimental sessions (from 1 hour after drug administration until approx. 3 hours after study medication administration, 4 samples).

Changes in oxytocin over time

Sex-specific differences in morphine effects on oxytocin levels measured in saliva.

Time frame: Throughout the experimental sessions (from before stress induction to approx. 10, 20, 30, 60 and 105 minutes after stress onset, 6 samples).

Early life stress

Modulation of the Questionnaire of Unpredictability in Childhood (QUIC) sum score on differences in secondary outcomes. Scores range from 0-38 with higher scores indicating greater exposure to instability and unpredictability during childhood.

Time frame: Prior to enrollment

Hair concentrations of chronic stress markers

Modulation of tonic endocannabinoid (2-AG, AEA, OEA, PEA, SEA) and glucocorticoid (cortisol, cortisone, ACTH) concentrations in hair on primary and secondary outcomes.

Time frame: At screening

Personality traits

Modulation of personality traits measured by the Neuroticism-Extraversion-Openness Five-Factor Inventory (NEO-FFI) on primary and secondary outcomes. Scores range from 0-48 per subscale. Higher scores indicate higher expression of the trait.

Time frame: Single measure, during experimental session

Trait assessment of loneliness

Modulation of loneliness measured by the German version of the UCLA loneliness scale on primary and secondary outcomes. Scores can range from 20-80 with higher scores indicating greater feelings of loneliness.

Time frame: Single measure, during experimental session

Rosenberg Self Esteem Scale

Modulation of self-esteem measured by the Rosenberg Self Esteem Scale (RSES) on primary and secondary outcomes. Scores range from 0 -30 with scores below 15 suggesting low self-esteem, 15 to 25 reflecting a normal or average range, and 26 to 30 indicating high self-esteem.