Randomized, Double-blind, Placebo-controlled, Crossover Study Investigating Sex-specific Effects of Mu-opioid Receptor Activation on Stress and Social Interaction and Its Modulation by Early Life Stress
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 72
- 试验地点
- 1
- 主要终点
- Self-report of subjective stress during stress exposure
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Placebo
Participants receive the non-active comparator (placebo) on Visit 1 or Visit 2.
干预措施: Placebo (Drug)
Morphine
Participants receive the active drug (morphine) on Visit 1or Visit 2.
干预措施: Morphine (Drug)
结局指标
主要结局
Self-report of subjective stress during stress exposure
时间窗: During the experimental stress task
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.
Endocrinological markers of stress response
时间窗: Throughout the experiment sessions (baseline and approx. 10, 20, 30, 60 and 105 minutes after stress onset, 6 samples).
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).
Psychophysiological stress response of heart rate measured by electrocardiogram
时间窗: During the experimental stress task
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).
Psychophysiological stress response of heart rate variability measured by electrocardiogram
时间窗: During the experimental stress task
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.
Psychophysiological measure of sympathetic activity
时间窗: During the experimental stress task
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).
Changes in self-reported subjective stress over time
时间窗: Throughout the experimental sessions (from before stress induction to 10, 20, 30, 60 and 105 minutes after stress onset, 7 times).
Sex-specific differences in morphine-mediated stress relief measured by changes in Visual Analogue Scales (VAS), ranging from 0-100 with the anchors " not at all " (0) and "extremely" (100) for the items: "I feel stressed", "I feel safe", "I feel relaxed", "I have a dry mouth", "I feel nauseous", "I feel confident", "I feel ashamed", "I feel vulnerable"
Self-reported feeling of shame post-stress
时间窗: ~10 minutes after stress onset
Sex-differences in morphine effects on the Experiential Shame Scale (ESS) score, ranging from 25 -100, with higher values indicating stronger feelings of shame.
Changes in self-reported affect over time
时间窗: Throughout the experimental sessions (from before stress induction to 10, 30, 60 and 105 minutes after stress onset, 6 times).
Sex-specific differences in morphine effects on changes of positive and negative affect measured using the Positive and Negative Affect Schedule (PANAS) scores. Scores for both subscales range from 10 to 50 with higher scores indicating stronger positive or negative affect, respectively.
Early life stress
时间窗: Prior to enrollment
Modulation of the Questionnaire of Unpredictability in Childhood (QUIC) sum score on differences in primary outcomes. Scores range from 0-38 with higher scores indicating greater exposure to instability and unpredictability during childhood.
次要结局
- Subjective differences in experiencing social interaction(During the experimental tasks)
- Behavioural differences of social approach and avoidance(During the experimental task)
- Psychophysiological cardiac markers of social interaction measured by heart rate using electrocardiogram(During the experimental tasks)
- Psychophysiological cardiac markers of social interaction measured by heart rate variability using electrocardiogram(During the experimental tasks)
- Psychophysiological measure of sympathetic activity during social interaction(During the experimental tasks.)
- State anxiety over time(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)(Throughout the experimental sessions (immediately after drug administration until approx. 3 hours after study medication administration, 7 times).)
- Drug concentration(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(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(Prior to enrollment)
- Hair concentrations of chronic stress markers(At screening)
- Personality traits(Single measure, during experimental session)
- Trait assessment of loneliness(Single measure, during experimental session)
- Rosenberg Self Esteem Scale(Single measure, during experimental session.)
- Brief Resilience Scale(Single measure, during experimental session.)
- Becker Depression Inventory(Single measure, during experimental session.)
- Trait anxiety level(Single measure, during experimental session.)
- Snaith Hamilton Anhedonia Pleasure Scale(Single measure, during experimental session.)
- Relationship Structures Questionnaire(Single measure, during experimental session.)
- Socioeconomic status ladder(Single measure, during experimental session.)
- Sex hormone concentration(Single measure at both experimental sessions.)
研究者
Sara L. Kroll
Principle Investigator
Psychiatric University Hospital, Zurich