Study of the Opioid Modulation of the Effect of Alcohol on the Dopaminergic Reward System

Opioid Modulation of the Effect of Alcohol on the Dopaminergic Reward System: a [18F]-Fallypride- and [18F]-Fluoro-DOPA-PET Study.

About 10% of the calculable loss of health and quality of life in industrial countries can be attributed to excessive alcohol consumption. Behavioural pharmacological, genetic and clinical studies on alcohol dependence suggest a multifactorial model for the development of the disease, which ascribes an important role in the development of the disease to genetic variance, educational style and continued substance use. Animal and human experimental studies suggest that continued alcohol consumption leads to a pathological activation of the mesolimbic reward system. In the presented study, the modification of the alcohol-mediated activation of the mesolimbic reward system by the administration of the opiate antagonist naltrexone will be investigated in a human in vivo model. The aim is to gain important insights for the further development of pharmacological treatment options for alcohol dependence. Further development of pharmacological treatment options for alcohol dependence seems urgently necessary in order to slow down the high tendency to relapse and prolong the short abstinence period.

Study Overview

• Status: Terminated
• Conditions: Alcohol Addiction
• Intervention / Treatment: Drug: Placebo; Drug: Naltrexone

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52074
    • University Hospital RWTH Aachen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• age: 21-45 years
• The subject is able to understand the nature, extent and individual consequences of the clinical trial
• Maintained ability to give consent, certified by a psychiatrist (specialist)
• A personally dated informed consent form signed by the test participant
• No current and/or historical psychiatric disorder (secured by standardized psychiatric interview (DIAX: Composite International Diagnostic Interview))
• Non-smokers (no nicotine addiction within the last 6 months prior to sequential allocation)
• OPRM1 Asp40 carrier (functional polymorphism in amino acid residue 40 of μ-opioid receptor gene (OPRM1)) (in AC for inclusion in first and third treatment arm)
• Highly effective contraception method with a failure rate of <1%: Hormonal contraceptive methods (oral: "contraceptive pill", incl. combined oral contraceptives; subcutaneous implants; injectable contraceptives); intrauterine pessary, vasectomy of the partner, tube ligation ("sterilisation") or sexual abstinence
• Persons who are legally competent and mentally able to understand and follow the instructions of the study staff
• MRI capability

Exclusion Criteria:

• hypersensitivity to the investigational product or a chemically similar substance or component of the investigational product
• Participation in other clinical trials during or within 6 months prior to this clinical trial
• Medical or psychological circumstances which may jeopardise the proper conduct of the clinical trial
• Physical illnesses which could interfere with the planned examinations according to their type and severity, could have an influence on the parameters to be examined or could endanger the volunteer during the course of the examination
• Inability to adhere to the study protocol
• Limited or completely revoked legal capacity
• Acute suicidal tendency or external hazard
• Poor overall condition
• Participation in a study using ionising radiation in the last five years.
• Regular medication (e.g. MAO inhibitors)
• Alcohol abuse, alcohol dependency or addiction illness / abuse of addictive substances in history
• Existence of other exclusion criteria for participation in MRI examinations (non-removable metal parts in the body, left-handedness, pacemakers)
• Known hypersensitivity to carbidopa or any of the other components
• Relevant organic diseases: in particular: Narrow angle glaucoma, vascular diseases, central nervous neurological diseases; body weight of more than 150 kg (contraindications PET - scan)
• Clinically significant deviations in clinical chemistry or haematology or clinically significant abnormalities
• Melanoma-specific skin lesions or anamnesis of a previous melanoma disease
• Persons who are accommodated in an establishment by court order or official order
• Persons who are dependent on or have an employment relationship with the sponsor or investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: First Arm; 7 days placebo intake - i.v. injection of physiological saline solution (0,9%) - PET followed by 7 days placebo intake - i.v. injection of ethanol solution (6 Vol.-%) - PET	Drug: Placebo; Placebo oral tablet daily
OTHER: Second Arm; 7 days placebo intake - i.v. injection of physiological saline solution (0,9%) - PET - 7 days naltrexone intake (Nemexin, 50 mg once daily during the first 2 days, 100 mg daily for the following 5 days) - injection of physiological saline solution (0,9%) - PET	Drug: Placebo; Placebo oral tablet daily; Drug: Naltrexone; Naltrexone (Nemexin) oral tablet 50 mg daily for 2 days, Naltrexone (Nemexin) oral tablet 100 mg daily for 5 days
OTHER: Third Arm; 7 days placebo intake - i.v. injection of ethanol solution (6 Vol.-%) - PET - 7 days naltrexone (Nemexin, 50 mg once daily during the first 2 days, 100 mg daily for the following 5 days) intake - i.v. injection of ethanol solution (6 Vol.-%) - PET	Drug: Placebo; Placebo oral tablet daily; Drug: Naltrexone; Naltrexone (Nemexin) oral tablet 50 mg daily for 2 days, Naltrexone (Nemexin) oral tablet 100 mg daily for 5 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pharmacological effect of naltrexone on the dopamine synthesis rate of a healthy OPRM1 Asp40-bearing men under the influence of alcohol measured with [18F]-fluoro-DOPA PET.	28 days
Dopamine D2 receptor availability in the structures of the ventral and dorsal striatum of a healthy µ-opioid receptor gen (OPRM1, Asp40 Allel)-bearing men under the influence of alcohol measured with [18F]-fallypride Positron Emission Tomography.	28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacological effect of ethanol on dopamine D2 receptor availability in healthy men measured with [18F]-fallypride Positron Emission Tomography.	28 days
Pharmacological effect of ethanol on the dopamine synthesis rate of the ventral and dorsal striatum in healthy men measured with [18F]-fluoro-DOPA PET.	28 days
Pharmacological effect of Naltrexone on dopamine D2 receptor availability in healthy men measured with [18F]-fallypride Positron Emission Tomography.	28 days
Pharmacological effect of Naltrexone on the dopamine synthesis rate of ventral and dorsal striatum in healthy men measured with [18F]-fluoro-DOPA PET.	28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modulation of extrastriatal dopamine D2/D3 receptor availability measured with [18F]-fallypride in structures of the anterior cingulum using Positron Emission Tomography.		28 days
Relationship between impulsive behaviour and functionality of the dopamine synthesis rate and dopamine D2 receptor availability	Evaluation of impulsive behaviour using BIS (Barratt Impulsiveness Scale) questionnaire	28 days
Relationship between impulsive behaviour and functionality of the dopamine synthesis rate and dopamine D2 receptor availability	Evaluation of impulsive behaviour using Neo-FFI (NEO-Fünf-Faktoren-Inventar) questionnaire	28 days
Relationship between impulsive behaviour and functionality of the dopamine synthesis rate and dopamine D2 receptor availability	Evaluation of impulsive behaviour using I7 (Impulsivitätsfragebogen (impulsivity questionnaire) nach Eysenck) questionnaire	28 days
Interaction between subjective alcohol effects and placebo/naltrexone effects	Exploratively, the interaction between subjective alcohol effects and placebo/naltrexone effects will be investigated using VAS (visual analogue scale of alcoholic desire) questionnaire.	28 days
Interaction between subjective alcohol effects and placebo/naltrexone effects	Exploratively, the interaction between subjective alcohol effects and placebo/naltrexone effects will be investigated using OCDS (Obsessive Compulsive Drinking Scale) questionnaire.	28 days
Interaction between subjective alcohol effects and placebo/naltrexone effects	Exploratively, the interaction between subjective alcohol effects and placebo/naltrexone effects will be investigated using ESA (Erfassung subjektiver Alkoholwirkungen (Determination of subjective alcohol effects)) questionnaire.	28 days

Collaborators and Investigators

• Sponsor: RWTH Aachen University

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 30, 2011
• Primary Completion (ACTUAL): December 13, 2017
• Study Completion (ACTUAL): December 13, 2017

Study Registration Dates

• First Submitted: February 18, 2019
• First Submitted That Met QC Criteria: February 25, 2019
• First Posted (ACTUAL): February 26, 2019

Study Record Updates

• Last Update Posted (ACTUAL): September 12, 2019
• Last Update Submitted That Met QC Criteria: September 10, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Alcoholism; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Alcohol Deterrents; Naltrexone
• Other Study ID Numbers: 10-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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