Validation of a Test System for Development of Medications for Alcoholism

Objective of this study is to show that a laboratory alcohol self-administration method can predict the therapeutic potential of new compounds to reduce relapse in alcohol-dependent patients.

The 'TEMA" translates several animal behavioral paradigms of alcohol self-administration into corresponding human experiments.

We will investigate the opiate antagonist Naltrexone, whose anti-relapse effect is well documented, as a reference drug for validation.

Main objective:

With TEMA (test system for development of medications for alcoholism ) it can be shown, that naltrexone administration reduces the willingness to perform work for alcohol infusion in a laboratory experiment.

Secondary objectives:

• administration of naltrexone in comparison to placebo leads to a reduction of alcohol craving and real-life drinking
• administration of naltrexone in comparison to placebo leads to reduction of the CDT-Level
• administration of naltrexone in comparison to placebo leads to a change in perception of subjective alcohol effects
• the effectiveness of naltrexone can be predicted by the A118G polymorphism of the OPRM1
• administration of naltrexone changes the baseline and alcohol-induced ability of motor inhibition
• administration of naltrexone changes the baseline and alcohol-induced regional cerebral perfusion
• administration of naltrexone changes the baseline and alcohol-induced cerebral resting state activity
• changes of alcohol effects to the brain activity induced by naltrexone in comparison to placebo correlate with effects of naltrexone on the willingness to work for alcohol self-administration

Inclusion criteria

• male and female volunteers aged 25 to 55 years
• at least weekly alcohol consumption at a medium risk level according to WHO in the Timeline Follow-back Interview over the last 45 day with an average amount of alcohol of 41 g/day (men) or 31 g/day (women)
• at least 6 days with an alcohol consumption of >100 g/day (men) or 75 g/day (women) and at least 4 non consecutive alcohol abstinent days in the last 45 days
• at least 1 drinking day in each full week between screening and visit 1 and not more than 6 abstinent days in the week before visit 1
• no demand of treatment of the risky alcohol consumption
• written consent after Information

Exclusion criteria

• a history of hypersensitivity against alcohol or one of the used medicinal products, of their ingredients or medicinal products with similar chemical structures
• participation in another clinical trial within the last 4 weeks before inclusion
• addiction or other disorders, which will not allow the subject to assess the character and importance or possible consequences of the clinical trial
• pregnant or breastfeeding women
• women capable of bearing children, except women who fulfil following criteria:- post-menopausal (12 months natural amenorrhoea or 6 month amenorrhoea and Serum FSH >40 ml U/ml) - post operative (6 weeks after ovariectomy on both sides with or without hysterectomy) - regular and correct use of a contraceptive method with an error Quote of < 1 % per year (for example implants, depot injections, oral contraceptive, IUP). It has to be recognized that a combined oral contraception - in contrast to pure progesterone compounds - have a failure rate of < 1 %. Hormone IUDs with a Pearl Index of 1 % are safer than copper IUDs. - sexual abstinence - vasectomy of the Partner
• evidence that the participant is not expected to comply with the protocol (for example lacking compliance)
• current or previous alcohol or substance dependence according to DSM-IV (exception: tobacco dependence)
• current or previous treatment because of alcohol, for example in an addiction advisory cen-tre, self-help group, detoxification treatment
• current or previous diseases, where an alcohol infusion can cause a clinically relevant hazard (e. g. pancreatitis, liver cirrhosis)
• current or planned intake of opiate analgesics
• current psychiatric treatment or intake of psychiatric drug or suffering from of a psychiatric disease requiring treatment
• a history of suicide attempt
• CIWA-Score >5 at Screening (alcohol withdrawal scale)
• a history of symptoms of alcohol withdrawal, epileptic seizures or delirium
• routine laboratory Parameters, indicating relevant liver-, pancreas- or kidney injury, an acute infection, anaemia or lack of vitamins (ASAT, ALAT > twofold of the standard at screening, gamma-GT, lipase >threefold of the standard, CRP < 15 mg/l, creatin indicating a moderate renal insufficiency ( eGFR <60 ml/min), leucocytes > 12000/µl, haemoglobin < 7,5 mmol/l (men) or 6,5 mmol/l (women), MCV > 100 fl)
• Body weight > 130 kg
• drug screening in urine: once positive at screening for opiate, cannabis, cocaine, amphetamines, benzodiazepines or positive once at visit 1 for opiates or positive twice at visit 1 for cannabis, cocaine, amphetamines, benzodiazepines
• breath alcohol concentration at screening once > 0,00 g/kg or twice >0,00 g/kg at visit 1
• unsuitable for fMRT (e. g. cardiac pacemaker, claustrophobia)
• specific contraindications against naltrexone: o acute hepatitis o severe or acute liver disease o severe kidney disease o rare hereditary galactose intolerance, Lapp-lactase-deficiency or Glucose-galactose-malabsorption