Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

• Published in: British journal of clinical pharmacology Vol. 68; no. 4; pp. 524 - 534
• Main Authors: Zoethout, Remco W. M., Schoemaker, Rik C., Zuurman, Lineke, Van Pelt, Hans, Dahan, Albert, Cohen, Adam F., Van Gerven, Joop M. A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2009; Blackwell; Blackwell Science Inc
• Subjects: Adolescent; Adult; alcohol; Area Under Curve; Biological and medical sciences; breath alcohol concentration; Breath Tests - methods; Central Nervous System Depressants - administration & dosage; Central Nervous System Depressants - adverse effects; clamping; CNS effects; Constriction; Dose-Response Relationship, Drug; Double-Blind Method; ethanol; Ethanol - administration & dosage; Ethanol - pharmacology; Female; Humans; Infusions, Intravenous; intravenous infusion; Male; Medical sciences; Pharmacodynamics; Pharmacology. Drug treatments; Young Adult; Human; alcohol; Intravenous administration; Ethanol; Healthy subject; Central nervous system; clamping; CNS effects; Alcoholic beverage; Infusion; Perfusion; breath alcohol concentration; Pharmacokinetics; intravenous infusion
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2009.03488.x

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The acute effects of alcohol are often studied after oral administration, and alcohol exposure is controlled by adaptation of the dose to weight, and sometimes to sex or demographic variables. • Measurements of the alcohol effects are usually performed at fixed time intervals after intake. • In only a few studies has alcohol been administered intravenously to by‐pass the variability in absorption, but plasma levels often vary after administration and efforts to maintain constant levels are rare. WHAT THIS STUDY ADDS • The pharmacodynamic central nervous system (CNS) effects of alcohol or drug–alcohol interactions can be more accurately investigated if alcohol is administered intravenously and alcohol levels are kept within tightly controlled limits. • In the current study we introduce a clamping procedure to study the acute effects of a constant alcohol level of 0.6 g l−1 for 5 h on a wide range of CNS domains. • The obtained pseudo‐steady‐state levels with very little inter‐ and intravariability allow the separation of concentration‐ and time‐dependent changes in alcohol effects. AIM In determining the acute effects of alcohol, it is helpful if alcohol concentrations are maintained at stable levels, to facilitate the interpretation of the results. Recently, an alcohol clamping method was developed that resulted in stable alcohol concentrations for hours. The aim of this study was to test a range of central nervous system (CNS) effects under pseudo‐steady‐state conditions. METHODS To achieve a pseudo‐steady state of 0.6 g l−1, breath alcohol concentrations (BrAC) were frequently measured and fed back into a spreadsheet‐based program to guide intravenous dosing. CNS effects were frequently measured throughout the clamp. RESULTS The clamping paradigm resulted in a pseudo‐steady‐state BrAC of 0.61 g l−1 (coefficient of variation 6.2%). A plateau was maintained from 25 to 300 min and caused significant effects on smooth pursuit eye movements [−9.7%, 95% confidence interval (CI) −12.4, −7.1], adaptive tracking (−3.4%, 95% CI −4.5, −2.2), visual analogue scale (VAS) alertness (−13 mm, 95% CI −20, −6), VAS alcohol effects (16 mm, 95% CI 7, 25) and body sway (21.3%, 95% CI 1.8, 45). Some effects (like smooth pursuit eye movements) closely followed the relatively stable alcohol concentrations, whereas others (such as body sway and VAS alcohol effects) fluctuated during the plateau phase. CONCLUSIONS Most CNS effects of alcohol showed a trend to change over time, despite stable concentrations. Other variables remained stable under pseudo‐steady‐state conditions. The intravenous clamping method provides precise control over BrAC levels and allows frequent repetition of different CNS measurements. These features make this technique eminently suitable to study the complex pharmacodynamic effects of acute alcohol administration.