Are electroencephalographic and psychomotor measures sensitive in detecting residual sequelae of benzodiazepine hypnotics?
OBJECTIVE
The recent development of short-acting benzodiazepines without active metabolites calls for a differentiation between the hangover effects of long-acting (LBD) and short-acting (SBD) benzodiazepines, when used as nighttime sedatives. The question now arises as to which electrophysiological and psychometric tests can record these effects with the highest degree of sensitivity.


METHODS
35 healthy volunteers participated in 3 randomized double-blind placebo-controlled studies. In the first 2 studies the short-acting benzodiazepine (LORMetazepam 2 mg), the medium-acting BD (FLUNitrazepam 2 mg) and the long-acting BDs (FLURazepam 30 mg and DIAZepam 10 mg) were administered in single oral doses at bedtime. Hangover was measured in the morning hours prior to administration, and 12, 36, and either 60 h (first study) or 156 h (second study) p.a. The measurements included the pharmaco-EEG, particularly the relative power in the beta band; visual analogue scales for assessing the subjective quality of sleep, EWL-adjective check list; pegboard test and radioreceptor assay. In the third study, a single oral dose of LORM 2 mg was given and the acute sedative effects were measured by the Adaptive Pursuit Tracking Test, Pauli memory test, pegboard and Pursuit Rotor.


RESULTS
The sleep-inducing properties of all BDs could be detected quite clearly on the first night p.a. Distinct hangover effects of LBD were apparent in the pegboard test and residual effects in different beta frequency bands after the first and, to a lesser degree, second nights. Such effects were barely detectable after the SBD. The time course of the RRA plasma levels of LORM and FLUN corresponded well to that of behaviour. The correspondence for DIAZ was less clear. The pharmaco-EEG proved to be the most sensitive measure of benzodiazepine effects, followed by continuous performance measures, such as the pursuit tracking test and driving simulator. Relatively low discriminability was observed with the discontinuous psychomotor tests, such as pegboard. These results have been interpreted within a concept of "activation theory" and it has been concluded that benzodiazepines more likely affect higher central nervous activities, such as the level of vigilance and attention, than simple activities, such as visumotor performance.
D000328:Adult; D014151:Anti-Anxiety Agents / Q000009:adverse effects*; D001569:Benzodiazepines; D003975:Diazepam / Q000494:pharmacology; D004311:Double-Blind Method; D004569:Electroencephalography; D005260:Female; D005445:Flunitrazepam / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects*; D008140:Lorazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011597:Psychomotor Performance / Q000187:drug effects*; D011869:Radioligand Assay; D012890:Sleep / Q000187:drug effects
D014151:Anti-Anxiety Agents; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; D005445:Flunitrazepam; C023842:lormetazepam; D008140:Lorazepam; D003975:Diazepam