A study of the effects of long-term use on individual sensitivity to temazepam and lorazepam in a clinical population.
OBJECTIVE
The central effects of benzodiazepines may be attenuated after chronic use by changes in pharmacokinetics, pharmacodynamics or both. This attenuation may be influenced by the dosing pattern and the characteristics of the user population. The objectives of this study were to evaluate drug sensitivity in long-term users of temazepam and lorazepam in a clinical population.


METHODS
The sensitivity to benzodiazepine effects in chronic users (1-20 years) of lorazepam (n = 14) or temazepam (n = 13) was evaluated in comparison with age and sex matched controls. Drug sensitivity was evaluated by plasma concentration in relation to saccadic eye movement parameters, postural stability and visual analogue scales.


RESULTS
Pharmacokinetics of lorazepam and temazepam did not differ between patients and control subjects. Chronic users of lorazepam showed clear evidence of reduced sensitivity, indicated by lack of any pharmacodynamic difference between patients and controls at baseline, when drug concentrations were similar to the peak values attained in the control subjects after administration of 1-2.5 mg of lorazepam. In addition, there was a two- to four fold reduction in the slopes of concentration-effect plots for measures of saccadic eye movements and body sway (all; P < or = 0.01). By contrast, sensitivity in chronic users of temazepam was not different from controls. The difference between the temazepam and the lorazepam group appears to be associated with a more continuous drug exposure in the latter, due to the longer half-life and a more frequent intake of lorazepam. This pattern of use may be partly related to the more anxious personality traits that were observed in the chronic users of lorazepam.


CONCLUSIONS
Chronic users of lorazepam show evidence of tolerance to sedative effects in comparison with healthy controls. Tolerance does not occur in chronic users of temazepam. The difference may be related to pharmacological properties, in addition to different patterns of use, associated with psychological factors.
van Steveninck
A L
AL
Centre for Human Drug Research, Leiden University Hospital, The Netherlands.
Wallnöfer
A E
AE
Schoemaker
R C
RC
Pieters
M S
MS
Danhof
M
M
van Gerven
J M
JM
Cohen
A F
AF
D000328:Adult; D000339:Affect / Q000187:drug effects; D000368:Aged; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D008140:Lorazepam / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D004856:Postural Balance / Q000187:drug effects; D012438:Saccades / Q000187:drug effects; D013693:Temazepam / Q000493:pharmacokinetics* / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D013693:Temazepam; D008140:Lorazepam