Different acute tolerance development to EEG, psychomotor performance and subjective assessment effects after two intermittent oral doses of alprazolam in healthy volunteers.
OBJECTIVE
Benzodiazepines (BZDs) are the most effective of the psychotropic drugs in the treatment of anxiety disorders. Tolerance has been reported for the majority of BZDs after chronic administration. However, little attention has been paid to the possibility that tolerance might be present after the intermittent oral administration of BZDs. The objectives of the present study were to assess tolerance development after the administration of two intermittent single oral doses of alprazolam given 15 days apart in healthy volunteers, and to compare the results obtained using measures from different domains: neurophysiological, psychomotor and subjective.


METHODS
Twenty-four healthy volunteers received 2 mg of alprazolam orally on two experimental days, 15 days apart. Plasma concentrations and pharmacodynamics (PD) were assessed before drug intake and at different times in the following 24 h. PD was assessed through EEG (relative alpha and relative beta-1 activities), cancellation task (total and correct number of responses) and visual analogue scales (activity and drowsiness).


RESULTS
No differences were observed in the PKs of alprazolam between occasions. A proteresis was present in both administrations for impairments of psychomotor performance and relative beta-1 activity, whereas it was present only after the second administration for subjective assessments and relative alpha activity. The proteresis on the second occasion was higher than on the first one.


CONCLUSIONS
The administration of two single oral doses of alprazolam, 2 weeks apart in healthy volunteers, yielded the same PKs on both occasions, but significant changes were observed in the PD profile. Acute tolerance was observed after the second administration. Two patterns of acute tolerance development were obtained: (1) impairments of psychomotor performance and relative beta-1 activity, and (2) subjective assessments and relative alpha activity.
Barbanoj
M J
MJ
Centre d'Investigació del Medicament, Institut de Recerca HSCSP, Servei de Farmacologia Clinica, Hospital de la Santa Creu i Sant Pau, and Departament de Farmacologia i Terapèutica (UAB), Barcelona, Spain. mbarbanoj@santpau.es
Urbano
G
G
Antonijoan
R
R
Ballester
M R
MR
Valle
M
M
D000293:Adolescent; D000328:Adult; D000525:Alprazolam / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D004333:Drug Administration Routes; D004361:Drug Tolerance / Q000502:physiology*; D004569:Electroencephalography / Q000187:drug effects*; D005069:Evaluation Studies as Topic; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D009483:Neuropsychological Tests; D010147:Pain Measurement / Q000379:methods; D011597:Psychomotor Performance / Q000187:drug effects*; D016037:Single-Blind Method; D013997:Time Factors
D006993:Hypnotics and Sedatives; D000525:Alprazolam