Development of acute tolerance after oral doses of diazepam and flunitrazepam

Abstract

Flunitrazepam (1 and 2 mg), diazepam (10 and 20 mg) or placebo was administered to healthy, male volunteers, and the time course of psychomotor impairment, as indicated by simple and complex choice reaction time and movement time, was studied during a period of 6 h after drug intake. To examine whether acute tolerance developed, the observed performance during decreasing drug plasma concentration was compared to the predicted performance based on kinetic-dynamic modelling of the observed performance during the first 1.5 h after intake when the drug plasma concentrations were increasing or at peak level. Placebo corrections of the test scores were accomplished to adjust for diurnal variation and the possible influence of learning during the test day. After the flunitrazepam treatments, the predictions overestimated the actual performance significantly with respect to simple and choice reaction time at the 6-h session after intake. After the diazepam treatments, however, no significant deviation was detected between predicted and observed performance. The results indicate that acute tolerance develops with respect to impairment of attention demanding performance after medium to large doses of flunitrazepam, and that tolerance is expressed after approximately 4-6 h following intake.

Zopiclone concentrations in oral fluid and blood after, administration of therapeutic doses of zopiclone

“…To my knowledge acute tolerance for zopiclone is only sparsely investigated in previous studies (195), but is investigated in a few studies regarding benzodiazepines. Ingum found that acute tolerance develops with respect to some psychomotor skills, most pronounced for simple reaction time after administration of a related hypnotic drug flunitrazepam (1 and 2 mg), and that tolerance is expressed after approximately 4-6 h following intake (233). In that study reaction time was measured, and our findings are in accordance to what Ingum found for flunitrazepam.…”

Emergence of anti-conflict effects of zolpidem in rhesus monkeys following extended post-injection intervals

“…Using a drug discrimination procedure, Gerak et al (2008) trained monkeys to discriminate midazolam from saline, and a single pretreatment with the benzodiazepine chlordiazepoxide resulted in a shift to the right in the midazolam dose-response function, consistent with an acute tolerance interpretation. In other studies, acute tolerance was observed in healthy volunteers on measures such as sedation, attention, and benzodiazepine-associated electroencephalogram (EEG) signals (e.g., Ingum et al 1994; Ihrnsen et al 2004; Barbanoj et al 2007), and, most importantly, at least one study with healthy volunteers has shown results consistent with acute tolerance with zolpidem (de Haas et al 2009). Therefore, the idea that acute tolerance occurs with benzodiazepine-type compounds is not without precedent.…”

Biomarkers for the effects of benzodiazepines in healthy volunteers

“…The literature search yielded 56 different studies using 16 different benzodiazepines, published since 1966 [14–67]. There were 173 different tests used, on average 3.1 tests per study.…”

“…This technique is sensitive to a wide range of centrally active substances, although the exact mechanism is hardly ever known [10–14]. EEG studies differ in numbers of leads, technical settings and EEG‐quantification methods, but they usually report effects per EEG‐frequency band, which are divided into delta (0.5–3.5 Hz), theta (3.5–7.5 Hz), alpha (7.5–11.5 Hz) and beta (above 11.5 Hz; subdivided into beta 1 (11.5–30Hz) and beta 2 (above 30 Hz) if possible).…”