Expanded studies of the pharmacokinetics and clinical effects of multidose sublingual triazolam in healthy volunteers.

Previous work described the pharmacokinetics and clinical effects of multidose sublingual triazolam (Halcion; Pharmacia & Upjohn Co, Kalamazoo, Mich). This laboratory study evaluated the hypothesis that incremental dosing of triazolam produces dose-dependent central nervous system depression that is profound and long lasting. Forty-nine healthy adults between the ages of 21 and 39 years, not receiving dental treatment, were randomly assigned to placebo (n = 12) or 1 of 3 triazolam groups (0.25-mg single dose, n = 12; 0.5 mg divided between 2 equal doses for 60 minutes, n = 12; or 0.75 mg divided among 3 doses for 90 minutes, n = 13). Plasma triazolam concentrations were determined. Bispectral index (BIS) and the Observer Assessment of Alertness/Sedation scale were used to assess sedation. Plasma triazolam concentrations increased with time in all subjects, with Tmax and Cmax both increasing dose dependently. Compared with placebo, all dosing paradigms produced dose-dependent BIS suppression and sedation. The single dose of 0.25 mg reached its peak BIS suppression at 90 (81 +/- 7) minutes and sedation at 120 (3.6 +/- 0.5) minutes and returned to baseline before 360 minutes. In contrast, incremental dosing of 0.5 and 0.75 mg produced profound and long-lasting BIS suppression and sedation that did not plateau until either 180 or 210 minutes as measured by the BIS index (67 +/- 14 and 60 +/- 16 at 0.5 and 0.75 mg, respectively) and 150 minutes as measured by the Observer Assessment of Alertness/Sedation scale (3.2 +/- 1.0 and 2.7 +/- 0.4 at 0.5 and 0.75 mg, respectively). These data more fully characterize the effects of incremental dosing with sublingual triazolam and provide additional insight for discharge safety recommendations.

Flumazenil reversal of sublingual triazolam: a randomized controlled clinical trial.

BACKGROUND: Incremental sublingual (SL) dosing of triazolam has emerged as a popular sedation technique. Nevertheless, few studies have evaluated the technique's safety or efficacy. Given its popularity, an easily administered rescue strategy is needed. METHODS: The authors conducted a randomized controlled clinical trial to investigate how intraoral submucosal flumazenil (0.2 milligram) attenuates central nervous system depression produced by incremental SL dosing of triazolam (three doses of 0.25 mg across 90 minutes) in 14 adults. The authors assessed outcomes by using the Observer's Assessment of Alertness/Sedation (OAA/S) scale, bispectral index (BIS) and physiological monitoring. RESULTS: The OAA/S and BIS scores increased after the flumazenil injection at the 30-minute observation point, but they were not sustained. Six hours after the initial dose of triazolam had been administered (four hours after the flumazenil or placebo challenge), all patients could be discharged from the dental clinic. CONCLUSIONS: Deep sedation from incremental SL dosing of triazolam is incompletely reversed by a single intraoral injection of flumazenil. The reversal did not persist. The authors discharged the patients from the dental clinic at 360 minutes. CLINICAL IMPLICATIONS: A single intraoral injection of flumazenil (0.2 mg) cannot immediately reverse oversedation with triazolam. A higher dose might be effective. Reversal for the purpose of discharging the patient early is neither appropriate nor safe.