Expanded Studies of the Pharmacokinetics and Clinical Effects of Multi-dose Sublingual Triazolam in Healthy Volunteers

Previous work described the pharmacokinetics and clinical effects of multi-dose sublingual (SL) triazolam (Halcion®). This laboratory study evaluated the hypothesis that incremental dosing of triazolam produces dose-dependent central nervous system (CNS) depression that is profound and long lasting. Forty-nine healthy adults 21–39 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 over 60 minutes, n=12; or 0.75 mg divided among 3 doses over 90 minutes, n=13). Plasma triazolam concentrations were determined. Bispectral index (BIS) and the Observer Assessment of Alertness/Sedation (OAA/S) were used to assess sedation. Plasma triazolam concentrations increased with time in all subjects, with T max and C max both increasing dose-dependently. Compared to 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 minutes (81±7) and sedation at 120 minutes (3.6±0.5), 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 measured by BIS (67±14 and 60±16 at 0.5 and 0.75 mg, respectively) and 150 minutes measured by OAA/S (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 SL triazolam and provide additional insight for discharge safety recommendations.