TIME-DEPENDENT SENSITIZATION TO TRIAZOLAM - AN OBSERVATION IN 3 STUDIES

Evidence of time-dependent sensitization (TDS) to triazolam was observed in three separate clinical studies. Study 1 was conducted in 12 normal-weight and 12 obese men; an intravenous bolus dose of triazolam, 0.5 mg, was administered on two occasions. Study 2 was a balanced crossover of three 0.25-mg oral doses and one 0.20-mg oral dose of triazolam in 11 men. Study 3 was a balanced crossover of one placebo, one 0.5-mg, and two 0.4-mg oral doses of triazolam. In all three studies, treatments were separated by 6 days and included serial blood sampling for characterization of pharmacokinetics. Psychomotor response was assessed with the Digit Symbol Substitution Test and the Continuous Performance Test (CPT). Sedation was rated by an observer. For each measure, an effect ratio was calculated as the area under the effect curve divided by the area under the triazolam concentration curve; this parameter relates the extent of response relative to drug concentration in plasma. Effect ratios increased progressively by week for CPT; the percentage increase ranged from 31.9% in the study 1 normal subjects (week 1 to week 2; p = 0.08) to 631% in study 2 (week 1 to week 4; p = 0.0013). Similar increases were observed for other responses. Overall, the effect ratio data demonstrate increasing responsiveness per unit of triazolam concentration when triazolam was administered as a single dose at 1-week intervals. This observation was incidental to the original objectives of the studies. However, the data suggest that definitive studies to verify the occurrence of this phenomenon need to be conducted. If verified, TDS to specific benzodiazepines could have important implications for the design of dosing regimens for therapeutic application as well as for the design of future studies.