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

Evidence of time-dependent sensitization (TDS) to triazolam was observ ed in three separate clinical studies. Study 1 was conducted in 12 nor mal-weight and 12 obese men; an intravenous bolus dose of triazolam, 0 .5 mg, was administered on two occasions. Study 2 was a balanced cross over of three 0.25-mg oral doses and one 0.20-mg oral dose of triazola m 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, trea tments were separated by 6 days and included serial blood sampling for characterization of pharmacokinetics. Psychomotor response was assess ed with the Digit Symbol Substitution Test and the Continuous Performa nce Test (CPT). Sedation was rated by an observer. For each measure, a n effect ratio was calculated as the area under the effect curve divid ed by the area under the triazolam concentration curve; this parameter relates the extent of response relative to drug concentration in plas ma. Effect ratios increased progressively by week for CPT; the percent age 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 ef fect ratio data demonstrate increasing responsiveness per unit of tria zolam concentration when triazolam was administered as a single dose a t 1-week intervals. This observation was incidental to the original ob jectives of the studies. However, the data suggest that definitive stu dies to verify the occurrence of this phenomenon need to be conducted. If verified, TDS to specific benzodiazepines could have important imp lications for the design of dosing regimens for therapeutic applicatio n as well as for the design of future studies.