Acute and Subacute Effects of Diazepam on Human Performance: Comparison of Plain Tablet and Controlled Release Capsule

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Abstract
The psychomotor performance of 9 healthy volunteers was measured in a randomized, double-blind, cross-over manner after single doses (Day 1) and one-week maintenance (Day 8) with diazepam given in uncoated tablets (DZ) or in controlled-release capsule (DZ-CR). The performance was measured objectively (simulated driving, digit symbol substitution. Maddox wing, flicker fusion, tapping rate) and subjectively (visual analogue scales, questionnaires) at baseline and 1.5 and 3 hrs after the intake of DZ 15 mg, DZ-CR 20 mg, or placebo. The maintenance dose for diazepam was 10 mg daily. Subjective, but not objective, responses to placebo were evident on Day 1, but not on Day 8. As expected, DZ impaired most objective test performance on Day 1, the strongest effects seen at 1.5 hr. Subjectively it caused drowsiness and impaired performance. These effects were weaker but still significant on Day 8. DZ-CR produced less effects on both objective and subjective measurements on Day 1. It was about inert on Day 8, yet exophoria and subjective muzziness increased after the last dose; the subjects did not experience their performance as impaired. Measurements of plasma benzodiazepine concentrations confirmed the different pharmacokinetic profiles of DZ and DZ-CR due to different rates of absorption, yet characteristic accumulation of diazepam and its active metabolites during maintenance was seen with both formulations. The results suggests that DZ-CR capsule with less acute psychomotor impairment and steady pharmacokinetic profile would well suit to the treatment of anxiety for longer periods.