A Double-blind, Placebo- and Flurazepam-controlled Investigation of the Residual Psychomotor and Cognitive Effects of Modified Release Zolpidem in Young Healthy Volunteers

Abstract

Short-acting hypnotic drugs, such as zolpidem, have minimal residual effects but may not provide optimal efficacy throughout the night for all insomnia patients. A modified-release formulation of zolpidem, zolpidem-MR, has been developed to overcome this limitation. This was a phase I, double-blind, 3-way crossover, placebo-controlled study to investigate the residual psychomotor and cognitive effects of a single oral dose of zolpidem-MR 12.5 mg in 18 healthy young adults. Flurazepam 30 mg was used as a positive control. No comparison with standard immediate-release zolpidem was made. Five neuropsychological tests and 2 subjective tests were performed 8 hours after dosing. The safety of zolpidem-MR was also investigated. Performance on the Critical Flicker Fusion Frequency test, Choice Reaction Time, Immediate and Delayed Word Recall, and the Compensatory Tracking Task was significantly impaired by flurazepam but not by zolpidem-MR (with the exception of the Compensatory Tracking Task) or placebo. No significant effects were observed on the Digit Symbol Substitution Test. The Leeds Sleep Evaluation Questionnaire showed that both drugs improved the ease of getting to sleep and perceived quality of sleep, whereas only flurazepam significantly impaired the ease of awakening. Neither drug scored significantly better than placebo on the Bond and Lader contentedness scale, but both induced a significant difference in calmness; only flurazepam significantly reduced alertness. The safety profile of zolpidem-MR was comparable to placebo. In conclusion, the study showed the good tolerance of zolpidem-MR in terms of residual neuropsychological effects as well as a beneficial effect on sleep quality in young healthy adults.

The Effect of Two Benzodiazepine Receptor Agonist Hypnotics on Sleep-Dependent Memory Consolidation

“…36 We do not believe residual sedation accounts for the reduced SDMC with zolpidem-ER 12.5 mg. since testing was done 9.5 hours post-dose and studies of this drug as a hypnotic indicate no residual sedation 8.5 to 9.5 hours post dosing. 25,26,37 Although DSST scores with zolpidem-ER were slightly lower than those with zaleplon and placebo, follow-up correlational analyses between DSST and WPT/FTT performance showed no significant findings, indicating that any residual sedation present in the zolpidem-ER condition did not predict performance on the memory tests. We also visually examined the data to determine if residual sedation was more likely to occur in females, since the FDA has recently lowered the recommended dosage of zolpidem-ER for women based on reports that some women eliminate zolpidem more slowly than men.…”

“…Zolpidem-ER has an estimated duration of action of 6-8 h, with a t 1/2 of 2.8 h and a t max of 1.5 h. 23 In contrast, zaleplon has an estimated duration of action of 3-4 h due to rapid absorption and elimination, with t 1/2 and t max both approximately one h. 24 These doses were chosen because, at the time of study, they were the recommended therapeutic doses for treatment of insomnia. In addition, residual morning sedation has not been detected with either drug at these doses when administered at bedtime, 25,26 or with zaleplon 10 mg when administered as little as 4 h before wake time (middle-of-the-night dosing). 27,28 Normal subjects were studied to avoid potential influence of the inherent sleep disruption of insomnia patients.…”

Sleep disturbance and the effects of extended-release zolpidem during cannabis withdrawal

“…This is consistent with prior research (cf. Blin et al, 2006). On the other hand, clinically significant sleep deficits have been associated with impaired cognitive abilities (cf.…”

Dynamics and Kinetics of a Modified‐Release Formulation of Zolpidem: Comparison With Immediate‐Release Standard Zolpidem and Placebo

“…The formulation consists of a 2-layer tablet that provides a biphasic release of zolpidem (immediate-release [IR], then slow-release) in the gastrointestinal tract. Several controlled studies have demonstrated the absence of residual effects of MR zolpidem at 8 hours postdose in elderly 27 and young healthy subjects 28 and in patients with insomnia. 24 A double-blind polysomnographic sleep study in normal volunteers utilized a model of sleep disruption through continuous exposure to pre-recorded traffic noise.…”