David Seiden

A 2-night, 3-period, crossover study of ramelteon's efficacy and safety in older adults with chronic insomnia

ABSTRACT Objective: To assess the efficacy and safety of ramelteon, a selective melatonin MT1/MT2-receptor agonist, for insomnia treatment in older adults. Methods: In a randomized, 9‑week, 3‑period crossover trial conducted at 17 sleep centers, older adults (N = 100) with chronic primary insomnia (37 men, 63 women; mean age [range], 70.7 [65–83] years) were administered placebo, ramelteon 4 mg, and ramelteon 8 mg in three treatment phases for two consecutive nights. Each phase was separated by 5- to 12‑day washout periods. Sleep was monitored via polysomnography. Subjective sleep parameters, using a Postsleep Questionnaire, were recorded, and residual pharmacologic effects were assessed. Results: Statistically significant reductions in latency to persistent sleep were observed with both ramelteon 4 mg and 8 mg compared to placebo (28.7 min vs. 38.4 min, p < 0.001; 30.8 min vs. 38.4 min, p = 0.005, respectively). Total sleep time (p = 0.036 and p = 0.007,respectively) and sleep efficiency (p = 0.037 and p = 0.007, respectively) were also significantly improved with ramelteon 4 mg and 8 mg compared to placebo. Statistically significant reductions in subjective sleep latency on a Postsleep Questionnaire were reported with ramelteon 4 mg versus placebo (p = 0.037), but not ramelteon 8 mg (p = 0.120); no significant differences on other subjective sleep assessments were reported. A lack of power limits interpretation of self-reported sleep parameters. Incidences of adverse events considered treatment related were placebo (7%), ramelteon 4 mg (11%), and ramelteon 8 mg (5%). No residual pharmacologic effects were observed via Digit Symbol Substitution Test, memory recall tests (immediate and delayed), visual analog scales (feelings and mood), and Postsleep Questionnaire (level of alertness and ability to concentrate). Conclusions: In older adults with chronic primary insomnia, ramelteon produced significant reductions in latency to persistent sleep and increases in total sleep time and sleep efficacy, and showed no evidence of adverse next-day psychomotor or cognitive effects.

Efficacy and tolerability of armodafinil: effect on clinical condition late in the shift and overall functioning of patients with excessive sleepiness associated with shift work disorder.

Objective: This study examined the effect of armodafinil on late-in-shift clinical condition, wakefulness, and overall functioning of patients with shift work disorder. Methods: Patients with clinically diagnosed shift work disorder received armodafinil or placebo on nights worked for 6 weeks. Patients included in the study experienced late-in-shift sleepiness between 4 AM and 8 AM (Karolinska Sleepiness Scale ≥6) and were functionally impaired (Global Assessment of Functioning <70). Efficacy was determined by improvements in clinical condition (Clinical Global Impression-Change), late-in-the-shift Karolinska Sleepiness Scale score, and overall Global Assessment of Functioning score. Tolerability was assessed. Results: Patients receiving armodafinil showed significant improvements in late-in-shift clinical condition, wakefulness, and global functioning, compared to placebo at final visit. Armodafinil was generally well tolerated. Conclusions: Armodafinil improved clinical condition and wakefulness late in the night shift of patients with shift work disorder. Overall patient functioning was also improved.

The Effect of Armodafinil on Patient-Reported Functioning and Quality of Life in Patients With Excessive Sleepiness Associated With Shift Work Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE To examine whether treatment with armodafinil for 6 weeks affected patient-reported overall functioning and daily quality of life compared with placebo in patients with excessive sleepiness associated with shift work disorder. METHOD This 6-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 45 sleep centers across the United States between February and October 2010. Patients included in the study were 18 to 65 years of age and diagnosed with excessive sleepiness associated with shift work disorder on the basis of the International Classification of Sleep Disorders: Diagnostic and Coding Manual, Second Edition and DSM-IV-TR criteria. These patients also experienced late-in-shift sleepiness between 4 AM and 8 AM (Karolinska Sleepiness Scale score ≥ 6) and were functionally impaired (Global Assessment of Functioning score < 70). Patients were administered 150 mg of armodafinil or placebo on nights worked, and efficacy measures included changes in patient-reported overall functioning (modified Sheehan Disability Scale [SDS-M]) and daily quality of life (10-question Functional Outcomes of Sleep Questionnaire [FOSQ-10]). RESULTS Patients treated with armodafinil had significantly greater improvement in SDS-M composite scores at final visit (last observation carried forward) (-6.8 vs -4.5, respectively, P = .0027) than those receiving placebo. Although the armodafinil group, compared to the placebo group, showed a greater improvement in total FOSQ-10 score from baseline to final visit (+3.4 vs +2.7, respectively, P = .0775), a statistically significant improvement was observed only at week 6 (+3.6 vs +2.7, respectively, P = .0351). CONCLUSIONS These findings are consistent with our previous report on clinician-rated measures of efficacy by demonstrating that armodafinil improves patient-rated functioning in patients with shift work disorder. Additionally, the current findings show for the first time that armodafinil may have benefits on quality of life after 6 weeks of treatment. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01080807.

A randomized, double-blind, single-dose, placebo-controlled, multicenter, polysomnographic study of gabapentin in transient insomnia induced by sleep phase advance.

STUDY OBJECTIVES To evaluate the effects of single doses of gabapentin 250 and 500 mg on polysomnographic (PSG) and participant-reported sleep measures in a 5-h phase advance insomnia model. METHODS Adults reporting occasional disturbed sleep received gabapentin 500 mg (n = 125), 250 mg (n = 125), or placebo (n = 127) 30 min prior to bedtime and were in bed from 17:00 to 01:00, ∼5 h before their habitual bedtime. Sleep was assessed by PSG, post-sleep questionnaire, and the Karolinska Sleep Diary (KSD). Next-day residual effects (Digit Symbol Substitution Test [DSST] and Stanford Sleepiness Scale [SSS]) and tolerability were assessed. RESULTS Demographics were comparable among groups. Among PSG endpoints, wake after sleep onset (primary endpoint) (135.7 [placebo], 100.7 [250 mg], and 73.2 [500 mg] min) was significantly lower and total sleep time (TST) (311.4, 356.5, and 378.7 min) significantly greater in both gabapentin groups versus placebo. Latency to persistent sleep was not significantly different among groups. Percent slow wave sleep (12.6%, 15.4%, and 17.0%, respectively) was significantly greater and percent stage 1 (15.1%, 11.8%, and 10.8%, respectively) significantly lower relative to placebo. Gabapentin was associated with significantly higher values of KSD Sleep Quality Index and reported TST versus placebo; no other reported outcomes were significant. Neither gabapentin dose produced evidence of next-day residual effects as measured by DSST and SSS. Adverse events were infrequent (< 5%). CONCLUSION Participants with occasional disturbed sleep treated with gabapentin showed significantly longer sleep duration and greater depth (versus placebo) in response to a phase advance manipulation known to disrupt sleep maintenance.