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.

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.

A polysomnographic placebo-controlled evaluation of the efficacy and safety of eszopiclone relative to placebo and zolpidem in the treatment of primary insomnia.

STUDY OBJECTIVES: To evaluate the polysomnographic efficacy and the safety of a range of doses of eszopiclone relative to placebo in patients with primary insomnia. Zolpidem 10 mg was included as an active control. METHODS: This multicenter, randomized, crossover study enrolled patients aged 21-64 years meeting the DSM-IV criteria for primary insomnia (n = 65). Patients received 2 nights treatment each with placebo, eszopiclone 1 mg, 2 mg, 2.5 mg, or 3 mg, and zolpidem 10 mg after randomization to one of 6 treatment sequences. Visits were separated by a 3-7 day washout. Objective efficacy was assessed by polysomnography (PSG). The primary endpoint was latency to persistent sleep (LPS); key secondary endpoints were sleep efficiency (SE) and wake time after sleep onset (WASO); other endpoints included wake time during sleep (WTDS) and number of awakenings (NAW), as well as patient-reported variables. RESULTS: LPS and SE were significantly different than placebo for all active treatments (p < 0.05 for all). Significant differences from placebo were noted in the 3 objective sleep maintenance measures (WASO, WTDS, and NAW) for eszopiclone 3 mg (p < 0.05), which was not the case for zolpidem 10 mg or the other eszopiclone doses. The incidence of central nervous system adverse events was 23.4% for zolpidem 10 mg, 6.2% to 12.5% for the eszopiclone doses, and 7.9% for placebo. CONCLUSIONS: Relative to placebo, all active treatments were effective in reducing LPS and increasing SE. Eszopiclone 3 mg was significantly different from placebo on the 3 PSG measures of sleep maintenance (WASO, WTDS, and NAW). Significant differences between zolpidem 10 mg and eszopiclone (2 mg or 3 mg) were not observed for PSG-measured outcomes, although the study was not powered to detect differences between the active drug conditions.

Evaluation of the safety of modafinil for treatment of excessive sleepiness.

STUDY OBJECTIVES: Modafinil is a wake-promoting agent shown to improve wakefulness in patients with excessive sleepiness (hypersomnolence) associated with shift work sleep disorder, obstructive sleep apnea, or narcolepsy. Safety and tolerability data from 6 randomized, double-blind, placebo-controlled studies were combined to evaluate modafinil across these different patient populations. METHODS: One thousand five hundred twenty-nine outpatients received modafinil 200, 300, or 400 mg or placebo once daily for up to 12 weeks. Assessments included recording of adverse events and effects of modafinil on blood pressure/heart rate, electrocardiogram intervals, polysomnography, and clinical laboratory parameters. RESULTS: Two hundred seventy-three patients with shift work sleep disorder, 292 with obstructive sleep apnea, and 369 with narcolepsy received modafinil; 567 received placebo. Modafinil was well tolerated versus placebo, with headache (34% vs 23%, respectively), nausea (11% vs 3%), and infection (10% vs 12%) the most common adverse events. Adverse events were similar across all patient groups. Twenty-seven serious adverse events were reported (modafinil, n = 18; placebo, n = 9). In modafinil-treated patients, clinically significant increases in diastolic or systolic blood pressure were infrequent (n = 9 and n = 1, respectively, < 1% of patients). In the studies, 1 patient in the modafinil group and 1 in the placebo group had a clinically significant increase in heart rate. New clinically meaningful electrocardiogram abnormalities were rare with modafinil (n = 2) and placebo (n = 4). Clinically significant abnormalities in mean laboratory parameters were observed in fewer than 1% of modafinil-treated patients at final visit. Modafinil did not affect sleep architecture in any patient population according to polysomnography. CONCLUSIONS: Modafinil is well tolerated in the treatment of excessive sleepiness associated with disorders of sleep and wakefulness and does not affect cardiovascular or sleep parameters.

Prevalence of sleep apnea in a population of adults with type 2 diabetes mellitus.

OBJECTIVE: To assess the prevalence of sleep apnea (SA) in adults with type 2 diabetes mellitus (T2DM) and examine whether demographics and comorbid factors were associated with SA in this population. METHODS: This study enrolled 330 consecutive adults with T2DM referred to a diabetes clinic, 279 of whom completed the study. Evaluation of the presence of SA was performed with use of a single-channel recording device that measures disordered breathing events from a nasal cannula airflow signal. The device was worn by the study participants in their home, after instruction in appropriate use by clinical staff at the diabetes center. The presence and severity of SA were determined by use of an apnea-hypopnea index (AHI), reflecting periods of diminished and absent breathing. Demographic and medical information data were collected to detect factors associated with SA in this study population. In addition, a time and cost analysis was conducted regarding the screening process for SA by clinical staff at the diabetes center. RESULTS: The results show a high prevalence of SA in adults with T2DM, ranging from 48% (AHI level of >or=10 events/h) to 29% (AHI level of >or=20 events/h). At an AHI cutoff value of >or=15 events/h, the overall prevalence rate was 36% (49% in male and 21% in female participants). The following variables were associated with SA: age >or=62 years, male sex, body mass index >or=30 kg/m2, snoring, and reports of stopping breathing during sleep. The time and cost analysis showed that the screening device involved minimal setup time, was simple to use, and was a cost-effective method to screen for SA. CONCLUSION: SA is a common disorder associated with major morbid conditions, including hypertension, obesity, cardiovascular disease, and insulin resistance. Predisposing factors for SA and T2DM are similar. This study showed that SA has a high prevalence in adults with T2DM and identified factors that may be associated with its presence in this population. Assessment for SA can be easily performed in an outpatient setting with a portable recording device such as the one used in this study. Screening for SA should be considered in the T2DM population.

Validation of the ApneaLink for the screening of sleep apnea: a novel and simple single-channel recording device.

STUDY OBJECTIVES: Screening for sleep apnea may be useful in a number of settings, such as preoperative testing, clinical research, and evaluation for referral to a sleep center. The purpose of the study was to validate the ApneaLink device (ResMed Corporation, Poway, Calif) for use as a screening tool for sleep apnea in clinical practice. METHODS: The ApneaLink device is a single-channel screening tool for sleep apnea that measures airflow through a nasal cannula connected to a pressure transducer, providing an apnea-hypopnea index (AHI) based on recording time. We compared the AHI from the ApneaLink device to that obtained during simultaneously conducted attended sleep-laboratory polysomnography to assess the sensitivity and specificity of the device in consecutive subjects with type 2 diabetes mellitus referred from a diabetes clinic. We also compared the AHI obtained from the ApneaLink device during a study in the subjects' homes to that obtained during the in-laboratory study. The laboratory study was performed within 2 weeks of the home study. RESULTS: Fifty-nine subjects completed the study. Mean age of subjects was 57 years; mean body mass index was 33 kg/m2. The results demonstrate a high sensitivity and specificity of the at-home ApneaLink AHI compared with the AHI from the simultaneous polysomnographic study at all AHI levels, with the best results at an AHI of > or =15 events per hour (sensitivity 91%, specificity 95%). The AHI comparison from the home and laboratory studies also demonstrates good sensitivity and specificity at AHI levels of > or =15 and > or =20 events per hour (sensitivity 76%, specificity 94%, for both). CONCLUSIONS: Given the prevalence of sleep apnea in the adult population and in specific comorbid conditions, a screening tool may be useful in many diagnostic settings. This study demonstrates that the ApneaLink device provides reliable information, is a simple, easy-to-use device, and is highly sensitive and specific in calculating AHI, when compared with the AHI obtained from full polysomnography.

Modafinil for excessive sleepiness associated with chronic shift work sleep disorder: effects on patient functioning and health-related quality of life.

OBJECTIVE: We evaluated the effects of modafinil, a wake-promoting agent, on patient functioning, health-related quality of life, and nighttime and daytime sleep in patients with excessive sleepiness associated with shift work sleep disorder (SWSD). METHOD: A 12-week, randomized, double-blind, placebo-controlled study was performed at 31 centers in the United States between February 2001 and March 2002. Adults (N = 278) with excessive sleepiness associated with chronic SWSD (International Classification of Sleep Disorders criteria) were randomly assigned to receive modafinil 200 or 300 mg or placebo, 30 to 60 minutes before each night shift. Effects on patient functioning and quality of life were assessed using the Functional Outcomes of Sleep Questionnaire (FOSQ) and the 36-item Short Form Health Survey (SF-36), respectively. Daily patient diaries were used as a sleep log. RESULTS: Modafinil 300 mg significantly improved mean FOSQ total score relative to placebo (2.3-point increase from baseline vs. 1.6 for placebo; p < .05). Both doses of modafinil significantly improved mean SF-36 mental component scores relative to placebo (mean changes from baseline of 3.2, 3.7, and 0.7 points in the modafinil 300-mg, modafinil 200-mg, and placebo groups, respectively; p < .05 for each comparison vs. placebo). Modafinil did not adversely affect sleep when sleep was desired or caffeine use. Modafinil was well tolerated. Headache (21.5%) and nausea (12.4%) were the most common adverse events in modafinil-treated patients. Differences between modafinil and placebo for vital sign measurements, physical examination findings, or electrocardiography results were not clinically meaningful. CONCLUSIONS: Modafinil significantly improves functioning and quality of life in patients with SWSD. Modafinil is an effective treatment for excessive sleepiness associated with SWSD.

Selected sleep disorders: restless legs syndrome and periodic limb movement disorder, sleep apnea syndrome, and narcolepsy.

Sleep disorders, including restless legs syndrome and periodic limb movement disorder, sleep apnea syndrome, and narcolepsy, are prevalent medical conditions, likely to be seen by practicing psychiatrists. Awareness of these conditions and their presentations, pathophysiology, and treatment allows psychiatrists to treat these conditions where appropriate, to minimize complications and health consequences associated with delayed diagnosis, and to reduce the burden of disease that these conditions may place on patients already experiencing primary psychiatric disorders.

Therapeutic options in the treatment of insomnia.

Pharmacologic and nonpharmacologic therapies both have roles in the treatment of insomnia. The benzodiazepines, when first introduced, were a major improvement over earlier treatments for insomnia in terms of their safety and efficacy. Since then, the nonbenzodiazepine benzodiazepine receptor agonists have been developed, which have provided advantages over the older medications and are currently first-line medication treatment for insomnia. Although antidepressants, antipsychotics, and anticonvulsants are often prescribed for the treatment of insomnia, they are not approved by the U.S. Food and Drug Administration for this indication and have side effects that are sometimes severe. New types of medications that have different modes of action from the benzodiazepine receptor agonists are now being developed, and one, a selective melatonin receptor agonist, has recently been approved for treatment of insomnia. Nonpharmacologic therapies can also help patients learn how to fall asleep faster and improve sleep quality. It is important for physicians to teach patients good sleep hygiene as part of their treatment. Cognitive-behavioral therapy is effective in the treatment of insomnia, alone and in combination with pharmacotherapy, but finding a qualified provider can be difficult and the patient must be willing to take the time to learn the therapies and wait for them to show effect.

Effects of temazepam 7.5 mg and temazepam 15 mg on sleep maintenance and sleep architecture in a model of transient insomnia.

OBJECTIVE: To compare the effects of temazepam 7.5 mg and temazepam 15 mg on sleep maintenance during the last third of the night (last 160 min) and on sleep architecture throughout the night. RESEARCH DESIGN AND METHODS: This was a retrospective analysis of a previously reported double-blind, randomized, uncontrolled, parallel-group, multicenter study. Healthy subjects with previous but no current complaints of transient insomnia were enrolled. Transient insomnia was induced in the sleep laboratory by means of the 'first night' effect and by implementing a 2-h phase advance. The effects of both doses of temazepam on polysomnographic measures of sleep were evaluated for 1 night. The primary, prospectively-defined analysis of this study showed that 7.5-mg and 15-mg doses of temazepam had equivalent effects on latency to persistent sleep, total sleep time, and the number of sleep interruptions recorded over an 8-h period. Both doses were well tolerated. The post hoc analysis reported here compared these 2 doses for their effects on sleep maintenance and architecture. Sleep efficiency during the last third of the night was designated as the primary endpoint. The methodology for this analysis was fully defined and documented prior to re-analysis of the database for these parameters. RESULTS: Sixty-five subjects received temazepam 7.5 mg and 66 received temazepam 15 mg. No statistically significant differences between doses were detected for sleep efficiency or number of sleep interruptions during the last third of the night. Sleep architecture (measured over 8 h) did not differ significantly between groups. CONCLUSIONS: The 7.5-mg and 15-mg doses of temazepam were equally effective for maintaining sleep during the last third of the night. Continuity of sleep throughout the night, as reflected by sleep architecture, was also similar regardless of dose. In keeping with current practice guidelines, initiation of treatment with temazepam for transient insomnia should begin with the 7.5 mg dose.

Comparison of temazepam 7.5 mg with temazepam 15 mg for the treatment of transient insomnia.

OBJECTIVE: To demonstrate the equivalent efficacy of temazepam 7.5 mg and temazepam 15 mg for the treatment of transient insomnia. RESEARCH DESIGN AND METHODS: This was a double-blind, parallel group, multicenter study. Healthy male and female subjects with previous but not current complaints of transient insomnia were enrolled. Transient insomnia was induced in the sleep laboratory by means of the 'first night' effect and by implementing a 2-h phase advance. The effects of both doses of temazepam on polysomnographic (PSG) measures of sleep were evaluated for one night. Latency to persistent sleep (LPS) and total sleep time (TST) were designated as the primary efficacy endpoints. RESULTS: One hundred and thirty-one subjects completed the study: 65 received the 7.5-mg dose, and 66 received the 15-mg dose. Treatment groups begin with the lowest effective dose, i.e., 7.5 mg. were well matched based on background demographics. No statistically significant differences between doses were detected for LPS, TST,or any other objective (PSG) measure of sleep. Furthermore, both doses were found to be clinically equivalent for LPS and TST based on predetermined criteria. Temazepam was well tolerated, and no significant differences between doses were found for adverse event (AE) incidence, mean score on the Digit Symbol Substitution Task, or mean scores on questions related to tolerability from the Leeds Sleep Evaluation Questionnaire. CONCLUSIONS: The 7.5-mg and 15-mg doses of temazepam were equally effective for the treatment of transient insomnia. In keeping with current practice guidelines, initiation of treatment with temazepam for transient insomnia should

Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea: a 12-week, open-label study.

STUDY OBJECTIVES: The purpose of this 12-week study was to evaluate the efficacy and safety of adjunct modafinil to treat excessive sleepiness in patients with obstructive sleep apnea (OSA) who experience residual sleepiness despite regular nasal continuous positive airway pressure (nCPAP) use. DESIGN: Twelve-week, open-label trial. SETTING: Twenty-two centers in the United States. PATIENTS: We studied 125 patients with moderate-to-severe OSA (ie, respiratory disturbance index > or =15) before nCPAP therapy and residual daytime sleepiness (Epworth sleepiness scale [ESS] score > or =10) despite effective and regular nCPAP therapy. Patients were studied after completing a 4-week, double-blind, placebo-controlled trial of nCPAP plus modafinil for the treatment of residual daytime sleepiness. INTERVENTIONS AND MEASUREMENTS: Patients received individually titrated doses of modafinil (200 to 400 mg qd). Sleepiness was assessed using the ESS, quality of life was evaluated using the Functional Outcomes of Sleep Questionnaire (FOSQ), and the overall clinical effect was indexed using the clinical global impression of change scale. Adverse events, nCPAP use, and vital sign measurements were also recorded. RESULTS: The significant improvements in daytime wakefulness and sleep-related functional status observed with modafinil treatment during the 4-week, double-blind study were maintained throughout 12 weeks of open-label treatment: week 12 ESS, 7.8 (4.7) vs 14.4 (3.1) at double-blind baseline; week 12 FOSQ, 3.3 (0.6) vs 14.4 (2.7) at double-blind baseline (mean [SD]). The percentage of patients rated as clinically improved increased from 83% after 1 week to > or =93% after 2 to 12 weeks of open-label treatment. Mean (SD) nCPAP use decreased from 6.3 (1.3) h/night at baseline to 5.9 (1.4) h/night (p = 0.004) during open-label treatment. The most common adverse events were headache (28%), anxiety (16%), and nervousness (14%). CONCLUSIONS: Modafinil remained effective and well tolerated as an adjunct therapy for residual daytime sleepiness even after 12 weeks of daily dosing in patients with OSA receiving nCPAP therapy.

Comparative efficacy of zolpidem and temazepam in transient insomnia.

This study compared hypnotic effects of zolpidem 10 mg, temazepam 15 mg and placebo in healthy adults. Two factors expected to promote insomnia, the 'first night effect' and a 2-hour phase advance, were combined in a single night laboratory-based double-blinded protocol. This was a multi-center study, with data collected in 13 sleep laboratories. Subjects with normal sleep histories and without prior sleep laboratory experience were randomly assigned to treatment groups. Medications were administered 15 min before lights out, with polysomnographic monitoring for 7.5 h. Subjective questionnaires and performance tests, digit symbol substitution test (DSST) and symbol copying test (SCT), were administered at study entry and after arising. 630 subjects completed the study and provided data analyzed using repeated measures ANOVAs. Neither agent significantly reduced objective sleep latency relative to placebo. Zolpidem reduced awakenings and wake after sleep onset (WASO); temazepam did not. Both agents improved sleep efficiency and most subjective sleep measures relative to placebo, with zolpidem superior for five of six subjective outcome measures compared to temazepam. SCT, morning sleepiness and morning concentration were not altered by any treatment. Zolpidem significantly reduced morning DSST performance; temazepam did not. Zolpidem 10 mg provided greater subjective hypnotic efficacy than temazepam 15 mg in this model of transient insomnia, with reduced polysomnographic awakenings and WASO. Impairment of DSST was seen with zolpidem but not temazepam. Copyright 2001 John Wiley & Sons, Ltd.