Individualizing therapy for early, middle-of-the-night and late-night insomnia.

Many patients with insomnia describe their sleep problems as an inability to remain asleep throughout the night, resulting in next-day fatigue that may adversely affect daytime functioning. To be most effective, insomnia treatment should be tailored to resolving underlying causes of the condition and managing specific sleep complaints. Therefore, hypnotic therapy administered prior to bedtime, as is currently recommended for most compounds, is not appropriate for all insomnia patients. Ideally, behavioral interventions should be combined with a rapid-acting agent that can be administered at virtually any time during the night without producing residual effects the following day. Zaleplon, a new non-benzodiazepine sleep medication, provides the clinician with an effective and safe pharmacotherapeutic option for insomnia management. Its rapid rates of absorption and elimination allow for treatment of symptoms when they occur, either at bedtime or later at night, without incurring significant risk for the development of next-day impairment of psychomotor and cognitive functioning.

Lack of residual sedation following middle-of-the-night zaleplon administration in sleep maintenance insomnia.

The present randomized, double-blind, placebo and active-drug controlled, crossover study assessed residual sedation after zaleplon 10 mg, flurazepam 30 mg (as an active control), and placebo, taken during a nocturnal awakening in patients with sleep maintenance insomnia. Twenty-two healthy sleep maintenance insomniacs (11 men; mean age, 42 y) received zaleplon, flurazepam, or placebo after an experimental awakening 3.5 hours after bedtime on two consecutive nights in each of three conditions. Residual sedation was measured with sleep latency testing (5 and 6.5 h postdrug), digit symbol substitution, symbol copying, and subjective sleepiness by visual analog scale, each twice each morning. Zaleplon did not differ from placebo on any measure of residual sedation; flurazepam showed significant sedation on all measures. No residual sedative effects were detected 5 or 6.5 hours after ingestion of zaleplon during the middle of the night by sleep maintenance insomniacs.

Zolpidem for persistent insomnia in SSRI-treated depressed patients.

BACKGROUND: Depressed individuals effectively treated with selective serotonin reuptake inhibitors (SSRIs) often report persistent insomnia and require adjunctive sleep-promoting therapy. METHOD: Men (N = 40) and women (N = 150) with a mean age of 41.6 years who had persistent insomnia in the presence of effective and stable treatment (at least 2 weeks) with fluoxetine (< or =40 mg/day), sertraline (< or =100 mg/day), or paroxetine (< or =40 mg/day) for DSM-IV major depressive disorder, dysthymic disorder, or minor depressive disorder of mild-to-moderate severity (and score of < or =2 on item 3 of the Hamilton Rating Scale for Depression [HAM-D]) participated in this randomized, double-blind, parallel-group study. At study entry, patients were required to score < or =12 on the HAM-D. During a 1-week single-blind placebo period, patients had to report on at least 3 nights a latency of > or =30 minutes or a sleep time of <6.5 hours and clinically significant daytime impairment. Patients received either placebo (N = 96) or zolpidem, 10 mg (N = 94) nightly, for 4 weeks and single-blind placebo for 1 week thereafter. Sleep was measured with daily questionnaires and during weekly physician visits. RESULTS: Compared with placebo, zolpidem was associated with improved sleep: longer sleep times (weeks 1 through 4, p<.05), greater sleep quality (weeks 1 through 4, p<.01), and reduced number of awakenings (weeks 1, 2, and 4; p<.05), together with feeling significantly more refreshed, less sleepy, and more able to concentrate. After placebo substitution, the zolpidem group showed significant worsening relative to pretreatment sleep on the first posttreatment night in total sleep time and sleep quality, reverted to pretreatment insomnia levels on the other hypnotic efficacy measures, or maintained improvement (fewer number of awakenings). There was no evidence of dependence or withdrawal from zolpidem (DSM-IV criteria). Incidence rates of adverse events were similar in both treatment groups (74% and 83% for placebo and zolpidem, respectively), but 7 zolpidem patients discontinued compared with 2 placebo patients. CONCLUSION: In this defined patient population, zolpidem, 10 mg, was effectively and safely co-administered with an SSRI, resulting in improved self-rated sleep, daytime functioning, and well-being.

Evaluation of sleep architecture and cyclic alternating pattern rates in depressed insomniac patients treated with nefazodone hydrochloride.

The standard methods of scoring sleep patterns do not ensure an accurate clinical impression of sleep quality. This is important especially in depressed insomniacs because persistent poor sleep increases the likelihood of recurrent depressive episodes. Changes in cyclic alternating patterns (CAP) in sleep have been shown to reflect corresponding changes in sleep quality. We evaluated the effects of nefazodone on CAP and standard sleep architecture in depressed insomniacs. The study was a single-center, single-blind, 6-week treatment of nefazodone hydrochloride followed by placebo withdrawal in 16 subjects meeting the DSM-IV criteria for depression who had a score of at least 18 on the 17-item Hamilton Depression Rating Scale, with insomnia-related items 4, 5, and 6 having a total score of 3 or greater. A mean daily dose of 339.1 +/- 141.7 mg at endpoint of nefazodone significantly reduced Hamilton Depression Scores from 21.7 +/- 3.0 on baseline to 5.8 +/- 5.3 (P <.05) by the end of the study. Polysomnography showed an improvement in sleep latency and sleep efficiency (P <.05), but no alterations in rapid-eye-movement or slow-wave sleep. Subjective estimates of sleep quality improved throughout the study, but CAP rates did not show a significant improvement. The disparity between CAP rates and sleep quality in depressed insomniacs is discussed.

Outcome evaluation of long-term nasal continuous positive airway pressure therapy in obstructive sleep apnea.

A study was conducted at the Tri-State Sleep Disorders Center of Cincinnati, Ohio, to evaluate both quantitative and qualitative daily function and productivity outcomes of treating obstructive sleep apnea (OSA) with nasal continuous positive airway pressure (NCPAP). This was a prospective outcome study conducted in 316 patients with diagnosed and treated OSA. There were 234 men and 82 women, mean age, 48.79 +/- 0.67 years; weight averaged 250.39 +/- 3.55 pounds; mean pretreatment respiratory disturbance index was 42.9 +/- 1.7 episodes per hour and 2.8 +/- 0.2 episodes per hour with NCPAP treatment. Patients were surveyed by questionnaire, administered on polysomnographic confirmation of OSA and after 6 months of nightly treatment with NCPAP as to their perceptions of their level of daytime functioning and quality of life over the previous 6 months. Main outcome measures included number of incidents of excessive daytime sleepiness; number of headaches on awakening; number of automobile accidents and near-miss automobile accidents; number of days absent from work; number of physician visits; and a series of subjective scales, measuring job productivity, quality of life, general physical and mental condition, short-term memory, and changes in blood pressure. Significant decreases were found in the number of incidents of excessive daytime sleepiness, headaches on awakening, physician visits, days absent from work, and automobile accidents or near misses with NCPAP therapy. Patients also reported subjective increases in productivity, quality of life, physical and mental condition, and short-term memory and reduction in both diastolic and systolic blood pressure. Effective treatment of OSA results in improvement both in preexisting symptoms and in quality of life. Improvement in many of the major problems experienced by patients seeking treatment has important implications for preventive medicine as well as health care cost containment.

Diagnostic and treatment implications of nasal obstruction in snoring and obstructive sleep apnea.

LEARNING OBJECTIVES: The purpose of this review is to highlight fundamental aspects of obstructive sleep apnea (OSA), and to present an overview of the medical literature that pertains to the clinical interplay between various allergy-related disorders, nasal patency, and OSA. This should enable the reader to play a more proactive role in the diagnosis, management, and prevention of OSA. DATA SOURCES: Relevant reviews, texts, and articles. The MEDLINE database was used to find related literature. CONCLUSIONS: In predisposed individuals, OSA, sleep fragmentation, and the sequelae of disturbed sleep often result from nasal obstruction. Since breathing through the nose appears to be the preferred route during sleep, nasal obstruction frequently leads to nocturnal mouth breathing, snoring, and ultimately to OSA. Allergists can thus play a vital role in assessing sleep problems in their patients with allergic rhinitis and other upper respiratory disorders, in treating these problems more aggressively, and in some instances, in preventing them.

Effect of gamma-hydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with fibromyalgia. Preliminary report.

OBJECTIVE: To evaluate the effects of using a gamma-hydroxybutyrate (GHB) administered in divided doses at night in 11 patients previously diagnosed with fibromyalgia (FM). METHODS: Subjects completed daily diaries assessing their pain and fatigue levels and slept in the sleep laboratory before and one month after initiating GHB treatment. Polysomnographic recordings were evaluated for sleep stages, sleep efficiency and the presence of the alpha anomaly in non-REM sleep. RESULTS: There was a significant improvement in both fatigue and pain, with an increase in slow wave sleep and a decrease in the severity of the alpha anomaly. CONCLUSION: Further controlled studies are needed to characterize the clinical improvement and the polysomnographic changes we observed.

Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients.

Sodium gammahydroxybutyrate (GHB) is an endogenous compound that has been under investigation in the management of narcolepsy for about two decades. The data confirm that GHB treatment decreases daytime sleepiness and episodes of cataplexy, sleep paralysis, and hypnagogic hallucinations. The current study evaluated the pharmacokinetics of GHB, given twice in one night to six narcoleptic patients who had been chronically taking GHB nightly on a similar basis. Results confirmed earlier reports and showed nonlinear pharmacokinetics. Maximum concentrations were reached in 40 +/- 6.2 and 35.7 +/- 7 minutes after the first and second dose respectively. Mean AUCinf was 17731.6 +/- 4867 mg/mL/m. Mean GHB T1/2 was 53 +/- 19 minutes. GHB elimination appears to be capacity-limited in some patients when administered at a fixed dose of 3 g twice nightly at a 4-hour interval.

Simultaneous stimulation of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate in normal young Men.

The aim of this study was to investigate, in normal young men, whether gamma-hydroxybutyrate (GHB), a reliable stimulant of slow-wave (SW) sleep in normal subjects, would simultaneously enhance sleep related growth hormone (GH) secretion. Eight healthy young men participated each in four experiments involving bedtime oral administration of placebo, 2.5, 3.0, and 3.5 g of GHB. Polygraphic sleep recordings were performed every night, and blood samples were obtained at 15-min intervals from 2000 to 0800. GHB effects were mainly observed during the first 2 h after sleep onset. There was a doubling of GH secretion, resulting from an increase of the amplitude and the duration of the first GH pulse after sleep onset. This stimulation of GH secretion was significantly correlated to a simultaneous increase in the amount of sleep stage IV. Abrupt but transient elevations of prolactin and cortisol were also observed, but did not appear to be associated with the concomitant stimulation of SW sleep. Thyrotropin and melatonin profiles were not altered by GHB administration. These data suggest that pharmacological agents that reliably stimulate SW sleep, such as GHB, may represent a novel class of powerful GH secretagogues.

Minimal rebound insomnia after treatment with 10-mg zolpidem.

This study examined rebound insomnia after discontinuation of chronic use of zolpidem (10 mg), a short elimination half-life imidazopyridine. The zolpidem group was bracketed by a placebo group and a positive control group taking 0.5 mg of triazolam (twice the recommended dose), which is known to produce rebound insomnia. Ninety-nine patients with sleep complaints that were polysomnographically documented participated in the study. After randomization, patients completed a 2-night, single-blind, placebo baseline period, a 28-night double-blind treatment phase, and a 3-night, single-blind, placebo substitution period. Polysomnographic and subjective sleep variables indicated a lack of rebound insomnia for the zolpidem group. The positive triazolam control group had rebound insomnia only on the first discontinuation night. There was no significant correlation between rebound insomnia and the level of initial insomnia, the degree of response to treatment in week 4, or the amount of tolerance that developed during drug use. During the 4-week treatment period, efficacy diminished for both drugs. From these data, it cannot be determined whether the lack of rebound insomnia with zolpidem is a result of drug dose or some property of the drug such as receptor selectivity.

Effects of estrogen replacement therapy on rates of cyclic alternating patterns and hot-flush events during sleep in postmenopausal women: a pilot study.

The objective of this pilot study was to evaluate the effects of conjugated estrogens on the rates of cyclic alternating patterns of sleep (CAPS) and nocturnal hot flushes in symptomatic postmenopausal women. Seven postmenopausal or posthysterectomy women aged 45 to 60 years with nocturnal diaphoresis and/or hot flushes participated in this study. The study was conducted with a single-masked design using a matching placebo. The placebo baseline was followed by a 4-week, single-masked treatment of conjugated estrogens 0.625 mg taken 4 hours before bedtime. Each patient's sleep was monitored in the laboratory for 3 consecutive nights during placebo baseline and again for 3 consecutive nights after an at-home period of at least 24 days of estrogen replacement therapy. Estrogen therapy resulted in a statistically significant decrease in the overall number of hot flushes and the number of hot hot flushes associated with awakenings, as well as improvement in sleep efficiency and a reduction in the rate of CAPS. These data confirm earlier well-established reports that estrogens reduce the frequency of hot flushes and suggest that the frequency of nocturnal arousals decreases and sleep quality improves in conjunction with a reduction in the rate of CAPS.

Comparative effects of sleep on a standard mattress to an experimental foam surface on sleep architecture and CAP rates.

The comparative effects of sleep patterns and rates of cyclic alternating patterns (CAP rate) in a high quality innerspring mattress were compared to those on a unique foam support mattress in 10 normal subjects. Results showed no differences in sleep stages, number of wakes, or total sleep time between the two conditions. CAP rates were significantly reduced on the foam surface. CAP rate was sensitive to the first-night effect on both surfaces, but was blunted on the foam mattress.

Effects of an external nasal dilator on sleep and breathing patterns in newborn infants with and without congestion.

BACKGROUND: We recently demonstrated that the use of an external nasal dilator reduced subjective snoring levels and improved sleep quality. Our study polysomnographically evaluated the effects of this device on the frequency of obstructive airway events during sleep in infants with and without congestion. METHODS: We used a crossover study to monitor 20 infants between the ages of 2 and 4 months (15 infants without congestion and 5 with congestion). Monitoring was conducted during two daytime sleep sessions in a crossover study in which infants slept with or without a cutdown version of an external nasal dilator (Breathe Right Nasal Strips, CNS, Inc., Bloomington, Minn.) in the first session with crossover to the other condition in the second session. A respiratory disturbance index consisting of apneas (pauses in respiration of at least 8 seconds) or hypopneas (decreased airflow resulting in oxygen desaturation of at least 3%) was determined. RESULTS: Babies without congestion showed a greater than 50% reduction in respiratory disturbance index from 3.2 +/- 2.8 to 1.2 +/- 1.2 events per hour (p < 0.005). Congested infants showed a decrease from 6.9 +/- 2.9 to 1.5 +/- 1.6 events per hour (p < 0.05). Babies with the greatest number of events showed the greatest improvement. CONCLUSION: The use of an external nasal dilator reduces the frequency of obstructive respiratory events in infants.

Cyclic alternating pattern sequences in non-apneic snorers with and without nasal dilation.

A study was conducted to polysomnographically evaluate the effects of external nasal dilation on sleep quality in mild snorers by examining the amount of sleep fragmentation and cyclic alternating pattern sequences (CAPS) rates. A two-night, open-label, one-way crossover polysomnographic evaluation, with and without use of an external nasal dilator, was done at the Tri-State Sleep Disorders Center in Cincinnati, Ohio. Nine snorers, polysomnographically determined to be free of clinically significant levels of obstructive sleep apnea, were studied. CAPS rates with nasal dilation were 28.4% as compared to 37.9% without nasal dilation (p < 0.05). We conclude that external nasal dilation reduces arousal instability in snorers without obstructive sleep apnea.

Computerized adjustable versus fixed NCPAP treatment of obstructive sleep apnea.

An automated positive airway pressure device that monitors respiratory patterns and provides dynamic, real-time, relational pressure has been developed for the treatment of obstructive sleep apnea (OSA). The purpose of this study was to compare self-adjusting pressure to classical nasal continuous positive airway pressure (NCPAP). Subjects were newly diagnosed patients with a minimum respiratory disturbance index (RDI) of 15 episodes per hour who had undergone NCPAP titration and been using classical NCPAP at home on a nightly basis for at least 2 weeks. Patients then underwent repeat standard polysomnographic (PSG) evaluations for 2 nights using a self-adjusting pressure mode and a standard NCPAP mode randomly assigned in a single-blind crossover fashion. Eight males and four females (n = 12), aged 48.4 +/- 12.2 years [mean +/- and standard deviation (SD)], completed the study. During initial diagnostic PSG, the RDI was 57.3 +/- 30.8 episodes per hour. The RDI and minimum oxygen saturation for both treatment nights were significantly improved from those of the diagnostic PSGs (p < 0.001). The subjects spent 63.1 +/- 34.2% of total sleep time below prescribed pressure while on automatic pressure Percent of total sleep time in stage 3/4 sleep was significantly higher during self-adjusting pressure, at 8.6 +/- 7.5%, compared to standard NCPAP, at 4.6 +/- 6.0% (p < 0.05). Computerized adjustable nasal positive airway pressure effectively controls OSA, fluidly providing the minimal pressure necessary to control respiratory events without causing sleep disruption.

A subjective evaluation of a nasal dilator on sleep & snoring.

A noninvasive external nasal dilator device was used by 20 subjects with a history of mild snoring in a 2 week open label study. The baseline assessments were obtained during the first week. Treatment effects were evaluated during the second week. Subjects were evaluated using: pre- and post-sleep questionnaires; Stanford Sleepiness Scales completed at breakfast, lunch and dinner; and post-sleep bed partner questionnaires. All twenty subjects completed the study. A significant number of subjects' scores improved for sleepiness. Mean scores for the subjective assessment for ease of breathing during sleep improved compared to baseline by 25.6%, snoring loudness improved by 34%, sleep quality improved by 21.8%, and the Stanford Sleepiness Scale revealed a 26% reduction in daytime sleepiness.

A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia.

BACKGROUND: Zolpidem is a short-acting, nonbenzodiazepine hypnotic with rapid onset of action. Even though it is not a benzodiazepine, it binds to one of three types of central benzodiazepine receptors, showing selective binding to the type 1 benzodiazepine receptor subtype. Therapeutic hypnotic dosages do not disturb normal sleep patterns (sleep architecture). METHOD: A randomized, double-blind, placebo-controlled, parallel group multicenter trial was conducted to determine the effectiveness of 10 mg and 15 mg of zolpidem in the long-term (35 nights) treatment of chronic insomnia in 75 patients. Sleep stage effects and motor and cognitive effects during the 35-night treatment period and the 3-night posttreatment period were also investigated. RESULTS: Within the first week of treatment, 10 mg of zolpidem had a significant effect on latency to persistent sleep and sleep efficiency. Efficacy was maintained throughout the 35 nights of drug administration. There was no evidence of residual effect with 10 mg of zolpidem. Stage 3-4 sleep was preserved at both the 10-mg and 15-mg zolpidem dosages. There was no evidence of tolerance at either dose and no significant treatment differences between the 10-mg zolpidem group and placebo in latency to persistent sleep or sleep efficiency during the posttreatment period. Also, the 10-mg zolpidem dosage was judged by the patients to have helped them fall asleep. Similar results were observed with the 15-mg zolpidem dosage. However, there were significant decreases in REM sleep at Weeks 3 and 4 with 15 mg of zolpidem compared with placebo. Overall, incidence rates of treatment-emergent adverse events in the zolpidem groups were similar to those in the placebo group. CONCLUSION: This is the first sleep laboratory study using a parallel placebo group to demonstrate efficacy for longer than 4 weeks with a hypnotic agent. In this study 10 mg of zolpidem was found to be safe and effective for the long-term treatment of chronic insomnia, demonstrating hypnotic efficacy without affecting sleep stages or producing tolerance effects, rebound effects, or detrimental effects on psychomotor performance. The 15-mg zolpidem dosage provided no clinical advantage over the 10-mg zolpidem dosage.

Feasibility of an every-other-night regimen in insomniac patients: subjective hypnotic effectiveness of quazepam, triazolam, and placebo.

BACKGROUND: Rebound insomnia, a worsening of sleep difficulty beyond baseline levels, can complicate the physician's attempt to use regularly scheduled drug holidays in the management of insomniac patients. Quazepam, a benzodiazepine with a long half-life, has been shown to exhibit carryover effectiveness for the first night or two following withdrawal. This finding suggests a potential utility for an alternate-night drug regimen in which the withdrawal features of the compound serve as a potential benefit. METHOD: A randomized, double-blind, three-compartment, parallel-group design of 5 weeks' duration, comparing quazepam 15 mg, triazolam 0.5 mg, and placebo, was conducted in 65 insomniac subjects. This study was a nonpolysomnographic study utilizing sleep questionnaires. RESULTS: No differences were noted between quazepam and triazolam on treatment nights. Evidence of carryover effectiveness with quazepam and rebound effects with triazolam were noted on off-treatment nights. CONCLUSION: The efficiency of alternate-night therapy with quazepam should be rigorously evaluated using polysomnographic determinations.

Comparative efficacy and safety of nortriptyline and fluoxetine in the treatment of major depression: a clinical study.

The safety and efficacy of nortriptyline and fluoxetine were compared in a double-blind, randomized, multicenter 5-week trial involving 205 outpatients with acute major depression of moderate severity. Seventy-two nortriptyline and 84 fluoxetine patients completed at least 2 weeks of medication and were included in the efficacy analysis; all patients were evaluated for side effects. Average total scores on the Hamilton Rating Scale for Depression (HAM-D) for both treatment groups declined from 22-23 at baseline to 11.5 at the conclusion of the 5-week period. At Week, 5, 71% of nortriptyline patients and 65% of fluoxetine patients were much or very much improved. Fluoxetine was associated more frequently with nausea (p less than .05), while nortriptyline was associated more frequently with dry mouth (p less than .05). These results are discussed in the context of selecting between nortriptyline and fluoxetine for a particular depressed patient.

Dose response effects of zolpidem in normal geriatric subjects.

The dose-related hypnotic effects and effects on memory, performance, and daytime alertness of zolpidem 5, 10, 15, and 20 mg were compared with those of placebo in 30 elderly non-insomniac volunteers in a randomized, placebo-controlled, three-period crossover study. Subjects were randomized into two groups and received either placebo, zolpidem 5 mg, or zolpidem 15 mg or placebo, zolpidem 10 mg, or zolpidem 20 mg for 2 consecutive nights followed by 1 night of placebo during the same 3 nights of 3 consecutive weeks. Polysomnographic results showed statistically significant decreases in sleep latency and increases in sleep efficiency at all doses. Subjective reports also showed improved sleep latency, total sleep time, and sleep quality. REM percent was slightly decreased at doses of 10 and 20 mg. No consistent effects on memory or performance were observed, and the Multiple Sleep Latency Test showed no effects on daytime sleepines. There was no objective evidence of rebound insomnia upon drug discontinuation.