Sleep Onset Insomnia Research Articles

A new sublingual formulation of zolpidem for the treatment of sleep-onset insomnia

Insomnia is a very frequent complaint that periodically or permanently affects up to 60% of the general population. Valuable therapeutic options rely on pharmacological and nonpharmacological management of insomnia complaints. Zolpidem is one of the most popular hypnotic drugs used to treat insomnia. The drug was synthesized by Synthélabo Recherche in the early 1980s and has proved to be a suitable and well-tolerated drug, especially with regard to efficacy in sleep initiation. The present review focuses on an alternate delivery form of zolpidem, Edluar™, a new sublingual formulation of zolpidem that has been developed for the treatment of sleep-onset insomnia. Studies have shown that Edluar has a faster sleep-induction effect, whereas it did not differ from the oral formulation in terms of sleep maintenance or side effects. This review also discusses the mechanism of action of zolpidem and its pharmacokinetic profile in comparison to Edluar. Efficacy studies in specific settings (such as non-nightly use or use in combination with cognitive behavioral therapy) and particular safety issues encountered with zolpidem use are also discussed.

A randomized controlled trial of intensive sleep retraining (ISR): a brief conditioning treatment for chronic insomnia.

To investigate the effectiveness of intensive sleep retraining in comparison and combination with traditional behavioral intervention for chronic primary insomnia. Seventy-nine volunteers with chronic sleep-onset insomnia (with or without sleep maintenance difficulties) were randomly assigned either to intensive sleep retraining (ISR), stimulus control therapy (SCT), ISR plus SCT, or the control (sleep hygiene) treatment condition. ISR treatment consisted of 50 sleep onset trials over a 25-h sleep deprivation period. Treatment response was assessed with sleep diary, activity monitoring, and questionnaire measures. The active treatment groups (ISR, SCT, ISR+SCT) all resulted in significant improvements in sleep onset latency and sleep efficiency, with moderate to large effect sizes from pre- to post-treatment. Wake time after sleep onset decreased significantly in the SCT and ISR+SCT groups. Total sleep time increased significantly in the ISR and ISR+SCT treatment groups. Participants receiving ISR (ISR, ISR+SCT) experienced rapidly improved SOL and TST during treatment, suggesting an advantage of rapid improvements in sleep in response to ISR. Although there were few statistically significant differences between groups on individual variables, ISR+SCT resulted in consistently larger effect sizes of change than other treatments, including questionnaire measures of sleep quality, sleep self-efficacy, and daytime functioning. The combination treatment group (ISR+SCT) showed trends to outperform other active treatment groups with fewer treatment dropouts, and a greater proportion of treatment responders with 61% reaching "good sleeper" status. Treatment gains achieved at post-treatment in the active treatment groups were largely maintained throughout follow-up periods to 6 months. This 25-hour intensive conditioning treatment for chronic insomnia can produce rapid improvements in sleep, daytime functioning, and psychological variables. Adding ISR to traditional interventions seems to result in a superior treatment response.

Altered Cerebral Perfusion of Motor Cortex in Patients with Periodic Limb Movement Disorder

Address for correspondence Seung Bong Hong, MD, PhD Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea Tel: +82-2-3410-3592 Fax: +82-2-3410-0052 E-mail: ejoo@skku.edu eyuns@paran.com Objectives: The pathophysiology of sleep-related motor diseases and sleep dysfunction in movement disorders is widely unknown as yet. Functional brain imaging, in particular radioisotope techniques, is considered to be powerful tool to investigate pathomechanisms of periodic limb movement disorder (PLMD). Methods: We performed Tc-ethyl cysteinate dimer brain single-photon emission computed tomography in 25 drug-naive patients with PLMD and 23 age-and gender matched normal cotrols during wakefulness. For statistical parametric mapping analysis, single-photon emission computed tomography images were spatially normalized to the standard template and then smoothed using a 14-mm full width at half maximum Gaussian kernel. Results: Mean age of patients and normal controls was 48.6 years and over half of them were male. Most patients reported the sleep onset and maintenance insomnia due to repetitive leg jerks. Average duration of insomnia was 7.5 years. They denied the history of restless leg syndrome and there was no sleep disorders such as obstructive sleep apnea syndrome which was confirmed by polysomnography. Mean PLM during sleep index and movement arousal index were markedly increased to 45.3/hr and 7.5/hr, respectively. Their sleep quality was poorer than that of normal patients. In PLMD patients, cerebral blood flow was significantly increased in the bilateral precentral gyri as compared to normal controls. There was no brain region showing decreased perfusion in patients. Regional cerebral perfusion was not correlated to any polysomnography parameter including PLMS index or movement arousal index. Conclusions: Different perfusion pattern in bilateral primary motor cortices may provide the evidences of motor cortical impairment in patients with PLMD. J Korean Sleep Res Soc 2011;8:35-39

Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures to detect change during a 14-week intervention. Supplemental melatonin improved sleep latency, as measured by actigraphy, in most children at 1 or 3 mg dosages. It was effective in week 1 of treatment, maintained effects over several months, was well tolerated and safe, and showed improvement in sleep, behavior, and parenting stress. Our findings contribute to the growing literature on supplemental melatonin for insomnia in ASD and inform planning for a large randomized trial in this population.

Use of a post-sleep questionnaire-interactive voice response system (PSQ-IVRS) to evaluate the subjective sleep effects of ramelteon in adults with chronic insomnia

Ramelteon is an MT(1)/MT(2) melatonin receptor agonist approved in the US and Japan for the treatment of sleep-onset insomnia. This study evaluated the effects of ramelteon 8mg on patient reported sleep parameters in adults with chronic insomnia in an at-home setting using a post-sleep questionnaire-interactive voice response system (PSQ-IVRS). Adults aged 18-64 years with chronic insomnia were randomized to receive ramelteon 8 mg or placebo nightly for 3weeks. Sleep parameters were assessed via PSQ-IVRS within 60 min of awakening each morning. Adverse effects were collected throughout the study. A total of 552 subjects (mean age 43.2 years) received treatment (274 ramelteon, 278 placebo). There was a reduction in mean sleep latency at weeks 1, 2, and 3 compared with placebo but none reached statistical significance (-4.1 min, p=0.088 week 1; -2.8 min, p=0.258 week 2; -4.9 min, p=0.060 week 3). There were no significant differences between placebo and ramelteon in other PSQ-IVRS sleep parameters. Only headache (18 [6.5%] placebo, 18 [6.6%] ramelteon) and somnolence (5 [1.8%], 12 [4.4%] ramelteon) occurred in>3% of subjects. Use of ramelteon 8 mg in an at-home setting did not demonstrate statistically significant improvements in subjective sleep latency compared with placebo, when measured by PSQ-IVRS.

Restless abdomen

A diagnosis of restless legs syndrome (RLS) requires an urge to move the legs in combination with sensory leg discomfort. Localization of the symptoms to other body areas in the absence of leg involvement is not recognized as part of the phenotypic spectrum of RLS. We describe 3 patients who presented with sensorimotor symptoms confined to the abdominal wall and, with the exception of not involving the legs, satisfied the primary and secondary diagnostic criteria for RLS. Patients underwent detailed clinical history, video-polysomnography, abdominal imaging, and serologic and genotyping assessment. Unpleasant abdominal symptoms emerged at night during periods of rest and were accompanied by an urge to move and temporized by movement. Patients reported sleep onset and sleep maintenance insomnia due to their abdominal symptomatology. Abdominal imaging was normal. Secondary features included periodic leg movements of sleep (PLMS), and dramatic symptom amelioration with the D(2)-D(3) dopaminergic agonist pramipexole. Two subjects were anemic. Conventional RLS emerged in one subject and resolved after dose escalation. Each subject was homozygous for the most common RLS/PLMS-associated risk allele in the BTBD9 gene. Our observations indicate that the restricted abdominal symptomatology manifest in our subjects represents a phenotypic variant of RLS. Physicians should be vigilant to the existence of this unique phenotype when encountering subjects who present with insomnia and abnormal abdominal sensations. Our experience emphasizes the importance of supportive clinical features in rendering a correct diagnosis such that the most cost-effective workups and treatment can be realized.

Melatonin and sleep effects on health, behavior problems and parenting stress

In children with sleep-onset insomnia and delayed dim-light melatonin onset, melatonin treatment not only improves sleep but also health, behavior and parenting stress. The aim of the present study was to see whether the latter effects are dependent on the direct effects on sleep. Data come from 41 children (24 boys, 17 girls; mean age = 9.43 years). They entered melatonin treatment (1–5 mg per day) for three weeks, then discontinued treatment by first taking a half dose for one week, and then stopped completely for another week. Sleep was measured with sleep diaries filled in by parents and with actometers. We found a positive effect of actual sleep duration on health but this disappeared after discontinuing treatment. We also found that melatonin treatment decreased behavior problems, which effect appeared to be stronger for children with an earlier dim-light melatonin onset. These results show that the melatonin effects on health and behavior problems may partly be dependent on sleep.

Event-Related Potentials During the Transition to Sleep for Individuals With Sleep-Onset Insomnia

Event-related potentials may be applied to directly measure information-processing deficits associated with the problem of insomnia. This study is a systematic investigation of cortical hyperarousal during the sleep-onset period in participants with sleep-onset insomnia complaints. Thirteen poor sleepers and twelve good sleepers (GS) were administered an oddball task while awake in the morning and evening and during repeated sleep-onset attempts. Participants signaled detection of a higher pitch target tone as they fell asleep. P2 amplitude was significantly smaller for poor sleepers compared to GS, following standard stimuli at all fronto-central sites, in the pre-sleep waking period at sleep onset. Groups did not differ for N1, N350, or P300 in wake, Stage 1, or Stage 2. The smaller P2 indicates that poor sleepers failed to inhibit the irrelevant standard stimuli. This hyper-attentiveness may explain chronic problems with sleep initiation and could be the target of behavioral and pharmaceutical treatment strategies.

How do pharmacists respond to complaints of acute insomnia? A simulated patient study

It is known that many people with insomnia choose to self medicate and present at community pharmacies, particularly in cases of acute insomnia. The objective of this study is to investigate how community pharmacists respond to complaints of acute insomnia from people who seek self treatment and determine the factors affecting this response. Community pharmacies in New South Wales, Australia. A simulated patient study was conducted in 100 randomly selected pharmacies located in Newcastle and Sydney, Australia. A standardized scenario of acute sleep onset insomnia and a scoring system was used in each pharmacy. Main outcome measures included supply/non supply of an over the counter sleep aid to the simulated patient, and scores for pharmacists for skills in eliciting information prior to supply of medication (Pre Supply Score), counseling about medication (Supply Score), or about sleep (Sleep Score). Of the 100 pharmacies, upon simulated patient presentation, 96% supplied a product, the remaining 4% referred to a physician. Non-pharmacological advice was provided in 42%. Pharmacists scored highly on advice provided with supply of a medication (Supply scores/4, 3.1 ± 0.9), but lower on skills in eliciting information prior to supply (Pre-supply score/8, 3.6 ± 1.9) and sleep related counselling (Sleep Score/9, 2.1 ± 1.7). Lower estimated pharmacist age, being in a chain type pharmacy, and having a visible symbol of quality accreditation were found to significantly improve (P < 0.05 the Sleep Score outcome. Lower estimated pharmacist age as also significantly associated with higher Supply Score (P < 0.05); whilst both lower estimated age an visible quality assurance signage were associated with higher Pre-Supply scores (P < 0.05). The results of this study suggest that many pharmacists are responding appropriately to complaints of sleeplessness in terms of eliciting insomnia type and counseling about medicines use. However more education for pharmacists would help to further promote good sleep health, and address behaviors including reliance on medicines taking that can progressively worsen insomnia.

Evaluation of sleep, puberty and mental health in children with long-term melatonin treatment for chronic idiopathic childhood sleep onset insomnia

ObjectivesTo establish whether long-term use of melatonin influences pubertal development, sleep quality and mental health development in children as compared with the normal Dutch population of the same age.MethodsThis follow-up research study was conducted in children included in a previous melatonin dose-finding trial. Outcomes were measured using questionnaires (Strength and Difficulties Questionnaire (SDQ), Children's Sleep Habits Questionnaire (CSHQ) and Tanner Stages) adopted for Dutch children. Mean duration of therapy, persistence of effect, adverse events and (other) reasons leading to cessation of therapy were additional objectives of this study.ResultsMean years of usage (n = 51) was 3.1 years (min 1.0 year, max 4.6 years), mean dose 2.69 mg (min 0.3 mg, max 10 mg). Mean SDQ score, mean CSHQ score and Tanner Stages standard deviation scores did not differ in a statistically significant way from published scores of the general Dutch population of the same age and sex.ConclusionsThis follow-up study demonstrates that melatonin treatment in children can be sustained over a long period of time without substantial deviation of the development of children with respect to sleep quality, puberty development and mental health scores, as compared with the general Dutch population.

Wake up to insomnia: future approaches to the management of insomnia

Wake up to insomnia: future approaches to the management of insomnia

The Relationship between Sleep Onset Insomnia and Coping

The Relationship between Sleep Onset Insomnia and Coping

Total sleep deprivation study in delayed sleep-phase syndrome

Delayed sleep-phase syndrome (DSPS) is characterized by delayed sleep onset against the desired clock time. It often presents with symptoms of sleep-onset insomnia or difficulty in awakening at the desired time. We report the finding of sleep studies after 24 h total sleep deprivation (TSD) in a 28-year-old DSPS male patient. He had characteristics of mild chronic DSPS, which may have been precipitated by his frequent night shift assignments. The TSD improved the patients sleep latency and efficiency but all other sleep variables showed marked differences.

Circadian Periods of Sensitivity for Ramelteon on the onset of Running-wheel Activity and the Peak of Suprachiasmatic Nucleus Neuronal Firing Rhythms in C3H/HeN Mice

Ramelteon, an MT1/MT2 melatonin receptor agonist, is used for the treatment of sleep-onset insomnia and circadian sleep disorders. Ramelteon phase shifts circadian rhythms in rodents and humans when given at the end of the subjective day; however, its efficacy at other circadian times is not known. Here, the authors determined in C3H/HeN mice the maximal circadian sensitivity for ramelteon in vivo on the onset of circadian running-wheel activity rhythms, and in vitro on the peak of circadian rhythm of neuronal firing in suprachiasmatic nucleus (SCN) brain slices. The phase response curve (PRC) for ramelteon (90 µg/mouse, subcutaneous [sc]) on circadian wheel-activity rhythms shows maximal sensitivity during the late mid to end of the subjective day, between CT8 and CT12 (phase advance), and late subjective night and early subjective day, between CT20 and CT2 (phase delay), using a 3-day-pulse treatment regimen in C3H/HeN mice. The PRC for ramelteon resembles that for melatonin in C3H/HeN mice, showing the same magnitude of maximal shifts at CT10 and CT2, except that the range of sensitivity for ramelteon (CT8–CT12) during the subjective day is broader. Furthermore, in SCN brain slices in vitro, ramelteon (10 pM) administered at CT10 phase advances (5.6 ± 0.29 h, n = 3) and at CT2 phase delays (−3.2 ± 0.12 h, n = 6) the peak of circadian rhythm of neuronal firing, with the shifts being significantly larger than those induced by melatonin (10 pM) at the same circadian times (CT10: 2.7 ± 0.15 h, n = 4, p < .05; CT2: −1.13 ± 0.08 h, n = 6, p < .001, respectively). The phase shifts induced by both melatonin and ramelteon in the SCN brain slice at either CT10 or CT2 corresponded with the period of sensitivity observed in vivo. In conclusion, melatonin and ramelteon showed identical periods of circadian sensitivity at CT10 (advance) and CT2 (delay) to shift the onset of circadian activity rhythms in vivo and the peak of SCN neuronal firing rhythms in vitro. (Author correspondence: mdubo@buffalo.edu)

Shedding Light on the Effectiveness of Melatonin for Circadian Rhythm Sleep Disorders

Shedding Light on the Effectiveness of Melatonin for Circadian Rhythm Sleep Disorders

Dexamethasone Therapy for Acute Lymphoblastic Leukemia Increases Sleep During the Night and During the Day In Young Children

AbstractAbstract 258Dexamethasone (Dex) or prednisone (Pred) are used in Acute Lymphoblastic Leukemia (ALL) therapy. It has long been recognized that dexamethasone effects both daytime behavior and nighttime sleep. The most commonly reported adverse effect of dexamethasone on sleep is sleep onset and sleep maintenance insomnia. An actigraph, recording 24 hours a day for 28 days, was used to evaluate sleep and wakefulness of patients with ALL in maintenance. Patients treated with Dex were evaluated at 3 windows: Dex-on days (1-5), Dex-washout days (6-15) and Dex-off days (16-28). Daytime and nighttime sleep parameters were analyzed from aggregated patient data for all three windows using the median and range. The non-parametric Friedman test was used to compare these parameters over the three windows, and the Wilcoxon Signed Rank Test was used for paired comparisons (used Bonferoni correction). Sleep patterns were also measured using the Childhood Sleep Habit's Questionnaire (CSHQ). The group included 41 ALL patients (29 received Dex, 8 received Pred, and 4 did not receive steroids); 18 females (43.9%), 23 males (56.09%); median age 5 years (range 2 –16). In the Dex treated group, wake during the 5 days of Dex treatment showed less daytime activity mean, greater total daytime sleep minutes, and greater numbers of sleep episodes (>5 minutes) compared to Dex-washout and Dex-off. Sleep during the 5 days of Dex treatment showed: earlier sleep onset time, increased number of sleep minutes, higher sleep efficiency, fewer number of wake episodes (>5 minutes) compared to Dex-washout days (6-15) and Dex-off days (16-28). The effect of dexamethasone on wake and sleep was greatest during the 5 days of treatment, was intermediate during the 10 day washout window and was least during the 13 days at the end of the treatment cycle. This effect was more evident in a subgroup of 28 children treated with Dex who are younger than 10 years old. No significant differences were found for age groups (less than 5 years vs. 5 years or above), gender and steroids (Dex vs. Pred). Interestingly, using the CSHQ 14/23 patients (61%) were identified as poor sleepers with a CSHQ score > 41; mean score for the whole group was 45. CSHQ wake up time strongly correlated with the actigraph data wake up time (r= 0.83). These findings suggest young children with standard risk ALL dexamethasone experience increased sleep both during the day and night. The increase in daytime sleepiness in these children cannot be attributed to nighttime sleep disruption; in fact these children went to sleep earlier and slept with fewer awakenings during dexamethasone treatment. The mechanisms for this change in daytime and nighttime sleep are not understood. Cerebral spinal fluid and plasma cytokines are being measured for these patients to evaluate their role in regulating their sleep. Disclosures:No relevant conflicts of interest to declare.

Gender and ethnic differences in prevalence of self-reported insomnia among patients with obstructive sleep apnea

Insomnia and obstructive sleep apnea (OSA) are the two most common sleep disorders. Studies have shown that complaints of insomnia are prevalent among sleep clinic patients evaluated for OSA. Less is known about the gender and ethnic variations in this association. This paper aims to study the influence of gender and ethnicity in the prevalence of insomnia in patients with OSA and explore the association between these two disorders with an emphasis on psychophysiologic insomnia. We reviewed case files, including self-reported questionnaires and polysomnography studies of 300 OSA patients [apnea-hypopnea index (AHI) of >10] from three ethnic groups--Caucasian, Hispanic, and African American, 50 patients each, male and female, seen at a tertiary care county hospital adult sleep center. Self-reported insomnia was classified as sleep onset insomnia, sleep maintenance insomnia, or insomnia with early morning awakening. Psychophysiologic insomnia was documented if the patient reported two of the following five symptoms: racing thoughts when trying to sleep, increased muscle tension when trying to sleep, fear of being unable to sleep, fear of being unable to fall back to sleep after waking up, and lying in bed worrying. Fischer exact tests for each contingency table were run using SPSS. Among OSA patients, women were older, had higher body mass index, and lower AHI at the time of diagnosis, compared to men. Insomnia was more prevalent among patients with OSA (84%) than the reported 30% among general adult population. Sleep onset insomnia was reported more frequently by women (62%) than men (53%) (p = 0.03). Similarly self-reported psychophysiologic insomnia also showed a female preponderance (53% vs. 45%, p = 0.03). Caucasian women had the highest rate of self-reported sleep maintenance insomnia (80%). Hispanic women are more likely to complain of symptoms suggestive of psychophysiologic insomnia (58%). There is a higher prevalence of insomnia in OSA patients. Ethnicity and gender possibly exhibit a complex and significant influence on the reported subtype of insomnia. Further larger studies may help confirm, as well as clarify, mechanisms that underlie the ethnic and gender differences that we have noted.

The Anxious Sleeper

The Anxious Sleeper

Dose finding of melatonin for chronic idiopathic childhood sleep onset insomnia: an RCT

RationalePharmacokinetics of melatonin in children might differ from that in adults.ObjectivesThis study aims to establish a dose–response relationship for melatonin in advancing dim light melatonin onset (DLMO), sleep onset (SO), and reducing sleep onset latency (SOL) in children between 6 and 12 years with chronic sleep onset insomnia (CSOI).MethodsThe method used for this study is the randomized, placebo-controlled double-blind trial. Children with CSOI (n = 72) received either melatonin 0.05, 0.1, and 0.15 mg/kg or placebo during 1 week. Sleep was assessed with log and actigraphy during this week and the week before. Outcomes were the shifts in DLMO, SO, and SOL.ResultsTreatment with melatonin significantly advanced SO and DLMO by approximately 1 h and decreased SOL by 35 min. Within the three melatonin groups, effect size was not different, but the circadian time of administration (TOA) correlated significantly with treatment effect on DLMO (r s = −0.33, p = 0.022) and SO (r s = −0.38, p = 0.004), whereas clock TOA was correlated with SO shift (r = −0.35, p = 0.006) and not with DLMO shift.ConclusionsNo dose–response relationship of melatonin with SO, SOL, and DLMO is found within a dosage range of 0.05–0.15 mg/kg. The effect of exogenous melatonin on SO, SOL, and DLMO increases with an earlier circadian TOA. The soporific effects of melatonin enhance the SO shift. This study demonstrates that melatonin for treatment of CSOI in children is effective in a dosage of 0.05 mg/kg given at least 1 to 2 h before DLMO and before desired bedtime.

Role of 5-HT2A receptor antagonists in the treatment of insomnia.

Insomnia encompasses a difficulty in falling asleep (sleep-onset insomnia) and/or a difficulty in staying asleep (SMI). Several selective serotonin-2A (5-HT2A) receptor antagonists have been in development as potential treatments for SMI. However, none have shown a sufficiently robust benefit-to-risk ratio, and none have reached market approval. We review the role of the 5-HT2A mechanism in sleep, the preclinical and clinical data supporting a role for 5-HT2A receptor antagonism in improving sleep maintenance, and the status of 5-HT2A receptor antagonists in clinical development. Overall, the polysomnography data strongly support an increase in slow-wave sleep and a decrease in waking after sleep onset following treatment with 5-HT2A receptor antagonists, although it has been more difficult to show subjective improvements in sleep with these agents. The incidence and prevalence of SMI, whether primary or secondary to psychiatric, neurologic, or other medical conditions, will increase as our population ages. There will be an increased need for safe and efficacious treatments of insomnia characterized by difficulty maintaining sleep, and there remains much promise for 5-HT2A receptor antagonism to play a role in these future treatments.