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An Expert Panel Review of Clinical Challenges in Primary Care and Psychiatry
Statement of Need and Purpose:
Patients with insomnia experience impaired daytime functioning and a decrease in quality of life. These patients are also at risk for substance abuse and problems with general mxedical and psychological health. Thus, recognition and treatment of insomnia is an important healthcare goal. Effective pharmacologic and behavioral therapies are available. Existing nonbenzodiazepine hypnotics are effective treatments for insomnia and have a low potential for next-day (hangover) effects. Patients often experience multiple insomnia symptoms—delayed sleep onset, frequent awakenings/difficulty sleeping after middle-of-the-night awakenings, and early waking. Modified-release formulations represent a unique entry into the hypnotics formulary. This monograph reviews preliminary data of modified-release formulations for insomnia and discusses possible uses of this formulation.
• Explore the role of modified-release formulations of hypnotic agents in the treatment of insomnia.
• Understand the current treatment needs by analyzing the epidemiology of insomnia and the symptomatology of patients with insomnia.
• Evaluate the specific benefits of newly developed modified-release hypnotic compounds in insomnia.
This activity is designed to meet the educational needs of psychiatrists.
Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide Continuing Medical Education for physicians.
Mount Sinai School of Medicine designates this Continuing Medical Education activity for a maximum of 1.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.
It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.
Faculty Affiliations and Disclosures:
Dr. Erman is clinical professor of psychiatry in the Department of Psychiatry at the University of California, San Diego. He is a consultant to Cephalon, Cypress, Elan, Janssen, King, Mallinckrodt, Somaxon, and Takeda; is on the speaker’s bureaus of Cephalon, Elan, King, Mallinckrodt, Neurocrine Biosciences, Orphan, Sanofi-Synthelabo, and Sepracor; has received grant/research support from Cephalon, Elan, King, Mallinckrodt, Merck, Neurocrine Biosciences, Pfizer, Pharmacia, Orphan, ResMed, Sanofi-Synthelabo, Somaxon, and Takeda; and has a financial interest or owns stocks in Cephalon, Forest, Neurocrine Biosciences, Merck, Pfizer, Sanofi-Synthelabo, and Sepracor.
Dr. Neubauer is assistant professor in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University and associate director of the Johns Hopkins Sleep Disorders Center in Baltimore, Maryland. He is a consultant to Neurocrine Biosciences, Pfizer, and Takeda; and is on the speaker’s bureau of Sanofi-Synthelabo.
Dr. Patel is an instructor in the Department of Medicine at Harvard Medical School and a staff physician in the Division of Sleep Medicine at Brigham and Women’s Hospital in Boston, Massachusetts. He has received grant/research support from the American Heart Association and the National Institutes of Health.
Dr. Young is professor of Population Health Sciences at the University of Wisconsin Medical School in Madison. She is a consultant to Neurocrine Biosciences; is on the speaker’s bureau of Sanofi-Synthelabo; and has received grant/research support from the National Institutes of Health.
To Receive Credit for this Activity:
Read this symposium monograph supplement, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Termination date: August 31, 2007. The estimated time to complete this activity is 1 hour.
Disclosure of Off-Label Usage:
This symposium monograph supplement includes references to unlabeled or investigational uses of drugs or devices.
In addition to the psychological and medical health risks associated with lack of adequate sleep, effects of insomnia include impaired daytime functioning and decreased quality of life. Many patients experience delayed sleep onset, frequent awakenings, early waking, or nonrestorative sleep. Longitudinal data on insomnia indicate that the prevalence of persistent/chronic insomnia is high and appears to be characterized by multiple symptoms related to initiating or maintaining sleep. Physiologic studies indicate that short-term sleep restriction can cause physiologic problems that lead to long-term health consequences, such as high blood pressure, impaired glucose tolerance, and systemic inflammation. Epidemiologic studies have shown that sleep deprivation is independently associated with increased risk of cardiovascular disease, diabetes, obesity, and mortality. While the available agents are effective, those with a long half life may have carryover effects while short-acting agents may not provide enough sleep continuity. Pharmacologic therapies available for patients who suffer from insomnia include immediate-release nonbenzodiazepine hypnotics, which have a positive benefit/risk profile compared to the benzodiazepines. Modified-release (MR) formulations of these agents may offer the additional benefit of improving sleep continuity throughout the night without sacrificing the rapid elimination properties that minimize next-day residual effects. MR agents in development include zolpidem MR and indiplon MR.
Milton K. Erman, MD—Moderator
Blessings on him who first invented sleep. It is meat for the hungry, drink for the thirsty, heat for the cold, and cold for the hot. It makes the shepherd equal to the monarch and the fool to the wise. There is but danger in it, in that sleep resembles death—Cervantes, Don Quixote
Despite the well-known risks associated with insufficient sleep and increased epidemiologic data about the negative impact of inadequate sleep on health and mortality, people are sleeping increasingly fewer hours. Over the last century, sleep time has been reduced by 20%. The annual number of work hours in the United States has increased by 158 hours since 1969, and social and economic pressures have created a society where people work 24 hours/day, 7 days/week.1
The number of sleep hours a person actually needs is that which allows the individual to feel well rested and energetic, and to function with full alertness throughout the day. For most people, this can be achieved with 7–8 hours of sleep per night. Specific needs vary considerably between individuals, and may be genetically determined.
The classic definition of insomnia is difficulty falling asleep, and/or difficulty staying asleep, and/or nonrestorative sleep, as well as next-day consequences.2,3 However, the National Institute of Health State of the Science Conference on Chronic Insomnia in Adults, held in June 2005, reported that because there are very limited data on nonrestorative sleep, this component of the definition should be replaced with waking too early.4 Thus, the new definition that has been posed for insomnia is difficulty falling asleep, and/or difficulty staying asleep, and/or waking too early, and next-day consequences (Slide 1).
Within a physiologic context, interaction between the homeostatic and circadian drives promotes a tendency for sleepiness in the afternoon and a great drive for sleep at night. In physiologic terms, it takes 8 hours of sleep for sleepiness to be depleted (Slide 2). However, 8 hours of sleep is not always enough, especially for people who are taking medications that impact sleep needs.
In clinical practice, patients do not necessarily report their complaints of insomnia. Data from the annual National Sleep Foundation polls show that the vast majority of insomniacs (69%) never discussed any sleep problems with their physicians; 26% discussed sleep problems during a visit for another purpose, and 5% visited the physician specifically to discuss sleep problems.5 Having a sleep disorder has numerous consequences, including impaired cognitive functioning6; negative impact on quality-of-life measures6; increased incidence of bodily pain/poorer general health6-8; increased risk of psychiatric disorders, including a 4-fold increased risk of new-onset depression9; decreased job performance/increased absenteeism5; increased risk of accidents10; and increased healthcare costs.11,12
There is an increasing number of effective and safe agents as well as an increasing realization of the importance of getting enough sleep. In the near future, more agents will become available that will allow additional treatment options and increased capacity to improve outcomes for patients with insomnia.
Terry Young, PhD
The Natural History of Chronic Insomnia
The Natural History Perspective
The natural history perspective is key to determining the causes and consequences of a disorder, as well as to understanding how the symptoms emerge and evolve over time. To describe the natural history, a large sample that is representative of the general population is studied at multiple time points to obtain longitudinal data. Occurrence, risk factors, and causal factors are assessed, how the condition progresses over time is monitored, and the outcomes of the condition in both those who have been diagnosed and treated, as well as those who remain undiagnosed, are determined (Slide 3).
The natural history perspective is particularly important for conditions like insomnia where most cases remain undiagnosed and untreated. Due to selection and referral biases, clinic patients with insomnia may be different from most people with insomnia; information from these patients are not likely to portray an accurate picture of the epidemiology of chronic insomnia. Insomnia may remain persistent over time; it may progress with an increase in severity and in the range of symptoms or it may regress, with a decrease in severity or change in symptom manifestation. It is difficult to know early on if insomnia in a particular patient will be transient/acute or chronic.
Longitudinal Data on Insomnia
There have been several cross-sectional surveys and ~50 reports on the occurrence of insomnia. Approximately 10% of people report having chronic insomnia that has a functional impact on their lives.1 However, the actual percentage is dependent on accurate recall. Insomnia is very prevalent in primary care, with ~50% of primary care populations expressing, when asked, some concern about having insomnia.1
There have been few studies that included longitudinal data. These are the data which provide information on incidence, chronicity/persistence, progression and regression, and modifiers of natural history (eg, environment, demographics, healthcare access, psychosocial aspects). Earlier longitudinal studies were based on the operational definition of insomnia in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition. Subjects were asked if they experienced a period of at least 2 weeks with daytime symptoms of impairment. In 1989, Ford and Kamerow2 reported a 1-year incidence of ~5% in men and ~7% in women. Only 2% of men and 4% of women had insomnia at baseline that persisted at follow-up. In a 3.5-year study3 of young adults enrolled in a health maintenance organization (HMO) in Michigan, the annual incidence of insomnia was 3% in men and 4% in women. In a 1-year study4 of older adults in Alameda County, the prevalence of insomnia that persisted for 1 year was 13%.
More recent studies have used questions on the usual frequency of onset and maintenance insomnia symptoms, similar to those recommended by the NIH State of Science conference in 2005.5 A 3-year study6 of older adults showed a yearly incidence of onset/offset insomnia of 5%, and a remission rate of ~15%. Quan and colleagues7 reported that the incidence per year in older adults was ~3% for onset insomnia, 12% for maintenance insomnia, 15% for persistence of onset insomnia over a 4-year period, and 23% for persistence of maintenance insomnia over a 4-year period. This study was the first to report a finding that older adults had a higher persistence of maintenance insomnia. In a 10-year prospective study8 of Swedish men, baseline insomnia was the strongest predictor of follow-up insomnia. People with baseline insomnia had 6.5 times the risk of having chronic insomnia 10 years later. In a study of general practice clinic patients in Germany, Hohagen and colleagues9 found that 87% of those with baseline insomnia still had insomnia 4 months later, but the specific symptoms had changed. This finding was the first clue that the symptoms in chronic insomnia change over time.
Preliminary Data on Chronic Insomnia
The Wisconsin Sleep Cohort Study was initiated in 1987 to investigate the natural history of sleep disorders in adults. In this study, 5,000 men and women were surveyed at baseline and at two 5-year follow-up surveys spanning 10 years. A subset of 1,500 men and women were studied, with an overnight protocol that included polysomnography at baseline and at 4-year intervals thereafter. Subjects were 30–60 years of age. Survey 1 was conducted in 1987, survey 2 in 1992, and survey 3 in 1997 (T. Young, unpublished data, 2005).
The study has a rich data set that allows for observation of sleep disorders as they change over time, and for investigating risk factors as well as outcomes. Questions about frequency of trouble initiating and maintaining sleep were asked at all data collection points and participants rated frequency on a 5-point scale (Slide 4). Chronic insomnia was defined as having at least one symptom (initiating or maintaining sleep) often or almost always at every survey. The prevalence across the three timepoints was fairly stable for most of the symptoms of insomnia (Slide 5). However, the prevalence by particular symptom changed over time; only ~50% of participants who reported having a particular symptom often, still reported having that symptom often on the next survey.
For the symptom of sleep onset insomnia, only 2% of participants who reported no sleep onset insomnia at survey 1 (baseline) reported having this symptom often or always at survey 2 (5 years later), suggesting the development of new-onset insomnia is not common in middle-aged adults. For those who reported having sleep onset insomnia “sometimes” at survey 1, 54% stayed in that frequency category, 12% progressed to having insomnia “often,” and 34% regressed to having no sleep onset insomnia. Finally, ~47% of patients who reported having sleep onset insomnia “often” at survey 1, were still reporting that 5 years later. This pattern was similar for all the symptoms of sleep onset or sleep maintenance insomnia (onset, wake after sleep onset, wake repeatedly, and offset).
With insomnia defined as having any insomnia symptom (onset or maintenance) often or always, 5-year dynamics were examined. The incidence of new insomnia over 5 years was 2%, and regression of existing insomnia was 2%. Strikingly, the prevalence of having persistent insomnia over a 5-year period was 24%.
Longitudinal data at three time points were used to describe 10-year chronic insomnia, defined as having some insomnia symptoms often or always at baseline (survey 1), 5-year follow-up (survey 2), and 10-year follow-up (survey 3). Eighteen percent of the sample reported chronic insomnia, with at least one symptom, on all three surveys, spanning 10 years. Of those, 86% had two or more symptoms at all three surveys, and 43% had three or more symptoms. Thus, most patients with chronic insomnia had multiple symptoms.
In addition, among subjects with persistent, 10-year insomnia, specific symptoms tended to change over time, with few people reporting only onset or maintenance symptoms at all time points. The best predictor of 10-year chronic insomnia was baseline status of the number of symptoms. Those at baseline who had four versus only one symptom were five times more likely to have 10-year insomnia.
Research in the general population is beginning to show that in middle age (30–60 years), the prevalence of persistent/chronic insomnia (5–10 years) is high. Symptoms of both onset and maintenance insomnia are more common than single symptoms. Symptoms reported occasionally (ie, a frequency <5 times/month) are more likely to regress than progress to a frequency of often or always. Chronic insomnia is a condition that seems to be characterized by multiple symptoms, and the best predictor of persistent insomnia is number of individual symptoms at baseline.
Sanjay R. Patel, MD, MS
Linking Sleep to Health: Lessons From Physiologic and Epidemiologic Studies
A poll from the National Sleep Foundation (NSF) reported that the mean nightly sleep duration is 6.8 hours; only 25% of the United States population obtain at least 8 hours of sleep per night, and 40% report ≤6 hours of sleep per night.1 These results indicate that chronic sleep deprivation is even more common that it was 4 years ago, when the NSF poll revealed that mean sleep duration was 7 hours; 38% slept ≥8 hours and 31% slept ≤6 hours per night.1 That inadequate sleep results in long-term health consequences has been demonstrated in physiologic and epidemiologic studies.
Short-Term Physiologic Studies
Tochikubo and colleagues2 looked at the effects of sleep duration on blood pressure in 18 Japanese men. Each subject went through one normal night of sleep (8 hours) and one night of partial sleep deprivation (3.6 hours). Blood pressure was noninvasively measured during the night as well as the following day. Both the systolic and diastolic blood pressure tended to be higher on the sleep-deprived nights than on the nights when the subjects got 8 hours of sleep. Averaged over the 24-hour day, systolic blood pressure was 7 mm Hg higher (128 versus 121) and diastolic was 3 mm Hg higher (77 versus 74) during the sleep deprivation period compared to the normal sleep period (P<.01). There were similar differences in blood pressure during the times the subjects were awake, but nonsignificant differences while they were asleep.
In 1999, Spiegel and colleagues3 conducted a study on the effects of sleep deprivation on metabolic function. Eleven young, healthy men were exposed to 4 hours of sleep/night for 6 nights, followed by 6 nights of recovery sleep (12 hours in bed). The mean sleep times between the two conditions were 3.8 hours versus 9.1 hours. The main study outcome was insulin sensitivity, measured with the intravenous glucose tolerance test. While the peak glucose was the same both in the sleep-deprived and the sleep-recovery conditions, the length of time it took for glucose levels to return to normal was much longer in the sleep-deprived condition. In the sleep-deprived phase, the subjects demonstrated impaired glucose tolerance, higher evening cortisol levels, and increased sympathetic nervous system activity (measured with heart rate variability) compared to the recovery period.
In 2004, Spiegel and colleagues4 looked at the effect of sleep on appetite and hunger. They recruited 12 young, healthy men who had a normal body mass index (BMI) and exposed them to 2 nights with 4 hours of sleep and 2 nights with 10 hours of sleep opportunity in random order. The mean sleep times were 3.9 versus 9.1 hours. They found that leptin and ghrelin levels were significantly affected by lack of sleep. Leptin, a hormone produced by adipose (fat tissue), activates satiety centers in the hypothalamus, reducing appetite and hunger. Ghrelin is produced in the stomach and tends to stimulate hunger centers in the brain. In the sleep-deprivation condition, leptin levels were suppressed, which would tend to increase hunger and appetite, while ghrelin levels were higher, which also tends to promote hunger. Questionnaire scales also revealed that hunger and appetite were increased in the sleep-deprived state compared to the normal sleep nights throughout the study. High sugar, high carbohydrate, and salty foods were the most craved foods.
Meier-Ewert and colleagues5 assessed the effects of sleep deprivation on systemic inflammation, which has been shown to be an independent risk factor for coronary disease. Ten young, healthy subjects were randomized to 8.2 hours or 4.2 hours of sleep/night over 10 nights. The subjects who were randomized to 4.2 hours initially had C-reactive protein levels that put them at low risk for a cardiovascular event. At the end of the study, after enduring this reduced sleep schedule, the CRP levels revealed high cardiovascular risk.
Epidemiologic Studies: Mortality
Kripke and colleagues6 conducted a study of 1.1 million men and women between 30 and 102 years of age, who participated in a health survey sponsored by the American Cancer Society. Subjects were enrolled in 1982, and were asked about how long they typically slept as well as a variety of other health-related questions. Using death certificates, the researchers tracked mortality over the next 6 years. At study initiation, the most common sleep time was 8 hours. Cross-sectional evaluation of BMI indicated that women with shorter sleep times tended to be heavier than women who slept 7–8 hours. This correlation was not as clear among men. Short sleep duration was associated with a modestly increased mortality rate that persisted even after controlling for a variety of confounders, such as race, BMI, education, exercise, medical disorders, and medication use.
Tamakoshi and colleagues7 studied 104,010 Japanese men and women 40–79 years of age. They were enrolled between 1988 and 1990, asked about sleep duration, and followed for nearly 10 years. Mortality was confirmed with death certificates (11,000 deaths). The lowest risk of death was found in those who reported sleeping 7 hours (Slide 6).
In the 1986 Nurses’ Health Study (NHS),8 nurses were asked to indicate their total hours of sleep in a 24-hour period. A total of 82,969 women responded to this question. There were 5,409 deaths between 1986 and 2000. The lowest risk of mortality was in those who reported sleeping 7 hours. After controlling for age, smoking, alcohol, exercise, depression, snoring, BMI, cancer, and cardiovascular disease, those who slept ≤5 hours had an 18% increased risk of death.
Epidemiologic Studies: Cardiovascular and Metabolic Disease
In addition to evaluating the association between sleep patterns and mortality, the NHS also looked at cardiovascular disease.9 The study used data from the same women who had answered the sleep duration question in 1986, excluding those who had a history of cardiovascular disease. A total of 71,617 women with no coronary disease at baseline were followed for 10 years for nonfatal or fatal myocardial infarction (MI) using World Health Organization (WHO) criteria. The study adjusted for covariates such as age, diabetes, hypertension, snoring, depression, shift work, family history, exercise, alcohol, smoking, and use of hormone replacement therapy. The lowest risk was in those who slept 8 hours; those who slept 5 hours had a ~45% increased risk of having an MI over the next 10 years.
The NHS was also used to evaluate risk of developing diabetes.10 A total of 70,000 women who did not have diabetes at baseline were followed for 10 years. The criteria used to make the diagnosis of symptomatic diabetes was fasting glucose >140 mg/dL or random >200 mg/dL, plus at least one of the following symptoms: excessive thirst, coma, polyuria, weight loss, or pruritus. After controlling for age, hypertension, cholesterol, snoring, depression, shift work, family history, exercise, alcohol, smoking, hormone use, and BMI, results showed that those who slept 7–8 hours had the lowest risk of diabetes; there was a 36% to 37% increased risk of diabetes among those who slept <5 hours or ≥9 hours.
Recently, the Sleep Heart Health Study11 looked at diabetes in relation to sleep duration in a cross-sectional fashion, using a subgroup of 1,486 subjects 53–93 years of age who had undergone an oral glucose tolerance test. The study used strict WHO criteria for diabetes and impaired glucose tolerance. The lowest risk for either diabetes or impaired glucose was in those who slept 7–8 hours. Those who slept ≤5 hours had a 2.5 times higher risk of having diabetes. Short sleep was associated with increased risk of diabetes, regardless of whether the lack of sleep was due to insomnia or other reasons.
In a longitudinal study from Switzerland, Hasler and colleagues12 looked at whether duration of sleep predicted future weight gain in 450 people 27 years of age. Weight was assessed at four timepoints over 14 years to determine how much BMI changed per year as a function of how much each person slept at the initiation of the study. They found that those who slept the least at baseline gained the most weight over the next 14 years. Those who slept ≤5 hours gained 0.4 kg/m2/year, which was much higher than those who slept 7–8 hours; those who slept >9 hours lost weight (Slide 7).
Physiologic studies indicate that short-term sleep restriction leads to a variety of adverse physiologic sequelae that can lead to long-term consequences. These include sympathetic activation/elevated blood pressure, deterioration in glucose control, increased hunger signaling, and increased inflammation. These data suggest that sleep restriction may have long-term consequences. In addition, there have been at least three large studies demonstrating that the lowest mortality is found in those who sleep 7 hours/night, that decreased sleep duration is modestly associated with increased mortality, and that this association persists after adjustment for a variety of confounders. Self-reported sleep deprivation has been shown to be independently associated with an increased risk of coronary heart disease, diabetes, obesity, and death. Inadequate sleep is common, and is associated with adverse physiological effects as well as an increased risk of developing chronic illness.
David N. Neubauer, MD
Extending a Compound’s Effect: Developing Modified-Release Formulations
Insomnia is a common chronic problem associated with several comorbidities and consequences. Important strategies toward achieving the primary goal of helping patients sleep better include optimizing treatment of the patient’s comorbid disorders, which can be psychiatric, medical, or another sleep disorder that is contributing to the insomnia. Educating the patient on sleep hygiene can be helpful to insure that they have the proper environment for their sleep to improve. In addition, behavior/schedule manipulations, as well as cognitive-behavioral therapy have been shown to be effective. To date, pharmacotherapy is the most common treatment strategy used in patients with insomnia. While several of the standard hypnotic medications work well for insomnia and help people sleep through the night, there may be an advantage to having modified-release (MR) preparations of these agents available.
Hypnotics: Specificity of Benzodiazepine Receptor Agonists
There are currently eight hypnotics that have a Food and Drug Administration indication for the treatment of insomnia (Slide 8). Hypnotics, which include traditional benzodiazepines and newer nonbenzodiazepines, are positive allosteric modulators of γ-aminobutyric acid (GABA)A receptors. GABA binding leads to the opening of a chloride channel enabling the negative chloride ions to enter the cell; this hyperpolarizes the membrane of the cell and causes a generalized inhibitory effect. Benzodiazepines enhance the normal activity of GABA by allowing more negative chloride ions to enter.
While the benzodiazepines tend to interact with most of the different a subunits, including α1, α2, α3, and α4, the nonbenzodiazepine hypnotics are much more selective for the α1 subunit. This selectivity is responsible for the efficacy/safety profile of the nonbenzodiazepines as other subunits are thought to influence the anxiolytic, anticonvulsant, and muscle relaxant effects of the traditional benzodiazepines. Nonbenzodiazepine hypnotics also have a minimal potential for tolerance, dependence, or abuse liability.
Eszopiclone, zaleplon, and zolpidem are nonbenzodiazepine hypnotics with α1 selectivity at therapeutic doses. Selectivity of zolpidem and zaleplon is about 10:1 and eszopiclone is about 2:1. (Benzodiazepines are 1:1, because they do not have selectivity).
The rate of drug absorption influences speed of drug distribution and, therefore, onset of pharmacologic action. Metabolism and excretion lead to a gradual decline in plasma concentration. The half-life represents the amount of time it takes for the concentration to be reduced by 50%, while the area under the curve is a reflection of the extent of a drug’s bioavailability and indicates the body’s exposure to a given drug (Slide 9).
With a relatively short-acting medication, the drug is absorbed quickly, reaches its peak, and decreases in concentration fairly rapidly. This becomes a problem in insomnia if the medication is needed to last all night, but it is an advantage if flexibility in dosing or timing of that medication is warranted. With a medication that has a 2–3-hour half-life, the duration of action is somewhat longer and is effective for most of the night. Medications with even longer half-lives may provide efficacy throughout the night, however, the plasma levels may remain above the minimum effective concentration for a longer period of time (Slide 10), which could lead to next-day effects in some patients. In addition, there is individual variability in drug metabolism, and the minimum effective concentrations will vary between compounds. Thus, there are pros and cons to choosing a hypnotic agent based on its half life.
Another option to consider to help insomnia patients sleep through the night is increasing the hypnotic dose. A larger dosage will increase the duration of time that the medication is above the minimum effective concentration threshold (Slide 11). However, there is a risk for adverse effects associated with higher peak levels.
Modified-Release Preparation for Insomnia
Some of the advantages to having a modified-release preparation are the ability to decrease the dosing frequency and increase patient adherence; reduce plasma level fluctuations; control the site of drug delivery in the gastrointestinal tract; and better control the onset and offset of action. Many medications, including paroxetine, venlafaxine, bupropion, and lithium, have become available in MR formulations. MR preparations include sustained release, where the delivery system slows release rate; controlled release, where there is constant release and a constant plasma level; and delayed release, where there is release after initial administration. Technologies used to create MR formulations include pharmaceutical modification, coated pellets, insoluble matrix, eroding matrix, osmotic pump, and pH-sensitive coating.
For patients with insomnia, the ideal medication is one that has rapid onset of action, plateaus the entire night, and then rapidly drops the moment before they wake up in the morning (Slide 12). MR preparations have the potential to maintain the initial onset of action, and allow for maintenance of plasma levels for a longer period of time without increasing the risk of residual effects.
For a MR preparation to promote a full night of sleep with no residual morning sedation, it should have a relatively short-acting parent compound so that plasma levels drop below the minimum effective concentration before the patient needs to get out of bed in the morning. A 4-hour half life may be too long, because if the drug level is kept high during the night and then allowed to drop off, it will remain above the minimum effective concentration for a longer period of time and have more potential for residual effects.
The current hypnotic medications all have standard pharmacokinetics. New pharmaceutical technologies allow alterations in the release of these medications. MR formulations of hypnotics may improve sleep continuity throughout the night and minimize next-day residual effects.
Milton K. Erman, MD
Application of Modified-Release Hypnotics
Rationale for Modified-Release Compounds
Existing hypnotic agents for patients with sleep continuity problems are effective, but there is room for improvement in many patients. There are several rationales for development of modified-release (MR) compounds for the treatment of insomnia. First, there is a perception that existing medications either do not adequately treat patients who have difficulty sleeping through the night or cause residual sedation. Second, there are new-release technologies available for use with hypnotic agents. Patients would like to have medications that have greater flexibility as well as those that will provide the exact duration of action needed.
All of the available hypnotic agents can be considered sleep-promoting agents. This means that the therapeutic effect that occurs during the night is present on the basis of promotion of sleepiness or reduction of alertness. Long half-life agents may have carryover effects such as sedation, drowsiness, performance impairment, or amnesia.1-3 Short-acting agents may have a reduced risk for carryover effects. Carryover effects may be reduced through the use of MR agents that concentrate the therapeutic action during sleep and minimize the probability of the residual sedation the next day. The ideal agent would be one that has an extremely short half-life (minutes rather than hours), where the patient can take the medication, have a continuous-release formulation throughout the night, and have it drop off right before they need to wake up. A potential problem with this model could arise if the patient did not have 8 hours to spend in bed, since arising at an earlier hour could lead to residual sedation.
Potential strategies for patients who have trouble sleeping through the night include higher doses of hypnotic agents; repeat dosing of short half-life hypnotic agents; use of long-half-life hypnotic agents; or off-label use of compounds with sedative properties such as antidepressants, antipsychotics, and anticonvulsants. Off-label use has become rather popular; however, at the June 2005 State of the Science conference, the National Institute of Health4 stated that antidepressants have potentially significant adverse events, raising concerns about their risk:benefit ratio. In addition, regarding other medications, specifically barbiturates and antipsychotics, they noted that studies demonstrating use of these agents for short- or long-term management of insomnia are lacking. They also stated that these agents have significant risk, and their use in treatment of insomnia cannot be recommended.
Modified-Release Formulations in Development
Modified-release agents in development include zolpidem MR and indiplon MR. Data for these drugs have been submitted to the Food and Drug Administration. Development of zolpidem MR included pharmacodynamic evaluation of formulations, characterization of zolpidem MR in healthy volunteers, and efficacy and safety data. Zolpidem MR is a chemical entity that has a rapid (within 30-minutes) onset of action with a half life of 2.8 hours and a tmax that occurs 1.5 hours post dose. The modified-release formulation that has been developed and submitted for FDA approval is a two-layered tablet with a biphasic release formulation that delivers initial and delayed-release doses. Clinical studies for indiplon MR have shown efficacy and safety in adults with chronic insomnia. Indiplon MR, which is a close relative of zaleplon, has a half-life of 1.5 hours and a tmax at about 1 hour. The formulation that has been developed is an immediate-release coating surrounding an extended-release matrix core.
Zolpidem MR Clinical Trials
The development of zolpidem MR involved selection of an optimal modified-release formulation. A 10-way single-center, double-blind, placebo-controlled, crossover study5 was conducted in 36 healthy volunteers. Eight MR formulations were evaluated, each containing a unique combination of immediate- and delayed-release zolpidem with doses up to 15 mg. Traffic noise was used to induce sleep difficulties. Polysomnographic outcome variables used were number of arousals (wakeful events ≤10 seconds), number of awakenings (wakeful events ≥15 seconds when assessed semiautomatically or 30 seconds when assessed manually), and duration of awakenings after sleep onset.
A 12.5-mg MR formulation was shown to be the most effective formulation in reducing number of arousals and is the one that has been submitted for FDA approval. Among the doses assessed, the 12.5 mg MR formulation was the most effective in reducing arousals as well as wake after sleep onset. Pharmacokinetics data demonstrated that area under the curve was increased in the 12.5-mg MR formulation with a lower maximum concentration than the 10-mg dosage. It would be expected that this combination of effects would lead to increased duration of action without increased next-day sedation.
In a one-way crossover study, Hindmarch and colleagues6 gave 54 healthy volunteers either standard zolpidem 10 mg or zolpidem-MR 12.5 mg on separate nights. Patients were awakened 3, 4, or 5 hours postdose. The subjects were kept awake for 30 minutes while performing a task, then allowed to go to sleep with a noise stimulus in the room. At 4 and 5 hours, the latency to return to sleep was significantly shorter with the MR formulation compared to placebo (Slide 13).
Two additional studies assessed the potential for residual effects 8 hours following zolpidem MR dosage in healthy adults (n=18)7 and healthy elderly (n=24).8 The studies used a crossover design with flurazepam 30 mg as an active comparator. In both studies, zolpidem MR showed no significant difference from placebo with regard to measures of residual next-day sedation, with the exception of one secondary parameter in compensatory tracking task mean response time in one study.7 In contrast, flurazepam did demonstrate evidence of residual sedation in both study populations, using measures of reaction time and immediate and delayed recall. These effects are presumably due to the long half-life and long duration of action of flurazepam.
Soubrane and colleagues9 conducted a randomized trial assessing safety and efficacy of zolpidem MR in 212 adults who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for primary insomnia. The study assessed sleep parameters including wake after sleep onset in hours 1–6 of sleep, latency to persistent sleep, and number of awakenings. Compared to placebo, zolpidem MR 12.5 mg showed shorter latency of persistent sleep; reduced wake after sleep onset; and decreased number of awakenings. The side-effect profile overall was relatively benign. There was fairly high incidence rates of headache for both active drug and placebo (18.6% versus 16.4%). Somnolence (14.7% versus 1.8%), dizziness (11.8% versus 5.5%), and nausea (6.9% versus 3.6%) were reported as well. A rebound effect was seen on the first night after discontinuation, but not on the second night, using a criterion for rebound of increase of sleep latency of >40% compared to baseline. There was no evidence of residual effects 8.5 hours post-dose.
Indiplon MR Clinical Trials
A 2-week double-blind, placebo-controlled, randomized trial10 assessed efficacy and safety of indiplon MR 30 mg in 211 adults with DSM-IV criteria for insomnia. Subjective data of total sleep time, wake after sleep onset, latency of sleep onset, and number of awakenings after sleep onset, were gathered through patient report. Psychomotor impairment was measured by the digit symbol substitution test and a verbal learning task. Indiplon MR showed significant separation from placebo with regard to improvements in subjective total sleep time (P<.001, Slide 14) and in reductions in wake after sleep onset at weeks 1 (P<.0001) and 2 (P<.0011). Finally, indiplon MR showed modest but significant improvement in sleep latency at weeks 1 (P<.01) and 2 (P<.05).
The adverse events data indicated that 41% of indiplon-treated patients reported at least one adverse event, compared to 22% taking placebo. Approximately 11% of indiplon-treated patients reported dizziness (5% mild, 5% moderate, <1% severe), compared to ~2% of patients who received placebo (<1% mild, <1% moderate, 0% severe).
This discussion has presented some of the data currently available on zolpidem MR and indiplon MR, both of which are in development and have been submitted to the FDA. It is expected that zolpidem MR will be available relatively soon. The hope is that MR hypnotics may improve sleep continuity without sacrificing the rapid elimination pharmacokinetics that minimize next-day residual effects.
Q: Other than its effects in increasing blood pressure and inflammation, are there any other mechanisms by which sleep deprivation increases cardiovascular risk? For example, have heart rate variability or platelet aggregation been studied in these subjects?
Dr. Patel: The effect of sleep deprivation on sympathovagal balance as measured by heart rate variability has been examined in several studies. The ratio of low frequency to high frequency power in the frequency spectrum of heart rate is a validated measure of the relative strength of sympathetic to parasympathetic neural output. This ratio was found to be elevated in the sleep deprivation condition in studies by Tochikubo and colleagues1 and Spiegel and colleagues,2 suggesting an elevation in sympathetic activity and/or a reduction in parasympathetic activity. The Tochikubo study1 also found elevated urine levels of norepinephrine after sleep deprivation, further supporting the hypothesis that sleep restriction increases sympathetic neural output. This elevation in sympathetic tone may represent one mechanism by which insufficient sleep leads to a rise in blood pressure and worsening of glucose metabolism.
To my knowledge, no studies of sleep deprivation have specifically examined its effect on platelet aggregation. However, sympathetic activation is known to stimulate platelet activation, so an effect of reduced sleep on platelet function is a very plausible hypothesis.
Q: Why does the relative risk for many health outcomes increase for those who sleep 8 or 9 hours?
Dr. Patel: There are several possibilities. First, the epidemiologic studies I discussed were observational; thus there is the possibility of residual confounding by things we did not assess. We do know that the people who sleep ≥9 hours tend to have worse health habits in general. For example, they tend to exercise less and drink alcohol more. In addition, they have much more depression, so it is possible that we missed depression or an underlying sleep disorder. Second, this was subjective, self-reported sleep; therefore, it is possible that patients were laying in bed for 9 hours, but were actually sleeping fewer hours. We have seen in several studies that people who claim to sleep ≥9 hours actually have more sleep-related complaints, including symptoms of insomnia. Third, there is a lot of variability, and some data suggest that there is a genetic basis for underlying sleep needs. Thus, the people who are sleeping more, may have an underlying genetic basis where they need more sleep to feel fully functional. In modern society, with 24-hour E-mail and cable television access, individuals with greater sleep needs may be at a survival disadvantage.
Q: Are there data available to indicate that treatment of insomnia should reduce some of the risks associated with the disorder?
Dr. Young: No, but it is an area where future research should be encouraged, as recommended at this year’s National Institute of Health State of the Science meeting in July. Some of the data that we do have looking at interventions has combined benzodiazepines, barbiturates, and over-the-counter medications. It will take some parsing out of different kinds of therapy to really answer that question.
Q: What were the causes of insomnia in the preliminary data discussed from the Wisconsin Sleep Cohort Study?
Dr. Young: We have not carefully examined the longitudinal data for causes of chronic insomnia. With the risk factors that we did look at, we had a hard time finding anything that was predictive of chronic insomnia. What we do see in the cross-sectional data are many correlates of insomnia, including restless legs, stress, menopausal symptoms, other comorbid conditions, pain, shift work, etc. It is very difficult to quantify the independent contributions for a disorder that has many factors related to cause, because there can be a lot of overlap, particularly in cross-sectional data. I think that we are going to need to look for large data sets and longitudinal analysis in the future to see if we can get some perspective on the causes of acute as well as chronic insomnia.
Q: Is there any risk associated with a greater sleep time in patients with sleep state misperception who are treated with a hypnotic?
Dr. Erman: By definition, a person with a sleep state misperception syndrome perceives that he is getting fewer hours of sleep than he is. This patient probably should not be given an agent to promote longer sleep, because in fact, it might increase the risk of the patient having residual sedation. The physician should work with the patient from a cognitive-behavioral therapy framework, trying to help them focus more on the hours of sleep that they feel they are getting. Daytime relaxation techniques can minimize arousals at night, in addition to use of an agent that will give them an appropriate duration of action.
Dr. Patel: Sleep state misperception syndrome is a somewhat controversial diagnosis, and it assumes that the current polysomnographic recording of sleep is the gold standard, which is probably not true since it is a rather crude measurement. If it were possible to accurately record deeper brain structures, they may indicate some abnormalities for those people who do have a different experience of sleep, even though by our standard criteria, they appear to be sleeping. I think we are probably going to understand much more about that population in the future, and come up with a better and realistic diagnosis for them rather than this peculiar, paradoxical insomnia.
Q: Patients with sleep state misperception may have elements of their sleep that do not fit into our scoring structures in terms of intrusion of arousing elements or patterns. Have you found that showing such patients data from a sleep study regarding this is helpful?
Dr. Neubauer: There may be some value in sharing such data sometimes in order to reassure a patient that they probably are getting the sleep they need to be reasonably healthy. On the other hand, it is not beneficial to try to force the patient into recognizing that he or she is getting enough sleep. Our patients in the inpatient psychiatric unit often complain about their sleep and our nurses have a checklist, so I know when the patients have been sleeping. I see little value in taking that checklist to them and telling them I know they really have been sleeping in spite of the fact that they say that they are not, because their own report is really what matters. I think there is a balance the physician needs to maintain about trying to convince patients that they are sleeping when they may feel that they are not.
Dr. Patel: I agree. I think it is a balance of both reassuring them that they are getting sleep as well as validating their subjective experience of being able to say there is an intrusion that could explain the subjective experience that they are having.
Dr. Erman: I strongly agree. It is helpful to reveal to patients that while their perception was having slept 4 hours the laboratory shows 5-1/2 or 6 hours, which is not very good sleep since there were disruptions, but it is more sleep than they thought they were getting. The physician should tell them that they can feel a bit reassured about their health, and that he or she will work with them to try to minimize these factors that are causing their sleep to be lighter.
Q: Other than treating any underlying medical or psychiatric conditions and promoting good sleep hygiene, what nonpharmacologic approaches do you recommend in the management of patients with chronic insomnia?
Dr. Erman: Use of pharmacologic therapy alone is never recommended for patients with chronic insomnia. Standard sleep hygiene recommendations are always beneficial, and regularity of habits, avoidance of alcohol and caffeine in the hours near bedtime, limitation of naps and education about their impact on sleep, and use of relaxation techniques in the hours before bedtime should always be emphasized. Additionally, there is good evidence that formal therapeutic regimens using techniques such as cognitive-behavioral therapy (CBT) are of benefit for the treatment of patients with insomnia. These approaches use techniques such as alteration of distortions that patients have about their sleep and sleep capabilities, education about sleep needs, and use of formal behavioral exercises to help promote sleep, combined with elements of sleep hygiene. Impediments to the use of CBT include the limited number of practitioners trained in this technique, the delay of at least several weeks before expected results, and a requirement that patients be willing to “buy in” conceptually to this approach as a therapy that will be of benefit for them in the long run.
Q: Considering that patients with narcolepsy get more sleep, does it follow that they would have decreased morbidity and mortality?
Dr. Erman: There are no data on this. First, while people with narcolepsy are sleepier, they are not necessarily the best sleepers. As a matter of fact, when hypnotics were first introduced, many narcoleptic patients were prescribed these medications to make them sleep better at night so that they would be more alert in the daytime. However, it did not work.
Dr. Neubauer: Right. Therefore, it seems unlikely that patients with narcolepsy would have better health because they sleep more.
Q: Is the 11% dizziness with indiplon modified release (MR) statistically significant?
Dr. Erman: We will probably have to await further publication to know the answer, and to know whether it will be replicated in other studies.
Q: How do MR agents affect slow-wave sleep and rapid eye movement sleep?
Dr. Neubauer: Probably no differently than the parent compounds themselves, and with this class of medications, there tends to not be any effect.
Q: How are MR agents formulated?
Dr. Neubauer: We do not really know because it is proprietary. We have discussed the little bit of public information that there is, but we will have to wait for further information.
– Erman (Introduction) –
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– Young –
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– Patel –
1. National Sleep Foundation. 2005 Sleep in American Poll. Available at: http://www.sleep-solutions.com/phys/education/2005_Sleep_In_America_Poll_Results.pdf. Accessed May 15, 2005.
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4. Spiegel K, Tasali E, Penev P, Van Cauter E. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141:846-850.
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12. Hasler G, Buysse DJ, Klaghofer R, et al. The association between short sleep duration and obesity in young adults: a 13-year prospective study. Sleep. 2004;27:661-666.
– Erman –
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2. Winokur A. Sleep disorders. In: Enna S, Coyle J, eds. Pharmacologic Management of Neurologic and Psychiatric Disorders. New York, NY: McGraw-Hill; 1998:213-235.
3. Kramer M, Schoen LS. Problems in the use of long-acting hypnotics in older patients. J Clin Psychiatry. 1984;45(4):176-177.
4. National Institute of Health statement. Available at: http://consensus.nih.gov. Accessed July 15, 2005.
5. Hindmarch I, Legangneux E, Emegbo S, Nixon A. A randomized double-blind placebo-controlled 10-way crossover study to show that a new zolpidem modified-release formulation improves sleep maintenance compared to standard zolpidem. Clin Pharmacol Ther. 2005;77:26. Abstract PI-68.
6. Hindmarch I, Stanley N, Legangneux E, Enegbo S. Zolpidem modified-release significantly reduces latency to persistent sleep 4 and 5 hours postdose compared with standard zolpidem in a model assessing the return to sleep following nocturnal awakening. Sleep. 2005;28(Suppl):A245. Abstract 0731.
7. Blin O, Micallef-Rolle J, Legangneux E, Zobouyan I. Zolpidem modified release 12.5 mg has no residual effects on psychomotor performance and cognitive function in healthy adult subjects. Sleep. 2005;28(Suppl):A246. Abstract 0733.
8. Legangneux E, Hindmarch I, Zobouyan I. Zolpidem modified-release 6.26 mg and double dose 12.5 mg have no residual effects on central nervous system integrative capacity, sensorimotor and psychomotor performance, and immediate and delayed memory recall in healthy elderly subjects. Sleep. 2005;28(Suppl):A245. Abstract 0729.
9. Soubrane C, Walsh JK, Roth T. Zolpidem modified-release improves sleep induction, sleep maintenance, sleep duration, and quality of sleep without next-day residual effects in adults with primary insomnia. Sleep. 2005;28(Suppl):A244. Abstract 0728.
10. Scharf MB, Roth T, Walsh JK, Jochelson PH, Garber M. Efficacy of indiplon MR in inducing and maintaining sleep in patients with chronic sleep maintenance insomnia. Presented at: 157th Annual Meeting of the American Psychiatric Association; May 1-6, 2004; New York, NY.
– QA –
1. Tochikubo O, Ikeda A, Miyajima E, Ishii M. Effects of insufficient sleep on blood pressure monitored by a new multibiomedical recorder. Hypertension. 1996;27:1318-1324.
2. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354:1435-1439.
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