Volume 2, Issue 1

 

Curent Update on Insomnia

January 19, 2011

Introduction

 Insomnia is common amongst 10-17% of the population. Such sleeplessness leads to a variety of functional impairments, including difficulty in coping, accomplishing tasks and entering into, developing and maintaining relationships that enhance and enrich one’s life. Additionally, those who suffer from insomnia often find themselves struggling with depression and anxiety, as well as lacking a zest for life. While many people are aware they suffer from a lack of or inability to maintain sleep, this condition is often not communicated to one’s health care professional; and, if it is, it is usually only after a patient has come to highlight another problem that may or may not be linked to the pre-existing insomnia. Therefore, when treating a person, it is important, and perhaps incumbent, upon the treating physician to inquire as to the patient’s sleep habits and patterns, and to be cognizant of other conditions that could potentially interrupt what would otherwise be normal sleep, leading to insomnia.

 

Normal Sleep

 Sleep is considered essential for normal and everyday functioning. Furthermore, sleep is considered a reversible behavioral state, unlike a coma. When one sleeps, he or she is considered to be “perceptually disengaged” from the surrounding environment, though not completely disengaged. During sleep, while the body and mind may be “at rest”, the activity of sleep involves every organ of the body and is controlled by the central nervous system (CNS). The sleep process involves two (2) remarkably different states: rapid eye movement, more commonly REM sleep, and non-rapid eye movement sleep, or NREM sleep.1

 

REM and NREM Sleep

 The sleep-wake cycle involves alternating periods of REM and NREM sleep, with REM sleep accounting for approximately 25% of one’s sleep pattern. During REM sleep, brain activity and oxygen consumption are increased, although this does not occur during NREM sleep.2 The heart rate is variable and respiration is irregular, where the body’s ability to regulate or maintain low levels of carbon monoxide is compromised. The result is an increase in the effects of certain breathing disorders, including chronic obstructive pulmonary disease, or COPD, sleep apnea and asthma.

 Furthermore, during REM sleep, voluntary skeletal muscles are actively paralyzed, except for certain muscle groups. Most dreaming occurs during REM sleep. With sleep disorders involved during the REM sleep cycle, patients are responsive to their dreams, which enables them to move. Such response or movements can be dangerous or threatening to the patient, and possibly others, if these dreams are violent in nature. NREM sleep accounts for the remaining 75% of sleep time, where the heart rate is steady and respiration is slow and monotonous. Brain activity and oxygen consumption also decrease during NREM sleep.

 

Sleep Architecture

 Since its discovery in 1953, REM sleep has been studied and evolved, providing a more profound understanding of this necessary life activity. Initially thought to be just an absence of wakefulness, REM has come to represent the intricate workings of the brain. REM sleep is now understood to be the result of the combination of the complex behavioral, physiologic, and psychological state produced by very active and very coordinated brain processing.

 Sleep occurs in an orderly progression through five stages, which occur throughout the night. This progression, or pattern, has come to be known as sleep architecture, a highly predictable and uniformed aspect of sleep. Throughout each of the five stages, there are unique characteristics and specific electroencephalographic (EEG) patterns associated only with that particular stage.3-5 When an awake person begins to become tired and drowsy, the EEG will reflect a rhythmic alpha activity of approximately eight-twelve cycles per second (cps). This is the beginning of the sleep cycle, with the transgression from the awake state to the first stage of the sleep process. The awake state is technically considered the first stage of sleep, though it is not denoted in this way.5

 

Stage 1:

During this stage, there is a decrease and eventually disappearance of  the rhythmic alpha activity and the introduction of a low voltage and mixed frequency pattern. Theta waves predominate, approximately three-seven (cps).5

 Stage 2:

During the second stage, postural control diminishes and eye movement ceases. New wave forms, known as sleep spindles and K complexes, appear on the EEG. A sleep spindle is considered to be a synchronized waveform resulting from simultaneous activation of a large number of neurons by one or more synchronizing pacemakers thought to be located in the thalamus. Sleep spindles are thought to have twelve-fourteen cps activity, lasting up to 1.5 seconds.5

 As for the K complexes present in this stage of sleep, their importance has yet to be determined. The K complexes appear as negative sharp waves, followed by a slower positive component. The K complexes only last for approximately one half of a second.5

 

Stage 3 & Stage 4:

Together, stages 3 and 4 of the sleep pattern are called the delta sleep, deep sleep and slow-wave sleep. High amplitude and slow delta activity, approximately .05-2 cps, dominate the EEG. During the third stage of sleep, delta waves comprise 20-50% of the tracing. During the fourth stage of sleep, delta waves comprise over half of the tracing.5

 Sleep progresses from stage 1 to stage 4 over a period of approximately 45 minutes after the onset of sleep. The first REM period develops within ninety minutes. Together, this is known as the NREM-REM pattern, which takes about ninety minutes and recurs repeatedly throughout the night.5

 The majority of delta sleep is experienced during the first third of the night. By the final third of the night, delta sleep disappears. With REM sleep, these periods grow longer with each sleep cycle and dominate the final third of the night.5

 The Effect of Age on Sleep

 Age has a direct correlation to the health of one’s sleep. The older the patient, the less time is spent in stages 3 and 4 and the more time is spent awake or in stage 1 of sleep.6 The decline in NREM stage 3 and 4 sleep starts between the ages of twenty and thirty, and continues to decline through the passing years, often reaching its near total by fifty-sixty years of age. Aging also influences the transitions between stages 1 and 2 of sleep, as well as the number of awakenings and arousals, all of which result in incomplete or fragmented sleep.

 

How Much Sleep Do We Need?

The National Sleep Foundation, or NSF, indicates that most people get seven- eight hours of sleep a night.7 However, the question becomes: is this really enough sleep? To answer this, one must examine an individual’s sleep requirements by assessing daytime sleepiness.

The Epworth Sleep Scale, or ESS, uses a scale of one to ten, to assess how likely a person is to fall asleep in everyday situations, such as driving or riding in a car. Any score greater than ten (>10) is considered abnormal and identifies a patient who has a sleep problem requiring attention. Based on the ESS, one third of Americans are too sleepy, in that they are either not getting enough sleep, sound sleep or a combination of the two.8

 When assessing a patient and his or her sleep behaviors and needs, it becomes important to ask two simple questions: 1. How much sleep do you require to feel refreshed and alert for the entire day? 2. How much sleep do you need to stay awake even during the most soporific conditions?

 

The Sleep-Wake Cycle

 Sleep and sleepiness are controlled by two major processes; one is homeostatic and the other circadian. The homeostatic factor is presumed to be the product of  “sleepiness factor” that accumulates within the brain during the waking hours. The circadian factor is a process based on an internal biological clock that determines various body circadian rhythms, including the sleep-wake rhythm. It is based on an approximate twenty-four hour cycle. This particular signal is not based on the amount of sleep, or lack thereof, from the preceding night, but rather may be based on many different clocks. The “master clock” of the circadian factor is thought to be in the suprachiasmatic nucleus (SCN). The effects of the circadian factor is evident in the distribution of many human functional impairments, such as the distribution of single-vehicle automobile accidents, which typically occur with the two peaks in sleepiness in the biological clock, the hours of 2:00 am – 6:00 am and 2:00 pm – 4 pm.9,10

 Other Influences

The sleep-wake cycle is also influenced by other factors, including environmental, anatomical and/or biochemical.11

 Light:

Light passing through the eye has a strong influence on the SCN. During the waking hours, the sunlight penetrates the eye, sending a message to the SNC that is morning and it is time to reset the body rhythms for the next twenty-four hours. Light is therefore an important component in setting our sleep-wake cycle as it relates to the twenty-four hour environmental time. Therefore, a patient suffering from insomnia should not sleep in late the next morning after failing to get restful sleep the night before; rather, the patient should wake at their usual time and expose themselves to the bright sunlight.

 

Melatonin:

Melatonin, which is released by the pineal gland, may be involved in the circadian sleep cycle as a hormone the guides the many body systems to follow the master clock’s timing.

 

Brain Structures:

 The brain, made of its many compartments and components, is thought to influence much of a person’s sleep-wake cycle. One of these components, the hypothalamus, is though to regulate the homeostatic sleep drive.

 

Neurotransmitters:

Certain neurotransmitters are involved in the sleep cycle. The homeostatic system is thought to rely on the activity of the gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, as well as on galanin. These substances are contained in areas such as the ventrolateral preoptic nucleus (VLPO). The tuberomammillary nucleus (TMN) is thought to be important for maintaining an awake state and is primarily controlled by histamine. The balance between the VLPO and TMN is likely responsible for the net production of either wakefulness or sleep. The neurotransmitters and modulators thought to be involved in the production of sleep include: adenosine, GABA, galanin and melatonin. The neurotransmitters and modulators thought to be involved in the production of wakefulness include: norepinephrine, serotonin, acetylcholine, histamine and orexin/hypocretin.

 

Primary Insomnia

Insomnia is defined as a problem falling asleep, staying asleep or waking too early. It has been further defined as some degree of daytime impairment or functional disturbance. It cannot be traced to some other medical or psychiatric disorder.12

 

Prevalence

  Insomnia is common, with 10-17% of our population being affected by it. The criterion for this diagnosis is based on sleep disturbance occurring every night for two weeks or more. Additionally, insomnia appears to be slightly more prevalent amongst women, though men tend to nap more. Further studies reveal that approximately 2.5% of primary care patients report having all three symptoms related to insomnia: difficulty in falling asleep, staying asleep and waking too early. Approximately 10% of the population reports a problem with just one of the three symptoms. Despite these numbers, only 6% of the population consult with their doctors specifically to address these sleep issues, while an astounding 70% never discuss sleep issues with their doctors.13-19

 

Consequences

Statistical data shows a correlation between insomnia and various functional impairments. Though a direct cause-and-effect relationship has yet to be determined, it has been reported that those patients who have trouble sleeping often report difficulty with coping, accomplishing tasks, maintaining satisfactory personal and familial relationships and controlling their moods or mood swings. Depression, anxiety and loss of vitality are more common amongst those suffering from insomnia. Additionally, insomnia affects one’s work or job performance, including the ability to appear for work. One study showed a 16% incidence of absenteeism at work in those suffering from insomnia. And, when at work, these same individuals performed poorly at their assigned tasks and were more dissatisfied with their jobs in general.20-23

Another consequence of insomnia is the reality of an accident, one that can be serious and sometimes fatal. One study found a 9% incident rate of serious accidents in chronic insomniacs, while another study showed that people with sleep problems were 3.5 times more likely to have a motor vehicle accident than those who slept well.23

 

Relationships with Psychiatric Disorders

 There is further data that suggests that insomnia predicts future psychiatric disorders, including major depression, anxiety disorders and alcohol abuse.24-30

 

Neurophysiologic Findings

 Studies in patients with primary insomnia suggest that there exists a generalized state of hyperarousal, which is often characterized by:

  • Activation of the hypothalamic-pituitary axis.
  • Increased sympathetic nervous system activity, such as the heart rate.
  • Enhanced EEG high-frequency activity during sleep, where the EEG studies show a reduction in delta activity (deep, restful sleep) and an increase in rapid brain activity.
  • Functional neuroimaging changes showing enhanced glucose uptake during sleep.
  • Cognitive arousal, such as a person’s inability to “turn off the mind” when going to bed or after awaking. 
  • Increased body metabolic rate.

 

The Three P’s

 Individuals predisposed to insomnia, whether such predisposition exists because of one’s personality, individual sleep-wake cycle or circadian rhythm can and often are influenced by a variety of life events, including but not limited to those events arising situationally, medically or environmentally. While such factors may precipitate insomnia, other factors, such as drug and alcohol abuse or poor sleep hygiene, can perpetuate it. Therefore, the “3 P’s” – predisposing factors, precipitating factors and perpetuating factors, help explain the progression of chronic insomnia.31-33

 Examples of Predisposing Factors

  • Personality
  • Sleep-wake cycle
  • Circadian rhythm
  • Coping mechanisms
  • Age

 Examples of Precipitating Factors

  • Situational
  • Environmental
  • Medical
  • Psychiatric
  • Medications

Examples of Perpetuating Factors

  • Conditioning
  • Substance abuse
  • Performance anxiety
  • Poor sleep hygiene

 Secondary, or co-morbid, insomnia results from another illness or condition, or perhaps even co-exists with it. Examples of such disorders that can influence or bring about this secondary insomnia include: medical conditions, neurological derangements, substance abuse, anxiety, depression, adjustment problems and bipolar disorder. When evaluating a patient, it is important to explore a variety of factors.33

 Depression

 The link between insomnia and depression is so strong that depression is always included in the differential workup of a person with deranged sleep.  One study found that the onset of insomnia more commonly preceded the depression. However, the same relationship does not apply to other psychiatric disorders.  Patients who exhibit major depression are more likely to be suicidal if they cannot sleep.34,35

 Substances and Medications

 Alcohol induces sleep quickly. However, it is not beneficial to sleep or as a sleep aid because alcohol is metabolized in the body rapidly, causing a withdrawal reaction that awakens the person. Caffeine is a short-acting substance but is best avoided after 2:00 pm because it can remain in the body for a long time and can interfere with sleep. Examples of medications that can cause insomnia, though not exhaustive, include antidepressants, anti-hypertensives, anti-neoplastic drugs, hormones and decongestants.36

 Medical Conditions

 Respiratory Disorders:

 Sleep can intensify the predisposition for diminished blood oxyhemoglobin saturation levels for patients with COPD, asthma and other respiratory illnesses. Low arterial oxygen saturation levels can in turn result in C NS irritability and poor sleep quality. Obstructive Sleep Apnea Syndrome, or OSA, is commonly characterized by poor sleep quality and interrupted sleep, daytime sleepiness and snoring. The underlying cause is a functional collapse of the airway that occurs because of a derangement in the sleep mechanism that normally stimulates the pharynx to remain open at night.37,38

 Gastroesophageal Reflux Disease (GERD):

The arousal process is important in producing proper acid clearance from the esophagus in patients with an incompetent lower esophageal sphincter, the basis of GERD.37,38

 Geriatric Conditions:

Prostate difficulties are a leading cause of insomnia in older men who are forced to make multiple trips to the bathroom at night.37,38

Restless Leg Syndrome (RLS):

Patients with RLS have an uncontrollable urge to move their extremities, which is often accompanied by sensations of itching, burning, crawling and/or cramping in the legs and other body parts. These sensations intensify at night and can awaken the patient.37,38

 

 Circadian Rhythm Sleep Disorders

 Circadian rhythm sleep disorders result from externally imposed sudden changes in sleep-wake times to which internal clocks cannot adapt properly, or from aberrations of the internal biological clock mechanisms themselves. Other body functions that follow a circadian pattern include: body temperature, melatonin, cortisol release, kidney output and hormonal regulation.39-41

Jet Lag and Shift Work Sleep Disorder

 Jet lag occurs following travel across at least two time zones, and can often be accompanied by malaise and gastrointestinal disturbances. It is presumed to result from a mismatch between the body’s rhythms and those of the environmental cycle, as well as a de-synchronization between the various endogenous rhythms. In shift work sleep disorder, the body is forced to change rhythms too rapidly and cannot adjust in a timely manner to repeated changes in sleep-wake times.39-42

 There are four guiding principles to help counteract the effects of jet leg and shift work:39-42

  1. Adjust rhythms gradually in increments of no more than three hours from one day or one shift to the next; delay and not advance the sleep schedule whenever possible.
  2. Plentiful exposure to light during waking hours helps body rhythms to re-synchronize quickly; sleeping in a darkened room is helpful.
  3. Take brief naps when sleepy; however, naps should occur at the same time every day to avoid confusing circadian rhythms.
  4. Keep sleep schedules as constant as possible, especially during shift work; sleep should occur at the same time every day, including days off and weekends.

 Irregular Sleep-Wake Rhythm

 Irregular sleep-wake rhythm is characterized by chronic insomnia and multiple (three or more) bouts of sleep that occur during a twenty-four (24) hour period. The repetitive pattern of sleeping and waking is involuntary. Though the cause of this disorder is unknown, it is more commonly seen in the elderly and those patients suffering from dementia or head trauma.39,41

 Delayed and Advanced Sleep Disorder

 Delayed sleep phase syndrome occurs primarily in children and adolescents. With this disorder, the timing of sleep is delayed relative to the usual day/night cycle. Affected persons are unable to fall asleep if they do go to bed earlier at night. Treatment for this disorder consists of good sleep hygiene and exposure to bright, artificial light in the morning. The schedule of light exposure is gradually advanced across one or two weeks until the child is falling asleep earlier in the evening.41-43

 Advanced sleep phase syndrome fall asleep early and wake up early. The elderly tend to be affected more than any other age group. Treatment for this disorder involves exposure to bright light in the evening and avoidance of early morning light.41-43

 Free-Running Circadian Rhythms

 Patients suffering from free-running circadian rhythms suffer from several days of insomnia, followed by sleep periods that endure from fourteen to eighteen hours a day. After patients with this disorder awaken from these lengthy bouts of sleep, they are unable to go back to sleep for a day. This disorder is more prevalent amongst the blind, which seems to support the theory that this particular disorder is caused by an absence of a light signal to the SCN.41-43

 Evaluating Insomnia

 When evaluating a person who has insomnia, a thorough medical and psychiatric history is necessary. Try and determine the pattern of insomnia, if it seems to be related to any life event(s) or changes in environment. Inquire as to the patient’s treatment with medication, or consumption of caffeine or alcohol. Discuss the patient’s sleep habits and patterns, such as being a light or heavy sleeper. Inquire as to whether there is a history of such condition within the family. An indication of an underlying psychological or psychiatric condition may necessitate further testing. Furthermore, a physical examination is an important element of the patient’s workup. Such testing should include a test for diabetes, heart disease, GERD, RLS and respiratory conditions, including allergies, asthma, OSA and COPD. Also examine the patient’s lifestyle, asking the patient to keep a sleep log, wherein the patient records the twenty-four hour sleep-wake cycle patterns over a two-week period. Keep in mind to inquire about the patient’s travel and work schedule, exercise and eating habits and activities prior to bed.44

Referral

 After a thorough medical evaluation, it may become necessary to refer the patient to a sleep specialist. This is especially true when the patient appears to have OSA and/or when the patient is having severe daytime sleepiness or the patient’s nocturnal behaviors are dangerous.

 Treatment

 A Multi-factorial Problem Permits a Multimodal Solution

 One’s ability to fall asleep, and stay asleep, is influenced by both internal and external factors. Whatever initiates the episode usually does not perpetuate the symptoms. Therefore, the best strategy for treating patients with insomnia involves an integrated combination of psychological interventions, behavioral changes and perhaps pharmacologic treatment.

 Non-pharmacologic Treatment

 There are a number of non-pharmacologic treatment options for insomnia available to such patients, including:45

 Good Sleep Hygiene:

This includes maintaining regular sleep-wake hours. Homeostatic and circadian processes predispose a patient to sleep at a particular time. It is important that patients listen to their body and not to fall into the “nap trap”, which can diminish the homeostatic drive that helps one fall asleep and stay asleep the following night. Napping can perpetuate insomnia.

 It is important to advise patients to keep caffeine to a minimum, especially after lunch, and caution the patient to beware of the effects of alcohol, which though initially may be sedating, as it leaves the body and is eliminated from the system, tends to be hyper-arousing.

 A small snack may be conducive to sleep; however, large or heavy meals just before bedtime can interfere with sleep, especially in a patient who suffers from a reflux disorder.

 Exercise can be an aid to reducing insomnia, though not necessarily within a few hours before sleep.

 Developing a relaxing evening routine is important in combating insomnia. It is important to do something soothing as bedtime approaches.

 A patient should be guided to use their bedroom for sleep and sex only.  This helps build strong and positive associations of one’s bed with sleep.

 Exposure to extreme temperatures, disturbing light and disruptive noises should also be avoided, though absolute silence can also be counter-productive.

 Relaxation Techniques:

The underlying principle behind relaxation techniques is that it reduces physiologic and cognitive arousal at bedtime, which can make falling asleep easier.

 A variety of techniques are available, including: progressive muscle relaxation, biofeedback, breathing exercises, yoga and meditation.

 Relaxation techniques should be practiced at a time other then bedtime. Once mastered, such techniques will more readily help the body and mind prepare for sleep.

 Stimulus Control Therapy:

This strategy is aimed at helping patients break associations of their bed with wakefulness and to build the association of their bed with sleep and sex.

 Stimulus control therapy combines de-conditioning with slight sleep deprivation to promote re-association of going to bed with a successful sleep onset. With this therapy, patients should be cautioned not to go to bed until they think they can fall asleep, and if they do not fall asleep within ten minutes of getting into bed, they should get up and go to another room, engaging in another activity. Despite the time of slumber, patients must maintain their regular wake-up time and refrain from napping during the day.45

 Sleep Restriction Therapy:

This strategy also seeks to break the negative association of the bed with wakefulness.  Under this theory, patients are to limit the time they spend in bed to their estimated total sleep time, maintaining the same wake-up time. Upon reporting more than 90% of their time spent in bed asleep, a patient can then go to bed a little earlier.46

Psychotherapy:

In some patients, insomnia develops because of issues and circumstances in the individual’s life, a circumstance or issue that he or she is not effectively responding to. A cognitive-behavioral therapy approach to insomnia incorporates education about sleep hygiene and elements of other non-pharmacologic strategies.47

 Comparison of Non-Pharmacologic Interventions:

A meta-analysis of fifty-nine controlled outcome studies of psychological intervention or insomnia patients revealed that patients who received one or more of these interventions fell asleep more easily and maintained their sleep better. The most effective strategies in this meta-analysis were stimulus control and sleep restriction.47

 

Pharmacologic Therapy

 Over-the-Counter Agents:

 Approximately 25% of patients suffering from some form or degree of insomnia attempt to address the issue initially with sleep aids from their local pharmacy or supermarket. One such over-the-counter agent comes in the form of dietary supplements and herbal preparations, items which, include ingredients such as: valerian root, kava kava, melatonin, chamomile and passiflora. However, because such items are not regulated in the same manner and degree as pharmaceuticals, little is known about the efficacy, purity or safety of most of these products.48

 Melatonin is one of the few dietary supplements promoted to treat insomnia that has been studied extensively, though the results of melatonin to treat insomnia have been equivocal regarding its efficacy.48

 When a patient resorts to such over-the-counter remedies, it often means a delay in seeking proper or appropriate medical attention for the problem, which in turn can and often does postpone effective therapy, as well as the diagnosis and treatment of any underlying medical conditions or disorders.48

 Other over-the-counter agents are antihistamines. The most common ingredient in antihistamines, both over-the-counter and prescription products is diphenhydramine. Diphenhydramine is well absorbed and widely distributed through the CNS and has an elimination half-life of about eight hours. Its principal mechanism of action is postsynaptic blockade of H1-receptors, which promotes sleep onset.48

 Despite being available over-the-counter, diphenhydramine can cause more problems than some prescription sleep aids. In addition to being a postsynaptic H1-receptor antagonistic, it is also a postsynaptic muscarinic receptor antagonist. Therefore, it can cause anticholinergic side effects that include dry mouth, blurred vision, constipation, urinary retention, memory impairment, confusion and delirium.48

 Also, because diphenhydramine has a long half-life, it may cause the patient to wake-up feeling groggy.48

 Antipsychotics and Antidepressants:

 These agents can be mildly to moderately sedating and have minimal abuse potential. These are beneficial in patients with insomnia who also have schizophrenia, bipolar disorder, or another comorbid psychiatric disorder. These agents are fairly long acting and thus can result in residual daytime sedation.

Many patients with depression also have trouble sleeping. A sedating antidepressant can be a good treatment choice, however no antidepressant has an FDA indication for insomnia.48,49

 Selective seratonin reuptake inhibitors (SSRIs) and other Sedating Antidepressants:

Often prescribed for insomnia, these medications do very little to promote sleep. Actually, they are mildly stimulating and can undermine sleep quality. Other antidepressants that are sometimes prescribed include trazadone, nefazadone, and mirtazapine. Trazadone is the most widely used, prescribed for insomnia more often than any other medication, including the hypnotics, that are indicated for the condition. Trazadone facilitates sleep primarily through postsynaptic blockade of 5HT-2A and H1 receptors.48-50

 A number of adverse affects are associated with trazadone. Because of its relatively long half-life (5-12 hrs depending on the patient’s metabolism), it often causes residual sedation. Trazadone is an alpha-1 receptor blocker and can cause orthostatic hypotension or dizziness in patients with hypotension. It may also cause arrhythmias, as well as priapism in men.48-50

Trazadone, in conjunction with other serotonergic medications have been implicated in causing seratonin syndrome, which is rarely brought on by a single medication. The initial symptoms of serotonin syndrome include agitation, restlessness, and confusion, which could progress to incoordination, myoclonus, hyperreflexia, diaphoresis, shivering, fever, and in worst cases coma, and death.50

 Sedative Hypnotics:

 The eight agents with an indication for insomnia include five older benzodiazepines (estazolam, flurazepam, quazepam, temazepam, and triazolam) and three newer, non-benzodiazepine medications (eszopiclone, zaleplon, and zolpidem). All of these drugs work by enhancing GABA activity. The GABA-A receptor complex is involved in the production of sedating, hypnotic effects. Each type of GABA receptor complex can be further divided into subunits, each of which has a number of subtypes. The five benzodiazepines are non-selective, they interact with many of the GABA-A subunit subtypes. The three newer agents, however, are more selective for the alpha-1 subtype. GABA-A1 subtype is highly correlated with sedation and amnesia.48-50

The elimination half-lives of sedative-hypnotics vary tremendously, and as a result, so does their duration of action. Halve lives range from 1 hour for zaleplon or 2.5 hours for zolpidem, to several days for flurazepam. Medications in this class can hasten sleep onset, decrease the number of awakenings, and increase total sleep time. If discontinued abruptly, however, these agents may produce some rebound insomnia. The benzodiazepines can decrease slow-wave and rapid eye movement sleep.48-50

  Abuse of these medications varies (the three non-benzodiazepines seem to have less abuse potential than the benzodiazepines), all agents in this class have some potential to be abused and have been classified as Schedule IV by the DEA.48-50

 The FDA indication for the two older benzodiazepines (zaleplon and zolpidem) is for short-term treatment of insomnia, while for the newest, eszopiclone, is for the treatment of insomnia. Long-term use of zaleplon or zolpidem may be safe as long-term use of eszopiclone.48-50

 Zaleplon has the shortest duration of action of all of the three hypnotics, up to 3-4 hours. This drug is best suited for patients whose principle difficulty is with falling asleep. It may be less helpful in reducing the number of awakenings later in the night. An advantage to zaleplon is that it has no lingering effects the next morning. Zolpidem has a half-life of 2.5 hours.  It can increase the duration of sleep and decrease sleep latency.51

 Eszopiclone is a slightly modified version of zoplicone.  It is the first sedative-hypnotic to have been studied in long-term double blind, placebo controlled clinical trials. The half-life of eszopiclone is approximately 6 hours. Due to its long duration of action it may have lingering morning after effects.51-53

 Selective Melatonin MT1/MT2 Receptor Agonists:

  Ramelteon was approved by the FDA in 2005 for the treatment of insomnia characterized by sleep-onset difficulty. It acts on the suprachiasmatic nucleus (SCN), a key region of the body’s sleep regulating mechanism, rather than on the CNS globally. Because it is not a CNS depressant, it has no sedating properties, no abuse liability, and is the first DEA non-scheduled medication approved for the treatment of insomnia.54

Ramelteon does not interact with the GABA system, histamine receptors, opioid receptors, noradrenergic receptors, or acetylcholine receptors. Rather, it interacts with melatonin MT1 and MT2 receptors. functioning as an agonist. The MT1 receptors have a sleep-promoting function, while the MT2 receptors are thought to be involved in the timing of circadian rhythms. Therefore, the mechanism of action can be classified as a chronobiotic effect. The drug’s affinity for both MT1 and MT2 receptors is significantly greater than that of melatonin itself. There are no significant endocrinopathies associated with ramelteon use, although there have been reports of mild increase in prolactin production in women.54,55

Ramelteon has an elimination half-life of 1-3 hours. It has an active, although less potent metabolite with a half-life of 2-5 hours that extends its duration of action. The drug is metabolized in the liver, primarily through the CYP1A2 system. It has minimal potential for drug-drug interactions. However, there is significant potential interaction with fluvoxamine, a major CYP1A2 inhibitor. The drug should be used with caution in patients with moderate hepatic impairment, and contraindicated in patients with severe hepatic impairment.55,56

 The Future

Other medications that target melatonin receptors are currently being developed, as is novel non-benzodiazepine hypnotics in controlled release formulas. As of 2005, the NIH state of science conference recognized that insomnia is a chronic, potentially lifelong illness. Due to the chronic nature of the disorder and the length of the clinical trials for the drugs that are reported to treat it, but the longest of which has lasted for only a year or less.57,58

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