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Sleep Disorders: Assisting Patients to a Good Night's Sleep
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PATIENT CARE
Sleep Disorders: Assisting Patients to a Good Night's Sleep More than 50 million Americans suffer from insomnia or intermittent sleep disorders, but effective treatments such as improved sleep hygiene and short-term pharmacotherapy can help.
A well-rested body and mind are essential to good health, optimal concentration, and productive work. Over 50 million Americans suffer from insomnia or intermittent sleep disorders, impacting their ability to function during waking hours. This symposium focused on assisting those patients to a good night's sleep. Gregory Toney, PharmD, BeCp, opened the session with a review of normal sleep physiology. An active rather than a passive process, sleep consists of a macrostructure of slow wave sleep (stages 1-4) and rapid eye movement (REM) sleep. Each night, individuals cycle between these stages. Sleep has a microstructure of brief periods of lightening of sleep depth alternating with a tonic state. Sleep also exhibits chronobiology, with sleep-wake cycles controlled by circadian rhythms. Jet lag and shift work offer clinical examples of interference with sleep chronobiology. Changing sleep patterns that occur with aging also appear to be related to chronobiology. Decreases in REM sleep, time spent in stage 4 (the deepest) sleep, and total sleep time appear to be caused by an age-related reduction in the circadian variation in melatonin production.
Melatonin and the Neurochemistry of Sleep . Melatonin, a hormone produced by the pineal gland, is regulated by light-dark stimulation from the retina. Its concentrations follow a circadian rhythm, increasing 1 to 2 hours prior to Based on presentations by Gregory Toney, PharmD, BCPP, clinical assistant professor ofpharmacy, University of Texas at Austin and clinical assistant professor ofpharmacology, University of Texas Health Science Center at San Antonio; and Larry Ereshefsky, PharmD, BCPP, professor ofpharmacy, pharmacology, and psychiatry, University of Texas at Austin and the University of Texas Health Science Center at San Antonio and associate director of the Clinical Research Unit, San Antonio State Hospital.
S46
Supplement to the Journal of the American Phannaceutical Association
sleep onset, and peaking approximately 8 hours after initial increase. Melatonin binds to receptors in the suprachiasmic nucleus, decreasing its firing rate and promoting a tendency to sleep. Working through this mechanism, exogenously administered melatonin has been shown to be an effective therapeutic option for relieving insomnia in the elderly and those with situational disruptions in circadian rhythms. All sleep rhythms are brought about by neurochemical processes in the brain. Serotonin plays a role in sleep induction. Norepinephrine, acetylcholine, dopamine, and gammaaminobutyric acid (GABA) are all involved in aspects of arousal. Anticholinergic agents, such as diphenhydramine, induce somnolence by blocking acetylcholine receptor sites. Most pharmacological sleep agents operate at GABA receptor sites, reducing vigilance and inducing sedation.
Assessment of Sleep Disorders Larry Ereshefsky, PharmD, further discussed these pharmacological agents and other modalities for management of insomnia. He noted that 70% of persons with insomnia do not discuss their sleep problem with their physicians. The first step in helping these patients is to elicit the history, which a pharmacist may suspect after observing repeated purchases of over-thecounter (OTe) sleep aids. Next, primary sleep disorders must be differentiated from those related to other conditions. The answer to the patient's problem may lie in lifestyle changes or treatment of an illness, rather than pharmacological intervention. Medical conditions, such as chronic obstructive pulmonary disease and chronic pain, may be interfering with normal sleep. Anxiety, depression, or substance abuse may also explain the problem. A pharmacist's most important contribution can be in recognizing insomnia as related to selected substances, OTe medications, and drugs which may be interfering with sleep (see Table 1). Withdrawal from hypnotics, antidepressants, or abused substances can also precipitate insomnia.
September/October 2000
Vol. 40, No.5, Suppl. 1
Sleep Disorders: Assisting Patients to a Good Night's Sleep
Table 1. Selected Drugs and Substances That May Cause Insomnia • Caffeine, alcohol, nicotine • Som e antidepressants • Anti hypertensives: Beta blockers Clonidine • Ch ronic hypnotic use • Sympathomimetic amines: Amphetamines Anorexics • Corticosteroids, levodopa, methylsergide, oral contraceptives, phenytoin, quinidine, theophylline, thyroid preparations
Primary Insomnia When secondary causes of insomnia have been ruled out, the problem can be defined as primary insomnia. This diagnosis is rarely made, since most insomnia occurs as part of another condition or psychiatric disorder. An exception may be age-related declines in neurotransmission integrity, resulting in primary insomnia. Instead of using primary insomnia as a diagnosis, descriptive terms such as difficulty falling asleep or maintaining sleep, and nonrestorative sleep are used to describe patient-related difficulties. Insomnia is then categorized according to its duration: Transient insomnia, which lasts no more than several days, usually results from situational stress, change in environment, or medical illness. These brief episodes of insomnia ordinarily resolve spontaneously, so treatment is elective. Short-term insomnia can be defined as insomnia lasting from several days to 3 weeks. This condition results from more significant factors, such as emotional trauma, bereavement, hospitalization, or other major life stressors. Treating patients with short-term insomnia is appropriate, because it may help them reestablish normal sleep cycles. In addition, adequate sleep can aid in dealing with stressful situations. Chronic insomnia is any insomnia lasting longer than 3 weeks. This condition is often associated with physical or emotional illness, and is usually exacerbated by anxiety about not being able to sleep. Pharmacological treatment for a week or two can help relieve this anxiety and restore sleep cycles. However, most of these patients will require attention to their medicalor psychological problems and a program to improve sleep hygiene. This may begin with such measures as regulating the sleep schedule and improving the bedroom environment, and extend to relaxation techniques and cognitive therapy.
Pharmacological Treatments
PATIENT CARE
blocking antidepressants, such as nefazodone and trazodone, can be efficacious. Sedating tricyclic antidepressants, such as doxepin and amitriptyline, can be effective in low doses for patients suffering anxiety and depressive disorders, but this indication has not been approved by the FDA, and may be accompanied by more adverse effects than other therapies. Benzodiazepines, particularly the newer, more selective agents, provide the mainstay of insomnia therapy today. Because they bind preferentially to the omega-1 receptor subunits of the GABA receptor, zolpidem (Ambien-Searle) and zaleplon (Sonata-Wyeth-Ayerst) do not exhibit the anxiolytic, anticonvulsant, and muscle relaxing properties of other benzodiazepines. These drugs also do not interfere with the deeper stages of sleep, as the older benzodiazepines did. Zolpidem and zaleplon appear to be equally effective in initiating sleep. However, because of subtle pharmacokinetic and pharmacodynamic differences, zaleplon has a slightly more rapid onset of action and a faster clearance time than zolpidem. Consequently, zolpidem increases total sleep time slightly more than does zaleplon. Zaleplon exhibited significantly fewer rebound and withdrawal effects with chronic use than zolpidem in recent studies, and has been associated with less cognitive and psychomotor impairment, especially if the patient awakens within 5 hours of taking a dose of the sedative hypnotic. This advantage is due to zaleplon's shorter duration of effect and possibly looser binding to the omega-1 receptor. Although these drugs provide notable benefits compared with older agents, they are approved only for short-term (7 to 14 days) use. Chronic insomnia remains a challenge for health care professionals, requiring willingness to employ counseling, education, and behavioral modification. On occasion, a benzodiazepine selective receptor agonist or 5-HT2A antagonist may be used for 2 to 4 months, along with behavioral therapy. Nonresponsive cases should be referred to a sleep specialist.
Summary • Sleep is an active process consisting of macro:' and microarchitectural rhythms, chronobiology, and neurochemical changes. • Disruptions in sleep chronobiology, which may occur in shift workers and the elderly or due to jet lag, often respond to exogenous melatonin. • Insomnia requires careful evaluation to determine contributions of comorbid medical conditions and drug effects. • Treatment options include sleep hygiene principles and sedative hypnotic therapy. • Zaleplon and zolpidem, short-acting benzodiazepines selective for omega-1 GABA receptors, are effective first-line agents for initiating sleep. This symposium was made possible by an unrestricted educational grant from Wyeth-Ayerst Pharmaceuticals.
Pharmacotherapy for insomnia has moved well beyond the chloral hydrate, bromides, and barbiturates of the past. Although not FDA-approved for insomnia, 5-HT2 receptorVol. 40, No.5, Suppl. 1
September/October 2000
Supplement to the Journal of the American Phannaceutical Association
S47
PATIENT CARE
Sleep Disorders: Assisting Patients to a Good Night's Sleep More than 50 million Americans suffer from insomnia or intermittent sleep disorders, but effective treatments such as improved sleep hygiene and short-term pharmacotherapy can help.
A well-rested body and mind are essential to good health, optimal concentration, and productive work. Over 50 million Americans suffer from insomnia or intermittent sleep disorders, impacting their ability to function during waking hours. This symposium focused on assisting those patients to a good night's sleep. Gregory Toney, PharmD, BeCp, opened the session with a review of normal sleep physiology. An active rather than a passive process, sleep consists of a macrostructure of slow wave sleep (stages 1-4) and rapid eye movement (REM) sleep. Each night, individuals cycle between these stages. Sleep has a microstructure of brief periods of lightening of sleep depth alternating with a tonic state. Sleep also exhibits chronobiology, with sleep-wake cycles controlled by circadian rhythms. Jet lag and shift work offer clinical examples of interference with sleep chronobiology. Changing sleep patterns that occur with aging also appear to be related to chronobiology. Decreases in REM sleep, time spent in stage 4 (the deepest) sleep, and total sleep time appear to be caused by an age-related reduction in the circadian variation in melatonin production.
Melatonin and the Neurochemistry of Sleep . Melatonin, a hormone produced by the pineal gland, is regulated by light-dark stimulation from the retina. Its concentrations follow a circadian rhythm, increasing 1 to 2 hours prior to Based on presentations by Gregory Toney, PharmD, BCPP, clinical assistant professor ofpharmacy, University of Texas at Austin and clinical assistant professor ofpharmacology, University of Texas Health Science Center at San Antonio; and Larry Ereshefsky, PharmD, BCPP, professor ofpharmacy, pharmacology, and psychiatry, University of Texas at Austin and the University of Texas Health Science Center at San Antonio and associate director of the Clinical Research Unit, San Antonio State Hospital.
S46
Supplement to the Journal of the American Phannaceutical Association
sleep onset, and peaking approximately 8 hours after initial increase. Melatonin binds to receptors in the suprachiasmic nucleus, decreasing its firing rate and promoting a tendency to sleep. Working through this mechanism, exogenously administered melatonin has been shown to be an effective therapeutic option for relieving insomnia in the elderly and those with situational disruptions in circadian rhythms. All sleep rhythms are brought about by neurochemical processes in the brain. Serotonin plays a role in sleep induction. Norepinephrine, acetylcholine, dopamine, and gammaaminobutyric acid (GABA) are all involved in aspects of arousal. Anticholinergic agents, such as diphenhydramine, induce somnolence by blocking acetylcholine receptor sites. Most pharmacological sleep agents operate at GABA receptor sites, reducing vigilance and inducing sedation.
Assessment of Sleep Disorders Larry Ereshefsky, PharmD, further discussed these pharmacological agents and other modalities for management of insomnia. He noted that 70% of persons with insomnia do not discuss their sleep problem with their physicians. The first step in helping these patients is to elicit the history, which a pharmacist may suspect after observing repeated purchases of over-thecounter (OTe) sleep aids. Next, primary sleep disorders must be differentiated from those related to other conditions. The answer to the patient's problem may lie in lifestyle changes or treatment of an illness, rather than pharmacological intervention. Medical conditions, such as chronic obstructive pulmonary disease and chronic pain, may be interfering with normal sleep. Anxiety, depression, or substance abuse may also explain the problem. A pharmacist's most important contribution can be in recognizing insomnia as related to selected substances, OTe medications, and drugs which may be interfering with sleep (see Table 1). Withdrawal from hypnotics, antidepressants, or abused substances can also precipitate insomnia.
September/October 2000
Vol. 40, No.5, Suppl. 1
Sleep Disorders: Assisting Patients to a Good Night's Sleep
Table 1. Selected Drugs and Substances That May Cause Insomnia • Caffeine, alcohol, nicotine • Som e antidepressants • Anti hypertensives: Beta blockers Clonidine • Ch ronic hypnotic use • Sympathomimetic amines: Amphetamines Anorexics • Corticosteroids, levodopa, methylsergide, oral contraceptives, phenytoin, quinidine, theophylline, thyroid preparations
Primary Insomnia When secondary causes of insomnia have been ruled out, the problem can be defined as primary insomnia. This diagnosis is rarely made, since most insomnia occurs as part of another condition or psychiatric disorder. An exception may be age-related declines in neurotransmission integrity, resulting in primary insomnia. Instead of using primary insomnia as a diagnosis, descriptive terms such as difficulty falling asleep or maintaining sleep, and nonrestorative sleep are used to describe patient-related difficulties. Insomnia is then categorized according to its duration: Transient insomnia, which lasts no more than several days, usually results from situational stress, change in environment, or medical illness. These brief episodes of insomnia ordinarily resolve spontaneously, so treatment is elective. Short-term insomnia can be defined as insomnia lasting from several days to 3 weeks. This condition results from more significant factors, such as emotional trauma, bereavement, hospitalization, or other major life stressors. Treating patients with short-term insomnia is appropriate, because it may help them reestablish normal sleep cycles. In addition, adequate sleep can aid in dealing with stressful situations. Chronic insomnia is any insomnia lasting longer than 3 weeks. This condition is often associated with physical or emotional illness, and is usually exacerbated by anxiety about not being able to sleep. Pharmacological treatment for a week or two can help relieve this anxiety and restore sleep cycles. However, most of these patients will require attention to their medicalor psychological problems and a program to improve sleep hygiene. This may begin with such measures as regulating the sleep schedule and improving the bedroom environment, and extend to relaxation techniques and cognitive therapy.
Pharmacological Treatments
PATIENT CARE
blocking antidepressants, such as nefazodone and trazodone, can be efficacious. Sedating tricyclic antidepressants, such as doxepin and amitriptyline, can be effective in low doses for patients suffering anxiety and depressive disorders, but this indication has not been approved by the FDA, and may be accompanied by more adverse effects than other therapies. Benzodiazepines, particularly the newer, more selective agents, provide the mainstay of insomnia therapy today. Because they bind preferentially to the omega-1 receptor subunits of the GABA receptor, zolpidem (Ambien-Searle) and zaleplon (Sonata-Wyeth-Ayerst) do not exhibit the anxiolytic, anticonvulsant, and muscle relaxing properties of other benzodiazepines. These drugs also do not interfere with the deeper stages of sleep, as the older benzodiazepines did. Zolpidem and zaleplon appear to be equally effective in initiating sleep. However, because of subtle pharmacokinetic and pharmacodynamic differences, zaleplon has a slightly more rapid onset of action and a faster clearance time than zolpidem. Consequently, zolpidem increases total sleep time slightly more than does zaleplon. Zaleplon exhibited significantly fewer rebound and withdrawal effects with chronic use than zolpidem in recent studies, and has been associated with less cognitive and psychomotor impairment, especially if the patient awakens within 5 hours of taking a dose of the sedative hypnotic. This advantage is due to zaleplon's shorter duration of effect and possibly looser binding to the omega-1 receptor. Although these drugs provide notable benefits compared with older agents, they are approved only for short-term (7 to 14 days) use. Chronic insomnia remains a challenge for health care professionals, requiring willingness to employ counseling, education, and behavioral modification. On occasion, a benzodiazepine selective receptor agonist or 5-HT2A antagonist may be used for 2 to 4 months, along with behavioral therapy. Nonresponsive cases should be referred to a sleep specialist.
Summary • Sleep is an active process consisting of macro:' and microarchitectural rhythms, chronobiology, and neurochemical changes. • Disruptions in sleep chronobiology, which may occur in shift workers and the elderly or due to jet lag, often respond to exogenous melatonin. • Insomnia requires careful evaluation to determine contributions of comorbid medical conditions and drug effects. • Treatment options include sleep hygiene principles and sedative hypnotic therapy. • Zaleplon and zolpidem, short-acting benzodiazepines selective for omega-1 GABA receptors, are effective first-line agents for initiating sleep. This symposium was made possible by an unrestricted educational grant from Wyeth-Ayerst Pharmaceuticals.
Pharmacotherapy for insomnia has moved well beyond the chloral hydrate, bromides, and barbiturates of the past. Although not FDA-approved for insomnia, 5-HT2 receptorVol. 40, No.5, Suppl. 1
September/October 2000
Supplement to the Journal of the American Phannaceutical Association
S47