CURRENT MANAGEMENT OF SLEEP DISORDERS Antonio Culebras, M.D. Veterans Affairs Medical Center Upstate Medical University Community General Hospital Syracuse, NY INTRODUCTION Therapeutic interventions in sleep medicine may be classified in four broad groups: a) sleep hygiene and prophylaxis of sleep disorders, b) psychotherapy, c) physical and surgical interventions and d) pharmacology. It is desirable to start with those treatments that are least aggressive and onerous, without forgetting that simple measures of sleep hygiene and the elimination of risk factors are as important as any other measure. Most people do not know how to sleep. In the United States, 40% of the population, or approximately 100 million people, are sleep deprived and have developed a sleep debt that in some way they will have to repay. Lack of regularity in the sleepwake schedule and the common practice of cheating hours from sleep lead to a state of chronic fatigue that reduces the physical and mental abilities of the individual causing loss of work productivity, social embarrassment, risk of accident, and decline in the quality of life. It has been estimated that 100,000 traffic accidents occurring annually in the United States are related to sleepiness and mental fatigue. Sleep hygiene should acquire as much importance as a balanced nutrition and the proper amount of exercise. Each individual requires a specified number of hours of sleep in the 24 hour cycle ranging between 6 and 9, with an average need of 8 hours. Differences among subjects are notable and each person must find the number of hours needed by gauging the level of satisfaction with sleep. It is possible to satisfy the sleep requirements by dividing sleep in two periods, a major one at night and a minor period in the middle of the day lasting 1 to 2 hours. The sum of both should equal the total number of hours needed in the 24 hours. Some individuals, like the owl, prefer to stay up late, work until late, go to bed late, and get up late in the morning. Others, like the lark, wake up with the break of dawn, work more efficiently in the early morning hours and find it pleasant to retire early to bed. As age progresses, the internal biologic clock tends to advance the sleep phase and the individual becomes increasingly inclined to implement an early sleep/wake schedule. To sleep properly the individual needs an environment free of noise, low in lighting, and with a temperature level that is neither cold nor hot. Body temperature decreases during nonREM sleep reaching a nadir (1ยบC lower than basal awake) 3 hours after falling asleep. In REM sleep the body ceases to regulate temperature and reduces perspiration, entering a state akin to poikilothermia. Studies in humans have shown that maximum amounts of both REM and nonREM sleep are achieved at the ambient temperature of 29ยบ C, decreasing when the temperature deviates in either direction of this
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thermoneutral level. At excessively high and low temperatures there is significant fragmentation of sleep. Meteorological conditions influence the progression of sleep such as the extremes of barometric pressure that produce somnolence. The seasons with long and short days also contribute to sleep variations. In the arctic environment, where days can be extremely short, inhabitants complain of difficulty initiating sleep along with daytime somnolence. Individuals who sleep on a hard bed tend to change position more often than when sleeping on a soft one. Young couples sharing a matrimonial bed sleep more deeply than older couples under the same conditions. Satiety is conducive to sleep and a good meal facilitates the siesta in midday. Acute loss of weight is typically associated with insomnia and weight gain with sound sleep. Individuals engaged in a weight-losing diet complain of sleep difficulties, since hunger is an enemy of sleep. Alcoholic beverages have a paradoxical effect over sleep. When the evening consumption exceeds three generous glasses of wine, representing approximately 420 g of wine or three shots of whiskey (84 g), there is an initial hypnotic effect that facilitates sleep, but several hours later withdrawal phenomena take hold as the hypnotic effect dissipates. The sympathetic tone increases and the level of catecholamines rises provoking arousals that fragmentate nocturnal sleep. Caffeine-containing infusions or drinks (coffee, tea, chocolate, sodas) alter the initiation and continuity of sleep, particularly if taken by the end of the day. A cup of regular coffee contains 100 mg of caffeine, a cup of tea 50 mg and a popular soda 75 mg. A daily dose exceeding 500 mg has a predictable inhibitory effect over sleep independently of the time of ingestion, since the half life of caffeine has a range of 8 to 14 hours. When a patient complains of insomnia it is important to review the medication intake to investigate potential alerting actions and introduce the necessary adjustments. SLEEP HYGIENE. DO’S AND DON’TS.* DO 1. Adhere to a sleep/wake schedule, the same for every day of the week, including weekends and holidays. 2. Get enough sleep to be satisfied in the morning. 3. Exercise daily but not before going to bed or late in the evening. 4. Adhere to a meal schedule. 5. Read or listen to soft music before turning the lights out. 6. Use a twin bed if bed-mate is a restless sleeper. 7. Eliminate or alleviate physical disturbances -- noise, light, heat, cold. Use ear plugs and eye shades if necessary. 8. Review with your physician medications you take and discontinue those with alerting effect. 9. Use a medium-soft mattress and a comfortable soft pillow. 10. Take nap at same time every day, if this is your habit. Do not sleep more than 45 minutes; after lunch is the best time.
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DON’T 1. Stay out late on weekends and holidays. 2. Exercise in the late evening or before bedtime. 3. Eat or drink heavily in the late evening or before going to bed. 4. Drink caffeine-containing beverages past 12 noon. 5. Use alcohol as a hypnotic or sedative: more than one glass of wine in the evening or its equivalent may cause rebound insomnia in the second half of the night. 6. Watch TV in the bedroom. 7. Bring paper-work to bed. 8. Turn on bright lights if you get out of bed at night. 9. Nap irregularly or frequently during the day. 10. Nap in the evenings. * From: Culebras A. Clinical Handbook of Sleep Disorders. ButterworthHeinemann, Boston, 1996. Many medications stimulate alertness and delay sleep; among this group are the sympathomimetic drugs (amphetamine, methylphenidate, pemoline), xanthines that compete for the adenosine receptor (caffeine, teophilline), and anorectics that have a central adrenergic action. Beta-blockers like propranolol inhibit REM sleep and may cause fragmentation of nocturnal sleep, precipitating nightmares if there is a rebound phenomenon upon withdrawal. Daytime sedation is a common phenomenon with neuroleptic medication, benzodiazepines, tricyclic antidepressants, antihistaminics, opioids, and analgesics, including aspirin. Some are used to facilitate nocturnal sleep. Stressing events occurring during the day alter sleep. Included in this group are habitual occurrences such as final examinations, deadlines, financial loss, grieving, conjugal conflicts, family pathology, work crisis, travel and other incidents and accidents of daily life. Deterioration of physical health is also a source of poor sleep. Acute or chronic pain, functional incapacity, paralysis, difficulty breathing, diarrhea, incontinence, nocturia, and other pathologic sensations cause interruption of sleep, altering its architecture and decreasing its quality resulting in secondary daytime fatigue and sleepiness. Alleviation of physical infirmities improves sleep and the wellbeing of patient and relatives. PHARMACOTHERAPY IN SLEEP MEDICINE INSOMNIA Insomnia is the inability to initiate or maintain sleep. It may be transient or chronic. Pharmacotherapy may seek any of three actions: facilitate onset of sleep, maintain sleep, and/or produce daytime sedation following sleep. Pharmacotherapy is an important component of the treatment of insomnia once defined goals have been determined. Therapy with hypnotics is perfectly adequate for the control of transient insomnias, as well as for chronic forms of insomnia as long as it is used as an adjunct to therapy. Dose escalation and frequency of use can be controlled with close supervision, though risk of dependency is related to the personality of the patient and less to the
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medication itself. Duration of activity is a function of distribution and elimination, and half life is a relative estimate of the duration of activity but fails to predict accumulation, a factor that underlies toxicity. Ultrashort acting compounds with half lives of 3 hours or less initiate sleep and do not accumulate in the body. Compounds with a half life of 5 hours or more maintain sleep better than short acting preparations but have a tendency to accumulate and cause toxicity over many days of administration particularly in susceptible individuals and in old persons with slow metabolism. Before recommending an hypnotic it is desirable to establish the goals of therapy. Insomnia may be treated with a variety of compounds with differing actions. The compound may be a sedative with hypnotic effect like the barbiturates, or a sedative with anxiolytic and hypnotic action like the benzodiazepines, a tranquilizer like the phenothiazines and haloperidol, an antidepressant with hypnotic action like the tricyclic compounds, an anxiolytic like the beta-blockers, or an antihistaminic, an anticonvulsant and even an analgesic like aspirin. When to use, how long to prescribe and in what amount will depend on a series of factors that depend on the medical assessment of the patient. Hypnotics. Barbiturates with short or intermediate action were the hypnotics most used until 1970. Following the introduction of flurazepam as an hypnotic in 1970, the use of benzodiazepines became widespread, and by 1985 virtually the only products used to combat insomnia in North America were the benzodiazepine derivatives flurazepam, temazepam and triazolam. Benzodiazepines are heterocyclic compounds known since 1891 but only used in clinical medicine since the introduction in 1960 of chlordiazepoxide. Modifications of the chemical structure gave way to a variety of compounds with differing actions. By 1999 there were 17 different preparations of the benzodiazepine family available to the physician in North America[See TABLE], with a wide spectrum of indications including epilepsy, movement disorders, psychiatric conditions and sleep disorders.
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PHARMACOKINETIC CHARACTERISTICS OF SOME BENZODIAZEPINE DERIVATIVES*/** BZDP-NAME
Daily dose mg
Max. action hrs
Duration 1/2 life hrs
Midazolam (Versed)
7.5 - 15
0.3 + 0.11
1.9 + 0.4
Triazolam (Halcion) young old
0.125 -0.25
--
2-6
0.25 0.125
0.96 + 0.10 0.95 + 0.11
2.43 + 0.16 3.03 + 0.25
Oxazepam (Serax)
15 - 30
2.2 + 1.0
7.8 + 1.7
Temazepam (Restoril)
10 - 30
0.8 + 0.3
8-20
Lorazepam (Ativan)
0.5 - 2
2
10 - 22
Alprazolam (Xanax)
0.25 - 2
1-2
12 - 15
Estazolam (Prosom)
1-2
2.7
17.1 + 1.3
Clonazepam (Klonopin)
0.5 - 2
1-2
18 - 50
Diazepam (Valium, Valrelease)
2.5 - 10
1.1 + 0.3
21 - 43
Chlordiazepoxide HCL (Librium, Librax) adult old
--
6
24 - 48
15 - 40 10 - 20
---
---
Quazepam (Doral) old
15
2
39 - 73
7.5
--
(metabolites)
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--
Flurazepam (Dalmane) old
15 - 30
Clorazepate (Tranxene) old
15 - 22.5
Prazepam
10
Halazepam
20
7.5
7.5 - 15
8.00 + 8.00 (metabolites) --
40 - 100
0.9 + 0.3 (metabolite) --
63.7 + 9.5
(metabolites)
--
(metabolites)
-long
-
long
* Arranged in order of their half-life duration ** From: Culebras A. Clinical Handbook of Sleep Disorders. ButterworthHeinemann, Boston, 1996. Benzodiazepine derivatives have three distinct actions in addition to the hypnotic effect: anxiolytic, muscle relaxant and anticonvulsant. Benzodiazepines differ from one another by their diverse clinical effect in any of the above properties and by the speed of action, although in general they have a low level of toxicity. In the central nervous system the benzodiazepines act directly on neuronal receptors that also include binding sites for picrotoxine and gamma-aminobutyric acid (GABA). Alcohol and barbiturates also bind to receptors that act on chloride channels, so that the general pharmacologic action is similar for all these compounds. Substances that antagonize the benzodiazepine action such as flumazenil (RO 15-1788) produce in human volunteers states of anxiety with tremors and insomnia, as well as convulsions in the experimental animal model. Hepatic clearance is ultimately responsible for elimination of benzodiazepine derivatives, but systemic blood concentrations also depend on distribution of drug in adipose tissue and muscle depots. Ultrashort and short acting benzodiazepines (midazolam: 7.5-15 mg; triazolam: 0.125-0.250 mg) facilitate the onset of sleep and do not cause daytime sedation. Intermediate acting benzodiazepines (temazepam: 10-30 mg) are effective to initiate, maintain, and consolidate fragmented sleep. Long acting benzodiazepines (diazepam: 2.5-10 mg; flurazepam: 15-30 mg; clorazepate: 7.5-22.5 mg; quazepam: 7,5 mg ; estazolam: 1-2 mg) have a sedative effect beyond the nocturnal period and serve to consolidate sleep as well as to bring sedation the following day to anxious patients. Clonazepam (0.5-1 mg) is used to eliminate the cortical arousals of leg myoclonus. All benzodiazepine derivatives should be administered in interrupted doses, for instance 5 days of the week, resting two days, in cycles not to exceed one month. Some patients use the hypnotic medication only on nights prior to important events, even though there is no proof that the quality of alertness improves following a pharmacologically induced, better night sleep. Benzodiazepine derivatives reduce the cycles of slow wave sleep while decreasing the amplitude of slow waves. Beta activity at 25-30 Hz increases in all
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cerebral locations and remains identifiable as many as 5 days following discontinuation of the drug. Hypnograms show shortening of sleep latency and reduction in stage transitions. Stage 2 increases at the expense of stages 1, 3, 4 and REM that are proportionately reduced. The effect on sleep architecture may be independent of subjective perceptions of satisfaction with sleep and restoration of alertness. Short-acting benzodiazepines tend to improve the ensuing level of alertness and even of anxiety, whereas long-acting compounds produce daytime sedation and decrease motor performance. Discontinuation of the medication needs to be conducted gradually to avoid withdrawal phenomena with extreme anxiety, persistent insomnia and agitation. When using ultra-short acting compounds the clinician should be aware of symptoms of miniwithdrawal manifested by anxiety between doses. The toxicity of benzodiazepine derivatives is much lower than that of other products with similar clinical action. Judicious use by knowledgeable physicians will preempt development of anterograde amnesia, frequent falls, and dependence. Benzodiazepines show an untoward sedative effect over respiratory centers, aggravating sleep apnea syndrome and other respiratory disturbances of central origin. Episodes of anterograde amnesia have been described in susceptible persons taking triazolam The FDA has ruled that when administered under proper supervision, triazolam is safe. Benzodiazepines should not be administered to patients with sleep apnea syndrome unless the respiratory condition is controlled with nasal CPAP or BiPAP. These drugs are not indicated for the treatment of insomnia in patients with a history of alcohol or drug abuse, or patients with untreated depression or psychosis. As with most other preparations the use of hypnotics is not indicated during pregnancy. In the elderly, particularly when there is a component of early dementia the benzodiazepine derivatives exhibit toxic activity with doses much lower than in younger persons, due to a slower elimination that maintains higher plasma concentrations for a longer period of time. Potential states of confusion, gait instability and falls are of particular concern in the very old. There is some evidence that the neurologic component of hepatic coma is the result of toxic compounds acting on benzodiazepine receptors. The administration of benzodiazepine derivatives and the concomitant ingestion of alcohol in large amounts produce highly toxic clinical effects that should be avoided. Barbiturates. Since the introduction of benzodiazepine derivatives, barbiturates are no longer used as hypnotics. Nonetheless, there remains some use for them in patients who do not tolerate or do not respond properly to benzodiazepines. Phenobarbital (100200 mg at bedtime) is a long-acting barbiturate with low lipid solubility. Its onset of action is 1 hour and the duration 12 hours with a mean plasma half-life of 79 hours. Pentobarbital (100 mg at bedtime) has a fast onset of action, 10 to 15 minutes, and a short duration, 3 to 4 hours. Barbiturates decrease REM sleep proportion while increasing its latency, provoking a REM sleep rebound when discontinued after prolonged administration. The EEG shows low voltage, high frequency beta activity, that with phenobarbital reaches a fixed frequency of 22 Hz. Barbiturates are far more toxic than
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benzodiazepine derivatives. In addition to causing dose-dependent respiratory depression, barbiturates may be habit-forming. The sleep inducing effect is lost after two weeks of continued administration. They potentiate the formation of hepatic microsomal enzymes that catabolize and alter the metabolism of other compounds. New hypnotics. Zolpidem is a benzodiazepine receptor ligand imidazopyridine of new appearance in the hypnotic market that has received a great deal of attention. At a dose of 5-10 mg it potentiates deep sleep and has an ultrashort half life of 2 to 3 hours that prevents accumulation in the body. Zolpidem may improve the perception of being asleep in insomniacs and may be useful to counteract the effects of jet-lag syndrome. Adverse effects are mild and include dizziness, somnolence, headaches, gastrointestinal distress, and dry mouth. There is no reported worsening of sleep apnea syndrome and there are no reports of drug dependence with serious consequences. Zaleplon is indicated for the short-term treatment of insomnia (7-10 days) and perhaps to initiate sleep in the west to east jet-lag syndrome. It is administered at doses of 5-10 mg at bedtime. It has a rapid onset of action and an ultra-short duration of action so that it can also be taken after middle of the night awakenings. It has mild CNS depressant activity and should be given in smaller doses (5 mg) and with caution to elderly patients. There are no known contraindications. Adverse reactions are limited to headache, fatigue and nausea. Other hypnotic drugs. Chloral hydrate (0.5 - 1 gm) is an old hypnotic compound that is still used to induce sleep in children undergoing EEG testing. It does not generate beta activity and sleep shows a relatively normal architecture. It has few adverse effects and the half life is 6 to 8 hours. The tricyclic antidepressants (amitriptyline sodium 50 - 100 mg, and protriptyline 5-10 mg ) administered at bedtime have shown some efficacy in idiopathic insomnia, and to overcome the sleeplessness of Parkinson’s disease and depression. These compounds suppress REM sleep; protriptyline, in particular, has a therapeutic anticataplectic effect in patients with cataplexy-narcolepsy. Antihistamine preparations with an hypnotic effect (diphenhydramine hydrochloride, 50 mg at bedtime) are useful in Parkinson’s disease because of the added mild antiparkinsonian action. Antihistamines produce daytime sedation and increase nonREM sleep at night. Beta-blockers, like propranolol, have anxiolytic effect and reduce REM sleep. Alcohol has a definite hypnotic effect along with a sedative action. An increase in the dose shortens sleep latency, increases the duration of sleep, reduces slow wave sleep and suppresses REM sleep, particularly in the early part of the night. This phenomenon may cause a compensatory increase of REM sleep by the end of the night, with intense dreaming and even nightmares. Alcohol also depresses central respiratory activity and may potentiate snoring and the sleep apnea syndrome.
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Non-opiate analgesics, like aspirin, improve sleep architecture and the quality of nocturnal sleep in patients with chronic pain of rheumatic origin. Aspirin also exhibits a soft hypnotic effect and improves somewhat the sleeplessness of chronic insomniacs. In large amounts it increases stage 2, decreases slow wave sleep and tends to increase sleep fragmentation. Inhibition of prostaglandins may be the mechanism of action. Opiate analgesics, like morphine, have a sedative effect and reduce REM sleep. Cocaine and heroin also reduce REM sleep. L-tryptophan, a serotonin precursor aminoacid increases total sleep and slow wave sleep. L-tryptophan was prohibited as an over-the-counter remedy for insomnia following reports of eosinophilia-myalgia syndrome caused by contaminants in the preparation. Zoplicone is a ciclopirrolone with a mechanism of action similar to that of the benzodiazepine derivatives. It has an ultra-short half life of 5 hours and no known active metabolites. Clinical reports indicate that zoplicone is well tolerated without causing respiratory center depression when administered at the therapeutic dose of 7.5 mg at bedtime. It should not be administered to patients with liver damage. EXCESSIVE DAYTIME SOMNOLENCE Stimulant drugs Amphetamines. The amphetamines have been known since the latter part of the XIX century, and introduced to clinical use in 1927 as an alternative to ephedrine. Amphetamines are potent stimulants of the central catecholamine and peripheral sympathetic systems. CLINICAL CHARACTERISTICS OF SOME AMPHETAMINE DERIVATIVES*
AMPH-NAME
DAILY DOSE STIMULATION STIMULATION ANOREXIA mg CENTRAL PERIPHERAL
Dextroamphetamine (Dexedrine)
10-60
++
++
++
Methylphenidate (Ritalin)
10-40
++
+
+
Phenmetrazine (Preludin)
25-75
++
+
+++
Fenfluramine (Pondimin)
20-60
scarce
scarce
+++
* From: Culebras A. Clinical Handbook of Sleep Disorders. Butterworth-Heinemann, Boston, 1996.
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Amphetamines cause desynchronization of cortical electrical activity through activation of the reticular system. They stimulate vigilance, increase mental and physical performance, enhance confidence, improve concentration, build resistance to fatigue, heighten mood, euphoria and loquacity, and decrease need to sleep. Adverse effects may include irritability, insomnia, headache, palpitations, nervousness and myokimias. Toxic doses trigger psychotic states that are undistinguishable from paranoid schizophrenia. Amphetamines also have an anorexic effect through their action on the lateral hypothalamic center, exhibit respiratory stimulant activity and have a mild antiparkinsonian action. Amphetamines may fail to stimulate alertness in patients with schizophrenia. The stimulant effect is more notable when the individual is physically tired, mentally fatigued, or somnolent. Polysomnographic studies have shown an increase in REM sleep latency, reduction of REM sleep in about 50%, and reduction of slow wave sleep. Typically the amphetamines induce tolerance and tachyphylaxis in near one half of subjects treated. Following abrupt discontinuation there is REM sleep rebound that may last up to 2 months. Intracranial hemorrhages secondary to cerebral angiopathy have been described in amphetamine abusers. Dextroamphetamine is more potent than levoamphetamine. It is a central stimulant that at high doses produces peripheral sympathetic hyperactivity manifested by high blood pressure, increased heart rate, hyperthermia, mydriasis and bladder sphincter contraction. Methylphenidate was introduced for the treatment of narcolepsy by Yoss and Daly because of lessened peripheral sympathomimetic activity. The amphetamines are typically used for the management of narcolepsy and other primary hypersomnias. The tricyclic antidepressants inhibit amphetamine catabolism and potentiate the behavioral effects. The tricyclic compounds can reduce by one third the clinically effective dose of amphetamines. The amphetamines are well absorbed by the gastrointestinal tract; one third is eliminated via the urine and the rest hydroxilated by the liver. The dose range for dextroamphetamine and for methylphenidate is 10-60 mg daily. Higher doses may induce unacceptable behavioral modifications that negate their clinical usefulness. The sympathomimetic effects of the amphetamines and derivatives include systolic and diastolic hypertension, variations in heart rate, rarely cardiac arrhythmias, mydriasis and hyperthermia. At therapeutic doses these side effects are rare. Intracranial hemorrhage, brain infarction, myocardial infarction and hypertensive crisis have been reported in drug abusers. Xanthines. Include caffeine and theophylline and are therefore the most commonly used stimulants of wakefulness. Xanthines compete for receptors occupied by adenosine, a neuromodulator with inhibitory action that intervenes in sleep mechanisms. Caffeine effects may last from 12 to 14 hours. A cup of strong coffee contains 200 mg of caffeine; 500 mg of caffeine, or more, taken at any time of the day will interfere with the generation of sleep. Ephedrine. Known since antiquity, ephedrine has some clinical efficacy in the treatment of narcolepsy and in the general treatment of somnolence when taken in amounts of 30 to 60 mg three times per day. It is a more potent drug than caffeine but less
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than the amphetamine derivatives. Toxic effects are manifested by tachycardia, perspiration and headache. Modafinil is a stimulant of vigilance not related to other stimulants; it does not activate dopaminergic mechanisms. Modafinil has central activity concentrated in the anterior hypothalamus distinct from that of amphetamines or methylphenidate. Double blind placebo-controlled trials in Europe and North America have established its usefulness for the treatment of narcolepsy at a dose of 200 mg given in the morning (halflife is 15 hours). It increases time to sleep onset in the MSLT and has no effect on nighttime sleep architecture. Adverse reactions are dominated by headache, nausea, and rhinitis. The recommended dose is 200 mg administered in the morning. Pemoline is an oxazolidine with central nervous system stimulant activity structurally dissimilar to the amphetamines.Because of its association with lifethreatening hepatic failure pemoline is not a first line drug. Liver enzyme tests are recommended at two week intervals during the duration of treatment. The daily dose is given in the morning starting at 18.75 mg and increasing to a maximum dose of 75 mg daily. Higher doses should be given with caution. PHARMACOLOGIC TREATMENT OF SPECIFIC SLEEP DISORDERS NARCOLEPSY The management of narcolepsy includes social aspects, behavioral modification and pharmacologic treatment. Patients and relatives should be made aware that excessive sleepiness is a medical condition and not a negative attitude or a depraved behavior indicating laziness. Behavioral counseling should include a discussion on vehicle driving and sleep hygiene. 15-20 minute naps are refreshing for most narcoleptics when taken at times when the pressure to fall asleep is most intense such as mid-morning, after lunch, in mid-afternoon, and after dinner. Napping regularly cuts down on the amount of stimulant medication required and decreases unscheduled falling asleep introducing some control over sleep. Pharmacologic treatment is the cornerstone of management of excessive daytime sleepiness and cataplexy. Excessive daytime sleepiness responds best to the administration of central nervous system stimulants. The risk to physical, mental and emotional wellbeing of uncontrolled narcolepsy is much higher than the risk of drug dependency. In the absence of controlled clinical therapeutic trials for most drugs in the treatment of narcolepsy management is largely based on consensus of opinions and on the results of a few small studies assessing the effect of drugs on the MSLT and Maintenance of Wakefulness Test. Excessive daytime sleepiness is most commonly treated with pemoline, modafinil, methylphenidate and dextroamphetamine. Modafinil has approximately a 60% potency compared to Ritalin. It is administered in the morning at a dose of 200 mg. to ‘de novo’ patients.
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Pemoline is also less powerful than Ritalin. The initial dose is 18.75 mg that can be increased to a total of 112.5 mg given in the morning. Because of potential liver damage it is not considered a first line treatment. Methylphenidate is a piperidine derivative related to amphetamine, that is perhaps the most commonly prescribed drug for narcolepsy, at least in the United States. It is administered orally in doses ranging from 10 mg to 65 mg per day. Drug holidays are effective in decreasing tolerance but may pose a risk of accident should the patient fall asleep inappropriately and constitute an annoyance to implement in most patients. When methylphenidate is insufficient, dextroamphetamine sulfate may be tried, starting at 10 mg/day, increasing the dose slowly to a maximum of 60 mg/day. In some patients, 5-15 mg of the sustained release form of dextroamphetamine administered in the morning may be sufficient. Other drugs useful in the treatment of narcolepsy are methamphetamine that has good CNS penetration but is more expensive than dextroamphetamine; and, selegiline, a MAO-inhibitor used also in the treatment of Parkinson’s disease, that is converted to levoamphetamine. Increased levels of alertness may be achieved by increasing the dose of CNS stimulants but this may come with the price of increasing side effects. Combining CNS stimulants with 15 minute naps helps to reduce the tendency to develop side effects. Stimulants taken after 5 pm may affect nocturnal sleep in persons who retire early to bed. Cataplexy is most effectively controlled with tricyclic antidepressants that probably inhibit cataplexy and sleep paralysis through blockade of serotonin and norepinephrine reuptake in addition to their well-known anticholinergic effect. Protryptiline, (5 - 15 mg in divided doses), is a powerful REM sleep suppressant with moderate cholinergic effect, well tolerated by most patients and the treatment preferred by many specialists in the United States. In Europe, clomipramine (25-200 mg per day) is the treatment of choice; this compound abolishes cataplectic attacks without affecting daytime sleepiness, but may potentiate the alerting effect of amphetamines. Imipramine (10 - 200 mg in divided doses) may be efficacious if protryptiline is not tolerated or fails to work. Fluoxetine, a relatively specific blocker of serotonin reuptake, is often useful at a recommended dose of 20 mg administered in the morning to avoid nocturnal disruption. Gamma-hydroxybutyrate, reported to be effective in consolidating nocturnal sleep and in increasing daytime alertness is also effective in reducing cataplexy. Abrupt discontinuation of anticataplectic drugs may lead to a rebound increase in cataplexy or even to continuous incapacitating cataplexy also known as status cataplecticus. Nocturnal disruption of sleep is a common complaint of many narcoleptics. Muscle twitches and nocturnal myoclonus that keep patients awake may be related to the effect of tricyclic medications. If the complaint is not resolved by reducing the dose of medication, Sinemet 10/100, Sinemet CR 25/100 in patients with more intense symptoms, or Clonazepam 0.5 mg may be helpful taken at bedtime. In some patients with severely
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disrupted nocturnal sleep, Zolpidem 10 mg at bedtime may be tried for short periods of time in an attempt to consolidate nocturnal sleep. RESTLESS LEGS SYNDROME PLUS PERIODIC LIMB MOVEMENT DISORDER Restless legs syndrome (RLS) is a relatively well known though poorly understood neurological condition. Reports note a familial incidence and the association with various metabolic, neurologic and vascular disorders. Periodic limb movements of sleep (PLMS) are generally associated and have become the preferred term. RLS is characterized by uncomfortable, unpleasant, crawling sensations localized in both legs, occasionally asymmetrical and alternating extremities. The shin and calf are more often affected than the foot, thigh and buttock, or rarely the lower back. Symptoms occur only while the patient is at rest particularly in the evening and at night. Long periods of rest at any time during the day precipitate symptoms. The discomfort may continue or reappear after the patient goes to bed provoking sleeplessness. Massaging the legs, taking hot or cold baths and moving about are some of the activities devised by patients to alleviate the unpleasant sensations. The urge to move the limbs and pace the floor for as long as 30 minutes ma become irresistible. Upon falling asleep patients with RLS commonly exhibit involuntary, repetitive, periodic movements of the lower limbs (PLMS) characterized by a partial flexion at the ankle, knee and sometimes the hip with extension of the big toe, followed by slow recovery of the extended posture. The entire movement lasts anywhere between 0.5 and 5 seconds, most typically 1,5-2,5 seconds, and is sometimes initiated by a small amplitude jerk of the foot or toes. The limb displacement is not myoclonic and thus the reticence by authors to call it myoclonus. RLS + PLMS disturbs sleep considerably either by preventing its occurrence or by provoking multiple awakenings. Consequent sleep deprivation causes excessive daytime somnolence and tiredness. ]. A variety of neurologic, metabolic and vascular disorders are associated with RLS and PLMS although the latter may occur in otherwise healthy individuals and remain asymptomatic. Iron deficiency anemia and folate deficiency have been reported with RLS + PLMS and indeed the correction of the hematologic disorder may improve the condition. RLS + PLMS has also been observed in pregnancy, chronic renal failure, hypothyroidism, rheumatoid arthritis and in neurologic disorders such as poliomyelitis, peripheral neuropathy in particular of diabetic origin, chronic myelopathy, and Parkinson’s disease. Caffeine abuse was originally cited by Ekbom and subsequently it was shown that the administration of a variety of drugs is a risk factor for development of RLS + PLMS including antidepressants, phenothiazines, lithium, calcium channel blockers, and barbiturate withdrawal. PLMS is commonly observed in patients treated with tricyclic compounds. RLS is considered idiopathic when there are no other associated disorders known to cause or increase the risk of developing the alteration. The treatment of RLS revolves around pharmacotherapy with dopaminergic drugs, opioids, anticonvulsants, benzodiazepines individually or in combination, and
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administration of iron supplements. Tolerance, habituation, augmentation and even addiction are risks that can be decreased by rotating medications or administering interrupted doses in mild cases. The American Academy of Sleep Medicine recommends treatment with levodopa/carbidopa in standard or sustained-release preparations starting at doses of 10/100 1-2 hours before bedtime and building slowly if necessary. Dopamine agonist agents (pergolide, bromocriptine, pramipexole, ropinirole) have also been reported to be useful. The Academy also recommends opioids, particularly if the component of RLS is more intense than PLMS. Propoxyphene (65 to 130 mg), oxycodone (5 mg, may be combined with acetaminophen), and codeine (30 mg) are usually effective when given in the evening or at bedtime. Escalating doses up to the maximum allowed, may be necessary in some patients but should be discouraged because of the addictive potential of these compounds. Methadone (15 to 20 mg single dose) has been successful in the hands of the few who have used it. Carbamazepine is administered in amounts equivalent to antiseizure therapeutic doses. It may add therapeutic efficacy when combined with first choice preparations in resistant patients. Clonazepam has been a popular choice at a starting dose of 0.5 mg at bedtime increasing to 4 mg if warranted. This preparation like other benzodiazepines may cause excessive sedation and should be used sparingly and in the minimum amount necessary to produce a therapeutic effect. Other short and ultrashort acting benzodiazepines may have a similar therapeutic benefit. Long-acting benzodiazepines like diazepam should be avoided to prevent accumulation of sedating effects. Other drugs tested and proposed by some are baclofen, clonidine and propranolol. PARASOMNIAS Arousal disorders are alterations of the waking mechanism that impede full control of volitional motor activity. Sleep inertia is prolonged and when awakened the individual appears slow, with memory impairment, poor judgment and inappropriate behavior. Two disorders are included in this section: sleep terrors and sleepwalking. Sleep terrors, pavor nocturnus, or incubus are virtually the patrimony of children between the ages of 4 and 12 years. Episodes are characterized by a sudden awakening out of deep sleep, heralded by a chilling scream that interrupts abruptly the sleep of parents. Children sit up in bed crying inconsolably, agitated, sweaty, exhibiting dilated pupils and goose-bumps, breathing heavily with a rapid pulse. If forcibly awakened the child appear confused and incoherent, but soon falls asleep having no recollection of the event on the morning that follows. With the passage of time episodes of pavor nocturnus disappear spontaneously. When sleep terrors appear once or more times per week management consists in eliminating precipitating factors while reducing the level of daytime stress and reassuring the parents of the benign character of the condition. In some cases, benzodiazepines, for instance diazepam 2-5 mg, that reduce the cortical arousal component, may be administered at bedtime. Sleep terrors that persist into
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adulthood are commonly associated with psychopathology and the response to treatment is weaker requiring a psychotherapeutic complement in many instances. Somnambulism or sleepwalking is a common automatism among children over 4 years of age characterized by an episode of walking during slow wave sleep in the first third of the night. It has been estimated that up to 15% of the general population has had at least one episode of sleepwalking in their childhood. Management consists in protecting the patient from harm and administration of small doses of benzodiazepines like diazepam 2-10 mg at bedtime depending on weight and age, a step only taken when episodes are frequent and pose a risk to the patient. REM sleep behavior disorder is characterized by a history of bizarre acts during nocturnal sleep associated with polygraphic evidence of loss of muscle atonia. Clinical manifestations range from aperiodic motor hyperactivity such as muscle twitches, jerks and restlessness to complex forms of organized motor activity in REM stage like flailing of arms, pointing with a finger, waving with the hand, punching, kicking, vocalizing, sitting up or getting out of bed, walking, running, screaming and jumping. Clonazepam, 0.5 mg at bedtime, is generally sufficient to suppress episodes and the associated violent dreams Other medications with reported RSBD-suppression effect in clonazepamintolerant patients are carbidopa/L-DOPA, clonidine and L-tryptophan.
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