The cautious and judicious use of pharmacological agents when treating sleep disorders will continue to have a prominent place in alleviating these problems
Humans have been seeking substances to keep them awake, put them to sleep, or otherwise alter consciousness for millennia. The history of drugs that affect sleep in some manner dates from antiquity, but even todays agents that affect sleep or the waking state continue to be developed; few areas of human endeavor have generated so much attention.
There are innumerable substances that affect the function of the brain where sleep is concerned. Many different molecules function as neurotransmitters that allow communication between various parts of the brain. Some of the substances are naturally occurring and are part of the normal physiological process governing nervous transmission. These substances often can be differentiated by their relationship to the sleep state. For example, substances such as acetylcholine function to maintain alertness in the awake state. Acetylcholine is also secreted during rapideye-movement (REM) sleep by the REM-producing area of the brain and is an important transmitter for the events that occur during this stage of sleep. Medications such as scopolamine induce sleepiness by interfering with the normal production of acetylcholine.
Many other compounds also influence the normal functioning of the brain during both sleep and wakefulness.
Neurotransmitters
Neurotransmitters are compounds found in the brain that help to convey information between brain cells. Since neurons are composed of a body as well as several appendages (the axon and dendrites) that project from the cell body, these cells do not actually touch each other, but the axon coming from one cell is very close to the dendrite of another cell. The minuscule gap between dendrite and axon is the synapse. Nerve cells communicate by releasing chemicals called neurotransmitters that spread across the synapse and trigger a chemical reaction in the other cell. This facilitates the transmission of information.
Histamine is a neurotransmitter that functions to maintain the awake state; cells that function to keep the brain awake use histamine as a major neurotransmitter. These cells and their connections are widely dispersed throughout the entire brain. Interference with the normal production or secretion of histamine by some types of antihistamine medications makes one sleepy by interfering with the proper cell-to-cell communication.
Over-the-counter medications such as diphenhydramine, intended originally for use as antihistamines for allergy sufferers, have found their way into other over-the-counter products advertised to promote sleep. By interfering with the normal function of histamine, these agents cause increased sleepiness in users.
Dopamine is a stimulating neurotransmitter that is used to mediate wakefulness. Experimental injection of this compound increases awareness, as well as motor activity. Antagonists for this neurotransmitter will decrease wakefulness and increase slow-wave sleep.
Serotonin is believed to play a crucial role in the production of sleep. Some researchers1 believe that some types of insomnia are due to decreased levels of this neurotransmitter. It has been shown2,3 that there is a circadian variation in the level of this hormone, which supports the belief that it is a sleep-inducing chemical. The highest blood levels of this substance are found during sleep.
Benzodiazepines
Among the most widely used sleep-related medications are the benzodiazepines. This class includes diazepam, lorazepam, alprazolam, and many others. Benzodiazepines are frequently used to treat patients with insomnia. They are also used as sedating medications for patients with generalized anxiety disorder. Known as hypnotics, these substances decrease sleep latency and decrease the number of awakenings (and the duration of wakefulness) during the night. Benzodiazepine medications modulate g-aminobutyric acid (GABA), a neurotransmitter that functions in an inhibitory fashion. This means that release of this compound decreases the spontaneous function of nerve cells (inhibits nervous transmission). As the benzodiazepines attach to the benzodiazepine receptors on the brain cells, they promote greater functioning of normal GABA-inhibiting nervous function and sleep induction. Benzodiazepines produce sleep in both people who have insomnia and those who do not. Benzodiazepine-receptor agonists are currently the drug of choice for the pharmacological treatment of insomnia, once all possibilities of alleviating the underlying cause have been eliminated. Currently, all hypnotics approved for use in the United States are benzodiazepine-receptor agonists.
Benzodiazepines can affect the staging of sleep by increasing stage-II non-REM sleep and suppressing K complexes and stage-III or stage-IV sleep. The latency of REM sleep usually increases, but there is often a more frequent cycling of REM periods. The electroencephalograms of patients taking alprazolam will often show more numerous, denser, and lengthier sleep spindles. Movements during sleep are also suppressed. Chronic use of the medication can markedly decrease the amount of REM sleep, and abrupt discontinuation of a benzodiazepine will cause REM rebound, which is manifested by a marked increase in total REM sleep. The reasons that benzodiazepines directly affect some stages of sleep and not others are not clearly understood.
There are four major categories of hypnotics, with classification based on duration of action. Commonly prescribed long-acting hypnotics are flurazepam and quazepam. Estazolam and temazepam are intermediate-acting hypnotics. Short half-lives characterize triazolam and zolpidem, and zalepon has an ultrashort half-life.
Benzodiazepine-receptor agonists should not be used until the underlying cause of a patients insomnia has been documented. If a patients complaint of inability to maintain sleep is the result of sleep-disordered breathing, such medication could be extremely harmful. If symptoms such as snoring, gasping while asleep, and daytime sleepiness accompany a patients complaint of insomnia, then sleep-disordered breathing should be ruled out in the sleep laboratory before the use of hypnotics is considered. Unfortunately, people with self-perceived or self-diagnosed insomnia often resort to the use of the antihistamines found in over-the-counter sleep aids, in addition to the self-administration of alcohol before bedtime. If a patient is unable to sleep due to clinical depression, stress, other psychiatric problems, or pain, then such problems should be dealt with pharmacologically or behaviorally.
Other Pharmacological Agents
Barbiturates such as phenobarbital also affect GABA function, but through a slightly different mechanism than that of benzodiazepines. Their overall effect on sleep, however, is similar.
Antidepressants affect sleep based on the class of the medication. The tricyclic antidepressants are the most commonly used. Tricyclic antidepressants such as imipramine and nortriptyline markedly decrease the amount of REM sleep. Stopping the medication will induce REM rebound. Most tricyclic antidepressants have sedating properties, especially at high doses, and have been shown to decrease sleep latency considerably.
Selective serotonin-reuptake inhibitors constitute another class of antidepressant medication. These agents can decrease the total amount of REM sleep. The overall effect on sleep latency is medication specific. For example, fluoxetine and sertraline have slightly stimulating effects and will increase sleep latency, whereas paroxetine can have a mildly hypnotic effect (decreasing sleep latency and increasing overall sleep efficiency).
Neuroleptics are used to treat schizophrenia. There are several classes of these medications, of which the most notable are the phenothiazines (such as thioridazine). Most neuroleptics have profound properties of sedation due to their binding to serotonin and histamine receptors. Binding of the receptors decreases the effect of these chemicals, which are ordinarily stimulating neurotransmitters. Neuroleptics do not have characteristic effects on sleep, although most tend to decrease sleep latency.
b-Blockers are frequently used to treat hypertension, as well as heart disease. In humans, these medications have a sedating effect and modify sleep staging. For example, propranolol decreases REM sleep. It is believed that these medications somehow interfere with serotonin-receptor function and catecholamine metabolism. b-Blockers may increase the likelihood of nightmares.4
Pain-killing narcotics such as morphine also have sedating properties. Their main effects on sleep are a decrease in REM and a slight increase in stage-I sleep.
Self-Administered Agents
Melatonin is a naturally occurring hormone that is released from the pineal gland in the brain specifically at sleep onset. If a person does not fall asleep, melatonin levels do not increase. Because of this fact, some believe that melatonin is the principal neurotransmitter of sleep. It is known that secretion of melatonin is important in seasonal timing and that it probably plays a role in seasonal affective disorder. Melatonin is thought to increase the sensitivity of the suprachiasmatic nucleus to sunlight, thus helping to maintain normal circadian rhythms. To date, there have been reports5,6 that supplemental melatonin, taken orally, will decrease sleep latency, but the medication is still undergoing experimental testing by sleep specialists. Recommendations to use melatonin as a hypnotic in patients with insomnia are not universally accepted.
Caffeine is a well-known stimulant that is a xanthine. Theophylline and amphetamine are similar compounds. These medications decrease the amount of sleep and delay the onset, as well as the duration, of REM sleep.
Consumption of alcohol leads to changes in sleep based on blood levels of alcohol and chronicity of usage. Low levels of alcohol in the blood can induce sleep and increase total sleep time. Higher levels of alcohol will decrease the amount of REM sleep. If alcohol consumption becomes chronic, slow-wave sleep disappears and there is a marked disturbance in sleep patterns. Withdrawal from chronic alcohol use results in marked REM rebound, producing the hallucinations seen in abstaining alcoholics. Self-administration of alcohol prior to sleep has long been the practice of many people making an effort to induce sleep; however, what is often unrecognized is that alcohol at or near bedtime may cause markedly disrupted sleep due to its propensity to increase the frequency and severity of sleep-related breathing disorders. Alcohol at bedtime should never be recommended as a soporific.
Nonpulmonary Sleep Disorders
Insomnia (or a less than restful nights sleep) may be due to excessive limb movements such as periodic limb movement disorder during sleep. After being documented in a sleep laboratory, this condition is often successfully treated using dopaminergic agonists such as carbidopa/levodopa, pergolide, or newer agents such as ropinirole. Benzodiazepine-receptor agonists such as clonazepam are also used for the treatment of limb-movement disorders.
Narcolepsy is a disease characterized by relentless daytime sleepiness. It is treated through the judicious use of stimulants that can include caffeine, amphetamines, methylphenidate, and modafinil, a newer agent. Narcolepsy must be diagnosed in a sleep laboratory using all-night polysomnography followed immediately (the next day) by a series of naps during which the time of onset to sleepand, particularly, to REM sleepis documented. This procedure is known as the multiple sleep latency test. Most cases of narcolepsy improve through medication use, although complete cures are rare. Determining the proper use of narcolepsy medications can be difficult and should be left to sleep specialists or neurologists with expertise in treating this disorder.
Cataplexy, a loss of muscle tone, often occurs in patients with narcolepsy. It can be effectively treated using tricyclic antidepressants or selective serotonin-reuptake inhibitors. These agents decrease REM sleep, therefore decreasing the REM-related atonia that is the cause of cataplexy.
Patients who present with sleep-related complaints should be thoroughly questioned regarding their use of medications (prescribed or over-the-counter), foods, and beverages. Many ill-advised remedies are self-administered by people trying to sleep or stay awake. The number of medications, foods, and environmental factors that adversely affect the sleep or waking state can be truly staggering. For example, eating turkey (high in tryptophan) helps to promote sleep, whereas many beverages containing caffeine prevent sleep. A hot drink at bedtime, long believed to induce sleep, can actually prevent it by raising the bodys core temperature. Cooling down induces sleep. Cheddar cheese and chocolate both stimulate wakefulness rather than promoting sleep; a cup of hot cocoa at bedtime is a bad idea on two counts. The use of nicotine prior to bedtime can also make it more difficult to go to sleep.
Conclusion
Modern medicine continues its pursuit of new, safer, and more effective agents to induce and maintain sleep, as well as to treat associated disorders such as restless leg syndrome, periodic limb movement disorder, and narcolepsy. Advances often come from unlikely places. Recently, scientists in India isolated a defensive secretion from the skin glands of the Indian toad (Bufo melanostictus) that does not poison or kill its enemies, but puts them to sleep while the toad hops away to safety. More may be heard about this novel molecule in the future.
The diagnosis and treatment of sleep-related disorders can be, at times, a simple, straightforward exercise. At other times, it can be enormously complex. The cautious, judicious use of pharmacological agents has always had, and will continue to have, a prominent place in the alleviation of these problems.
Thomas M. Kilkenny, DO, is director, and Steve Grenard, RRT, is clinical coordinator, Sleep Apnea Center, Staten Island University Hospital, Staten Island, NY.
References
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