Anti-insomnia drugs
Anti-insomnia drugs are medications that help people who have difficulty falling asleep, staying asleep, awakening early, or who have disturbed sleep patterns resulting in insufficient sleep. Physicians prescribe anti-insomnia drugs for short-term or intermittent treatment of insomnia.
Sleep-related complaints such as insomnia and ensuing daytime drowsiness impair the lives of 20-50% of Americans. Sleep problems have been associated withdecreased work productivity and absenteeism, increased healthcare utilization, and short-term memory impairment. Also, an estimated 200,000 automobile accidents each year are caused by excessive drowsiness or falling asleep at thewheel. Thus, insomnia and excessive daytime fatigue may be viewed as significant public health problems.
Although sleep is necessary for survival, exactly how it contributes to maintaining health and well-being is unknown. Individual requirements vary widely,ranging from four to ten 10 hours every 24 hours in healthy individuals. Insomnia may be primary (long-standing, with little or no apparent relationshipto immediate physical or psychological events). The sleep environment (a roomthat is too hot, cold, or dry) may play a role in sleep problems. Insomnia may also be related to depression (an estimated 80% of depressed individuals complain of disturbed sleep), stress, anxiety, disease, pain, medications, sleep disorders, or poor sleep habits. For example, excess alcohol consumption in the evening can curtail sleep and lead to withdrawal effects in the early morning, so that the individual is restless on awakening or, if severely dependent, fearful and tremulous.
Women are twice as likely to develop insomnia than men. In addition, althoughinsomnia affects people of all ages, with advancing age, total sleep time often decreases, deep sleep may disappear, and sleep becomes more interrupted.These changes, although normal, may be distressing and lead the elderly to seek treatment with anti-insomnia medications (also called hypnotics.
Sleep Cycles
The first period of sleep is called nonrapid eye movement (NREM) sleep (75-80% of total sleep time). Characterized by slow, regular brain activity, slow,regular breathing, relaxed muscles, and minimal body movements, this state issometimes called "quiet sleep." Ironically, it is during NREM sleep, however, that people snore. Nonrapid eye movement sleep is further subdivided into four stages of progressively deeper sleep, each clearly differentiated by itsdistinct brain wave patterns. As the night progresses, the sleeping person advances through each of these stages, beginning with Stage 1 (the lightest sleep), until the deepest stage of NREM sleep, Stage 4, is achieved. He or she then begins to ascend into progressively lighter sleep, to Stage 3, Stage 2, and back again to Stage 1 sleep.
This NREM sleep is then followed by the first REM, or "active" sleep of the night. Rapid eye movement sleep is characterized, obviously, by rapid eye movements, irregular breathing and heart rate, and more intense brain waves thanin NREM sleep. Although the body is immobilized, the fingers and facial muscles may twitch. When awakened from REM sleep, most people report vivid dreams.
The amount of time from the first onset of sleep through the first REM periodis called the first "sleep cycle."Although individual cycles may differ substantially, the average adult sleep cycle takes about 90 to 100 minutes. Nonrapid eye movement sleep and REM sleep continue to alternate throughout the night, so that an average night of about eight hours of sleep is likely to include about five complete cycles.
Sleep Disturbances
Some of the sleep disturbances that may cause insomnia requiring treatment include: initial insomnia, early morning awakening, sleep rhythm reversals, andrebound insomnia.
Initial insomnia (difficulty in falling asleep) is commonly associated with an emotional disturbance (anxiety, a phobic state, depression), pain, respiratory problems, stimulant drugs, withdrawal of sedative drugs, poor sleep hygiene (a variable sleep schedule), and sleep disorders such as sleep apnea (a breathing disorder with loud snoring and brief periods when breathing stops) ordelayed sleep phase syndrome. Delayed sleep phase syndrome is a circadian (pertaining to events that occur at about 24-hour intervals) rhythm disturbancein which the individual has delayed sleep and waking times and cannot advance his or her sleep schedule (cannot move to an earlier bedtime with an earlier awakening time).
In early morning awakening, the individual falls asleep normally but awakensearly and cannot fall asleep again or drifts into a restless, unsatisfying sleep. This pattern is a common problem of aging individuals but is sometimes associated with depression. Tendencies to anxiety, self-reproach, or self-chastisement, often amplified in the morning, may contribute to early morning awakening.
Sleep rhythm reversals usually reflect a circadian rhythm disorder (for example, jet lag). Misuse of sedatives or working irregular night-shift hours cansometimes induce such reversals, as can obstructive sleep apnea. Individualswith obstructive sleep apnea become drowsy in the morning, sleep or doze muchof the day, and have fitful, interrupted sleep at night. If the dose of a sedative is increased because of an incorrect diagnosis, restlessness and wandering in a clouded or confused state may occur at night.
Rebound insomnia occurs when an individual stops taking a drug and experiences one or two nights of insomnia that is worse than they experienced before treatment. This type of insomnia commonly occurs when hypnotic drugs are withdrawn from an individual who regularly takes heavy doses. Most individuals wrongly interpret this effect as recurrence of chronic insomnia. Rebound insomniacan be avoided by gradually decreasing (tapering) the dose.
Anti-insomnia Medications
Treatment for insomnia depends on the underlying cause. For individuals withinsomnia due to emotional disturbance other than depression and for those suffering from chronic insomnia, a hypnotic drug may be temporarily required, especially if sleeplessness impairs the individual's efficiency and sense of well-being. The hypnotic is usually prescribed for short-term usage (two to four weeks) or episodically (no more than a few times a week) because toleranceand addiction can result. Depressed individuals should be given limited amounts to reduce the risk of attempting suicide with the hypnotic. Individuals who awaken because of pain should receive analgesics (pain relievers) at bedtime as the mainstay of treatment.
During an acute depressive episode, characteristic changes are noted in the sleep EEG. These changes include difficulty falling asleep, reduced total sleep time, frequent awakenings, and reduced deep sleep. For insomnia accompanying depression, a sedating tricyclic antidepressant such as nefazodone (Serzone) and mirtazapine (Remeron) taken about one hour before bedtime is often advised.
Terms such as hypnotic, sedative, antianxiety drug, minor tranquilizer, and anxiolytic are often used interchangeably to describe anti-insomnia medications. However, the most accurate term for drugs used primarily to induce sleep is hypnotic. The major types of medications used to combat insomnia include: barbiturates, benzodiazepines, nonbenzodiazepine hypnotics, antidepressants, and over-the-counter (OTC) sleep aids.
Barbiturates consist of a group of organic compounds derived from barbituricacid. All barbiturates, such as secobarbital (Seconal), phenobarbital, or amobarbital (Amytal) and barbiturate-like drugs such as chloral hydrate and glutethimide depress the central nervous system (CNS) and depress respiration, affect heart rate, liver enzymes, and decrease blood pressure and temperature.These drugs can be habit forming and are not recommended as hypnotics. Attempts to discontinue barbiturates may lead to withdrawal symptoms, thereby intensifying dependence on the drug. They also have a higher suicide risk than other hypnotics. For sedative action, these drugs have been replaced by safer drugs such as the benzodiazepines and the newer nonbenzodiazepine compounds.
The benzodiazepines, a group of hypnotics developed in the 1960s, have long been regarded as the treatment of choice when a sleep medication is deemed clinically indicated. The benzodiazepines work by acting in areas of the brain thought to be involved in sleep promotion. Although most benzodiazepines havesedative and hypnotic effects, those with the greatest safety and efficacy are listed below:
- clorazepate (Tranxene)
- diazepam (Valium)
- estazolam (ProSom)
- flurazepam (Dalmane)
- lorazepam (Ativan)
- midazolam (Versed)
- nitrazepam (Mogadon)
- oxazepam (Serax)
- temazepam (Restoril)
- triazolam (Halcion)
- quazepam (Doral)
All benzodiazepine hypnotics are effective in the short-term management of insomnia. They decrease the time taken to fall asleep, decrease the number andduration of nighttime awakenings, and increase total sleep time and sleep efficiency. Selecting a particular agent partly depends on the nature of the insomnia. Drugs with a rapid absorption rate are better suited for sleep-onset insomnia, whereas those with a slower action are more effective for sleep-maintenance problems.
Temazepam (Restoril), for example, is a benzodiazepine with an intermediate half-life and produces a moderate degree of accumulation with multiple dosage.It is absorbed relatively slowly and is a better agent for sleep-maintenanceproblems than for sleep-onset problems. Because it is better suited for sleep-maintenance difficulties and has minimal daytime residual effects, temazepam is sometimes regarded as the best hypnotic to use for late-life insomnia.
Several nonbenzodiazepine hypnotics, such as zolpidem (Ambien), an imidazophyridine, has a rapid onset of action and short duration (short half-life). Drugs with a short half-life are usually preferred so that daytime functioning is not impaired on awakening or the next day. Zolpidem has been found effective in decreasing the time it takes to fall asleep but not in decreasing eitherthe number or duration of awakenings. As for most short-acting hypnotics, there is evidence of rebound insomnia when the medication is withdrawn.
Zaleplon (Sonata), approved in 1999 by the Federal Food and Drug Administration for short-term insomnia in adults, is the first in a new chemical class ofnonbenzodiazepines called the pyrazolopyrimidines. Since its effects last for only four hours, zaleplon can also be used during the night when individuals have difficulty falling asleep. In clinical trials, zalephon did not show evidence of next-day grogginess or hangover.
Tricyclic antidepressants with sedative effects are usually recommended wheninsomnia is associated with an affective (mood) disorder. This is probably abetter choice than the benzodiazepines, especially among patients with suicidal risk. Amitriptyline (Elavil) and trimipramine (Surmontil) reduce sleep-onset latency and improve sleep continuity.
Trazodone (Desyrel), a nontricyclic, has been increasingly used for insomniain depressed patients. This compound appears to have less anticholinergic action (for example, dry mouth, urinary retention, constipation) and fewer cardiovascular side effects than tricyclics such as doxepin or amitriptyline, forexample. As a general rule, insomniacs with major depression should receive the entire dosage of antidepressant at bedtime in order to maximize the sedative effects.
There is an increasing trend among physicians to prescribe antidepressant medications rather than benzodiazepines for treating insomnia even in nondepressed individuals. Because of their sedating properties, some antidepressants are prescribed in subtherapeutic dosage. Although the potential for abuse or physical dependency is lower with these agents, there is a higher potential fordrug interaction than with benzodiazepines.
Over-the-counter sleep aids are probably used in greater proportions than prescribed hypnotics. The active ingredient in most OTC sleep aids is an antihistamine, and because the most common side effect of antihistamines is drowsiness, people use them to induce sleep at night. However, these drugs are considered to produce few, if any, beneficial effects on sleep.
Drugs such as Sominex, Unisom, or Sleep-Eze should not be taken by individuals using alcohol or other drugs with sedating effects. Such OTC sleep aids should also be avoided by people with breathing problems, glaucoma, chronic bronchitis, or difficulty urinating because of an enlarged prostate gland. In fact, antihistamines can cause constipation, urinary retention, blood pressure changes, blurred vision, and confusion, especially in the elderly. Pregnant ornursing women should also avoid these medications.
Melatonin is a hormone that has become increasingly popular OTC sleep aid. The hormone, which is closely linked to the circadian system and is normally released by the pineal gland (located in the brain) at night, decreases with age. Because melatonin can reset circadian rhythms, it has been tested as treatment for initial insomnia and jet lag. However, it is not recommended by mostsleep experts; some believe that morning exposure to bright light is more effective than melatonin at resetting rhythms for healthy individuals.
Investigators raise concerns regarding the cardiac side effects of melatonin.In addition, nutritional supplements such as melatonin or valerian (an herbal root that is also available in tea or capsule form) are unregulated by thefederal government, so content and purity cannot be assured. The effects of long-term exposure to melatonin supplementation are unknown. Thus, sound studies on the proper dose, efficacy, and safety of melatonin are needed.
Side Effects of Hypnotics
Because hypnotics work on the CNS, they may increase the effects of alcohol and other drugs that slow down the CNS, such as antihistamines, cold medicine,allergy medicine, medicine for seizures, tranquilizers, some pain relievers,and muscle relaxants. Therefore, doses should be reduced when these drugs are used concurrently.
The combined effects of zolpidem and alcohol or other CNS depressants (drugsthat slow the central nervous system) can be very dangerous, leading to unconsciousness or even death. Anyone who shows signs of an overdose or of the effects of combining zolpidem drugs with alcohol or other drugs should have immediate emergency help. Warning signs include severe drowsiness, severe nauseaor vomiting, breathing problems, and staggering.
Before taking these medications, it is important to let the physician know about any allergies; pregnancy or breast-feeding; chronic lung diseases such asemphysema, asthma, or chronic bronchitis; liver or kidney disease; current or past alcohol or drug abuse; depression; or sleep apnea.
The most common minor side effects are daytime drowsiness or a "drugged" feeling, vision problems, memory problems, nightmares or unusual dreams, vomiting, nausea, abdominal or stomach pain, diarrhea, dry mouth, headache, and general feeling of discomfort or illness, especially after excessiveintake of certain hypnotics. Hypnotics may cause a special type of temporarymemory loss, in which the person does not remember what happens between thetime they take the medicine and the time its effects wear off. This is usually not a problem, because people go to sleep immediately after taking the medicine and remain asleep until its effects wear off. But taking hypnotics couldpose a problem for anyone who has to wake up before getting a full night's sleep (seven to eight hours). More serious side effects are not common, but may occur.
After using such drugs, individuals should avoid activities requiring mentalalertness, judgement, and physical coordination (for example, driving, operating machinery) for several hours (generally eight to twelve hours, but sometimes longer). Hypnotics should also be used with caution in patients with respiratory problems. Rarely, skin eruptions and gastrointestinal disturbances (for example, nausea or vomiting) occur. In the elderly, any hypnotic, even insmall doses, can cause restlessness, excitement, or exacerbation of deliriumand dementia due to a slower metabolism and decreased tolerance for medications.
Many patients take higher doses of hypnotics than they admit; slurring of speech, lack of coordination, tremors, and nystagmus (constant, involuntary, circular movement of the eyeball) should arouse suspicion of overdosage. If necessary, blood levels of many drugs can be measured.
Benzodiazepines have less addictive potential than other hypnotics. Doses that induce serious respiratory and vital center depression are considerably larger for benzodiazepines than for barbiturates and most other hypnotics. Someindividuals report an increase in daytime anxiety after repeated use or withdrawal.
Combining Drugs with Behavioral Strategies
To break the cycle of insomnia, in addition to drug therapy, there are some behavioral strategies that can help. Although these strategies often take timeand patience to learn and implement, they can provide more long-term benefits than drugs.
Developing good sleep habits is one behavioral strategy used to combat insomnia. In this strategy, it is important to
- maintain a regular wake time
- avoid excessive time in bed
- avoid naps, except in shift workers
- use the bed only for sleeping and intimate contact
- avoid nicotine, caffeine, and alcohol before bedtime
- exercise regularly early in the day
- do something relaxing before bedtime
- do not watch the clock
- eat a light snack before bedtime if hungry
Other behavioral techniques that can be used alone or in combination with drug therapy include relaxation training (biofeedback, progressive muscle relaxation) and psychotherapy.
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