Insomnia

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Chapter 182 Insomnia

Michael T. Murray, ND

Diagnostic Summary

• Difficulty falling asleep (sleep-onset insomnia)

• Frequent or early awakening (sleep-maintenance insomnia)

• Affects one of every four people in the United States

General Considerations

Insomnia represents one of the most common complaints seen by physicians. Within the course of a year, up to 30% of the population suffers from insomnia, and roughly 10% of the adult population has chronic insomnia.¹ Many use over-the-counter (OTC) medications to combat the problem, and others seek stronger sedatives. Approximately 12.5% of the adult population uses a prescribed anxiolytic or sedative hypnotic in the course of a year; about 2% of the population takes one on any given day. More than one half of these drugs, especially benzodiazepines, are prescribed by primary care physicians. Nearly 100 million prescriptions are written each year for these drugs.²

A thorough history and physical examination are indicated in the patient presenting with insomnia, because it is a symptom that can have many causes (Table 182-1). Psychological factors account for 50% of all insomnias evaluated in sleep laboratories.¹ Insomnia is closely associated with affective disorders (see Chapter 142). Cognitive behavioral therapy is often indicated and can produce effective improvements in sleep quality.³ A detailed recreational, prescription, and nonprescription drug-use history, along with a dietary and beverage history, are also required to determine whether the patient is consuming any stimulants or other agents known to interfere with sleep. The following agents may be responsible:

• Thyroid preparations

• Oral contraceptives

TABLE 182-1 Causes of Insomnia ^*

Sleep-onset insomnia	Sleep-maintenance insomnia
Anxiety or tension	Depression
Environmental change	Environmental change
Emotional arousal	Sleep apnea
Fear of insomnia	Nocturnal myoclonus
Phobia of sleep	Hypoglycemia
Disruptive environment	Parasomnias
Pain or discomfort	Pain or discomfort
Caffeine	Drugs
Alcohol	Alcohol

^* The boundary between the categories is not entirely distinct.

Among serious diseases to be considered in the differential diagnosis are narcolepsy and sleep apnea syndromes. Sleep apnea is the most common example of sleep-disordered breathing. First described in 1965, sleep apnea is a breathing disorder characterized by brief interruptions of breathing during sleep. These breathing pauses are almost always accompanied by snoring between apneic episodes, although not everyone who snores has this condition. Sleep apnea can also be characterized by choking sensations. The frequent interruptions of deep, restorative sleep often lead to excessive daytime sleepiness and may be associated with an early-morning headache. Approximately 18 million Americans are thought to suffer from sleep apnea.

Early recognition and treatment of sleep apnea are important because it is associated with marked daytime fatigue, irregular heartbeat, high blood pressure, heart attack, and stroke as well as a loss of memory function and other intellectual capabilities. The patient usually does not know he or she has a problem and may not believe it when told. If a person snores heavily or his or her sleep partner has noted periods of interrupted breathing during sleep, it is important that such a person see a doctor. Sleep apnea should also be considered in anyone with significant daytime drowsiness or changes in intellectual function. Sleep apnea can be properly diagnosed only through the services of a sleep disorder specialist, usually in a sleep laboratory.

Sleep apnea is most often caused by narrowing of the airway by an excess accumulation of fatty tissue, causing obstructive sleep apnea. With a narrowed airway, the person continues efforts to breathe, but air cannot easily flow into or out of the nose or mouth. This narrowing results in heavy snoring, periods of no breathing, and frequent arousals (causing abrupt changes from deep sleep to light sleep). Ingestion of alcohol and sleeping pills increases the frequency and duration of breathing pauses in people with sleep apnea. In some cases sleep apnea occurs even if no airway obstruction or snoring is present. This form of sleep apnea, central sleep apnea, is caused by a loss of perfect control over breathing by the brain.

In both obstructive and central sleep apneas, obesity is the major risk factor, and weight loss is the most important aspect of long-term management. People with sleep apnea experience periods of anoxia (oxygen deprivation of the brain) with each apneic episode, which ends in arousal and a reinitiation of breathing. Seldom does the sufferer awaken enough to be aware of the problem. However, the combination of frequent periods of oxygen deprivation (20 to several hundred times per night) and the greatly disturbed sleep can greatly diminish the sufferer’s quality of life and lead to serious problems.⁴

The most common treatment of sleep apnea is the use of nasal continuous positive airway pressure (CPAP). In this procedure, the patient wears a mask over the nose during sleep and pressure from an air blower forces air through the nasal passages. The air pressure is adjusted so that it is just enough to prevent the throat from collapsing during sleep. The pressure is constant and continuous. Nasal CPAP prevents airway closure while in use, but episodes of apnea return when CPAP is stopped or used improperly. Surgery to reduce soft tissue in the throat or soft palate should be used only as a last resort because it often does not work or can make the problem worse. Laser-assisted uvulopalatoplasty is a highly promoted surgical option. In this procedure lasers are used to surgically remove excessive soft tissue from the back of the throat and the palate. It works well initially in about 90% of sleep apnea sufferers, but within a year many people are the same as or even worse than before because of the scar tissue that invariably forms.⁴

Normal Sleep Patterns

Human sleep is perhaps one of the least understood physiologic processes. Its value to human health and proper functioning is without question. Sleep is absolutely essential to both the body and the mind. Impaired sleep, altered sleep patterns, and sleep deprivation impair mental and physical function.

Normal adult sleep-wake patterns repeat themselves on an approximately 24-hour cycle, of which sleep constitutes one third. Exactly how much sleep is required varies from one person to the next. Sleep tends to decrease with age, but whether this tendency is a normal or abnormal progression is unknown. A 1-year-old baby requires about 14 hours of sleep a day, a 5-year-old about 12 hours, and adults about 7 to 9 hours. Women tend to require more sleep than men. The elderly tend to sleep less at night but doze more during the day than do younger adults.

From observations of eye movement and electroencephalographic (EEG) recordings, sleep is divided into two distinct types: rapid eye movement (REM) sleep and non-REM sleep. During REM sleep, the eyes move rapidly and dreaming takes place. When people are awakened during non-REM sleep, they report that they were thinking about everyday matters but rarely report dreams.

Non-REM sleep is divided into stages 1 through 4 according to level of EEG activity and ease of arousal. As sleep progresses, there is a deepening of sleep and slower brainwave activity until REM sleep ensues, when suddenly the brain becomes much more active. In adults, the first REM sleep cycle is usually triggered 90 minutes after going to sleep and lasts about 5 to 10 minutes. After the flurry of activity, brainwave patterns return to those of non-REM sleep for another 90-minute sleep cycle.

Each night most adults experience five or more sleep cycles. REM sleep periods grow progressively longer as sleep continues; the last sleep cycle may produce a REM sleep period that can last about an hour. Non-REM sleep lasts approximately 50% of this 90-minute sleep cycle in infants and about 80% in adults. As people age, in addition to less REM sleep, they tend to awaken at the transition from non-REM to REM sleep.

The Importance of Adequate Sleep

Adequate sleep is absolutely necessary for long-term health and regeneration. Many physiologic processes occur during sleep, but perhaps the most important are the increased secretion of growth hormone (GH) and the scavenging of free radicals in the brain.

Many of the benefits of sleep are probably mediated through GH. As an anabolic hormone, GH has been called by some the “antiaging” hormone. Several research projects are now studying its rejuvenating effects when it is injected. The reason for the excitement is that GH stimulates tissue regeneration, liver regeneration, muscle building, breakdown of fat stores, normalization of blood sugar, and a host of other beneficial processes in the body. It also helps convert fat to muscle. Small amounts of GH are secreted at various times during the day, but essentially all secretion of GH occurs during sleep.

Sleep functions as an antioxidant for the brain because free radicals are removed during it. Sleep is required to ensure minimal neuronal damage from free radicals accumulated during waking. Most people can tolerate a few days without sleep and fully recover. However, chronic sleep deprivation appears to accelerate aging of the brain, to cause neuronal damage, and to produce nighttime elevations in cortisol.⁵

Therapeutic Considerations

Because insomnia is largely due to psychological and physiologic factors, the clinician should consider and handle these factors before simply inducing sleep pharmacologically. Counseling and/or stress-reduction techniques (including biofeedback and hypnosis) may be indicated in many cases. The following topics are discussed below as they relate to the promotion of sleep:

• Exercise

• Progressive relaxation

• Nocturnal glucose levels

• Serotonin precursor and cofactor therapy

• 5-Hydroxytryptophan (5-HTP)

• Cofactors for serotonin synthesis

• Melatonin

• Restless legs syndrome and nocturnal myoclonus

• Botanicals with sedative properties

Lifestyle

Exercise

Regular physical exercise is known to improve general well-being as well as to promote improvement in sleep quality.³ Exercise should be performed in the morning or early evening, not before bedtime, and should be of moderate intensity. Usually 20 minutes of aerobic exercise at a heart rate between 60% and 75% of maximum (approximately 220 minus the patient’s age in years) is sufficient.

Progressive Relaxation

Numerous techniques can promote relaxation and prepare the body and mind for sleep. One of the most popular and easy-to-use techniques is progressive relaxation. It is based on a very simple procedure of comparing tension with relaxation. Many people are not aware of the sensation of relaxation. In progressive relaxation, an individual is taught what it feels like to relax by comparing relaxation with muscle tension. Each muscle is first made to contract forcefully for a period of 1 to 2 seconds and then to give way to a feeling of relaxation. Because the procedure goes progressively through all the muscles of the body, a deep state of relaxation eventually results. The procedure begins with contraction of the muscles of the face and neck, with the contraction held for at least 1 or 2 seconds, and then relaxation of the muscles. Next the upper arms and chest are contracted and then relaxed, followed by the lower arms and hands. The process is repeated progressively down the body—abdomen, buttocks, thighs, calves, and feet. This whole practice is repeated two or three times or until sleep is produced.

Nocturnal Glucose Levels

Increased nocturnal blood glucose volatility may be an important cause of sleep-maintenance insomnia, especially when there are rapid drops in blood glucose levels. The brain is highly dependent on glucose as an energy substrate, and a quick drop in blood glucose level promotes awakening via the release of glucose regulatory hormones (i.e., epinephrine, glucagon, cortisol, and GH). Increased nocturnal blood glucose volatility and/or hypoglycemia must be ruled out in maintenance-type insomnia (see Chapter 176).

Serotonin Precursor and Cofactor Therapy

Serotonin is an important initiator of sleep. The synthesis of central nervous system (CNS) serotonin depends on the availability of tryptophan (discussed in more detail in Chapter 98). L-Tryptophan has shown modest effects in the treatment of insomnia⁶^–⁸; it is certainly not a panacea. However, excellent results have been reported even in severe cases. Although not every patient has responded to L-tryptophan in the clinical trials, those who have experienced dramatic relief. It is generally more effective in sleep-onset insomnia and less effective in sleep-maintenance insomnia. The key advantage of L-tryptophan over OTC and prescriptions pills is that, unlike these agents, it does not produce any significant distortions of normal sleep processes whether it is taken only once or for a prolonged period, nor does it cause symptoms upon withdrawal. Doses smaller than 2000 mg are generally ineffective.

Current knowledge of the sleep-inducing effects of L-tryptophan is consistent with the finding that its effectiveness is somewhat limited to sleep-onset insomnia.⁶ The sleep-promoting effect is often thought to be due to enhanced serotonin synthesis, but there is evidence to suggest that other mechanisms may also be responsible or contributory, including L-tryptophan–enhanced melatonin synthesis. Administration of L-tryptophan causes a massive elevation of plasma melatonin concentration.⁹ Although L-tryptophan reduces sleep latency, it exerts effects in normal subjects that are at odds with the serotonin system, such as reducing REM sleep and increasing non-REM sleep.^10,¹¹ Drugs that prevent the conversion of tryptophan to serotonin enhance these effects. From this information, it is concluded that some of L-tryptophan’s effects on sleep do not involve the serotonin or melatonin system. As discussed in Chapter 98, the effects of L-tryptophan can be negated by conversion via the kynurenine pathway. This conversion can be partially inhibited by niacin (30 mg is an appropriate dose), thereby enhancing the effects of L-tryptophan.

It appears that the insomnia-relieving and sleep-promoting actions of L-tryptophan are cumulative in that it often takes a few nights for L-tryptophan to start working, as shown by the results from one of the double-blind studies. In that study, the effects of 3 g of L-tryptophan on sleep performance, arousal threshold, and brain electrical activity during sleep were assessed in 20 males with chronic sleep-onset insomnia.¹² After a sleep laboratory screening night, all subjects received placebo for three consecutive nights; then 10 subjects received L-tryptophan and 10 placebo for six nights. All subjects received placebo on two withdrawal nights. L-Tryptophan had no effect on sleep latency during the first three nights of administration. However, on nights four through six of administration, sleep latency was significantly reduced. Consistent with other studies, this study found that unlike sleeping pills (benzodiazepines especially), L-tryptophan did not alter sleep stages, impair performance, or alter brain electrical activity during sleep. This study indicates that L-tryptophan should be used for a minimum of 1 week to gauge its effectiveness in chronic insomnia. L-Tryptophan does have good sleep-promoting effects with a single administration, as shown by the fact that it is often effective when given to subjects sleeping in a “strange place” who otherwise regularly experience insomnia under such circumstances.

Administration of high-dose L-tryptophan (4 g) during the day can promote sleep. This research information indicates that the consumption of foods high in tryptophan during the day may contribute to daytime sleepiness. Conversely, an evening meal high in tryptophan in relation to competing amino acids may promote sleep.

The important cofactors vitamin B₆, niacin, and magnesium should be administered along with the tryptophan to ensure its conversion to serotonin. Also, because other amino acids compete with tryptophan for transport into the CNS across the blood-brain barrier and insulin increases tryptophan uptake by the CNS, protein consumption should be avoided near administration and a carbohydrate source such as fruit or fruit juice should accompany the tryptophan.

Niacin has been reported to have a sedative effect, probably owing to its peripheral dilating action and shunting of tryptophan metabolism toward serotonin synthesis.

5-Hydroxytryptophan

5-HTP is one step closer to serotonin than L-tryptophan and does not depend on a transport system for entry into the brain. Several clinical studies have shown 5-HTP to produce dramatically better results than L-tryptophan in promoting and maintaining sleep.¹³^–¹⁶

One of the key benefits of 5-HTP is its ability to increase REM sleep (typically by about 25%) while increasing deep sleep stages 3 and 4 without lengthening total sleep time.^10,¹¹ The sleep stages that are reduced to compensate for the increases are non-REM stages 1 and 2—the least important stages.

The dosage recommendation to take advantage of the sleep-promoting effects of 5-HTP is 100 to 300 mg, 30 to 45 minutes before retiring. The patient should start with the lower dose for at least 3 days before increasing it. For more information, see Chapter 98.

Melatonin

The most popular natural aid for sleep is melatonin. Supplementation with melatonin has been shown in several studies to be very effective in helping induce and maintain sleep in both children and adults and in both people with normal sleep patterns and those with insomnia. However, the sleep-promoting effects of melatonin are most apparent only if melatonin levels are low.¹⁷ In other words, using melatonin is not like taking a sleeping pill or even 5-HTP. It has a sedative effect only when its levels are low. When melatonin is taken by normal subjects just before going to bed or by patients with insomnia who have normal melatonin levels, it produces no sedative effect. This is because just before going to bed, people normally have a rise in melatonin secretion. Melatonin supplementation is effective as a sedative only when the pineal gland’s own production of melatonin is very low. Melatonin appears to be most effective in treating insomnia in the elderly, in whom low melatonin levels are common.¹⁸

In one of the most interesting studies, 26 elderly insomniacs with lower than normal melatonin levels were given 1 to 2 mg of melatonin 2 hours before the desired bedtime for 1 week. Rapid- and slow-release melatonin preparations were used. Both sleep latency and sleep quality were evaluated. Although there was no discernible difference in sleep onset or sleep efficiency (time asleep as a percentage of total time in bed) between the two forms, the slow-release form yielded better effects on sleep maintenance.¹⁹

A dose of 3 mg at bedtime is more than enough, because doses as low as 0.1 and 0.3 mg have been shown to produce a sedative effect when melatonin levels are low.²⁰ Although melatonin appears to have no serious side effects at recommended doses, melatonin supplementation could conceivably disrupt the normal circadian rhythm. In one study, a dosage of 8 mg/day for only 4 days resulted in significant alterations in hormone secretions.²¹ For more information see Chapter 103.

Restless Legs Syndrome and Nocturnal Myoclonus

Restless legs syndrome and nocturnal myoclonus are significant causes of insomnia. The restless legs syndrome is characterized during waking by an irresistible urge to move the legs. Almost all patients with restless legs syndrome have nocturnal myoclonus,¹ a neuromuscular disorder characterized by repeated contractions of one or more muscle groups, typically of the leg, during sleep. Each jerk usually lasts less than 10 seconds. The patient is normally unaware of the myoclonus and complains only of either frequent nocturnal awakenings or excessive daytime sleepiness, but questioning of the sleep partner often discovers the myoclonus.

If there is a family history of restless legs syndrome (present in about one third of all cases of the syndrome), high-dose folic acid, 35 to 60 mg daily, can be helpful.²² Doses in this range require a prescription, because the U.S. Food and Drug Administration limits the amount available per capsule to 800 mg. Patients with familial restless legs syndrome appear to have a higher need for folic acid. Restless legs syndrome is also a common finding in patients with malabsorption syndromes.²²

If there is no family history, serum ferritin levels should be measured to determine iron stores. The association between low iron levels and the restless legs syndrome was documented in clinical studies more than 30 years ago. A later study reproduced these observations, finding serum ferritin levels to be lower in the 18 patients with the restless legs syndrome than in 18 control subjects.²³ Serum iron, vitamin B₁₂, folic acid, and hemoglobin levels did not differ in the two groups. A rating scale with a maximum score of 10 was used to assess the severity of symptoms of the restless legs syndrome. Serum ferritin levels were inversely correlated with the severity of symptoms. Fifteen of the patients with the syndrome were treated with iron (ferrous sulfate) at a dosage of 200 mg three times daily for 2 months. The severity of restless legs syndrome improved by an average of 4 points in 16 patients with an initial ferritin level lower than 18 mg/L, by 3 points in 4 patients with ferritin levels between 18 and 45 mg/L, and by 1 point in 5 patients with ferritin levels between 45 and 100 mg/L. The conclusion of the study is an important contribution to the understanding of the development of restless legs syndrome in elderly patients, and iron supplements were found to produce a significant reduction in symptoms.

In addition to the restless legs syndrome, low serum ferritin levels have been found in psychiatric patients experiencing a condition called akathisia, coming from a Greek word meaning “cannot sit down.” Akathisia is a drug-induced state of agitation. The drugs that most commonly produce akathisia are antidepressants, such as fluoxetine (Paxil, Prozac) and sertraline (Zoloft). The level of iron depletion correlates with the severity of akathisia. Anyone suffering from drug-induced akathisia should ask his or her physician to perform a serum ferritin assessment. If serum ferritin levels are below 35 mg/L, the physician should recommend that the patient take 30 mg of iron bound to either succinate or fumarate twice daily between meals. If this recommendation causes abdominal discomfort, the patient should try 30 mg with meals three times daily.