CHAPTER 12 Insomnia
Insomnia is a term used to describe the chronic inability to sleep at times when sleep is normally expected to occur. Insomnia may consist of difficulty falling asleep or difficulty remaining asleep. The most common sleep disorder, insomnia reportedly affects at least 60 million Americans.1 Of people who see primary care physicians, an estimated 69% have had insomnia, but this figure is considered low because only one third of those with insomnia speak to their physicians about the problem,2 as many believe it is not a legitimate health problem.
Insomnia is more common in women than in men.3 During menopause, women may experience sleep problems as a result of hot flashes, night sweats, or psychological stressors.4 A longitudinal study in which women were monitored over a 3-year period, as they moved from perimenopause to menopause, revealed significant increases in the incidence and severity of sleep disturbances.5 Women taking hormone replacement therapy experienced far less severe instances of these sleep disturbances, suggesting that therapies that reduce unpleasant symptoms such as hot flashes and night sweats may also improve sleep.
Patients often have difficulty quantifying the amount of time they actually sleep. Scientists have conducted research on patients with insomnia to determine whether patients could reliably detect whether they were asleep or awake by comparing diaries against polysomnograph readings.6 Researchers found that insomniacs have a reduced ability to discriminate sleeping from waking and that they are prone to misclassify a sleeping episode as one in which they were awake. It appears that some insomniacs greatly overestimate the extent and duration of their insomnia.
TREATMENT OPTIONS
Lifestyle and Diet
A healthy diet is important to everyone, especially anyone who does not feel adequately rested. The B vitamins are important in improving the quality and quantity of sleep. Vitamin B6 is involved in the synthesis of serotonin, a neurotransmitter used by the brain to regulate sleep. Vitamin B6 deficiency can lead to insomnia, depression, and increased irritability, all of which are reversible when adequate levels of the vitamin are supplied. Restless legs syndrome has been linked to abnormalities in iron stores in adults and adolescents.7 Sleep specialists recommend evaluation of iron status, including serum iron, total iron-binding capacity, and ferritin levels, in any patient with chronic insomnia of unexplained origin, even when anemia is mild or absent. A high-magnesium diet seems to provide the highest-quality sleep time with the fewest nighttime awakenings.
SIMPLE TIPS FOR GETTING TO SLEEP
Establish a regular sleep-wake schedule. A good way to begin is by getting up at the same time every morning, no matter what time you go to sleep. Yes, this means weekends, too!
The bed should be used only for sleeping and making love, not for working, studying, or watching TV.
A patient with insomnia should be advised to avoid caffeinated beverages. Any consumption of coffee, tea, or soda should be limited to early in the day and kept to a minimum. Coffee consumption causes a decrease in the total amount and quality of sleep, as well as an increase in the amount of time it takes to fall asleep. Researchers have also found that consumption of caffeine decreases the level of 6-sulfoxymelatonin, the main metabolite of melatonin in urine.8
Over-the-Counter Medications
A survey of adults ages 18 to 45 years revealed that self-medication for insomnia is relatively common.9 Thirteen percent of respondents reported using alcohol, 10% reported using over-the-counter (OTC) medications, and 5% reported using prescription drugs. The main ingredients of most OTC insomnia remedies are the antihistamines diphenhydramine hydrochloride and doxylamine succinate. Diphenhydramine should be taken at bedtime, whereas doxylamine products should be taken half an hour before bedtime. During this 30-minute interval, the individual should not drive or perform any activity requiring vigilance.10
Although OTC antihistamines are effective and relatively safe for the treatment of insomnia, the U.S. Food and Drug Administration requires that manufacturers warn patients not to take the drugs if they are younger than 12 years or have a breathing problem (e.g., emphysema or chronic bronchitis), glaucoma, enlarged prostate or if they are pregnant or breastfeeding. The labels of these antihistamines carry a required caution to patients to stop use and consult a physician if sleeplessness lasts for more than 2 weeks. The labeling also advises individuals against taking the drugs with alcohol and encourages them to check with a health care provider before using them at the same time as sedatives or tranquilizers.10
Melatonin
Melatonin (N-acetyl-5-methoxytryptamine), a neurohormone produced in the pineal gland, is involved in the regulation of the sleep-wake cycle. Melatonin is normally secreted during darkness in response to the release of norepinephrine from retinal photoreceptors. Levels begin to rise at nightfall, with peak serum concentrations typically occurring between 2 and 4 AM in adults. Individuals with impaired melatonin production or secretion may experience chronic disturbances in the onset and duration of sleep. In these patients, exogenous melatonin may be beneficial to help regulate the sleep-wake cycle.11
Although most consider melatonin a dietary supplement, in 1993 the Food and Drug Administration classified it as an orphan drug for the entrainment of circadian rhythm in blind people (the absence of light cues results in disturbances of sleep and sleep-related neuroendocrine patterns). In a double-blind crossover study, 12 totally blind individuals received 5 mg of oral melatonin or placebo 1 hour before bedtime, starting at 11 PM. This dose of melatonin increased total sleep time and reduced time spent awake (P < 0.05) while normalizing pituitary-adrenal activity.12
In addition to improving the sleep-wake cycle in blind people, melatonin has been shown to be remarkably effective in preventing or reducing jet lag. Cochrane reviewers state that “it should be recommended to adult travelers flying across five or more time zones, particularly in an easterly direction, and especially if they have experienced jet lag on previous journeys. Travelers crossing 2-4 time zones can also use it if need be.”13
Melatonin is often given to children and adolescents with severe neurodevelopmental disabilities. Turk et al conducted a literature review and concluded that melatonin is a potentially useful and safe adjunct to psychological and social approaches to the treatment of severe sleep disturbances in these children.14 Melatonin is sometimes recommended for children with attention deficit/hyperactivity disorder, but whether it is beneficial in this group is less clear. The National Sleep Foundation notes that melatonin may be useful in teenagers who are unable to fall asleep during the early nighttime hours and consequently experience problems awakening the next morning.15
Oral melatonin therapy appears to be well tolerated. No adverse effects have been noted in most clinical trials and case series. Headache, excessive sedation, and transient depression have been reported with dosages greater than 8 mg/day. The typical dose of melatonin is 3 mg/day. The effect of melatonin in people with epilepsy is not completely understood. In a 1998 study published in the Lancet, melatonin administration to six children with underlying seizure disorders produced a worsening of seizures in three.16 Melatonin may also interact with warfarin; patients should be monitored if taking these substances concurrently.13
Botanical Remedies
Valerian (Valeriana officinalis).
Valerian is a common ingredient in products sold as mild relaxants and the relief of nervous tension and insomnia (Figure 12-1). The genus Valeriana includes more than 250 species, but V. officinalis, in root and rhizome form, is the species most often used in the United States and Europe. The herb is sold as a single ingredient but is more commonly found in combination products. Valerian has been used medicinally since at least the time of ancient Greece and Rome; in the second century AD, Galen recommended valerian as a treatment for insomnia. During World War II, valerian was used in England to relieve the stress of air raids.17 The German Commission E endorses the use of valerian for restlessness and sleeping disorders caused by nervous conditions. The World Health Organization lists the following uses for valerian: mild sedative, sleep-promoting agent, milder alternative to or possible substitute for stronger sedatives (e.g., benzodiazepines), and treatment for nervous excitation and sleep disturbances induced by anxiety.18 The European Scientific Cooperative on Phytotherapy lists the following therapeutic indications for valerian: tenseness, restlessness, and irritability accompanied by difficulty falling asleep. Valerian root, root powder, and root extract are official (with legally recognized standards of identity, strength, quality, purity, packaging, and labeling) in the United States Pharmacopoeia (25th edition).19
Although valerian is recognized in many countries as a traditional medicine to aid sleep and reduce nervousness and herbalists strongly believe in its beneficial effects, clinical trials have yielded conflicting results. In a systematic review, nine randomized, placebo-controlled, double-blind clinical trials of valerian and sleep disorders were identified and evaluated for evidence of efficacy of valerian as a treatment for insomnia.20 Three of the nine trials earned the highest rating (5 on a scale of 1 to 5), although the reviewers concluded overall that the evidence supporting the efficacy of valerian in the treatment of insomnia is inconclusive and that more rigorous trials are necessary. The following text provides a quick review of the three best studies cited in the review, all of which yielded positive findings.
In a 1982 study by Leathwood et al, 128 volunteers were randomly assigned to take one of the three preparations three times in random order on nine consecutive nights. The study preparations included a 400-mg dose of an aqueous extract of valerian, a combination preparation containing 60 mg of valerian and 30 mg of hops, and a placebo.21 Each participant filled out a questionnaire on the morning after each treatment. Compared with the placebo, the valerian extract resulted in a statistically significant subjective improvement in the time required to fall asleep, quality of sleep, and the number of nighttime awakenings. The combination preparation did not produce a statistically significant improvement in any of these three measures, although this would not be unexpected given the low levels of both valerian and hops in the product. Although the study scored high rating for its design, it had two major drawbacks: a participant-withdrawal rate of 22.9% and, more important, the fact that volunteers were not screened for insomnia, meaning that some participants had trouble sleeping but others did not.
In another study, Leathwood et al compared 450- and 900-mg dosages of valerian aqueous extract to placebo in eight patients with mild insomnia. Patients were randomly assigned to receive one of the three test samples each night, Monday through Thursday, for 3 weeks. Results were based on nighttime motion as measured with the use of activity meters worn on the wrist and responses to questionnaires about sleep quality, latency, depth, and morning sleepiness that were completed the morning after each treatment. The 450-mg dosage of valerian extract reduced sleep latency from 16 to 9 minutes; no statistically significant shortening of sleep latency was observed with the 900-mg dose. The time required to fall asleep was shortened by 7 minutes and was therefore a statistically significant result, but this finding may not be clinically significant. The 900-mg sample increased the patients’ perception of sleep improvement, but participants noted increased sleepiness the next morning.22
A more recent study, published by Vorbach et al in 1996, also received a rating of 5 from the review team. This is the only one of the three studies in which the sustained use of valerian extract over an extended period was examined. One hundred twenty-one individuals with documented nonorganic insomnia received either 600 mg of a standardized extract of dried valerian root (LI 156, Sedonium; Lichtwer Pharma AG, Berlin, Germany; each tablet contains 300 mg of extract of valerian with a drug/extract ratio of 5:1) or placebo for 28 days.23 Three different questionnaires were provided to participants; one evaluated the therapeutic effect on days 14 and 28, one evaluated change in sleep patterns on day 28, and one evaluated change in sleep quality and well-being on days 0, 14, and 28. After 28 days, the group receiving the valerian extract showed a decrease in insomnia symptoms, compared with the placebo group, on all questionnaires. The differences in improvement between valerian and placebo increased between the assessments conducted on days 14 and 28. The findings of this study are consistent with my own clinical experience that individuals with insomnia experience better results with valerian when they take it every night for an extended period, usually 4 to 6 weeks. Patients often tell me that occasional use of valerian to relieve sleeplessness has hit-or-miss results.
Not included in the review was a double-blind, randomized study by Ziegler et al comparing the effects of a 6-week course of 600 mg/day standardized valerian extract (LI 156 Sedonium) or 10 mg/day of oxazepam in 202 patients ages 18 to 73 years with nonorganic insomnia. Changes in sleep quality were assessed with the use of Sleep Questionnaire B (CIPS [Collegium Internationale Psychiatrie Scalarum] 1996), which revealed that 600 mg of valerian extract was at least as efficacious as treatment with 10 mg of oxazepam. Both treatments markedly increased sleep quality compared with baseline (P < 0.01). Other Sleep Questionnaire B subscales (e.g., feeling of refreshment after sleep, dream recall, duration of sleep) showed similar effects for the two treatments. The Clinical Global Impressions scale and Global Assessment of Efficacy by investigator and patient showed similar effects of the two treatments. Adverse events occurred in 29 patients (28.4%) receiving valerian extract LI 156 and in 36 patients (36.0%) taking oxazepam; all were rated as mild to moderate. No serious adverse drug reactions were reported in either group. Most patients assessed their treatment as very good (82.8% in the valerian group, 73.4% in the oxazepam group).24
The aforementioned studies were all conducted with the use of monopreparations of valerian, although most consumers likely purchase combination products. Three double-blind, placebo-controlled studies showed that the combination of valerian and lemon balm (Melissa officinalis), an herb with documented anxiolytic activity, was effective in improving sleep quality among individuals with insomnia. Combinations of valerian, hops, and lemon balm yielded similarly positive effects.25 Although most practitioners associate the use of valerian with sleep and, to a lesser extent, anxiety, two clinical trials of a combination of valerian and St. John’s wort for the treatment of depression have been conducted. The combination was equivalent or superior to the tricyclic antidepressants amitriptyline and desipramine when given for a period of 6 weeks.26 It is unclear whether the antidepressant effect was primarily the result of St. John’s wort or whether synergism exists between the two herbs.
Controversy over the active constituents of valerian continues. Most research has been focused on two main groups of substances: the volatile oil fraction and the valepotriates. Three cyclopentane sesquiterpenoids (valerenic acid, acetoxyvalerenic acid, and valeranal) are present only in V. officinalis, distinguishing it from other species of the genus.18 The volatile oil fraction is responsible for only part of the sedative effect; likewise, the valepotriates do not account for all the sedative activity of the plant extract.27 The isolation of 6-methylapigenin, a flavone derivative that acts as a ligand for the benzodiazepine-binding site of the GABAA receptor28; and 2S(−)-7-rhamnoglucosyl-hesperetin, a flavanone glycoside with sedative and sleep-enhancing properties from both V. wallachii and V. officinalis, continues to expand our understanding of the complex biochemistry of this genus.
Valerian’s mechanism of action is poorly understood. Compounds in valerian have been shown to have a direct effect on the amygdaloid body of the brain, and valerenic acid has been shown to inhibit enzyme-induced breakdown of γ-aminobutyric acid (GABA) in the brain, resulting in sedation.29 The valepotriates act as prodrugs, which are transformed into homobaldrinal, a compound found to reduce the spontaneous motility of mice, and a lignan, hydroxypinoresinol, which has been shown to bind to benzodiazepine receptors.29 The proprietary valerian extract LI 156 has been found to act on the melatonin receptor in a dose-dependent manner in vitro.30
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