Pharmacologic Treatment of Insomnia

Pharmacologic Treatment of Insomnia Thomas Freedom, MD Chronic insomnia is estimated to affect 10% of Americans.1 Transient insomnia may affect approximately 30% of the population.2 Fifty percent to 69% of patients under medical care meet the diagnostic criteria for insomnia.3,4 Most patients do not report sleep disorders.5 The sleep difficulties are uncovered by careful questioning, focused physical examination, and, if needed, laboratory investigations. Sleep and wake habits, sleep disruptions, daytime symptoms, medical and psychiatric comorbidities, medications, and lifestyle as they relate to insomnia should be assessed. Vital signs, head and neck, cardiac, lung, extremities, and neurologic examinations are pertinent to look for medical and features of other sleep disorders (ie, sleep apnea and upper airway) that may predispose to insomnia.6 Questionnaires and sleep logs may also be of benefit.7 Referral to a sleep specialist and polysomnography can be considered if sleep apnea is suspected, excessive daytime sleepiness is present, or there is no response to initial behavioral and/or pharmacologic treatment.5 Criteria for insomnia set by the second edition of the International Classification of Sleep Disorders (ICSD-2) include difficulty initiating sleep or maintaining sleep, waking up too early, or chronically nonrestorative or poor-quality sleep. This occurs despite adequate opportunity and circumstances for sleep. It is associated with at least 1 of the following: fatigue or malaise; attention, concentration, or memory impairment; social or vocational dysfunction or poor school achievement; mood disturbance or irritability; daytime sleepiness; motivation, energy, or initiation reduction; proneness for errors or accidents at work or while driving; tension headaches, or gastrointestinal symptoms in response to sleep loss; or concerns or worries about sleep.8 Criteria for insomnia from the Diagnostic and Statistical Manual of Mental Disorders, text revision, 4th ed. (DSM-IV-TR) are difficulty initiating or maintaining sleep, or suffering from nonrestorative sleep, for at least 1 month. The sleep disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.9 Dis Mon 2011;57:345-352 0011-5029/2011 $36.00 ⫹ 0 doi:10.1016/j.disamonth.2011.04.005 DM, July 2011

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TABLE 1. Insomnia Classification (Adapted from ICD-2)5 Adjustment insomnia Psychophysiologic insomnia Paradoxical insomnia Idiopathic insomnia Insomnia due to mental disorder Inadequate sleep hygiene Behavioral insomnia of childhood Insomnia due to drug or substance Insomnia due to alcohol Insomnia due to medical condition Insomnia not due to substance or known Physiologic condition, unspecified Physiologic (organic) insomnia, unspecified

The International Statistical Classification of Diseases and Related Health Problems-10th edition has similar criteria but adds that the sleep disturbance occurs at least 3 times a week for at least 1 month.10 Insomnia may be considered transient or chronic. There are various criteria for the time frame, but the ICSD-2 uses insomnia lasting 3 months or longer for chronic insomnia.8 Insomnia may also be primary, or secondary, to other factors or diseases.9 Insomnia may be classified into various subtypes (Table 1).8 Transient insomnia is self-limited. A short course of hypnotics may be effective, if needed.11 Behavioral techniques can be of benefit to prevent the evolution to chronic insomnia. Chronic insomnia generally responds to pharmacologic and behavioral therapy. Medications are used adjunctively or when behavioral techniques alone do not manage the problem.12 They are also useful when there are comorbidities complicating and interfering with therapy.13 The initial hypnotics were botanicals. Alcohol also played a role in inducing sleep. Early hypnotics included bromine salts, chloral, paraldehyde, urethane, and sulfanol. Barbiturates were used in the early 20th century, but were supplanted by benzodiazepines. Thalidomide was removed as a hypnotic in the 1950s due to teratogenicity.14 The American Academy of Sleep Medicine guidelines call for certain conditions using hypnotics for insomnia. They state that various agents available, over-the-counter and prescription drugs, and so-called natural products or supplements can be used to aid in the management of insomnia. Psychological and behavioral interventions are effective and recommended in the treatment of chronic primary and comorbid (secondary) insomnia for adults of all ages and chronic hypnotic users. Initial therapy should include at least 1 behavioral intervention. Short-term 346

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TABLE 2. Benzodiazepines Generic Name Estazolam Flurazepam Quazepam Temazepam Triazolam

Trade Name

Absorption

Half-Life (h)

Dosage (mg)

Prosom Dalmane Doral Restoril Halcion

Rapid Rapid Rapid Intermediate Rapid

8-24 48-120 48-128 8-20 2-6

1.0-2.0 15.0-30.0 15.0-30.0 7.5-30.0 0.125-0.25

hypnotic treatment should be supplemented with behavioral and cognitive therapies when possible. Choice of medications should be guided by symptoms, goal of treatment, past response, patient preference, cost, alternatives, comorbidity, contraindications, medication interactions, and side effects. One should start with short-acting agents and change to short-intermediate agents if the initial treatment is not effective. Sedating antidepressants, anticonvulsant medications, or atypical antipsychotics may be of benefit from the primary action of these drugs as well as from the sedating effect when comorbidities are present. Over-the-counter antihistamine or antihistamine/analgesic-type drugs and herbal and nutritional substances are not recommended because of relative lack of efficacy and safety data. Pharmacologic treatment should be accompanied by patient education. Patients should be followed on a regular basis. Efforts should be made to employ the lowest effective maintenance dosage of medication and to taper medication when conditions allow. Long-term prescribing should be accompanied by consistent follow-up, ongoing assessment of effectiveness, monitoring for adverse effects, and evaluation for new onset or exacerbation of existing comorbid disorders. Long-term administration may be nightly or intermittent.15

Prescription Medications Benzodiazepines bind to the GABA receptor. They have hypnotic/ sedative, anxiolytic, muscle relaxant, and anticonvulsant properties. They can have side effects, including tolerance and withdrawal, complex sleep behaviors, and associated cognitive impairments16 (Table 2). Nonbenzodiazepine hypnotics have a greater selectivity than benzodiazepines. The potential for abuse and side effects are less but still can limit their use in some patients. These include rare but serious effects, such as anaphylaxis, angioedema, and complex sleep-related behaviors (driving while asleep, making phone calls, and preparing and eating food). Their effects on memory and psychomotor performance, and abuse liability are also of concern.17 (Table 3). DM, July 2011

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TABLE 3. Nonbenzodiazepine Receptor Agonists Generic Name

Trade Name

Absorption

Half-Life (h)

Dosage (mg)

Zaleplon Zolpidem Zolpidem-extended release Eszopiclone

Sonata Ambien Ambien-CR Lunesta

Rapid Rapid Intermediate Intermediate

1 1.4-3.8 1.6-4 6

5-10 5-20 6.25-12.5 1-3

TABLE 4. Antidepressants and Antipsychotics Generic Name Amitriptyline Doxepin Mirtazapine Trazodone Quetiapine

Trade Name

Absorption

Half-Life (h)

Dosage (mg)

Elavil Sinequan Remeron Desyrel Seroquel

Intermediate Intermediate Intermediate Rapid Rapid

10-50 5-8 20-40 5-0 7

10-50 3-6 15 25-100 25-100

Benzodiazepines and nonbenzodiazepines are effective for short-term treatment of insomnia. There is the suggestion that they may be effective for longer term therapy. It is unclear that there is any advantage to newer nonbenzodiazepine hypnotics compared to the older benzodiazepines. There is also concern over risk/benefit ratio in elderly patients.18 Ramelteon (Rozerem) is a melatonin receptor agonist. It has high affinity for MT1 and MT2 receptors, and minimal affinity for MT3. There is no appreciable affinity for other receptors involved in sleep. Endogenous melatonin acting upon the MT1 and MT2 receptors is thought to be involved in the maintenance of the circadian rhythm during the normal sleep-wake cycle. The activity of ramelteon at these receptors is believed to contribute to its sleep-promoting properties. It has a rapid onset and a half-life of 0.8-2 hours. The dose is 8 mg. It is generally well tolerated. Common adverse events include headache, somnolence, dizziness, fatigue, and nausea (3%). In clinical trials, 5% of patients stopped use due to side effects. It should not be used in patients with severe hepatic disease.19 Sedating antidepressant or antipsychotics can be considered when insomnia occurs with comorbid psychiatric issues (Table 4). Side effects and increased drug interaction may limit their use. Suicide risk is of concern with antidepressants. There is a lower potential of abuse than with benzodiazepines or nonbenzodiazepine hypnotics.20 Due to side effects, quetiapine should be considered only if primary and secondary intervention fail.21 Anticonvulsants can be effective in the treatment of insomnia (Table 5). 348

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TABLE 5. Anticonvulsants Generic Name Gabapentin Pregabalin Tiagabine

Trade Name

Absorption

Half-Life (h)

Dosage (mg)

Neurontin Lyrica Gabatril

Intermediate Rapid Rapid

5-9 4.5-7 8

100-900 50-300 2-16

TABLE 6. Nonprescription agents Generic Name

Trade Name

Absorption

Half-Life (h)

Dosage (mg)

Diphenhydramine Doxylamine Melatonin Valerian

Benadryl Unisom

Rapid Rapid

5-11 6-12

25-50 25-50 1-3 400-500

Gabapentin was shown to increase the amount of slow-wave sleep (stage N3) and improve sleep quality in primary insomnia, However, there is concern over side effects, such as tolerance, dependence, abuse, delirium, nightmares and hallucinations, and loss of memory reported in the literature.22 Pregabalin improved sleep and anxiety in patients with generalized anxiety disorder23 and sleep and pain in patients with fibromyalgia.24 Tiagabine increased slow-wave sleep in primary insomnia, but did not improve other parameters. Patients reported dizziness, nausea, somnolence, headache, and anxiety. Daytime symptoms were worse with the 10 mg dose compared to placebo.25 Tiagabine increased slow-wave sleep in an elderly population, but did not improve ether night or daytime symptoms. Adverse effects and decreased alertness occurred at the 8 mg dose.26 A third study showed positive effects in primary insomnia. There was increased slow-wave sleep and improvement of sleep maintenance at higher doses, in a dose-dependent manner. Improvement in daytime measures was marginal. Side effects also worsened at higher doses.27 Further studies are required to clarify efficacy and safety.

Nonprescription Medications and Supplements Over-the-counter agents include antihistamines, herbal preparations, and supplements (Table 6). Their use is prevalent. One study found 15% had used nonprescription sleep aids as opposed to 11% taking prescription medications.28 A recent review looked at the evidence for passionflower, valerian, Jamaican dogwood, hops, California poppy, chamomile, lemon balm, St DM, July 2011

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John’s wort, kava kava, wild lettuce, skullcap, Patrinia root, firstgeneration histamine-1-receptor antagonists, alcohol, calcium, vitamin A, nicotinamide, magnesium, vitamin B12, L-Tryptophan, 5-hydroxytryptophan, dietary changes, Natrum muriaticum, and Yoku-kan-san-kachimpi-hange. Randomized, placebo-controlled studies found efficacy for some compounds. There was a lack of rigorous scientific data supporting efficacy for the majority. Some preliminary but conflicting evidence was available suggesting that valerian officinalis and first-generation histamine-1-receptor antagonists could be beneficial for short-term use. Significant risks were found for Jamaican dogwood, kava kava, alcohol, and L-Tryptophan.29 Melatonin may be effective in secondary and age-related insomnia.30 A recent study demonstrated that melatonin is not effective in the treatment of primary insomnia.31 Current evidence suggests that melatonin is not effective in treating most primary or secondary sleep disorders, although is safe with short-term use. There is no evidence suggesting that melatonin is effective in alleviating the sleep disturbance aspect of jet lag and shift-work disorder. It may be effective in treating delayed sleep phase syndrome with short-term use.32

Summary Hypnotics can be effective in short-term treatment of insomnia. It is important to determine characteristics of insomnia (sleep onset, sleep maintenance), length of symptoms (transient vs chronic), and comorbid conditions. Generally short-acting agents are preferred for sleep onset insomnia and longer half-life agents may be used for sleep maintenance problems. There is suggestion that hypnotics may be appropriate for longer term use. Antihistamines may be considered, but efficacy and safety have not been adequately studied. Antidepressants, antipsychotics, and anticonvulsants may be useful when comorbid conditions are present or if conventional therapies fail. There is little evidence for the efficacy of most nonprescription medications or supplements and some may be dangerous. US Food and Drug Administration-approved medications for insomnia include eszopiclone, zaleplon, various formulations of zolpidem (immediate-release, extended-release, oral spray, and sublingual tablet), estazolam, flurazepam, quazepam, temazepam, triazolam, and ramelteon. Other medications are used off-label when treating insomnia. Only eszopiclone and ramelteon are approved for long-term use. Chronic insomnia is a major public health problem that affects millions of people. It also affects their families and community. There is evidence for the efficacy of cognitive behavioral therapy and benzodiazepine 350

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receptor agonists. There is little evidence for most other treatments. There is much to learn about insomnia and a major need for more education.33

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